Baris Kocaoglu

Lior Laver
Laura de Girolamo
Riccardo Compagnoni
Editors

ESSKA
Musculoskeletal
Injections Manual
Basics, Techniques and
Injectable Agents
Musculoskeletal Injections Manual
Baris Kocaoglu • Lior Laver
Laura de Girolamo
Riccardo Compagnoni
Editors

Musculoskeletal
Injections Manual
Basics, Techniques and Injectable
Agents
Editors
Baris Kocaoglu Lior Laver
Acibadem Mehmet Ali Hilll Yaffe Medical Center (HYMC)
Aydinlar University Technion University Hospital
Faculty of Medicine Hadera, Israel
Department of Orthopedics
and Traumatology Riccardo Compagnoni
Istanbul, Türkiye Clinica Ortopedica, 1°
Istituto Ortopedico Gaetano Pini
Laura de Girolamo Milano, Italy
Orthopaedic Biotechnology Laboratory
Ospedale Galeazzi Sant'Ambrogio
Milano, Italy

ISBN 978-3-031-52602-2    ISBN 978-3-031-52603-9 (eBook)

[Link]

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Preface

In recent years, the field of injection therapy for the treatment of pathologies
in joints has witnessed remarkable advancements, particularly in combina-
tion with orthobiologics. These innovations have transformed the way we
diagnose and treat various musculoskeletal conditions, providing patients
with new hope and improved outcomes. It is with great pleasure that ESSKA
U45 Committee and ORBIT introduce this comprehensive book, which
serves as an essential guide to these front-line techniques and therapies spe-
cially for young orthopedics and sports medicine specialists.
Musculoskeletal Injections Manual: Basics, Techniques and Injectable
Agents is a testament to the collective expertise and dedication of the appreci-
ated authors who have contributed their knowledge and experiences to this
remarkable resource. As a multidisciplinary field, injection therapies rely on
the collaboration of specialists from various fields, including orthopedics,
sports medicine, and basic science. This book brings together the insights of
these experts, providing a comprehensive and confident reference for espe-
cially young surgeons.
The book encompasses a wide range of topics, covering the fundamental
principles and techniques of musculoskeletal injections, orthobiologics, and
their usage. From basic concepts to advanced procedures, the surgeons will
find detailed discussions on joint injections and regenerative therapies. The
integration of orthobiologics, such as platelet-rich plasma (PRP), cell-based,
and blood-derived products, adds another dimension to the field, offering
innovative approaches to tissue healing and regeneration.
What sets this book apart is its emphasis on evidence-based practice. Each
chapter combines the authors’ clinical experience with the latest scientific
research, ensuring that readers have access to the most up-to-date information
and treatment recommendations. Additionally, the book includes practical
tips, step-by-step procedural guidelines, and illustrative figures, enabling cli-
nicians to apply these techniques with confidence and exactness.
Whether you are young surgeon who is seeking to improve your skills or
a novice exploring the world of musculoskeletal medicine, this book will
prove to be an invaluable resource. It serves as a comprehensive reference for
sports medicine doctors, surgeons, physical therapists, and other healthcare
professionals involved in the management of musculoskeletal conditions. By
incorporating the latest advancements and emerging therapies, this book
enables clinicians to provide optimal care to their patients, improving their
quality of life and functional outcomes.

v
vi Preface

As ESSKA U45 Committee and ORBIT, we would like to express our

deepest appreciation to the authors for their dedication to advancing the field
of musculoskeletal medicine and for sharing their expertise through this
remarkable publication. We are confident that Musculoskeletal Injections
Manual: Basics, Techniques and Injectable Agents will become an essential
publication for young surgeons who are motivated to deliver the best possible
care in the scene of sports traumatology.

Istanbul, Turkey Baris Kocaoglu

Hadera, Israel  Lior Laver
Milano, Italy  Laura de Girolamo
Milano, Italy  Riccardo Compagnoni
Contents

Part I Basics of Musculoskeletal Injections

1 
Philosophy of Musculoskeletal Injections��������������������������������������   3
Behiç Çelik and Gökhan Meriç
2 
The Evidence-Based Medicine for Injection Therapy������������������   9
Marko Ostojić
3 
Contraindications and Potential Side Effects of Injections���������� 15
Riccardo Compagnoni, Rossella Ravaglia, and Pietro Randelli
4 Informing Patients �������������������������������������������������������������������������� 21
Daniel Pérez-Prieto, Ana Soria, Marta Torruella,
and Narcís Pérez de Puig
5 
Sterilization and Injection Materials �������������������������������������������� 25
F. De Filippo and Maristella F. Saccomanno
6 Things to Take into Consideration in Injection
and Aspiration���������������������������������������������������������������������������������� 29
Thorkell Snaebjörnsson
7 
Postinjection Care and Education�������������������������������������������������� 33
Thorkell Snaebjörnsson

Part II Non Biologic Agents for Injections

8 Corticosteroids and Local Anesthetics ������������������������������������������ 39

Matthieu Ollivier and Ahmed Mabrouk
9 Viscosupplementation Agents �������������������������������������������������������� 45
Camila Grandberg, Svenja Höger, and M. Enes Kayaalp
10 Radiosynovectomy �������������������������������������������������������������������������� 53
Goksel Dikmen, Vahit Emre Ozden, and Kayahan Karaytug
11 Deproteinized Hemoderivative of Calf Blood-Natural
Botanical and Mineral Extracts������������������������������������������������������ 59
Berhan Bayram and Baris Kocaoglu

vii
viii Contents

Part III Ortho-biologic Agents for Injections

12 Orthobiologics: Background���������������������������������������������������������� 67
Paola De Luca, Michela Maria Taiana, and Laura de Girolamo
13 
Platelet-Rich Plasma for Osteoarthritis���������������������������������������� 73
Trifon Totlis and Angelo V. Vasiliadis
14 
Platelet-Rich Plasma Treatment for Meniscal Tears�������������������� 81
Yosef Sourugeon, Yaniv Yonai, Yaron Berkovich,
and Lior Laver
15 PRP in Tendinopathy ���������������������������������������������������������������������� 85
Ferran Abat, Ignacio De Rus Aznar, Federico Ibañez,
and Charlotte Raflé
16 
Platelet-Rich Plasma (PRP) for Rotator Cuff Tears �������������������� 91
Ron Gilat, Ilan Y. Mitchnik, Derrick Knapik, Grant Garrigues,
Nikhil Verma, and Brian J. Cole
17 
Platelet-Rich Plasma Treatment for Muscle Injuries ������������������ 99
Yosef Sourugeon, Yaniv Yonai, Yaron Berkovich,
and Lior Laver
18 
Bone Marrow Aspirate Concentrates for Knee OA���������������������� 105
Peter A. Everts, Ignacio Dallo, José Fábio Lana,
and Luga Podesta
19 
Fat-Derived Orthobiologics for Knee OA�������������������������������������� 117
Peter A. Everts, Raphael Barnabe, Luga Podesta,
and Rowan Paul
20 
Autologous Conditioned Serum (ACS)������������������������������������������ 127
Tahsin Beyzadeoglu and Onur Cetin
21 Alpha-2-Macroglobulin Concentrate as Orthobiologic
in Osteoarthritis ������������������������������������������������������������������������������ 133
Peter A. Everts, Luga Podesta, José Fábio Lana,
Gayan Poovendran, Gabriel Silva Santos,
and Stephany Cares Huber

Part IV Injections of Anatomical Regions and Diseases

22 
Injections of Anatomical Regions and Diseases: Shoulder���������� 143
Mocini Fabrizio, Candura Dario, Proietti Lorenzo,
Ciolli Gianluca, Brancaccio Vincenzo, and Cerciello Simone
23 
Injections of Anatomical Regions and Diseases: Elbow �������������� 155
Eduard Alentorn-Geli and Jorge Ramírez Haua
Contents ix

24 Injections of Anatomical Regions and Diseases:

Wrist and Hand�������������������������������������������������������������������������������� 167
Gamlı Alper and Gereli Arel
25 Injections of Anatomical Regions and Diseases: Hip�������������������� 183
Bruno Capurro, Francesco Vecchi,
Beatriz Álvarez de Sierra, Alex Ortega,
Laura Gimeno-Torres, and Eva Llopis
26 
Injections of Anatomical Regions and Diseases: Knee ���������������� 201
Sarper Gursu, Ahmet Sukru Mercan, Anıl Erbas,
Serda Duman, and Ozgur Ismail Turk
27 Injections of Anatomical Regions and Diseases:
Ankle and Foot �������������������������������������������������������������������������������� 211
Tekin Kerem Ulku and Berhan Bayram
 Part I
Basics of Musculoskeletal Injections
 Philosophy of Musculoskeletal
Injections
1
Behiç Çelik and Gökhan Meriç

1.1 Introduction musculoskeletal system to relieve pain, inflam-

mation, and other symptoms. Musculoskeletal
While providing orthopedic healthcare services, injections can be used to treat a variety of condi-
various invasive interventions are applied to tions, including arthritis, tendonitis, bursitis, and
patients according to their clinical status. other inflammatory or degenerative diseases like
Injection, which is an invasive procedure, is one osteoarthritis. The common use of injections,
of the most commonly used medical procedures their use for preventive, therapeutic, or recre-
in the world. Many other invasive procedures ational purposes, and their varied routes of
also require injections. In addition, injections are administration make one forget that the person
also applied to healthy individuals for the pur- credited with inventing the method over a century
pose of maintaining health and protection apart years ago was merely looking to treat the agony
from its therapeutic purpose. According to the of neuralgia. The goal is to provide targeted relief
2002 data of the World Health Organization to the affected area while minimizing systemic
(WHO), it is estimated that 16 billion injections side effects that can occur with oral medications.
are made annually in developing countries, 95% Modern medicine followed the footsteps of
of which are therapeutic in purpose [1]. Providing nature, just as in any other field which has techno-
health care without injections through needles is logical aspects that have to stay up to date. Sharp
merely possible. And here is how to paint this as objects which were necessary for hunting and
a theme; the needle represents the ability to heal piercing through thing were always necessary in
through pain. As Brokensha portraits in 1999, the the ancient times. Snake bites and arrows loaded
needle, like the hollow teeth of the serpent that with poison were fine examples. Even though
wraps around Aesculapius’ staff, penetrates and many references were present in nature, it still
reinforces doctors’ authority [2]. took several centuries for the syringe and the nee-
The philosophy of musculoskeletal injections dle, which are the current must-have devices for
in medicine is based on the idea of delivering modern medicine, to be developed. Before any
therapeutic agents, such as medications or local medical subdivision even occurred, invasive pro-
anesthetics, directly into the affected area of the cedures such as dissections, injections, etc. were
all part of the general medical practice in countries
that were forerunners of science and research. It is
B. Çelik · G. Meriç (*) no coincidence that these developments took place
Department of Orthopedics and Traumatology, in Europe, where medicine took its modern turn
Yeditepe University Medical Faculty, via experimentations arising from its ancient roots.
Istanbul, Turkey

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 3

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
4 B. Çelik and G. Meriç

1.2 Philosophy Pravaz, and Luer resulted in increased utilization,

of Musculoskeletal safety, and accuracy. As a result, the Luer syringe
Injections was designed for aseptic heating and a sharp nee-
dle that could easily pierce the skin. Pasteur,
Physicians have experimented with a multitude Chamberland, and Koch created autoclave steril-
of strategies to get medications into the body over ization after regulating aseptic conditions.
the decades. Rubbing of ointments and oils onto Another invention, Limousin’s ampoule, intro-
the skin, one of the earliest procedures, was duced in 1886, provided a secure technique for
described in the Old Testament, Homer’s storing sterile injectates, followed by the advent
Odyssey, and by Aristotle and was employed by of multi-dose containers. Nowadays, with the
practically all ancient physicians. However, emergence of transdermal drug delivery via
severe adverse effects and questionable results micron-scale needles and monitored drug deliv-
prompted the search for alternate treatments. ery, the evolution of the syringe and its needle
According to our knowledge, the earliest intrave- goes on [5].
nous injection trials were conducted in 1642 in Considering all the historical processes and
eastern Germany and in 1656 in England by developments that took place, just as there is a
Christopher Wren [3]. need for improvement, management and keeping
The philosophy of injections, just as any other things up-to-date in any practice in medical sci-
invention that ever took place in the history of ence, the practice of injection depends on the
mankind, got his origin idea from nature. In purpose, the right indication, the dose, the mate-
1628, William Harvey presented fresh knowl- rial and sterility, the right patient selection, and
edge about human blood circulation, which the right agent. It is a clear fact that research and
spurred these studies. According to our knowl- inventions under appropriate conditions must be
edge, the earliest intravenous injection trials were done, keeping things up to date, and while doing
conducted in 1642 in eastern Germany and in that, all the following must be taken into account:
1656 in England by Christopher Wren. the right place and timing, the right method and
Subcutaneous injection was also one of the new circumstance of application, the right follow-up,
methods; predecessors of this application either ideal doctor and patient communication, the
used a vaccination-lancet to introduce the medi- patients’ expectation, and all that might affect the
cation beneath the epidermis or they’d remove outcome in terms of improvement of the patients’
the epidermis before introducing the medication condition and well-being. An understanding of
to the stripped epidermal layer. Lafargue, the determinants of current injection practices in
Lembert, and Lesieur reported these procedures the sociocultural-economic context is necessary
starting early in the 1800s, and they remained in in order to plan relevant and effective
use until the discovery of subcutaneous injection interventions.
in the second half of the century. From a doctor’s perspective, we use injections
The syringe for subcutaneous injection was with various application methods in cases that do
invented by Alexander Wood of Edinburgh and not respond to conservative treatment, with the
Charles-Gabriel Pravaz of Lyon. In Lyon in 1853, logic of transitioning to a higher-level treatment.
the French surgeon C. Pravaz devised a miniature At the same time, various injection techniques
syringe, the piston of which could be moved by a can be used in advanced cases where surgery is
screw, allowing precise dosage. Using a sharp not considered, in patients who do not want sur-
needle with a trocar, he eliminated the need for a gery but need an outpatient invasive procedure
dissection. Pravaz used his syringe to obliterate that does not require surgery. From a patient’s
artery aneurysms with ferric chloride injections. perspective, there are several reasons why injec-
His device sparked the development of calibrated tions may be necessary. Injections are often
syringes made of glass or metal coupled with required when oral medications or alternative
glass [4]. The gradual steps introduced by Wood, treatments are not as effective or suitable for a
1 Philosophy of Musculoskeletal Injections 5

particular condition. Injections allow medica- for pain and inflammation, facilitate healing, and
tions to be delivered directly into the body, ensur- enhance performance. Here are some ways in
ing quicker and more potent effects. which injections are important in sports medi-
Musculoskeletal injections are an important cine. Injections can be used to provide rapid pain
diagnostic and therapeutic technique for orthope- relief to athletes who have sustained injuries or
dist. Some medical conditions require ongoing are experiencing chronic pain. Platelet-rich
treatment and management. While regular injec- plasma (PRP) injections, for instance, contain
tions may be inconvenient, they can significantly growth factors that can stimulate the repair and
improve the patient’s quality of life and overall regeneration of damaged tissues. Injections of
health outcomes (Fig. 1.1). Injections are some- hyaluronic acid can also help improve the health
times used as part of diagnostic procedures to of damaged joint cartilage by lubricating and
help identify or evaluate certain medical condi- cushioning the joint [7]. In some cases, injections
tions. It can help with pain management and can be used to enhance athletic performance. For
overall function [6]. The choice of injection tech- example, erythropoietin (EPO) injections can
nique and medication depends on the specific increase the production of red blood cells, which
condition being treated, as well as the patient’s can improve an athlete’s endurance by delivering
individual needs and preferences. Overall, the more oxygen to the muscles [8].
philosophy of musculoskeletal injections is to Musculoskeletal pain is a prevalent problem
provide safe, effective, and minimally invasive that many primary care physicians, orthopedic
treatments for musculoskeletal conditions, with surgeons, and pain specialists identify and try to
the goal of improving patients’ quality of life and treat on a daily basis. Treating pain with a multi-
functional outcomes while minimizing the use of modal strategy is critical to provide patients with
more invasive interventions, such as surgery. safe and effective results. In addition to this com-
Injections play a crucial role in sports medi- mon ground of application, each specialty has its
cine as they can provide targeted and rapid relief own particular aspects. When we take a look at
the top of the specialties which use musculoskel-
etal injections in their practice routine, we see
orthopedics, physical therapy and rehabilitation,
algology, and anesthesia. It is possible to extend
the list depending on the application of some
regimes of therapy. Physicians should compre-
hend the target anatomy and injection indica-
tions. Injections can be used to both identify the
source of discomfort and reduce pain to allow for
a more thorough evaluation. Aspiration may be
used in injections to aid in diagnostics, provide
pain relief, and restore joint motion. It is critical
to explain activity restrictions, postinjection pain
expectations, and the planned treatment course,
and as always, just before any other medical
intervention, informed consent should always be
acquired prior to the procedure [9, 10]. Injections
could be performed blind or through guiding.
When compared to landmark guiding, ultrasound
guidance has been shown in numerous trials to be
more accurate and effective [6].
Musculoskeletal injections also differ accord-
Fig. 1.1 Injection for peroneal tendon synovitis ing to the specific agent that is used and its spe-
6 B. Çelik and G. Meriç

cific mechanism of action. Anesthetic drugs are peutic purpose in which the underlying principle
mostly used in injections to reduce pain and help is the promotion of health and the alleviation of
to diagnose the medical condition [10]. suffering; secondly, the autonomy and informed
Corticosteroids are effective immune suppres- consent, which ensures that individuals under-
sants and pain relievers. Intra-articular cortico- stand the potential benefits, risks, and alternatives
steroid injections might reduce pain temporarily, before agreeing to undergo an injection; and
especially when used to treat osteoarthritis [11]. thirdly, and maybe most importantly, beneficence
Hyaluronic acid (HA) is a naturally occurring and non-maleficence which emphasizes the duty
polysaccharide chain that the synovium secretes to promote benefit and avoid harm at all costs.
into the joint area. In the mid- to long-term treat-
ment of knee osteoarthritis, higher molecular
weight formulations seem to be more helpful and 1.3 Conclusion
efficient [12, 13]. Trigger point injections are a
treatment option for myofascial trigger points, In conclusion, musculoskeletal injections can
particularly in symptomatic individuals. Chronic provide a safe and effective treatment option for
or episodic headaches, temporomandibular joint a variety of conditions affecting the bones, joints,
pain, back pain, restricted range of motion due to and muscles. Whether it be corticosteroids for
trigger points, and groin pain are common con- inflammation, hyaluronic acid for joint lubrica-
current symptoms. Trigger point injections can tion, or platelet-rich plasma for tissue regenera-
produce meaningful results and should be con- tion, there are a variety of injection therapies that
sidered as a therapy option in the right circum- can help alleviate pain and improve mobility.
stances [14]. Dry needling is a procedure that However, it is important to note that these injec-
uses a small needle which pierces the epidermis, tions should only be administered by qualified
subcutaneous tissues, and muscle in order to healthcare professionals and that patients should
mechanically disrupt tissue without the use of an be thoroughly evaluated beforehand to ensure
anesthetic. The physiological mechanism under- that they are suitable candidates for the proce-
lying the effects of dry needling is still unknown. dure. Overall, with careful consideration and
Dry needling, on the other hand, has been hypoth- appropriate use, musculoskeletal injections can
esized to elicit both local and central neural be a valuable tool in the management of muscu-
responses to restore homeostasis at the site, loskeletal conditions. Overall, our chapter
resulting in a reduction in both peripheral and emphasizes the critical role that injections play in
central sensitivity to pain [15]. Prolotherapy, also modern medicine and underscores the impor-
known as regenerative injection therapy, is a tance of ongoing research and education in this
medical procedure used to treat chronic musculo- area. By continually striving for safer, more
skeletal pain and promote tissue healing. It effective injection techniques, we can improve
involves the injection of a substance, typically a patient outcomes and advance the field of health
proliferant solution, into damaged or weakened care as a whole.
ligaments, tendons, or joints to stimulate the
body’s natural healing response [16].
It is important to note that the philosophy of
injections is a broad topic that encompasses vari- References
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 The Evidence-Based Medicine
for Injection Therapy
2
Marko Ostojić

2.1 Introduction beneficial effects. Approaches to injection ther-

apy as a field of treatment have been known for a
As a therapeutic modality, injections have been lack of standardization. A more evidence-based
widely used in treating musculoskeletal disor- approach to this field is necessary to oppose some
ders, usually in an outpatient clinic setting. This well-established dogmas with the final goal of
treatment modality is defined as a method delivering the best available care to patients. For
whereby therapeutical agents are delivered to the future studies, it is of outmost importance to
selected location with the use of a syringe and define the outcome measures leading to clinical
hypodermic needle. It is common practice that improvement, with a special focus on “respond-
injection therapy, in terms of treatment sequence, ers” and “nonresponders.” The remission of
finds a place between the conservative first-line symptoms and the deceleration of disease pro-
treatment (physical therapy, lifestyle modifica- gression are not the sole objectives of an optimal
tion, pain management, etc.) and the surgical injectable. A scientific research perspective
intervention. The type and timing of injections would pronounce the importance of developing
depend on many factors: from the pathology that an injectable agent with disease-modifying prop-
is being treated and the patient’s functional erties. In other words, an agent that reverses dis-
demands to the modus operandi of the attending ease progression, by breaking the vicious circle
physician. Regarding the latter, some physicians of tissue deterioration and leads to tissue healing
are prone to deliver conservative treatment, while [1, 2]. Since orthobiologic agents show a pro-
others favor the operative approach. Some physi- nounced healing potential, it is not a surprise that
cians are quick to adopt new emerging tech- some people see it as the holy grail of nonsurgical
niques, yet others are skeptical and require hard treatment.
clinical evidence to be convinced. A plethora of Let us briefly go through the available options
different factors affect the type of treatment that in an evidence-based and critical manner. First, it
patients will receive. During medical training, is of paramount importance to make a clear dis-
doctors gain a lot of anecdotal knowledge in this tinction between intra-articular and extra-­
field, mostly concerning corticosteroids and their articular injections.

M. Ostojić (*)
Department of Orthopaedics and Traumatology,
University Hospital Mostar,
Mostar, Bosnia and Herzegovina

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 9

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
10 M. Ostojić

2.2 Intra-Articular Injections short-term effect is beneficial concerning pain

relief, but, unfortunately, their long-term positive
Intra-articular injections are used for the treat- effect has not been observed [10, 11]. As men-
ment of osteoarthritis and other degenerative dis- tioned before, corticosteroids are often given
eases on one hand and for fresh injuries where we with local anesthetics, which are proven to be
strive for faster tissue healing and pain manage- chondrotoxic, causing the apoptosis of the chon-
ment on the other. A joint is an enclosed organ drocytes [12]. Corticosteroids also have a time-
possessing its equilibrium. The synovial mem- and dose-­dependent negative effect on hyaline
brane of a joint acts as a barrier that holds in any cartilage, being beneficial at low doses and detri-
injected substance for a defined period. Any kind mental at high doses [13]. In combination with
of arthritis or fresh injury affecting a part of the local analgesics, the chondrotoxicity of cortico-
joint causes an inflammatory reaction that leads steroids is more pronounced due to the synergis-
to a vicious circle that leads to further tissue dam- tic effect these two injectables possess [14, 15].
age [3, 4]. This induces the release of ­inflammatory Hyaluronic acid, a large molecule that binds
factors in the synovial fluid that promote further water and that is naturally produced by the syno-
synovial inflammation [5, 6]. There is a (proba- vial membrane, has anti-inflammatory and shock
bly oversimplified) rule that any intra-­articular absorption effects and acts as a lubricant during
injection that is given in a conventional medicine joint motion, with possible disease-modifying
setting leads to the improvement of clinical effects [16]. Theoretically, it has all the necessary
symptoms in osteoarthritic joints. For example, qualities to be a highly successful intra-articular
in hip osteoarthritis, the injection of saline into an injectable agent. Indeed, meta-analyses have
osteoarthritic hip joint resulted in symptomatic shown the superiority of hyaluronic acid as com-
relief that was comparable to some of the com- pared to corticosteroids. However, HA falls
mercially most often used treatments [7]. Many behind when compared to orthobiologic agents
studies evaluating the treatment of osteoarthritis [17, 18]. Orthobiologic therapies that have gained
use saline as a placebo, which is a methodologi- popularity in the last two decades, including
cally questionable procedure. Saline, the isotonic platelet-­
rich plasma (PRP) and cellular-based
solution of sodium chloride and water, has the products (e.g., stem cells), show the most promis-
effect of diluting the synovial fluid and “washing ing results in the middle- and the long-term
out” inflammatory factors. It does not have a results in the treatment of early osteoarthritis.
long-term effect, but it does bring on the tempo- The main difference to the previously mentioned
rary improvement in clinical function and pain agents is that, due to their biological origin, they
[8]. A true placebo for this kind of trials should are autotransplants that possess more disease-
be a “sham procedure” in which the joint capsule modifying effects. Meta-analyses have demon-
is not penetrated and where the injectable pla- strated the superiority of orthobiologic agents to
cebo agent is given subcutaneously [9]. other injectables. However, some controversies
Corticosteroids are naturally produced in the cor- exist due to the diversity of the products and a
tex of adrenal glands. Synthetic variants have lack of high-quality randomized control trials
been used for over 70 years, and they still are one [17]. PRP is the most widely used blood-derived
of the most widely used anti-inflammatory medi- product, and therefore, details on other blood-
cines. In orthopedics, long-releasing (depo) prod- derived products are not going to be discussed
ucts are routinely used in the form of injections, (e.g., alpha-2 macroglobulin, autologous condi-
both intra- and extra-articularly. In combination tioned serum). Let’s try to clarify how PRP works
with local analgesics, they are a potent injectable practically. After most injuries, bleeding occurs,
agent. This combination has a quick effect and and blood is the first source of healing agents.
brings on short-term pain relief. This translates to With PRP, the fraction of venous blood from
patients walking out of their physician’s office which we expect the strongest healing potential
satisfied. Studies have indeed shown that their (serum with growth factors and platelets) is
2 The Evidence-Based Medicine for Injection Therapy 11

extracted and applied to the desired site. Platelets

that has the least adverse effects on the surround-
comprise several growth factors, which play cru- ing tissues. It is known that corticosteroids can
cial roles in tissue repair and regeneration mecha-cause weakening of the tendon tissue. For exam-
nisms [2]. To put it in a nutshell, a fresh injury is
ple, using corticosteroids is effective in the treat-
mimicked to start the healing cascade. The litera- ment of tendovaginitis, but potentially negative
ture supporting the use of PRP is growing, with side effects can occur, iatrogenic tendon rupture
meta-­analyses and ESSKA “ORBIT Delphi con- being of the most disastrous one [21]. Hyaluronic
sensus” supporting its use for knee osteoarthritis acid can be used as an extra-articular injection
[18]. The injectable agents, which the orthopedic but preferably delivered inside the space that is
community is putting most hopes in recently, are encircled by a tendon sheath. This space partially
cellular-­based products, which show promising resembles the intra-articular milieu and has hyal-
long-term effects. Mesenchymal stem cells uronic acid produced naturally in small quanti-
(MSCs) are multipotent cells that are usually ties. Again, orthobiologic agents, particularly
derived from fat tissue or bone marrow and can PRP, show the most promising results with their
be used as autotransplant or homotransplant. anti-inflammatory properties that oppose extra-­
They can be given immediately after the explan- articular inflammation. For acute injuries, like
tation process, in a minimal manipulation man- muscle and tendon rupture, corticosteroid and
ner, or they can also be expanded in vitro for hyaluronic acid use does not have a biological
application at a later date. New insights show thatrationale, and PRP is advised to be first option as
most of their therapeutic potency is due to their injection therapy [22]. The other therapy modal-
paracrine effect. Hence it is suggested that the ity that is commonly used for extra-articular tis-
MSC abbreviation should stand for medicinal sue disorders is prolotherapy. It is a modality that
signaling cells [19]. In vivo studies have shown uses irritative agent (like hyperosmotic dextrose
that there is a scarce chance of these cells surviv-
or saline) causing a local inflammatory response
ing for a longer period of time after intra-articular
that leads to fibrosis and potential healing of the
injection and, afterward, transforming to the diseased tissue. It is mostly used in tendinopa-
desired missing chondrocyte cells in the diseased thies, where it shows successful results [23]. The
joint. More hope is put in their exosome, which is use of botulinum toxin is common in neuromus-
expected to have a healing potential, through the cular disorders, where spastic muscles are relaxed
previously mentioned paracrine effect. Due to the by intramuscular application. Botulinum toxin
heterogeneity of MSCs products, the results, blocks the neuromuscular junction thus paralyz-
although promising, have some confronting con- ing the muscle. It has shown clinical improve-
clusions, with high-quality randomized con- ment in patients with the spastic type of cerebral
trolled studies still needed to support long-lasting
palsy.
effects of this therapeutic agent [20]. The most important factor in getting a suc-
cessful outcome in this type of treatment is care-
ful selection of the adequate injectable agents for
2.3 Extra-Articular Injections a certain patient. All of the beforementioned have
their advantages and disadvantages. It is there-
Extra-articular injections are most commonly fore crucial to choose an agent that brings on an
used in inflammatory conditions, degenerative improvement and minimizes iatrogenic harm.
conditions (e.g., tendinopathies), and acute inju- The primum nil nocere rule is of headmost impor-
ries. Some of the chronic overuse injuries have tance in this field, where paramedical factors
characteristics of chronic inflammation and often influence the physician’s decision-making
degenerative conditions, so they are treated where the desire for a lucrative practice can cloud
accordingly. In the case of inflammatory condi- her/his judgment. Also, we have to outline that
tions, it is crucial to seek benefit of anti-­ placebo effect could be encountered, but we can-
inflammatory potential of the therapeutic agent not, in any instance, rely on it.
12 M. Ostojić

In the hands of a trained professional, muscu- 2.4 Conclusion

loskeletal injections have a low percentage of
complications [24]. The learning curve is not In conclusion, musculoskeletal injections are
trivial, but it is far quicker than that of surgeries. safe and affordable and require less logistics than
Ultrasound has been used to improve precision, operative treatment. By its widely used defini-
even in the case of joints that are easily approach- tion, evidence-based medicine is the conscien-
able and positioned close to the skin [25]. For tious, explicit, and judicious use of current best
deeper joints, like the hip joint and the smaller evidence in making decisions about the care of
joints of the spine, anatomical landmark orienta- individual patients. Physicians should put their
tion with fluoroscopic control is advised [26, 27]. effort into providing adequate care to their
It is important to stress that when it comes to pre- patients by giving them the best possible treat-
cision in extra-articular applications, the use of ment, in this instance the best possible injection,
imaging guidance is necessary. Without skillful based on updated, critically reviewed literature
orientation in surface anatomy and the usage of and their clinical expertise.
imaging guidance, there is a high chance of miss-
ing the desired spot [28]. When the correct spot is
missed, not only will the therapeutic agent have References
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strong scientific evidence nor consensus on the 8. Saltzman BM, Leroux T, Meyer MA, Basques BA,
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2 The Evidence-Based Medicine for Injection Therapy 13

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ter outcomes than hyaluronic acid and saline in knee
 Contraindications and Potential
Side Effects of Injections
3
Riccardo Compagnoni, Rossella Ravaglia,
and Pietro Randelli

3.1 Introduction articular injections cannot be performed in

patients with an unstable coagulopathy for the
Musculoskeletal injections are considered rela- risk of hemarthrosis.
tively safe procedures, if performed following Intra-articular or osteochondral fractures are a
the indications and avoiding cases in which there contraindication to a corticosteroid injection. The
are absolute contraindications. Contraindication presence of joint prostheses represents a relative
of intra-articular injections is a known hypersen- contraindication. Other relative contraindication
sitivity to any component of the injection, skin would be the lack of response to prior injections
cellulitis, or broken skin over the needle entry and more than three prior injections in the last
site. The risk of infection is increased in these year to a weight-bearing joint [1].
cases and in cases of joints with septic effusion If delivered properly and with correct indica-
of a bursa or a periarticular structure. Intra- tions, injections can be very rewarding for both
the patient and the clinicians. Nonetheless, litera-
ture reports some possible complications.
It is possible to classify these complications in
three groups (Table 3.1): intra-articular effects,
surrounding tissue effects, and systemic effects.
R. Compagnoni (*)
Department of Biomedical, Surgical and Dental
Sciences, Università degli Studi di Milano. Via della
Commenda, Milan, Italy
e-mail: [Link]@[Link]
R. Ravaglia Table 3.1 Types of different complications after
1° Clinica Ortopedica, ASST Centro Specialistico injections
Ortopedico Traumatologico Gaetano Pini-CTO, Intra-articular Surrounding
Milan, Italy effect tissue effects Systemic effects
e-mail: [Link]@[Link] Flare of pain Pericapsular Cushing syndrome
P. Randelli calcification
1° Clinica Ortopedica, ASST Centro Specialistico Infection Tendon rupture Hyperglycemia
Ortopedico Traumatologico Gaetano Pini-CTO, Pseudoseptic Skin alteration Facial flushing
Milan, Italy arthritis
Steroid Anaphylaxis
Laboratory of Applied Biomechanics, Department of
arthropathy
Biomedical Sciences for Health, Università degli
studi di Milano, Milan, Italy Neuropsychiatric
e-mail: [Link]@[Link] changes

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 15

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
16 R. Compagnoni et al.

3.2 Intra-Articular Effects septic arthritis continues to be a challenging task

for clinicians. Accurate diagnosis is crucial; in
Regarding the first group, the most common fact, delayed diagnosis may lead to irreversible
complication of intra-articular injection is a joint damage, while overdiagnosis may cause
postejection flare of pain which has a 2–10% patients to undergo unnecessary medical and sur-
chance of occurrence. In this setting, the patient gical treatments. A positive culture from the
develops a flare of pain in the immediate 6- to affected joint is the gold standard diagnostic test
12-h period after an injection. The etiology is not [6].
sure, considering the timing of the reaction is Cultures often take days to produce results;
thought to be secondary to a local reaction to for this reason, alternative laboratory data are
microcrystalline steroid suspension. This compli- necessary for clinicians to initiate prompt treat-
cation is generally self-limiting and may be ment. Common blood tests are ESR, CRP, and
treated with activity modification, ice, and a short CBC. In addition, the synovial fluid cell count
course of a nonsteroidal anti-inflammatory drug and percentage of synovial fluid polymorphonu-
(NSAID). When, despite these precautions, pain clear cells from the joint aspiration are perhaps
persists after 36 h, patients should be evaluated the most critical determinant of native septic
for a septic joint. Infection is the most feared and arthritis [6]. A synovial fluid cell count of 50,000
dangerous local complication. Iatrogenic septic cells/mm3 or higher is typically concerning for
arthritis has been reported in patients following septic arthritis, while lower values are more con-
hyaluronic acid, steroids injections, and even sistent with a crystalline or inflammatory arthrop-
ozone [2]. The risk of this complication has been athy [7]. However, the literature to support this
estimated at 0.005% and 0.0002% for joint injec- cutoff is rather limited, yet this value is treated in
tions [3]. Risk factors include preexisting joint a dogmatic manner.
diseases such as rheumatoid arthritis, alcoholism, Although synovial cultures are the gold stan-
diabetes, cutaneous ulcers, previous steroid injec- dard, they are estimated to be only 75–95% sensi-
tions, previous knee surgery intravenous drug tive [8]. It is thought that if synovial cultures are
abuse, and immunosuppression. The likelihood used in isolation, then some instances of septic
of infection increases if these risk factors are all arthritis may be missed.
associated with a poor intra-articular injection In 1976, Newman defined four criteria to diag-
technique [2, 4]. nose septic arthritis. According to his study, only
Staphylococcus aureus is the most common one of four needs to be present to make a
pathogen (51.4%), including methicillin-resistant diagnosis:
Staphylococcus aureus (MRSA). It is followed
by gram-negative enteric bacillus such as E. coli 1. An organism isolated from the affected joint.
(5.7%), which is more prevalent in elderly 2. An organism isolated from elsewhere with a
patients, immunocompromised patients, and clinically swollen, painful joint.
patients with intravascular devices and urinary 3. No organism isolated, but histologic or radio-
catheters. Streptococcus pyogenes is less com- logic evidence of infection.
mon (4.7%) [4]. 4. Turbid fluid aspirated from the joint in a
The most common acute clinical aspects are patient that has previously received antibiot-
poor articular functionality, local erythema, and ics [9].
swelling, all associated with laboratory abnor-
malities (elevated ESR and CRP) [5]. This definition remains popular today and is
Knee is the joint involved in about 50% of often used. Septic arthritis following joint injec-
cases of infection after injection [2]. Potentially tions is much feared due to its various complica-
any joint after injection is prone to develop an tions described in literature: mortality appears to
infection, but hip, shoulder, and elbow infection be approximately 11% in monoarticular septic
are less common than knee [2]. The diagnosis of arthritis and a permanent loss of joint function
3 Contraindications and Potential Side Effects of Injections 17

nearly 40% [10]. Different treatment options in severity should be maintained [11]. Another pos-
managing acute septic arthritis have been pro- sible complication is steroid arthropathy..
posed, ranging from oral/e.v. antibiotic therapy, Avascular necrosis of the femoral or humeral
arthroscopic/open articular washing/debride- heads may follow systemic steroids of varying
ment, antibiotic cemented spacers, and joint dose and duration. After intra-articular adminis-
replacements/arthrodesis to amputations, with tration, there may be a rapid progression of pre-
obvious costs for the health system and often existing degenerative joint disease or frank
poor patient’s outcomes [2]. aseptic necrosis [16].
Pseudo septic arthritis is a rare complication
of hyaluronic acid injections that can be difficult
to differentiate from septic arthritis. In most 3.3 Surrounding Tissue Effects
cases, pseudo sepsis develops when patients are
sensitized to the agent, following the second or The second group of injections complications
third injection. Nevertheless, more rarely, the involves effects on surrounding tissue, such as
symptoms may develop after the first injection. pericapsular calcification, tendon rupture, and
Usually, it has been reported within 2 and 48 h skin alteration. Pericapsular calcification occurs
after the injection [11]. Even after completing in more than 40% of cases. The accumulation of
appropriate investigations, it can be difficult to insoluble steroid acts as a foreign body and
differentiate between pseudo septic arthritis and induces a chronic granulomatous inflammatory
septic arthritis. Investigations for pseudo septic process, with subsequent dystrophic calcification
arthritis generally include blood work and joint [17]. Tendon rupture is another important com-
aspiration to rule out septic arthritis. Patients can plication described following steroid injection. It
present with elevated leucocyte counts, C-reactive can have significant consequences, particularly in
protein (CRP), erythrocyte sedimentation rates an active or athletic cohort. It is difficult to imply
(ESRs), and joint aspirates with elevated synovial causality between injection and tendon rupture
leucocyte counts. Most notably, patients present despite the number and variety of reported cases.
with negative culture results, and their symptoms For example, the previous condition of the ten-
improve without antibiotics or operative inter- don that requires the injection can be implicated.
vention [12]. The incidence of tendon rupture increases with
The pathophysiology responsible for pseudo the number of injections undergone by the patient
septic arthritis has not yet been fully explored. [18]. This may reflect that worsening native ten-
Multiple theories have been suggested with mini- don abnormality, the accumulative effect of mul-
mal evidence, including inaccurate extra-­articular tiple injections, or a combination of these factors
hyaluronic acid injection [13]. The currently may be involved in the etiopathology of tendon
most accredited theory suggests a proinflamma- rupture [19]. Injection technique must be consid-
tory process, likely in keeping with a type IV ered, given the potentially deleterious mechani-
cell-mediated hypersensitivity reaction with sec- cal effects of intratendinous needle placement.
ondary activation of the complement pathway There is some evidence that the choice of cortico-
[14]. The sensitization theory suggests that new steroid may affect the incidence of tendon rup-
antigenic material (a second injection) triggered ture following injection: triamcinolone acetonide
a new inflammatory cascade mediated by com- is associated with a higher incidence of rupture
plement C5a and C5b-9, in addition to a chronic than betamethasone, methylprednisolone acetate,
macrophagic reaction [15]. This concept explains or hydrocortisone [19]. The postinjection tears
why pseudo septic arthritis occurred more sig- most frequently encountered in the literature
nificantly in patients receiving more than a single regards patellar, quadriceps, Achilles, and biceps
course of injection. Hence, no parameters to sug- tendons. Tears of the common extensor origin at
gest pseudo septic arthritis can be concluded, and the lateral epicondyle, the supraspinatus, tibialis
a high suspicion for septic arthritis given its anterior, biceps femoris, triceps, and the small
18 R. Compagnoni et al.

flexor tendons of the hand are less commonly Cytochrome P450 3A4 inhibitors appear to sig-
described [18]. nificantly reduce the clearance of administered
Skin alteration may occur when local steroid corticosteroids from the patient’s system, while
is applied too close to the surface of the skin. they not affect absorption [20]. Exogenous
Alteration may include depigmentation or hyper- Cushing syndrome can occur from locally
pigmentation. These changes may be irreversible. injected glucocorticoids [20]. Cushing’s syn-
Furthermore, intramuscular injection of cortico- drome derives from an excessive production of
steroids may lead to atrophy of the skin and sub- cortisol. It is associated with several physiologi-
cutaneous tissue at the site of administration. cal changes, including facial and trunk obesity,
This occurs because of the dose-dependent stretch marks, hypertension, weakness, facial
­inhibitory action of corticosteroids on the prolif- hair growth in females, and osteoporosis.
eration of fibroblasts and the accelerated decom- Hyperglycemia after intra-articular injection has
position of collagen. Clinically, the disappearance been demonstrated in patients with diabetes. It
of the subcutaneous adipose tissue is observed may consist in short-term difficulties with glyce-
without evidence of an inflammatory type. mic control. More rarely, an increase in serum
Generally, the subcutaneous atrophy is reversible glucose can also occur in patients without diabe-
within a year, but in some cases, it is necessary totes. Usually, this situation has no real conse-
resort to the injection of a “fat bolus,” which quences and resolves between 24 h and 1 week.
often causes cysts and calcifications associated Facial flushing is a much more frequent com-
with necrosis. plication, developing in 15% of cases. It is
described mostly in women, and it occurs sec-
ondary to a histamine-mediated response [22]. It
3.4 Systemic Effects almost always resolves within a short time. As
with any situation in which a medication is
The third group includes systemic complications, administered, anaphylaxis must be considered;
developing above all after corticosteroid injec- however, this is extraordinarily rare in the setting
tions. The systemic side effects associated with of corticosteroid injection. This may occur more
both intra- and extra-articular corticosteroid commonly secondary to polyethylene glycol
injections are not completely understood. The (macrogol) which acts as a solvent for particulate
systemic absorption of corticosteroid occurring corticosteroids. Injected glucocorticoids can lead
following a local injection is variable. In most to temporary mania and psychosis in some
cases, particularly where there is accurate intra-­ patients. There are multiple case reports, but no
articular administration, systemic absorption of known incidence or dose correlation. Most of
locally injected musculoskeletal corticosteroid is these cases involve patients with preexisting psy-
minimal [20]. Less soluble corticosteroid formu- chiatric conditions, but many do not [20].
lations, such as triamcinolone and methylpred-
nisolone acetate, appear to deliver a greater and
more prolonged suppression of endogenous 3.5 Conclusion
serum cortisol than more soluble corticosteroid
preparations such as betamethasone [21]. Patients Musculoskeletal injections can be an effective
who are concomitantly receiving certain medica- treatment option, but they are not without risks.
tions, in particular cytochrome P450 3A4 inhibi- To ensure safety, the doctor must carefully review
tors such as ritonavir, appear to be at risk of the patient’s medical history and current medica-
suffering very severe and prolonged systemic tions, including any recent glucocorticoid injec-
side effects attributable to corticosteroids follow- tions in other areas. During the process of
ing even a single intra-articular injection, includ- obtaining informed consent and making deci-
ing Cushing’s syndrome and adrenal suppression. sions, it is important to clearly educate all patients
3 Contraindications and Potential Side Effects of Injections 19

receiving injections about the possible local and of pseudoseptic arthritis following hyaluronic acid
injection is a rare complication: a systematic review. J
systemic side effects. Patients should be informed ISAKOS. 2021;6(2):94–101.
that these effects can vary among individuals. 12. Leopold SS, Warme WJ, Pettis PD, Shott S. Increased
frequency of acute local reaction to intra-articular
hylan GF-20 (Synvisc) in patients receiving more
than one course of treatment. J Bone Joint Surg.
References 2002;84(9):1619–23.
13. Adams ME, Lussier AJ, Peyron JG. A risk-benefit
1. Stephens MB, Beutler AI, O’Connor assessment of injections of hyaluronan and its deriva-
FG. Musculoskeletal injections: a review of the evi- tives in the treatment of osteoarthritis of the knee.
dence. Am Fam Physician. 2008;78(8):971–6. Drug Saf. 2000;23(2):115–30.
2. Larghi MM, Grassi M, Placenza E, Faugno L, 14. Marino AA, Waddell DD, Kolomytkin OV, Pruett S,
Cerveri P, Manzotti A. Septic arthritis follow- Sadasivan KK, Albright JA. Assessment of immu-
ing joint injections: a 17 years retrospective study nologic mechanisms for flare reactions to Synvisc®.
in an Academic General Hospital. Acta Biomed. Clin Orthop Relat Res. 2006;442:187–94.
2021;92(6):e2021308. 15. Dragomir CL, Scott JL, Perino G, Adler R, Fealy S,
3. Geirsson ÁJ, Statkevicius S, Víkingsson A. Septic Goldring MB. Acute inflammation with induction of
arthritis in Iceland 1990–2002: increasing inci- anaphylatoxin C5a and terminal complement com-
dence due to iatrogenic infections. Ann Rheum Dis. plex C5b-9 associated with multiple intra-articular
2008;67(5):638–43. injections of hylan G-F 20: a case report. Osteoarthr
4. Mohamed M, Patel S, Plavnik K, Liu E, Casey K, Cartil. 2012;20(7):791–5.
Hossain MA. Retrospective analysis of septic arthritis 16. Miller WT, Restifo RA. Steroid Arthropathy1.
caused by intra-articular viscosupplementation and 1966;86(4):652–657. [Link]
steroid injections in a single outpatient Center. J Clin org/10.1148/86.4.652.
Med Res. 2019;11(7):480–3. 17. Conti RJ, Shinder M. Soft tissue calcifications
5. García-Arias M, Balsa A, Mola EM. Septic arthritis. induced by local corticosteroid injection. J Foot Surg.
Best Pract Res Clin Rheumatol. 2011;25(3):407–21. 1991;30(1):34–7.
6. Rasmussen L, Bell J, Kumar A, et al. A retrospec- 18. Hynes JP, Kavanagh EC. Complications in image-­
tive review of native septic arthritis in patients: can guided musculoskeletal injections. Skelet Radiol.
we diagnose based on laboratory values? Cureus. 2022;51(11):2097–104.
2020;12:6. 19. Nichols AW. Complications associated with the use
7. Mathews CJ, Coakley G. Septic arthritis: current of corticosteroids in the treatment of athletic injuries.
diagnostic and therapeutic algorithm. Curr Opin Clin J Sport Med. 2005;15(5):370–5.
Rheumatol. 2008;20(4):457–62. 20. Stout A, Friedly J, Standaert CJ. Systemic absorption
8. Li SF, Cassidy C, Chang C, Gharib S, Torres and side effects of locally injected glucocorticoids.
J. Diagnostic utility of laboratory tests in septic arthri- PM&R. 2019;11(4):409–19.
tis. Emerg Med J. 2007;24(2):75–7. 21. Horani MH, Silverberg AB. Secondary Cushing’s
9. Newman JH. Review of septic arthritis throughout the syndrome after a single epidural injection of a corti-
antibiotic era. Ann Rheum Dis. 1976;35(3):198–205. costeroid. Endocr Pract. 2005;11(6):408–10.
10. Mathews CJ, Weston VC, Jones A, Field M, Coakley 22. Common Injections in Sports Medicine: General
G. Bacterial septic arthritis in adults. Lancet. Principles and Specific Techniques | Musculoskeletal
2010;375(9717):846–55. Key.
11. Sedrak P, Hache P, Horner NS, Ayeni OR, Adili A,
Khan M. Differential characteristics and management
 Informing Patients
4
Daniel Pérez-Prieto, Ana Soria, Marta Torruella,
and Narcís Pérez de Puig

4.1 Possible Complications to be informed about the risks and benefits of the
of Injections treatment before the intervention [3].
Among the different types of complications, it
Infiltrations and musculoskeletal injections are should be distinguished between adverse events
common procedures in the treatment of various at the local level and systemic complications that
musculoskeletal conditions such as arthritis, ten- may arise from the process. It is also important to
dinopathy, or osteoarthritis. These procedures have in mind that adverse reactions can appear
involve the injection of medications into the even after several weeks after the injection has
affected soft tissues and joints to reduce inflam- been performed.
mation and pain and improve function. Some of the most common complications are
Musculoskeletal infiltrations and injections are explained hereafter.
generally safe and effective, but like any medical
procedure, they carry risks and potential compli- • Infection [4, 5]: Injections into the skin or
cations [1, 2]. Therefore, it is essential for patients joints can lead to bacterial or fungal infec-
tions. Symptoms of an infection may include
redness, swelling, pain, and fever. The inci-
D. Pérez-Prieto (*) dence of infection after an injection varies
Orthopedic Surgery Department, Hospital del Mar, depending on the injection site and the tech-
Barcelona, Spain
nique used for the injection. It is crucial to
Department of Traumatology and Orthopaedic perform the injection under sterile conditions
Surgery, Hospital del Mar, Barcelona, Spain
(see correspondent chapter). The presence of a
IcatKnee – Hospital Dexeus, Barcelona, Spain particular germ may vary depending on the
Universitat Autònoma de Barcelona (UAB), environment, patient population, and other
Barcelona, Spain factors. Additionally, the risk of infection may
e-mail: dperezprieto@[Link]
also be influenced by the aseptic technique
A. Soria · M. Torruella used during the injection and individual
Orthopedic Surgery Department, Hospital del Mar,
Barcelona, Spain
patient characteristics, such as immunity and
e-mail: [Link]@[Link]; the presence of comorbidities. It is always rec-
[Link]@[Link] ommended to follow appropriate aseptic and
N. P. de Puig sterilization guidelines to prevent infections
Legal Department, Hospital del Mar, associated with musculoskeletal injections.
Barcelona, Spain
e-mail: nperez@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 21

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
22 D. Pérez-Prieto et al.

• Pain and discomfort [1]: After an injection, • Bleeding [1]: Bleeding after musculoskeletal
patients may experience pain or discomfort at injections is a potential complication, espe-
the injection site, which can last for several cially if damage to blood vessels occurs dur-
days. In some cases, the pain can be intense ing the injection. Some common causes of
and may require analgesics. bleeding include incorrect injection technique,
• Nerve injury [1, 2, 4]: Nerve injuries are a inappropriate needle gauge, or the use of anti-
potentially serious complication of musculo- coagulant medications that increase the risk of
skeletal injections. Although relatively rare, bleeding. Bleeding can manifest in different
they can occur due to various factors such as ways, depending on the severity of the bleed-
incorrect injection technique, improper needle ing and the location of the injury. Some signs
placement, lack of image guidance, injection and symptoms of bleeding after a musculo-
in an area near a nerve, or the presence of ana- skeletal injection may include:
tomical abnormalities. Peripheral nerves, such –– Bleeding at the injection site. There may be
as the median nerve in carpal tunnel syndrome excessive bleeding at the site where the
or the radial nerve in elbow region injections, injection was performed. The bleeding
can be affected during the injection. This can may be visible externally or may form a
result in symptoms such as pain, numbness, hematoma beneath the skin.
weakness, or loss of motor function in the area –– Hematomas may appear in the injection
innervated by the affected nerve. area, which are accumulations of blood
• Allergic reactions [4]: These reactions can beneath the skin. Hematomas can vary in
occur due to an immune response of the body size and may cause pain and tenderness in
to one or more components of the injection, the affected area.
such as the drug, injection vehicle, or preser- –– In general, bleeding may be controlled by
vatives used in the medication. Some signs compression and cryotherapy. In excep-
and symptoms of an allergic reaction include tional cases, if a big vessel is damaged, a
the following: pseudo-aneurism may be formed, and sur-
–– Hives. Appearance of red, elevated wheals gery can be required to correct it.
on the skin, which can cause intense • Muscular tissue injury [2]: In rare cases, the
itching. injection can directly damage the muscular
–– Sensation of itching on the skin or through- tissue. This can cause localized pain, muscle
out the body. weakness, and difficulty in moving the
–– Edema. Localized or generalized swelling affected muscle.
of the skin or mucous membranes. • Articular cartilage and ligament injury. This is
–– Redness of the skin at the injection site or a rare but possible complication. This injury
in other areas of the body. can occur if the needle used during the injec-
–– Difficulty breathing, chest tightness, or tion comes into contact with the articular car-
wheezing. In type 1 allergy, a more severe tilage or injures the ligaments in the joint. It is
allergic reaction can trigger an anaphylac- also important to note the potential concern
tic reaction, which is a potentially life-­ that repeated corticosteroid infiltrations may
threatening medical emergency. increase the risk of tendon or ligament rupture
–– To reduce the risk of allergic reactions, it is in some patients [6].
necessary to inquire about patient allergies • Effects of corticosteroids [4]: Corticosteroids
prior to administering any medication or have anti-inflammatory properties and can
performing a musculoskeletal injection. help reduce inflammation and pain in joints
Additionally, if an allergy is suspected, and soft tissues. However, they can also
specific allergy tests can be conducted to weaken connective tissue, such as tendons and
identify the responsible allergens. ligaments, when administered at high doses or
4 Informing Patients 23

for prolonged periods. Moreover, they can including the possible complications men-
produce hypopigmentation of the skin in the tioned above.
site of infiltration and fat tissue atrophy that in • Alternatives: The physician should explain
severe cases may produce important deformi- any alternatives to the musculoskeletal infil-
ties in the site of infiltration. tration or injection procedure.
• Questions: The patient should have the oppor-
Several factors can increase the aforemen- tunity to ask questions about the procedure
tioned risks (specially tendon or ligament rupture and the associated risks and benefits.
after corticosteroid infiltrations) such as repeated
injections in the same location, high doses of cor- Whether the informed consent for infiltrations
ticosteroids, systemic diseases like diabetes, should be oral or written is still of controversy
advanced age, preexisting tendon or ligament [10, 11]. There is not a uniform regulation among
weakness, and intense physical activity after the different countries regarding how patients should
infiltration. The tendons most commonly associ- express his/her informed consent to a certain
ated with rupture after corticosteroid infiltrations treatment, nor a uniform practice. For instance,
are the Achilles tendon, the patellar tendon, and the European Alliance of Associations for
the rotator cuff tendons [2]. Rheumatology (EULAR) recommends that the
patient must be fully informed of the nature of
the procedure, the injectable, and potential bene-
4.2 Obtaining Consent fits and risks; informed consent should be
from the Patient obtained and documented according to local hab-
its [9]. In a recent survey, only 10% of UK upper
It is important to note that the incidence of com- extremity surgeon used written informed consent
plications after a musculoskeletal injection may [11].
vary depending on the patient, the treated condi- It is generally accepted that any serious or fre-
tion, and the technique used for the injection. quently occurring risks of any procedure must be
Therefore, it is crucial for patients to be informed explained to the patient, and the most frequent
about the risks and benefits of the treatment by complications should be also discussed. Then,
obtaining their informed consent [7, 8]. written informed consent could be recommended
Informed consent is a process by which a to prove that this process of explanation, advice,
patient agrees to receive medical treatment after and patient’s acceptance has been duly performed
being provided with information about the risks by physicians. There is a clear obligation to
and benefits of the treatment. It is important for obtain written informed consent in certain inva-
physicians to obtain informed consent from sive procedures, such as surgical interventions or
patients before performing a musculoskeletal invasive diagnostic or therapeutic procedures
infiltration or injection. The process of obtaining (Spanish law 41/2002, 14th November). Even in
informed consent should include the following those cases, in which written informed consent is
information [9]: mandatory, physicians must notice that it is not a
contract but the result of a permanent dialogue
• Procedure description: The physician should with patients for the decision-making that should
explain in detail the procedure of the musculo- be noted in the medical records at least [12].
skeletal infiltration or injection, including how Therefore, although the aforementioned different
it will be carried out and what can be expected regulations, a general recommendation would be
after the procedure. to explain risks, benefits, and alternatives to the
• Risks and benefits: The physician should dis- patient and to write down the patient acceptance
cuss the risks and benefits of the procedure, in the medical records.
24 D. Pérez-Prieto et al.

References intra-articular corticosteroid injections for osteoar-

thritis at 3 months and beyond: a systematic review
and meta-analysis in comparison to other injectables.
1. Hynes JP, Kavanagh EC. Complications in image-­
Osteoarthr Cartil. 2022;30(12):1658–69.
guided musculoskeletal injections. Skelet Radiol.
7. Aly MNS. Intra-articular drug delivery: a fast grow-
2022;51(11):2097–104.
ing approach. Recent Pat Drug Deliv Formul.
2. Nichols AW. Complications associated with the use
2008;2(3):231–7.
of corticosteroids in the treatment of athletic injuries.
8. Cole BJ, Schumacher HR. Injectable corticoste-
Clin J Sport Med. 2005;15(5):370–5.
roids in modern practice. J Am Acad Orthop Surg.
3. Stephens MB, Beutler AI, O’Connor
2005;13(1):37–46.
FG. Musculoskeletal injections: a review of the evi-
9. Uson J, Rodriguez-García SC, Castellanos-Moreira
dence. Am Fam Physician. 2008;78(8):971–6.
R, O’Neill TW, Doherty M, Boesen M, et al. EULAR
4. Brinks A, Koes BW, Volkers ACW, Verhaar JAN,
recommendations for intra-articular therapies. Ann
Bierma-Zeinstra SMA. Adverse effects of extra-­
Rheum Dis. 2021;80(10):1299–305.
articular corticosteroid injections: a systematic
10. Beitzel K, Allen D, Apostolakos J, Russell RP,
review. BMC Musculoskelet Disord. 2010;11:206.
McCarthy MB, Gallo GJ, et al. US definitions, current
5. Baums MH, Aquilina J, Pérez-Prieto D, Sleiman
use, and FDA stance on use of platelet-rich plasma in
O, Geropoulos G, Totlis T. Risk analysis of peri-
sports medicine. J Knee Surg. 2015;28(1):29–34.
prosthetic knee joint infection (PJI) in total knee
11. Lim CS, Miles J, Peckham TJ. Current practice of
arthroplasty after preoperative corticosteroid injec-
obtaining informed consent for local steroid injection
tion: a systematic review : a study performed by
among the shoulder and elbow surgeons in United
the ­Early-­Osteoarthritis group of ESSKA-European
Kingdom. Scott Med J. 2010;55(3):32–4.
Knee Associates section. Arch Orthop Trauma Surg.
12. Broggi MA. ¿Consentimiento informado o desinfor-
2022;
mado? El peligro de la medicina defensiva. Med Clin
6. Donovan RL, Edwards TA, Judge A, Blom AW,
(Barc). 1999;112:95–6.
Kunutsor SK, Whitehouse MR. Effects of recurrent
 Sterilization and Injection
Materials
5
F. De Filippo and Maristella F. Saccomanno

5.1 Introduction be easily visualized, so the needle trajectory can

be fine-tuned in accordance.
Joint injections are a useful diagnostic and thera- In any case, three main rules must be fulfilled
peutic skill in a surgeon portfolio. Although it is before performing an injection:
a simple procedure, it requires a correct training.
Diagnostic indications include the aspiration of • Good knowledge of the anatomy of the area to
fluid for cytologic or microbiological analysis as be injected, in order to avoid neuromuscular
well as to provide pain relief and range of motion bundles as well as skin and subcutaneous fat
recovery in swollen joints. Therapeutic indica- injections.
tions include the delivery of several biologic or • Aseptic technique.
non-biologic agents such as local anesthetics, • The indications and contraindications of the
corticosteroids, hyaluronic acid, growth factors, agent you are about to inject should be care-
and stem cells. Side effects are few, but one of the fully considered. The procedure should always
worse is surely the development of a postinjec- be performed when acute or chronic symp-
tion infection [1]. Moreover, joint and soft-tissue toms are present. Proper timing can help mini-
injections can be performed with or without mize complications that are directly associated
imaging guidance. Imaging guidance, such as with the type of agent being used, as well as
ultrasound, is meant to increase accuracy [2], and potential interactions with other therapies.
it is very helpful when the articular space cannot
be easily palpated, such in case of hip injections.
Advantages are mainly related to the fact that 5.2 Injection Equipment
anatomic structure (capsule, vessels, nerve) can
Injections or aspiration techniques require
aseptic conditions to minimize the risk of infec-
F. De Filippo
Department of Medical and Surgical Specialties,
tion [2].
Radiological Sciences, and Public Health, University The following items are mandatory:
of Brescia, Brescia, Italy
M. F. Saccomanno (*) • Alcohol and or povidone-iodine (Betadine)
Department of Medical and Surgical Specialties, solution
Radiological Sciences, and Public Health, University • Sterile and nonsterile gloves
of Brescia, Brescia, Italy
• Sterile drapes
Department of Bone and Joint Surgery, Spedali • 21- to 23-gauge needle
Civili, Brescia, Italy

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 25

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
26 F. De Filippo and M. F. Saccomanno

• 3–60 mL syringe for aspirations or povidone-iodine solution on sterile gauzes to

• 1–10 mL syringe for injections adequately prepare the injection site.
• Sterile gauzes
• Injectable agent
• Laboratory tubes for culture (in case of 5.3 Preparation of Injection Site
aspiration)
• Adhesive bandage or other adhesive dressing A good exposure of the entire area is required.
Disinfection of the target area is an important step.
An optimal setting includes a professionally The goal is to minimize risk of infection at the site.
clean, quiet, private, well-lit room, with the It is recommended to start from the entry point and
patient in a comfortable position. Careful patient then to gradually include a bigger area with circular
positioning before the procedure facilitates safe movements (Fig. 5.2). This step will allow the phy-
and efficient access to the joint. For shoulder, sician to have access to the entire joint (Fig. 5.3). In
elbow, and wrist injections, the patient can be this way, it will be easier to find the entry point.
seated. In contrast, for hip, knee, or ankle injec- Soft tissue spot or bony landmarks must be pal-
tions, the patient should be placed in the supine pated. The entry point can be marked with an
position. This helps prevent or mitigate the effects impression from a needle cap. At this point, the
of a vasovagal or syncopal episode. injection can be safely performed. An important tip
Once all the necessary equipment has been is to always perform aspiration before injecting to
gathered, the operative field can be prepared, fol- prevent intravascular injection. The injection
lowed by the preparation of the injection site. should flow smoothly and should not cause dis-
Begin by wearing non-sterile gloves and placing comfort to the patient. Most pain experienced dur-
a sterile drape. Then, put on sterile gloves, and ing the procedure is due to tissue stretching, and it
arrange the needles, gauzes, syringe, and adhe- can be minimized by injecting slowly. If there is
sive bandage on the sterile drape (Fig. 5.1).
If ultrasound guidance is utilized, a preproce-
dural scan is performed to plan the needle trajectory,
locate the target site, and identify nearby neurovas-
cular structures and tendons to avoid. Sterile gloves
can now be worn. An assistant will provide alcohol

Fig. 5.1 Sterile field: gloves, needles, gauzes, syringe, Fig. 5.2 Right shoulder: it is recommended to disinfect a
and adhesive bandage large area
5 Sterilization and Injection Materials 27

significant resistance encountered while injecting,

it is advisable to readjust the needle trajectory.

References
1. Zacay G, Heymann AD. Intra-articular and soft-­
tissue corticosteroid injections and risk of infections:
population-­based self-controlled-risk-interval design.
Pharmacoepidemiol Drug Saf. 2023;32:718–25.
[Link]
2. Uson J, Rodriguez-García SC, Castellanos-Moreira
R, et al. EULAR recommendations for intra-articular
Fig. 5.3 The physician can palpate several landmarks to
therapies. Ann Rheum Dis. 2021;80:1299–305. https://
ensure the entry point, even without imaging guidance
[Link]/10.1136/annrheumdis-­2021-­220266.
 Things to Take into Consideration
in Injection and Aspiration
6
Thorkell Snaebjörnsson

6.1 Indication for Treatment 6.2 Settings

When a healthcare provider gives an injection or The first thing to address when preparing for
does an aspiration, the underlying disease or con- either aspiration or injection is the indication for
dition can vary considerably. In recent years, treatment as well as the appropriate environment
injections have become a more widespread prac- for the chosen treatment form. Many patients are
tice for degenerative spinal diseases with a range sensitive to vasovagal fainting under these cir-
of different elective spinal injections available cumstances and are therefore at risk of falling
[1]. Another branch of healthcare providers treats and injuring themselves during the procedure. It
patients with a great variety of injections with is therefore important to inform the patient about
agents like neurotoxins and fillers [2]. In this the planned procedure and possible side effects.
chapter, the guidelines from WHO regarding After the information is given, it is time to make
injections and related procedures [3] have been sure that the patient is in a stable position with
taken into consideration. Within orthopedics, appropriate support, preferentially lying on his
there is a long tradition of intra-articular injec- back. It is equally important that the healthcare
tions in the knee and shoulder joints, either for provider is well prepared and has good access to
therapeutic [4] or diagnostic purposes [5]. Other the area of interest with a satisfactory environ-
indications for treatment include aspiration from ment and sources to perform the task ahead.
cysts or abscesses for diagnostic purposes in case
of infection or treatment in case of drainage. In
this chapter, our focus lays on traditional superfi- 6.3 Medical History
cial injections as well as intra-articular injections
and aspirations of joints [6], bursa, [7] or Every patient should be evaluated according to
abscess’s. prior health problems, risk of infection, medica-
tions before treatment, and accessibility to the
anatomical area of interest. If patients are on anti-
T. Snaebjörnsson (*) coagulation treatment, the healthcare provider
Department of Orthopaedics, Institute of Clinical must be sure that the benefit of the treatment
Sciences, Sahlgrenska Academy, Gothenburg given is bigger than the possible risk of bleeding
University, Gothenburg, Sweden after the operation. It is worth noting that accord-
Department of Orthopaedics, Sahlgrenska University ing to Kotecha et al. [8], it is fairly uncommon for
Hospital, Mölndal, Sweden a patient on anticoagulant therapy to have bleed-
e-mail: [Link]@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 29

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
30 T. Snaebjörnsson

ing complications after aspiration or injection. 6.5 Minimize Risk of Infection

Prior history of allergic reactions to vaccinations
or injections should be thoroughly evaluated It is important to emphasize the careful prepara-
before choosing to perform the injection. tion of the injection site with a focus on any signs
Another supplementary option to conven- of redness, swelling, scratch marks, wounds, or
tional injection or aspiration is the ultrasound-­ other actual skin changes. This is especially
guided approach to be able to penetrate the area important in elective procedures where it is rec-
of interest more accurately. This form of treat- ommended to postpone the procedure to lower
ment can be especially valuable when treating the risk of local infection or an infectious abscess
patients that are overweight, the anatomical area if any signs of damage to the skin barrier arise. In
is challenging, it is difficult to palpate manually, acute settings, the clinical decision of aspiration
or even where it is difficult for the patients to or injection must outweigh the risk of adverse
position themselves to expose the area of interest. effects and every patient evaluated separately.
Ultrasound-guided aspiration is even a valuable The decision to proceed with aspiration or injec-
treatment option to measure the amount of fluid tion in acute settings must be taken separately
in suspected arthroplasty infections and therefore from the elective settings, bearing in mind that
provides a guide to the clinical treatment of mea- one does not always have the luxury to postpone
suring the amount of fluid and deciding if aspira- the treatment without consequences to the patient.
tion is a feasible option. The aspiration can then
be performed subsequently with greater accuracy
compared with conventional methods. According 6.6 The Procedure
to Hoeber et al. [9], who performed a review and
meta-analysis on the accuracy of hip injection, Firstly, clean the skin before using local anesthe-
the accuracy of the injection is significantly bet- sia. Then wait for 10–15 min, and make sure that
ter when performed ultrasound guided when the skin is numbed before you proceed. When
compared with landmark-guided injections. penetrating the skin, the needle should be injected
perpendicularly through the skin before adjusting
to the point of interest. As previously mentioned,
6.4 Anatomical Landmarks a sterile method is recommended for all proce-
dures, but it is even more important when pene-
In order to be able to provide the best possible trating joints to lower the risk of infections
treatment for the patient, the healthcare provider (Table 6.1). The local anatomy of the injection
must know the local anatomical landmarks such site must be accurately known to avoid neuro-
as osseous points, palpate, and mark accordingly. muscular structures (damages) in the region. As
The marking of the area then serves as an indica- an example, there is a risk of skin necrosis if cor-
tor for the draping or the sterile preparation. The ticosteroids are injected into the subcutaneous fat
physician marks the site of injection point; this is tissue of the skin. This is especially important
often done by skin marking pen, and unfortu- when using steroid injections on muscle tendons
nately, this marking often disappears when the to avoid skin necrosis. When performing an
skin is cleaned. It is therefore recommended to injection, negative aspiration must be performed
make an indentation in the skin, using an instru- to avoid intravenous injection (Table 6.1).
ment like the cap of a pen and pressing the skin After the negative aspiration, the injection is
for several seconds, leaving a mark that does not then performed steadily and without causing any
disappear when the skin is prepared with antisep- pain to the patient. Patients can experience pain
tics [10]. caused because of tissue expansion; this can be
6 Things to Take into Consideration in Injection and Aspiration 31

Table 6.1 Preparation for the healthcare provider Table 6.2 Preparation of the patient
 • An aseptic technique is the golden rule using  • Safely position the patient so the patient and the
sterile equipment. muscles can relax.
 • Prepare the patient using gloves for you own  • Identify the surface anatomy and the relevant
protection. landmarks.
 • It is not mandatory to use sterile gloves when  • Any marking to identify point of entry should be
using no touch technique. made before sterilization.
 • Alcohol wiper or other disinfectant (chlorhexidine/  • Clean the overlying skin with alcohol swab or
povidone-iodine). other disinfectant.
 • Sterile drape.  • Local anesthetic can be applied (always for
 • Choose appropriate size of needles depending on children, occasionally for adults).
your task.  • If ultrasound is required, use sterile gel on the ultra
   Local anesthesia requires approximately 25–30 sound probe.
gauge needle.  • Prepare wound dressing if necessary.
   Injection requires a needle of approximately
22–25 gauge.
   Aspiration requires a needle of approximately apply pressure with a gauze or other wound
18–20 gauge. dressing and control hemostasis before the
 • Choose an injector of adequate size for either
aspiration or injection.
patient can be allowed to return home.
 • Choose suitable local anesthetic agent,
corticosteroid, or other agents.
 • Prepare laboratory tubes for assembling or for 6.7 Conclusion
storing aspirate.
 • Prepare a gauze or wound dressing for
compression. Injections and aspirations are valuable methods
 • Control hemostasis, especially important when for patient treatment and are currently used
performing both aspiration and injection with the within many branches of the healthcare system.
same needle.
 • Apply wound dressing.
As a general rule, the healthcare provider must
thoroughly evaluate the indication for treatment
and, together with the patient, decide that the
managed by lowering the speed of the injection. advantage of the treatment is greater than the
The injection should then flow easily, if there is possible disadvantage. Patient’s medical history
any obstruction or strong resistance, care must be should always be evaluated, with special empha-
taken to make sure the needle is within the joint. sis on medications with anticoagulation effects
The feeling of injection resistance may include or previous allergic reactions. Preparation for
the placement of a needle within the muscle, ten- treatment includes marking the area, sterile envi-
don, bone, or cartilage. If sharp pain is felt during ronment, and anatomical knowledge of the
the injection, the reason often is that the injection healthcare provider. A valuable treatment option
is going into the synovia; it is therefore recom- in difficult cases like suspicious arthroplasty
mended to temporarily stop the injection and infection is an ultrasound-guided aspiration. To
adjust the tip of the needle before resuming the let the patient relax, it is important that the skin
injection (Table 6.2). According to a systematic is numb and the needle is perpendicular to the
review performed by Hermans et al. [11], the skin during insertion. When an injection is per-
accuracy of knee injections varied from 91% formed, a negative aspiration is necessary to
using the superolateral approach to 67% accu- avoid intravenous injection. If sharp pain is felt
racy using the anterolateral approach of the knee during the intra-articular injection, it is wise to
joint. Bearing in mind the frequency of knee adjust the needle, since sharp pain is often found
injections, it is therefore of great importance to if the needle is located in the synovia. When
follow guidelines and train your methods to intra-articular injection is given, there should not
increase the rate of successful procedure, even be any significant resistance. Before applying
for more difficult or smaller joints. After the pro- wound dressing, satisfactory hemostasis should
cedure is performed, care should be taken to be achieved.
32 T. Snaebjörnsson

References 7. O'Shea NE, Tadi P. Olecranon Bursa aspira-

tion. StatPearls. Treasure Island (FL): StatPearls
Publishing. Copyright © 2023, StatPearls Publishing
1. Gimarc DC, Stratchko LM, Ho CK. Spinal injections.
LLC.; 2023.
Semin Musculoskelet Radiol. 2021;25(6):756–68.
8. Kotecha J, Gration B, Hunt BJ, Goodman AL, Malaiya
2. Alam M, Tung R. Injection technique in neurotoxins
R. The safety of continued oral anticoagulation ther-
and fillers: indications, products, and outcomes. J Am
apy in joint injections and aspirations: a qualitative
Acad Dermatol. 2018;79(3):423–35.
review of the current evidence. J Clin Rheumatol.
3. WHO Guidelines Approved by the Guidelines Review
2022;28(4):223–8.
Committee. WHO Best Practices for Injections and
9. Hoeber S, Aly AR, Ashworth N, Rajasekaran
Related Procedures Toolkit. Geneva: World Health
S. Ultrasound-guided hip joint injections are more
Organization. Copyright © 2010, World Health
accurate than landmark-guided injections: a sys-
Organization.; 2010.
tematic review and meta-analysis. Br J Sports Med.
4. Bennell KL, Paterson KL, Metcalf BR, Duong
2016;50(7):392–6.
V, Eyles J, Kasza J, et al. Effect of intra-articular
10. Chalmers PN, Ellman MB, Chahal J, Verma
platelet-rich plasma vs placebo injection on pain and
NN. Injection therapy in the Management of
medial tibial cartilage volume in patients with knee
Musculoskeletal Injuries of the knee. Oper Tech
osteoarthritis: the RESTORE randomized clinical
Sports Med. 2012;20(2):172–84.
trial. JAMA. 2021;326(20):2021–30.
11. Hermans J, Bierma-Zeinstra SM, Bos PK, Verhaar
5. Hecker A, Jungwirth-Weinberger A, Bauer MR,
JA, Reijman M. The most accurate approach for
Tondelli T, Uçkay I, Wieser K. The accuracy of joint
intra-articular needle placement in the knee joint:
aspiration for the diagnosis of shoulder infections. J
a systematic review. Semin Arthritis Rheum.
Shoulder Elb Surg. 2020;29(3):516–20.
2011;41(2):106–15.
6. Courtney P, Doherty M. Joint aspiration and injection.
Best Pract Res Clin Rheumatol. 2005;19(3):345–69.
 Postinjection Care and Education
7
Thorkell Snaebjörnsson

Table 7.1 Information about aftercare for patients

7.1 Introduction  • Remain at the clinic until feeling well after the
procedure
With the modern standard of health care for  • Who to contact in case of emergency
patients, it is of great value for every healthcare  • When to remove the dressing
 • When to shower or take a bath
provider to be able to offer accurate and up-to-­
 • Any physical restrictions
date patient-specific aftercare after injection  • Need to keep journal of symptoms
treatment. Specific details are described in subse-
quent chapters.
patients is therefore of great value, and special
care should be taken when treating patients who
7.2 Immediate Aftercare have previously had reactions to injections or
aspirations (Table 7.1). In clinical settings, intra-­
In the immediate aftercare after injection, it is articular injections of either platelet-rich plasma
important to place the patient under observation or hyaluronic acid are not known to be a source
for approximately 30 min. Although the risk of of great discomfort [3], according to a recent
type 1 hypersensitivity reactions (urticaria, ana- study by Park et al.
phylaxis, angioedema) is much lower than, for
example, in vaccinations, the risk of these adverse
effects is to be found especially when injecting 7.3 Dressing
other agents than corticosteroids [1]. Other
delayed immunological reactions have mostly It is important to slowly remove the needle and
been described concerning vaccinations and may use cotton wipes or other wound dressing to
include type IV hypersensitivity, including large maintain pressure for 10–15 s before you can
local lesions or other autoimmune-mediated skin observe if there is any bleeding or swelling in the
reactions [2]. The prior medical history of area after the procedure. If there is an actual
bleeding or swelling in the area, it is recom-
T. Snaebjörnsson (*) mended to apply pressure for 5–10 min either
Department of Orthopaedics, Institute of Clinical with a cotton swab or a compression and even
Sciences, Sahlgrenska Academy, Gothenburg elevate the area when possible. Further prolonged
University, Gothenburg, Sweden compression to stop bleeding is occasionally
Department of Orthopaedics, Sahlgrenska University required. Appropriate wound dressing is then
Hospital, Mölndal, Sweden subsequently applied after hemostasis is secured.
e-mail: [Link]@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 33

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
34 T. Snaebjörnsson

If no bleeding or swelling is to be found, a simple anesthetic agent should affect the nerve ends in
band aid is sufficient to close cover the incision. the joint and provide symptom relief if the injec-
If bleeding occurs in the dressing, the wound tion was correctly performed, noting injection
should be examined again the following day and accuracy and indication for the procedure. There
new dressing applied if needed. If the patient are no scientifically proven guidelines about
wants to take a shower after the procedure, the activity after injections. It is of value to ask the
dressing must be waterproof, and the usage of patient to keep a journal of symptoms and activi-
soaps or lotions should be avoided; likewise the ties the following days, especially if the proce-
usage of bath or swimming pool the following dure is extra-articular or for a diagnostic purpose.
24 hours after procedure should be avoided. It is a common practice to ask the patients to rest
or only do moderate activities approximately
24 hours after an intra-articular injection given
7.4 Pressure and Cooling the fact there is an increased amount of fluid in
the joint that can cause pain and soreness in activ-
Cold and compression therapy is often used in ities. This is especially important for load-­bearing
acute trauma or injury. Similar methods can be joints, but even for other joints, excessive train-
applied when performing injections or aspira- ing is not recommended the following days after
tions. The rationale is that the cold suppresses the treatment. Return to physically demanding work
metabolic rate in the local soft tissues [4]. This should be delayed until the day after an injection,
decrease in metabolism reduces then the tissue while patients only undergoing aspiration should
damage caused by hypoxia [5]. Hypothermia sig- now need to have the same restrictions. Operating
nificantly lowers microcirculation and induces a vehicle cannot be recommended directly after
vasoconstriction with the cooling effect lasting injection, especially if the area is still numb after
up to 60 minutes [6]. The cold therapy is depen- local anesthesia. This information must be avail-
dent on time length since the local area must be able before treatment in order for patients to be
cooled down for several minutes to achieve the able to react accordingly.
hypoxic state. Similar effects on edema and blood
microcirculation can be achieved with local pres-
sure, but the maximum effect is accomplished 7.6 Postinjection Pain: General
when both methods are used simultaneously. In Complications
clinical settings, this treatment is often given by
applying compression socks or elastic bandages Many patients experience discomfort while
with cooling units or custom-made orthosis or receiving treatment like injection or aspiration.
braces with hypothermal function. Treatment is The majority of these symptoms are vasovagal
applied for 5–10 min initially, and then the length and can be treated with a professional approach
of treatment can vary depending on symptoms. and adequate patient information before treat-
ment. These symptoms are most often self-­
limiting and are frequently described the following
7.5 Mobilization and Return 24 hours after injection. In the case of adverse
to Activity effects after platelet-rich plasma or hyaluronic
acid injections, symptoms are often nonspecific
After intra-articular injections, which are most [7] and include headache, dizziness, nausea, gas-
often combined with a short-acting local anes- tric complaints, stiffness, or syncope. If the local
thetic, it is recommended to cycle the joint at anesthetic agent is given in combination with
least ten times or 1–2 min to achieve diffusion other ingredients, extra care should be taken to
within the joint space. It is then important to reg- give patients appropriate pain medication when
ister any changes in symptoms, since the local the effect of the local anesthetic fades away.
7 Postinjection Care and Education 35

7.7 Postinjection Pain: Local Studies have shown evidence of an increased

Complications risk of adverse effects following surgery if the
time interval between injection and surgery is too
Local swelling and discomfort during either aspi- short. In a recent article by Lee et al. [8], the risk
ration or injection is a common nonspecific com- of infection following cortisone injection in the
plication. It can depend on the nerve endings in knee was increased if an arthroscopy of the knee
the skin, bleeding, or volume expansion. There is was performed within 2 weeks of the injection.
also another important factor in the deeper tissues When patients are set to do a total joint arthro-
because of the increased volume of fluid that is plasty, there is a current consensus of avoiding
injected in the joint or the soft tissues, causing intra-articular injections 3 months before the
expansion of volume, swelling, and pain because operation to lower the risk of adverse effects [9].
of local pressure increase on the adjacent tissues. With this evidence in mind, it is wise to either
In smaller joints, the margin of error is smaller avoid injections under the aforementioned time
with a higher risk of complication or local pain. frame before elective surgery or postpone elec-
This is mostly because of the relatively large vol- tive surgeries if patients have recently undergone
ume of fluid injected in a small cavity, compared intra-articular injection in order to lower the risk
with injections in larger joints that seldom give of unnecessary adverse effects.
similar symptoms. The pressure in the small joint
is therefore temporarily increased with subse-
quent discomfort, causing pressure on adjacent 7.9 Conclusion
tissues and in some cases even pain following
extra-articular injection in sensitive areas. Patients Injections offer a valuable treatment option for
experiencing pain, especially during injections to many patients. Standardized settings with clini-
small joints, should be given pain medication if cal guidelines provide safety for both patients
they experience pain during the treatment. and healthcare providers. Information and treat-
ment for allergic reactions should be available at
all times. Applying pressure with or without the
7.8 Elective Surgery after aid of hypothermal treatment after injection or
Injection aspiration is recommended in all cases.
Mobilization with the cycling of a joint is advised
In many cases, the injections given to patients are directly after injection for the diffusion of the
aimed to complement rehabilitation or to treat agent injected. If treatment is performed for a
pain and discomfort until the time comes to do diagnostic value, the patients should keep a diary
more definitive surgery. While this is a common of symptoms in the following hours or days,
clinical practice, care should be taken not to do depending on the agent given. Patients should be
any injection shortly before elective surgery, advised to only do activities that require moder-
since studies have shown that the risk of infection ate physical effort the following 24 h after treat-
can be increased following steroid injection to ment. Many patients experience nonspecific
the knee (Table 7.2). symptoms like headache or nausea during or
shortly after either aspiration or injections.
Table 7.2 Information about aftercare for healthcare Information regarding pain after injection should
providers be provided by the healthcare provider before
• Inform restrictions after the procedure treatment. Intra-articular injection results in the
• When to remove dressing expansion of volume in the joint cavity and there-
• Schedule a follow-up fore even swelling and pain because of local pres-
• Avoid doing arthroscopy for 2 weeks after injection
• Avoid doing total joint arthroplasty 3 months after sure increase on the adjacent tissues. Elective
injection surgery should not be planned directly after
• Provide contact information in case of adverse effects injection. The appropriate time frame between
36 T. Snaebjörnsson

injection and arthroscopy is 2 weeks, while a 4. Block JE. Cold and compression in the management
total joint arthroplasty should not be performed of musculoskeletal injuries and orthopedic operative
procedures: a narrative review. Open Access J Sports
until 3 months from injection. Med. 2010;1:105–13.
5. Wright JG, Araki CT, Belkin M, Hobson RW 2nd.
Postischemic hypothermia diminishes skeletal muscle
reperfusion edema. J Surg Res. 1989;47(5):389–96.
References 6. Yanagisawa O, Homma T, Okuwaki T, Shimao D,
Takahashi H. Effects of cooling on human skin and skel-
1. Peng S, Liang Y, Xiao W, Liu Y, Yu M, Liu etal muscle. Eur J Appl Physiol. 2007;100(6):737–45.
L. Anaphylaxis induced by intra-articular injection of 7. Shen L, Yuan T, Chen S, Xie X, Zhang C. The tempo-
chitosan: a case report and literature review. Clin Case ral effect of platelet-rich plasma on pain and physical
Rep. 2022;10(12):e6596. function in the treatment of knee osteoarthritis: sys-
2. Gambichler T, Boms S, Susok L, Dickel H, Finis C, tematic review and meta-analysis of randomized con-
Abu Rached N, et al. Cutaneous findings following trolled trials. J Orthop Surg Res. 2017;12(1):16.
COVID-19 vaccination: review of world literature 8. Lee W, Bhattacharjee S, Lee MJ, Ho SW, Athiviraham
and own experience. J Eur Acad Dermatol Venereol. A, Shi LL. A safe interval between preoperative intra-­
2022;36(2):172–80. articular corticosteroid injections and subsequent knee
3. Park Y-B, Kim J-H, Ha C-W, Lee D-H. Clinical effi- arthroscopy. J Knee Surg. 2022;35(1):47–53.
cacy of platelet-rich plasma injection and its associa- 9. Tang A, Almetwali O, Zak SG, Bernstein JA,
tion with growth factors in the treatment of mild to Schwarzkopf R, Aggarwal VK. Do preoperative intra-­
moderate knee osteoarthritis: a randomized double-­ articular corticosteroid and hyaluronic acid injections
blind controlled clinical trial as compared with hyal- affect time to total joint arthroplasty? J Clin Orthop
uronic acid. Am J Sports Med. 2021;49(2):487–96. Trauma. 2021;16:49–57.
 Part II
Non Biologic Agents for Injections
 Corticosteroids and Local
Anesthetics
8
Matthieu Ollivier and Ahmed Mabrouk

8.1 Background The injectable corticosteroids are mainly gluco-

corticoids, and they exert their anti-inflammatory
Corticosteroids and local anesthetics are two effects by decreasing local infiltration of inflam-
classes of drugs that revolutionized the medical matory cells and mediators such as cytokines [6,
practice. Since corticosteroids were discovered in 7].
the 1940s, they have been utilized worldwide and There are three main types of injectable corti-
were proven to be effective in a wide array of costeroids: hydrocortisone, triamcinolone, and
medical conditions including inflammatory con- methylprednisolone. Each of these corticoste-
ditions, allergic reactions, and autoimmune dis- roids has unique properties that make them effec-
orders [1, 2]. Conversely, local anesthetics were tive for certain conditions. Hydrocortisone is
first introduced in the nineteenth century and often used for acute inflammation, triamcinolone
have since become a cornerstone of modern anes- for longer-term inflammation, and methylpred-
thesia [3–5]. nisolone for severe inflammation [8]. The origi-
nal corticosteroid is hydrocortisone acetate.
However, this was replaced by longer-acting
8.1.1 Corticosteroids (CS) alternatives such as methylprednisolone acetate,
triamcinolone acetonide, and triamcinolone hex-
CS are synthetic equivalents to the natural steroid acetonide. Triamcinolone hexacetonide has been
hormones produced by the adrenal cortex and proven to be the most effective with clinical
include glucocorticoids and mineralocorticoids. effects lasting up to several months [9].
These synthetic agents vary in their mineralocor- The injectable corticosteroids differ in their
ticoid/glucocorticoids attributes. Glucocorticoids crystal and chemical structure, solubility, and
have immunosuppressive, anti-inflammatory, and duration of action [6]. An injectable compound
vasoconstrictive effects, besides their chief role with low solubility has a tendency to stay longer
in metabolism, whereas mineralocorticoids are at the injection site and with low systemic absorp-
involved in electrolytes and water balance [2]. tion when compared to a highly soluble
compound.

M. Ollivier (*)
Institut du Mouvement et de L’appareil Locomoteur
Marseille, Marseille, France
A. Mabrouk
Leeds Teaching Hospitals, Leeds, UK

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 39

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
40 M. Ollivier and A. Mabrouk

8.1.2 Local Anesthetics (LA) cal rehabilitation due to their analgesic effects as
in cases of rotator cuff syndrome and lateral epi-
LA blocks transduction and transmission of noci- condylitis [15].
ception [10]. This means that LA block nerve Corticosteroids can serve diagnostic purposes
impulses in a specific area of the body, thus pre- and can be utilized for postoperative pain control
venting pain signals from being transmitted to the [16]. The addition of a local anesthetic can also
brain. LA can be administered through injection help to confirm the diagnosis of musculoskeletal
or topical application and are available in a vari- conditions by providing temporary pain relief.
ety of formulations and strengths [11]. There are Chou et al. [17] reported that the addition of a
two types of local anesthetics: esters and amides. local anesthetic to a corticosteroid injection pro-
Esters, such as procaine and cocaine, are typi- vided greater pain relief compared to a cortico-
cally short-acting and may cause allergic reac- steroid injection alone in patients with knee
tions. Amides, such as lidocaine and bupivacaine, osteoarthritis. Intra-articular steroid injections
are longer-acting and less likely to cause allergic make pain relief in rheumatoid arthritis and
reactions [12]. osteoarthritis. Corticosteroid injections have
The first local anesthetic was cocaine, which been shown to be effective with improvements in
was isolated from the leaves of the coca plant in pain and function in patients with osteoarthritis,
the 1850s. However, cocaine’s addictive proper- tendinitis, and bursitis. Jüni et al. [18], in a sys-
ties and potential for toxicity led to the develop- tematic review, found that corticosteroid injec-
ment of newer, safer local anesthetics, such as tions were effective in reducing pain and
procaine and lidocaine [4]. Among the most com- improving function in patients with knee osteoar-
monly used local anesthetics in combination with thritis. Similarly, a systematic review by Coombes
steroids are the lidocaine, bupivacaine hydro- et al. [19] found that corticosteroid injections
chloride, and ropivacaine [13, 14]. A few merits were effective from an analgesic and functional
have been reported for their combined use with perspectives in patients with rotator cuff
steroids, such as increasing the volume of the tendinitis.
injectate which allows better dissemination of
steroids throughout the injected tissue.
Additionally, they could provide a degree of 8.3 Contraindications
immediate symptom relief and reduction in
patient’s discomfort due to the rapid onset of Despite the benefits of injectable corticosteroids
action and the relative durable anesthetic criteria and local anesthetics, their use is contraindicated
[13, 14]. in some patients. However, these contraindica-
tions could be absolute or relative [20]. Local
infection, bacteremia, and sepsis are absolute
8.2 An Overview contraindications for corticosteroid injections as
of the Indications CS can suppress the immune system and exacer-
bate the infection. An increased risk of intraop-
Corticosteroid injections in combination with erative and postoperative infection has been
local anesthetics are commonly used in the man- reported if hip joint arthroplasty is performed
agement of a variety of musculoskeletal condi- within 3 months of the steroid injection to the hip
tions. Corticosteroids are injected into articular, [21]. Additionally, due to the suppressive effect
periarticular, or soft tissue structures for pain of corticosteroids on bone healing, intra-articular
relief, inflammation control, and enhancing fractures are another contraindication. Similarly,
mobility. Additionally, corticosteroids can be due to the risk of subchondral osteonecrosis and
used as a definitive treatment in cases such as weakening of other articular structures, CS are
De-Quervain tenosynovitis and trochanteric bur- contraindicated in joint instability. Also, patients
sitis [15]. Corticosteroids can supplement physi- with a history of allergy to corticosteroids or
8 Corticosteroids and Local Anesthetics 41

local anesthetics should not receive injections of systemic toxicity which can result in a disability
these agents [20]. or pose a threat to life [29].
More relative contraindications include
patients with bleeding disorders, or those on
anticoagulant therapy should also be cautious, 8.5 Applications
as these agents can increase the risk of bleed- of Corticosteroids and Local
ing. Other contraindications include pregnancy, Anesthetic in the Knee Joint
breastfeeding, and certain medical conditions,
such as diabetes, hypertension, and congestive The knee joint is one of the most frequently joints
heart failure. The use of corticosteroids can to receive corticosteroids with or without local
increase blood glucose levels and blood pres- anesthetic injections [26], in scenarios such as
sure, while the use of local anesthetics can early osteoarthritis of the knee which is a com-
affect fetal heart rate and cause neonatal depres- mon condition that can cause pain and disability.
sion [22]. Intra-articular corticosteroid injections have been
Certain risk factors for adverse events of local shown to reduce pain and improve function in
anesthetics should be noted. Individual risk fac- patients with early knee osteoarthritis [30]. In
tors should also be taken into consideration such 2012, the American College of Rheumatology
as medical comorbidities with higher pulmonary, (ACR) guidelines weakly recommended the use
cardiac, and nervous susceptibilities, other con- of IA CS in patients with OA, whose cases were
comitant medications, the site of LA injection, refractory to basic treatment [31]. In 2014, the
e.g., vessel rich tissue. In addition to care towards Osteoarthritis Research Society International
specific local anaesthetics and large total dose of (OARSI) guidelines for the nonsurgical manage-
LA [23, 24]. ment of knee osteoarthritis also recommended
intra-articular corticosteroid injections as a treat-
ment option irrespective of the osteoarthritis sub-
8.4 Complications type or patients’ comorbidities [32].
In a 2015 update of a 2006 Cochrane review
With the increased usage of corticosteroids and [33], including a total of 27 trial (14 new) [18],
local anesthetics, major adverse events and com- with all studies included were either RCTs or
plications are being more reported. Despite rare, quasi-RCTs, and a control group receiving sham
physicians who are performing these injections or no intervention. And a median of 76 partici-
should be aware of these complications as some pants (range 16–205) were randomized across all
of them can be potentially dramatic. trials. A median prednisolone equivalent dose of
Complications can vary from trivial ones such as 50 mg was reported across all trials, and the
skin depigmentation or a more serious complica- median number of CS injections was one.
tions such as septic arthritis [20]. Furthermore, Based on the metanalysis, at the end of
concerns have been raised about the possibility of 4–6 weeks of treatment, Jüni et al. [18] reported
chondrotoxicity following intra-articular cortico- more effective pain reduction and function when
steroids [25–27]. In a systematic review, compared to other control interventions. The dif-
Wernecke et al. [28] suggested that the effect of ference in pain scores, between corticosteroids
steroids on the articular cartilage is time and dose and other interventions, was 1 cm on a 10 cm
dependent. So, low doses over a short period of VAS scale, which corresponds to 17% improve-
time would have beneficial effects, whereas large ment and when compared to sham injection, cor-
doses over prolonged periods of time could have ticosteroids had 13% more functional
devastating effects [28]. Similarly, LAs can result improvement. However, IA CS had no effect on
in a wide range of complications that vary from quality of life or joint space narrowing when
either minor symptoms and signs to more severe compared to control interventions [18]. The
42 M. Ollivier and A. Mabrouk

a b

c d

Fig. 8.1 Peri-meniscal injection of a degenerative menis- the steroid injection can be seen (c), once the needle is
cus tear, the tear is visualized under ultrasonography (a), removed, the steroid liquid surrounds the meniscus tissues
the needle approaches the lesion under direct control (b), (d)

American Academy of Orthopedic Surgeons In patients with degenerative tears of the pos-
(AAOS), in their recent guidelines for non-­ terior horn of the medial meniscus, intra-articular
arthroplasty management of knee OA, advised steroid injections have been shown to result in
that intra-articular corticosteroids may offer short- and medium-term pain relief in the major-
short-term relief for patients with symptomatic ity of the patients (81.7%) [38]. And more
knee OA, with reported moderate strength rec- recently, peri-meniscal corticosteroid injections
ommendations [34]. (Fig. 8.1) were demonstrated to result in signifi-
Another application in knee joint for IA CS is cant symptom relief at 6 weeks in patients with
meniscal injuries. Meniscal damage can set off meniscal pain [39].
an inflammatory cascade in the knee with local
synovitis, effusion, and subsequent chondrosis
[25]. Intra-articular corticosteroids can neutralize 8.6 Conclusion
the inflammatory mediators and reverse the
inflammatory cascade, hence can also be effec- Injectable corticosteroids and local anesthetics
tive in treating meniscus or cartilage issues. The can be effective in the management of a variety of
injection itself does not alter the meniscus; how- musculoskeletal conditions. Multiple knee joint
ever, pain reduction or absence allows recovery disorders are frequently addressed with cortico-
of some biological and mechanical stability steroids with or without local anesthetics injec-
[35–37]. tion. The use of corticosteroids should be
8 Corticosteroids and Local Anesthetics 43

carefully considered and monitored by a health- 15. Stephens MB, Beutler AI, O’Connor
care professional. Patients should also be FG. Musculoskeletal injections: a review of the evi-
dence. Am Fam Physician. 2008;78(8):971–6.
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these medications. TJ. Musculoskeletal injection. Mayo Clin Proc.
2009;84(9):831–6. quiz 837
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 Viscosupplementation Agents
9
Camila Grandberg, Svenja Höger,
and M. Enes Kayaalp

9.1 Background gin, preparation, molecular weight, rheological

characteristics, and concentration [1].
Viscosupplementation is a procedure in which The American College of Rheumatology
gel-like hyaluronic acid (HA) is injected into (ACR) recognized viscosupplementation as a
affected joints. The aim is to restore the visco- therapeutic option for pain management in knee
elastic properties of the synovial fluid (SF) and osteoarthritis (OA) in 2000 [2], following several
alleviate joint inflammation and pain. The princi- randomized controlled trials (RCTs), which dem-
pal ideas behind the use of HA are that it helps to onstrated that HA yielded superior functional and
enhance the physiologic viscoelasticity of the SF pain-related outcomes compared to placebo.
and it exhibits downregulatory effects on pro-­ Since then, the data on the use of HA has largely
inflammatory factors and enzymes contributing evolved. After a decade of research, there is now
to joint matrix degradation. Presently, many dif- solid evidence both supporting and contradicting
ferent HA products exist, varying widely in ori- its use. Nevertheless, current practice incorpo-
rates the use of HA very frequently despite many
reputable guidelines advising against it. The
increase of studies on HA can be attributed to the
C. Grandberg
Department of Orthopaedic Surgery, UPMC Freddie increasing prevalence of OA in modern society,
Fu Sports Medicine Center, University of Pittsburgh, the high numbers of unresponsive or unfit patients
Pittsburgh, PA, USA for other treatments, and the potential biases in
e-mail: grandbergc@[Link]
treatment selection by care providers [3].
S. Höger This chapter aims to provide insights into the
Department of Orthopaedic Surgery, UPMC Freddie
current literature and shed light on the reasons
Fu Sports Medicine Center, University of Pittsburgh,
Pittsburgh, PA, USA behind the divergent approaches to the use of HA
in the clinical setting.
Department of Sports Orthopaedics, Technical
University of Munich, Munich, Germany
e-mail: hogers@[Link]
M. E. Kayaalp (*)
Department of Orthopaedic Surgery, UPMC Freddie
Fu Sports Medicine Center, University of Pittsburgh,
Pittsburgh, PA, USA
Department of Orthopaedics, Istanbul Kartal Training
and Research Hospital, Istanbul, Turkey
e-mail: mek@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 45

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
46 C. Grandberg et al.

9.2 Mechanism of Action 9.3 Viscosupplementation

Agents
In the presence of shear stress, the physiological
viscosity and elasticity of the SF present in human HA is a natural compound present in SF, the
joints can alter significantly [2]. The concentra- physiologic solution present in synovial joints
tion of HA in the SF is thought to have a substan- with the purpose of lubricating the joint and
tial effect on these native properties, with lower minimizing friction during joint movement [1].
concentrations of HA promoting an increase in SF The medical use of HA, the main component of
viscosity [2]. In OA, the joint’s SF has a charac- viscosupplementation, was initiated in the late
teristically lower concentration of HA, as well as 1960s, employing purified human umbilical
a higher turnover and lower molecular weight. cord and rooster comb as a product source [7].
These combined factors generate various adverse The physiologic volume of SF present in the
biomechanical effects, possibly leading to pain human knee is about 2 ml, with a HA concen-
and loss of function [2]. Therefore, viscosupple- tration of 2.5–4.0 mg/ml and a molecular
mentation treatment aims to reinstate the physio- weight of 4 to 5 × 106 Da [7]. Exogenous HA
logic viscoelasticity of human SF and to provide may be produced from two origins: avian or
improvement of OA symptoms [1, 4]. non-avian. HAs from avian origin are purified
Viscosupplementation essentially exerts its natural products made from rooster combs,
action through two main mechanisms: a bio- while non-avian products are made using fer-
chemical effect and a mechanical effect. mentation with bacteria (Streptococcus zooepi-
Mechanically, the HA lubricates the joint, lessen- demicus) [5]. These two types of HAs can be
ing the friction generated by joint movement. It further classified as non-­cross-­linked (hyaluro-
also promotes force distribution and shock nans) or cross-linked (hylans). The first has
absorption, diminishing the effects of weight long-chain molecules with a molecular weight
bearing and movement impact exerted upon the of 0.5 to 1.8 × 106 Da. The latter is a chemi-
joint [3, 5]. Biochemically, the HA promotes cally modified molecule formed by cross-link
direct analgesia through joint nociceptor inhibi- connections between hyaluronans or other
tion [2, 5, 6] and provides a moderate anti-­ molecules, such as chondroitin sulfate, sorbi-
inflammatory effect by reducing the expression tol, and mannitol, in different concentrations.
of pro-inflammatory cytokines, via interaction These cross-linked HAs exhibit a liquid phase
with joint synoviocytes, and suppressing macro- of molecular weight around 6 × 106 Da and a
phage production of prostaglandin E2, via down- solid phase of infinite molecular weight [4, 5,
regulation of NF-kappaB [1, 2, 5, 6]. Lastly, HA 8].
exerts a chondroprotective effect through proteo- Currently, there are over 100 HA products
glycan and glycosaminoglycan synthesis, stimu- available globally. These products have appre-
lation of chondrocyte proliferation, promotion of ciable differences, not only in terms of origin and
synoviocyte-mediated endogenous HA produc- molecular properties but also in concentrations,
tion, and inhibition of metalloproteinases pro- dosage, and intervals between injection adminis-
duction and cartilage degradation [1–3, 5, 6]. tration (Table 9.1) [8].
9 Viscosupplementation Agents 47

Table 9.1 Characteristics of the main HA products currently available [1, 4, 5, 9, 10]
Molecular weight
Product name Origin Structure (×106 Da) Injection interval Dosage
Synvisc Avian Cross-linked 6.0 1 per week over 2 ml (16 mg)
3 weeks
Euflexxa Bacterial Non-cross-­ 2.4–3.6 1 per week over 2 ml (20 mg)
fermentation linked 3 weeks
Supartz Fx Avian Non-cross-­ 0.6–1.2 1 per week over 2.5 ml
linked 3–5 weeks (25 mg)
Gelsyn-3 Bacterial Non-cross-­ 1.1 1 per week over 2 ml
(Sinovial®) fermentation linked 3 weeks (16.8 mg)
Durolane Bacterial Cross-linked 1.0-1.8 Single injection 3 ml (60 mg)
fermentation
Hyalgan Avian Non-cross-­ 0.5-0.7 1 per week over 2 ml (20 mg)
linked 3–5 weeks
Gel-One Avian Cross-linked Not reported Single injection 3 ml (30 mg)
Synvisc-One Avian Cross-linked 6.0 Single injection 6 ml (48 mg)
Monovisc Bacterial Non-cross-­ 1.0–2.9 Single injection 4 ml (88 mg)
fermentation linked
Orthovisc Bacterial Non-cross-­ 1.0–2.9 1 per week over 2 ml (30 mg)
fermentation linked 3–4 weeks
Hymovis Bacterial Non-cross-­ 0.5–0.7 1 per week over 3 ml (24 mg)
fermentation linked 2 weeks

9.4 Contraindications skin infection, severely compromised immune

and Adverse Events status, and suspected or confirmed bacteremia or
infectious arthritis. Relative contraindications
Viscosupplementation is a generally well-­ comprise diagnosed coagulopathies, joint pros-
tolerated procedure, with less systemic side thesis, and poorly controlled diabetes mellitus.
effects than other intra-articular injections or Additionally, contraindications to viscosupple-
more aggressive interventions used for mentation include hypersensitivity to previous
OA. However, adverse events are still a possibil- HA products or other avian products, previous
ity, and local reactions may happen more often lack of efficacy, and pediatric patients [1, 4].
than with other treatment options [4]. The litera-
ture on possible adverse events associated with
viscosupplementation is still scarce and presents 9.5 Evidence
a wide variety of incidence rates. Nevertheless,
frequently reported adverse events are injection There are numerous guidelines available world-
site pain, local skin reactions and erythema, local wide that provide up-to-date recommendations
joint pain and effusion, septic arthritis, and for health care professionals [11–15]. However,
pseudo septic reactions [1, 4]. differences in methodology in their preparation,
Therefore, HA injections should be indicated as well as publication timelines, can lead to varia-
with caution, and contraindications should be tions in their recommendations. For instance, the
fully respected. General contraindications of Osteoarthritis Research Society International
intra-articular injections are likewise applied to (OARSI) has provided a conditional recommen-
viscosupplementation injections. Absolute con- dation for patients with OA [12]. The American
traindications include fracture site, overlying Academy of Orthopaedic Surgeons (AAOS) does
48 C. Grandberg et al.

not endorse the use of HA injection, with ACR/ 9.6.1 Shoulder

Arthritis Foundation (AF) indicating conditional
recommendation against their use [13]. The The guidelines provided by AAOS regarding gle-
European Society for Clinical and Economic nohumeral OA strongly discourage the use of
Aspects of Osteoporosis, Osteoarthritis and HA, providing robust evidence for this recom-
Musculoskeletal Diseases (ESCEO) has issued a mendation [19]. OARSI and ACR do not have
weak recommendation for HA use, suggesting it special recommendations regarding the use of
only be used when patients have contraindica- HA in shoulder OA. Additionally, although a
tions to the use of nonsteroidal anti-inflammatory meta-analysis conducted in 2019 concluded that
drugs (NSAIDs) or experience insufficient pain HA use in the shoulder was safe and offered pain
relief on NSAID therapy [14]. Similarly, the pre- relief, ultimately it was determined that that the
vious AAOS guidelines advised strongly against pain improvement observed in both the HA and
HA use for knee OA [15]. However, the latest control groups was due to placebo effect [20].
AAOS guidelines indicated significant advances Therefore, HA seems unsuitable for use in shoul-
with high molecular weight cross-linked HA der OA, considering scientific justifications.
therapy, modifying their recommendation from
strongly to moderately against the use of HA [13,
15]. 9.6.2 Ankle
First and foremost, it is crucial to acknowl-
edge that the evidence regarding the use of HA is The National Institute for Health and Care
characterized by inconsistent and conflicting Excellence (NICE) guidelines for OA care and
findings. While certain RCTs demonstrated sig- management in adults is opposed to the use of
nificant pain improvement, others do not yield HA in ankle OA [11]. Further guidelines did not
similar positive outcomes. Moreover, compre- make any statements on the use of HA in the
hensive systematic reviews and meta-analyses ankle joint [2]. Furthermore, a systematic review
conducted on a larger scale have concluded that evaluating the use of HA in ankle OA indicated
the effectiveness of HA may not extend signifi- improved pain scores [21]. In addition, a
cantly beyond the placebo effect [1]. Additionally, Cochrane systematic review reported that HA use
an expert opinion on this matter suggested that was associated with lower pain score on the
comparing HA with placebo may not reflect Ankle Osteoarthritis Scale at 6 months, although
actual clinical outcomes, as placebo should not the clinical significance of this observation
be considered a treatment for knee OA [16]. remains unclear [22].
Taking into consideration the significant placebo
effect of saline injections, there is some rationale
to this approach [17, 18]. In fact, this raises fur- 9.6.3 Knee
ther doubts about the cost-effectiveness and clini-
cal benefits compared to intra-articular saline. A systematic review conducted in 2020 analyzed
Therefore, high-quality RCTs are necessary to 27 sets of guidelines on intra-articular therapies
assess the effect of HA in osteoarthritic knees to for knee OA, including guidelines from AAOS
enrich the existing literature. and NICE [23]. Among these guidelines, 74%
(n = 20) provided strong or conditional recom-
mendations in favor of using intra-articular HA;
9.6 Joint-Based Applications approximately 15% (n = 4) offered uncertain or
weak recommendations; and 11% (n = 3) strongly
The available evidence on the use of HA primar- recommended against its use [23].
ily focuses on knee OA. This section aims to In the past, previous studies primarily focused
offer a concise overview of the existing evidence, on the pain-reducing effects of HA, known as
categorized by anatomic location. “symptomatic slow-acting drugs in osteoarthritis.”
9 Viscosupplementation Agents 49

lines specifically advise against its use [2].

Several meta-analyses have been conducted on
the use of HA in hip OA in the literature.
Lieberman et al. found that the observed change
in their analysis had uncertain clinical relevance,
as the decrease in VAS was only −0.27 in the six
RCTs and most studies had a follow-up duration
of less than 6 months [27]. Another meta-analysis
which included eight RCTs concluded that visco-
supplementation for hip OA is not recommended
[28]. The analysis revealed limited evidence
compared to placebo, scarce evidence showing
an efficacy up to 3 months, and suggested no dif-
ference at the 6-month mark [28]. Moreover, a
third meta-analysis of RCTs showed that the use
Fig. 9.1 Intra-articular knee injection using a lateral of HA for hip OA provided only comparable
approach
improvements to those achieved with intra-­
articular saline injections [29].
Currently, emerging evidence suggests that high
molecular weight HA may also impact cartilage
metabolism itself, suggesting a potential disease- 9.6.5 Hand
modifying effect (Fig. 9.1). Intra-­articular admin-
istration of high molecular weight HA has shown Recent ACR and NICE guidelines both advise
promise in reducing C-telopeptide of type II col- against the use of HA in the hand. Conversely,
lagen, indicating improved cartilage metabolism AAOS and OARSI guidelines do not provide
[24, 25]. This suggests that HA could be classified specific recommendations regarding the manage-
as a “disease-modifying osteoarthritis drug” ment of OA in the hand [2]. According to a 2019
instead of solely as a symptomatic agent [8]. meta-analysis analyzing 9 RCTs, with a total of
Based on RCTs that compared viscosupple- 504 patients, that compared HA, corticosteroid,
mentation with placebo and with no intervention saline placebo, and dextrose injections, for base
for knee OA treatment, the evidence strongly of thumb OA, none of the evaluated studies found
indicates that viscosupplementation offers only a a therapy superior to placebo [30]. Furthermore,
minor reduction in knee OA pain compared to a different meta-analysis found no difference
placebo. However, this difference falls below the between HA and corticosteroid until 12 weeks
minimal clinically important threshold. posttreatment when comparing 428 patients
Furthermore, the RCTs also demonstrate a higher across six RCTs involving HA, corticosteroid,
risk of serious adverse events associated with vis- and placebo injections [31]. However, HA
cosupplementation compared to placebo. appeared to improve function by pulp pinch
Consequently, these findings do not support the force, although HA had less effective outcomes
widespread use of HA for the treatment of knee in terms of pain control than corticosteroid injec-
OA [26]. tions [2, 31].

9.6.4 Hip 9.7 Conclusion

Regarding hip OA, there is currently no major In conclusion, viscosupplementation is widely

international guideline that recommends the use acknowledged as a safe treatment option for OA,
of HA. Recent NICE, AAOS, and ACR guide- not only providing symptomatic management but
50 C. Grandberg et al.

possibly altering the disease course due to HA’s vations in cartilage regeneration strategies for the
chondroprotective properties. However, clinical treatment of primary osteoarthritis of the knee:
intra-articular injections. Orthop J Sports Med.
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Guidance.
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analysis. BMJ. 2022;378:e069722. [Link] [Link]
org/10.1136/bmj-­2022-­069722.
 Radiosynovectomy
10
Goksel Dikmen, Vahit Emre Ozden,
and Kayahan Karaytug

10.1 Introduction death, occlusion of capillary system, and further

fibrosis and sclerosis of the synovial membrane
Local intra-articular injection of colloidal beta-­ [4]. Improvement of pain-related restriction,
emitting radionuclides solution, radio synovec- daily living activities, and range of motion with
tomy (RSV), was first described by Fellinger less effusion takes over 3 months after RSV [5].
et al. in 1952 for treatment of persistent synovitis The best clinical recovery is observed in
of a rheumatoid arthritis (RA) patient with gold-­ patients who suffer from highest inflammatory
based colloid [1]. RSV is a salvage procedure for activity and within early phase of their underlying
chronic synovitis of individual joints after failure disease. The evaluation of clinical history is the
of long-term systemic pharmacotherapy and key point before RSV including duration symp-
repeated other non-biological injections. toms and underlying disease, duration and doses
The 90yttrium citrate (90Y), 186rhenium sulfide of systemic pharmacotherapy, previous surgical
(186R), and 169erbium citrate (169E) were common application, and previous other injections [6].
approved radiopharmaceuticals for RSV in Swelling, hyperthermia, disability, and physical
Europe [2] (Table 10.1). Mechanism of action functions of the effected joints should be evalu-
stars with their high-energy beta participles after ated in clinical examination. Clinical history of
injection and homogenous distribution in joint. the patient and disability of the joint are not
Beta particles show limited tissue penetration of enough to decide RSV, and a dedicated interdisci-
up to 10 mm to minimize nontarget tissue radia- plinary team (e.g., hematology, rheumatologist,
tion [3]. The radiation-absorbed dose nearly orthopedic surgeon, and nuclear medicine physi-
100 Gy leads to synovectomy via pronounces cell cian) consisting of referring physician should be
necessary to consider RSV application.
Legal issues including indications, approval,
G. Dikmen (*) and radiation protection protocols of different
Acibadem Mehmet Ali Aydinlar University,
Faculty of Medicine, Department of Orthopedics and radionuclides may vary from country to country,
Traumatology, Istanbul, Türkiye and each physician must follow their national
International Joint Centre (IJC), Acıbadem Maslak health laws. In Europe, 169E for smaller size joints
Hospital, Sarıyer, Istanbul, Türkiye as the carpometacarpal joints (CMC) and meta-
e-mail: [Link]@[Link] tarsophalangeal (MTP) joints; 186R for medium
V. E. Ozden · K. Karaytug size joints—ankle, shoulder, elbow, wrist, and
Acibadem Mehmet Ali Aydinlar University, hip; and 90Y for larger size joint, e.g., knee and
Faculty of Medicine, Department of Orthopedics and re-RSV cases (Table 10.1).
Traumatology, Istanbul, Türkiye

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 53

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
54 G. Dikmen et al.

Table 10.1 Common radiopharmaceuticals, according to the European Association of Nuclear Medicine (EANM)
guideline for RSV [2]
90
Yttrium 186
Rhenium Erbium
169

Half-life (days) 2.7 3.7 9.4

Average penetration (mm) 3.6 1.1 0.3
Particles Citrate/silicate Colloid/sulfide Citrate
Joints Recommended activities (MBq)
Knee 185–222
Hip 74–148
Shoulder 74–148
Elbow 74–111
Wrist 37–74
Ankle 74
Subtalar 74
CMC I/SIJ 20–80
MCP others 20–40
PIP/SCJ 10–20
DIP 10–15
MTP 30–40
TMT 20–40
ACJ/TMJ 20–40
CMC carpometacarpal joints, SIJ sacroiliac join, MCP metacarpophalangeal joints, PIP proximal interphalangeal joint,
SCJ sternoclavicular joint, DIP distal interphalangeal joint, MTP metatarsophalangeal joints, TMT tarsometatarsal joint,
ACJ acromioclavicular joint, TMJ temporomandibular joint

10.2 Indications oligoarthritis of chronic inflammatory rheu-

and Contraindications matologic diseases, and hemophilic
of Radiosynovectomy arthroplasty.
• 186R is indicated for the mono- or oligoarthritis
The main indications for RSV in patients with of the medium-sized joints, RA, hemophilic
joint pain were persistent synovitis of RA, inflam- arthroplasty, and chondrocalcinosis. In
matory joint diseases (Lyme’s borreliosis) and Switzerland, 186R is additionally approved for
seronegative spondyloarthropathy (psoriatic the knee joint in patients younger than 20 years
arthritis, ankylosing spondylitis, reactive arthri- [2].
tis), persistent synovial effusion (e.g., adjuvant • 169E is used for the treatment of mono- or oli-
therapy after endoprosthesis placement or goarthritis of smaller-sized joints, especially
arthroscopic synovectomy, open synovectomy). in hand and feet small joints after failure of
(Fig. 10.1), osteoarthritis characterized by sec- intra-articular corticosteroid infections.
ondary synovitis resistant to other treatments,
giant cell tumor/pigmented villonodular synovi- If the first RSV application failed, RSV could
tis (for the prevention of relapse after arthroscopic be repeated three times within 3 months inter-
or open surgery), hemarthrosis, and synovitis vals. Repeated RSV treatments have more chance
associated with hemophilia (for prevention of to decrease synovial hypertrophy than single
intra-articular hemorrhage and further arthro- treatments with higher activity. Pregnancy and
plasty) and undifferentiated arthritis character- postpartum breastfeeding, local and systemic
ized by synovitis [5, 7]. infection, massive hemarthroses of the target
joint (except for hemophiliac patients), recent
• Y is mainly used in adults for persistent
90 joint surgery or arthroplasty, within ruptured 6
synovial hypertrophy of the knee, mono- or weeks Baker cyst’s are the main absolute contra-
10 Radiosynovectomy 55

Fig. 10.1 30-year male refers our clinic with right hip 3 cc were used for the RSV after 3 months from index
pain and limited range of motion. Safe dislocation with surgery. Patient was not complaining any discomfort, and
trans-trochanteric approach was used for open synovec- last radiological MRI showed no relapse at an average
tomy due to synovial chondromatosis. 186Rhenium infu- 8.7-year follow-up
sion with subsequent betamethasone and saline infusion

indications for RSV [5]. Extensive joint instabil- 10.3 Informed Concept
ity, high-grade bone destruction, children and and Procedure
younger ager patients (indication should be
restricted for the patient’s age < 20 years old) are RSV decision should be made by a multidisci-
the relative contraindications according to plinary team consisting of referring physician
EANM guideline [2]. according to national regulations and national
Patients who are candidates for RSV treat- approved indication for the RSV treatment.
ment should have radiograph or MRI of target Finally, specialist nuclear medicine physician is
the joint at no more than 6 months previously. the main responsible for ultimate RSV indication
MRI also should be taken for hemophilia and possible RSV-related complications, who
patients with younger age group and children should apply the final intra-articular radiocolloid
due to lack radiation exposure [2]. In addition, injections. Patients must be informed about nature
joint ultrasonography may be useful to evalu- of the radioactive treatment, its mechanism, indi-
ate synovial hypertrophy of the joint and to cations, contraindications, and complications
exclude a ruptured Baker’s cyst or massive including the risks involving puncture of a joint,
hemarthrosis [8, 9]. Two- or three-phase bone such as infection, local hemorrhage, extravasa-
scan with 99mTc-­ phosphonate is still the tion, radiation burden, and the risk of radionecro-
method of choice to evaluate the severity of sis. If it is not restricted intra-­ articularly,
active soft-tissue inflammation of the mono- theoretical malignancy risk, postinjection pyrexia
and/or oligoarticular involvements in patients or allergy, and risk of thromboembolic events
with systemic inflammatory disease and activ- after immobilization of the lower limb for 48 h
ity in bone of the target joints for RSV [10, may occur after RSV. The patient should be
11]. informed that the RSV application has recovery
56 G. Dikmen et al.

of 60–80% chance and may face recurrent syno- gauge 25-mm length needle from dorsal into
vial attack after at least 6 months [7]. the cruciate fossa perpendicular to the skin.
According to EANM, RSV procedure should • Hip joint RSV injection should be performed
be administered in a dedicated room equipped for under fluoroscopy or ultrasonography. Supine
sterile injection procedures and approved for the position and slightly internal rotation of the
use of beta emitters [10]. Hygienic requirements hip are helpful. A21 gauge 50 mm or 20 gauge
of patients, regular infection prophylaxis of the 9–10 mm needle can be used.
room, and facility requirements should be • Shoulder joint anterior, superior, and posterior
considered. Sterile disposable cannulas and
­ approaches can be used for RSV. A 50 mm or
syringes must be used. Measurement of activity 40 mm 21-gauge needle mostly used diameters
or calculation of activity by volume, the selection to inject in patients’. The most common injec-
of suitable syringe, and shielding device for tion positions used for shoulder joint are supine
radionuclides should be prepared by nuclear position, arm in external rotation, and injection
medicine physician. Intra-articular injections through the anterior route. The needle must be
should be done based on the published guidelines positioned in the lower third of the joint space
and most favorable and simplest access routes to and should be checked with fluoroscopy.
decrease extravasation risk and neurovascular • Elbow joint RSV can be done in patient sitting
complication. in an upright position with the elbow flex to
Ultrasonography or arthrography and fluoros- 90° and forearm in maximum pronation posi-
copy with image documentation are necessary tion. Anatomical triangle of olecranon, the lat-
during injection. The contrast agents should be eral humeral epicondyle, and the radial head is
used to evaluate correct needle placement into the target for puncture. An 18-gauge needle
the joint, and physiological saline may improve should be used in the direction of the radial
the homogeneous distribution of the injected head under fluoroscopy.
radionuclide [12]. Concomitant use of subse-
quent glucocorticosteroids, e.g., triamcinolone
hexacetonide, triamcinolone acetonide, or beta- 10.3.2 RSV in Rheumatoid Arthritis
methasone, increases the effect of RSV [7]. Some
authors advice not to use glucocorticosteroids The most common type of inflammatory arthritis
due to possibility of avascular necrosis of the is rheumatoid arthritis (RA). RA is a chronic
femoral head after RSV treatment. autoimmune disease and is primarily considered
an inflammatory joint disease. In the USA and
northern Europe, the annual incidence is about 40
10.3.1 Joints Specific Approaches per 100,000 [13, 14]. Pharmacological treatments
and Needle Sizes for RSV are the first steps for RA-related synovial hyper-
trophy which include nonsteroidal anti-­
• Knee joint preferred approach is generally inflammatory drugs (NSAIDs), systemic or
ultrasonography-guided superolateral intra-articular glucocorticosteroids (GC), and
approach with positioning of needle to the non-biological and biological disease-modifying
suprapatellar recess. Removal of synovial antirheumatic drugs (DMARDs) [15]. Persistent
fluid even if it is present in small amount is synovitis of one or more joints can be treated
important before radionuclide injection. 21 with intra-articular injections of GC, and RSO is
gauge needle is advanced 40 or 50 mm. A indicated after at least one failed intra-articular
three-way valve should be used not to change injection of GC in RA patients treated with
the needle’s position for subsequent glucocor- DMARDs [2, 6]. Liepe et al. reported success
ticosteroids and saline injections. rates (excellent or good response) in 57% of the
• RSV for wrist and finger/toe joints should be treated knees, 63% of shoulders, 60% of wrists,
performed under fluoroscopy control with 25 64% of ankles, 54% of thumb bases, 55% of
10 Radiosynovectomy 57

MCPs, 54% of PIPs, 53% of DIPs, and 54% of tis (Kellgren-Lawrence grade I/II) demonstrated
MTPs. The best results for RSO are reported for higher functional scores than grade III patients.
joints with minimal or moderate joint damage, Success rate could decrease with continuing
and RSO should be considered by early in RA in severe degenerative changes of the joint [6].
case of persistent synovitis [16]. Recent two double-blind controlled prospective
studies for upper extremity and thumb showed
significant reduction of inflammation and symp-
10.3.3 RSV in Hemophilia toms within 1-year follow-up [24]. Szerb et al.
reported that RSV could prevent radiologic
Hemophilia is a bleeding disorder due to an deterioration among 70.6% of the hip patients
inherited X-linked deficiency or absence of clot- and in 79.1% of the treated ankle joint patients
ting factors. As a result, affected patients often at an average 9.2 years of follow-up time [25].
experience bleeding that causes synovitis in the
musculoskeletal system, particularly in the joints
[17]. The pathophysiology is mainly driven by an 10.4 Conclusion
inflammatory response to the iron load which
results in neo-angiogenesis and increased fragil- RSV should be considered the initial fast-acting
ity of the synovial membrane and further and patient-friendly therapeutic option for the
increased bleeding tendency [18, 19]. RSV is treatment of patients with hemophilic hemarthro-
indicated if synovitis can be demonstrated despite sis. RSV therapy should be performing early
coagulation factor substitution or if three joint stages of diseases, before the development of
hemorrhages occur within 6 months [2]. 70% to advance stage of cartilage loss. RSV is still classi-
90% of patients benefit from RSO concerning fied as “helpful” in patients with chronic synovitis
bleeding frequency, the intensity of pain, joint secondary to RA or active osteoarthritis. The inter-
function, and thickness of the synovium [17, 19, disciplinary teamworks with nuclear medicine
20]. The primary goal of RSV, namely, to stop physician are essential for the therapy protochol.
bleeding, is usually achieved. The best results are
obtained before the onset of hemarthropathy and
are best obtained in the ankle joints, followed by References
the elbow and knee joints [21]. Therefore, same
as the RA disease, RSV should be used as early 1. Fellinger K, Schmid J. Local therapy of rheumatic
phase as possible before hemarthropathy devel- diseases. Wiener Zeitschrift fur innere Medizin und
ops, and RSV should be used as first-line therapy ihre Grenzgebiete. 1952;33(9):351.
2. Kampen W, Boddenberg-Pätzold B, Fischer M,
in chronic synovitis. Finally, if the synovitis per- Gabriel M, Klett R, Konijnenberg M, Kresnik E,
sists or recurs after the first RSV, it is recom- Lellouche H, Paycha F, Terslev L. The EANM guide-
mended that the procedure could be repeated up line for radiosynoviorthesis. Eur J Nucl Med Mol
to three times. If synovitis persists after the third Imaging. 2021;1
3. Ingrand J. Characteristics of radio-isotopes for intra-­
RSO, it should be treated surgically [20, 22]. articular therapy. Ann Rheum Dis. 1973;32(Suppl):3.
4. Bowring C, Keeling D. Absorbed radiation dose in
radiation synovectomy. Br J Radiol. 1978;51(610):836.
10.3.4 RSV in Osteoarthritis 5. Knut L. Radiosynovectomy in the therapeutic manage-
ment of arthritis. World J Nucl Med. 2015;14(01):10.
6. Kresnik E, Mikosch P, Gallowitsch H, Jesenko R, Just
RSV could be used in selected patients with H, Kogler D, Gasser J, Heinisch M, Unterweger O,
osteoarthritis after failure of long-term systemic Kumnig G. Clinical outcome of radiosynoviorthesis:
pharmacotherapy and repeated other non-­ a meta-analysis including 2190 treated joints. Nucl
Med Commun. 2002;23(7):683.
biological injections. The improvement rate 7. Schneider P, Farahati J, Reiners C. Radiosynovectomy
after RSV reported from 40% to 89% for knee in rheumatology, orthopedics, and hemophilia. J Nucl
joint [23]. Patients with early-grade osteoarthri- Med. 2005;46(1 suppl):48S.
58 G. Dikmen et al.

8. Pirich C, Schwameis E, Bernecker P, Radauer M, 16. Liepe K. Efficacy of radiosynovectomy in rheumatoid

Friedl M, Lang S, Kritz H, Wanivenhaus A, Trattnig arthritis. Rheumatol Int. 2012;32(10):3219.
S, Sinzinger H. Influence of radiation synovectomy 17. Srivastava A, Santagostino E, Dougall A, Kitchen
on articular cartilage, synovial thickness and enhance- S, Sutherland M, Pipe SW, Carcao M, Mahlangu J,
ment as evidenced by MRI in patients with chronic Ragni MV, Windyga J. WFH guidelines for the man-
synovitis. J Nucl Med. 1999;40(8):1277. agement of hemophilia. Haemophilia. 2020;26:1.
9. Takase-Minegishi K, Horita N, Kobayashi K, 18. Wyseure T, Mosnier LO, von Drygalski A. Advances
Yoshimi R, Kirino Y, Ohno S, Kaneko T, Nakajima and challenges in hemophilic arthropathy. In:
H, Wakefield RJ, Emery P. Diagnostic test accuracy Seminars in hematology. Elsevier; 2016. p. 10.
of ultrasound for synovitis in rheumatoid arthritis: 19. van Vulpen LF, Thomas S, Keny SA, Mohanty
systematic review and meta-analysis. Rheumatology. SS. Synovitis and synovectomy in haemophilia.
2018;57(1):49. Haemophilia. 2021;27:96.
10. Sandrock D, Backhaus M, Burmester G, Munz D, 20. Haberman B. S2k-Leitlinie Synovitis bei
Rheumatologie fdKBVdDGf. Imaging techniques in Hämophilie 2018. Gesellschaft für Thrombose-und
rheumatology: scintigraphy in rheumatoid arthritis. Z Hämostaseforschung e V(GTH).
Rheumatol. 2003;62:476. 21. Walsh DA, McWilliams DF, Turley MJ, Dixon MR,
11. Stollfuss JC, Freudenberg LS, Wieder H. 99mTc-­ Fransès RE, Mapp PI, Wilson D. Angiogenesis and
DPD SPECT/CT for localisation of inflammatory nerve growth factor at the osteochondral junction in
and chronic osteoarthritis of the foot and ankle. rheumatoid arthritis and osteoarthritis. Rheumatology.
Nuklearmedizin-NuclearMedicine. 2016;55(04):145. 1852;49(10):2010.
12. Franssen M, Koenders E, Boerbooms AT, Buijs W, 22. Rodriguez-Merchan EC, Heim M, Wallny T. The
Lemmens J, Van De Putte L. Does application of hemophilic joints. J Blood Disord Transfus.
radiographic contrast medium in radiation synovec- 2011;2(3):111.
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British Journal of Rheumatology. 1997;36(04);506. prospective observational study on the long-term
13. Myasoedova E, Crowson CS, Kremers HM, Therneau results of 90 yttrium citrate radiosynoviorthesis of
TM, Gabriel SE. Is the incidence of rheumatoid arthri- synovitis in osteoarthritis of the knee joint. Eur J Nucl
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1955–2007. Arthritis Rheum. 2010;62(6):1576. 24. Van der Zant F, Jahangier Z, Moolenburgh J, Swen
14. Hunter TM, Boytsov NN, Zhang X, Schroeder K, W, Boer R, Jacobs J. Clinical effect of radiation syno-
Michaud K, Araujo AB. Prevalence of rheumatoid vectomy of the upper extremity joints: a randomised,
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 Deproteinized Hemoderivative
of Calf Blood-Natural Botanical
11
and Mineral Extracts

Berhan Bayram and Baris Kocaoglu

11.1 Introduction ries are still very limited. There are clinical stud-
ies describing the treatment methods of muscle
Muscle injuries are one of the most common inju- injuries in the literature; however, the underlying
ries among sports-related injuries, with an inci- mechanisms leading to the accelerated recovery
dence of 30–55% [1]. More than 90% of muscle time reported to date have not been fully identi-
injuries are caused either by excessive contusion fied and proven with randomized controlled trials
or strain of muscle. In professional sports, some [4]. Rest, immobilization, physical therapy, and
of these injuries can cause significant pain and sometimes nonsteroidal anti-inflammatory drugs
injury, resulting in loss of training and competi- (NSAIDs) are the main components of treatment
tion time. Muscle strain may be a consequence of for grade 1 and 2 muscle injuries [5].
eccentric exercise, when the muscle develops ten- Immobilization can lead to better granulation of
sion during this type of lengthening contraction. injured muscle fibers and shorten the healing pro-
These types of injuries are more common in sports cess but will cause significant atrophy and joint
that require sprinting or jumping [2]. For injuries stiffness in healthy myofibers [1]. The aim of the
like this, in professional sports, medical staff face treatments used in the acute phase is to minimize
pressure to return the player to training and com- the formation of a large hematoma that has the
petition as soon as possible. Physical examination potential to affect the size of the scar tissue at the
is very important to diagnose muscle injuries. end of the repair process. While some studies
Ultrasonography and magnetic resonance imag- have shown that the administration of NSAIDs
ing (MRI) can be useful in confirming the diagno- promotes muscle recovery by reducing degenera-
sis and helping the clinician make treatment tion and inflammation [6], another research has
decisions. The muscle healing process consists of shown that NSAIDs are detrimental to the entire
several consecutive stages: myofibril degenera- healing process [7]. For this reason, studies on
tion, inflammation, regeneration, and fibrosis [3]. treatment methods that lead to faster recovery in
The treatment options for structural muscle inju- the treatment of muscle injuries have increased.
Injection therapy in sports muscle injuries has
B. Bayram a history of safe use of approximately 60 years.
Acibadem Altunizade Hospital, Department of As a result of studies conducted in recent years,
orthopedics and Traumatology, Istanbul, Turkey several new injection methods have been reported
B. Kocaoglu (*) that shorten the recovery time after muscle strain
Acibadem Mehmet Ali Aydinlar University, Faculty injuries. For example, growth factor injection
of Medicine, Department of Orthopedics and
Traumatology, Istanbul, Turkey therapy has shown good therapeutic results.

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 59

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
60 B. Bayram and B. Kocaoglu

However, due to their performance enhancing proinflammatory cytokines such as TNF-alfa and
and anabolic properties, growth factors have been IL-1beta [11]. The authors suggested that Tr14
banned by the World Anti-Doping Agency injection solution acts by accelerating the healing
(WADA). Local anesthetics, calf blood com- process rather than blocking the development of
pound (CPC) (Actovegin), and homeopathic drug edema from the beginning [12]. The oral applica-
(Tr14) (Traumeel) or injection of platelet-rich tion of Tr14 has been demonstrated to have ben-
plasma (PRP) are the other most commonly eficial effects on epicondylitis and different
reported drugs. musculoskeletal disorders [13]. Although ath-
letes have been reported to be successfully treated
in practice, there is limited scientific evidence in
11.2 Most Used Deproteinized the literature to support the general use of these
Hemoderivative of Calf agents in the treatment of muscle injuries. The
Blood-Natural Botanical mechanism of action of calf blood compound
and Mineral Extracts (CPC) and Tr14 in the muscle recovery process is
still not fully understood.
Calf blood compound (CPC) (Actovegin) is a Another homeopathic solution, Zeel comp. N
biological drug manufactured from a natural (Zeel, Heel, GmbH, Baden-Baden, Germany), is
source. It is a calf blood hemodialysate and con- a homeopathic medication that has been widely
tains typical salts, trace elements, and high con- used for many years for the treatment of arthritic
centrations of various amino acids [8]. It can be disorders in many countries around the world.
administered orally as tablets, topical formula- Zeel’s formulation includes a combination of
tions, intramuscular or intravenous injections, or highly diluted extracts from Arnica montana
infusions. Because calf blood compound (CPC) (arnica root), Sanguinaria canadensis (blood-
is a complex of blood dialysate with many differ- root), Rhus toxicodendron (poison oak), Solanum
ent active molecules, it is difficult to identify the dulcamara (climbing nightshade), and sulfur.
single pharmacologically active component. Zeel is available as tablets or injection solution
Traumeel (Tr14), on the other hand, is a with slightly different compositions. Clinical
homeopathic solution with a fixed combination observational studies have shown that Zeel
formula of 12 botanical and 2 mineral substances reduces symptoms of osteoarthritis, including
with proven anti-inflammatory, antiedema, as stiffness and pain, and is generally well tolerated
well as anti-exudative properties [9]. It has been with a good safety profile [14]. Initial preclinical
on the market in Germany since 1937 and is cur- data suggested that Zeel has an inhibitory effect
rently available in approximately 60 countries on cartilage degradation; however, the mecha-
around the world. The constituents of Traumeel nism of action of Zeel is still not fully under-
are used traditionally and in homoeopathy for the stood. The mechanism of action of Zeel and its
broad spectrum of symptoms associated with efficacy in the treatment of osteoarthritis will be
various traumas such as contusions, sprains, better understood with future studies with a large
wounds, pain, inflammation, neuralgia, etc. number of patients.
Various cellular and biochemical pathways The use of deproteinized hemoderivative of
appear to be modulated by the components in calf blood-natural botanical and mineral extracts
Tr14. Homeopathic drug has shown efficacy in training regimes by high profile athletes has
comparable to NSAIDs in terms of anti-­ led to the anecdotal opinion that the blood prod-
inflammatory property, but it has been suggested uct is ergogenic, enhancing athlete performance.
that the Tr14 injection solution does not inhibit Calf blood compound (CPC) has been used clini-
the cyclooxygenase (COX) or lipoxygenase cally for decades to improve blood circulation in
enzyme pathways as does nonsteroidal anti-­ the brain after ischemic injury caused by impaired
inflammatory drugs (NSAIDs) [10]. In vitro stud- peripheral blood circulation. In vitro studies have
ies showed that Tr14 inhibits the production of suggested that these types of drugs have
11 Deproteinized Hemoderivative of Calf Blood-Natural Botanical and Mineral Extracts 61

membrane-­stabilizing effects to interrupt oxida- toxic when administered intramuscularly, but

tive stress and cell death processes while increas- there is no information in the studies that calf
ing the efficiency of energy balance in cells blood compound (CPC) and Tr14 are myotoxic.
during postischemic metabolic events. Actovegin This feature is one of the most important advan-
contains physiological components, electrolytes, tages that distinguish CPC and Tr14 from other
and essential trace elements. 30% of organic agents. In addition, no other side effects were
components are amino acids, nucleosides, inter- reported in the studies on Actovegin and
mediates of carbohydrates, and fat metabolites. Traumeel. However, previously published data
Ultrafiltered up to 6000 daltons, therefore it con- have suggested beneficial effects of CPC on
tains no growth factors or hormone-like sub- numerous diseases, including acute and chronic
stances. It can be administered as tablets, topical wounds and circulatory disorders [18]. CPC has
formulations, injections, or infusions by intra- neuroprotective and antioxidative properties and
muscular or intravenous routes [15]. For exam- is intended to have ergogenic qualities and play
ple, a recent in vitro model of cell injury has an important role in muscle tissue metabolism
shown that Actovegin (a biological drug pro- [19]. CPC improves muscle cell proliferation and
duced by Nycomed GmbH, Linz, Austria, which has been successfully applied clinically in com-
in 2015 was taken over by Takeda Pharmaceutical bination with Tr14 for the treatment of muscle
Ltd., Japan) improves intrinsic mitochondrial injuries. A result of another in vivo clinical study
respiration capacity in injured human skeletal showed that Actovegin has no effect on peak aer-
muscle fibers. It was concluded that the findings obic capacity in humans [20].
of this study support and explain the reported
ergogenic properties [16]. The mechanism of
action with Actovegin can potentially protect 11.3 Conclusion
ischemic cells, modulate the inflammatory pro-
cess, and help the initial phase of recovery from In conclusion, injection therapies with deprot-
acute muscle injuries become more efficient. einized hemoderivative of calf blood-natural
Skeletal muscle is a very vascular structure botanical and mineral extracts are frequently
and is highly energy dependent. Once injured, used as a possible treatment option for acute
blood flow often is disturbed, which leads to cell muscle injuries and osteoarthritis. The use of
ischemia and energy imbalance. Therefore, these drugs in the acute phase of muscle injuries
Actovegin injection therapy to the injury site suggests that it may be a promising intervention
might aid recovery and limit further ischemic for athletes who experience muscle injuries by
effects and control cellular damage from initial shortening the recovery period. Based on previ-
injuries. Another publication reported that ous studies, these agents appear to be safe and
Actovegin may inhibit the release of inflamma- well tolerated. There is no new evidence to ques-
tory mediators and therefore potentially speed up tion the long-standing, good safety profile of
the muscle recovery process [17]. In a study with these drugs. Compared with conventional con-
football players, the Actovegin injection therapy servative RICE and NSAID therapy, these agents
regimen described for grade 1 hamstring injuries propose an exciting and legal alternative for
appears to significantly reduce the number of high-performance athletes. Although athletes
days to return to play, with an average reduction have been reported to be successfully treated in
of 8 days compared to rehabilitation therapy practice, there is only limited scientific evidence
alone [15]. The career life span for the profes- to support the general use of the abovementioned
sional elite athlete is often short lived, and short- agents in the treatment of skeletal muscle inju-
ened recovery time could mean continuing with ries in athletes. The limited number of high-
training, increased game play, and benefit to the quality studies makes it difficult to compare the
team and club. And some agents administered effectiveness of injection therapy with these
after muscle injuries have been found to be myo- agents in muscle injuries and osteoarthritis.
62 B. Bayram and B. Kocaoglu

Further research should be encouraged to inves- 6. Abramson SB, Weissmann G. The mechanisms
tigate the effects of these drugs. Also, there are of action of nonsteroidal antiinflammatory drugs.
Arthritis Rheum. 1989;32(1):1–9. [Link]
no established doses and its frequency to use in org/10.1002/ANR.1780320102.
the treatment of acute muscle injury and osteoar- 7. Shen W, Li Y, Tang Y, Cummins J, Huard J. NS-398,
thritis. It is also unclear when and which solution a cyclooxygenase-2-specific inhibitor, delays skeletal
was considered. Furthermore, Actovegin can be muscle healing by decreasing regeneration and pro-
moting fibrosis. Am J Pathol. 2005;167(4):1105–17.
shown to improve muscle cell proliferation [8]. [Link]
This may help explain the positive effects of 8. Reichl FX, et al. Comprehensive analytics of
Actovegin on muscle injuries. Another important Actovegin® and its effect on muscle cells. Int
point is that the intramuscular use of such drugs J Sports Med. 2017;38(11):809–18. [Link]
org/10.1055/S-­0043-­115738/ID/R6256-­0028.
is not prohibited by the regulatory authority, the 9. Vanden Bossche L, Vanderstraeten G. A multi-­
World Anti-Doping Agency (WADA). Based on center, double-blind, randomized, placebo-controlled
the most recent literature, it suggests that depro- trial protocol to assess Traumeel injection vs dexa-
teinized hemoderivative of calf blood-natural methasone injection in rotator cuff syndrome: the
TRAumeel in ROtator cuff syndrome (TRARO) study
botanical and mineral extracts is a safe injectable protocol. BMC Musculoskelet Disord. 2015;16:1.
therapy that has demonstrated some efficacy in [Link]
the treatment of muscle injuries and is unlikely 10. Schneider C. Traumeel - an emerging option to non-
to be ergogenic. It should be noted that an injec- steroidal anti-inflammatory drugs in the management
of acute musculoskeletal injuriesInt J Gen Med. 2011;
tion therapy that will prove to shorten the heal- 25(4):225–34. [Link]
ing process could potentially revolutionize the 11. Porozov S, Cahalon L, Weiser M, Branski D, Lider O,
treatment of muscle injuries. In addition, with Oberbaum M. Inhibition of IL-1beta and TNF-alpha
studies on the use of these drugs in the treatment secretion from resting and activated human immu-
nocytes by the homeopathic medication Traumeel
of osteoarthritis, they may be an alternative in S. Clin Dev Immunol. 2004;11(2):143–9. [Link]
the clinical follow-up of these patients. org/10.1080/10446670410001722203.
12. Lussignoli S, Bertani S, Metelmann H, Bellavite
P, Conforti A. Effect of Traumeel S, a homeopathic
formulation, on blood-induced inflammation in rats.
References Complement Ther Med. 1999;7(4):225–30. https://
[Link]/10.1016/S0965-­2299(99)80006-­5.
1. Järvinen TAH, Kääriäinen M, Järvinen M, 13. Schneider C, Schneider B, Hanisch J, van Haselen
Kalimo H. Muscle strain injuries. Curr Opin R. The role of a homoeopathic preparation compared
Rheumatol. 2000;12(2):155–61. [Link] with conventional therapy in the treatment of inju-
org/10.1097/00002281-­200003000-­00010. ries: an observational cohort study. Complement Ther
2. Garrett J. Muscle strain injuries. Am J Med. 2008;16(1):22–7. [Link]
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[Link]/10.1177/036354659602406S02/ 14. Sanchez C, et al. Reduction of matrix metallopep-
ASSET/[Link].PNG_V03. tidase 13 and promotion of chondrogenesis by Zeel
3. Harmon KG. Muscle injuries and PRP: what does T in primary human osteoarthritic chondrocytes.
the science say? Br J Sports Med. 2010;44(9):616–7. Front Pharmacol. 2021;12 [Link]
[Link] FPHAR.2021.635034/FULL.
4. Wright-Carpenter T, Klein P, Schäferhoff P, Appell 15. Lee P, Rattenberry A, Connelly S, Nokes L. Our
HJ, Mir LM, Wehling P. Treatment of muscle inju- experience on Actovegin, is it cutting edge? Int
ries by local administration of autologous conditioned J Sports Med. 2011;32(4):237–41. [Link]
serum: a pilot study on sportsmen with muscle strains. org/10.1055/S-­0030-­1269862.
Int J Sports Med. 2004;25(8):588–93. [Link] 16. Søndergård SD, Dela F, Helge JW, Larsen
org/10.1055/S-­2004-­821304. S. Actovegin, a non-prohibited drug increases oxida-
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11 Deproteinized Hemoderivative of Calf Blood-Natural Botanical and Mineral Extracts 63

17. Lee P, Kwan A, Nokes L. Actovegin—cutting-edge 19. Elmlinger MW, Kriebel M, Ziegler D. Neuroprotective
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Rep. 2011;10(4):186–90. [Link] actovegin on primary rat neurons in vitro. doi: https://
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 Part III
Ortho-biologic Agents for Injections
 Orthobiologics: Background
12
Paola De Luca, Michela Maria Taiana,
and Laura de Girolamo

12.1 Introduction immunomodulatory, and regenerative properties

that can promote the restoration of tissue homeo-
Orthobiologic therapy for regenerative medicine stasis counteracting the inflammatory microen-
applications has gained increasing interest in vironment or increase tissue repair native
recent years in the orthopedic field from the sci- biologic potential through multifactorial mecha-
entific and clinical community due to the promis- nisms [2–4]. Their mechanisms of action are
ing results obtained in preclinical and clinical based on the therapeutic potential of soluble fac-
studies. Defined as biological materials and sub- tors as well as exosomes and micro-vesicles car-
strates derived from the body that promote bone, rying DNA, proteins/peptides, lipids, organelles,
ligament, muscle, and tendon healing in muscu- mRNA, and miRNA [5] that exert antiapoptotic,
loskeletal injuries and degeneration [1], orthobio- anti-­catalytic, trophic, and immunomodulatory
logics represent a category of innovative products activities. Indeed, inflammation is a frequent
that exploit the biological properties of their con- hallmark of musculoskeletal diseases such as
stituent elements to enhance the reparative and osteoarthritis, tendinopathy, and muscle injuries
regenerative capacity of damaged tissue. These and is often responsible of the degenerative cas-
products open the frontiers to innovative thera- cade onset that results in long-term tissue
peutic strategies, and they can be both used as destruction. Based on these premises, the pro-
conservative injectable treatments and/or in com- motion of cell proliferation and inhibition of
bination with surgical procedures providing a pro-inflammatory mechanisms in the early stage
viable alternative to more conventional of tissue homeostatic alteration result in improve-
treatments. ment of the pain status of patients with musculo-
Orthobiologics are heterogeneous products skeletal diseases due to tissue damage. Therefore,
including bioactive molecules such as cytokines, the use of orthobiologics represents a promising
growth factors, and/or cells and their released strategy also for the development of new pain
products with anti-inflammatory, reparative therapies.

P. De Luca · M. M. Taiana · L. de Girolamo (*)

Orthopaedic Biotechnology Laboratory, Ospedale
Galeazzi Sant’Ambrogio, Milan, Italy
e-mail: [Link]@[Link];
[Link]@[Link];
[Link]@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 67

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
68 P. De Luca et al.

12.2 Types and Effects However, particularly in case of extended dam-

of Orthobiologics age, muscle recovery is not clearly evident, and
further investigations are needed to validate the
Orthobiologics come in many different forms efficacy of BDP in muscle healing [7].
derived from blood or adult tissue cells obtained In BDPs, the regenerative potential derives
from adipose tissue, bone marrow, or fetal mainly from the high content of growth factors,
annexes (placenta, cord blood, amniotic mem- cytokines, and bioactive molecules stored in
brane) through procedures with variable com- platelet α-granules that are released after degran-
plexity. Because of regulatory matter, the most ulation and that promote healing process and
used orthobiologics are those prepared by mini- modulate inflammation, ECM synthesis, and new
mal manipulation at the point to care. This allows blood vessel formation by paracrine mechanisms.
to avoid fall into the more complex regulations of The procedure for obtaining these products is
the advanced therapy medicinal products usually rapid and technically simple. After being
(ATMPs). Among the most used minimally harvested, the blood usually undergoes a centrif-
manipulated orthobiologics, blood-derived ugation cycle—differing in speed and duration—
­products (BDPs) are widely employed for the and directly injected into the site of treatment.
injective treatment of musculoskeletal condi- The centrifugation procedure leads to a platelet
tions. This category includes platelet derivatives concentration of three to six times than whole
products such as platelet-rich plasma (PRP), blood, and based on the preparation method, the
growth factors-rich plasma (PRGF), autologous final product composition can vary significantly.
protein solution (APS), autologous conditioned BDPs can be classified according to different
plasma (ACP), and other blood products such as platelet and/or leukocyte content. More in detail,
autologous conditioned serum (ACS) and PRGF is a type of plasma enriched of proteins,
α2-macroglobulin (A2M). circulating growth factors, and coagulative fac-
Platelet concentrate was first proposed as a tors that are pre-­ activated exogenously before
strategy to promote tissue healing in regenerative injection [8]. It can improve the healing process
medicine in 1998 by Marx and colleagues for by forming blood clots that release their content
bone healing in maxillofacial surgery [6]. After at the site of the injury. According to different
this publication, numerous clinical trials and case centrifugation methods, it is possible to obtain
series have provided promising results in terms of platelet-rich plasma products with different leu-
safety and efficacy of platelet-based products in cocyte content, labeled as leucocyte-poor PRP
patients with osteoarthritis demonstrated by (LP-PRP) or leucocyte-­rich PRP (LR-PRP) [9].
reduction of symptoms and tissue degeneration. Leukocytes can secrete several molecules
Some studies have shown an opposite trend, but it involved in inflammation and in wound healing;
should be considered that procedures for PRP however, the optimal formulation of platelet and
production and administration in different trials leukocyte ratio in PRP has not been defined and
were not univocal and also some studies suffer could vary for different pathologies. To date,
from intrinsic flaws. However, despite some con- clinical recommendation suggests LR-PRP injec-
troversial results, the current literature seems to tion for lateral epicondylitis and LP-PRP for
report more and more positive findings. BDP osteoarthritis of the knee [10].
injection has been proposed also as therapy for APS is a novel LR-PRP containing high con-
tendinopathy. Indeed, neovascularization pro- centration of leukocytes, cytokines involved in
moted by BDPs in tendon tissue could be particu- inflammation, and anabolic cytokines, and it has
larly relevant, although also in this case conflicting been proposed as an autologous treatment for
results are reported, likely due to the aforemen- patients with joint conditions specifically osteo-
tioned reasons. Recent studies showed positive arthritis [11].
effect of BDP injection in treatment of muscles Autologous conditioned serum (Orthokine) is
injuries too, without negative side effects reported. another autologous blood product whose pecu-
12 Orthobiologics: Background 69

liarity is the enrichment in the interleukin-1 ing BMSCs as well as leukocytes and platelet
receptor antagonist (IL-1Ra); therefore, its appli- [19]. As for other cell therapies, BMAC composi-
cation is suitable for pathologies resulting from tion, and consequently its effectiveness, depends
altered levels of IL-1β such as osteoarthritis, on the donor characteristics and on the harvest
degenerative joint diseases, but it is also indi- site. Indeed, BMAC harvested from the iliac crest
cated for muscle regenerative treatment [12]. It is has the highest concentration of mononuclear
obtained after blood monocytes selection, plate- cells compared to other sites. Given the preclini-
lets degranulation, and release of anti-­cal and clinical promising results, BMAC therapy
inflammatory proteins such as IL-1Ra [13]. is often chosen for the treatment of several mus-
A2M is the most abundant blood proteinase culoskeletal and spinal conditions. In particular,
inhibitor able to bind and to inhibit metallopro- BMAC has resulted to be efficacious in treatment
teinase and endoproteases included many carti- of knee osteoarthritis, for which a significant pain
lage catabolic factors; for these reasons, it would relief and function improvement have been
seem to attenuate cartilage degeneration and reported, as well as in osteochondral repair
osteoarthritis disease [14]. It is obtained after mostly when associated with a scaffold.
whole blood centrifugation to separate the PRP Moreover, in rotator cuff repair setting, BMAC
from the platelet poor plasma (PPP) from which resulted to be more efficacious than PRP [20, 21].
larger molecules including A2M (720 kDa) are Standardized reproducible procedures for clini-
isolated and concentrated [15]. cal application have not yet been defined, and
In addition to BDPs, orthobiologics include long-term studies are needed to clearly establish
also product whose efficacy relies on cells, the therapeutic efficacy of BMAC injection.
mainly mesenchymal stem/stromal cells (MSCs), More recently, it has become evident that also
obtained through one-step procedures which adipose tissue, which is easier to obtain than
have pro-regenerative ability crucial for the treat- bone marrow, represents a relevant resource of
ment of damaged musculoskeletal tissues [16]. MSCs, namely, adipose-derived MSCs (ASCs).
MSCs can produce and release active molecules Moreover, from adipose tissue, it is possible to
able to stimulate the resident cell population to obtain the stromal vascular fraction (SVF), a het-
cellular repair, as well as to act as immunomodu- erogeneous cell population comprising endothe-
lators on the local immune system, reducing lial cells, pericytes, lymphocytes, and
fibrous scarring processes and cell apoptosis, and pre-adipocytes, excluding mature adipocytes.
to stimulate angiogenesis [17]. MSCs have been Several studies demonstrate the SVF efficacy
more recently described as a subtype of pericytes, in inhibiting inflammation, promoting repair of
quiescent cells wrapped around vasculature net- cartilage damage, and reducing pain in osteoar-
work present in all the vascularized tissue, includ- thritis patients through paracrine mechanisms.
ing adipose tissue and in bone marrow. In fact, However, different patients showed variable out-
those two tissues are the most common sources come probably due to individual differences in
of autologous MSCs for clinical use in regenera- donors and different product preparations that
tive medicine. can affect the therapeutic effectiveness [22].
Bone marrow has been the first and widely Alternatively, adipose tissue can be minced to
used source of isolation of MSCs (BMSCs, bone obtain microfragmented adipose tissue (micro-­
marrow stem/stromal cells) due to the high yield. fat or MFAT) through the mechanical fragmenta-
For practical reason related to a simpler proce- tion of lipoaspirate using devoted medical devices
dure and smother regulations, to date autologous [23]. The resulting product maintains the adipose
concentrate of bone marrow aspirate (BMAC) is tissue microarchitecture and preserves the so-­
the most common form of bone marrow-dried called stem cell niche therefore respecting the
products [18]. BMAC is obtained by harvesting physiological cell environment [24].
and centrifuging the bone marrow aspirate to Also, in this case, the different devices for
concentrate the mononuclear cell phase contain- obtaining micro-fat, including harvesting, pro-
70 P. De Luca et al.

cessing washing, and centrifugation steps, in define standardized protocols and provide con-
addition to donor variability led to different prod- crete guidelines for clinicians according to scien-
ucts [25, 26]. Extensive in vitro evidence encour- tific findings and recommendation.
ages the use of bone marrow and adipose It is not possible to identify yet the best ortho-
tissue-derived products for the treatment of mus- biologic injective treatment for each given pathol-
culoskeletal conditions [16], but several issues ogy, as different orthobiologics can exert different
have still limited translation of cell-based prod- efficacies in specific patients. Literature, although
ucts into clinical practice. These treatments can rich of reports about these therapeutic proce-
be used in one-step procedure through minimally dures, often also of good level of evidence (level
manipulated procedures as for BMAC, SVF, or I studies), suffers from some inconsistencies due
micro-fat or can be expanded in vitro, generating to the different preparation methods resulting in
more characterized products that are however different efficacy and results. Moreover, orthobi-
more expensive and complex to manage from a ologics prepared at the POC do not undergo spe-
regulatory perspective. Indeed, when MSCs cific quality control analysis or evaluation of
undergo consistent manipulation, the resulting their potential clinical effectiveness prior to
products fall within the ATMPs category of thera- administration, making more difficult to find a
peutics. ATMPs are subject to very stringent reg- consistent correlation between the product qual-
ulation that classifies and categorizes them as ity and the clinical outcomes. The literature
sterile drugs, and therefore, they must be pro- reports a stable percentage of patients who does
duced in accordance with the “Good not respond to treatment as expected, despite the
Manufacturing Practices” (GMPs) outlined in the indication for the treatment is in line with the cur-
Regulation (EC) No 1394/2007, Directive rent knowledge. In this view, it is essential to
2001/83/EC on Sterile Medicines. To facilitate understand how variable factor as age, nutrition
the MSC translation into orthopedic clinical state, lifestyle, medical comorbidities, and site or
practice, several solutions have been proposed time of harvest can influence the composition and
with a low degree of tissue and cell manipulation, then the outcome of orthobiological treatments
therefore not recognized as ATMPs, which have [27]. Therefore, study of biomarker profile cor-
given rise to the category of the products pre- related with the clinical outcome is ongoing to
pared at the point of care (POC). define potential predictive elements of potency
and biologic activity that should be considered in
order to choose the optimal personalized
12.3 Conclusion therapy.

Because of the strong rationale behind their use,

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 Platelet-Rich Plasma
for Osteoarthritis
13
Trifon Totlis and Angelo V. Vasiliadis

13.1 Introduction [6, 7]. Recently, there has been an increasing

interest in nonoperative treatment options for
Osteoarthritis (OA) is considered the most common knee OA, primarily focusing on intra-articular
type of arthritis and the most prevalent joint disease injectable therapies [8]. Intra-articular injections
in adults [1]. It is characterized by articular cartilage traditionally included corticosteroids and hyal-
degeneration that affects patient’s mobility and uronic acid (HA) with integral roles in improving
quality of life [2]. The World Health Organization joint lubrication and anti-inflammatory effects
(WHO) estimates that approximately 10% of all [8–10]. More recently, orthobiologics have
men and 13% of all women aged over 60 have OA emerged as potential adjunctive therapies to treat
[3]. Articular cartilage degradation results from a mild to moderate OA. Agents such as platelet-­
disruption in homeostasis, due to an imbalance rich plasma (PRP), bone marrow aspirate con-
between chondrocyte catabolic and anabolic path- centrate (BMAC), adipose tissue, and allogenic
ways, driven by local production of metalloprotein- amniotic fluid products are more commonly
ases and multiple inflammatory mediators [4]. The being used as injectable therapies for OA [7, 9].
most commonly affected joint is the knee followed PRP is an autologous formulation derived
by the hip, hands, and spine [3, 5]. from centrifugation of the patient’s whole blood.
Α stepwise approach is recommended for OA It is defined as a volume of autologous plasma
management, including non-pharmacological, with a platelet concentration greater than the
pharmacological, and surgical treatment for average in peripheral blood (150,000–350,000
patients with a more advanced stage of disease platelets/μl) [11, 12]. PRP preparation protocols
vary widely. There are essentially three different
methods for PRP production: single centrifuga-
T. Totlis (*)
The-MIS Orthopaedic Center, St. Luke’s Hospital,
tion, double centrifugation, or blood filtration
Thessaloniki, Greece and plateletpheresis. This is done on manual or
School of Medicine, Faculty of Health Sciences,
automatic systems operated in open or closed cir-
Aristotle University of Thessaloniki, cuits. The high number of variables involved has
Thessaloniki, Greece led to the development of several custom proto-
e-mail: totlis@[Link] cols and to a large number and variability of com-
A. V. Vasiliadis mercially available PRP systems. These devices
Orthopaedic Department, St. Luke’s Hospital, vary in PRP collection volumes and preparation
Thessaloniki, Greece
protocols that result in distinctive PRP bioformu-
Research Fellow Hôpital de la Croix-Rousse, lations and properties.
Lyon, France

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 73

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
74 T. Totlis and A. V. Vasiliadis

The critical variables to characterize PRPs Table 13.1 Platelet-rich plasma classification systems
usually include the following [13]: Classification system Criteria
Ehrenfest classification Presence of cell content
1. The proportion of platelets in PRP to platelets Fibrin architecture
in whole blood called platelet enrichment fac- PAW classification Platelets
tor (PEF). Activation
White blood cells
2. The presence or absence of WBCs. Leukocyte
PLRA classification Platelet count
rich-PRP (LR-PRP) is defined as having a Leucocyte content
greater number of leukocytes when compared Red blood cell content
to whole blood. In leukocyte poor PRP (LP-­ Activation
PRP), the concentration of leukocytes is DEPA classification Dose of injected platelets
equivalent or reduced when compared to Efficiency of production
baseline. Purity of PRP
Activation process
3. The method of activation. Platelet activation
MARSPILL classification Method
can be triggered by exogenous agents, such as Activation
calcium chloride or thrombin. Alternatively, Red blood cells
direct injection of nonactivated PRP allows Spin
local tissue factors to endogenously activate Platelet concentration
platelets. Image guided
Leucocyte concentration
Light activation
Based on those three variables and other PRP
characteristics, several classification systems
have been put forward over the years for a more by binding to receptors on the cell membrane
complete and standardized description of differ- [17]. This results in a cascade of events, such as
ent PRP categories (Table 13.1) [12, 14]. chondrocyte proliferation, chemotaxis, cell
The rationale for PRP use in patients with OA migration and differentiation, matrix production
is based on evidence that intra-articular PRP stimulation, angiogenesis, and inflammation
injection may reduce pain and inflammation as modulation [12]. This mechanism favors the res-
well as influence joint homeostasis promoting toration of a homeostatic balance in degenerative
both the healing process and immunoregulation joints, slowing down the inflammatory, catabolic,
(Fig. 13.1a, b) [12, 15, 16]. PRP contains biologi- and degenerative processes, thus offering benefits
cally active proteins, cytokines, and growth fac- in terms of symptom relief, functional improve-
tors derived from platelets a-granules, which ment, and potentially on disease progression.
have inflammation reduction and cell regenera- Moreover, PRP is considered to be cost-effective
tive properties (Table 13.2) [14, 17]. Once and convenient for patients [18–20]. Very rarely
injected and activated, platelets degranulation leads to complications, it is easy to prepare and
releases a great number of GFs that act through administer, and it is less invasive compared to
autocrine, paracrine, or endocrine mechanisms other orthobiologic therapeutic options [21, 22].
13 Platelet-Rich Plasma for Osteoarthritis 75

Matrix more resistant to enzymatic

degradation of arthrosis process

Extracellular Matrix (ECM)

Regeneration of ECM
Bioactive proteins and GF
Matrix-cells and intermatrix ligands

PRP action mechanism

Fig. 13.1 (a) Pro-inflammatory factors interleukin-1 (IL- receptors block the action of IL-1 and TNF-α by preferen-
1) and tumor necrosis factor alpha (TNF-α) bind to recep- tially binding to the receptor on chondrocytes and inhibit
tors on chondrocytes and promote synthesis of matrix production of MMPs. The growth factors (GF) produced
metalloproteinases (MMPs) and cartilage breakdown, from activated platelets stimulate synoviocytes to synthe-
contributing to osteoarthritis pathogenesis (Fig. a, left). size hyaluronic acid. (b) PRP promotes cell migration and
Intra-articular platelet-rich plasma (PRP) injection has proliferation but also enhances the extracellular matrix
immunoregulatory effects and creates a regenerative remodeling (proteoglycans, fibronectin, type II collagen)
microenvironment. A number of anti-inflammatory fac- via the stimulation of angiogenesis
tors including IL-1 receptor antagonist and TNF-α soluble
76 T. Totlis and A. V. Vasiliadis

Table 13.2 Platelet-rich plasma-based growth factors increase over time, being not significant at earlier
Growth follow-ups, but becoming clinically significant
factor Function through 6 and 12 months [27]. However, these
PDGF Stimulates chemotaxis and mitogenesis in improvements remain partial, and the level of
fibroblast
evidence for some of the outcomes is still low
Regulates collagenase secretion and
collagen synthesis [27]. Whether PRP can affect cartilage regenera-
TGF-β Stimulates MSC proliferation tion and OA progression is yet to be confirmed in
Regulates mitogenesis clinical studies, although 68% of relevant animal
Regulates collagen synthesis and studies showed disease-modifying effect [31].
collagenase secretion There are also RCTs and meta-analyses which do
Stimulates chemotaxis and angiogenesis
not support the use of autologous PRP as an
VEGF Increases angiogenesis and vessel
permeability effective treatment for the management of knee
Stimulates mitogenesis OA [32, 33].
FGF Promotes growth and differentiation of The plethora of RCTs favoring PRP injections
chondrocytes and osteoblasts for knee OA [27] provides adequate evidence for
Regulates mitogenesis for MSC, PRP use in daily practice. Nevertheless, this
chondrocytes, and osteoblasts
treatment is not recommended by most of the
IGF-1 Stimulates chemotaxis
Regulates proliferation and maturation of international societies’ guidelines. Only recently,
chondrocytes the American Academy of Orthopaedic Surgeons
PDGF platelet-derived growth factor, TGF transforming (AAOS) in their guidelines for the management
growth factor, VEGF vascular endothelial growth factor, of osteoarthritis of the knee (non-arthroplasty),
FGF fibroblast growth factor, IGF insulin-like growth released in 2021, stated that PRP may reduce
factor, MSC mesenchymal stem cells
pain and improve function in patients with symp-
tomatic osteoarthritis of the knee. To address this
issue, the European Society of Sports
13.2 PRP Outcomes for OA Traumatology, Knee Surgery and Arthroscopy
(ESSKA) launched a consensus study in 2022
The role of PRP in alleviating pain and improv- and concluded that there is currently enough pre-
ing functional outcomes in patients with OA has clinical and clinical evidence to recommend the
been well established both in basic science and use of PRP in knee OA, mainly in mild and mod-
clinical studies over the last two decades [23, 24]. erate degrees. The principal drawback of the rel-
There are many randomized controlled trials evant literature is the high heterogeneity and lack
(RCTs) and meta-analyses about the efficacy of of standardization in terms of PRP preparation
intra-articular PRP injections, documenting posi- and content. To overcome these issues, further
tive results in terms of pain relief and functional double-blinded RCTs are needed, in which the
improvement up to 12 months following admin- preparation of PRP should be analyzed with
istration [23, 25–27]. Compared with placebo platelets and cells counting and standardized.
(normal saline injections) in patients with mild to The sample size needs to be adequate based on a
moderate knee osteoarthritis, PRP showed sig- priori sample size analysis. Patient compliance
nificant superiority in providing symptomatic and follow-up should be maintained at a high
relief [27, 28]. Furthermore, intra-articular PRP level for 12 months. Furthermore, it is essential to
injections provide superior outcomes compared establish strict inclusion and exclusion criteria
to hyaluronic acid and corticosteroids for symp- with highly specific indications and adhere to
tomatic management of knee OA, including pain specific reporting requirements.
relief, improving joint function and participation Several studies have consistently found that
in physical activities at 12 months follow-up [26, PRP injections showed better efficacy in younger
28–30]. Particularly, a recent meta-analysis per- patients with mild to moderate structural changes
formed on 34 RCTs reported that these benefits on plain radiographs (Kellgren-Lawrence grade
13 Platelet-Rich Plasma for Osteoarthritis 77

1, 2, and 3) than in older patients with severe alone [7] and PRP alone [45]. The potentially
knee OA (Kellgren-Lawrence grade 4) [13, 34– synergistic effects of PRP and HA may be con-
36]. In patients with moderate to severe knee OA sidered in the management of knee OA to maxi-
[37], PRP treatment did not present a statistically mize outcomes; however, whether combination
significant improvement in pain and function, therapy is cost-effective remains unclear [46].
although some authors suggested a possible ben-
eficial effect despite the lack of statistical differ-
ence [38, 39]. In recent years, the application of 13.3 Application Protocol
biological treatments, such as PRP injections, in
moderate knee OA has been reported to decrease Several factors in the PRP application process
the rate of cartilage loss and may contribute to and injection protocol may influence the out-
delay or avoid the need of total knee replacement come. The optimal number and interval between
[23, 35, 40]. One of the main advantages of PRP PRP injections have not been clearly defined yet.
therapy is that the procedure uses an autologous Several randomized controlled trials [47–49]
blood product with no known systemic side comparing single to multiple PRP injections have
effects but only local adverse effects, such as been reported. Moreover, a recent meta-analysis
bleeding, bruising, swelling, stiffness, and sore- concluded that within a 6-month interval, a single
ness [24, 34]. These symptoms, when present, are injection was as effective as multiple (n = 2 or 3)
transient and usually resolved within a few hours PRP injections in pain improvement; however,
to days without any specific treatment [34]. multiple injections (n = 3) were more effective
Interestingly, the incidence of adverse effects than a single injection in terms of knee function-
after intra-articular PRP injections has been asso- ality improvement [50]. Interval between injec-
ciated with the concentration of leukocytes, with tions vary among clinical trials between 1 week
the LR-PRP increasing the risk [24]. and 1 month [42, 47, 51–56]. However, the
As for the clinical superiority of LP-PRP ver- majority of studies have shown that protocols
sus LR-PRP, it remains controversial. The role of with more than one injection (up to three injec-
leukocytes has been a subject of debate because tions) are better than a single injection with the
of their positive as well as negative properties. In most common regimen being the application of
a meta-analysis by Riboh et al., LP-PRP showed three weekly PRP injections (1-week intervals)
significantly better WOMAC scores than did HA, [51–53, 57, 58].
but LR-PRP did not [41]. However, the latter Injection techniques are also very diverse.
study [41], a comparative clinical study [42] and Various approaches have been used including lat-
two recent meta-analyses [24, 43] found no sig- eral suprapatellar and lateral mid-patellar with
nificant difference in clinical outcomes when the patient supine or anterolateral and anterome-
LP-PRP was directly compared to LR-PRP. The dial with the patient seated. The skin is typically
LP-PRP has been suggested to be preferable to sterilely prepped with an alcohol or iodine-based
LR-PRP for the treatment of knee OA [43]; how- solution, and optionally a sterile drape is placed
ever, further comparative studies are necessary to over the prepped skin. The use of local anesthet-
confirm this. ics during PRP injections has been associated
Delivering PRP with hyaluronic acid has also with a possible detrimental effect on platelet
gained interest in recent years under the assump- aggregation [59]. However, it is unclear whether
tion that the combined application could provide a local subcutaneous injection of a local anes-
a synergistic effect resulting in inflammatory thetic without penetrating the capsule, as opposed
inhibition and inducing cartilage regeneration to an intra-articular injection, would have similar
through targeting both agents’ biological path- adverse effects on platelet function. A 21 to 23G
ways [44]. The relevant literature has shown needle is inserted into the joint under ultrasound
greater improvements in pain and function for the guidance or blindly with surface landmark tech-
combined injection compared with both HA nique. Aspiration of synovial fluid confirms
78 T. Totlis and A. V. Vasiliadis

proper needle placement and could relieve effu- could be considered a valid first-line injectable
sion when present. If an effusion is present, it is treatment option for nonoperative management
recommended to aspirate/evacuate it before of knee OA, mainly for KL grades 1–3.
injecting the PRP in order to avoid dilution of the
PRP.
Postinjection recommendations also vary. A
frequent approach includes: The patient is asked References
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 Platelet-Rich Plasma Treatment
for Meniscal Tears
14
Yosef Sourugeon, Yaniv Yonai, Yaron Berkovich,
and Lior Laver

14.1 The Anatomy of the Menisci of the genicular artery), while the remaining por-
tions receive nutrition via diffusion. As demon-
The menisci are semilunar, fibrocartilaginous strated by Arnoczky and Warren, only 10 to 25
structures that primarily seek to transform axial percent of the periphery of the meniscus is vascu-
loads from the femoral condyles more evenly larized in adults, which reduces with age [3].
along the tibial plateaus. They are also responsi- This lack of vascularity is the principal challenge
ble for lubrication, stress reduction, stabilization, in meniscal restoration.
and congruency in the knee joint [1, 2].
Traditionally, the meniscus is divided into three
zones based on its vascularization (from outside 14.2 Meniscal Injuries
to inside): (1) the red zone, (2) the red-white or and Rationale for Use of PRP
pink zone, and (3) the white zone. Only the lat-
eral and medial peripheral areas of the menisci Several inherent factors contribute to the unfa-
are supplied directly by blood vessels (branches vorable healing environment of a meniscus tear.
These include the avascular nature of the menis-
cus, the presence of synovial fluid and pro-­
inflammatory cytokines, and the repetitive load
subjected to the meniscus. Arnoczky and Warren
previously showed that only the peripheral
Y. Sourugeon
10–30% of the meniscus is vascularized [3].
Department of Orthopedic Surgery, Chaim Sheba
Medical Center, Rama Gan, Israel Moreover, the synovial fluid and presence of pro-­
inflammatory cytokines has been shown to have a
Y. Yonai · L. Laver (*)
Department of Orthopedic Surgery and Sports catabolic effect on meniscal healing [4].
Medicine Unit, Hillel Yaffe Medical Center (HYMC), The improved understanding of the role of the
Hadera, Israel meniscus in knee preservation in the last two
Rappaport Faculty of Medicine, Technion (Israel decades has brought much focus toward preserv-
Institute of Technology), Haifa, Israel ing and saving the meniscus, exploring various
Y. Berkovich methods to improve healing when meniscal inju-
Rappaport Faculty of Medicine, Technion (Israel ries occur. As a result, being one of the main
Institute of Technology), Haifa, Israel
directions explored for improved meniscal heal-
Department of Orthopedic Surgery, Hillel Yaffe ing, there has been growing interest in the role of
Medical Center (HYMC), Hadera, Israel
orthobiologics in the treatment of meniscal
e-mail: YARONB@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 81

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
82 Y. Sourugeon et al.

pathology. Techniques to improve meniscal heal- letes. Each patient received three sequential
ing based on enhancing one’s own biologic prop- injections with 7-day intervals. They reported six
erties have been explored in the past, such as patients (60%) showed clinical improvement and
meniscal trephination (to promote bleeding in the improved sports activity [9]. Delen et al. exam-
red zone of the meniscus) and microfractures to ined the clinical effect of PRP injections on
the notch area during arthroscopy. Several other symptomatic meniscal tears in 41 patients (12
modalities for biologic augmentation of meniscal males, 29 females; mean age 38.2 + 8.37 years;
repair include the use of a fibrin clot, cytokines range 21 to 50 years) with grade 2 or 3 meniscal
and growth factors, PRP, and cell-based thera- tears. Three PRP injections were administered
pies. Several animal studies have explored the (2.7 mL, 1.2–1.5 million platelets per mL) at
potential of PRP use for nonoperative manage- 1-week intervals, in a lateral patellofemoral
ment of meniscal tears. Xiao et al. reported that approach. Authors reported at posttreatment
the application of PRP alone or in combination weeks 1 and 4, both VAS and Lequesne Index
with BMSCs promoted the healing rate of menis- scores significantly decreased, suggesting that
cal white-white zone injury in a dog model [5]. PRP injections may improve short-term pain and
Shin et al. found no significant differences in disability in patients with meniscal tears [10].
meniscal healing between the LR-PRP group and In another small retrospective study with
controls when applied to horizontal medial 6 months follow-up, Guenoun et al. examined the
meniscus tears in a rabbit model [6]. In an in vitro effect of ultrasound-guided intra-meniscal PRP
and an in vivo study in a rabbit model, Ishida injection (4 mL, 1999 ± 616 million platelets, 2 ± 2
et al. demonstrated increased healing with menis- million leukocytes) in ten patients with degenera-
cal defect filling using a gelatin hydrogel delivery tive meniscal tears of the knee (grades 1–3), with-
system for PRP [7]. out knee osteoarthritis. They reported KOOS score
was significantly improved and that all patients that
were regularly practicing sports were able to return
14.3 PRP Use for Meniscal Tears: to competition or training activities, and VAS
Clinical Data wasn’t significantly improved; however, a decrease
from the baseline was described [11].
Treatment strategy for meniscal tears is dictated Another option for utilizing of PRP for menis-
by a plethora of variables including tear type and cal tears management is augmentation of menis-
pattern, zone involvement, age, tear location and cus repair. A randomized controlled trial
extent, time from injury (acute or chronic), previ- comparing PRP augmentation of repaired verti-
ous meniscus injuries, additional injuries (i.e., cal tears vs. isolated suture repair showed favor-
ligamentous, cartilage), and symptoms (i.e., exis- able results in the PRP-augmented group, with
tence of mechanical symptoms). While for many statistically significant functional outcome
years surgical management has been the center- improvement, lower failure rates, and better heal-
piece of treatment of meniscal tears, primarily ing on second look arthroscopy at 42 months
arthroscopic partial meniscectomy (APM) [8], post-surgery [12]. Another study by Everhart
the management goal has shifted in recent years et al. reported that PRP augmentation of isolated
toward preservation rather than resection of the meniscus repairs resulted in significantly
meniscus, and there is a growing interest in ortho- decreased failure rates at 3 years post-surgery
biologic treatments, including PRP. [13]. However, a number of smaller studies
Only a handful of studies examined PRP reported more variable results, with some show-
injections as a sole treatment for meniscal tears, ing modest benefits in functional outcomes, while
while the majority of studies focused on the use others finding no benefits when compared to pla-
of PRP as augmentation for meniscus repair. cebo [14–17]. While showing promising poten-
Blanke et al. used percutaneous PRP injections tial, it is still difficult to draw clear conclusion
under fluoroscopic guidance for intra-substance with regard to the full potential of PRP use for
meniscal tears (grade 2) in ten recreational ath- meniscal tears due to the relatively small number
14 Platelet-Rich Plasma Treatment for Meniscal Tears 83

of existing studies, especially high level ones, the 14.4 Conclusion

significant heterogeneity in PRP preparation
techniques used in the different studies, the PRP treatment for meniscal tears shows promis-
­injection timings, as well as the type of tear being ing results in promoting tissue repair and regen-
treated, and therefore future well-designed stud- eration, potentially reducing the need for invasive
ies are required to better understand the role of surgical procedures and fostering quicker recov-
PRP use in meniscal tears management. eries. The use of PRP, a concentrated solution of
autologous platelets and growth factors derived
from the patient’s blood, has emerged as a poten-
Tip Box 1 PRP Use for Meniscal Tears tial therapeutic option to enhance the healing
–– Can be considered for stable, non-­ process and improve clinical outcomes. The
displaced meniscal tears. potential of PRP use for the management of
–– Should not be used for displaced tears meniscal tears has been shown in several animal
(i.e., bucket-handle tears, flap tears, model studies as well as in several clinical studies
complete root tears), tears with mechan- exploring its use in nonoperative management of
ical symptoms. meniscal tears as well as for augmentation of
–– In acute tears extending to the periphery meniscus repairs. By promoting natural healing
or acute horizontal tears, intra-articular mechanisms, PRP treatment may offer a nonsur-
injections could be combined with intra-­ gical and minimally invasive alternative, and this
meniscal injections performed under can be particularly advantageous for patients who
ultrasound guidance from the periphery wish to avoid the risks and prolonged recovery
of the meniscus with multiple penetra- associated with surgery.
tions in various trajectories (an outside-
­in trephination) to stimulate the red-zone
and menisco-capsular area. References
–– In acute horizontal tears, PRP could be
1. Fox AJS, Bedi A, Rodeo SA. The basic science of
injected intra-meniscally in a gel form; human knee menisci: structure, composition, and
however, high volumes should be function. Sports Health. 2012;4(4):340–51.
avoided intra-meniscally to prevent 2. Patel H, Skalski MR, Patel DB, White EA, Tomasian
A, Gross JS, Vangsness CT, Matcuk GR. Illustrative
extending the tear.
review of knee meniscal tear patterns, repair and
replacement options, and imaging evaluation. Clin
Imaging. 2021;69:4–16.
3. Arnoczky SP, Warren RF. Microvasculature
of the human meniscus. Am J Sports Med.
Tip Box 2 PRP Use Following Meniscus 1982;10(2):90–5.
Repair 4. Taylor SA, Rodeo SA. Augmentation techniques for
isolated meniscal tears. Curr Rev Musculoskelet Med.
–– A PRP clot or PRP gel could be injected 2013;6(2):95–101.
into and around the repair site 5. Xiao W, Yang Y, Xie W, He M, Liu D, Cai Z, Yu D,
intraoperatively. Li Y, Wei L. Effects of platelet-rich plasma and bone
–– Intra-articular injection at the end of marrow mesenchymal stem cells on meniscal repair in
the White-White zone of the meniscus. Orthop Surg.
surgery is not ideal as there is often rem- 2021;13(8):2423–32.
nant fluid and bleeding which could 6. Shin KH, Lee H, Kang S, Ko YJ, Lee SY, Park JH,
dilute the PRP and affect its activity and Bae JH. Effect of leukocyte-rich and platelet-rich
effectiveness. plasma on healing of a horizontal medial meniscus
tear in a rabbit model. Biomed Res Int. 2015; https://
–– If considering PRP injections postoper- [Link]/10.1155/2015/179756.
atively following a repair, injections 7. Ishida K, Kuroda R, Miwa M, Tabata Y, Hokugo
should start at around 2 weeks post-­ A, Kawamoto T, Sasaki K, Doita M, Kurosaka
surgery when swelling has subsided. M. The regenerative effects of platelet-rich plasma
on meniscal cells in vitro and its in vivo application
84 Y. Sourugeon et al.

with biodegradable gelatin hydrogel. Tissue Eng. mented with platelet-rich plasma. Biomed Res Int.
2007;13(5):1103–12. 2018;2018:9315815.
8. Bhan K. Meniscal tears: current understanding, diag- 13. Everhart JS, Cavendish PA, Eikenberry A, Magnussen
nosis, and management. Cureus. 2020; [Link] RA, Kaeding CC, Flanigan DC. Platelet-rich plasma
org/10.7759/CUREUS.8590. reduces failure risk for isolated meniscal repairs but
9. Blanke F, Vavken P, Haenle M, von Wehren L, provides no benefit for meniscal repairs with anterior
Pagenstert G, Majewski M. Percutaneous injections cruciate ligament reconstruction. Am J Sports Med.
of platelet rich plasma for treatment of intrasubstance 2019;47(8):1789–96.
meniscal lesions. Muscles Ligaments Tendons J. 14. Dai W-L, Zhang H, Lin Z-M, Shi Z-J, Wang J. Efficacy
2015;5(3):162–6. of platelet-rich plasma in arthroscopic repair for dis-
10. Delen V, Ediz L, Alpaycı M. The clinical effect of coid lateral meniscus tears. BMC Musculoskelet
platelet-rich plasma injections on symptomatic menis- Disord. 2019;20:113.
cal tears of the knee. East J Med. 2021;26(3):367–70. 15. Griffin JW, Hadeed MM, Werner BC, Diduch DR,
11. Guenoun D, Magalon J, de Torquemada I, Vandeville Carson EW, Miller MD. Platelet-rich plasma in menis-
C, Sabatier F, Champsaur P, Jacquet C, Ollivier cal repair: does augmentation improve surgical out-
M. Treatment of degenerative meniscal tear with comes? Clin Orthop Relat Res. 2015;473(5):1665–72.
intrameniscal injection of platelets rich plasma. Diagn 16. Kemmochi M, Sasaki S, Takahashi M, Nishimura T,
Interv Imaging. 2020;101(3):169–76. Aizawa C, Kikuchi J. The use of platelet-rich fibrin
12. Kaminski R, Kulinski K, Kozar-Kaminska K, with platelet-rich plasma support meniscal repair sur-
Wielgus M, Langner M, Wasko MK, Kowalczewski J, gery. J Orthop. 2018;15(2):711–20.
Pomianowski S. A prospective, randomized, double-­ 17. Pujol N, Salle De Chou E, Boisrenoult P, Beaufils
blind, parallel-group, placebo-controlled study evalu- P. Platelet-rich plasma for open meniscal repair
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complete vertical meniscal tears (bucket handle) aug-
 PRP in Tendinopathy
15
Ferran Abat, Ignacio De Rus Aznar,
Federico Ibañez, and Charlotte Raflé

15.1 Introduction This chapter will examine platelet-rich plasma

(PRP) treatment in tendinopathies. It will also
Currently, the treatment of tendinopathies encom- explain how it is suggested to be combined with
passes various therapeutic options. However, other biological and mechanical therapies.
their standardized use as well as the way in which
they should be combined remains uncertain. It is
important to know the basic pathophysiology of 15.2 Fundamentals of PRP
tendinopathy in order to understand the overall in Tendinopathy
process of tendon degeneration and regeneration.
A comprehensive understanding of the tendon The term PRP refers to a preparation obtained by
would allow to apply the most appropriate ther- centrifuging peripheral blood in a small volume
apy and to know how to combine biological and of plasma where platelet concentration is
mechanical stimulation as both are of fundamen- increased over baseline [1]. The erythrocytes
tal importance in the quest for tendon present in these preparations must be discarded.
regeneration. However, the need to include leukocytes and
their quantity is currently being questioned [2].
The healing response triggered at the tendon
F. Abat (*) · F. Ibañez
level when it is injured consists of three well-­
Sports Orthopaedic Department, ReSport Clinic studied phases. The first is referred as an inflam-
Barcelona, Universitat Pompeu Fabra, Escola matory phase, followed by the proliferative and,
Superior de Ciències de la Salut TecnoCampus, Grup finally, a maturation phase [3]. During that first
de recerca GRACIS (GRC 01604), Barcelona, Spain
phase, platelets play a key role, since their
I. D. R. Aznar appearance and activation trigger a regulatory
Hospital Universitario de Torrejón: Torrejon de
Ardoz, Madrid, Spain
response of homeostasis, inflammation, neovas-
cularization, and tissue remodeling [4].
Hospital Olympia Quironsalud, Madrid, Spain
Specifically, to control homeostasis, various
C. Raflé growth factors capable of modulating the process
Investigation Department, ReSport Clinic Barcelona i
Mataró, Universitat Pompeu Fabra, Escola Superior
of tissue repair and remodeling are released. It
de Ciències de la Salut TecnoCampus, Grup de has been proven, via in vitro studies, that these
recerca GRACIS (GRC 01604), Barcelona, Spain factors increase their concentration in injured

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 85

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
86 F. Abat et al.

tendons when PRP is applied [5]. One of them is cation of LR-PRP not being recommended in
the transforming factor β (TGF-β1). It is present pathologies such as osteoarthritis [9].
in all stages of tendon healing and has mitogenic Finally, the monocytes, precursors of macro-
properties for fibroblasts and favors the produc- phages, can be classified into classically activated
tion of extracellular matrix. There is also the M1 (phenotype 1) and alternatively activated M2
group of growth factors derived from platelets (phenotype 2) in the microenvironment of a
(platelet-derived growth factors, PDGF) that are lesion. M1 have a pathogen-killing function
key in the activation and recruitment of macro- through the production of IFN-Ɣ and nitric oxide,
phages and fibroblasts as well as in the synthesis whereas M2 are capable of repairing damaged
of collagen [6]. It has been proven that the con- tissue and have anti-inflammatory properties.
centration of deposited platelets is relevant to They produce components of the extracellular
inducing the mechanisms they mediate [7]. matrix, interleukin 10 (IL-10), and angiogenic
Conversely, PRP concentrates are capable of factors. The presence of the two phenotypes
inducing the differentiation of tenocyte progeni- depends on the physiopathology of the environ-
tor cells into active tenocytes [4]. As seen in ani- ment, and the switching process from M1 to M2
mal studies, PRP seems to shorten the healing or vice versa (macrophage polarization) is
time of tendon, favors the organization of colla- affected by the type of PRP used [10]. It seems
gen fibers, and reduces proinflammatory macro- justifiable to try to get PRP concentrates able to
phages, which confirms the gene modulation polarize M1 toward M2.
observed in in vitro studies [8].

15.4 Leukocyte-Rich PRP

15.3 Role of Leukocytes and Leukocyte-Poor PRP
in the Treatment in Tendinopathy
of Tendinopathies with PRP
There are numerous works in the literature that
The leukocytes present in PRP may have a proin- show variable efficacy when using PRP in the
flammatory, immunomodulatory, and nociceptive treatment of tendinopathy [11–13]. However, it is
effect, eventually contributing to tissue repair and difficult to find studies that specifically compare
remodeling [1]. The optimal concentration of the two treatment modalities: leukocyte-rich PRP
leukocytes in PRP preparation is currently a con- (LR-PRP) and leukocyte-poor PRP (LP-PRP).
troversial issue [2]. The leukocyte population A recent meta-analysis [14] presents the avail-
contains lymphocytes, neutrophils, and mono- able in vitro studies related to the application of
cytes. In leukocyte-rich PRP (LR-PRP), the pre- leukocyte-rich PRP (LR-PRP) in tendinopathy.
dominant population is lymphocytes. They There are two works [15, 16] that analyze the
produce two types of cytokines, interferon results of samples of the supraspinatus tendon of
gamma (IFN-Ɣ) and interleukin 4 (IL-4), both the shoulder. Rubio-Azpeitia et al. [16] describe
involved in the noninflammatory cellular an increase in cell migration and proliferation, a
response through the modulation of regulation of the genes associated with the
macrophages. remodeling of the extracellular matrix, as well as
Neutrophils are also well represented in a an increase in inflammatory proteins when com-
mixed leukocytes population. The need for their pared to the control group at 96 h. Cross et al.
presence in PRP concentrates is controversial. [15] report an increase in the expression of cata-
Although they have been shown to play a role in bolic genes and remodeling of the extracellular
angiogenesis and tissue regeneration, which matrix (COL1:COL3 ratio), the latter data differ-
could play a key role in the management of tendi- ing from those presented by Rubio-Azpeitia [16].
nopathy, it has been reported that they trigger an When specifically comparing LR-PRP to
inflammatory reaction that have led to the appli- LP-PRP, it can be seen that the release of growth
15 PRP in Tendinopathy 87

factors, the proliferation of the tenocytes, and/or growth factors to the wounded region, PRP can
the gene expression of genes related to the teno- improve the healing process in this situation [4,
cytes are quantitatively greater in the former [17]. 5, 8].
In clinical studies, the injection of LR-PRP at the However, the inflammatory response may not
level of the lesion in gluteus medius tendinopathy occur or may not be sufficiently potent in chronic
significantly improves pain and function com- tendon disorders [22, 23]. The essential signaling
pared to corticosteroid injection at the 2-year and cellular responses that PRP depends on to
follow-up [18]. However, when this data is promote tissue regeneration may be slowed down
looked at closely, the confidence intervals of the in the absence of inflammation. The recruitment
scores obtained in both groups show that the clin- of platelets, growth factors, and immune cells to
ical differences might not be so relevant even the affected region may be reduced as a result of
though significant. Conversely, in a randomized the decreased inflammatory environment in
multicenter trial focusing on patellar tendinopa- chronic tendon disorders.
thy [19], no differences were found in the scores To solve this problem, scientists have investi-
on the functional or pain scales with different gated several methods to trigger or intensify the
treatment groups (LR-PRP, LP-PRP, or saline inflammatory response in chronic tendinopathy
solution associated with an exercise program) at [24]. The ultrasound-guided galvanic electrolysis
1-year follow-up. technique (USGET), which applies galvanic cur-
Finally, a systematic review compares the rent to the afflicted tendon, is one that promotes
effectiveness of both types of preparations in lat- this inflammation activation. This infiltrative act
eral elbow tendinopathy [20]. Although patients induces a regulated localized inflammatory
see improvement in terms of pain and functional response that encourages the recruitment of
results with PRP treatment, no differences were platelets and growth factors and speeds up tissue
found between the two preparations, even though repair [25, 26].
an increase in the rate of complications in During USGET, a small needle electrode is
LR-PRP was notable [21]. inserted into the affected tendon under ultrasound
guidance. A localized chemical reaction occurs
within the tissue once a galvanic current is intro-
15.5 Importance of the Activation duced after the electrode is suitably positioned.
of the Inflammatory Process As a result of this reaction, certain elements are
in the Use of PRP produced, including hydrogen and hydroxide
ions, which support localized inflammation in the
The interaction between PRP and the inflamma- treated region [25].
tory milieu is thought to be essential to the thera- It is thought that the regulated inflammatory
peutic efficacy of PRP-based treatment options. response brought on by electrolysis procedures
It has been determined that PRP administration has several beneficial effects on tendon recovery
in the absence of an active inflammatory reaction [26]. It can encourage angiogenesis (formation of
may additionally yield suboptimal results. new blood vessels) and the production of growth
Conversely, the presence of an active inflamma- factors, which are essential for tissue regenera-
tory process at the time of PRP application has tion. The inflammatory reaction can also encour-
been associated with better tissue healing and age the recruitment of cells necessary for the
regenerative responses [1, 2]. healing process and aid in the breakdown of scar
The body’s natural response to an acute injury tissue [26]. The extracellular matrix (ECM) of
is to start an inflammatory process. The removal connective tissue at the tendon level supports
of injured tissue, the prevention of infection, and most of the physical loads of the body. Those
the beginning of the healing process are all made ECM, like collagen, fibronectin, and proteogly-
easier via acute inflammation. By directly pro- cans, are produced by tenocytes to maintain ten-
viding a significant concentration of platelets and don homeostasis and repair injured tendons [27].
88 F. Abat et al.

The mechanical stimulus of exercise on the ditions, including tendinopathy (Fig. 15.1). Basic
tendons can be translated into chemical signals, science studies have repeatedly demonstrated a
triggering multiple cellular responses [28]. positive effect of PRP on tendon cell prolifera-
McBeath et al. showed that mechanical stimula- tion, increase of expression of anabolic genes and
tion, in combination with specific growth factors, proteins, and reduction of tendon inflammation.
can act as a switch that controls the differentia- Nevertheless, the literature shows controver-
tion of mesenchymal stem cells [29]. Zhang et al. sial results, with some RCTs showing very good
[30] discovered that mice subjected to intensive outcomes whereas other poor or no results. This
use of a wheel in their cage had a greater number conflicting evidence is due to differences in
of myofibroblasts in the patellar tendons than the terms of PRP type, protocol of applications and
control group without this stimulus. indications, as well as flaws in study methodol-
Myofibroblasts are activated fibroblasts and are ogy. A relevant factor affecting study result is
involved in the repair and remodeling of injured PRP composition. LR- and LP-PRP are often
tissues [31]. Therefore, applying moderate ten- considered as the same products, although the
sion to the tendons is beneficial to their healing. basic science studies show consistent differences
among them. Often the same PRP type is admin-
istered to patients regardless of age, gender, dis-
15.6 Conclusion ease history, and others, and this may result in
conflicting or unclear results. In some cases, ten-
Tendinopathy is a highly prevalent tendon disor- dinopathy would require a more personalized
der affecting a wide range of individuals, regard- approach. In example, the combination of PRP
less of age and activity level, with a consistent and electrolysis may offer a synergistic strategy
socioeconomic impact. Although the mecha- that makes use of the positive effect of inflam-
nisms of tendinopathy are not completely under- mation to promote tendon regeneration and
stood, in the last years, it has emerged a clear role recovery.
of inflammation. PRP is a popular autologous Currently available evidence is still insuffi-
therapy used worldwide to treat a variety of con- cient to indicate PRP as a totally effective treat-

a b

Fig. 15.1 Ultrasound-guided injection of L-PRP in the in the ultrasound images in longitudinal view (b, c) how
patellar tendon. (a) Infiltration was made in the long axis the PRP penetrate the tissue in the injured area
with a linear probe in the zone of tendon injury. Observe
15 PRP in Tendinopathy 89

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H, GRIP (Groupe de Recherche sur les Injections
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 Platelet-Rich Plasma (PRP)
for Rotator Cuff Tears
16
Ron Gilat, Ilan Y. Mitchnik, Derrick Knapik,
Grant Garrigues, Nikhil Verma, and Brian J. Cole

16.1 Introduction when evaluating patient symptoms, examination

findings, imaging, results, and patient expecta-
The rotator cuff is composed of four tendons and tions. Nonoperative treatments include physio-
muscles that surround the shoulder joint and aid therapy, nonsteroidal anti-inflammatory drugs
in glenohumeral joint mobility and stability. (NSAIDs), and/or injections [3, 4]. When indi-
Rotator cuff injuries are a common cause of sig- cated, potential operative interventions include
nificant shoulder pain and functional limitations rotator cuff repair, superior capsular reconstruc-
[1], leading to muscle atrophy, fatty infiltration, tion, reverse total shoulder arthroplasty, tendon
and degenerative changes if not properly diag- transfers, debridement, and subacromial decom-
nosed and managed [2]. Rotator cuff injuries are pression [1]. Recent investigations have sug-
classified based on acuity (acute versus chronic), gested that operative management may not be
severity (partial versus full-thickness), location superior to conservative treatment when examin-
(bursal-sided versus articular-sided), the extent ing outcomes based on strength, range of motion,
of tendon retraction or muscle atrophy, as well as functional outcomes, and recurrent tear rates [2,
tear size. These factors may reflect the extent of 3, 5]. This controversy has sparked a growing
damage, which dictate appropriate treatment interest in the use of orthobiologics, namely,
platelet-rich plasma (PRP), as a biologic augment
R. Gilat (*) for the treatment of rotator cuff injuries, espe-
Midwest Orthopaedics at Rush University Medical cially for patients with smaller tears [4, 6–8].
Center, Chicago, IL, USA The purpose of this chapter is to provide a
Department of Orthopaedic Surgery, Shamir Medical comprehensive overview evaluating the use of
Center and Tel Aviv University, Tel Aviv, Israel PRP injections for the treatment of rotator cuff
I. Y. Mitchnik injuries. By helping promote healing and reduc-
Department of Orthopaedic Surgery, Shamir Medical ing inflammation, the use of PRP is theorized to
Center and Tel Aviv University, Tel Aviv, Israel
stimulate the growth of new tissue, offering a
D. Knapik viable alternative to operative intervention in
Department of Orthopaedic Surgery, Washington
University Sports Medicine, St. Louis, MO, USA select cases. However, the effectiveness of PRP
injections in the treatment of patients with rotator
G. Garrigues · N. Verma · B. J. Cole
Midwest Orthopaedics at Rush University Medical cuff injuries is still a subject of ongoing research
Center, Chicago, IL, USA and debate in the medical community.
e-mail: [Link]@[Link];
[Link]@[Link];
[Link]@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 91

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
92 R. Gilat et al.

16.2 Healing Rotator Cuff Injuries as a result of the presence of platelet-derived

with PRP Therapy growth factor (PDGF) and vascular endothelial
growth factor (VEGF) [4]. PDGF supports the
Following injury, the rotator cuff tendons possess proliferation of fibroblasts and matrix deposition
a minimal degree of intrinsic healing, undergoing while also modulating the proliferation of vascu-
a three-phase healing process that includes lar smooth muscle [10, 11]. This phase also
inflammation, proliferation, and remodeling [4, includes upregulation of the receptor for the
8] (Fig. 16.1). During the inflammatory phase, angiogenic VEGF [10, 13]. Finally, the remodel-
lasting around a week, vascular permeability ing phase, which may last several months or
increases, and immune cells enter the healing years, involves the continuous reshaping of the
site. This triggers the production of growth and regenerated tissue under the influence of external
cellular factors such as insulin-like growth factor forces. Unfortunately, when the rotator cuff tear
1 (IGF-1), which promotes the accumulation of retracts more than a few millimeters, this process
macrophages and the proliferation of tenocytes is not enough to bridge the tear gap, and conse-
[9, 10]. In addition, inflammatory expression of quentially structural healing tends not to occur.
tissue growth factor beta (TGF-B) promotes PRP consists of autologous blood, centrifuged
fibrosis and scar formation by increasing type I to create a supraphysiologic concentration of
and III collagen [10, 11]. This scar tissue is platelets containing various cytokines and che-
important for the healing of tendon to bone at the mokines, including IGF-1, TGF-B, VEGF, and
enthesis where the tendons contact with the PDGF, the growth factors involved in the three
greater tuberosity [12]. The proliferative phase healing phases of rotator cuff injuries [4, 14]. The
then lasts several weeks, during which an increase procedure involves the extraction of peripheral
in myofibroblasts and regenerative tissues occurs blood from the patient, which is then processed

Fig. 16.1 Three-phase healing of rotator cuff tendons. IGF-1 insulin-like growth factor 1, TGF-B tissue growth factor
beta, VEGF vascular endothelial growth factor; PDGF platelet-derived growth factor, PRP platelet-rich plasma
16 Platelet-Rich Plasma (PRP) for Rotator Cuff Tears 93

via centrifugation to separate the platelets [8]. functionality compared to standard corticosteroid
PRP can be applied in either a gel or liquid form. injections [23–26].
The gel state of PRP allows for it to be secured in
a specific area of injury along the rotator cuff,
believed to result in an extended effect period [4]. 16.3.1 PRP Injections as Isolated
When PRP is applied to injured areas, it is Treatment for Rotator Cuff
believed to have both anabolic and anti-­ Tears
inflammatory effects. Specifically, the high con-
centration of IGF-1 in PRP stimulates cell In cases with rotator cuff tendinitis, subacromial
proliferation and matrix synthesis, while TGF-B impingement, and partial rotator cuff tears,
increases collagen production improving tissue patients are generally initially treated with a trial
strength; additionally, VEGF and PDGF promote of nonoperative management, which may include
angiogenesis, additional cell proliferation, and the use of PRP. However, the benefits of PRP
matrix synthesis. injections for shoulder injuries have been a sub-
Using a rabbit model, Chung et al. have shown ject of debate. PRP injections may be performed
that the use of PRP for rotator cuff repairs with intervals reported from 1 week to 1 month,
enhanced the tendon to bone healing [15]. At the consisting of two to four consecutive injections
4-week mark, vascularity and cellularity were [19, 20, 24]. PRP may be injected into the sub-
increased in PRP-treated rabbits. After 8 weeks, acromial space, or intralesionally into injured
collagen fibers were more regularly arranged and tendons [19, 20, 24]. When compared to modali-
continuous with PRP treatment. In a murine ties such as physiotherapy or corticosteroid injec-
model, Peng et al. have also shown that PRP tions, the use of PRP has been reported to be
improved tendon-­to-­bone healing [16]. After 4 associated with a potentially more steady and
and 8 weeks, PRP was associated with a larger sustained response. Lin et al. and Feltri et al.
fibrocartilaginous layer and increased subchon- reported no added benefit in shoulder pain or
dral bone trabeculae number and thickness. function up to 3 months following PRP injection
Using a rat model, Beck et al. also showed [19, 27]. Meanwhile, additional studies have
increased vascularity and fibroblast proliferation reported worse functional results on 3-month
[17]. Furthermore, collagen fibers were oriented follow-ups [23–25]. However, Jiang et al.
more linearly toward the tendon-to-bone inter- observed that after 3 months, PRP injections
face. These studies have all shown increased bio- resulted in improved functional outcomes [24–
mechanical strength for rotator cuffs repaired 26]. Adra et al., Jiang et al., and Lin et al. also
with PRP addition. reported PRP injections to be associated with less
shoulder pain after 6 months [19, 24, 26]. While
PRP injections may be considered safe based on
16.3 The Effectiveness of PRP the low rate of reported adverse events [20], they
for Rotator Cuff Tears have also been reported to be associated with
fewer repeat shoulder interventions [25].
Multiple meta-analyses have demonstrated that
intraoperative PRP application may significantly
reduce pain levels, although measured functional 16.3.2 PRP as an Adjunct to Rotator
outcome improvements have generally failed to Cuff Repairs
demonstrate the achievement of minimal clini-
cally important differences (MCID) [18–22]. As Large and massive rotator cuff tears have a high
an intermediate treatment option between nonop- retear rate of up to 94% [28]. PRP has been uti-
erative and operative management, PRP injec- lized in an attempt to augment the healing biol-
tions have shown promising results in improving ogy with intraoperative PRP application during
94 R. Gilat et al.

rotator cuff repair. PRP use as an adjuvant during et al. and Malavolta et al. have shown that PRP
surgery has been described as being applied gel and liquid, respectively, conserve the struc-
either as a gel over the site of injury or injected as tural integrity of the rotator cuff on follow-ups
a liquid [18, 29]. Intraoperative application of [37, 38].
PRP demonstrates several early ­clinical benefits.
At 3- to 6-month follow-up, Chen et al., Xu et al.,
and Yang et al. reported the incorporation of PRP 16.4 Discussion
to be associated with less shoulder pain and bet-
ter functional outcomes [18, 21, 22]. At longer Despite increasing interest in the use of PRP as
follow-ups, PRP augmentation has shown contin- an isolated and adjunct treatment for patients
ued improvement in functional outcomes [18, with rotator cuff tears, additional investigations
21]. Importantly, Xu et al. reported that the addi- are warranted to better understand the indica-
tion of PRP was not associated with an increase tions, outcomes, ideal method, and timing of
in adverse events [21]. application, as well as the potential risks associ-
ated with PRP use (Table 16.1). Namely, there
remains a lack of standardization in the prepara-
16.3.3 Effects on the Rotator Cuff’s tion of PRP, with multiple systematic reviews
Structural Integrity discussing various methods with varying centrif-
ugation protocols and the use of activating agents.
Most structural failures of the rotator cuff occur As such, PRP preparation likely consists of dif-
at the tendon-bone interface, and application of fering platelet concentrations, leukocyte compo-
PRP to this site may be more beneficial [30]. sitions, and fibrin networks, introducing a
Although structural failure may bring temporary substantial degree of heterogeneity in the final
pain relief, structural integrity is important to PRP product utilized between studies [39–43].
preserve muscle mass and shoulder function [31]. Furthermore, the addition of local anesthetic
Thus, assessing short-term pain level outcomes is injections at the site of injury may reduce the
often not enough. It is also important to remem- effects of PRP, with some studies suggesting that
ber that while most full-thickness tears are likely the function of platelet function in PRP com-
to progress over time, partial-thickness tears tend pounds being compromised secondary to changes
to remain unchanged [32, 33]. Unfortunately, not in the local pH levels which is decreased by the
all the meta-analysis described thus far have con- anesthetic [44, 45]. The clinical benefit of PRP is
trolled for these two factors. Despite these limita- typically observed when the platelet concentra-
tions, a large body of evidence exists to support tion is two to eight times greater than that found
that PRP use is associated with less retear rates in native blood [20]. PRP can be prepared as leu-
[18, 21, 22, 27, 29]. However, it is important to kocyte-poor (LP) or leukocyte-rich (LR), depend-
note that Vavken et al. have suggested that this ing on the concentration of leukocytes present
may not be a cost-effective indication for the use [42, 43, 46]. The presence of leukocytes in PRP
of intraoperative PRP [34]. Carr et al. were the can prompt fibroblasts to release matrix metallo-
first to show that PRP injections alter the rotator proteinases (MMP) [47, 48]. Thus, LR-PRP may
cuffs tendon cellular tissue in such a way that have tissue-degrading effects on the recovering
may increase retear rates due to reduced vascu- rotator cuff [4, 49]. Indeed, Cross et al. demon-
larity and increased apoptosis [35]. However, this strated that LR-PRP is associated with an
may be attributed to the use of a leukocyte-rich increased expression of tissue-degrading MMP-9
PRP preparation. Pandey et al. have shown [50]. Furthermore, several meta-­ analyses have
increased vascularity at PRP injection sites up to shown that LP-PRP lowers retear rates following
1 year and decreased retear rates, as assessed by tendon repair [51–54]. LP-PRP has also been
ultrasound (US), for large tears [36]. Using mag- reported to improve postoperative pain and func-
netic resonance imaging (MRI), both Dukan tional outcomes [51, 52]. However, the reported
16 Platelet-Rich Plasma (PRP) for Rotator Cuff Tears 95

Table 16.1 Effectiveness of PRP injections for rotator cuff injuries

Treatment type Pain Function Retear Adverse effects
Intraoperative PRP Early pain reduction Early general May reduce No difference from
augmentation that may not be improvement that may not retear rates standard operative
clinically important be clinically important treatment
PRP as an alternative Promising results, Early benefits may be Unknown Fewer adverse effects
to other conservative improvement may be less significant compared than corticosteroid
treatment more gradual and to corticosteroid injections
sustained injections
LP-PRP compared to Better short-term Better short-term Reduced LR-PRP may have
LR-PRP reduction in improvement in retear rates tissue-degrading effects
postoperative pain functional scores on the recovering rotator
cuff
PRP platelet-rich plasma, LP leukocyte poor, LR leukocyte rich

effects of LP-PRP are mostly limited to studies to enhance tendon healing and recovery. However,
with short-term follow-up [53], where modest the effectiveness of PRP injections in treating
improvement has not surpassed the MCID thresh- rotator cuff injuries remains a subject of debate
old [54]. The current lack of consensus on the due to the high heterogeneity in PRP preparation
optimal preparation and dosing of PRP for treat- methods and variable outcomes in clinical stud-
ing rotator cuff tears represents a substantial limi- ies, warranting further investigations.
tation impacting the validity of the currently
reported evidence [18, 43, 55, 56]. Larger, well-­
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 Platelet-Rich Plasma Treatment
for Muscle Injuries
17
Yosef Sourugeon, Yaniv Yonai, Yaron Berkovich,
and Lior Laver

17.1 Introduction imaging parameters [4]. Conservative/nonsur-

gical management has been the mainstay of
Muscle injuries (MI) are common, especially in treatment for most muscle injuries and usually
sports. For instance, MIs represent more than consists of protection, rest, ice, compression,
30% of all injuries in professional soccer and and elevation (PRICE protocol); physiotherapy;
more than 20% in basketball [1, 2]. Muscle NSAIDs; and time.
injuries in the athlete can be classified into Traditionally, NSAIDs treatment was avoided
intrinsic and extrinsic injuries with intrinsic in the acute phase of injury due to fear of pro-
muscle injuries occurring most commonly at longed recovery; however, recent works suggest
the myotendinous junction during eccentric the NSAIDs may be beneficial in reducing
contraction with various degrees of tearing of strength loss, soreness, and blood creatine kinase
the muscle fibers, while extrinsic muscle inju- levels [5]. Despite the excellent results with non-
ries in the athlete occur most commonly as a surgical treatment, such treatment failure may be
result of a direct trauma such as a contusion devastating for the injured athlete, leading to
injury [3]. These injuries are graded using clini- reinjury and postponing the return to physical
cal, sonographic, and magnetic resonance activity for weeks and even many months in some
parameters or a combination of clinical and instances [6, 7].
New treatment modalities have been explored
and introduced into this field with the aim to pro-
Y. Sourugeon
mote early return to play, decrease recurrence
Department of Orthopedic Surgery, Chaim Sheba
Medical Center, Rama Gan, Israel rates, and minimize fibrosis and subsequent mus-
cle weakness. Such new treatment modalities
Y. Yonai · L. Laver (*)
Department of Orthopedic Surgery and Sports which have been introduced in recent years in the
Medicine Unit, Hillel Yaffe Medical Center (HYMC), treatment of muscle injuries are orthobiologic
Hadera, Israel therapies such as PRP and cell-based therapies
Rappaport Faculty of Medicine, Technion (Israel (bone marrow based or adipose tissue based) [3,
Institute of Technology), Haifa, Israel 8, 9]. This chapter will focus on the use of PRP
Y. Berkovich for muscle injuries.
Rappaport Faculty of Medicine, Technion (Israel
Institute of Technology), Haifa, Israel
Department of Orthopedic Surgery, Hillel Yaffe
Medical Center (HYMC), Hadera, Israel
e-mail: YARONB@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 99

B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
100 Y. Sourugeon et al.

17.2 Muscle Healing tion, along with decreased fibrosis in the experi-
Pathophysiology mental group [15]. In an in vitro study, Li et al.
and Rationale for Using PRP have shown that PRP use can lead to myoblast pro-
liferation, but not to myoblast differentiation,
Skeletal muscle is a well-organized tissue, com- which is important in producing muscle tissue [16].
posed of cylindrical syncytial cells that are cov- Dimauro et al. have examined the effect of PRP
ered by an endomysium tissue which constitutes injection on the early phases of muscle regeneration
the single muscle fiber. Parallel muscle fibers are in rats. They have found that PRP injection enhanced
then bundled into groups (fascicles) that are the number of myogenic precursor cells and their
­surrounded by perimysium. These fascicles are proliferation rate. On the other hand, PRP adminis-
further grouped up, and finally they are enclosed tration raised the number of catabolic cytokines and
in another connective tissue layer, the epimy- pro-fibrotic growth factors such as TGF-β1 and
sium. Satellite cells function as adult muscle myostatin that may induce fibrotic healing instead
stem cells that lie in opposition to the muscle of muscular regeneration [17]. Enhanced catabo-
fibers. These cells have a limited ability to dif- lism and pro-­fibrotic recovery of muscle tissue may
ferentiate into myoblasts; thus, the muscle fibers affect recovery and performance and increase the
have a limited ability to regenerate [10]. risk of injury recurrence. This double-edged sword
Muscle healing follows a consistent path, nature of PRP treatment in muscle injuries must be
regardless of the injury category. This path con- taken into consideration when choosing which PRP
sists of three phases, with an overlap between the to use for muscle injuries or even which fraction to
end of the previous phase and the start of the fol- use (i.e., a solution with relatively low levels of
lowing phase: (1) destruction of myofibrils, for- TGF-β1). In addition, the timing of injection should
mation of hematoma, and proliferation of also be taken into consideration—with the initial
inflammatory cells; (2) phagocytosis of necrotic local tissue damage still forming even in the first
tissue upon arrival of platelets, formation of scar 24–48 h from injury with local bleeding/hematoma
tissue, blood vessels, and neural growth; and (3) formation still taking place; it is recommended that
remodeling of scar tissue and myofibrils [6, 11]. the administration of PRP should therefore be
Muscle tissue regeneration is mainly limited avoided in the first 24 and even 48 h post injury.
by scar tissue formation rather than by muscle Current understanding of PRP biology and the
regeneration rate [12, 13]. Therefore, the ratio- exact role of growth factors (GFs) in the setting of
nale and potential benefit of PRP use for muscle muscle injuries is limited, especially due to the
injuries are not only aimed at early return to fact that the healing process requires a degree of
sports but also improved tissue healing with inflammation to progress. GFs and cytokines
improved structural properties, thus potentially influence chemotaxis and proliferation, and artifi-
reducing the risk of recurrence. However, most cially adding those factors may greatly impact the
clinical studies have only focused on return to healing process in an unexpected manner. The
sports rates and durations rather than assessing exact composition, concentration, and timing of
the healed tissue quality as well. Hence, using the PRP application in MIs are subject to further
PRP in the treatment of muscle injuries allows a in vivo research, but a new and more targeted strat-
simple, easily accessible, nonsurgical method to egy is being developed for PRP application in MIs.
introduce an abundance of naturally occurring A recent work by Tsani et al. from 2021 has
growth factors to the site of injury, in order to examined the effect of a combined treatment of
enhance the natural healing process as well as PRP and Suramin (an antifibrotic agent, a TGF-β
improve the healing properties of the tissue [14]. inhibitor) on MI model of rats and compared it
In a preclinical study assessing muscle healing with a PRP monotherapy. They have found that
of contusion-injured tibialis anterior muscle in Suramin successfully reduced fibronectin expres-
mice with combined treatment of an oral antifi- sion, without significant differences between the
brotic agent (Losartan) and PRP, Terada et al. groups in muscle histological of myofibril evalu-
reported increased muscle regeneration and func- ation and injured muscle strength. However, both
17 Platelet-Rich Plasma Treatment for Muscle Injuries 101

groups had significantly better results than the double-­ blind, placebo-controlled, randomized
untreated group, and the combination therapy study on 80 professional and recreational athletes
group had the best overall results [18]. with acute hamstrings injuries treated with two
This study joins previous studies from 2016 intramuscular injections of PRP or isotonic saline,
by Li et al. and from 2013 by Satoshi et al., exam- Reurink et al. reported no benefit for PRP injec-
ining the effect of combined PRP and antifibrotic tions [26].
agents that block TGF-β, on MI models (rats and In a systematic review from 2018, Grassi et al.
mice, respectively). Both of these studies have examined six randomized controlled trial studies
found that the combined therapy group had sig- (RCTs) that included mostly professional athletes
nificantly less fibrosis when compared to the PRP that suffered injuries to different locations (ham-
monotherapy group, without significant histolog- strings, rectus femoris, quadriceps, gastrocnemius,
ical results regarding myofibril regeneration. Li thigh, foot and ankle, and shoulder), reporting sta-
et al. have also found that there were more satel- tistically significant shorter time to return to sports
lite cells and higher infiltration of M2 macro- in the PRP-treated groups. However, they high-
phages, contributing to the overall better efficacy lighted the fact that not all RCTs were of the high-
of the augmented PRP treatment [15, 19]. est quality and also the large variability and
heterogeneity in the various regarding injury type
and PRP preparation method [27].
17.3 Platelet-Rich Plasma It is also important that it is quite challenging
for Muscle Injuries: Clinical to perform high-level studies in professional ath-
Experience letes due to their limited availability for continu-
ous repeated assessments. Another important
Several studies have reported positive outcomes issue is that while it is not easy to cite statistical
with the use of PRP for the treatment of muscle significance in shorter return to sport timings,
strains. Sanchez et al. analyzed the use of PRP in even 2–3 days would make a difference in com-
different grades of muscle injuries in 21 professional petitive athletes who often compete two to three
soccer players, reporting the PRP group required times a week, which means that even 2–3 days
half the time to resume normal training activities could make the difference of playing or missing
compared to matched historical controls [8]. Rossi the next competition/match.
et al. performed a randomized controlled trial com-
paring a rehabilitation program plus a PRP injection
vs. a rehabilitation program alone for muscle injury 17.4 Tips for PRP Use for Muscle
(hamstrings, quadriceps, and gastrocnemius), report- Injuries
ing significantly earlier full recovery and signifi-
cantly lower pain scores in the PRP group [20]. When considering the use of PRP for muscle
Hamstrings injuries are one of the most com- injuries, the extent of muscle injury should be
mon injuries in athletes, usually resulting in a pro- taken into consideration, especially in cases
longed rest period and delayed return to sport even where true and significant muscle fiber disruption
in mild injuries. In a randomized controlled trial of is confirmed with imaging studies. If a hematoma
28 patients comparing PRP with a rehabilitation or a seroma is present, it is recommended to evac-
program for hamstrings injury vs. a rehabilitation uate it under ultrasound guidance to decompress
program alone, Hamid et al. reported a signifi- the area of injury and approximate the injured
cantly shorter time to return to play in the PRP muscle fibers; once the hematoma is evacuated, a
group (26.7 days) when compared to the rehabili- platelet poor fraction (i.e., fraction F1 in PRGF)
tation alone group (42.5 days) [21]. In another pro- could be injected into the injury site and adjacent
spective study, Bezuglov et al. reported similar peripheral healthy muscle (Fig. 17.1). The rec-
results in 40 soccer players [22]. However, several ommendation is to use either a PRP product with
other studies have shown contradictory results for low levels of TGFβ-1 or to use the platelet-poor
PRP use for acute hamstrings tears [23–25]. In a fraction, since it has a reduced concentration of
102 Y. Sourugeon et al.

a d

b c

Fig. 17.1 (a) Ultrasound image of an extensive soleus plasma (PRGF F1 fraction, Endoret® System, Spain)
muscle injury and the area of surrounding hematoma intramuscular injection using a 10 cc syringe; (d) PRGF
(arrow; black area inside the muscle); (b) hematoma evac- fractions distribution following centrifugation
uation using a 10-cc syringe; (c) injection of platelet poor

the pro-fibrotic factor TGFβ-1, unlike the platelet-­

rich fraction, which is adjacent to the buffy coat Tip
layer or leukocytes sediment; repeated ultrasound –– When injecting PRP for acute muscle
(US) or MRI imaging can be used to follow heal- injury, it is preferable to wait 3–4 days
ing progression and assess for fibrosis levels after the injury and not inject immedi-
which may predispose to reinjury. Repeated ately after the injury.
injections may be applied (often considered in –– If a hematoma or seroma is present, it is
higher grades of injury) at a minimum of 1-week recommended to evacuate/aspirate the
intervals, and decision should be based on injury hematoma/seroma under US guidance
grade, US imaging (to assess muscle tissue dam- prior to PRP injection.
age and healing progression), and symptoms. –– It is recommended to use either a PRP
product with low levels of TGFβ-1 or to
use the platelet-poor fraction, since it
17.5 Conclusion has a reduced concentration of the pro-­
fibrotic factor TGFβ-1.
Despite promising biological reasoning, positive –– Repeated injections are usually consid-
preclinical findings, and early clinical success, ered in higher injury grades and should
the efficacy of PRP for the management of mus- be performed at a minimum of 1-week
cle injuries has not been strongly established as intervals, and decision should be based
of yet. Further higher quality studies are neces- on injury grade, US imaging (to assess
sary to properly explore the full potential of PRP muscle tissue damage and healing pro-
for this indication. gression), and symptoms.
17 Platelet-Rich Plasma Treatment for Muscle Injuries 103

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 Bone Marrow Aspirate
Concentrates for Knee OA
18
Peter A. Everts, Ignacio Dallo, José Fábio Lana,
and Luga Podesta

18.1 Introduction with knee OA. This procedure can be safely per-
formed by well-trained physicians at POC. The
Orthobiology and regenerative medicine, nonsur- reader should be familiar with their national reg-
gical interventional procedures, involve the use ulatory requirements to utilize BMAC, which is
of autologous-prepared biologics to stimulate the beyond the scope of this chapter.
body’s natural healing processes. These biologics
act as a scaffold for tissue repair, immunomodu-
lation, painkilling, and tissue regeneration. The 18.1.1 Safety and Contraindications
most well-known orthobiological treatment prod-
ucts include platelet-rich plasma (PRP), BMAC, Before performing a BMA procedure, patients
and adipose tissue (AT) preparations. In this should be well informed about the procedure, and
chapter we will focus on how to perform a bone it is essential to obtain an informed written con-
marrow aspiration procedure to extract BMA to sent. Patients need to be informed about potential
prepare a BMAC product for injection in patients risks, like infection, hematoma, and anemia [1].
After obtaining an informed consent, any medi-
P. A. Everts (*) cations, supplements, or activities of daily living
Research and Education Division, Gulf Coast that might have an impact in the BMA extraction
Biologics, Fort Myers, FL, USA procedure, bone marrow cell viability, or poten-
OrthoRegen Group, Max-Planck University, tial therapeutic effect need to be reviewed and
Indaiatuba, SP, Brazil discussed with the patient. It is important that
e-mail: peter@[Link]
patients avoid specific medications to maintain
I. Dallo bone marrow cell viability and post BMAC treat-
Department of Orthopaedic Surgery and Sports
Medicine, Sport Me Medical Center, Unit of
ment cellular function in the recipient environ-
Biological Therapies and MSK Interventionism, ment. These medications include nonsteroidal
Seville, Spain anti-inflammatory drug (NSAIDs), corticosteroid
J. F. Lana injections, systemic and inhaled steroids, antibi-
OrthoRegen Group, Max-Planck University, otics (fluoroquinolone), anticoagulants, and
Indaiatuba, SP, Brazil statins [2–5]. Contraindications to perform a
Department of Orthopaedics, The Bone and Cartilage BMA procedure are severe anemia, active sys-
Institute, Indaiatuba, SP, Brazil temic or local infection at the BMA extraction
L. Podesta and injection site, and active cancer.
Bluetail Medical Group and Podesta Orthopedic
Sports Medicine, Naples, FL, USA

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 105
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
106 P. A. Everts et al.

18.2 Bone Marrow Tissue marrow consists of a hematopoietic component

(parenchyma) and a vascular component
The bone is composed of cortical and trabecular (stroma). The parenchyma includes hematopoi-
bone, cartilage, and connective tissues. Spongy, etic progenitor and hematopoietic stem cells
or trabecular, bone is composed of a lattice of (HSCs), which are localized close to the endos-
fine bone plates filled with hematopoietic mar- teum and around the blood vessels. Bone marrow
row, fat-containing marrow, and arterial-venous stroma cells, including endothelial cells, are rec-
sinusoidal blood vessels. Furthermore, it consists ognized as multipotential non-hematopoietic
of bone cells at different developmental stages progenitor cells, capable of differentiating into
(including pre-osteoblasts, osteoblasts, and various tissues of mesenchymal origin, including
osteocytes), collagen fibrils, and calcium and osteoblasts, chondrocytes, tenocytes, endothelial
phosphate deposits [6]. Bone marrow tissue is cells, myocytes, fibroblasts, and adipocytes [11,
soft, similar to the peripheral blood. Two catego- 12].
ries of bone marrow tissue exist, the red and yel-
low marrow. Depending on age, the red marrow
is replaced by the yellow marrow. Friedenstein 18.2.2 Bone Marrow Niches
and colleagues reported first on the isolation of
bone marrow-derived stem cells from bone mar- Bone marrow niches are three-dimensional
row stroma in plastic culture dishes and identified microenvironments. In Table 18.1, an overview
mesenchymal stem cells as colony-forming unit of the classical bone marrow niches is presented.
fibroblasts (CFU-Fs) [7]. The bone marrow It is assumed that they control genes and proper-
stroma is made up of a network of many different ties that define “stemness,” including the control
cells, like fibroblast-like cells, and includes a and balance between quiescence, self-renewal,
subpopulation of multipotent cells which are able proliferation, and differentiation of diverse cell
to generate the mesenchyme, cells that are types. Stem cell niches are defined as specific
referred to as mesenchymal stem cells (MSCs) cellular and molecular microenvironments, regu-
[8]. lating bone marrow HSC, MSC, and progenitor
The red bone marrow is a rich source of bone functions, consisting of autonomous signaling
marrow-derived cells and present in most skeletal molecules and mechanisms and facilitates inter-
system bones of the iliac crest, tibia, spine verte- cellular contact, and the interaction between stem
brae, humerus, calcaneus, ribs, and near point of cells and their neighboring extracellular matrix
attachment of long bones of legs and arms. It has [13, 14]. Harvested bone marrow stem cells and
been estimated that more than 500 billion cells subsequently injected into a totally different
per day can be produced in the bone marrow, in microenvironment can potentially differentiate
particular erythrocytes, leukocytes, and platelets into cell types of this new local environment [15].
[9]. Orthobiological BMAC procedures focus on Zhao et al. revealed the plasticity potential of
the extraction of marrow from the red bone mar- bone marrow MSCs, as these cells were capable
row as it contains myeloid and lymphoid stem of de-differentiation into cells from other cell lin-
cells and MSCs. eages [16]. Their finding has potentially great
clinical implications for orthobiological treat-

18.2.1 Bone Marrow-Specific Regions Table 18.1 Classical bone marrow niches
Arteriolar niche
The bone marrow cavity can be partitioned into Endosteal niche
four regions: endosteal, sub-endosteal, central, Hematopoietic stem cell niche
and perisinusoidal regions, according to the Megakaryocyte niche
model of Lambertsen and Weis, have been Mesenchymal stem cell niche
adopted and modified [10]. In general, the bone Perivascular niche
18 Bone Marrow Aspirate Concentrates for Knee OA 107

ments, since autologous BMAC originates from Table 18.2 Anatomical location for BMA
their specific and original bone marrow niche but Calcaneus
are frequently used in other pathoanatomic tissue Iliac crest: anterior and PSIS
types to treat various pathologies. Proximal humerus
Sternum
Tibia: distal and proximal
Vertebral body
18.2.3 Bone Marrow Aspiration

Clinicians utilizing orthobiological, regenerative calcaneus [20–22], and other harvesting sites
medicine applications have a growing interest in (Table 18.2) [23].
harvesting BMA to prepare a minimal manipula-
tive BMAC, as this is a plentiful source of bone
marrow stem cells and their progenitor cells, 18.3.2 Imaging Options
megakaryocytes, platelets, leukocytes, and other
cells, easily accessible via a BMA harvesting A certain volume of BMA needs to be extracted
procedure [17, 18]. to produce a BAMC. It is imperative to precisely
locate the donor site, as most MSCs are located in
endosteal and subendosteal areas [24, 25]. Safe
18.3 BMAC Procedural trocar placement to penetrate the cortical bone is
Preparations accomplished by using image guidance during
aspiration procedure. Here, we focus on a BMA
Patients should be informed to hydrate in the procedure from the PSIS sites, as it is the most
days before the procedure, and they should avoid frequently reported anatomical site for BMA.
eating solid food 3–5 h prior the BMA harvesting
to avoid nausea. The extraction procedure can be [Link] Ultrasound
performed in an office setting and should be exe- When the PSIS is targeted, patients are posi-
cuted using aseptic skin preparation techniques, tioned in the prone position. A pillow is placed
including harvesting tissue site draping. It is rec- under the waist to elevate the pelvis and avoiding
ommended that the physician is wearing sterile lumbar lordosis and superficially positioning the
gloves, a hair cover, and a facemask. Consider PSIS. Sonographic assessment using a portable
wearing a sterile gown. Under normal circum- ultrasound system with either a high-frequency
stances, patients can be monitored with a pulse linear or 5–2-MHz low-frequency curvilinear
oximeter that includes heart rate monitoring. transducer is positioned in a transverse plane
Supplemental oxygen, blood pressure, automated over the hyperechoic L5 spinous process. The
external defibrillator, and crash cart supplies transducer is then translated laterally toward the
should be available. physician until the hyperechoic iliac crest comes
into view. The transducer can then be toggled to
identify the broadest and flattest portion of the
18.3.1 BMA Harvesting Sites PSIS. Once identified, skin markings are made
adjacent to the center of the transducer’s width
It is important to choose a harvesting site that has and length. Transecting lines drawn from the X
the most MSCs that can be extracted, as they rep- and Y skin markings localize the center and nee-
resent a small population of the total of bone dle target point of the PSIS, as shown if Fig. 18.1
marrow cells [19]. In humans, the most common [26]. With the ultrasound transducer in the trans-
anatomical location to obtain bone marrow with verse plane over the PSIS, the top (most superfi-
the highest potential for MSCs is the posterior cial depth) and slope of the PSIS is noted for
superior iliac spine (PSIS), compared to the tibia, correct angulation of the trocar. This mark is
108 P. A. Everts et al.

Fig. 18.1 Surface anatomy of the PSIS and view with probe in transverse plane. (Courtesy of L. Podesta, MD)

maintained during the delivery of local anesthet- 18.3.3 Cortical Bone Penetration
ics and antiseptic skin preparations prior to the Options
introduction of the needle trocar.
Following ultrasound or fluoroscopic imaging,
[Link] Fluoroscopy with visualization of the PSIS, a sharp trocar is
Fluoroscopic imaging, using ipsilateral or contra- used to penetrate the cortical bone, using either a
lateral oblique beam angulations for viewing the manual force only technique, perpendicular and
PSIS site, is initiated. The perpendicular fluoro- slightly lateral to the patient at 9–12
scopic approach requires a beam angle around counterclockwise-­clockwise rotations, or a mal-
15° ipsilateral to the PSIS, entering laterally with let. Some physicians prefer to use a battery-­
angulation toward the sacroiliac joint. This angle powered drill to pass the cortical bone. However,
will view the lateral ilium outer wall, and a nee- at all times, regardless of the approach, avoid
dle is directed anteromedially. Fluoroscopic increased manipulation and tissue trauma using
images support in positioning the tip of the trocar the sharp trocar, as this will increase the risk for
above the target area for entering the PSIS. The neurovascular injury, bleeding, tearing of lateral
parallel fluoroscopic approach results in viewing gluteal muscle origins, and post-procedural pain.
down the PSIS table, at a 25° contralateral
oblique beam position. This results in a classic
view of the “teardrop,” as shown in Fig. 18.2. 18.3.4 Anesthetic Considerations
Imaging can confirm the entry point into the PSIS
table and visualize the angle through the cortex, A local anesthetic is required to control pain. It is
allowing for safe trocar advancement through the injected around the PSIS cortex and periosteal
cortical bone in the marrow cavity [27]. Using sleeve, making sure to “walk off” the PSIS in
the parallel approach technique allows for a safe four directions (superiorly, medially, laterally,
deeper marrow penetration. and inferiorly). Typically, 1% lidocaine is used,
18 Bone Marrow Aspirate Concentrates for Knee OA 109

Fig. 18.2 Fluoroscopic imaging. Fluoroscopy imaging borders, as shown in the monitor. The tip of a needle
of the PSIS, with the patient in prone on a fluoroscopic (black circle), in the numbed skin, is marking the entry
table. The parallel fluoroscopic approach results in view- site of the bone marrow trocar to be placed in the marrow
ing down the PSIS table, at a 25° contralateral oblique cavity, while the physician is on the ipsilateral side of the
beam position. This results in a classic view of the “tear- fluoroscope, viewing the correct position on the monitor
drop,” referring to the outline of the medial and lateral (red circle) (courtesy of G. Flanagan II, MD)

without epinephrine, up to 10 mL total per have been using the Jamshidi™ harvesting nee-
­aspiration side. Alternatively, 0.25–0.5% ropiva- dle (Ranfac Corporation, Avon, MA). Recently,
caine can be used as well. A 22- to 27-gauge, 2- the Aspire Bone Marrow Harvesting System™
to 3.5-­ inche needle is typically used. Local (EmCyte Corporation, Fort Myers, FL) and the
anesthetic should be applied to the skin at the Marrow Cellution Bone Marrow Aspiration
needle entry site, soft tissue trajectory of the nee- Device™ (Ranfac Corporation, Avon, MA) have
dle, and the surface of the bone/periosteum. The been introduced. A significant difference between
needle used to anesthetize the bone should never the latter two harvesting systems is that the
be longer than the needle used to harvest the bone Aspire™ system has a separate introducer and an
marrow. This helps to avoid needle length mis- aspiration needle with a closed, blunt, tip for
match in reaching the bone for harvesting. Never minimal peripheral blood aspiration from the
inject anesthetic through the trocar or needle marrow cavity. Aspirating BMA is only feasible
used to aspirate marrow, as this can have a delete- through the three aspiration needle side orifices
rious effect on the viability of the bone marrow [28]. In Fig. 18.4, the Marrow Cellution device is
cells. After the anesthetic is administered, wait at developed for a low volume of BMA aspiration
least 3–5 min until an adequate level of anesthe- with direct patient injection, without concentra-
sia is achieved. tion, whereas the BMA following Aspire™ har-
vesting is intended for centrifugation processing
to produce a high-concentration MSC product
18.3.5 BMA Harvesting Needle [29].
Devices

Different bone marrow needle harvesting sys- 18.3.6 Anticoagulation with Heparin
tems are available on the market, with distinctive Solution
different design characteristics, affecting the
marrow harvesting dynamics and bone marrow Prior to a BMA procedure, it is highly recom-
cellularity (Fig. 18.3). Traditionally, physicians mended that all the bone marrow harvesting com-
110 P. A. Everts et al.

a b c

Fig. 18.3 Three different BMA needle systems. (a) (EmCyte Corporation®, Fort Myers, FL); (c) Marrow
Jamshidi™ harvesting needle (Ranfac Corporation, Avon, Cellution Bone Marrow Aspiration Device™ (Ranfac
MA); (b) Aspire Bone Marrow Harvesting System™ Corporation, Avon, MA)

as bone marrow tissue has the potential for fast

clotting during the extraction procedure [30].
Clot formation will prevent an adequate BMAC
procedure to concentrate MSCs and other mar-
row constituents. Contingent on the desired
amount of bone marrow, the total needed volume
of heparin to be used, at a concentration of 1000
IU/mL, is calculated. Good laboratory practice
indicates a ratio of 1 mL of 1000 IU heparin con-
centration to 9 mL of bone marrow. For example,
when using a 10 mL collection syringe, add 1 mL
of heparin to the syringe, and mix 9 mL of BMA
thoroughly to ensure an adequate level of antico-
agulation. Depending on the instructions for use
and physicians’ preference, the heparinized
BMA can be filtered through a 200-micron, hepa-
Fig. 18.4 Detailed aspect of fenestrated blunt aspirating rin rinsed, filter to eliminate potential particles,
canula for BMA aspiration. The aspiration cannula has a fibrin strands, and fat tissue.
blunt tip and triple core side ports for quiescent BMA and
progenitor stem cell collection from the endosteal and
sub-­endosteal bone marrow niche, minimizing RBC con-
tamination in the collected BMA volume (Aspire™ bone 18.3.7 Extraction/Collection Syringes
marrow harvesting system, EmCyte Corporation®, Fort
Myers, FL) Hernigou et al. indicated to use small (10 mL)
syringes for bone marrow collection, as this
ponents, collection syringes, and all the resulted in significantly higher BMA MSC and
processing accessories that will be in contact progenitor cell concentrations, when compared
with bone marrow are thoroughly heparin rinsed to a 50 mL syringe [17]. Furthermore, filling the
18 Bone Marrow Aspirate Concentrates for Knee OA 111

Fig. 18.5 Aspect of BMAC and cellular densities follow- BMAC cells are located in this multicellular stratum,
ing a two-spin procedure. After the second spin, the according to their individual cellular densities. Note, the
BMAC is resuspended and extracted from the concentra- MSC density is close to the density of erythrocytes.
tion chamber of the BMAC device (a) (PureBMC® Therefore, avoiding collecting a fraction of erythrocytes
Supraphysiologic, EmCyte Corporation®, Fort Myers will decrease the capture rate of MSCs
FL). (b) Magnification of the BMAC buffy coat layer. All

extraction syringe to 10–20% of its total volume Double-spin centrifugation protocols, performed
capacity resulted in an improved yield of MSCs. at POC, create a layered BMAC buffy coat stra-
Lately, physicians tend to use 10 ml syringes, tum, based on different centrifugal forces that
employing a fast and intermittent pull technique accomplish density cellular separation, because
to collect small volumes from different intra-­ of the specific cellular gravity of the individual
trabecular depths and or cortical sites. Another marrow components, as shown in Fig. 18.5.
advantage for using 10 ml syringes is that antico-
agulation protocols can be better managed, since
smaller syringes fill considerably faster than 18.4 BMC Injection Knee
larger syringes. Osteoarthritis

18.4.1 Background
18.3.8 BMAC Device Function
Osteoarthritis (OA) of the knee is a common pro-
An effective BMAC injection is reliant on the gressive degenerative joint disease, with a high
performance of the BMA procedure, with mini- percentage of chronic pathoanatomic degenera-
mal cellular trauma, while maximizing MSC cel- tive changes with loss of cartilage, subchondral
lular yields, avoiding peripheral RBC infiltration bone changes, synovial inflammation, and vari-
[28, 31]. Dedicated, national regulatory compli- ous meniscal pathologies. Safe, nontraditional,
ant and registered processing kits are commer- and nonsurgical treatment plans for knee OA
cially available for BMAC preparations and may include orthobiological therapies, using
orthobiological treatment procedures. Kits may autologous preparations derived from whole
include a BMA concentration device and a BMA blood (PRP), bone marrow (BMAC), and adipose
harvesting needle system. BMAC preparation tissue [32–34]. These orthobiologics play a ben-
protocols and techniques are streamlined and eficial role in reducing local inflammation and
validated methods to concentrate marrow cells. promote synovial and cartilage anabolism by
112 P. A. Everts et al.

Fig. 18.6 BMAC injection via the superolateral approach

releasing a series of proteins, like platelet-derived tibia, proximal fibula, and patella, involving
growth factors, HSCs, MSCs, and particular leu- femorotibial, patella-femoral, and tibiofibu-
kocytes and their specific phenotypes, to provide lar articulations.
pain relief and functional improvement. The goal (b) Patient positioning: Supine or seated for a
of BMAC treatment in knee OA is aiming at superolateral injection approach is preferred
achieving restoration of all impaired articular for intra-articular knee injections, especially
components. The paracrine impact of the MSCs when an effusion is present [41]. The physi-
present in BMAC is essential in tissue repair and cian is standing/seated on the injection side
the regenerative ability by stimulating immuno- of the affected knee (Fig. 18.6).
modulatory, anti-catabolic, anti-apoptotic, and (c) Imaging: Ultrasound high-frequency linear
chondrogenic effects [35]. Hence, BMAC has array transducer; with transducer in in short
been used successfully to treat a variety of MSK axis to quadriceps tendon; needle position
pathologies, including patients with moderate to in-plane (long axis), lateral to medial
severe knee OA [36]. Favorable outcomes are approach.
thought to be associated with the presence of (d) Needles: 22–18 gauge, 1.5–2.0 inch for effu-
MSCs in the BMAC [37]. More specifically, sion evacuation
higher BMAC MSC concentrations, measured as 27–22 gauge, 1.5–2.0 inch for biological
colony-forming unit fibroblast (CFU-F)®, indi- injection
cate more positive patient reported outcomes (e) Injection volume: Dependent on the amount
[38–40]. of BMAC prepared, ranging 2–10 mL total.

In a recent systematic review on BMAC for

18.4.2 Intra-articular Setup the treatment of knee OA (keeling), 8 studies met
the inclusion criteria, including a total of 299
(a) Anatomical structures: The knee joint is an knees with a mean follow-up of 12.9 months.
encapsulated hinge-type synovial joint, con- BMAC injections were effective in improving
sisting of four bones: distal femur, proximal pain and patient-reported outcomes in patients
18 Bone Marrow Aspirate Concentrates for Knee OA 113

with knee OA (P < 0.01 and P < 0.05, respec- 10. Lambertsen RH, Weiss L. Studies on the organization
tively) [42]. and regeneration of bone marrow: origin, growth, and
differentiation of endocloned hematopoietic colo-
Before BMAC injection, the synovial fluid is nies. Am J Anat. 1983;166(4):369–92. [Link]
evacuated via the superolateral approach. After org/10.1002/aja.1001660402.
evacuation of the effusion, the BMAC is injected. 11. Muguruma Y, Yahata T, Miyatake H, Sato T,
All manipulations are ultrasound guided. Uno T, Itoh J, et al. Reconstitution of the func-
tional human hematopoietic microenvironment
derived from human mesenchymal stem cells in
the murine bone marrow compartment. Blood.
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 Fat-Derived Orthobiologics
for Knee OA
19
Peter A. Everts, Raphael Barnabe, Luga Podesta,
and Rowan Paul

19.1 Introduction biological source of various cellular tissue com-

ponents, and it contains one of the best MSC
Over the past decades, PRP- and mesenchymal populations [4]. AT is abundantly present in
stem cell (MSC)-based autologous products have humans and relatively easy to harvest through a
been broadly applied in orthobiology and regen- mini-liposuction procedure, at point-of-care [5].
erative medicine applications. MSC-based bio- In this chapter we focus on the harvesting AT via
logics can be prepared from bone marrow and a mini-liposuction procedure (MLS) and the
adipose tissue, and they are ideal cell types for preparation of several fat-derived products.
the treatment of damaged tissues given their
restorative and pro-regenerative properties [1].
MSCs cells can be found in particular in most of 19.1.1 Safety and Contraindications
the vascularized tissues, being a subtype of peri-
cytes with pro-regenerative properties, and in Before performing a fat-derived orthobiological
particular in bone marrow and adipose tissue treatment, patients should be well informed about
(AT) [2, 3]. Autologous AT is a heterogeneous the procedure and MLS. It is essential to obtain
an informed written consent. Patients need to be
P. A. Everts (*) informed about potential risk factors and compli-
Research and Education Division, Gulf Coast cations [6]. Reported complications include
Biologics, Fort Myers, FL, USA ecchymosis, edema, surgical site infection,
OrthoRegen Group, Max-Planck University, seroma, and venous thromboembolism.
Indaiatuba, SP, Brazil Contraindications to perform an MLS and a fat-­
e-mail: peter@[Link]
derived procedure are ongoing infections, severe
R. Barnabe diabetes, and active cancer.
Instituto de Pesquisa Clinica Anna Vitoria Lana,
Indaiatuba, SP, Brazil
e-mail: [Link]@[Link]
L. Podesta
19.2 Adipose Tissue Background
Bluetail Medical Group and Podesta Orthopedic
Sports Medicine, Naples, FL, USA Adipose tissue, otherwise known as body fat, is
R. Paul loose connective tissue that extends throughout
Department of Community and Family Medicine, the body and is mainly composed of adipocytes
Dartmouth Geisel School of Medicine, and acts as a central metabolic organ in the regu-
Hanover, NH, USA
lation of whole-body energy homeostasis.
e-mail: Rowan_Paul@[Link]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 117
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
118 P. A. Everts et al.

Adipocytes have secretory capacities, as they ASCs contribute in the reduction of proinflam-
release a variety of effector cells like endocrine matory cytokines, chemokines, and cellular
hormones, exosomes, lipids, inflammatory cyto- apoptosis [15, 16]. Plentiful literature has dem-
kines, and peptide hormones, impacting local and onstrated the anti-inflammatory and adaptive
systemic metabolic responses [7]. Autologous properties of ASCs based on environmental con-
AT-prepared products consist of a heterogeneous ditions, with anti-inflammatory effects on chon-
source of various cellular tissue components that drocytes and synoviocytes [17]. These AT
can be used as a cell-based, disease modifying, characteristics have great potential in clinical
therapies in orthobiological and other regenera- orthobiological tissue repair applications [18], to
tive medicine procedures. Furthermore, concen- counteract inflammatory processes, but also to
trated adipose tissue provides clinicians with a promote regenerative processes in the joint
physiological 3D multicellular scaffold, includ- synovium and chondral surfaces [19]. These non-­
ing adipose-derived stem cells (ASCs) and stro- lipid-­
laden stromal cells can be isolated from
mal cells. These features are of high interest suction-aspirated adipose tissue by either enzy-
when treating MSK disorders [8, 9]. matic collagenase or mechanical emulsification.

19.2.1 Adipose Tissue Structure 19.2.3 Adipose Harvesting

Technique Considerations
Adipose tissue is a highly vascularized connec-
tive tissue, abundantly present throughout the Subcutaneous AT harvesting is performed using
human body. White AT (WAT) is responsible for a mini-liposuction technique. The procedure is
energy storage and plays a pivotal physiological executed by means of aspiration cannulas, intro-
role in maintaining metabolic homeostasis in the duced through small skin incisions, assisted by
body by releasing release of several adipocyto- controlled suction. Its basic principles have
kines, growth factors, and cytokines that may act been elaborated by Illouz, who was the first to
in an endocrine or paracrine fashion [10]. Brown introduce the modern, safe, and widespread
AT (BAT) plays a significant role in thermogen- method of liposuction with a blunt-tipped can-
esis and have the ability to diffuse energy by pro- nula and subcutaneous infiltration to facilitate
ducing heat to ensure body temperature adipose breakdown and controlled fat aspiration
regulation, rather than storing it as triglycerides [20]. The procedure preserves neurovascular
[11]. structures with minimal patient discomfort. In
1985, Klein introduced the tumescent liposuc-
tion technique, using a specific adipose infiltra-
19.2.2 Adipose-Derived Tissue Stem tion fluid to optimize harvesting of AT
Cells (Table 19.1) [21].
Later, Coleman introduced a new three-step
ASCs are prevalent in adipose connective tissue technique to decrease trauma to adipose tissue
and surrounding blood vessels [12]. The first following liposuction, employing manual low
characterization of adult mesenchymal stem cells negative pressure lipo-aspiration. Harvested fat is
in lipoaspirates, was performed by Zuk in 2002 transferred to a dedicated (concentration) pro-
[13], followed by several others, confirming that cessing device to purify the AT, using minimal
adipose mesenchymal stem cells have a high pro- manipulative processing steps [22]. Properly exe-
liferation capacity and multilineage cell differen- cuted lipo-aspiration procedures, followed by AT
tiation potential, capable of differentiating into processing, will not affect ASC viability and
adipogenic, chondrogenic, myogenic, osteo- functionality, while yielding significant concen-
genic, and neurogenic cells [14]. Furthermore, trations of AD-tSVF cells [23].
19 Fat-Derived Orthobiologics for Knee OA 119

Table 19.1 Classical formulation of Klein’s tumescent solution (80)

Ingredient Concentration Volume Activity
Sodium chloride 0.9% 1L Diluent
Lidocaine 1% 50 mL Anesthesia
Epinephrine 1:1000 1 mL Vasoconstriction
Sodium bicarbonate 8.4% 10 mL Acidity compensation

Table 19.2 Detailed representation of the preparation

19.3 Preparation of Minimally steps to produce ATC
Manipulated Products  A. Tumescent fluid preparation: a sterile NaCl
from Adipose Tissue solution consisting of anesthetics (lidocaine for pain
relieve and epinephrine for blood vessels to constrict
There are various protocols and preparation to minimize RBC contamination in fat tissue during
harvesting)
methods available to produce different AT-derived
 B. Tumescent injection: via small skin cuts, a thin
minimally manipulated orthobiological adipose blunt injector needle is injected in the target adipose
products. Overall, the objective is to have access harvesting area
to ASCs and other reparative adipose-derived  C. Waiting time: reports indicate to wait at least 20
cells that are present in the stroma portion of AT minutes before starting the fat harvesting procedure.
This time is needed for the fluid to cause the injected
[12, 24]. Furthermore, AT provides clinicians area to swell and stiffen, supporting in easy in fat
with a physiological 3D multicellular scaffold, removal
including AT extracellular matrix, ASCs, and  D. Adipose harvesting: with a dedicated harvester
other SVF constituents, that can be utilized in tis- cannula, fat tissue is harvested using liposuction, by
applying manually negative pressure to a collection
sue grafting like tendon tears. In Table 19.2, more syringe fat is removed from the area that was
detailed ATC preparation steps are presented. injected with tumescent fluid
 E. Racking and decanting: syringes filled with
harvested fat is placed in a rack, with plunger in
upward direction. After the adipose harvesting, leave
19.3.1 Adipose Tissue Concentrate all syringes in the in the rack for 10-15 minutes, with
the Luer end of the syringe capped. Decant the
supernatant (tumescent fluid) by removing the cap,
Similar to the preparation of PRP and BMAC, until adipose tissue starts to block the Luer
cellular density gradient centrifugation can also  F. Transfer the decanted fat into a disposable
be used to create a viable biological AT concen- processing device and place it in a dedicated
trate specimen (ATC) (Table 19.2) [3]. centrifuge to concentrate the AT specimen
Centrifugation techniques have proven to be an  G. Centrifugation protocol: density layer separation
by centrifugation, producing ATC. Follow the
effective means to produce a clean and viable instruction for use of the preparation device to
ATC. Both, single- and double-spin centrifuga- extract ATC
tion procedures have been used to separate the  H. Mechanical emulsification: a method to emulsify
residual infranatant extracellular fluid, residual the ATC, by moving the two syringes back and
forward through a restraining device to size the ATC,
pro-inflammatory oil, and adipose tissue debris making it suitable for tissue injection
from the final ATC product, based on the princi-
ple of density separation, as demonstrated in
Fig. 19.1. Thereafter, the ATC is aspirated from 19.3.2 Micro-fragmented Adipose
the concentration tube. Subsequently, the ATC Tissue (MFAT)
can be subjected to micro fat homogenization
techniques to produce an intact stromal vascular After AT harvesting, the fat is processed with the
environment, which subsequently can be applied devoted device [25]. In this closed-loop device,
to tissue sites. the AT is rinsed with saline solution to remove
120 P. A. Everts et al.

1.2 mm, and a parcel diameter of less than

1.2 mm.
Nanofat: fat grafts extracted using a 1.2- to
2.4-mm-diameter cannula, 400–600 μm emul-
sifier, and 400–600-μm parcel diameter.

19.3.3 Stromal Vascular Fraction

(SVF)

The use of AT in orthobiological applications is

based on the separation of the stromal fraction
(SVF) contained in adipose tissue, allowing for
access to ASCs and other AT constituents [24].
This heterogeneous mixture of cells which
includes all the cell population excluding adipo-
cytes can be created by different AT disruption
techniques, like enzymatic digestion, or mechan-
ical emulsification preparation methods. The
overall processing of adipose harvesting and
Fig. 19.1 Centrifugated density separation of adipose preparations is illustrated in Fig. 19.2. AT-derived
tissue. After a single centrifugation spin, the AT is clean orthobiologics comprise of ASCs, acting as the
and concentrated. Typically, with adipose centrifugation,
principal therapeutic effector cells [27], in com-
the first, top, layer consists mainly of inflammatory oil
and adipose tissue cell residues. The middle layer is com- bination with precursor and mature endothelial
prised of ATC, and the third bottom layer contains resid- cells, pericytes, lymphocytes, pre-adipocytes,
ual tumescent fluid and some RBCs (Progenikine® macrophages, and mature adipocytes [3, 4], as
Adipose Concentration System, EmCyte Corporation®,
shown in Table 19.3. Noteworthy, ASCs meet the
Fort Myers, FL, with permission)
four criteria for MSCs as defined by the
International Society for Cellular Therapy
cellular debris, oil, erythrocytes, and other con- (ISCT) [4].
taminants. During this washing process, the fat is
mechanically sized to isolate ASCs, to produce
micro-fragmented adipose tissue graft (MFAT) 19.3.4 SVF by Enzymatic Digestion
[26], without the use of enzymes. AT is gently
micro-fractured and washed, leaving oil and Enzymatic digestion techniques use enzymes
blood residues behind in the process. The final (mainly collagenase) to isolate ASCs and stro-
adipose product is then collected and ready to be mal cells by digesting the AT peptide collagen
delivered to treatment sites. bonds, while destructing extracellular struc-
Additional emulsification steps can lead to the tures. Centrifugation techniques are used to
preparation of microfat or nanofat, differing in separate the floating adipocytes from the pel-
the adipose tissue cluster size. leted SVF [28]. Collagenase-based SVF proto-
cols produce an adipose-derived cellular SVF,
1. Macrofat: fat grafts are harvested larger than which is directly applied, without the need for
2.4 mm; indicated for filling a wide range of in vitro cell expansion. Additionally, erythro-
tissue sites. cytes are usually routinely removed during this
2. Microfat: fat grafts are harvested using a can- enzymatic processing protocol. This is a signifi-
nula with a hole diameter ranging from 1.2 to cant dissimilarity compared with BMACs,
2.4 mm, an emulsifier with a hole diameter of which contain a significant number of erythro-
19 Fat-Derived Orthobiologics for Knee OA 121

Fig. 19.2 Mechanical SVF preparation method. Adipose Adipose Concentration System, and Adicen™ Emulsifier
tissue is harvested following lipo-aspiration and subse- device, EmCyte Corporation®, Fort Myers, FL, with per-
quently processed in a centrifuge for density cellular lay- mission). AT adipose tissue, ATC adipose tissue concen-
ering. After centrifugation, the oil and tumescent fluid are trate, SVF stromal vascular fraction, MSC mesenchymal
removed from the concentration device. Thereafter, ATC stem cells, HSCs hematopoietic stem cells, EPC endothe-
is extracted and collected in a syringe for micro-­ lial progenitor cell
fragmentation of the ATC prior application. (Progenikine®

Table 19.3 SVF cellular distribution

Cell type Percentage range in SVF Cells
Stromal 15–30 ASC
Pre-adipocytes
Fibroblasts
Hematopoietic origin 34–45 Platelets
Neutrophil
Lymphocyte
Monocyte/macrophage
Erythrocyte
HSCs and progenitor 1–15
Pericytes 3–5
Endothelial cells
Smooth muscle cells 5–15
ASC adipose mesenchymal stem cells, HSC hematopoietic stem cells

cytes [27]. In the current regulatory landscape, 19.4 SVF by Mechanical

enzymatic-prepared SVF products are listed as Disruption
“more than minimal manipulative preparations”
and are therefore in many countries not allowed There are various fat-sizing devices available on
to be used as an orthobiological treatment the market that can generate an emulsified AT
product. treatment specimen to produce adipose-derived
122 P. A. Everts et al.

mechanical SVF. This method signifies to the that are regulators and influencers in adipose
cellular population in adipose SVF in a bioactive immunomodulatory activities are adipokines,
scaffold or extracellular matrix [29]. In this case antioxidative, pro-angiogenic, anti-apoptotic,
adipose tissue is mechanically sized by a growth factors (like, VEGF, FGF, TGF), and spe-
mechanical disruption achieved by different
­ cific interleukins (IL-6, IL-7) [37]. Interestingly,
commercially available systems, among which several studies compared the immunomodulatory
mechanical emulsification. Depending on the abilities of ASCs and BMSCs and found similar
mechanical method, the yield of SVF can differ, effects when used in chronic inflammatory con-
with some methods being more efficient in terms ditions [38, 39].
of cell purification (Table 19.3) [30]. An advan-
tage of mechanical SVF is that it is composed of
both cellular and native structural fat fragments, 19.5.2 Angiogenesis
providing a bioactive cellular adipose tissue
matrix [31]. Compared to enzymatic digestion, AT and its SVF cellular variations secrete angio-
mechanical SVF preparations are not a 100% genic factors such as angiopoietin-2, VEGF, and
concentrated cellular product, a distinct differ- several adipokines (e.g., leptin and adiponectin),
ence compared to enzymatic SVF. Noteworthy, capable of modulating angiogenesis and vascular
mechanical SVF is therefore more likely to be structures [40]. The plasticity of AD-MSCs have
approved by national regulatory administrations. demonstrated to enhance (neo)angiogenetic pro-
A graphical schematic presentation shows the cesses, through endothelial cell activities, which
processing steps from lipoaspirate collection to is essential in the treatment of tissue repair [41].
mechanical SVF (Fig. 19.2). These specialized adipose characteristics were
also well demonstrated by Miranville et al.,
revealing the differentiation of AD-MSCs into
19.5 Adipose Tissue endothelial cells, ultimately contributing to
Orthobiological Properties angiogenesis [42]. Additionally, AD-MSCs stim-
ulate angiogenesis through paracrine activities,
Several studies have indicated the potential for with SVF releasing various pro-angiogenic fac-
ASCs to demonstrate paracrine activity and tors like growth factors and macrophages [43,
exhibit differentiation potential toward different 44].
cell lineages (adipogenic, osteogenic, chondro-
genic, and myogenic lineages), while providing
immunosuppressive and angiogenetic properties 19.6 Adipose-Derived Products
[32, 33]. in Knee Osteoarthritis

Sharma et al. described the by-products of adi-

19.5.1 Immunomodulation pose tissue with regenerative potential, including
expanded ASCs, microfat, nanofat, SVF, and
Cells contained in AT preparations are proficient other AT-derived products [45]. In MFAT pro-
in secreting anti-inflammatory and immunosup- cessing, the lipoaspirate is refined to a cluster of
pressive factors that can exert immunomodula- 0.2–0.8 mm, while the supportive vascular stro-
tory effect [32]. In particular, ASCs regulate the mal niche remains intact and ASCs stay in their
immune system via direct cell-cell communica- natural habitat prior to intra articular knee injec-
tion and indirectly through the secretion of solu- tions [46]. In a recent systematic review by Aletto
ble mediators, growth factors, and extravascular et al., a total of 24 clinical trials were analyzed
vesicles [34, 35], regulating the activities of T using AT-SVF products [47]. The application sig-
cells, B cells, and macrophages [36]. Pro-­ nificantly increased clinical outcomes in all stud-
inflammatory and anti-inflammatory molecules ies. VAS and WOMAC were the most used scores
19 Fat-Derived Orthobiologics for Knee OA 123

to analyze clinical outcomes. Additionally, Koh (ISCT). Cytotherapy. 2013;15(6):641–8. Available

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42. Miranville A, Heeschen C, Sengenès C, Curat S0976566222000091.
CA, Busse R, Bouloumié A. Improvement of 48. Koh YG, Choi YJ, Kwon SK, Kim YS, Yeo
postnatal neovascularization by human adi- JE. Clinical results and second-look arthroscopic
pose tissue-derived stem cells. Circulation. findings after treatment with adipose-derived stem
2004;110(3):349–55. [Link] cells for knee osteoarthritis. Knee Surg Sports
CIR.0000135466.16823.D0. Traumatol Arthrosc. 2015;23:1308–16.
43. Koh YJ, Koh BI, Kim H, Joo HJ, Jin HK, Jeon J, et al. 49. Jeyaraman M, Maffulli N, Gupta A. Stromal vascu-
Stromal vascular fraction from adipose tissue forms lar fraction in osteoarthritis of the knee. Biomedicine.
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reassembly of blood endothelial cells. Arterioscler com/2227-­9059/11/5/1460.
 Autologous Conditioned Serum
(ACS)
20
Tahsin Beyzadeoglu and Onur Cetin

20.1 Background behind ACS therapy lies in its ability to modulate

inflammation, promote tissue repair, and stimu-
Musculoskeletal disorders, including osteoarthri- late the regenerative capacity of the affected site.
tis, tendinopathies, ligament injuries, and muscu- It offers a potentially safer and more targeted
lar injuries, pose significant challenges to patients approach compared to traditional interventions
and healthcare systems worldwide. Traditional such as corticosteroid injections or non-steroidal
treatment options for these conditions often focus anti-inflammatory drugs (NSAIDs) [4]. By utiliz-
on symptom management and may not address ing the patient’s own blood, ACS therapy reduces
the underlying pathological processes or promote the risk of adverse reactions and immune
tissue regeneration. As a result, there is a growing responses. The World Anti-Doping Agency
interest in regenerative therapies that harness the (WADA) approved the ACS-Orthokine therapy
body’s innate healing mechanisms. In the last for the use of intraarticular or soft tissue injec-
decades, local injections of autologous blood tions with other autologous blood products such
preparations begin to be a solid option in the con- as PRP.
servative treatment of the musculoskeletal inju-
ries and degenerative changes.
Autologous conditioned serum (ACS) therapy 20.2 Mechanisms of Action
has emerged as a promising regenerative treat-
ment modality and is one of the methods of autol- Autologous conditioned serum (ACS) therapy
ogous blood preparations which produce harnesses the regenerative potential of the
anti-inflammatory cytokines and growth factors patient’s own blood components to promote tis-
from the patient’s own blood to facilitate tissue sue healing and repair. The therapeutic effects of
repair and regeneration [1–3]. The rationale ACS therapy are mediated through various mech-
anisms, including the modulation of inflamma-
T. Beyzadeoglu (*)
tion, growth factor, and cytokine regulation.
Faculty of Health Sciences, Halic University,
Istanbul, Turkey
Orthopedics and Traumatology, Beyzadeoglu Clinic, 20.2.1 Inflammatory Modulation
Istanbul, Turkey
e-mail: tbeyzade@[Link] One of the key mechanisms of ACS therapy is the
O. Cetin modulation of inflammatory processes. ACS con-
Orthopedics and Traumatology, Medar Atasehir tains anti-inflammatory cytokines, particularly
Hospital, Istanbul, Turkey

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 127
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
128 T. Beyzadeoglu and O. Cetin

interleukin-1 receptor antagonist (IL-1Ra), which sue healing; this response will result in a good
competitively inhibits the binding of interleukin- outcome by activating endothelial cells and leu-
­1 (IL-1) to its receptors 1 and 2 [1–3]. IL-1 is a kocytes if it is transient. But in chronic inflamma-
potent pro-inflammatory cytokine involved in the tion such as chronic osteoarthritis, tendinitis, or
pathogenesis of various musculoskeletal disor- autoimmune disease, cytokines such as IL-1,
ders. By blocking the IL-1 signaling pathway, IL-17, IL-18, and TNFα can be the major role
ACS therapy reduces inflammation and mitigates players for the detrimental effects on tissues and
its detrimental effects on tissues. In addition to impair the healing, degrade the matrix, and erode
IL-1Ra, ACS also contains other anti-­the articular surface with the enhanced synthesis
inflammatory cytokines, such as IL-4, IL-10, and of collagenases (MMP-1, MMP-8, MMP-9,
IL-13, which further contribute to the downregu- MMP-13) and aggrecans (ADAMTS4,
lation of inflammatory responses. They have ADAMTS5) [6]. ACS therapy harnesses the
been shown to exert anti-inflammatory effects by regenerative potential of various growth factors
increasing the synthesis of IL-1Ra and reducing and cytokines present in autologous serum. These
the pro-inflammatory cytokine production. IL-1 bioactive molecules play crucial roles in tissue
pro-inflammatory effects can go passive on the healing and repair processes.
tissue if the IL-1Ra folds it by 10 to 1000 [4, 5].
Cytokine production with recombinant DNA
techniques is technically challenging. A limited 20.3 Clinical Applications,
number of them are approved for clinical treat- Indication, and Dosage
ment, which are IL-1Ra, IL-2, IFN, IGF-1, EPO, of Autologous Conditioned
PDGF BB, G-CSF, GM-CSF, and BMP2+7. Serum Therapy
Because of strong potency, these factors need to
be used with care in the safe dosages. However, Autologous conditioned serum (ACS) therapy
IL-1Ra is free of side effects and can be applied has demonstrated promising clinical applications
in high doses. in various musculoskeletal disorders. The regen-
erative and anti-inflammatory properties of ACS
make it a potential treatment option for condi-
20.2.2 Growth Factors and Cytokines tions where tissue healing and repair are impaired.
The following are some of the clinical applica-
The discovery of the cytokines made us under- tions of ACS therapy.
stand the biological and inflamatuar effect of
osteoarthritis and gives us a chance to create
point shot treatments. There has been found many 20.3.1 Osteoarthritis
cytokines, and the nomenclature is heterogenic
such as group of interleukins (IL) named in order Osteoarthritis (OA) is a degenerative joint dis-
of their discovery, other group named according ease characterized by cartilage degradation,
their first described functions such as TNF (tumor inflammation, and pain. ACS therapy has shown
necrosis factor), GCSF (granulocyte colony-­ promising results in alleviating symptoms and
stimulating factor), and another group named of improving joint function in patients with
their cellular origin such as monocyte-derived OA. Several clinical studies have reported reduc-
monokine. IL and interferons (IFN) have immu- tions in pain, improved physical function follow-
nomodulator effects having the potential to be ing autologous anti-inflammatory therapies [6,
specifically treat the joint and connective tissue 7]. A randomized controlled study compared and
diseases. demonstrated the superiority of ACS injection
IL-1, TNFα, and IL-6 cytokines are playing an over Hyaluronan and saline injections on the
important role in acute phase response and in tis- patients with grade 2–3 knee osteoarthritis. A
20 Autologous Conditioned Serum (ACS) 129

study by Hashemi et al. reviewed 60 patients with 20.3.4 Other Musculoskeletal

knee osteoarthritis and compare the ACS and Conditions
hyaluronan within two groups. After 6-month
follow-up, ACS group showed a significantly bet- A study conducted by Wright-Carpenter et al.
ter results that hyaluronan group [8]. Fotouhi showed that muscle injuries can be treated with
et al. studied ACS along with the PRP and SVF ACS, injecting into the affected muscle. It is
(stromal vascular fraction). ACS injections on compared to the Actovegin®/Traumeel® injec-
knee osteoarthritis gives an excellent result with tions in athletes. Return to full training time is
major decrease in WOMAC score [9]. reduced by 5.7 days (16.6 vs 22.3 days) in the
ACS group [12]. A mouse model study with a
severe contusion on the gastrocnemius muscle
20.3.2 Tendinopathies showed 30 vs 48 hours accelerated tissue recov-
ery with three injections of ACS compared to
Tendinopathies, including Achilles tendinopathy saline injections. IL-1a may inhibit the myogenic
and lateral epicondylitis, are characterized by terminal differentiation, and IL-1Ra in ACS may
degenerative changes in tendons, resulting in block it to regenerate the muscle much faster
pain and functional impairment. ACS therapy has [13].
shown promise in the management of tendinopa-
thies by promoting tendon healing and reducing
pain. Majewski et al. conducted a study on rat 20.3.5 Epidural Peri-radicular
models to demonstrate Achilles tendon healing Injection for Back Pain
after dissection and re-suturing with ACS vs
saline injections. At 4 weeks, ACS group showed Radicular pain can be the cause of chronic inflam-
a better tendon strength biomechanically, but at 8 mation of spinal nerve roots. Becker et al. dem-
weeks, both groups have similar results. In con- onstrated that ACS injection via epidural
clusion, ACS may not accelerate the healing, but peri-radicular approach is superior to 5 mg and
tendon may gain a better quality when inflamma- 10 mg triamcinolone groups after 6 months [14].
tion is reduced and growth factors are supplied Becker et al. reported a study on patients with
[10]. A retrospective study by Godek et al. discopathies. Regardless of the size of the hernia,
reported an excellent or good results on rotator excellent and good results demonstrated with
cuff tendinopathy (72%), Achilles tendon tendi- cervical discopathies with a 56% rate and lumbar
nopathy (75%), and tennis elbow enthesopathy discopathies with a 62% rate. However with the
(88.2%) [11]. lumbar stenosis group, unsatisfactory results are
much higher [15].

20.3.3 Ligament Injuries

20.4 Application of ACS
ACS therapy has been investigated as a potential
adjunctive treatment in ligament injuries to Injection frequency and dosage with indication
enhance the healing process and improve out- and application sites were given in Table 20.1.
comes. Another hypothesis that IL-1 thought to There are several products to prepare ACS at the
be responsible is the bone lysis of the tibial tun- market. In Orthokine® (Orthogen GmbH,
nel after ACL surgery. Darabos et al. showed the Düsseldorf, Germany) system, 10 mL of patient’s
postoperative intraarticular ACS injection venous blood is taken and stored in a tube with
reduces the tibial tunnel widening compared to glass spheres and incubated 24 h at 37
placebo, but the clinical results about the laxity °C. Including IL-1Ra, anti-inflammatory cyto-
are open to debate [11]. kines which produced by leukocytes are found in
130 T. Beyzadeoglu and O. Cetin

Table 20.1 Injection frequency and dosage with indica- optimizing the treatment protocols for ACS ther-
tion and application site apy. This includes determining the optimal con-
Total Volume centration of growth factors and cytokines in
number Frequency of doses ACS, refining the processing techniques to maxi-
Application area of doses in a week (mL)
mize their bioavailability, and identifying the
Hip joint 4–6 2–3 2–4
Knee joint 6 2–3 2–4 most effective dosing regimens. By fine-tuning
Ankle joint 4 2–3 2–4 these parameters, clinicians can enhance the ther-
Shoulder joint 4 2–3 2–4 apeutic efficacy of ACS therapy and improve
Small joints 4 2–3 0.5–2.5 patient outcomes.
Tendinopathies 4 1–2 1–4 Although there is growing clinical evidence
Muscle injuries 5–6 3 2.5–5 supporting the use of ACS therapy, further
Post-surgery of 4 1 0.5–2.5
tendon repairs (4–6 research is needed to expand the evidence-base.
weeks later) Large-scale randomized controlled trials, long-­
Cervical spine 3–4 1–3 3–4 term follow-up studies, and comparative effec-
Lumbar spine 4–6 1–3 4 tiveness research can provide more robust
evidence on the efficacy, safety, and cost-­
a richer amount in the serum. After the incuba- effectiveness of ACS therapy in various musculo-
tion, serum is centrifuged, and ACS is extracted skeletal conditions. Additionally, the exploration
and ready for use or can be stored at ≤18 °C, up of novel applications, such as in cartilage repair
to 12 months in the deep freezer. or spinal disorders, can further expand the clini-
A recent product, Idria S+® (Biological cal utility of ACS therapy. With ongoing advance-
Innovations, Switzerland) prepares ACS from 30 ments and collaborative efforts, ACS therapy has
mL of venous blood without any incubation and the potential to revolutionize the management of
with only centrifugation claiming to get more musculoskeletal conditions, offering improved
IL-1Ra through small but highly surfaced glass outcomes and quality of life for patients.
beads and positive-charged ions.

References
20.5 Side Effects
and Contraindications 1. Dinarello CA, Thompson RC. Blocking IL-1: inter-
leukin 1 receptor antagonist in vivo and in vitro.
There have been no serious side effects attributed Immunol Today. 1991;12(11):404–10.
to the ACS therapy. Side effect rate is nearly 2. Dinarello CA. Interleukin-1 and interleukin-1 antago-
nism. Blood. 1991;77(8):1627–52.
1.3% and has the same frequency with the pla- 3. Granowitz EV, Clark B, Mancilla J, Dinarello
cebo injections like heat, swelling, and pain at the C. Interleukin-1 receptor antagonist competi-
application area. It is advised to inject ACS with tively inhibits the binding of interleukin-1 to
a 0.2-μm filter. the type II interleukin-1 receptor. J Biol Chem.
1991;266(22):14147–50.
4. Firestein G, Berger A, Tracey D, Chosay J, Chapman
D, Paine M, et al. IL-1 receptor antagonist pro-
20.6 Future Perspectives tein production and gene expression in rheumatoid
and Conclusion arthritis and osteoarthritis synovium. J Immunol.
1992;149(3):1054–62.
5. Arend WP, Welgus H, Thompson RC, Eisenberg
Autologous conditioned serum (ACS) therapy S. Biological properties of recombinant human
has shown promising results in the management monocyte-­derived interleukin 1 receptor antagonist. J
of various musculoskeletal disorders. However, Clin Invest. 1990;85(5):1694–7.
6. Van Buul GM, Koevoet WL, Kops N, Bos PK, Verhaar
there are still several areas that warrant further JA, Weinans H, et al. Platelet-rich plasma releasate
investigation and hold potential for future inhibits inflammatory processes in osteoarthritic chon-
advancements. Future research should focus on drocytes. Am J Sports Med. 2011;39(11):2362–70.
20 Autologous Conditioned Serum (ACS) 131

7. Kon E, Mandelbaum B, Buda R, Filardo G, 12. Darabos N, Haspl M, Moser C, Darabos A, Bartolek
Delcogliano M, Timoncini A. Platelet-rich plasma D, Groenemeyer D. Intraarticular application of autol-
versus hyaluronic acid viscosupplementation as treat- ogous conditioned serum (ACS) reduces bone tunnel
ments for cartilage pathology: from early degeneration widening after ACL reconstructive surgery in a ran-
to osteoarthritis. Arthroscopy. 2011;27:1490–501. domized controlled trial. Knee Surg Sports Traumatol
8. Hashemi M, Taheri M, Adlkhoo H, Dadkhah P, Arthrosc. 2011;19:36–46.
Abbasian MR. Comparison of the effect of intra-­ 13. Heisterbach PE, Todorov A, Flückiger R, Evans CH,
articular injection of autologous (orthokine) inter- Majewski M. Effect of BMP-12, TGF-β1 and autolo-
leukin-­1 receptor antagonist (il-1ra) and hyaluronic gous conditioned serum on growth factor expres-
acid in pain control of knee osteoarthritis. Novelty sion in Achilles tendon healing. Knee Surg Sports
Biomed. 2019;7(4):210–7. Traumatol Arthrosc. 2012;20(10):1907–14.
9. Fotouhi A, Maleki A, Dolati S, Aghebati-Maleki 14. Wright-Carpenter T, Klein P, Schäferhoff P, Appell
A, Aghebati-Maleki L. Platelet rich plasma, stro- H, Mir L, Wehling P. Treatment of muscle injuries by
mal vascular fraction and autologous conditioned local administration of autologous conditioned serum:
serum in treatment of knee osteoarthritis. Biomed a pilot study on sportsmen with muscle strains. Int J
Pharmacother. 2018;104:652–60. Sports Med. 2004;25(8):588–93.
10. Majewski M, Ochsner PE, Liu F, Flückiger R, Evans 15. Becker C, Heidersdorf S, Drewlo S, de Rodriguez SZ,
CH. Accelerated healing of the rat Achilles tendon Krämer J, Willburger RE. Efficacy of epidural peri-
in response to autologous conditioned serum. Am J neural injections with autologous conditioned serum
Sports Med. 2009;37(11):2117–25. for lumbar radicular compression: an investigator-­
11. Godek P, Szajkowski S, Golicki D. Evaluation of initiated, prospective, double-blind, reference-­
the effectiveness of orthokine therapy: retrospective controlled study. Spine. 2007;32(17):1803–8.
analysis of 1000 cases. Ortop Traumatol Rehabil.
2020;22(2):107–19.
 Alpha-2-Macroglobulin
Concentrate as Orthobiologic
21
in Osteoarthritis

Peter A. Everts, Luga Podesta, José Fábio Lana,

Gayan Poovendran, Gabriel Silva Santos,
and Stephany Cares Huber

21.1 Introduction are still limited, other than the use of autologous
biologics like PRP and bone aspirate marrow
Osteoarthritis (OA) is a degenerative and debili- concentrate (BMAC), or similar derived products
tating joint disease and is one of the most preva- [3]. It has been suggested that A2M, a serum pro-
lent diseases in the United States [1]. OA is tease inhibitor protein, inhibits the many endog-
characterized by a painful inflammatory disease, enous and exogenous proteinases presenting in
causing progressive articular cartilage destruc- the pathogenesis of OA [4], despite the fact that
tion, limiting patients in their activities. An only few clinical studies report on the application
increase in prevalence and incidence in osteoar- of A2M in OA pathologies [5]. Unfortunately,
thritis can be attributed to many factors, with age robust clinical trials are lacking regarding the
and obesity being the most frequent factors [2]. A2M treatment efficacy and mid- to long-term
Currently, many orthobiologic treatments options results.
are available to treat various osteoarthritic pathol-
ogies (Fig. 21.1). Nonsurgical treatment options
21.1.1 Safety and Contraindications

P. A. Everts (*) A2M proteins are naturally occurring macromol-

Research and Education Division, Gulf Coast
ecules and are present in a low concentration in
Biologics, Fort Myers, FL, USA
the circulation or in the synovial fluid of joints. In
OrthoRegen Group, Max-Planck University,
order to be an effective orthobiologic product, it
Indaiatuba, SP, Brazil
e-mail: peter@[Link] has been suggested to use concentrated A2M as
an orthobiologic injectate [6]. Zhu et al. postu-
L. Podesta
Bluetail Medical Group and Podesta Orthopedic lated that A2M is an autologous proteinase inhib-
Sports Medicine, Naples, FL, USA itor with no autoimmune rejection potential and
J. F. Lana only one active ingredient, while inhibiting vari-
OrthoRegen Group, Max-Planck University, ous inflammatory factors and degenerative pro-
Indaiatuba, SP, Brazil teinase [7]. They mentioned no negative effects
G. Poovendran of A2M injections, or adverse events following
Pro-Institute Poovendran Regenerative Orthopedics, the preparation method, which in part is very
Davie, FL, USA
similar to the preparation of PRP.
G. S. Santos · S. C. Huber
Brazilian Institute of Regenerative Medicine (BIRM),
Indaiatuba, Brazil

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 133
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
134 P. A. Everts et al.

Fig. 21.1 At point-of-care autologous orthobiologic plasma matrix, PRP platelet-rich plasma, PRF platelet-­
preparations. Many orthobiologic products are available rich fibrin, PL platelet lysate, BM bone marrow, AT adi-
to treat a plethora of musculoskeletal pathologies. In this pose tissue, NR-PRP neutrophil-rich PRP, NP-PRP
figure an overview is presented only from autologous pre- neutrophil-poor PRP, P-PRP pure PRP, PRP-G PRP gel,
pared products, prepared at point-of-care, and a combina- BMA bone marrow aspirate, BMAC bone marrow aspirate
tion of this products. POC point-of-care, MSC concentrate, ATC adipose tissue complex, t-SVF tissue
mesenchymal stem cell, ACS autologous conditioned stromal vascular fraction, c-SVF cellular stromal vascular
serum, A2M alpha-2-marcoglobulin, PPP-M platelet-poor fraction, AT autologous thrombin

21.2 General Background A2M 21.2.1 Pharmacological Aspects A2M

Protein Complex
A2M proteins interact with a broad range of pro-
Human A2M is a homo-tetrameric glycoprotein teolytic endo-proteinases that break peptide
with four identical subunits each with a molecu- bonds of nonterminal amino acids, by acting as
lar mass of 180 kDa; consequently the entire an inhibitor of active catalytic proteins A2M pro-
A2M weight is more than 720 kDa. A2M is one tein complexes have a broad inhibition range,
of the largest plasma proteins in the human body, mainly because of their unique mechanisms of
produced in the liver and present in plasma [8]. action [9]. By forming a tetrameric cage around
A2M proteins occur primarily in serum at 1.5 active proteases, A2M inhibits protease-substrate
mg/ml in healthy patients, and at approximately a interaction physically, a mechanism referred to as
tenth of that concentration in healthy synovial the protease “snap-trap” mechanism [10]. This
fluid (SF) [6]. A2M acts as protease inhibitor, leads to the fact that proteases that are “trapped”
transporting hormones and enzymes; displays by A2M are prevented from cleaving large sub-
effector and inhibitor functions in the develop- strate molecules (e.g., collagen), while small
ment of the lymphatic system; and hinders com- peptides (which escape the A2M cage) will be
ponents of the complement system and hemostasis digested as normal. By cleaving the bait region
system. More specifically, A2M treatments are with a protease, A2M becomes activated (a-A2M)
hypothesized to act as a treatment modality due and undergoes a conformational change, thereby
to inhibitory properties, suppressing proteinates trapping active proteases in its cage. Furthermore,
that are known to be harmful to cartilage. along with sterically capturing proteases, a-A2M
21 Alpha-2-Macroglobulin Concentrate as Orthobiologic in Osteoarthritis 135

also exposes a reactive thioester that forms 21.2.2 Growth Factors, Cytokines,
covalent A2M/protease complexes with small
­ and A2M Application
primary amines [11, 12]. However, during con-
formational rearrangements that take place dur- It has been implied that the presence of A2M in
ing the transition into a-A2M, the receptor SF acts to reduce concentrations of various pro-
binding domains (RBDs) are exposed onto the teinases harmful to cartilage, potentially attenu-
surface of the protease-­a-A2M complex during ating OA symptoms and encouraging
conformational rearrangements, wearying. In chondrogenesis. Studies on biochemical interac-
turn, this causes a-A2M complexes to be flagged tion revealed that many growth factors and cyto-
by low-density lipoprotein receptor-related pro- kines bind to A2M-binding proteins. In particular,
tein-1 for uptake by cells [13]. In Fig. 21.2, a growth factors such as transforming growth fac-
graphical representation of the various A2M bio- tor (TGF)-β1, fibroblast growth factor (FGF)-2,
logical activation steps is presented. macrophage activation factors (MACFs), and

a b c d

Fig. 21.2 Illustration of the A2M interactions with prote- trapping and A2M activation (a-A2M), as shown in (c),
ases. The four monomer subunits of the nonactivated followed by conformational rearrangement of the protein
A2M tetramer, each 180 kDa in molecular weight, each and subsequent development of covalently bonding
with their own bait regions (BRs) (red stars), are shown in between A2M and the protease residues (orange stars),
(a). Furthermore, each monomer contains receptor-­ setting up for an a-A2M-protease complex and change in
binding domains (RBDs). In (b), active proteolytic endo-­ RBDs, as they are now open to the A2M protein surface,
proteinases (P) will cleave the BR, resulting in protease represented in (d)
136 P. A. Everts et al.

tumor necrosis factor-alpha (TNF-α) have a high 21.3.1 The Protective Effects of A2M
binding affinity for a-A2M and reach a binding in Synovial Fluid (SF)
equilibrium within 15 min after binding to
a-A2M [14–17]. Additionally, mild evidence Specific studies like Western blot analysis, protein
hints toward the potential of A2M to inhibit acti- mass spectrometry, ELISA, and immunohisto-
vated matrix metalloprotease-13 (MMP-13) chemistry have indicated that A2M is an element
in vivo [18]. Other experimental and in vitro of joint synovial fluid (SF). However, the A2M
studies demonstrated that A2M can capture concentration in SF is much lower than in serum,
MMPs by the creation of A2M/MMP complexes even in patients with knee OA [7]. Wang et al.
[19] in the presence of their natural occurring tis- demonstrated that the A2M concentration in SF is
sue inhibitors of matrix metalloproteinase too low to adequately inhibit catabolic proteinases
(TIMPs), even when there is a surplus of active to counteract on intra-articular inflammation [26].
MMPs [18]. Extracellular proteases known as a In this way, the concept behind employing c-A2M
disintegrin and metalloproteinase with thrombos- is based on the idea that its molecular structure
pondin motifs (ADAMTS) are known for their enables it to perform a unique mechanistic func-
roles in extra cellular matrix (ECM) degeneration tion in binding inflammatory mediators in a spe-
and OA [20]. Furthermore, reports indicate that cific way. OA inflammation and degradation
ADAMTS-1, ADAMTS-4, ADAMTS-5, might be limited by providing supplemental intra-
ADAMTS-7, and ADAMTS-12 were inhibited articular c-A2M injections to facilitate chondro-
by A2M, in a dose-dependent manner [20]. genic and chondroprotective effects.
Cuellar et al. showed that A2M can additionally
reduce cytokine-induced upregulation of collage-
nases in chondrocytes via trapping IL-1β and 21.4 Procedural Steps Producing
TNF-α [21]. A2M as Orthobiologic
Injectate

21.3 Modulating Inflammation A2M preparation methods involve a unit of fresh

and Cartilage Degradation autologous peripheral blood, a whole blood den-
in OA sity separation procedure, and the use of ultrafil-
tration devices. PRP preparation methods will
In OA, chronic inflammation contributes to pain not be discussed here and are presented previ-
mediated by TNF-α, interleukin (IL)-1β and ously in this book.
IL-6, and other cytokines and chemokines [22].
Also, they downregulate ECM protein produc-
tion, while inducing the up regulation of MMPs 21.4.1 Ultrafiltration Process
and ADAMTS leading to the degradation colla-
gen [23, 24]. Subsequently, the degradative prod- Microfiltration and ultrafiltration techniques have
ucts of cartilage catabolism will stimulate the been used widely used for decades as blood-­
production of inflammatory proteases, in addi- plasma contact devices in blood apheresis [27].
tion to cytokines, which further contributes to Later, these techniques were used to concentrate,
increases in inflammatory proteases, specifically increase, the hematocrit of diluted blood, in par-
elastase and cathepsins [25]. It has been shown ticular in infant cardiac surgery [28]. Thereafter,
that A2M decreases cartilage catabolism, inhibit- modified ultrafiltration techniques were success-
ing the protease activity of MMPs, ADAMTS, fully developed to alleviate inflammatory
TNF-α, and IL-1β and other mediators of the responses caused by cytokines [29]. Ultrafiltration
pathologic cartilage catabolism process and ECM techniques are sterile, convective processes,
breakdown [6]. wherein PPP is either mechanically or manually,
21 Alpha-2-Macroglobulin Concentrate as Orthobiologic in Osteoarthritis 137

transported through a microporous membrane. techniques to eliminate plasma water, small pro-
Plasma proteins with a molecular mass, molecu- teins, proteases, and chemokines, while increas-
lar weight, less than the pore size of are filtered ing the larger plasma protein concentrations
out of the device. Ultrafiltration devices are made (albumen, fibrinogen, and A2M).
of high-performance medical-grade polymers, A predetermined unit of whole blood is cen-
elastomers. Devices should offer an excellent trifugated, producing PRP, PPP, and a concen-
biocompatibility and viscoelasticity, with weak trated layer of erythrocytes. After the PRP density
intermolecular forces. Furthermore, they should separation procedure [31], the PPP fraction is not
present a consistent performance with a minimal discarded, but properly isolated and collected,
residual volume in the device after processing. using aseptic techniques. The PPP fraction is
Ultra-filtrating plasma water will occur at a rate exposed to plasma ultrafiltration, employing dedi-
proportional to a transmembrane pressure gradi- cated disposable ultrafiltration systems, using
ent of the ultrafiltration device. either mechanical or manual preparation tech-
niques to transport the PPP through the synthetic
fibers of the ultrafiltration device. Ultrafiltration
21.4.2 Clinical A2M Preparation techniques will result in concentrating, yielding,
Techniques large plasma proteins, like A2M and other pro-
teins. The final c-A2M treatment vial is, ideally,
The preparation of concentrated A2M can be image guided delivered to pathoanatomic tissues.
executed as an office-based preparation proce- The initial technique for concentrating autolo-
dure, and requires approximately 60 minutes, gous plasma, producing A2M concentrate, with the
depending on the PRP preparation technology intent to prepare an orthobiologic treatment prod-
used, plasma concentration method, and total uct capable of regulating endogenous catabolic
whole blood volume needed to prepare the cytokines and inhibiting the activities of serine pro-
desired amount of concentrated plasma volume teases and MMPs in OA, is a method described by
for the therapeutic application [30]. A2M therapy Cuellar et al. They described the use of Autologous
involves a unit of fresh peripheral blood that is Platelet Integrated Concentration system (APIC™,
processed by single or double spin PRP prepara- Cytonics, Jupiter FL, USA), to prepare an orthobi-
tion devices, and ultimately PPP ultrafiltration ologic injectate, as shown in Fig. 21.3 [32].

Fig. 21.3 The Cytonics APIC™ A2M mechanical prepa- the filter to eliminate water and other plasma constituents
ration setup. The Cytonics setup includes a concentration that can pass the filter poor size. The manufacturer indi-
kit with a plasma concentration filter pump tubing and cates that the filtration process only takes 20 min, apart
collection bags. The PPP is mechanically pumped through from the whole blood centrifugation steps
138 P. A. Everts et al.

a b

Fig. 21.4 The EmCyte Corporation® CORE™ retentate, or ultrafiltrate volume, is collected in an effluent
Ultrafiltration System for PPP protein concentrtion. In (a), syringe, attached to the effluent port. When the desired vol-
the CORE™ ultrafiltration device is placed in a black table ume of protein concentrate (including A2M proteins) is
manifold for easy processing. The plasma in the syringes is reached, the protein concentrate can be extracted, while
injected back and forth through the device. The plasma emptying the filter with an air filter attached, as shown in (b)

Thereafter, more ultrafiltration devices have knee osteoarthritis with Kellgren-Lawrence grade
entered the orthobiologic market to concentrate 2 or 3, revealed that c-A2M was not significantly
PPP following a PRP procedure to prepare c-A2M, better than regular PRP, assessing visual analog
along with other large plasma proteins. Figure 21.4 scale scores, Western Ontario and McMaster
illustrates the latest ultrafiltration device, using a Universities Osteoarthritis Index (WOMAC),
simple, pumpless manual force syringe technique Knee Injury and Osteoarthritis Outcome Score
for the ultrafiltration process to produce protein (KOOS), and Lysholm and Tegner scores [36].
concentrates, that includes A2M (Core™ ultrafil- Nevertheless, large clinical studies have not
tration device, EmCyte Corp, Fort Myers FL). (yet) been performed and are needed to assess its
true potential benefits for OA, including compar-
ative studies using accepted and well-published
21.5 Clinical Data orthobiologic products like PRP and mesenchy-
mal stem cell-based tissue concentrates [37].
There are several distinct clinical applications of
employing autologous concentrated A2M,
including the treatment of painful intra-articular 21.6 Future Directions
and extra-articular joints, following mild to mod-
erate OA of the knee, hip, and shoulder, as well as Early data from experimental and small clinical
spinal discogenic pain [33, 34]. case series are encouraging, indicating the poten-
Human clinical trials addressing the efficacy of tial of c-A2M supplementation in a variety of
concentrated A2M are scarce. According to musculoskeletal disorders. Larger, prospective,
Clinical [Link], some studies are underway and comparative clinical trials need to be
and yet to be published [3]. However, several ani- designed to further support and enhance the cur-
mal studies have reported positive outcomes [22, rent available preliminary results.
35]. Klein et al., in 75 patients randomized con- Based on available scientific data, new
trolled clinical trial, patients had symptomatic research and scientific steps should be directed
21 Alpha-2-Macroglobulin Concentrate as Orthobiologic in Osteoarthritis 139

towards further understanding the activities of 5. Thompson K, Klein D, Campbell K, Gonzlez-Lomas

proteolytic endo-proteinases and application of G, Alaia M, Strauss E, et al. The effectiveness of
alpha-2-macroglobulin injections for osteoarthri-
c-A2M mechanisms, effective concentrations, tis of the knee. Arthrosc J Arthrosc Relat Surg.
and activation about a better comprehension of 2021;37(1):e80. Available from: [Link]
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lating the local tissue immune microenviron- 6. Wang S, Wei X, Zhou J, Zhang J, Li K, Chen Q,
et al. Identification of α2-macroglobulin as a master
ment, related to cartilage pathologies. This inhibitor of cartilage-degrading factors that attenu-
includes further characterization of anti-­ ates the progression of posttraumatic osteoarthri-
proteinase proteins to specifically target mecha- tis: α2 M attentuates posttraumatic OA progression.
nisms responsible for joint pathophysiology, Arthritis Rheumatol. 2014;66(7):1843–53. [Link]
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disease progression, and hopefully an ability for 7. Zhu M, Zhao B, Wei L, Wang S. Alpha-2-­
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Lastly, A2M is easily isolated as a major con- inhibitor, prevents cartilage degeneration disease by
tributor of PRP therapies. The combination of inhibiting majority of catabolic enzymes and cyto-
kines. Curr Mol Biol Rep. 2021;7(1):1–7. [Link]
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 Part IV
Injections of Anatomical Regions
and Diseases
 Injections of Anatomical Regions
and Diseases: Shoulder
22
Mocini Fabrizio , Candura Dario,
Proietti Lorenzo, Ciolli Gianluca,
Brancaccio Vincenzo, and Cerciello Simone

22.1 Sternoclavicular Joint supply of the joint is from the medial suprascapu-
lar nerve and the nerve to the subclavius. The
22.1.1 Anatomy and Biomechanics normal SCJ achieves 35° of movement both in
the coronal and horizontal plane during shoulder
The sternoclavicular joint (SCJ) is the only joint abduction along with 45° of rotation. The muscu-
between the axial skeleton and the upper limb. It lar stabilizers which also move the SC joint
is a saddle-shaped diarthrodial joint with the two include the sternocleidomastoid, pectoralis
articular surfaces covered with hyaline cartilage. major, deltoid, trapezius, and rhomboids. These
The joint is concave in the vertical axis and con- muscles work together to stabilize the joint dur-
vex in the anteroposterior axis. The articulating ing movements of the upper limb [1].
surfaces are separated by an articular disc. The
joint is stabilized medially by the anterior and
posterior sternoclavicular ligaments and laterally 22.1.2 Pathologies and Indication
by the interclavicular and costoclavicular liga- for Injections
ments. The anterior and posterior sternoclavicu-
lar ligaments fix the clavicle to the sternum and The SCJ can be affected by many pathologic con-
provide anterior and posterior stability to the ditions such as dislocation and subluxation (ante-
joint. The interclavicular ligament connects the rior and less frequently posterior),
two clavicles together, while the costoclavicular synovitis-acne-pustulosis-hyperostosis-osteitis
ligament connects the clavicle to the first rib. (SAPHO), avascular necrosis (Friedrich disease),
Vascular supply to the SCJ comes from the supra- rheumatic arthritis, and crystalline arthropathies.
scapular artery and internal thoracic artery. Nerve Besides these, the most common pathologic con-
dition of the SCJ is osteoarthritis (OA), which is
asymptomatic in most cases [2]. Cadaveric stud-
M. Fabrizio (*) · P. Lorenzo ies in patients aged over 60 years have shown OA
Casa di Cura Villa Betania GIOMI, Rome, Italy to be present in over 50% of subjects. Pain caused
C. Dario · B. Vincenzo by OA of the SCJ is typically increased with
Fondazione Universitaria Policlinico Agostino abduction or forward flexion beyond 90°. The
Gemelli, Roma, Italy
treatment is usually conservative with NSAIDs
C. Gianluca · C. Simone and/or steroid injections [3]. Surgery is recom-
Casa di Cura Villa Betania GIOMI, Rome, Italy
mended for symptomatic patients unresponsive
Fondazione Universitaria Policlinico Agostino to conservative treatment. Surgical options are
Gemelli, Roma, Italy

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 143
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
144 M. Fabrizio et al.

arthroscopic or open resection arthroplasty. SCJ bed elevated at 30–40°. In most cases, the clavicle
injections can be also performed as diagnostic is more prominent than the sternum, so a step is
purpose: the patient’s pain is relieved following easily palpable as a landmark of the SCJ. In the
the injection; it can be concluded that the joint iscase of difficulty in identifying the SCJ due to
the source of the pain. anatomical abnormalities, the shoulder can be
passively abducted and externally rotated in order
to increase the joint space. Sterile technique is
22.1.3 Appliances applied, and structures are marked. A small
amount of local anesthetic may be injected to
The type of injector, needle, and syringe used numb the skin and deeper tissues around the injec-
depends on the preference of the healthcare pro- tion site. Once the SCJ is localized, a 25- to 27-G
vider and the specific pathologic conditions. 25- to 38-mm needle is introduced with an ante-
Usually, a 25- to 27-G, 25- to 38-mm needle is rior-to-posterior approach, and the SCJ is injected
used, and the SCJ is injected with 1–3 mL of with usually 1–3 mL of injectate to avoid overdis-
injectate to avoid overdistension. tension (Fig. 22.1). An overall accuracy of 78%
for palpation-guided SCJ injections in cadavers
has been demonstrated [4]. To facilitate visualiza-
22.1.4 Agents tion of the SCJ and increase accuracy, injections
can be performed under CT or, more easily, ultra-
Corticosteroids, local anesthetics, visco-­sound guidance. The SCJ is best visualized using
supplements, and orthobiologic agents. a high-frequency (>10 MHz) linear transducer
placed long axis to the clavicle (short axis to the
joint) with the center of the joint in the center of
22.1.5 Injection Technique the transducer. Color Doppler can be helpful to
identify the carotid artery which is located deep to
The patient is placed in supine position with the the SCJ [5]. The needle is then removed, and a
head turned to the opposite side and the top of the sterile dressing is applied to the injection site.

Fig. 22.1 Sternoclavicular joint injection: patient placed by palpation, and 1–3 mL are injected with a 25- to 27-G
in supine position with the head turned to the opposite 25- to 38-mm with an anterior-to-posterior approach
side and the top of the bed at 30–40°, the joint is identified
22 Injections of Anatomical Regions and Diseases: Shoulder 145

22.1.6 Aftercare 22.2.2 Pathologies and Indication

for Injections
The patient is observed for a while. In the first
24–48 h, information is given about the symp- The main indications for injection of the ACJ are
toms that may worsen. Rest is recommended for rheumatic arthritis, osteolysis of the distal clavi-
at least 24–48 h after the injection. Avoiding cle, and mainly primary or post-traumatic
activities that may stress the joint, such as heavy OA. Patients with chronic ACJ pain are usually
lifting, is recommended. Applying ice to the older than 40 years and complain a focal pain
injection site for 20 min at a time, several times a located over the superior aspect of the ACJ. The
day, for the first 48 h can help reduce pain and pain is insidious and exacerbated with direct pal-
swelling. Pain medication such as paracetamol or pation of ACJ or with cross-body adduction of
NSAIDs can help relieving pain. It is obviously the shoulder. Patients may also describe a grind-
important to watch out for side effects in the ing sensation. Conservative treatment with physi-
injection site such as redness, swelling, or drain- cal therapy, NSAIDs, and intraarticular injections
age that could indicate an infection. Depending represents the first therapeutic approach in most
on the underlying condition that led to the sterno- cases [8]. Surgery is recommended for symptom-
clavicular joint injection, physical therapy may atic patients unresponsive to conservative mea-
be recommended to help improve joint mobility sures and include arthroscopic and open distal
and strength. clavicle excision, but the current scientific litera-
ture has not shown significant differences
between conservative and surgical treatment [9].
22.2 Acromioclavicular Joint ACJ injections can be both diagnostic and thera-
peutic, resulting in significant pain relief for
22.2.1 Anatomy and Biomechanics affected patients. The duration can last weeks to
months, and it is variable among patients. Steroid
The acromioclavicular joint (ACJ) is a small diar- injections can be repeated, but multiple injections
throdial joint that connects the distal clavicle to should be avoided because they can result in deg-
the acromion process of the scapula. The two radation of joint cartilage over time.
articular extremities are separated by a fibrocarti-
laginous disc, and the joint is surrounded by a
synovial membrane. The acromioclavicular liga- 22.2.3 Appliances
ments provide horizontal stability to the joint,
whereas the coracoclavicular ligaments (trape- The type of injector, needle, and syringe used
zoid and conoid) provide vertical stability. depends on the preference of the healthcare pro-
Additional stabilization is provided by coracoac- vider and the specific condition being treated.
romial ligament and the attachments of the del- Usually, a 22- to 27-G 25- to 38-mm curved or
toid and trapezius muscles [6]. The biomechanics straight needle is used for the injection of a vol-
of the ACJ is complex and involves multiple ume of 5–10 mL.
structures: during shoulder abduction, the scap-
ula rotates upward and outward, and the clavicle
moves upward and rotates posteriorly at the AC 22.2.4 Agents
joint. Moreover, the ACJ transfers forces from
the arm to the trunk during activities such as Corticosteroids, local anesthetics, visco-­
throwing or pushing, allowing the arm to gener- supplements, and orthobiologic agents.
ate more force [7].
146 M. Fabrizio et al.

22.2.5 Injection Technique moved laterally until the ACJ; then the needle is
introduced and described before but now under
The patient is placed in supine or seated position direct visualization, and the ACJ is injected under
with the arm at the side. To identify the ACJ, pal- with the desired amount of injectate (usually <10
pate the clavicle distally until a small depression mL) avoiding excess overdistension of the joint.
just lateral to termination of the bone. The ACJ
has a very variable anatomy, further worsened by
the OA changes [10]. After aseptic preparation of 22.2.6 Aftercare
the skin, a local anesthetic can be used to numb
the skin and underlying tissues to reduce discom- The patient is observed for a while. In the first
fort during the injection. Insert a 22- to 27-G 25- 24–48 h, information is given about the symp-
to 38-mm needle from the superior-anterior toms that may worsen. Rest is recommended for
approach with the needle perpendicular to the at least 24–48 h after the injection. Avoid activi-
joint (Fig. 22.2). The needle should not meet any ties that may stress the joint, such as heavy lift-
resistance. Once in the joint, if fluid is present in ing. Applying ice to the injection site for 20 min
the joint and creates overdistension, the provider at a time, several times a day, for the first 48 h can
may use the needle to withdraw the fluid for test- help reducing pain and swelling. Pain medication
ing or to relieve pressure in the joint. Any solu- such as paracetamol or NSAIDs can help relieve
tion must be injected slowly. Accuracy of blind pain. It is obviously important to watch out for
needle placement for ACJ is very low, since it side effects in the injection site such as redness,
was found to be about 40% [11]. Fluoroscopy or swelling, or drainage that could indicate an infec-
ultrasound, if available, can significantly improve tion. Depending on the underlying condition that
the accuracy of ACJ injections up to 100% [12]. led to the ACJ injection, physical therapy may be
A high-frequency (>10 MHz) linear-array trans- recommended to help improve joint mobility and
ducer is placed short axis to the clavicle and strength.

Fig. 22.2 Acromioclavicular joint injection: patient 38-mm needle from the superior-anterior approach per-
placed in seated position, the joint is identified by palpa- pendicular to the joint
tion, and the fluid is injected with a 22- to 27-G 25- to
22 Injections of Anatomical Regions and Diseases: Shoulder 147

22.3 Subacromial Bursa not validated in the literature, many authors agree
to the use of subacromial infiltrations with corti-
22.3.1 Anatomy and Biomechanics sone in the acute phase of calcific tendinopathy
together with NSAIDs and physiotherapy for the
The subacromial bursa (SB) is a virtual synovial maintenance of ROM [16]. Finally, subacromial
space that is located deep to the deltoid muscle, corticosteroid injections have also been described
acromion, and the coracoacromial (CA) ligament for the treatment of adhesive capsulitis with
and superficial to the supraspinatus tendon, rota- results comparable to the glenohumeral joint
tor interval (RI), greater tuberosity, and intertu- injections [17]. In addition, hyaluronic acid (HA)
bercular groove [13]. The bursa is composed of injections have also been described in the attempt
subacromial and subdeltoid portions, with a sub- of a conservative approach of cuff and bursal dis-
coracoid extension in some cases. The subdeltoid orders. They have proven to be a valuable safe
bursa lies between the deltoid muscle and the alternative to other conservative methods for the
acromion, while the subacromial bursa proper treatment of rotator cuff disorders [18].
lies between the rotator cuff tendons and the
acromion. The anterior portion of the bursa under
the CA arch has a significant role in outlet 22.3.3 Appliances
impingement [14]. The SB is about 1 mm in
thickness in normal conditions, and it is covered The type of injector, needle, and syringe used
superficially by a layer of peri bursal fat. During depends on the preference of the healthcare pro-
movement of the shoulder joint, the rotator cuff vider and the specific condition being treated.
tendons slide back and forth beneath the acro- Usually, a 21- to 25-G 38-mm needle is used for
mion. The subacromial bursa acts as a lubricated the injection of a volume of 5–10 mL.
cushion, reducing friction and preventing dam-
age to the rotator cuff tendons. It also helps to
distribute the force of movement evenly across 22.3.4 Agents
the joint.
Corticosteroids, local anesthetics, visco-­
supplements, and orthobiologic agents.
22.3.2 Pathologies and Indication
for Injections
22.3.5 Injection Technique
SB bursopathy is a very common pathologic con-
dition that can be a primary or secondary cause of The most common sites of injection are the stan-
shoulder pain. The pathologic conditions most dard posterior and anterolateral (lateral) arthros-
often associated are subacromial impingement copy portals.
and rotator cuff tears. The use of subacromial
injections of corticosteroid and local anesthetic Posterior Approach The patient is placed in
represents an inexpensive and efficacious way seated or prone position with the affected arm in
both to diagnose and treat symptomatic rotator a relaxed position. After palpatory identification
cuff disease and subacromial impingement. of the posterolateral corner of the acromion,
Although corticosteroids will not heal the rotator insert the needle about 2 cm inferiorly and 1 cm
cuff tear, they can reduce the associated inflam- medially (soft spot), and direct it anteriorly aim-
mation of the bursa and the tendons, reducing ing upward at a 10° angle (Fig. 22.3). Gently pull
pain and allowing patients their activities of daily back on the plunger as you advance to rule out
living (ADL) [15]. Subacromial infiltrations may intravascular placement. Slowly inject and with-
also play a role in calcific tendinopathy. Although draw the needle.
148 M. Fabrizio et al.

Fig. 22.3 Subacromial bursa injection (posterior mion, a 21- to 25-G 38-mm needle is inserted about 2 cm
approach): patient placed in seated position, after palpa- inferiorly and 1 cm medially and directed anteriorly
tory identification of the posterolateral corner of the acro- upward at a 10° angle

Fig. 22.4 Subacromial bursa injection (lateral approach): 38-mm needle is inserted about 2 cm below the border and
patient placed in seated position, after palpatory identifi- 1 cm posterior to the anterior edge of the acromion
cation of the lateral border of the acromion, a 21- to 25-G

Lateral Approach The patient is placed in seated may be in contact with the acromion or within the
or lateral decubitus on the contralateral side. supraspinatus tendon. Partially withdraw the nee-
After palpatory identification of the lateral border dle, and then readvance in a slightly different
of the acromion, insert the needle about 2 cm direction so as not to encounter any resistance.
below the border and 1 cm posterior to the ante-
rior edge of the acromion (Fig. 22.4). If the nee- The provider may withdraw any fluid that may
dle or the injections meet resistance, the needle be present in the bursa for diagnostic purposes or
22 Injections of Anatomical Regions and Diseases: Shoulder 149

to relieve pressure within the joint. Once the nee- MHz) linear-array transducer placed long axis to
dle is properly positioned in the subacromial the supraspinatus tendon fibers. The needle is
bursa, the fluid is gently injected into the bursa. introduced under direct visualization of the ultra-
The accuracy of the blind subacromial injec- sound image to ensure proper placement within
tions is about 80%, and no difference has been the SB, and the desired amount of drug is injected.
demonstrated between the two approaches [14].
To improve the visualization of the anatomical
structures and increase the accuracy, the proce- 22.3.6 Aftercare
dure can be performed under ultrasound guid-
ance (Fig. 22.5). Being a superficial structure, the The patient is observed for a while. In the first
SB is best visualized using a high-frequency (>10 24–48 h, information is given about the symp-
toms that may worsen. Rest is recommended
for at least 24–48 h after the injection. Avoid
activities that involve heavy lifting or overhead
movements for a few days to a few weeks fol-
lowing the injection. Gentle range of motion
exercises are recommended to help prevent
stiffness in the shoulder joint. Applying ice to
the injection site for 20 min at a time, several
times a day, for the first 48 h can help reduce
pain and swelling. Pain medication such as
paracetamol or NSAIDs can help relieve pain.
It is obviously important to watch out for side
effects in the injection site such as redness,
swelling, or drainage that could indicate an
infection. Depending on the underlying condi-
tion that led to the SB injection, physical ther-
apy may be recommended to help improve joint
mobility and strength.

22.4 Glenohumeral Joint

22.4.1 Anatomy and Biomechanics

The glenohumeral joint (GHJ) is a diarthrodial

multiaxial joint with a ball-and-socket configura-
tion. It is composed of the hyaline-covered spher-
ical humeral head and the flat hyaline-covered
glenoid fossa of the scapula with a fibrocartilagi-
nous labrum that increases the congruence and
the stability of the joint. The joint is surrounded
by a fibrous capsule that is reinforced by liga-
Fig. 22.5 To increase the accuracy, shoulder injections ments that attach the humerus to the scapula.
can be performed under ultrasound guidance. The needle
(arrow) is introduced under direct visualization of the Moreover, there are several joint recesses associ-
ultrasound image to ensure proper placement, and the ated including the axillary and the subscapular
desired amount of drug is injected recesses and the LHBBT sheath [19, 20].
150 M. Fabrizio et al.

The biomechanics of the GHJ is complex: the or open) may be indicated depending on the path-
joint is inherently unstable due to the shallow ological conditions.
socket of the glenoid fossa. This anatomic con-
figuration allows a wide ROM (flexion, exten-
sion, abduction, adduction, internal and external 22.4.3 Appliances
rotation, and circumduction). To provide stabil-
ity, the joint relies on a complex network of liga- The type of injector, needle, and syringe used
ments, muscles, and tendons, including the depends on the preference of the healthcare pro-
rotator cuff muscles, which work to keep the vider and the specific condition being treated.
humeral head centered in the glenoid fossa. The Usually, a 21- to 25-G needle is used. The needle
forces acting on the GHJ during movement can should be long enough to reach the joint space,
be quite high, especially during activities such as but not so long that it risks damaging surrounding
throwing or lifting heavy objects. The joint is structures. A needle length of 4–7 mm is typi-
designed to distribute these forces across the joint cally used, although shorter or longer needles
surfaces and surrounding tissues, including the may be used depending on the patient’s anatomy.
labrum, articular cartilage, and rotator cuff mus- The amount of fluid injected is usually 10–20
cles [21, 22]. mL. Larger volumes (20–40 ml) can be used in
hydro-dilatation procedures in the case of adhe-
sive capsulitis [31, 32].
22.4.2 Pathologies and Indication
for Injections
22.4.4 Agents
The GHJ can be affected by several post-­
traumatic or idiopathic pathologic conditions. Corticosteroids, local anesthetics, visco-­
The most common are rotator cuff tear (partial supplements, and orthobiologic agents.
articular or complete), labral injury, inflamma-
tory diseases such as rheumatoid arthritis and
adhesive capsulitis, OA, and cuff tear 22.4.5 Injection Technique
arthropathy.
Conservative treatment often represents the The glenohumeral joint can be injected from an
first line of treatment, and it consists of physical anterior or posterior approach. The accuracy rate
therapy, oral NSAIDs, and intra-articular GHJ of GHJ injections in cadaveric setting was dem-
injections [23, 24]. Depending on the type and onstrated to be between 50% and 96% [33] with
severity of pathological condition, the type of the anterior approach being considered slightly
patient treated, these therapies can have a good more accurate than the posterior [34]. As for the
effect. A good efficacy of GHJ intra-articular previously described anatomic regions of the
infiltrations of corticosteroids or orthobiologic shoulder, also in this case, the procedure can be
agents has been demonstrated in improving performed under fluoroscopically or ultrasound
symptoms in adhesive capsulitis and in partial guidance to increase the accuracy up to 100%
rotator cuff tears at mid- and long-term follow-up [35].
[25–28]. Even in shoulder OA and rotator cuff
arthropathy, intraarticular GHJ injections with Anterior Approach The patient is placed in
HA or orthobiologic agents can give excellent supine or seated position with the arm affected in
results in the improvement of pain symptoms at a slight external rotation. A 23- to 25-G 50-mm
short- and mid-term [29, 30]. When conservative needle is introduced just medial to the head of the
therapy does not produce the desired effect on humerus and 1 cm lateral to the coracoid process
GHJ pathologies, surgical therapy (arthroscopic and directed posteriorly and slightly superiorly
22 Injections of Anatomical Regions and Diseases: Shoulder 151

Fig. 22.6 Glenohumeral joint injection (anterior 1 cm lateral to the coracoid process and directed posteri-
approach): patient placed in seated position with the arm orly and slightly superiorly and laterally into the joint
in a slight external rotation. A 23- to 25-G 50-mm needle space through the rotator interval
is introduced just medial to the head of the humerus and

and laterally into the joint space through the into the GHJ, and the desired amount of drug
­rotator interval (Fig. 22.6). If available, a high-­ (usually 5–10 mL) is injected.
frequency (>10 MHz) linear-array transducer is
placed in the anatomic axial plane over the rota- In the case of adhesive capsulitis, a higher vol-
tor interval, short axis to the long head of the ume of injectate can be utilized to produce capsu-
biceps tendon. The needle is introduced under lar distension, both from posterior or anterior
direct visualization into the GHJ and the desired approach. Volumes of up to 20 mL have been
amount of drug (usually 5–10 mL) in injected. reported with good clinical outcomes [31, 32]. In
this case, a bigger needle (21-G or larger) is used
Posterior Approach the patient is placed in to allow easier capsular distension. Care must
seated, prone, or lateral position with the arm also be taken to avoid overdistension of the joint.
affected at the side. After palpatory identification
of the posterolateral corner of the acromion, a 22-
to 25-G 50- to 70-mm needle is introduced about 22.4.6 Aftercare
2 cm inferiorly and 1 cm medially (soft spot), and
direct it anteriorly toward the coracoid process The patient is observed for a while. In the first
that can be easily palpated. It is important to 24–48 h, information is given about the symp-
avoid puncture of the glenoid labrum because it toms that may worsen. Rest is recommended for
could be very painful for the patient (Fig. 22.7). at least 24–48 h after the injection. Avoid activi-
If available, a 7.5- to 14-MHz linear array trans- ties that involve heavy lifting or overhead move-
ducer is positioned long axis to the fibers of the ments for a few days to a few weeks following
infraspinatus in the anatomic axial oblique plane the injection. Gentle range of motion exercises
to the GHJ. Passive shoulder motion may be used and stretches are recommended to help prevent
to make the joint space more conspicuous. The stiffness. Applying ice to the injection site for
needle is introduced under direct visualization 20 min at a time, several times a day, for the first
152 M. Fabrizio et al.

Fig. 22.7 Glenohumeral joint injection (posterior mion, a 22- to 25-G 50- to 70-mm needle is introduced
approach): patient placed in seated position, after palpa- about 2 cm inferiorly and 1 cm medially and direct it ante-
tory identification of the posterolateral corner of the acro- riorly toward the coracoid process

48 h can help reduce pain and swelling. Pain 6. Ha AS, Petscavage-Thomas JM, Tagoylo
medication such as paracetamol or NSAIDs can GH. Acromioclavicular joint: the other joint in the
shoulder. AJR Am J Roentgenol. 2014;202(2):375–85.
help relieve pain. It is obviously important to 7. Bontempo NA, Mazzocca AD. Biomechanics and
watch out for side effects in the injection site treatment of acromioclavicular and sternoclavicular
such as redness, swelling, or drainage that could joint injuries. Br J Sports Med. 2010;44(5):361–9.
indicate an infection. Depending on the underly- 8. Merrigan B, Varacallo M. Acromioclavicular joint
injection. In: StatPearls. Treasure Island: StatPearls
ing condition that led to the GHJ injection, physi- Publishing; 2022. Available from: [Link]
cal therapy may be recommended to help improve [Link]/books/NBK547727/.
joint mobility and strength. 9. Soler F, Mocini F, Djemeto DT, Cattaneo S,
Saccomanno MF, Milano G. No differences between
conservative and surgical management of acromiocla-
vicular joint osteoarthritis: a scoping review. Knee Surg
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pany impingement. Cochrane Database Syst Rev. interventions including exercise, manual therapy and
2013;4:CD007427. medical management in adults with shoulder impinge-
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Taeymans J, et al. Effectiveness of conservative
 Injections of Anatomical Regions
and Diseases: Elbow
23
Eduard Alentorn-Geli and Jorge Ramírez Haua

23.1 Elbow adequate evidence for efficacy in some condi-

tions and is also a promising field. Injections can
23.1.1 Anatomy, Diagnosis, be applied after palpation, under ultrasound, or
and Indications under fluoroscopy. It is obvious that image-­
guided injections will be more precise and may
The elbow is a complex joint with a number of help better improve the patients’ symptoms. The
specific features. Surgical procedures of the goal of this chapter is to report the existing evi-
elbow not uncommonly produce stiffness, het- dence regarding injections of different medica-
erotopic ossification, or infection due to its close tions for some of the most common elbow
proximity with the skin. Therefore, the goal is to disorders.
avoid surgery whenever possible, or to improve
symptoms with a less invasive treatment strategy.
Injections of the elbow can easily help in both 23.1.2 Type of Injections and Agents
goals. Several agents can be used for a number of
conditions. Most commonly used medications Injections can be classified regarding its way of
are corticosteroids, hyaluronic acid, anesthetics application or the agent applied. The former
(diagnostic injections), or orthobiologics. The refers to the use of image guidance, i.e.,
field of orthobiologics includes platelet-rich ultrasound-­guided injections or fluoroscopy-­
plasma (PRP) or stem cells. Nowadays, this field guided injections. The latter refers to the type of
is still growing, but there is enough evidence to medication given, typically corticosteroids, local
conclude that orthobiologics in the elbow has anesthetic, hyaluronic acid, collagen-tenocytes,
or orthobiologics (platelet-rich plasma and stem
cells).
E. Alentorn-Geli (*) Numerous studies have determined that the use
Instituto Cugat, Barcelona, Spain
of ultrasound increases the injection accuracy
Fundación García Cugat, Barcelona, Spain compared to “blinded” conditions [1]. On occa-
Mutualidad de Futbolistas, Delegación Cataluña, sions, the use of fluoroscopy is needed in order to
Barcelona, Spain assure intraosseous or intraarticular location of the
e-mail: ealentorn@[Link]
needle in certain joins. Corticosteroid injections
J. R. Haua cannot be generally recommended as a predictable
Mutualidad de Futbolistas, Delegación Cataluña,
Barcelona, Spain
treatment option. Despite some patients may get
benefit from this treatment modality when applied
Haua Sports Medicine, Granollers, Barcelona, Spain

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 155
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
156 E. Alentorn-Geli and J. R. Haua

in an inflamed bursa or in the peritendinous area,

its repetitive use is not recommended due to poten-
tially severe modification of tissue quality, particu-
larly if applied intratendinously. Infiltration of
corticosteroids inside the tendon decreases cellular
activity and collagen formation and produces dis-
organization and even necrosis of collagen fibers
and, therefore, is not recommended [2–5].
Interestingly, the application of PRP improved tis-
sue quality after ­corticosteroid injections [5]. This
is because PRP has been shown to increase teno-
cyte proliferation in vitro [6–9] and is in fact
Fig. 23.1 General, panoramic view of an elbow
accepted as a safe and efficacious way of support-
ultrasound-­guided injection. The ultrasonographist com-
ing tendon and ligament healing [10]. Moreover, fortably seats next to the patient with the screen in front so
PRP has demonstrated better outcomes for tendi- that there is no need to twist the head to look at the screen
nopathies at long term compared to corticosteroid and injection site
injections, despite similar or even superior out-
comes at the short term (first 4–8 weeks) with cor- mended, but the use of a fenestrated drape is
ticosteroid injections [11]. In addition, care should controversial because coverage of the examined
be taken with corticosteroids to avoid subcutane- joint may prevent adequate visualization of land-
ous atrophy and local depigmentation. In general, marks and optimal orientation. The probe of the
this type of injection is useful at providing a tem- ultrasound has to be adequately isolated using a
porary relief that may help other concomitant ther- sterile cover, as well. The ultrasonographist has
apies (i.e., physical therapy) to be more effective. to be in a comfortable position that facilitates
Even in cases of improvement, lack of preventive both the performance of the injection and an ade-
measures easily can predispose to recurrence, as quate visualization of the screen without cervical
they do not improve tissue quality. In general, cor- spine rotation (Fig. 23.1). During ultrasound-­
ticosteroid injections are not recommended as a guided injections, it is highly recommended to
continuous therapy for elbow tendinopathies, but identify the infiltration side from both the axial
as a single-use, second-line treatment option. and longitudinal views right before entering the
Hyaluronic acid injections have also been tried in needle. This will increase the precision of the
elbow tendinopathies with good outcomes injection.
[12–14].

23.1.4 Aftercare
23.1.3 Technique/Tricks/Pitfalls
After the injection, the patient is observed for
The preparation of an injection is universal. 15 min for the development of any early symp-
Despite infection after injections are very rare, toms. Depending on the injected agent, if no con-
the maximum care must be taken in order to min- traindication is present, icing for 15 min may be
imize its incidence. Thus, sterile conditions must helpful. Then, the patient is informed about rela-
be assured. The area to be infiltrated is first tive rest and low activity in first 24–48 h. And
cleaned for macroscopic dirtiness. Then, iodine patient should be warned about red flags for com-
or chlorhexidine solution is applied to the injec- plications such as redness, swelling, or drainage
tion side. Sterile gloves are strongly recom- from the injection zone.
23 Injections of Anatomical Regions and Diseases: Elbow 157

23.2 Radial Tuberosity (Biceps

Tendon Insertion)

23.2.1 Anatomy, Diagnosis,

and Indications

Most common distal biceps tendon disorders

include bicipitoradial bursitis, symptomatic dis-
tal biceps tendinosis including high-grade intra-
substance tears, partial tear of the distal biceps, or
complete tears. The insertion of the distal biceps
is a complex area in terms of anatomical mor-
phology and close proximity of neurovascular
structures. Therefore, the first consideration
when dealing with this condition is the need for
accurate infiltrations. In this regard, the use of
image-guided techniques is especially relevant. Fig. 23.2 General overview of the patient’s positioning,
ultrasonographist position, and anterior approach to the
Sellon et al. conducted a cadaveric study where
distal biceps tendon injection. The patient is lying supine
peritendinous (18 cases) and intratendinous (15 with the elbow in extension and the forearm supinated
cases) distal biceps tendon infiltrations were con-
ducted under ultrasound guidance by a single sur-
geon [15].

23.2.2 Technique/Tricks/Pitfalls

The authors performed the injection with the

patient lying supine in a semi-supinated forearm
position, infiltrating from distal to proximal
under the long axis view of the ultrasound with
the transducer in the antecubital fossa. This is the
standard position for an ultrasound-guided injec-
tion through an anterior approach to the distal
biceps tendon (Figs. 23.2 and 23.3). Despite the Fig. 23.3 Detail of an ultrasound-guided anterior
approach to the distal biceps. The transducer is first posi-
study lacks a control, comparative group, only 1 tioned to identify the antecubital bursa and the distal
of the 33 cases was not injected in the desired biceps. Then, the needle is advance following the long
location. Therefore, they concluded that axis of the transducer until it is seen on the screen
ultrasound-­guided distal biceps tendon injections
were very accurate. Similarly, van der Vis et al.
observed that manual injections around the distal 23.2.3 Type of Injections and Agents
biceps tendon (without ultrasound guidance)
were not accurate enough (21% inaccuracy) [16]. Regarding the type of medication, Barker et al.
The authors performed the injections through reported the outcomes of PRP infiltration for dis-
either an anterior or lateral approach and were tal biceps tendinopathy [17]. The authors used
conducted by upper limb specialist, general ultrasound guidance and infiltrated the PRP intra-
orthopedic surgeons, and orthopedic surgery resi- tendinously but using a preparation rich in leuko-
dents. Both studies used a cadaver model and cytes without platelet activation and with a
infiltrated latex and acrylic dye. concentration of platelets up to five times the
158 E. Alentorn-Geli and J. R. Haua

serum. Barker et al. reported significant improve- PRP at 24 weeks [25]. In a very nice descriptive
ment in the Mayo Elbow Performance Score review by Kwapisz et al., a total of 15 studies
(MEPS) and visual analogue scale (VAS) for pain investigated the effects of PRP injection for lat-
at rest and with movement. No complications eral epicondylitis [8]. Eleven of the 15 studies
occurred. Similarly, Sanli et al. reported the out- compared PRP to steroid injections, and 9 (81%)
comes of a single injection of PRP for refractory of them found a superiority of PRP over cortico-
biceps tendinopathy [18]. They found significant steroid injections. In most of the studies, the cor-
improvement in pain (at rest and during activity), ticosteroid injection group improved at the
function, and strength. Both studies had no com- beginning (very short term) but worsened over
parative control group, which is a major ­limitation time, whereas the PRP group maintained their
to obtain robust and meaningful conclusions. improvement at the end of the study period. The
periods for which PRP was still better than corti-
costeroid injections were at 3 months [21, 26], 6
23.2.4 Aftercare months [23, 27], 1 year [24, 28], and 2 years [11].
Besides a favorable comparison of PRP over cor-
After the injection, the patient is observed for ticosteroid injections in the literature, the efficacy
15 min for development of any early symptoms. of PRP for the treatment of lateral epicondylitis
Depending on the injected agent, if no contrain- has been systematically reproduced in various
dication is present, icing for 15 min may be help- other systematic reviews and meta-analyses.
ful. Then, the patient is informed about relative Chen et al. published a couple of systematic
rest and low activity in first 24–48 h, especially review and meta-analysis involving 37 studies
avoiding elbow flexion and supination move- (1031 participants) in 1 article [10] and 16 level I
ments. And patient should be warned about red studies (581 participants) in another article [19].
flags for complications such as redness, swelling, The authors found significant improvement with
or drainage from the injection zone. PRP for pain and function at the long-term.
Niemiec et al. reported another systematic review
and meta-analysis where the effectiveness of
23.3 Lateral Epicondylitis PRP to achieve a minimal clinically important
difference for the treatment of lateral epicondyli-
23.3.1 Anatomy, Diagnosis, tis was evaluated [29]. The authors found that all
Indications, and Type scores (VAS, DASH, patient-rated tennis elbow
of Injection Agents evaluation, Mayo Clinic Performance Index)
exceeded the respective minimal clinically
Lateral epicondylitis is the most common and important difference in almost all-time intervals
most studied elbow disorder [8, 10, 19]. This evaluated. This finding occurred for both types of
condition is caused by repetitive microtrauma or PRP preparation, leukocyte-rich and leukocyte-­
overload causing tendon fibers tearing and degen- poor PRP [29]. One complication described for
eration [20]. Given the previously mentioned evi- PRP injections has been temporary increase in
dence, it is not surprising that corticosteroid pain [30]. However, this complication was most
injections are not helpful for lateral epicondylitis commonly observed in the leukocyte-rich as
over time. Gosens et al. observed better pain opposed to leukocyte-poor PRP injections [30].
relief at short-term compared to PRP, but inferior This is most likely explained by the appearance
outcomes at 2 years [11]. Other authors have also of a leukocyte-mediated inflammatory response
observed this finding [21–24]. In a systematic in leukocyte-rich PRP preparations. Interestingly,
review and meta-analysis of studies comparing Kim et al. conducted a systematic review and
corticosteroid and PRP for lateral epicondylitis, meta-analysis comparing the outcomes of PRP
Li et al. observed a superiority of the former at 4 infiltration with surgical treatment for lateral epi-
and 8 weeks, but inferior outcomes compared to condylitis [31]. The investigation included 5
23 Injections of Anatomical Regions and Diseases: Elbow 159

studies, involving 154 patients treated with PRP When infiltration is needed, the use of ultrasound
infiltrations and 186 patients undergoing surgical guidance is recommended to increase precision
treatment. The authors did not find significant and accuracy.
differences for any of the outcomes for any of the
follow-up periods: VAS at 2 months, 6 months,
and 12 months, and patient-related tennis elbow 23.3.2 Technique/Tricks/Pitfalls
evaluation score at 12 weeks, 24 weeks, and 52
weeks. The patient is placed in the supine position with the
Other products like autologous blood injec- arm at the side with the hand in the belly or with
tion do not seem to provide any benefit over PRP 60° of abduction and internal rotation of the shoul-
[8]. On the other hand, bone marrow aspirate der so that the forearm is on the bed or a resting
concentrate has provided promising results, but table (Figs. 23.1 and 23.4). Lying supine is always
further research is needed in this field [32]. This preferred in any infiltration because the patient
is also the case for direct autologous tenocyte may get dizzy. The physician prepares the elbow
injection, a two-step surgical procedure where using the standard protocol. The ultrasound is first
tenocytes are injected after harvesting and cultur- used to identify the location where the tendon is
ing [33]. Lastly, a comparative study to investi- mostly affected, and the transducer positioned in
gate the effectiveness of hyaluronic acid and the long axis (Fig. 23.4). The medication is infil-
saline (control group) injections was conducted trated after triangulation and identification of the
by Zinger et al. [14]. The authors observed a sig- needle in the screen. The idea is to place the PRP
nificant improve in pain and function mostly at 3 around the tendon and within the tendon (very low
months, lasting until 12 months despite a decrease quantity) to improve high-grade degeneration or
in the improvement. However, the follow-up rate partial tearing. A series of three PRP infiltrations
of the control group was less than 50% and could are recommended, about 2 weeks apart. In general,
not be used as a comparative group. A compari- as the tendon becomes stronger in its intratendi-
son between hyaluronic acid and corticosteroid nous area, the infiltration of PRP becomes more
injections was conducted by Yalcin and Kayaalp difficult. This is a positive sign, as it represents an
[34]. Both treatment options yielded significant improvement of the tendon, especially if the first
improvement in pain and function, but lasted for injection inside the tendon offered only mild resis-
a short period. In general, hyaluronic acid can be tance. It is important to feel at least mild resistance
considered a safe and effective treatment modal- during the first injection. Otherwise, it might be a
ity [12], but further comparative studies are sign that the tendon has an important tear or that the
needed before it can be considered a first-line needle is not in the correct location.
injection agent.
As a result of the existing evidence, cortico-
steroid injection are no longer recommended
except in cases that temporary, short-term relief
is needed, provided not too many injections are
accumulated over time. In terms of injection
agents, PRP can be now considered the gold stan-
dard for treating lateral epicondylitis according
to the conclusions from many systematic review
and meta-analyses [8, 35]. The first line of treat-
ment for lateral epicondylitis is physical therapy
and activity modification. This is generally rec-
ommended before infiltration is performed Fig. 23.4 Detail of lateral epicondylitis PRP infiltration
through a lateral approach. The transducer is placed in the
because many patients may get full recover with- long axis of the tendon, and the needle advanced form dis-
out any further more aggressive treatments. tal to proximal until it is seen in the screen
160 E. Alentorn-Geli and J. R. Haua

23.3.3 Aftercare epicondylitis [36]. An improvement of pain dur-

ing the first 6 weeks was noted, but not main-
After the injection, the patient is observed for tained at 3 months. Similar outcomes were
15 min for development of any early symptoms. observed by Lee et al., with initial improvement
Depending on the injected agent, if no contrain- at 2 weeks followed by a plateau for up to 8
dication is present, icing for 15 min may be help- weeks [37]. PRP has an added potential benefit.
ful. Then, the patient is informed about relative Because the medication can be administered
rest and low activity in first 24–48 h, especially inside the tendon, the mechanical effect of needle
avoiding wrist and finger extension movements. trephination may stimulate bleeding and tendon
And patient should be warned about red flags for healing [38]. Suresh et al. observed improved
complications such as redness, swelling, or drain- VAS for pain and Nirschl scores at 10 months
age from the injection zone. after a combination of needle stimulation and
autologous blood injected into the disrupted ten-
don [38]. Although the authors did not inject PRP
23.4 Medial Epicondylitis itself, it is likely that the benefits are also observed
after PRP. In fact, there are two studies compar-
23.4.1 Anatomy, Diagnosis, ing the effectiveness of PRP and surgical treat-
Indications, and Type ment (one was the Tenex procedure) for medial
of Injection Agents epicondylitis [39, 40]. Both studies obtained
similar conclusions: improvement in pain scores
Medial epicondylitis is a flexor-pronator tendon and functional outcomes (Mayo Clinic
degeneration as a result of chronic repetitive Performance Score, Oxford Elbow Score) were
movements (overuse). As in any other chronic comparable between the two groups (PRP and
tendon disorders, injections include corticoste- surgery).
roids, hyaluronic acid, collagen, and PRP. The Despite the evidence for medial epicondylitis
existing evidence for medial epicondylitis is way regarding PRP or corticosteroid injections are
inferior than for lateral epicondylitis. However, significantly inferior compared to lateral epicon-
the effects of corticosteroid injections on the dylitis, its similar etiopathogenesis makes con-
common extensor-supination tendons should also clusions from the latter potentially applicable to
apply to medial epicondylitis because both con- medial epicondylitis. In fact, the outcomes and
ditions deal with the same type of tissue (ten- conclusions from the existing evidence seem to
dons). Therefore, tendon tissue quality point out toward the same direction, although to a
impairment with corticosteroid injections pre- different extend in terms of the amount of studies
vents its recommendation also for medial published.
epicondylitis.
Accuracy issues with “blinded” injections are
also relevant in medial epicondylitis. Ultrasound 23.4.2 Technique/Tricks/Pitfalls
guidance will also improve the precision of the
infiltration, which is even more important consid- Injections for medial epicondylitis may be con-
ering that if corticosteroid injection is decided, it ducted in the supine or lateral decubitus. Lateral
is paramount that the medication is not placed decubitus has the advantage to provide a very
within the tendon. Therefore, ultrasound direct good access to the medial side of the elbow in a
observation in the screen is very convenient. In comfortable position for both the patient and
addition, the close proximity of the ulnar nerve physician in cases where limited shoulder exter-
makes the ultrasound even more important than nal rotation is present. In general, the transducer
in other pathologies. is positioned in the long axis of the tendon and
Stahl and Kaufman reported the outcomes of the needle advanced distal to proximal following
corticosteroid injections in 60 elbows with medial the long axis (Fig. 23.5). Once the ulnar nerve is
23 Injections of Anatomical Regions and Diseases: Elbow 161

Fig. 23.5 Infiltration of PRP for medial epicondylitis.

The patient is placed lying supine with shoulder abduction
and external rotation. The medial aspect of the elbow is Fig. 23.7 Detail of medial epicondylitis infiltration using
prepared and evaluated with the ultrasound. The trans- the alternative patients’ positioning (lying supine with the
ducer is placed following the lines of tendon fibers, and arm at 40° of abduction). The ulnar nerve and the tendons
the PRP administered in the long axis around and/or are identified, and the transducer is placed in the long axis
inside the tendon. Special care should be taken to locate of the tendons. The needle is then advanced from distal to
and avoid the ulnar nerve proximal in the long axis

difficult, the patient can move the elbow toward

the edge of the bed so that the clinician can per-
form the injection easily.

23.4.3 Aftercare

After the injection, the patient is observed for

15 min for development of any early symptoms.
Depending on the injected agent, if no contrain-
dication is present, icing for 15 min may be help-
ful. Then, the patient is informed about relative
rest and low activity in first 24–48 h, especially
avoiding wrist and finger flexion movements.
And patient should be warned about red flags for
complications such as redness, swelling, or drain-
Fig. 23.6 General view of the alternative patients’ posi- age from the injection zone.
tioning, lying supine with the arm at the side with 40° of
shoulder abduction
23.5 Olecranon Bursitis
located, and the needle is seen on the screen, the
PRP can be infiltrated around the tendon, or 23.5.1 Anatomy, Diagnosis,
inside the tendon for a small amount if high-­ Indications, and Type
grade degeneration or partial tearing is present. If of Injection Agents
the patient has shoulder problems preventing
adequate abduction and external rotation, medial Aseptic olecranon bursitis is not an uncommon
epicondylitis can also be injected with the arm at inflammatory process due to direct trauma, repet-
the side as an alternative position (Figs. 23.6 and itive microtrauma, or an inflammatory disorder.
23.7). If access to the medial side of the elbow is In this condition, fluid effusion is accumulated in
162 E. Alentorn-Geli and J. R. Haua

the olecranon bursa, causing increase in volume, [45]. Those patients receiving injections had the
pain, redness, and limited elbow function. The fastest decrease in bursal swelling as soon as at 1
first line of treatment is noninvasive modalities week, improvements that were kept at 6 weeks.
like ice, rest, immobilization (to avoid friction on At 6 months, groups not treated with injections
the inflamed bursa), oral anti-inflammatory med- had the higher rate of re-aspirations. One con-
ication, compression dressing, and physical ther- founding factor for the outcomes of this study is
apy. If this conservative treatment fails, the application of a compression dressing in the
US-guided drainage with or without injections injection groups, as this treatment has been
would be indicated. shown to improve the outcomes of olecranon bur-
The outcomes of infiltrations for olecranon sitis [43]. Interestingly, Smith et al. did not find
bursitis are controversial. To the best of our infection or skin atrophy. The authors reasoned
knowledge, there are no studies evaluating the that the use of a thin needle entering laterally and
effects of PRP for olecranon bursitis. The only placing a sterile dressing after the injection could
agent tested in a decent amount of studies is cor- be related to the absence of septic complications.
ticosteroid. In a systematic review, Sayegh and The careful and meticulous use of sterile injec-
Strauch found five studies (of 29 included) using tions with bursal access through a normal,
corticosteroid injections for the treatment of healthy-looking skin area is paramount to
aseptic olecranon bursitis [41]. The authors found decrease post-injection infection. A more recent
that corticosteroid injections were associated investigation conducted by Wu et al. evaluated
with increased overall complications and skin the efficacy of ultrasound-guided corticosteroid
atrophy. However, when evaluating the studies in injections for olecranon bursitis in a group of 45
a more individual way good outcomes have also patients [46]. The authors observed a recurrence
been reported. Weinstein et al. observed that rate of olecranon bursitis of 40% after one injec-
those patients treated with corticosteroid injec- tion (2 weeks later), and recurrence rate of 13%
tions (25 patients) had a faster reduction in bursal after a second injection (at 4 weeks from the first
effusion compared to those treated with fluid injection). There was a significant decrease in the
aspiration (22 patients) [42]. As stated by Sayegh depth of the synovial effusion, synovial thick-
and Strauch, Weinstein et al. observed long-term ness, and blood flow signal at 4 weeks.
(mean 31 months, range 6 to 62 months) adverse
effects including infection in three patients, skin
atrophy in five patients, and local pain in seven 23.5.2 Technique/Tricks/Pitfalls
patients. Kim et al. observed that patients treated
with aspiration and corticosteroid injection into For an appropriate infiltration of the olecranon
the bursa was associated with the faster resolu- bursa, the patient lies either supine or prone. In
tion of symptoms, at an average of 2.3 weeks the supine position, the elbow is flexed with some
[43]. However, the authors failed to find any other shoulder abduction, so that the hand lies in the
significant difference in the outcomes, maybe patient’s belly. Ideally, the patient should lie
explained by a limited sample size. These out- close to the edge of the table so that a medial to
comes were similarly reported by Jaffe and Fetto, lateral approach with the needle can be made
who reported a 100% clinical resolution of asep- (Fig. 23.7). The entry point in an olecranon bursi-
tic olecranon bursitis after aspiration and cortico- tis depends on the most affected area. On occa-
steroid injection in five patients [44]. In a sions, there is redness that has to be avoided. The
double-blind prospective study comparing corti- recommendation is that the entry point of the
costeroid injections (with or without oral anti-­ needle is made through normal-looking skin, to
inflammatory medications) to oral prevent complications with the infiltration. The
anti-inflammatory or placebo treatments, Smith bursitis is visualized using axial and longitudinal
et al. found a clear benefit in the injection groups views. The area of the bursa mostly affected is
23 Injections of Anatomical Regions and Diseases: Elbow 163

should be warned about red flags for complica-

tions such as redness, swelling, or drainage from
the injection zone.

23.6 Conclusions

Injections can be very helpful as therapeutic

option for a number of elbow conditions. It is
highly recommended that all injections are con-
ducted under ultrasound guidance to improve
accuracy and precision. For tendon-related disor-
ders (lateral epicondylitis, medial epicondylitis,
Fig. 23.8 Infiltration of olecranon bursa under ultra-
sound guidance medial to lateral in the short axis. The
and distal biceps tendinopathy), the gold standard
patient is lying supine with the elbow flexed and the olec- in terms of injection agents is the PRP, which
ranon area at the edge of the table so that a medial have demonstrated to be a very good option to
approach (desired in this case) is possible improve patients’ symptoms and function at the
short- and long-term. Corticosteroid injections
identified and drainage is recommended. There are only recommended for a short-term improve-
are no structures at special risk for this injection. ment of tendon disorders in very selected clinical
The needle is advanced in the short axis scenarios, but its repetitive use is not recom-
(Fig. 23.8). Very little pressure with the trans- mended because of potentially significant impair-
ducer is advised in order to avoid fluid moving ment in tendon tissue quality. In contrast, it seems
away from the view. The infiltration has to be that corticosteroid injections can be a reasonable
with low volume of medication and typically option when conservative treatment fail to
using a 16/18 G needle. improve aseptic olecranon bursitis. However,
In conclusion, it seems that ultrasound-guided very strict sterile conditions and access through
corticosteroid injection can be considered a very healthy-looking skin, followed by a sterile com-
good option for the treatment of aseptic o­ lecranon pressive dressing is recommended in order to
bursitis if more conservative therapeutic options avoid infection. During ultrasound-guided injec-
do not improve the patients’ symptoms. Injections tions, it is highly recommended to identify the
need to be conducted in very strict sterile condi- infiltration side from both the axial and longitudi-
tions, performed through normal-­looking skin, nal views right before entering the needle. This
and followed by a compression dressing. will increase the precision of the injection.
Further research is needed for aseptic olecranon
bursitis in order to evaluate efficacy and safety of
23.5.3 Aftercare PRP injections into the olecranon bursa.

After the injection, the patient is observed for

15 min for development of any early symptoms.
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 Injections of Anatomical Regions
and Diseases: Wrist and Hand
24
Gamlı Alper and Gereli Arel

24.1 Wrist Joint 24.1.2 Indication and Diagnosis

Arthritis of the radiocarpal and intercarpal joints Degenerative wrists present as painful, stiff, and
are typically secondary to inflammatory diseases weak joints. Numerous operative options are
or carpal instability due to previous fracture and available for permanent solution, but many
dislocations. If left untreated, lunate avascular patients prefer to delay surgery. In such cases,
necrosis and lunate impingement progress to corticosteroid injections are effective in reducing
wrist arthritis. Primary osteoarthritis of the wrist symptoms. Tenosynovitis can cause diffuse
is rare and occurs when a late-stage trapezio- swelling and effusion and should be ruled out. A
metacarpal arthritis spreads to the carpal joints. standard X-ray of the wrist provides sufficient
information to prove the arthritis.

24.1.1 Anatomy
24.1.3 Appliances
Radiocarpal and intercarpal joints, along with the
eight carpal bones and multiple extrinsic and Approximately 1 ml of liquid can be injected by
intrinsic ligaments, are responsible for complex a 23-G or thinner syringe tip.
wrist biomechanics. The tendons pass close to
Local
both palmar and dorsal side of the wrist joints.
Needle Syringe Corticosteroid anesthetic
Lister’s tubercle is a prominence on the dorsal 23 G 2–3 40 mg 1% lidocaine
side of the distal radius and serves as a pulley for mL triamcinolone (1 (0.5 mL)
the extensor pollicis longus (EPL) tendon. mL)
5 mg betamethasone
(1 mL)

G. Alper (*) 24.1.4 Agents

Acibadem Altunizade Hospital, Department of
Orthopedics and Traumatology, Istanbul, Turkey
Corticosteroids and local anesthetics.
G. Arel
Acibadem Mehmet Ali Aydınlar University,
Faculty of Medicine, Department of Orthopedics and
Traumatology, Istanbul, Turkey

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 167
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
168 G. Alper and G. Arel

24.1.5 Technique/Tricks/Pitfalls until the microbiologic culture results are seen. If

the synovial fluid is decided to be sterile, all agents
The patient is seated next to the table, with the are then administered intraarticularly as a bolus.
elbow flexed and the forearm pronated. The
patient’s hand is relaxed, and the palm faces the
table. Lister’s tubercle at the distal radius is pal- 24.1.6 Aftercare
pated and marked (Fig. 24.1). EPL is easily found
when the first finger is lifted off the table. A soft Ice packs, paracetamol, and nonsteroidal anti-­
spot should be discovered 1 cm distal to the inflammatory drugs (NSAIDs) are needed in the
Lister’s tubercle, just along the ulnar border of the first days until the inflammatory response is
EPL. A 23-G needle is then placed perpendicular resolved. Splinting may help until the steroids
and slightly angled caudally at the soft point and take effect. Heavy lifting and repetitive move-
aspirated (Fig. 24.2). If the joint is penetrated, ments should be avoided. Repeated injection may
some synovial joint fluid should be ­visible in the be needed if the osteoarthritis is advanced.
syringe. The aspirated material can be examined
for crystalline deposition, but if infection is sus-
pected, no further injection should be administered 24.2 Distal Radioulnar Joint

Distal radioulnar joint (DRUJ) pain with instabil-

ity and limited motion of the forearm supination
and pronation after a distal radius fracture is com-
mon. Patients diagnosed with rheumatoid arthritis
frequently suffer from DRUJ arthritis. Triangular
fibrocartilage complex (TFCC) is an essential
support for the DRUJ; their traumatic or degen-
erative injuries may cause ulnar-sided wrist pain.

24.2.1 Anatomy

DRUJ is a synovial joint and responsible from

supination and pronation of forearm. Palmar and
dorsal radioulnar ligaments accounts for the sta-
Fig. 24.1 Wrist joint dorsal soft spot (asterisks) is 1 cm bility of the joint. The radius has a concavity
distal to the Lister’s tubercle (arrow) and just ulnar border
of the extensor pollicis longus called sigmoid notch, fits the ulnar head, which
should be kept in mind during any injection.

24.2.2 Indication and Diagnosis

Snapping, crepitus, and decreased forearm

supination-­pronation may be seen in advanced
arthritis. Grip strength loss may occur.
Provocative tests are performed to assess DRUJ
tenderness. To rule out the pain of nonunion asso-
ciated with an ulna styloid fracture, any previous
Fig. 24.2 Wrist joint injection. Needle is perpendicular
initial trauma should be questioned, where a
and slightly angled caudally radiograph can be taken for confirmation.
24 Injections of Anatomical Regions and Diseases: Wrist and Hand 169

Repetitive wrist flexion and extension and over- a

use may result with extensor carpi ulnaris (ECU)
tendinopathies, whereas acute trauma may bring
out instability and subluxation of the tendon. The
ECU synergy test is useful in diagnose [1].
Magnetic resonance imaging (MRI) is useful in
identifying pathologies where the diagnosis is
uncertain (Fig. 24.3). Ulnar neuropathy should be
evaluated in the differential diagnosis. All these b
situations may benefit more or less from steroid
injection; therefore, injection may be considered
in the first visit for ulnar-sided wrist pain.

24.2.3 Appliances

Approximately 1 ml of liquid can be injected by

a 23-G or thinner syringe tip.

Local
Needle Syringe Corticosteroid anesthetic Fig. 24.4 (a, b) Distal radioulnar joint (DRUJ) injection
23 G 2–3 20 mg triamcinolone 1% lidocaine
mL (0.5 mL) (0.5 mL)
2.5 mg 24.2.5 Technique/Tricks/Pitfalls
betamethasone (0.5
mL)
With the patient sitting comfortably, the patient’s
hand is placed flat on the examination table. The
forearm is in pronation and the elbow is in flex-
24.2.4 Agents ion. The dorsal medial border of the ulnar head
is palpated and marked. In a sterile fashion, a
Corticosteroids and local anesthetics. 23-G needle is advanced in medial of the ulnar
head (Fig. 24.4a, b). Ultrasonography-guided
methods are more accurate, but the outcomes
are similar to palpation-guided methods [2]. If
an ECU tendinopathy accompany the DRUJ
arthropathy, second injection to the ECU sheath
may attempt. ECU is palpated dorsal site of the
ulnar head and injection is performed with 27-G
needle.

24.2.6 Aftercare

Since the splint is a reminder to avoid overuse,

it is needed in the first days until the inflamma-
tory response is resolved. Ice pack and
paracetamol may help the steroids effect.
Fig. 24.3 Magnetic resonance imaging right left wrist Repeated injection may be needed if the osteo-
with distal radioulnar joint effusion (arrows) arthritis is advanced.
170 G. Alper and G. Arel

24.3 Trapeziometacarpal Joint 24.3.2 Indication and Diagnosis

(Carpometacarpal Joint
of the Thumb) A progressive degenerative process is generally
observed. During the consultation, patients often
Osteoarthritis of the first carpometacarpal joint is complain of pain around the joint that increases
common and presents with a pain and difficulty with activity. Grind test at the TMTJ is painful.
by pinching and grasping. A contracture by An X-ray is sufficient to show the TMTJ arthritis.
adduction of the thumb may be seen in severe Injection is indicated at the first visit.
arthrosis. Scaphotrapeziotrapezoidal (STT)
arthrosis accompanies in the late-stage disease.
24.3.3 Appliances

24.3.1 Anatomy Approximately 0.5–1 ml of liquid can be injected

by a 23-G or thinner syringe tip.
The trapeziometacarpal joint (TMTJ) between
Local
the trapezium and the first metacarpal is a “bicon- Needle Syringe Corticosteroid anesthetic
cave saddle” type joint and is located just proxi- 23 G 1–3 20 mg triamcinolone 1% lidocaine
mal to the thenar eminence, within the “fovea mL (0.5 mL) (0.5 mL)
radialis” anatomically. The fovea radialis or the 2.5 mg
anatomical snuffbox is the area between the ten- betamethasone (0.5
mL)
dons extensor pollicis brevis (EPB) and extensor
pollicis longus (EPL) tendons. The deep branch
of the radial artery and the terminal branches of
the radial nerve are lying in the base of this region 24.3.4 Agents
(Fig. 24.5).
Corticosteroids, local anesthetics, visco-­
supplements, and orthobiologic agents.

24.3.5 Technique/Tricks/Pitfalls

The patient should be supported in a sitting posi-

tion and the forearm should be placed on the
table. Wrist rests on a towel in semi-supination.
Ulnar deviation of the wrist and flexion and
adduction of the first finger place the TMTJ more
superficial. The injection may be more difficult in
these patients, as osteophytes around the degen-
erative joint narrow the joint space. Flexion and
traction may be applied from the thumb to the
joint during injection, to make the joint wider and
more superficial (Fig. 24.6a, b). The first meta-
carpal is palpated, and the joint gap is determined
Fig. 24.5 Left hand fovea radialis (asterisks) injection and marked after the anatomical “fovea radialis”
site, radial artery (red), n radialis digitalis dorsalis (yel-
low). EPL extensor pollicis longus tendon, EPB extensor
is tapped. The needle should be aimed to the
pollicis brevis tendon, APL abductor pollicis longus TMTJ perpendicularly proximal to distal with the
tendon 30 degrees of angle (Fig. 24.7a, b).
24 Injections of Anatomical Regions and Diseases: Wrist and Hand 171

a b

Fig. 24.6 TMTJ (asterisks) under fluoroscopy, dotted line shows the skin. (a) Neutral position without traction. (b)
Flexion position with traction

a b

Fig. 24.7 (a, b) Right hand first carpometacarpal joint injection

To protect the radial artery, the needle should injection “thumbs-up” sign may be seen with
be placed on the dorsal ulnar side of the EPB ten- proper injection [3].
don. The superficial branch of the radial nerve
should also be kept in mind. First, an injection is
made to the proximal of the first metacarpi under 24.3.6 Aftercare
the skin and is waited for 20–30 s. As soon as the
joint border is identified, the needle is advanced Patient should be motivated for gentle active
perpendicular to the capsule from the dorsal sur- motion within the pain-free range and is advised
face. The content should be given at once after against overuse of the thumb. In severe pain,
aspiration. Fluoroscopy or ultrasonography splinting may help in the first days until the
(USG) may assist for better accuracy and efficacy inflammatory response resolves. Patient should
of the injection (Figs. 24.8 and 24.9). During the be informed that late-stage osteoarthritis may
172 G. Alper and G. Arel

24.4.1 Anatomy

In each hand, there are five metacarpophalangeal

joints and nines interphalangeal joints. There is a
single interphalangeal joint in the first finger, and
there are two interphalangeal joints, each proxi-
mal and distal in the other fingers. Joints are
strengthened by collateral ligaments. Flexor and
extensor tendons pass through volar and dorsal
aspects of the phalangeal bones. Digital artery
and nerve packages located in the medial and lat-
eral of the joints should be kept in mind. The
volar plate is a thick fibrocartilaginous tissue
close to the palmar side of the joints.

Fig. 24.8 Fluoroscopy-guided TMTJ injection 24.4.2 Indication and Diagnosis

The main purpose of steroid injections to the

phalangeal joints is to reduce the synovitis and
pain and improve the range of motion. The
patient can precisely localize the affected joint.
The limitation of motion and tenderness in the
joint during physical examination confirms the
diagnosis. In some cases, edema is evident in the
affected joint. In the interphalangeal joints, flex-
ion and extension are affected. Injection may be
indicated in patients who do not benefit from
nonsteroidal anti-inflammatory drug (NSAID)
Fig. 24.9 USG-guided injection (asterisks) TMTJ therapy.

have little benefit or only in short period [4].

After 6–12 weeks, the need for further treatment 24.4.3 Appliances
should be discussed.
Approximately 0.2 ml of liquid can be injected
by a 27-G syringe tip. Local anesthetic may cause
24.4 Metacarpophalangeal a numbness distal to the injection area due to the
and Interphalangeal Joints neighborhood of the digital nerves to the capsule.
Due to the limited volume of these joints, addi-
The most common causes of pain or limitation of tional amounts of local anesthetic may be
movement in the metacarpophalangeal and inter- unnecessary.
phalangeal joints are degenerative and inflamma- Local
tory arthritis. Rheumatology patients with pain in Needle Syringe Corticosteroid anesthetic
their fingers are seeking for pain killers. 27–30 1 mL 20 mg triamcinolone 1%
Corticosteroid injections is one way to suppress G (0.5 mL) lidocaine
2.5 mg betamethasone
the inflammation, but access to an interphalangeal
(0.5 mL)
joint is challenging for any injection or aspiration.
24 Injections of Anatomical Regions and Diseases: Wrist and Hand 173

24.4.4 Agents

Corticosteroids and local anesthetics.

24.4.5 Technique/Tricks/Pitfalls

The patient is placed or seated with support.

Sterile technique is applied. The dorsolateral
edge of the joint line is palpated, identified, and
marked. Needle is advanced from the radial or
ulnar side of the extensor tendon into the joint as
the finger is in the full extension position
(Fig. 24.10). The space between joint surfaces Fig. 24.11 Volar injection of the proximal interphalan-
under the capsule should be identified with the tip geal joint of the second finger with 27-G needle
of the needle. As osteophytes from degenerative
arthritis further narrow the joint space, the possi- effective, but better result has been shown with
bility of a viable intracapsular injection is further the intraarticular injection [6]. A palmar approach
reduced. Unfortunately, the joint interval cannot has been shown for proximal interphalangeal
be expanded by traction as desired to be. joint (PIPJ) (Fig. 24.11) [7]. With the flexion of
Experienced clinicians cannot penetrate into the the joint, it is possible to relax the volar plate, and
joint [5]. Periarticular injections may still be empty space is created between the volar cortex
of the bone and the capsule (Fig. 24.12). Various
angles for injection have been suggested in the
literature, but since the measurement of these
angles is not practical during any attempt, 40°–
60° flexion of the PIPJ and the same angulation
of the needle will allow access into the capsular
space [8]. Since the position of the needle is
affected by the motion of the flexor tendons, the
finger should flex before entering the needle
(Fig. 24.13). Dorsal side of the joint is well medi-
cated with the approach (Fig. 24.14a–c).

24.4.6 Aftercare

Patients should be reminded that there may be an

increase in their complaints in the first several
hours after injection. High-volume injection may
limit full joint movement for a while. It is sug-
gested that the injected finger should rest for 2
weeks. It is not recommended to use ice packs on
fingers. Repeated steroid injections that miss the
Fig. 24.10 Dorso-radial injection of the distal interpha-
joint may damage the pericapsular soft tissue and
langeal joint of the second finger with 27-G needle tendon.
174 G. Alper and G. Arel

Fig. 24.13 Volar injection of the proximal interphalangeal

joint. The effect of the flexor tendon motion to the needle
position and angle with flexion of the finger is demonstrated

Fig. 24.12 Volar approach of the proximal interphalan-

geal joint of the second finger under fluoroscopy with
27-G needle. Proximal interphalangeal joint should be
held in 50° flexion, and the volar plate is relaxed to create
a capsular space. The needle is 50° angled to the proximal
phalanx and the joint fulfilled with radiopaque material to
demonstrate joint space Fig. 24.14 Fluoroscopy (a, b) and arthrography (c) of the
proximal interphalangeal joint after the volar injection.
(arrow) The dorsal escape of the volar injection material
proves an appropriate joint infiltration. The capsular space
(asterisks) created with the relaxation of the volar plate
demonstrated with radiopaque material. (a) Extension of
the finger brings the volar plate close to the proximal pha-
lanx. (b) Flexion of the finger relaxes the volar plate and
forms a capsular gap. (c) Arthrography, 30 min after the
injection. Material is well dispersed within the joint
24 Injections of Anatomical Regions and Diseases: Wrist and Hand 175

24.5 Ganglion Cyst

Ganglion cysts are among the most common

tumors in the wrist and hand. These synovial
cysts are filled with mucin and can originate from
any type of a synovial joint. It is found mostly on
the dorsal side of the wrist; however, it can be
seen less frequently on the volar side. Ganglion
cysts are also associated with the tendon and the
tendon sheaths conditions like de Quervain’s dis-
ease. They are identified as mucous cysts, if
attached dorsolateral side of the distal interpha-
langeal joint.

24.5.1 Anatomy

Ganglion cysts are collagen fiber sacs connecting

with a duck to the joint or tendon sheath. Dorsal-­
sided cysts arise from scapholunate ligament.
Volar ganglions originate from radiocarpal joint Fig. 24.15 Dorsal wrist ganglion cyst (asterisk) aspira-
tion and steroid injection
and may wrap the radial artery or its branches.
principles. After the aspiration, corticosteroids
injection through the same needle reduces the
24.5.2 Indication and Diagnosis
symptoms for a while. Injected steroid will dis-
perse all over the joint through its pedicle.
Patients refer with a pain on the ganglion with the
full flexion or extension of the wrist like when
Local
they push the door or do push-ups. Inability to Needle Syringe Corticosteroid anesthetic
exercise, cosmetic concerns, worries of malig- 18 G 2 mL 40 mg triamcinolone 1% lidocaine
nancy, or exacerbation of pain with intense use of (1 mL)
the arm are the main complaints of admission. 5 mg betamethasone
Big cysts may compress the adjacent median or (1 mL)
ulnar nerve and cause neuropathies.
Transillumination of the cysts, anechoic lesion
with well-defined margins in USG without any 24.5.4 Agents
vessel, and the aspiration of the viscous jelly-like
mucin without any blood are efficient for diagno- Corticosteroids.
sis (Fig. 24.15). If any doubt arises in differential
diagnosis, magnetic resonance imaging (MRI) is
needed before any intervention. 24.5.5 Technique/Tricks/Pitfalls

The patient is placed or seated with support.

24.5.3 Appliances Sterile technique is applied. Ganglion cysts is
palpated. Dorsal wrist ganglions become evident
Eighteen-gauge needle is needed to aspirate the with the wrist flexion (Fig. 24.16). Needle is
highly viscous and sticky content. It is easy to inserted into the cyst without any hesitation for
apply force to a smaller syringe due to hydraulics dorsal large cyst. Small ganglia, especially those
176 G. Alper and G. Arel

Fig. 24.17 First extensor compartment with separate

tendon sheaths (asterisks). White dotted line: abductor
pollicis longus tendon (APL). Black dotted line: Extensor
pollicis brevis tendon (EPB). Gray dotted line: Extensor
Fig. 24.16 Dorsal wrist ganglion cyst aspiration and ste- pollicis longus tendon (EPL)
roid injection

each tendon (Fig. 24.17). This septum may

originating from the tendon sheath, may slip off
inhibit the injected steroid from spreading into
the tip of the needle. The syringe should be kept
both sheaths.
at negative pressure, and the procedure should be
repeated until the aspiration material is visible in
the syringe. After the cyst is emptied, the syringe
is changed, and steroid injection is applied if
24.6.2 Indication and Diagnosis
desired.
A sharp pain is felt on the radial side of the wrist
and aggravated by the ulnar deviation of the wrist
while holding the thumb fist. Physical examina-
24.5.6 Aftercare
tion is sufficient for diagnosis and further imag-
ing studies are not needed. Corticosteroid
Aspiration, perforation of the cyst wall, and
injection attempt at the first visit is logical since
injection of steroids can manage pain for weeks.
it is more efficacious than the splinting alone [9].
The patient should be told that most of the cyst
will relapse. Wrist splint will help control the
symptoms.
24.6.3 Appliances

Approximately 1 ml of liquid can be injected by

24.6 De Quervain’s Tenosynovitis
a 27-G syringe tip. Local anesthetic may cause a
numbness in the innervation area of the superfi-
De Quervain’s tenosynovitis is the entrapment of
cial branch of the radial for several hours.
the abductor pollicis longus (APL) and the exten-
sor pollicis brevis (EPB) at the radial side of the
wrist. Repeated wrist bending and twisting activ- Local
Needle Syringe Corticosteroid anesthetic
ities are the main risk factors for tendinopathy. 25–27 1–3 20 mg 1% lidocaine
G mL triamcinolone (0.5 (0.5 mL)
mL)
24.6.1 Anatomy 5 mg betamethasone
(1 mL)

Both APL and EPB tendons run through the first

dorsal extensor compartment on the radial sty-
loid. Distal to the bone edge, both tendons build 24.6.4 Agents
the anterior border of the fovea radialis. This reti-
nacular compartment may have a septation for Corticosteroids.
24 Injections of Anatomical Regions and Diseases: Wrist and Hand 177

24.6.5 Technique/Tricks/Pitfalls Patients should be warned that the effect of the

steroid begins after a few days. The patient should
The patient is seated; the forearm is held in the rest and avoid painful movements. Additional
neutral position. The wrist is supported with a splinting may reduce the symptoms till the ste-
towel in ulnar deviation. The two tendons are pal- roid take effect [10]. A splint should limit the
pated on the styloid process of radius. The needle wrist and thumb motion for proper care.
inserted along the line of the tendon to the distal
edge of the extensor compartment and advanced
retrogradely toward into the tendon sheaths 24.7 Carpal Tunnel Syndrome
(Fig. 24.18). With the injection of the liquid, a
bump will appear above the proximal edge of the Carpal tunnel syndrome is the most diagnosed
first compartment. The needle should be pulled site of nerve compression in the upper extremity.
slowly before draining all the solution, and it Nocturnal paresthesia of the median nerve distri-
should hit the neighbor tendon sheath by passing bution area is almost pathognomonic with the
the septum. The patient may benefit from the weakness of the thenar muscles.
allocation of the steroid to both tendon sheaths.

24.7.1 Anatomy
24.6.6 Aftercare
Carpal tunnel is bordered dorsally by the carpal
Superficial injection of the corticosteroid injec- bones and the volar by the transverse carpal liga-
tion has the risks of adipose tissue atrophy, skin ment (flexor retinaculum). Flexor retinaculum
hypopigmentation, and thinning. The patient extend from the hamate and triquetrum to the
must be informed about these risks and repeated scaphoid and trapezium and beneath the roof
multiple injection should be avoided. Because pass the median nerve and the flexor tendons of
the local anesthetics will affect superficial branch the hand. Palmaris longus tendon is just above
of the radial nerve over tendon, numbness of the and slightly on the ulnar side of the median
dorsal skin of the thumb will be felt for an hour. nerve.

24.7.2 Indication and Diagnosis

The Phalen test is a provocation test for the evalu-

ation of carpal tunnel syndrome. Flexion of the
wrist for a minute increases the pressure on the
median nerve, revealing the symptoms of pain and
numbness. Direct digital pressure or percussion on
the median nerve at the wrist by the examiner may
give similar findings. The patient may complain of
a tingling sensation that radiates into the sensory
distribution of the median nerve. Electrodiagnostic
studies are used to confirm physical findings and
determine the extent of disease. Carpal tunnel
injection can be applied in patients with median
Fig. 24.18 Injection position for de Quervain’s nerve compression, when in physiotherapy, resting
tenosynovitis splint and when NSAIDs are unresponsive.
178 G. Alper and G. Arel

24.7.3 Appliances

Approximately 0.5 ml of liquid can be injected

by a 23-G syringe tip. Local anesthetic may cause
an uncomfortable numbness in the fingers and
palm for several hours.

Local
Needle Syringe Corticosteroid anesthetic
23–25 1–3 20 mg triamcinolone Nil Fig. 24.20 Injection site for median nerve, ulnar of the
G mL (0.5 mL) (asterisks) palmaris longus tendon (demonstrated)

the needle is in the superficial of the deep fascia.

24.7.4 Agents
The sense of the flexor tendons motion toward
the tip of the needle indicates that the needle is at
Corticosteroids.
the proper depth. If the needle moves with finger
movements, the needle is inside the tendon and
must be removed. Corticosteroid should be
24.7.5 Technique/Tricks/Pitfalls
injected slowly, without any resistance. If the
needle encounters resistance or patients experi-
The patient is seated with some support, the fore-
ence paresthesia, the needle should be retracted
arm is kept in supination, and the wrist is
and redirected a little bit more toward the ulna.
extended. Before the injection, the proximal wrist
The injection is administered slowly but with
is folded, and the palmaris longus tendon are pal-
continued pressure. In patients without palmaris
pated. The palmaris longus tendon is best noticed
longus tendon, the midline formed between the
when all fingertips are clenched in the neutral
thenar and hypothenar regions during the thumb
position of the wrist (Fig. 24.19). Digital flexor
and fifth finger opposition helps the location of
tendons are palpated with the fingers in flexion
the medial nerve within the carpal tunnel.
and extension. The median nerve is at the radial
of the palmaris longus and between this tendon
and the flexor carpi radialis.
Sterile technique is applied; structures are
24.7.6 Aftercare
marked. The injection is applied from the proxi-
The patient is observed for a while. In the first
mal wrist fold right from the ulnar edge of the
24–48 h, information is given about the symp-
palmaris longus tendon (Fig. 24.20). The angle of
toms that may worsen due to corticosteroids.
the needle should be 30° to the flexor tendons in
Similarly, NSAIDs are recommended. Normal
the carpal tunnel.
activities can be resumed after resting for a few
The needle is advanced gently and the injec-
days after the injection. Night splinting helps
tion is continued. Swelling in the skin means that
reduce the symptoms.

24.8 Trigger Finger (Stenosing

Tenosynovitis)

The snapping or locking of the flexor tendons of

the thumb or other fingers as a result of stenosing
Fig. 24.19 Opposition of the thumb and fifth finger dis- tenosynovitis is called “trigger finger,” named by
tinct the palmaris longus tendon the analogy with the movement of the finger on
24 Injections of Anatomical Regions and Diseases: Wrist and Hand 179

the trigger of a gun. Mostly the ring finger is 24.8.3 Appliances

affected, and the thumb comes second.
Approximately 0.5 ml of liquid can be injected
by a 27-G syringe tip. Patients may experience an
24.8.1 Anatomy exacerbation of symptoms with the high volume
of injections.
The tendon pathology is observed at the A1 pul-
ley level. A1 pulley is a rigid, fibrous annular Local
Needle Syringe Corticosteroid anesthetic
band located volar to the metacarpophalangeal
25–27 1–3 10 mg 1% lidocaine
joint. A1 pulley projection to the skin is about G mL triamcinolone (0.25 (0.25 mL)
1 cm distal to the distal palmar crease. mL)
The digital nerves are located near both sides 2,5 mg
betamethasone (0.5
of the tendon. The radial digital nerve may inter-
mL)
sect the A1 pulley, specifically when the thumb is
held in pronation. To protect the nerve from an
injury of the needle tip, first wrist should be
flexed to face the volar side to the examiner cor- 24.8.4 Agents
rectly (Fig. 24.21a, b).
Corticosteroids and local anesthetics.

24.8.2 Indication and Diagnosis

24.8.5 Technique/Tricks/Pitfalls
Patients typically blame their proximal interpha-
langeal joint for catching and pain. A1 pulley Unlike the aforementioned diseases, corticoste-
should be palpated to identify the source of com- roid injection can be applied for treatment in the
plaints. Diagnosis is usually made only by physi- early phase of this stenosing tenosynovitis in the
cal examination. Differential diagnosis with first visit. The patient is supported in a sitting
Dupuytren’s contracture and tendon sheath position; the forearm is comfortably held in the
tumors should be made before any injection. supine position. The flexor sheath is palpated on

Fig. 24.21 Digital

nerves are adjacent to a b
the A1 pulley (asterisks)
of the thumb. (a) In
relaxed position of the
hand, the radial digital
nerve overlaps the A1
tendon from the
examiners view. (b)
Entry site is clear when
all of the volar thumb
area faces the examiner
180 G. Alper and G. Arel

Fig. 24.22 Corticosteroid injection to the triggering ten-

don of the fourth finger

the affected finger, and its line is determined with

the tip of the finger. The nodule due to tenosyno-
vitis can often be palpated at the level of the Fig. 24.23 The needle passes the A1 pulley penetrates
the tendon. If the needle is deep enough, it accompanies
metacarpal bone head where the affected tendon the finger movement
passes. If not found, active flexion and extension
of the fingers may uncover the area of triggering.
The needle is inserted with the bevel down, distal
to a1 pulley and at an angle of about 30° to the
palmar face and advanced retrogradely toward
the nodule (Fig. 24.22). If the needle is advanced
too deep, the flexor tendon will be penetrated. In
this situation, the needle will move along with the
finger movements. Some authors suggest this test
to be sure that the needle bevel is under the pulley
in the tendon sheath (Fig. 24.23).
After the penetration of the tendon, move the
Fig. 24.24 Percutaneous release of the A1 pulley
needle bevel away from the tendon into the ten-
don sheath with a pressure of the syringe, where
it can be observed that the fluid passes through 24.8.6 Aftercare
when the resistance is gone. After the penetration
of the tendon, move the needle bevel away from Patients may experience an exacerbation of
the tendon into the tendon sheath with a slight symptoms that resolve within the first 48 h. The
pressure to the syringe, where it can be observed local anesthetics will affect the digital nerve
that the fluid passes through the space between beside the tendon; because of that numbness of
the tendon and its sheath, when the resistance the finger will be felt for an hour. Patients should
gone. It is still effective, if the sheath is passed be warned that the effect of the steroid begins
and the steroid has been applied over the A1 pul- after a few days. Pain and triggering resolve com-
ley under the skin [11]. pletely by 6 weeks. No restriction is mandatory.
Percutaneous release can be tried after the Surgical A1 pulley release is a definite solution if
effect of local anesthetics is seen. The needle the symptoms persist.
should be replaced with 21 G or lower (thicker)
(Fig. 24.24) [12].
24 Injections of Anatomical Regions and Diseases: Wrist and Hand 181

References intraarticular injections? J Rheumatol. 2009;36:1892–

902. [Link]
7. McClelland WB, McClinton MA. Proximal inter-
1. Ruland RT, Hogan CJ. The ECU synergy test:
phalangeal joint injection through a volar approach:
an aid to diagnose ECU tendonitis. J Hand Surg
anatomic feasibility and cadaveric assessment of suc-
Am. 2008;33:1777–82. [Link]
cess. J Hand Surg Am. 2013;38:733–9. [Link]
jhsa.2008.08.018.
org/10.1016/[Link].2013.01.014.
2. Nam SH, Kim J, Lee JH, Ahn J, Kim YJ, Park
8. Saito S, Suzuki S, Ishikawa K. Letter regarding “prox-
Y. Palpation versus ultrasound-guided corticosteroid
imal interphalangeal joint injection through a volar
injections and short-term effect in the distal radioul-
approach: anatomic feasibility and cadaveric assess-
nar joint disorder: a randomized, prospective single-­
ment of success”. J Hand Surg Am. 2013;38:1261–2.
blinded study. Clin Rheumatol. 2014;33:1807–14.
[Link]
[Link]
9. Ashraf MO, Devadoss VG. Systematic review and
3. Erpelding JM, Shnayderman D, Mickschl D, Daley
meta-analysis on steroid injection therapy for de
RA, Grindel SI. The “thumbs-up” sign and trapezio-
Quervain’s tenosynovitis in adults. Eur J Orthop Surg
metacarpal joint injection: a useful clinical indica-
Traumatol. 2014;24:149–57. [Link]
tor. Hand. 2015;10:362–5. [Link]
s00590-­012-­1164-­z.
s11552-­014-­9683-­1.
10. Mardani-Kivi M, Karimi Mobarakeh M, Bahrami
4. Fowler A, Swindells MG, Burke FD. Intra-­
F, Hashemi-Motlagh K, Saheb-Ekhtiari K,
articular corticosteroid injections to manage trape-
Akhoondzadeh N. Corticosteroid injection with or
ziometacarpal osteoarthritis—a systematic review.
without thumb spica cast for de quervain tenosyno-
Hand. 2015;10:583–92. [Link]
vitis. J Hand Surg Am. 2014;39:37–41. [Link]
s11552-­015-­9778-­3.
org/10.1016/[Link].2013.10.013.
5. Pichler W, Grechenig W, Grechenig S, Anderhuber
11. Kazuki K, Egi T, Okada M, Takaoka K. Clinical out-
F, Clement H, Weinberg AM. Frequency of suc-
come of extrasynovial steroid injection for trigger fin-
cessful intra-articular puncture of finger joints:
ger. Hand Surg. 2006;11:1–4. [Link]
influence of puncture position and physician experi-
S0218810406003115.
ence. Rheumatology. 2008;47:1503–5. [Link]
12. Eastwood DM, Gupta KJ, Johnson DP. Percutaneous
org/10.1093/rheumatology/ken295.
release of the trigger finger: an office procedure.
6. Sibbitt WL, Peisajovich A, Michael AA, Park KS,
J Hand Surg Am. 1992;17:114–7. [Link]
Sibbitt RR, Band PA, Bankhurst AD. Does sono-
org/10.1016/0363-­5023(92)90125-­9.
graphic needle guidance affect the clinical outcome of
 Injections of Anatomical Regions
and Diseases: Hip
25
Bruno Capurro, Francesco Vecchi,
Beatriz Álvarez de Sierra, Alex Ortega,
Laura Gimeno-Torres, and Eva Llopis

Technical Note the procedure where the correct path of the

As a common denominator for all the tech- needle is observed. For anesthetic purposes,
niques described in the next chapter, an ethyl chloride can be applied to the skin, but
informed consent must be read and signed it should not come into direct contact with
by the patient prior to the infiltrations. A the transducer as it can damage it. It should
sterile technique will be required, where the always be aspirated prior to the infiltration
patient’s skin area to be treated is sterilized to ensure that it is not in a blood vessel, and
with a chlorhexidine swab (avoid Betadine afterward the infiltration can be proceeded.
as it can stain the ultrasound transducer); Once the injection is completed, the needle
sterile ultrasound gel is used just above the should be withdrawn maintaining visualiza-
target injection site. In addition, it is advis- tion and a small bandage applied so that the
able to capture the image before and after patient can mobilize.

A. Ortega
B. Capurro (*)
Department of Orthopaedics and Sports
Department of Orthopaedics and Sports
Traumatology, IMSKE Hospital - European
Traumatology, IMSKE Hospital - European
Musculoskeletal Institute, Valencia, Spain
Musculoskeletal Institute, Valencia, Spain
Hospital Clínico Universitario de Valencia,
European Hip Preservation Associates, ESSKA–
Valencia, Spain
EHPA, Eich, Luxembourg
L. Gimeno-Torres
Iberian Group of Hip Preservation Surgery (GIPCA),
Department of Orthopaedics and Traumatology,
Portugal, Spain
Centro Hospitalario Durango, Ciudad de México,
Muscle and Tendon Study Group (GELMUT) México, Mexico
Asociación Española de Artroscopia – AEA,
E. Llopis
Madrid, Spain
Department of Orthopaedics and Sports
F. Vecchi Traumatology, IMSKE Hospital - European
Department of Orthopaedics and Sports Musculoskeletal Institute, Valencia, Spain
Traumatology, IMSKE Hospital - European
Department of Radiology, IMSKE Hospital -
Musculoskeletal Institute, Valencia, Spain
European Musculoskeletal Institute, Valencia, Spain
B. Álvarez de Sierra
Department of Radiology, Clínica Universidad de
Navarra, Madrid, Spain

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 183
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
184 B. Capurro et al.

25.1 Hip Joint 6 MHz. Inspection of the hip anatomy is per-

formed with the long axis allowing visualization
The intra-articular ultrasound-guided (US) injec- of the anterior edge of the acetabulum, femoral
tion technique in the hip performed in-office has head, femoral neck, and joint capsule (if there is
shown superiority compared to injections guided effusion, its aspiration can be planned in
by fluoroscopy [1]. It presents high reliability, an advance). In addition, routine Doppler visualiza-
excellent degree of satisfaction and convenience tion of the femoral neurovascular bundle (located
for patients, in addition to requiring a minimal medially) and the lateral circumflex femoral
learning curve for its execution [1]. artery is recommended to avoid iatrogenesis
This technique can be used to infiltrate interar- (Fig. 25.2a) [5].
ticular corticosteroids for the conservative treat- Injection technique: Using a sterile and asep-
ment of hip osteoarthritis and in non-arthritis tic method, the needle should enter the joint cap-
diseases such as femoroacetabular impingement, sule as lateral as possible while maintaining
where its use has also increased, mainly for diag- long-axis visualization of the femoral neck and
nostic purposes [2]. It can also be used for intra-­ joint capsule to avoid contact of the needle with
articular viscosupplementation and in the the femoral vessels (Fig. 25.3) [5]. Under in-­
expanding role of orthobiologics [3]. The advan- plane visualization with the transducer, a 3.5-­
tages and disadvantages of this infiltration tech- inch 22-G sterile spinal needle is inserted, bevel
nique are indicated in Table 25.1. up, approximately 1 cm from the distal portion of
the ultrasound transducer until it pierces the joint
capsule at the femoral head neck junction. When
25.1.1 Procedure the needle is in the correct position within the
capsule, the drug can be injected and visualized
Aim: To enter the joint capsule on the anterolat- entering the joint capsule (Fig. 25.2b).
eral surface of the femur neck at the femoral Technical note: If the patient is obese or if it is
head-neck junction to avoid chondral damage. difficult to immediately find the femoral neck in
Position: Supine position, neutral rotation of a long-axis view, the greater trochanter can be
the leg, or slight internal rotation 15° (Fig. 25.1). visualized in the short axis and followed to the
US preview: A linear probe can be used with a femoral neck, and then rotate the axis 35–45°
frequency between 8 and 14 MHz and preferably proximal and then allow the femoral head neck
a convex probe with a frequency between 3 and junction to be seen on the long axis.

Table 25.1 Ultrasound-guided intra-articular injection: advantages and disadvantages (adapted from Bardowsky et al.
[4])
Advantages Disadvantages
 1. Fast learning curve  1. User dependent
 2. Cost effective and convenient for the patient  2. The provider uses more in-office time to
perform
 3. More accurate than landmark injections  3. Upfront cost of ultrasound equipment and
supplies
 4. Less painful than fluoroscopic guided and no radiation  4. Limited by the characteristics of the patient’s
exposure body
 5. Can visualize joint effusion and aspirate if needed
 6. Allows for immediate postinjection reassessment/
real-time information
25 Injections of Anatomical Regions and Diseases: Hip 185

a b

Fig. 25.1 Position for optimal US hip joint visualization. (a) Infiltration position with US preview. (b) Long axis and
position for infiltration of a normal hip

a b

Fig. 25.2 Intra-articular US-guided hip injection. (a) observed as the intra-articular fluid has penetrated the
Ultrasound-guided approach in the anterior joint recess of anterior recess, elevating the capsule (white arrow).
the hip (anechoic), it is recommended to look for the cir- Needle direction (yellow arrow) avoiding damaging the
cumflex vessels (red Doppler area). (b) Intra-articular hip circumflex vessels
ultrasound-guided injection technique. A flash effect is
186 B. Capurro et al.

25.2 Trochanteric Bursitis (a) The subgluteus maximus (greater trochan-

teric) bursa is the largest and is located over
The greater trochanter is located on the proximal the posterior and lateral facets, being sepa-
femur and is a large bulge that arises from the rated from the trochanter by the insertions of
junction of the femoral neck and shaft [6]. The the gluteus medius.
anatomy of the greater trochanter is made up of (b) The subgluteus medius bursa is located
four facets: anterior, lateral, posterior, and supero- between the lateral facet and gluteus medius
posterior [7] and seven muscles attach to the tendon and can extend posteriorly in the
greater trochanter, but their anatomical relation- trochanter.
ships are complex to understand and not always (c) The subgluteus minimus bursa is located
constant due to anatomical variants of the tendons. between the anterior facet and gluteus mini-
Schematically the gluteus medius is inserted on mus tendon.
the lateral and superoposterior facets, the gluteus Greater trochanteric pain syndrome (GTPS) is
minimus is inserted on the anterior facet, the piri- a common pathology that can affect up to 17.6%
formis is located superomedially without present- of the population [10]. It mainly affects women
ing a specific facet insertion, the external obturator in their fourth to sixth decade, presenting lateral
is more medial, and the internal obturator is adja- hip pain and tenderness, which worsens with
cent together with the superior and inferior walking, lying on the affected side and/or stair
Geminus insert into the trochanteric fossa [6, 8, 9]. climbing [11]. Multiple diagnoses are included
There are three trochanteric bursae described, within the GTPS; US and MRI can be used for
and it is important to understand that they are not diagnosis and most often reveal pathologic con-
visualized in all cases unless they are filled with ditions involving the gluteus medius and mini-
synovial fluid (Fig. 25.3) [7]: mus tendons, including tendinosis, calcifications,
and tears. Although, the gluteal tendinopathy
with or without bursitis has been identified as the
primary source of pain and dysfunction, other
causes such as trochanteric bursitis, external
snapping hip, proximal iliotibial band syndrome
should also be considered [12].
Initial conservative treatment for GTPS
includes activity modification, weight loss, ice,
and physical therapy to address strength and flex-
ibility deficits [6, 13]. Corticosteroid injections
are frequently used concomitantly with conserva-
tive treatment, resulting in pain reduction in the
first 4–8 weeks in mild and moderate tendinopa-
thy and improvement in function and pain at rest
and during activity. However these effects do not
last more than 3–6 months, and their effective-
ness decreases as time goes by [14, 15].
Corticosteroid US-guided infiltration targeting
the greater trochanteric bursae carries a low risk
Fig. 25.3 Hip joint and trochanteric bursae illustration.
Illustration of the intra-articular infiltration of the hip and
of side effects and is shown to be more effective
the direction where the needle must go in relation to the than blind or fluoroscopy infiltrations; however,
anatomy to avoid contact of the needle with the femoral prolonged steroid use can result in possible ten-
vessels and the three trochanteric bursae: subgluteus max- don degeneration and rupture, which is why it is
imus bursa (green arrow); subgluteus medius bursa
(orange arrow); and subgluteus minimus bursa (black
not recommended to repeat it more than once
arrow) every 3–4 months [16]. Additionally, studies have
25 Injections of Anatomical Regions and Diseases: Hip 187

demonstrated inhibitory effects of tendon repair ment should be considered [11, 12]. However,
and delayed tendon sheath healing [12, 13]. more randomized controlled trials are needed to
Platelet-rich plasma (PRP) infiltrations have compare the efficacy of these treatments to deter-
increased their use compared to corticosteroids in mine the best treatment for GTPS.
gluteal tendinopathy, as they promote tissue heal-
ing through a high concentration of platelet-­
derived growth factors that help activate the 25.2.1 Procedure
healing cascade and reverse the degenerative pro-
cess [17]. Systematic reviews have been reported Aim: To infiltrate the greater trochanteric bursa
showing improved outcomes for PRP at 2 years and the others when they are inflamed; in the case
compared to a CSI as measured by the Harris Hip of corticosteroids associated with local anesthetic
Score [18] and reported a sustained benefit outside the tendon or with PRP that allows intra-
through 2 years following PRP in randomized tendinous infiltration if the tendon is affected and
controlled trials [12, 19]. Other conservative associated with ultrasound needling to seek reso-
treatment modalities, such as ultrasound-guided lution of enthesopathy and dissolution of
percutaneous needle tenotomy, prolotherapy, and enthesophytes.
shock waves, have been described and may be Position: Lateral decubitus on the unaffected
considered [8, 20]. Although all of these injec- side, hip and knee semi-flexed for patient com-
tions and therapeutic options can improve symp- fort and visualization in both axes with the US
toms, physical therapy should be used after (Fig. 25.4).
corticosteroids and PRP injections as it improves US preview: A linear probe can be used with a
modifiable factors, including hip abductor weak- frequency between 8 and 14 MHz and preferably
ness, band tension iliotibial pain, and loss of pel- in obese patients a convex probe with a frequency
vic control in the frontal plane, which are present between 3 and 6 MHz. It is recommended to
in the pathophysiology of GTPS [12]. Also when visualize systematically in the long axis and in
conservative treatment fails, surgical manage- the short axis on the trochanter maximus and to

a b

Fig. 25.4 Ultrasound positions for greater trochanteric verse axis of the greater trochanter, which is the
infiltration techniques. (a) Visualization of the longitudi- recommended position to carry out the infiltrations due to
nal axis of the greater trochanter. (b) Position in the trans- less sensitivity in the posterior skin area
188 B. Capurro et al.

search on the facet anterior to the gluteus mini- mus-iliotibial band and the deep gluteus medius
mus and on the facet posterior to the gluteus tendon, where the injection is delivered
medius. It is also recommended to visualize the (Fig. 25.5). It is not recommended to infiltrate
posterior area given the extension of the trochan- more than 2–3 ml.
teric bursa so that the bursitis can be previously Technical note: For optimal ultrasound visual-
drained if necessary (Fig. 25.5). ization (in the short axis) of the gluteal tendons in
Injection technique: US is placed in the the greater trochanter, it is recommended to start
transverse axis of the trochanter, with an with the leg in a neutral position from proximal
oblique path toward the posterosuperior facet to distal to find the insertion of the gluteus medius
and the needle is placed under the plane until it in the posterosuperior facet. Then, to see the
reaches the gluteal major bursa. Following a insertion of the gluteus minimus on the anterior
needle (22 G, 64–89 mm) is advanced in plane facet of the greater trochanter, it is recommended
with the transducer using a posterior to anterior to perform external rotation of 15° and slide the
approach under direct US guidance into the tis- transducer slightly anteriorly in the short axis
sue plane between the superficial gluteus maxi- (Fig. 25.6).

a b

Fig. 25.5 Transverse axis view of the greater trochanter. ized (anechoic). (b) Infiltration of PRP in the gluteus
(a) An insertional tendinopathy of the gluteus medius and medius; previously, the aspiration of the bursal fluid has
an inflamed greater subgluteus maximus bursa (greater been carried out, followed by the intratendinous infiltra-
trochanteric bursae) where the peritendon fluid is visual- tion together with the needling technique

a b

Fig. 25.6 Gluteus medius and minimus trochanteric insertions. (a) Gluteus medius: US short-axis view. (b) Gluteus
minimus: US short-axis view
25 Injections of Anatomical Regions and Diseases: Hip 189

25.3 Osteitis Pubis FABER test results, sacroiliac joint dysfunction,

and abductor or adductor weakness may be asso-
Osteitis pubis (OP) is an idiopathic inflammatory ciated with clinical findings [24].
condition that affects the pubic symphysis and Diagnosis is challenging because of the ana-
surrounding soft tissues and is caused by overuse tomical complexity of the groin area, biomechan-
or trauma [21]. The etiology of OP is not fully ics of the pubic symphysis area, and large number
understood [22], and the imbalance between the of potential sources of groin pain. Differential
adductors of the abdomen and hip (most often the diagnoses include intra-articular pathologies
adductor muscles) is currently considered the such as femoroacetabular impingement syn-
most important pathogenic factor in the develop- drome (FAI), acetabular labral tears, and chon-
ment of osteitis pubis (Fig. 25.7). A chronic dral lesions, as well as extra-articular pathologies
imbalance between these muscles causes abnor- such as insertional adductor and rectus abdomi-
mal forces across the pubic symphysis, affecting nis tendinopathy, adductor injuries, sports hernia,
the biomechanics of the joint and resulting in inguinal hernia, urinary tract infection, and
damage to bone and cartilage degeneration. For prostatitis.
these reasons, OP is more common in high-level Imaging is not pathognomonic, but radiogra-
athletes, such as football, rugby, distance run- phy, three-phase scintigraphy, and MRI can aid
ning, and ice hockey players, with a prevalence physical examination and confirm the diagnosis
ranging from 0.5% to 8% [23]. and/or exclude other pathological conditions and
OP is a self-limiting disease characterized by possible sources of groin pain [24]. As the gold
pain in the pubic symphysis and medial groin standard, MRI provides a more detailed view of
area, which radiates to the adductors, suprapubic, the pubic symphysis and surrounding soft tissues
and lumbar regions and worsens with physical as well as the bony pelvis and hip. The most com-
activity. Tenderness upon palpation in the sym- mon finding in athletic osteitis pubis lasting less
physis area is common; however, clinical exami- than 6 months is the presence of a hyperintense
nation is not standardized and includes various signal on T2-weighted images in the symphysis
tests such as lateral compression and the pubic and adjacent parasymphyseal region, while sub-
symphysis gap test with isometric adductor con- chondral sclerosis, subchondral resorption with
traction. Limited hip range of motion, positive bony irregularities, and osteophytosis or pubic
beaks are characteristic of the chronic phase [25].
Some studies report similar bone marrow edema
in asymptomatic athletes as well, so correlation
between MRI and clinical examination is
mandatory.
Osteitis pubis is described as a self-limiting
condition that improves with activity modifica-
tion and individualized conservative treatment,
while surgical treatment is required in approxi-
mately 5–10% of patients. However, not all ath-
letes are eligible for conservative treatment due
to difficulties in pain management and the long or
unpredictable time frame of conservative treat-
Fig. 25.7 Illustration of osteitis pubis. On the left side, it
ment [23]. Conservative treatment includes rest,
is shown the anatomical relationship of the insertion of the limited activity, ice, and anti-inflammatory medi-
adductor longus and the structures at risk, which are the cations, followed by an individualized progres-
genitofemoral and ilioinguinal nerves together with the sive multimodal rehabilitation program [26].
spermatic cord in men that emerge from the inguinal canal
and the external pudendal artery. On the right side, there is
Noninvasive treatment aims to correct muscle
an illustration in red of osteitis pubis imbalances around the pubic symphysis and usu-
190 B. Capurro et al.

ally consists of a progressive exercise program

involving stretching and strengthening of the pel-
vic floor muscles.
If the symptoms do not improve with conser-
vative measures, local injections can be adminis-
tered. Corticosteroid injections into the symphysis
and surrounding tissues have been used in vari-
ous studies; however, there is little evidence to
support this. Choi et al. described pain relief at
short-term follow-up with corticosteroid injec-
tions; however, a high proportion of patients did
not respond [27]. Despite a successful return to
sports, a large percentage of these patients con-
tinue to report pain and/or require multiple injec-
tions [27].
Surgical intervention is required in 5–10% of
patient’s refractory to conservative approaches
and may be indicated after a minimum of 3
months of a well-conducted rehabilitation proto-
col if conservative treatment fails [28].
Fig. 25.8 Position to visualize the proximal adductor
longus insertion on the long axis and how the infiltration
of the adductor longus would be performed
25.3.1 Procedure

Aim: To perform an intra-articular infiltration of imaging of long adductor tendinopathy is charac-

symphysis pubis. terized by the presence of hypoechoic images
Patient position: Patient in supine or lateral associated with small intratendinous tears as well
position, with the thigh abducted and externally as thickening of the tendon and the presence of
rotated so that the adductors are relaxed and the small calcifications and may also show increased
adductor longus tendon is accessible if needed vascularity in the area of tendon degeneration on
(Fig. 25.8). a Doppler US scan. In other patients, there is a
US preview: A linear probe with a frequency rupture of the myotendinous junction, which
between 8 and 14 MHz is used; the sensor is presents as a large anechoic defect at the site of
placed longitudinally at the level of the pubic interruption.
bone. The examination begins with a study of the Injection technique: Using a sterile and asep-
pubic symphysis, which appears as a darker tic method, a 21-G needle is advanced using an
hypoechoic line between the two pubic bones. out-of-plane technique superior to the transducer
The articular surfaces are oval in shape with a until it reaches the symphysis pubis joint
mean length of 30–35 mm and a mean width of (Fig. 25.9). Infiltration can be performed under
10–12 mm [29]. The examination of the adduc- direct ultrasound guidance when the needle is in
tors is then carried out in both the superficial and the correct position inside the capsule. After the
deep plane of the inner thigh with special focus needle is removed, the pubic bone should be
on the adductor longus, which is the most com- scanned to ensure there is no bleeding after the
mon site of tendinopathy at this level. Ultrasound procedure.
25 Injections of Anatomical Regions and Diseases: Hip 191

a b

Fig. 25.9 Symphysis pubis joint infiltration. (a) US sym- for intraarticular symphysis pubis joint. Yellow circle
physis pubis anatomy. AL adductor longus, BA adductor shows the needle out of plane
brevis, AM adductor magnus. (b) Out-of-plane technique

25.4 Iliopsoas Bursitis The iliopsoas musculotendinous unit and ilio-

psoas bursa are exposed to continuous m­ echanical
The psoas major is a long muscle that originates stress owing to their proximity to the acetabular
from the transverse processes, vertebral bodies, rim and hip joint. This can lead to iliopsoas tendi-
and intervertebral discs T5 to L5. The iliacus is a nosis or tear. Pathological conditions of the ilio-
shorter muscle originating from the upper two-­ psoas tendon can be accompanied by abnormal
thirds of the iliac fossa, ventral lip of the iliac tendon movement, and the source of internal
crest, and sacral ala. The medial and lateral bun- snapping hip is described as painful audible and/
dles are connected to the iliac [30]. The psoas or palpable snapping of the iliopsoas over the
major and iliacus converge to form the iliopsoas iliopectineal eminence [33]. The tendon may
muscle at the L5 to S2 levels and are inserted into cause anterior hip pain after total hip arthroplasty
the lesser trochanter of the femur as the iliopsoas because of friction between the tendon and the
tendon. The psoas major tendon is located medial protruding acetabular component or impinging
to the lateral iliac tendon [31]. The deep part of on the collar of the femoral prosthesis (anterior
the iliopsoas muscle is anterior and lateral to the impingement), with a prevalence of 0.4–18%
labrum of the hip joint. The iliopectineal or ilio- [34, 35]. In this case, nonoperative management
psoas bursa is the largest bursa in the human of iliopsoas impingement, including physical
body, located between the iliopsoas muscle, bony therapy, nonsteroidal anti-inflammatory drugs
surface of the pelvis, and proximal femur. (NSAIDs), and ultrasound-guided iliopsoas ten-
The iliopsoas is the primary hip flexor that can don sheath corticosteroid injections, led to groin
help tilt the pelvis forward. It also functions as an pain resolution in 50% of patients [36]. With its
external hip rotator and is considered a core mus- location between the deep surface of the iliopsoas
cle due to its attachment to the spine. As the ilio- tendon and the acetabular rim and hip joint, ilio-
psoas muscle connects the spine to the lower psoas bursopathy may accompany iliopsoas ten-
limbs, it plays an important role in many activi- don pain. Because of the connection between the
ties of daily life, including sports. For example, hip joint and iliopsoas bursa in some individuals,
the psoas major muscle helps in sitting and main- iliopsoas distention is often associated with path-
taining an upright spine position. The iliopsoas ological conditions of the hip joint, including
contributes significantly to running, particularly rheumatoid arthritis, osteoarthritis, villonodular
to the initiation of the swing phase, and plays a synovitis, synovial chondromatosis, and septic
crucial role during the kicking and deceleration arthritis [37]. Iliopsoas bursitis can also indicate
of the thigh [32, 33]. an underlying pathological condition typically
192 B. Capurro et al.

associated with a previous injury or overuse syn- with a frequency of 3–6 MHz. The sensor is ini-
drome [37]. In this sense, it is important to tially placed in the transverse plane, above the
remember that injury to the iliopsoas muscle is femoral head. The transducer is then translated
the second most frequent among professional superiorly and at an angle parallel to the inguinal
soccer players [38]. ligament in the oblique axial plane. On the proxi-
Image-guided injections can help in the diag- mal side of the femoral head, the bony contours
nosis and treatment of iliopsoas disorders. of the femoral head and acetabulum can be visu-
Accurate diagnostic iliopsoas injections should alized, together with the iliopsoas muscle and
be administered to identify the source of the pain tendon. Transducer switching may be necessary
(suppression test). US-guided iliopsoas bursa to optimize the visualization of the iliopsoas ten-
injection provides pain relief and predicts good don secondary to anisotropy. Moving the trans-
outcomes after iliopsoas tendon release surgery ducer superiorly allows visualization of the hip
in patients with anterior iliac crest pain and sus- joint at the level of the iliopectineal eminence and
pected iliopsoas tendon rupture. In addition, allows continued imaging of the iliopsoas muscle
ultrasound-guided iliopsoas peritendon injec- and tendon. If a snapping iliopsoas is suspected,
tions have been described in patients with previ- a US scan of the iliopsoas tendon can be per-
ous hip pain following total hip arthroplasty. formed, while the patient is performing provoca-
tive maneuvers. If the patient cannot reproduce
snapping, US can be performed as the hip moves
25.4.1 Procedure from flexion, external rotation, and abduction to
full extension, adduction, and internal rotation.
Aim: It is crucial to identify the interval between Preprocedural scanning includes evaluation of
the deep layer of the iliopsoas tendon and upper anechoic or hypoechoic distention of the ilio-
margin of the iliacus muscle, which is the most psoas bursa and, if present, assessment of com-
common site of bursitis. It is essential to remain munication between the bursa and hip joint.
extracapsular and avoid the neurovascular bundle Injection technique: The transducer is placed
by using a lateral-to-medial in-plane technique transverse to the iliopsoas tendon in an oblique
(Fig. 25.10). axial plane, parallel to the inguinal ligament and
Position: The patient is placed in a supine above the femoral head. The skin at the lateral
position with the hip in neutral rotation. edge of the traducer is marked with a marking
Infiltration can be done in the longitudinal axis or pen, and the area is prepared in a sterile manner.
out of plane (short or transverse axis) (Fig. 25.11). After application of local anesthesia, a 22-G
US preview: US evaluation of the iliopsoas 89-mm needle is advanced in plane with the
region is usually performed using a convex probe transducer using a lateral-to-medial approach to

a b c d e

Fig. 25.10 Clinical case of iliopsoas bursitis (yellow guided bursitis aspiration avoiding the neurovascular
arrow). (a) MRI axial section. (b) MRI coronal section. bundle and where the posterior infiltration is performed
(c) Visualization of the femoral neurovascular bundle with (yellow circle)
Doppler. (d) Visualization of bursitis. (e) Ultrasound-­
25 Injections of Anatomical Regions and Diseases: Hip 193

a b

Fig. 25.11 Position for the US-guided techniques of infiltration of psoas bursitis. (a) Out of plane infiltration (trans-
verse axis). (b) Infiltration in plane (longitudinal axis)

avoid vessels. The needle is then advanced under

direct US guidance into the deep lateral part of
the iliopsoas tendon, where it is directed between
the deep surface of the iliopsoas tendon and the
superficial surface of the ilium at the level of the
iliopectineal eminence, or alternatively, between
the iliopsoas tendon and the rim of the acetabu-
lum. When the injection is administered, fluid is
seen between the iliopsoas tendon and the ilium,
as well as on the medial side of the iliopsoas ten-
don (Fig. 25.11).
Technical note: Hydrodissection may be use-
ful for identifying a plane deep to the iliopsoas
tendon but superficial to the hip capsule to avoid
inadvertent penetration of the capsule (Fig. 25.12;
Fig. 25.12 Iliopsoas bursitis in plane hydrodissection/
Table 25.2).
infiltration illustration
194 B. Capurro et al.

Table 25.2 Ultrasound-guided iliopsoas bursa: advan-

tages and disadvantages [39, 40]
Advantages Disadvantages
 1. Safe and low-impact  1. User dependent
procedure as it does not
involve the use of
radiation
 2. It can be both diagnostic  2. The provider uses
and therapeutic at the more in-office
same time time to perform
 3. It provides greater  3. Upfront cost of
anatomical detail ultrasound
compared to equipment and
fluoroscopy-guided supplies
infiltration
 4. It is possible to visualize  4. Limited by the
the target area and characteristics of
neurovascular bundle in the patient’s body
real-time
 5. Visualization of joint
effusion is possible and
aspiration can be done if
needed
 6. It allows for immediate Fig. 25.13 Hamstring infiltration illustration. The close
post injection relationship and precaution that must be taken with the
reassessment/real-time sciatic nerve is observed laterally
information

25.5 Hamstring Origin and Ischial

Bursitis

Ultrasound-guided (US) injection solutions for

the treatment of proximal hamstring tendinopa-
thy and hamstring bursitis is a good alternative to
treat chronic hamstring tendinopathy where other
conservative treatments have failed (Fig. 25.13)
[41].
Surgical intervention has been shown to have
good results in the treatment of pain and function
of hamstring tendinopathy, but has potential risks
such as sciatic nerve injury, infection, and re-­
rupture, as well as a longer time to return to nor-
mal physical activity than conservative treatments Fig. 25.14 Ultrasound-guided position for approach of
the proximal hamstring insertion infiltration
[42].

Position: Patients in prone position and neu-

25.5.1 Procedure tral rotation of the leg (Fig. 25.14).
US preview: A linear probe can be used with a
Aim: To perform intratendinous injections at the frequency between 8 and 14 MHz and preferably
origin of the hamstrings and ischial bursitis. a convex probe with a frequency between 3 and
25 Injections of Anatomical Regions and Diseases: Hip 195

6 MHz. The examination focuses on the ischium, vascular bundle. Images were obtained on the
specifically the origin of the common BF/ST long and short axes (Fig. 25.16).
(biceps femoris/semitendinosus) tendon, which Injection technique: Using a sterile and asep-
is located lateral to the ischial tuberosity, and tic method, the needle should enter the origin of
close to the section of the sciatic nerve the hamstrings. Under in-plane visualization with
(Fig. 25.15). Additionally, it is necessary to con- the transducer, a sterile 3.5-inch, 22-G spinal
duct routine Doppler visualization of the sciatic needle is inserted at a 45° angle to the skin in the
longitudinal plane, due to the lateral-medial
approach, until the spinal trocar reaches the lat-
eral aspect of the ischium, avoiding the sciatic
nerve pathway. At this level, at the origin of the
proximal tendon, 3 ml or 5 ml of intratendinous
solution was injected, while real-time imaging
was performed.
Technical note: If it is difficult to detect the
common hamstrings, we can see the fibers of the
ST muscle there, because it is the only hamstring
with muscle fibers that go directly to the ischial
tuberosity.

Fig. 25.15 Ultrasound-guided approach of the ham-

strings (yellow arrows) and the ischium. The sciatic nerve
(yellow circle) is also seen close to the semimembranosus
tendon

a b

Fig. 25.16 Proximal hamstring tendinopathy. (a) Longitudinal and (b) transversal ultrasound section of the proximal
semimembranosus tendon on the ischial tuberosity
196 B. Capurro et al.

25.6 Deep Gluteal Space

Deep gluteal syndrome (DGS) is a posterior hip

pain and/or radicular pain due to non-discogenic
entrapment of the sciatic nerve in the subgluteal
space [43].
The ultrasound-guided (US) injection in the
subgluteal space makes it possible to detect the
nerve along its entire length and to perform a
dynamic study, which is particularly interesting
in the case of entrapment in the ischiofemoral
space. This technique can be used to achieve a
greater therapeutic effect in the piriformis muscle
or the perisciatic region [44].

Fig. 25.17 Illustrates the positioning utilized for a DGS

25.6.1 Procedure Ultrasound-guided injection employing a lateral to medial
approach with a spinal needle. The patient is positioned
prone, maintaining a neutral rotation
Aim: To enter into the deep gluteal space between
the greater trochanter (GT) and the ischial tuber-
The transducer is moved caudally along the
osity (IT) and identify the sciatic nerve in order to
sciatic nerve with the IT on its medial aspect, the
avoid its damage.
origin of the hamstrings on its lateral aspect, the
Position: Patient in prone position and neutral
gluteus maximus on its superior aspect, and the
rotation (Fig. 25.17).
pelvitrochanteric muscles (superior gemellus,
US preview: A linear probe can be used with a
obturator internus, inferior gemellus, and quadra-
frequency between 8 and 15 MHz. During US
tus femoris) on its inferior aspect (Fig. 25.17).
examination, the patient lies in prone position. In
Injection technique: Using a sterile and asep-
a morphometric cadaveric study, it is described
tic method, the needle should enter the deep glu-
for a safer approach to identifying the SN in the
teal space between the GT and the IT (Fig. 25.18).
deep gluteal space, the use as a constant land-
Under in-plane visualization with the transducer,
marks relative to the SN the reference between
a sterile 3.5-inch 22-G spinal needle is inserted at
the GT-SN and IT-SN, showing that the distance
a 45° angle to the skin in the longitudinal plane,
between tip of the GT to SN = 7.23 cm (±0.83)
due to the lateral-medial approach, until the spi-
and the center of the IT to SN = 5.28 cm (±0.73)
nal trocar reaches the medial aspect of the sciatic
[45]. The sciatic nerve appears as an oval-shaped
nerve (Figs. 25.19 and 25.20).
hypoechoic (Fig. 25.18).
25 Injections of Anatomical Regions and Diseases: Hip 197

a b

Fig. 25.18 Clinical case: DGS secondary to hamstrings cle. (a) Ultrasound transverse plane with enlargement of
proximal enthesopathy. Acute ischiofemoral impingement hamstrings common tendon. (b) MR axial PD FS with
in a 40-year-old female shows a narrowing ischiofemoral secondary muscle edema. Sciatic neuritis is also shown
space causing impingement of the quadratus femoris mus-

Technical note: If the patient is obese or if it is

difficult to immediately find the deep gluteal
space, the sciatic nerve was located lateral to the
semimembranosus origin in the ischial tuberosity
(Table 25.3).

Fig. 25.19 Illustration of the DGS of the hip and the

direction where the needle must go in relation to the
anatomy
198 B. Capurro et al.

a b

Fig. 25.20 DGS ultrasound-guided injection technique. halo is observed as hydrodissection of the sciatic nerve
(a) Ultrasound-guided injection with the spinal needle lat- (orange arrows). IT ischial tuberosity; SN sciatic nerve
eral to medial approach (yellow arrows). (b) An anechoic

Table 25.3 Ultrasound-guided deep gluteal space injec-

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 Injections of Anatomical Regions
and Diseases: Knee
26
Sarper Gursu, Ahmet Sukru Mercan, Anıl Erbas,
Serda Duman, and Ozgur Ismail Turk

26.1 Knee Joint the friction between the bones. The knee joint is
supported by a couple of ligaments and tendons
Knee is the body’s largest joint and has a very which are located both inside and outside of the
complex structure composed of bone, cartilage, joint space. The knee joint capsule surrounds the
meniscus, and the ligaments. joint and consists of two layers: the outer layer
being made up of fibrous tissue and the inner
layer also known as synovial membrane. The
26.1.1 Anatomy synovial membrane produces the knee joint fluid
and helps reduce the friction between the joint
The knee joint is a complex diarthrodial joint. surfaces and nourishes the cartilage tissue, cover-
Medial and lateral femoral condyles, plateau ing the articular surfaces [1, 2].
tibia, and the patella make up the joint, and the
joint surfaces are covered with hyaline cartilage.
The knee joint has three compartments as fol- 26.1.2 Indication and Diagnosis
lows: medial tibiofemoral compartment, lateral
tibiofemoral compartment, and patellofemoral Knee joint injections are mostly performed for
compartment. Between the femur and the tibia, patients with osteoarthritis. Other common indi-
there are two crescent-shaped structures known cations are rheumatoid arthritis, crystal arthropa-
as meniscus which absorb the shock and reduce thies, psoriatic arthritis, and other inflammatory
diseases affecting the knee joint. Degeneration of
the cartilage, along with changes in subchondral
S. Gursu (*) tissues, is usually encountered in these patients,
Baltalimani Bone and Joint Diseases Hospital, leading to many different symptoms. Pain is the
Istanbul, Turkey
most prominent symptom for most diseases in
Health Sciences University, Athlete’s Health and the knee joint, and relieving pain is the main tar-
Sports Sciences Institute, Istanbul, Turkey
get of most agents used for injections. Relieving
A. S. Mercan pain usually improves functional status and
Nisantasi University, Istanbul, Turkey
increases range of motion. Pathologies of the
A. Erbas · S. Duman knee may be diagnosed on the basis of clinical
Baltalimani Bone and Joint Diseases Hospital,
presentation and findings in various imaging
Istanbul, Turkey
studies. Simple AP (anteroposterior) and lateral
O. I. Turk
X-rays reveal the damage occurring in the joint
Cevre Hastanesi, Istanbul, Turkey

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 201
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
202 S. Gursu et al.

very clearly in most cases; however, true differ- beneath the insertion site of the quadriceps ten-
ential diagnose may require specific blood tests don. The injection is done gently and not against
or further imaging studies such as MRI (mag- resistance. If any resistance is encountered, this
netic resonance imaging) [3–5]. could mean that the tip of the needle is within soft
Inserting a needle to the knee joint may also tissues and not in the pouch. In this case, the nee-
be required for aspirating joint fluid or blood in dle should be retracted and re-inserted at an angle
cases with a suspicion of septic arthritis or directing more toward the center of the joint
­hematoma. Samples for further evaluation may [6–8].
also be obtained by aspiration [6]. Another very well-known and highly pre-
ferred injection site is the superolateral aspect of
the knee joint. Similar to the superomedial
26.1.3 Appliances approach, the patient holds the knee fully
extended with a pad underneath for relaxation.
Approximately 5 ml of liquid can be injected by After stabilizing the patella from the medial side
a 21-gauge (G) or 22-G, 2-inch-long syringe tip with the clinician’s thumb, the needle is inserted
and a 5-ml syringe. For aspiration an 18-G or underneath the superolateral part of the patella,
20-G syringe would be more appropriate. directing toward to the center of the joint space
posterior and inferomedial. Both the superolat-
eral and the superomedial approaches are known
26.1.4 Agents as rather safe for performing intraarticular injec-
tions to the knee joint [6–8].
Corticosteroids, local anesthetics, visco-­ Intraarticular knee injections may also be per-
supplements, and orthobiologic agents (PRP, formed through the anteromedial or anterolateral
PRGF, stem cell solutions, etc.) approaches (Figs. 26.1 and 26.2). These two
approaches are also known as the arthroscopic
approaches. For these two approaches, the patient
26.1.5 Technique/Tricks/Pitfalls should either be sitting or lying with the knees
flexed to 90°. The needle is inserted to the lateral
There are various approaches for infiltrating or side of the patellar tendon (for the anterolateral
aspirating the knee joint. The best approach is the approach) or medial side of the patellar tendon
one with least obstruction and easier access to the (for the anteromedial approach) 1 cm above the
synovial cavity. tibial plateau. The needle should be directed to
If the superomedial approach is preferred, the the space between the medial and lateral femoral
patient either sits while the knee is extended or condyles at an angle of 30–45°. If the medial
lays supine with a thin pad under the knee for approach is preferred for injection, the track of
support. The medial edge of the patella is pal- the saphenous nerve should be considered in
pated and marked. Marking the edge is strongly order to avoid saphenous neuropathy [6–8].
recommended especially in overweight individu- Lateral and medial mid-patellar approaches
als. The clinician may push the patella’s lateral may also be preferred for either infusions or aspi-
edge gently, widening the medial entrance of the rations of the knee. The patient is seated with the
suprapatellar pouch and also stabilizing the knees fully extended. The needle is directed to
patella. Sterile technique is applied, and the nee- the center of the knee, while the patella is pushed
dle is inserted 1 cm medial to the patella at the medially or laterally [6–8]. Ultrasonography may
intersection point of upper one third of the patella be used to increase the accuracy of injections and
and the middle part. Then it is further inserted helps giving the medication properly to the syno-
laterally at an angle of 45° directing to the center vial joint [9]. The size of the needle to be used
of the knee joint and into the suprapatellar pouch, during the injection should be decided according
26 Injections of Anatomical Regions and Diseases: Knee 203

Fig. 26.1 The use of the anterolateral approach for above the tibial plateau. The needle should be directed to
intraarticular knee injection. Patient should either be sit- the space between the medial and lateral femoral condyles
ting or lying with the knees flexed to 90°. The needle is at an angle of 30–45° (P patella, TT tuberositas tibia)
inserted to the lateral side of the patellar tendon 1 cm

Fig. 26.2 The use of the

anteromedial approach for
intraarticular knee injection. The
needle is inserted to the medial
side of the patellar tendon 1 cm
above the tibial plateau. The
needle should be directed to the
space between the medial and
lateral femoral condyles at an
angle of 30–45 degrees (P patella,
TT tuberositas tibia)
204 S. Gursu et al.

to the viscosity of the fluid to be injected. For the 26.2.2 Indication and Diagnosis
purpose of arthrocentesis, smaller sizes (18–20
G) should be preferred for easier flow of the joint Pes anserine bursitis is usually known as a self-­
fluid. limiting injury. Conservative treatment modali-
ties lead to very satisfactory results and complete
healing in most cases. Injection of pes anserine
26.1.6 Aftercare bursa should be regarded as a second-line treat-
ment and reserved for patients not responding to
The patient is observed for a while and let for NSAIDs, rest, use of ice, and physical rehabilita-
walking immediately, although undue weight-­ tion. Pain located in the medial aspect of the
bearing should be avoided for at least 5–7 days. proximal tibia is the most common symptom of
NSAID use is recommended. Normal activities the disease. Pain which is increasing while aris-
can be resumed afterward along with strengthen- ing from seated position is a typical finding.
ing exercises to be performed at home. Further Tenderness over the bursa and local swelling may
repeat injections can be performed to the same also be encountered. History of recent athletic
knee after 3 months, at earliest. activity is present in some cases. Runners, swim-
mers, and dancers are prone to pes anserine bur-
sitis. During a proper physical examination, it is
26.2 Pes Anserine Bursa possible to palpate the painful bursa, and the
symptoms may be reproduced with resisted flex-
Pes anserine bursitis occurs usually as an overuse ion of the knee. Pes anserine bursitis is usually
injury and may be significantly painful in some accompanied by degenerative diseases of the
cases. It is an inflammatory condition. Frequent knee making further imaging studies necessary.
and forced flexion of the knee increases the fric- If there is suspicion about the diagnosis, a diag-
tion, leading to irritation of the bursa. Trauma, in nostic injection with a local anesthetic may be
the form of direct blow to the pes anserine, may performed, with alleviated symptoms being in
also lead to bursitis [10]. favor of present pes anserine bursitis [13].

26.2.1 Anatomy 26.2.3 Appliances

The pes anserine, also known as goose foot, is Approximately 2–3 ml of liquid can be injected
the name given to the insertion site of the con- by a 22-G or 23-G, 1.5-inch-long syringe tip and
joined medial knee tendons. These tendons are a 5-ml syringe.
sartorius, gracilis, and semitendinosus, and
they are supplied by three different lower
extremity nerves: femoral, obturator, and tibial 26.2.4 Agents
nerves. They are located superficial to the
medial collateral ligament of the knee. The ten- Corticosteroids, local anesthetics, and orthobio-
dons making up the pes anserine are primarily logic agents (PRP, PRGF, stem cell solutions,
flexors of the knee, but they also contribute to etc.)
the rotatory stability of the knee. The insertion
site of the pes anserine is just below the knee
joint line, on the medial aspect of proximal 26.2.5 Technique/Tricks/Pitfalls
tibia. The bursa, known with the same name,
lays between the conjoined tendon and the The patient sits with the knees extended or
medial collateral ligament on the medial tibia slightly flexed and supported. The pes anserine is
surface [10–12]. palpated, while the patient is asked to flex the
26 Injections of Anatomical Regions and Diseases: Knee 205

Fig. 26.3 Injection technique for the pes anserine bursi- easier to involve the MCL within the injection. The needle
tis. The patient sits with the knees extended or slightly is inserted with an angle of 45° to the point of maximal
flexed and supported. The bursa is located immediately tenderness until it touches bone. The needle is slightly
before the insertion point of the tendons and this point is retracted and injection is done (P patella, PAB pes anser-
marked. Making the injection 0.5–1 cm higher than the ine bursa)
hamstring tendons is important as in this location it is

knee against resistance. The bursa is located three in 1 year. Furthermore, it should be kept in
immediately before the insertion point of the ten- mind that if the initial injection does not lead to
dons, and this point is marked. Making the injec- any improvements in the symptoms, the possibil-
tion 0.5–1 cm higher than the tendons is important ity of getting better results with further injections
as in this location it is easier to involve the MCL is very low [7, 8, 14].
(medial collateral ligament) within the injection Injection for pes anserine bursitis is generally
site as MCL may be contributing to the current regarded as a safe method of treatment; however,
pain. Sterile technique should be used. The nee- care should be given not to injure the saphenous
dle is inserted with an angle of 45° to the point of nerve which lies on the medial side of the knee,
maximal tenderness until it touches bone. The descending vertically between the tendons of sar-
needle is slightly retracted and injection is done torius and the gracilis muscles [15].
(Fig. 26.3). Little resistance during injection is
possible; however, if there is significant resis-
tance, the tip of the needle may be within the ten- 26.2.6 Aftercare
dons, and in this case, the angle of the needle
should be rearranged for better access to the After the injection an elastic bandage is applied
bursa. Injection to the tendons may not only and use of local cold is initiated. NSAID could be
worsen the pain but also affects them. Repeated given if needed. The patient is observed for a
injections may be performed for resistant pain, while and let for walking immediately. Overuse
but a number of injections should not exceed activities are avoided 7–10 days. Graded ham-
206 S. Gursu et al.

string stretching and strengthening exercises are detailed history and physical examination are
initiated afterward. Patients must be educated enough for a true diagnosis. However, laboratory
about the importance of proper exercises, and tests may be required for diagnosing infection,
especially in athletic settings, both the patients and imaging studies may be required for patients
and the trainers must be informed about the with possible patella fractures.
importance of gradually increasing the activity Prepatellar bursitis usually heals by conserva-
levels. tive means and does not require any injections or
aspirations in most cases. Aspiration may be indi-
cated in cases with a suspicion about the diagno-
26.3 Prepatellar Bursa sis for further evaluation of the fluid within the
bursa. Aspiration for septic bursitis may help
Prepatellar bursa lies just below the skin and in faster recovery [19]. Corticosteroid injection is
front of the patella. Similar to all other bursae, reserved for cases with recurrent bursitis and
prepatellar bursa also decreases the friction aris- should be performed only when the possibility of
ing during the flexion-extension movements of infection is eliminated and the symptoms of the
the knee. It is important to make a discrimination bursitis does not respond to ice and NSAIDs.
between non-septic bursitis and septic bursitis as
the treatment differs accordingly. Prepatellar bur-
sitis, also known as housemaid’s knee or carpen- 26.3.3 Appliances
ter’s knee, may occur due to acute trauma;
however, repeating microtrauma is a more com- Approximately 2 ml of liquid can be injected by
mon cause. Septic bursitis usually arises from a 22-G or 23-G, 1.5-inch-long syringe tip and a
skin lesions but may also be due to spread of 5-ml syringe. For aspiration 18-G or 20-G
infection from other sources within the body. syringes should be preferred for better flow of the
Other rare causes include some inflammatory fluid.
conditions like gout, pseudogout, rheumatoid
arthritis, and tuberculosis [16, 17].
26.3.4 Agents

26.3.1 Anatomy Corticosteroids and local anesthetics.

The prepatellar bursa is located between the skin

and patella with a thin synovial lining, and it is 26.3.5 Technique/Tricks/Pitfalls
rather superficial. The bursa has no contact with
the joint space. Typically, there is a minimum The injection or the aspiration may be performed,
amount of fluid within the bursa, but in cases of while the patient is either sitting with 90° of
prepatellar bursitis, it significantly increases. flexed knees or lying supine with the knees
Usually there is only one sac, but it is possible to slightly flexed and supported. The sterile tech-
encounter lobulated structures as well [18, 19]. nique is applied, and the needle is inserted to the
center of the fluctuated bursa, perpendicular to
the skin. If an injection is also indicated after
26.3.2 Indication and Diagnosis aspiration, the needle is left in the bursa, and the
corticosteroid is given with a new syringe. The
Prepatellar bursitis is the second most common injection should be made without any resistance,
bursitis after olecranon bursitis and usually pres- and if any resistance is encountered, the needle
ents with excessive swelling and erythema in should be pulled slightly (Fig. 26.4) [8].
front of the patella. In cases with infected bursi- It should be always kept in mind that injection
tis, pain is accompanied with other findings. A to the prepatellar bursa is rarely indicated and the
26 Injections of Anatomical Regions and Diseases: Knee 207

multiloculate nature of the bursa. In such cases

ultrasonography may be helpful to assist aspira-
tion for better approach to various sacs. Aspiration
may be more successful if the bursa is milked
toward the needle by the tips of the clinician’s
other hand [22].
The injection or the aspiration may also be
performed from the bottom of the fluctuated
bursa instead of the center, with the needle again
targeting the center of the bursa (Fig. 26.4).

26.3.6 Aftercare

After the injection an elastic compressive ban-

dage is applied, and the use of local cold is initi-
ated. Compressive bandage helps preventing
re-accumulation of fluid in traumatic bursitis.
NSAID could be given if it is needed. The patient
is observed for a while and let for walking imme-
diately. Kneeling or putting pressure on the
patella should be avoided for at least 48–72 h,
and occupational modifications should be made
especially for patients with specific jobs like car-
penters, housemaids, and gardeners. Special cau-
tion is recommended to the patient for possible
complications.

Fig. 26.4 Injection to the prepatellar bursa. The injection

may be performed while the patient is either sitting with 26.4 Iliotibial Band
90° of flexed knees or lying supine with the knees slightly
flexed and supported. The needle is inserted to the center Iliotibial band is one of the major stabilizers of
of the fluctuated bursa, perpendicular to the skin. If an
injection is also indicated after aspiration, the needle is
the lateral part of the knee joint. It also helps in
left in the bursa and the corticosteroid is given with a new the stabilization of the hip. In some individuals,
syringe (P patella, PT patellar tendon, TT tuberositas excessive numbers of knee extension and flexion
tibia) like in runners lead to iliotibial band syndrome,
which is due to friction between the iliotibial
bursitis observed in this localization is usually band and the lateral femoral epicondyle. Iliotibial
healed without any invasive procedures. band syndrome is an overuse injury. The result is
Corticosteroid injection to the prepatellar bursa a painful chronic inflammation [23, 24].
has significantly higher risks of complications
when compared to injections to most other bursa
within the body as the subcutaneous tissue at this 26.4.1 Anatomy
site is very thin, making the bursa prone to infec-
tion or skin atrophy [20–22]. It starts from the iliac crest and the capsule of the
When doing aspiration, there is the possibility hip and includes parts of tensor fascia lata and the
of aspirating less fluid than expected due to the gluteus maximus. It extends through the lateral
208 S. Gursu et al.

aspect of the thigh and passes two major joints: 26.4.4 Agents
the hip and the knee. The insertion point is the
Gerdy tubercle, located on the anterolateral Corticosteroids, local anesthetics, and orthobio-
aspect of the proximal tibia [25, 26]. Along with logic agents (PRP, PRGF, stem cell solutions,
the stabilization of the hip and the knee, the ilio- etc.).
tibial band has a postural function and helps
maintain the erected position. The bursa, known
as the iliotibial bursa, lies between the band and 26.4.5 Technique/Tricks/Pitfalls
the lateral femoral condyle and helps to decrease
the friction between the band and the bony struc- The patient sits with the knees extended or
tures during motion. slightly flexed and supported. The injection is
performed using the sterile technique.
Localization of the iliotibial band bursa may be
26.4.2 Indication and Diagnosis detected by palpation as a tender area on the lat-
eral aspect of the distal femur. Another method of
The iliotibial band syndrome is typically more finding the iliotibial band is tracing it backward
common in young active adults. Most important from its insertion point at the Gerdy tubercle. The
symptom is pain arising during motion. The pain needle is inserted at this point to touch the bone
is worst at 30 degrees of knee flexion as the fric- and retracted slightly. Both the anterolateral and
tion, and the tension on the band is highest at this posterolateral approaches may be used for injec-
level of action [27]. Pain usually starts with tion. The solution to be injected is deposited. If
5–10 min of exercise and improves with rest. the insertion point and the distal end of the band
Clinical findings are enough for a diagnosis; are also tender, this part may also be infiltrated at
however, further imaging studies are helpful in the same time without injecting the corticosteroid
confirming the diagnosis and making a differen- to the tendon (Fig. 26.5) [7, 8]. The injection is
tial diagnosis especially in repetitive cases. An done gently and not against resistance. If any
MRI will reveal local inflammatory findings and resistance is encountered, this could mean that
presence of a small amount of fluid at the friction the tip of the needle is within the band and not in
site. the bursa. In this case, the needle should be
Nonsurgical treatment is the mainstay of the retracted and reinserted at an angle directing
treatment for iliotibial band syndrome. The more toward the bursal space. The tract of com-
symptoms may be treated successfully by mon fibular nerve should be considered during
NSAIDs, rest, activity modulation, and physio- the injection (Fig. 26.6).
therapy focusing on strengthening of gluteal Ultrasonography may be used to increase the
muscles. If conservative treatment fails, injection accuracy of injections and helps in giving the
therapy may also be preferred. Corticosteroid medication properly to the iliotibial band bursa.
injection helps improve swelling and ease reha- Making the injection under ultrasonography
bilitation [27–30]. Aspiration may also be per- guidance is proved to have superior outcomes
formed through the same approach for cases with and better pain relief when compared to injec-
significant swelling. tions without ultrasonography guidance [23, 31].

26.4.3 Appliances 26.4.6 Aftercare

Approximately 2 ml of liquid can be injected by Resting after injection is strongly recommended

a 23-G, 1.5-inch-long syringe tip and a 5-ml for about a week along with avoiding strenuous
syringe. activity for the first 48 h. NSAID could be given
26 Injections of Anatomical Regions and Diseases: Knee 209

Fig. 26.5 Iliotibial bursa injection. The patient sits with is tracing it backward from its insertion point at the Gerdy
the knees extended or slightly flexed and supported. tubercle. The needle is inserted at this point to touch the
Localization of the iliotibial band bursa may be detected bone and retracted slightly. The solution to be injected is
by palpation as a tender area on the lateral aspect of the deposited (FH fibular head, P patella, ITBB iliotibial band
distal femur. Another method of finding the iliotibial band bursa, ITB iliotibial band)

Fig. 26.6 Ultrasonography may be

used to increase the accuracy of
iliotibial band bursa injection
(P: patella, ITBB: iliotibial band bursa)

if it is needed. Once the symptoms are relieved, a rences, activity modulation and gradual return to
few sessions of rehabilitation should be initiated fully functional status should be recommended to
in order to achieve stretching and strengthening the patient.
in most patients. In order to prevent any recur-
210 S. Gursu et al.

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 Injections of Anatomical Regions
and Diseases: Ankle and Foot
27
Tekin Kerem Ulku and Berhan Bayram

27.1 Ankle Joint joint. Static stabilizers consist of bony structures

and ligamentous structures, while dynamic stabi-
27.1.1 Anatomy and Biomechanics lizers include tendons around the joint.

Ankle joint is a hinged synovial joint formed by

the articulation of the tibia fibula and talus. Medial 27.1.2 Pathologies and Indications
border is formed by articular facet of medial mal- for Injections
leolus; lateral border is formed by articular facet
of fibula-lateral malleolus. The upper border of Pathologies in the ankle joint mainly consist of
the joint forms the most distal articular surface of impingement syndromes (anteromedial, antero-
tibia. Ankle joint is surrounded by a thin broad lateral, and posterior), intraarticular cartilage
and fibrous capsule anteriorly. Capsule thickened pathologies, rheumatoid conditions such as rheu-
on lateral side and transversed on the posterior matoid arthritis and crystalline arthropathies and
side. Joint is surrounded by strong ligamentous osteoarthritis. Ankle impingement syndrome is
attachments both on medial and lateral side, common in football players, track and field ath-
which increase the inherent stability of the ankle. letes, and in ballets [1]. Injections can both be
Two important bundle of neurovascular structures used to diagnose and treat the pathology.
cross the joint from anterior and posteromedially Evidence shows that fluoroscopic-guided injec-
which innervate most of the anatomic structures tions can improve the symptoms of 84% of ath-
of the foot and ankle. letes with ankle impingement syndromes [2, 3].
Static and dynamic stabilizers of ankle joint Soft tissue impingement syndromes have a better
play an important role in biomechanics of the response to intraarticular injections. However,
surgery may be recommended in nonresponsive
population. Surgical options may include open or
T. K. Ulku (*) arthroscopic procedures.
Acibadem Mehmet Ali Aydınlar University, Faculty
of Medicine, Department of Orthopedics and
Traumatology, Istanbul, Turkey
Acibadem Altunizade Hospital, Department of
27.1.3 Appliances
Orthopedics and Traumatology, Istanbul, Turkey
B. Bayram
Since ankle joint is a relatively superficial joint
Acibadem Mehmet Ali Aydınlar University, Faculty and easy to penetrate, usually a 25- to 27-G nee-
of Medicine, Department of Orthopedics and dle with 25–38 mm length can be used. Depending
Traumatology, Istanbul, Turkey

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024 211
B. Kocaoglu et al. (eds.), Musculoskeletal Injections Manual,
[Link]
212 T. K. Ulku and B. Bayram

on the preference of the treating physician, thin-

ner needles should be preferred for elite athletes
to avoid injection site any discomfort or pain.
Usually, a 3–5 ml of injectate is enough to avid
overdistension of the joint.

27.1.4 Agents

Injectable agents include local anesthetics, ste-

roid of different potencies, or combination of
these two, viscosupplementations, and orthobio-
logic agents.

27.1.5 Injection Technique

Injections can be performed with freehand direct

palpation technique, under fluoroscopy or ultra-
sound guidance. For anterior technique, the
patient is positioned supine, and a small pillow
can be placed under the hip joint to prevent exter-
Fig. 27.1 Patient is placed supine with a pillow under
nal rotation of the lower extremity to get a better extremity to correct internal rotation and gentle dorsiflex-
orientation. Injection site is prepared for sterile ion is applied to increase anterior joint space
technique and to prevent contamination of the
joint. Bony and tendinous landmarks can be syringe containing local anesthetic is infused,
marked with a sterile marker for freehand tech- and low resistance of joint to fluid is confirmed
nique. Gentle dorsiflexion can help to prevent without removing the needle. Second, syringe
tightening of the anterior capsule and avoid containing corticosteroid is infused after con-
extraarticular injection of the fluid (Fig. 27.1). firming the position of the needle in the joint.
For lateral-sided injections, extensor digitorum
tendon is palpated, and the soft spot just lateral to
the tendon is used about 2 cm above the level of 27.1.6 Aftercare
lateral malleolus. For medial-sided injections
tibialis anterior tendon is palpated, and the soft After the injection the patient is observed for
spot just medial to tibialis anterior tendon and 15 min for development of any early allergic
1.5 cm above the medial malleolus is used to pen- symptoms. Depending on the injected agent, if
etrate the skin (Fig. 27.2). When performing no contraindication is present, icing for 15 min
combined local anesthetics and steroids for treat- may be helpful. After, the patient is informed
ment purposes, one needle and two separate about relative rest, low activity for the first 24–48
syringes, one containing local anesthetic agent h, and warned about red flags for complications
and the other one containing steroids, can be such as redness, swelling, or drainage from the
used. After penetrating the joint capsule, first, joint.
27 Injections of Anatomical Regions and Diseases: Ankle and Foot 213

Tendon serves as plantarflexor approximately

93% of all plantarflexor force that is generated. It
is very important in ambulation and propulsion
[5, 6]. Tendon receives its blood supply from the
posterior tibial artery and peroneal artery. Its
innervation is from the sural nerve and tibial
nerve [7].

27.2.2 Pathologies and Indications

for Injections

Achilles tendon is susceptible to injury with

repetitive overuse. Mostly sports like running
soccer and field sports can cause tendon patholo-
gies [8]. Different parts of the tendon can be
affected, and different pathologies can cause ten-
dinopathies. Overuse of Achilles tendon injuries
can be either insertional or non-insertional.
Insertional tendinopathies are classified as retro-
calcaneal bursitis, insertional tendinitis, or super-
ficial calcaneal bursitis. Non-insertional
Fig. 27.2 Tibialis anterior is palpated, and the soft spot
which is just medial to the tendon and 1.5 cm above
tendinopathies are classified as midportion
medial malleolus is marked for the entry point Achilles tendinopathy and Achilles paratendinitis
[9]. Injections for the Achilles tendon can be used
27.2 Achilles Tendon Pathologies for both diagnostic and treatment purposes.

27.2.1 Anatomy and Biomechanics

27.2.3 Appliances
Achilles tendon is the thickest tendon in the
human body, and it is the most common tendon Since the Achilles tendon is a relatively superfi-
formed by gastrocnemius, soleus, and plantaris cial structure and easy to penetrate, usually a 25-
muscle tendons in the posterior side of the ankle to 27-G needle with 25–38 mm length can be
joint. After fusion of the tendon fibers, tendon used. Depending on the preference of the treating
wings about 90° causing soleus-oriented fibers to physician, thinner needles should be preferred for
attach medially and gastrocnemius fibers later- elite athletes to avoid injection site any discom-
ally. Plantaris tendon attaches to most medial fort or pain. Usually, a 3–5 ml of injectate is
side of the tendon just proximal to attachment enough to avid overdistension of the area. For
site. Tendon attaches to posterior surface of cal- some midportion tendinopathies, high-volume
caneus and is supported by a deep retrocalcaneal injections of about 10 ml can be used to create
bursa. Superficially tendon is separated from the hydrodissection effect around the tendon and
skin by superficial calcaneal bursa [4]. paratenon.
214 T. K. Ulku and B. Bayram

27.2.4 Agents

Injectable agents include local anesthetics, ste-

roid of different potencies, or combination of
these two, viscosupplementations, and orthobio-
logic agents. High-volume injections can be used
for midportion Achilles tendinitis.

27.2.5 Injection Technique

Injections around the Achilles tendon can both

be performed by freehand technique and under
ultrasound guidance. Patient is placed prone
and a supportive pillow is placed just anterior to
ankle joint. Injection area is prepared sterile,
and anatomical landmarks can be marked with
a sterile marking pen. For midportion injections
injection site is identified, and just ventral to
the tendon, the needle is inserted oblique to
midline and the injection is performed
(Fig. 27.3).
Fig. 27.4 Skin marking of calcaneus and Achilles attach-
ment site

For retrocalcaneal injections after skin mark-

ing, the needle is inserted just ventral to the ten-
don and dorsal to calcaneus in transverse
direction. A lateral entry point is usually pre-
ferred (Figs. 27.4 and 27.5).
For superficial calcaneal bursa injections, the
most painful zone in posterior bursal region is
located, palpated, and skin marked. Then the nee-
dle is inserted perpendicular to the skin long
enough to penetrate subcutaneous bursa without
injecting the tendon itself, and injection is per-
formed at the bursal tissue (Fig. 27.6).

27.2.6 Aftercare

After the injection patient is observed for 15 min

for development of any early symptoms.
Depending on the injected agent if no contraindi-
cation is present, icing for 15 min may be helpful.
After, the patient is informed about relative rest,
Fig. 27.3 For midportion tendinopathies after detecting low activity for the first 24–48 h, and warned
and marking the pathologic zone using the medial and about red flags for complications such as redness,
ventral entry point, the needle is progressed swelling, or drainage from the injection zone.
27 Injections of Anatomical Regions and Diseases: Ankle and Foot 215

27.3 Plantar Fasciopathy

27.3.1 Anatomy and Biomechanics

Plantar aponeurosis (facia) is the modification of

the deep fascia starting from calcaneal tubercles
to metatarsal head region [10]. It is a thick con-
nective tissue that supports the arch and protects
the underlying vital structures of the foot. It can
be divided to three main distinct parts: medial
part, central part, and lateral part. The central part
is the thickest and largest part of the fascia.
Plantar fascia is an important structure biome-
chanically. It supports the plantar arches, acts as
a shock absorber, distributes the plantar contact
pressures during static and dynamic loading, acts
as a site for muscular attachments, and prevents
excessive dorsiflexion [11, 12].

27.3.2 Pathologies and Indications

for Injections
Fig. 27.5 Penetration of the needle in a transverse fash-
ion under the Achilles insertion
Plantar fasciopathy is the most common cause of
medial heel pain. It constitutes about 1% of all
orthopedics outpatient clinics visits. The pathol-
ogy is generally caused by repetitive microtrauma
to plantar fascia and is closely related to obesity,
age, gastrocnemius tightness, and planovalgus
feet and is common among runners [13].
Pain generally worsens after weight bearing
following long periods of resting. The term plan-
tar fasciitis which refers to an inflammatory
pathology has increasingly changed with “fasci-
opathy” or “Fasciosis.” Studies showed that there
is an absence of inflammatory cells, and the
pathology is actually a chronic degenerative pro-
cess [14].

27.3.3 Appliances

Usually, a 25- to 27-G needle with 25–38 mm

length can be used. Usually, a 5 ml of injectate is
enough to avid overdistension of the area.

Fig. 27.6 Superficial bursal injection a perpendicular

penetration over the painful bursal site
216 T. K. Ulku and B. Bayram

27.3.4 Agents

Injectable agents include local anesthetics, ste-

roid of different potencies, or a combination of
these two and orthobiologic agents such as PRP.

27.3.5 Injection Technique

Injections around the plantar fascia can be per-

formed by freehand technique or under ultrasound
guidance. Two different techniques can be used.

[Link] Supine Technique

The patient is placed supine; a supportive pillow
beneath the unaffected hip is placed to help the
medial side of the affected heel be exposed.
Injection area is prepared sterile, and anatomical
landmarks can be marked with a sterile marking
pen. The needle is inserted from the medial side
of the heel at junction of the lines from the poste-
rior side of the medial malleolus and about 1 cm
Fig. 27.7 The needle is inserted from the medial side of
above the plantar surface until it reaches the the heel at the junction of the lines from posterior side of
medial side of the plantar facia. The injection is medial malleolus and about 1 cm above the plantar sur-
performed all through the medial side of plantar face until it reaches the medial side of the plantar facia
facia (Fig. 27.7).

[Link] Prone Technique

The patient is placed prone, the knee is flexed,
and the ankle is in neutral position. Injection area
is prepared sterile, and anatomical landmarks can
be marked with a sterile marking pen. The needle
is inserted from the medial side of the heel on the
plantar surface to the area that the patient feels
most pain with direct palpation. When the resis-
tance of facial tissue is felt with the needle, the
injectate is given to the area (Fig. 27.8).

27.3.6 Aftercare

After the injection patient is observed for 15 min

for development of any early symptoms.
Depending on the injected agent, if no contrain-
dication is present, icing for 15 min may be help-
ful. After, the patient is informed about relative
rest, low activity for the first 24–48 h, and warned
about red flags for complications such as redness,
Fig. 27.8 The patient is placed prone, the knee is flexed,
swelling, or drainage from the injection zone. and the ankle is in neutral position
27 Injections of Anatomical Regions and Diseases: Ankle and Foot 217

27.4 Morton’s Neuroma pression, percussion, and a palpable click

(Mulder’s click) may be felt. Initial treatment
27.4.1 Anatomy and Biomechanics modalities include shoe-wear modification, use
of metatarsal lifting insoles, and nonsteroidal
The tibial nerve forms the medial and lateral anti-inflammatories. However, in resistant cases,
plantar nerves. Common plantar digital nerves injection to relevant intermetatarsal space can be
are branches of medial and lateral plantar nerves. considered both for therapeutical and diagnostic
The first, second, and third common plantar nerve purposes as last resort before surgical
arises from the medial plantar nerve, while the intervention.
fourth and fifth from the lateral plantar nerve.
Each common plantar digital nerve then
­bifurcates into two proper plantar digital nerves 27.4.3 Appliances
supplying opposing sides of the adjacent toes.
Morton’s neuromas occur at the terminal bifurca- Usually, a 25- to 27-G needle with 25–38 mm
tion of the common plantar digital nerve. There length can be used. Usually, a 5 ml of injectate is
are four intermetatarsal spaces between metatar- enough to avid overdistension of the area.
sal bones. Each of these spaces is separated to
two levels by the deep transverse ligament.
Neurovascular bundle is plantar to this transverse 27.4.4 Agents
ligament layer. Distally the nerve makes a sharp
turn dorsally along the anterior free edge of trans- Injectable agents include local anesthetics, ste-
verse metatarsal ligament. The bursal tissue is roid of different potencies, or a combination of
present dorsal to transverse ligament. In the first these two and orthobiologic agents such as PRP.
and fourth space, the bursal tissue does not extend
distal to transverse ligament. However, in the sec-
ond and third space, the bursal tissue extends dis- 27.4.5 Injection Technique
tally [15].
Exact pathomechanism is not clearly estab- The patient is placed supine with a supportive pil-
lished for Morton’s neuroma. Entrapment theory, low underneath the hip joint to avoid external
chronic microtrauma theory, intermetatarsal bur- rotation of the lower extremity and better orienta-
sitis theory, and ischemic theory are among the tion. Injection area is prepared and made sterile,
most commonly accepted ones. and anatomical landmarks are marked with a
sterile marking pen. Metatarsal heads are pal-
pated from dorsal and plantar, and then the nee-
27.4.2 Pathologies and Indications dle is inserted dorsally perpendicular to
for Injections intermetatarsal space (Fig. 27.9). Until the tip of
the needle is felt from the plantar side, the needle
Morton’s neuroma is very common among the is advanced, and injectate is slowly injected mov-
middle-aged female population increased due to ing the needle dorsally.
high-heeled and/or narrow toe box shoes. Most
of the neuromas occur in the third intermetatarsal
space followed by second. Patients present with 27.4.6 Aftercare
localized pain on the plantar surface of the foot at
the level of metatarsal heads usually worsened After the injection the patient is observed for
after shoewear. Pain can radiate to the toes with 15 min for development of any early symptoms.
paresthesia and tingling [16]. Depending on the injected agent, if no contrain-
On physical examination, characteristic find- dication is present, icing for 15 min may be help-
ings of a metatarsal space tenderness on com- ful. After, the patient is informed about relative
218 T. K. Ulku and B. Bayram

joined by intersesamoid ligament. The intersesa-

moid ligament is the roof of a canal in which
flexor hallucis longus tendon runs.

27.5.2 Pathologies and Indications

for Injections

Pathologies in the toe joint mainly consists of

impingement syndromes with dorsal osteophytes,
intraarticular cartilage pathologies, and rheuma-
toid conditions such as rheumatoid arthritis and
crystalline arthropathies and osteoarthritis.
Sesamoid pathologies include sesamoiditis, frac-
tures of sesamoid bones, and avascular necrosis.
Injections can both be used to diagnose and treat
the pathology. For toe joint pathologies like
osteoarthritis, first-line treatment consists of the
use of rocker bottom shoes, nonsteroidal anti-­
inflammatories, and activity modification [17]. In
resistant cases, intraarticular injections can be
preferred. For sesamoid pathologies insoles,
Fig. 27.9 After metatarsal heads are marked with a ster-
shoe-wear modifications, and nonsteroidal anti-­
ile marker, the needle is inserted perpendicular and
advance until felt underneath plantar surface inflammatories can be used, and if these methods
fail, injections to the sesamoidal area can be
rest, low activity for the first 24–48 h, and warned preferred.
about red flags for complications such as redness,
swelling, or drainage from the injection zone.
27.5.3 Appliances

27.5 Toe Joint: Sesamoids Since the toe joint and sesamoids are relatively
superficial joints and easy to penetrate, usually a
27.5.1 Anatomy and Biomechanics 25- to 27-G needle with 25–38 mm length can be
used. Depending on the preference of the treating
Toe joint is formed by the first metatarsal bone, physician, thinner needles should be preferred for
two sesamoids, and proximal phalanx. It is a elite athletes to avoid injection site any discom-
­condyloid synovial joint supported by its syno- fort or pain. Usually, a 1–3 ml of injectate is
vial capsule around. Metatarsal head has two enough to avid overdistension of the joint.
concave facets at the plantar surface, one for each
sesamoid separated by a crista. The distal part of
the first metatarsal is convex, and the proximal 27.5.4 Agents
phalanx has a concave contour. There are two
sesamoids in plantar surface: the medial sesa- Injectable agents include local anesthetics, ste-
moid is in the medial head of the flexor hallucis roid of different potencies, or a combination of
brevis, and the lateral sesamoid is in the lateral these two and viscosupplementation and ortho-
head of the flexor hallucis brevis. Sesamoids are biologic agents.
27 Injections of Anatomical Regions and Diseases: Ankle and Foot 219

27.5.5 Injection Technique

[Link] MTP Joint Injection

The patient is placed supine with a supportive pil-
low underneath the hip joint to avoid external
rotation of the lower extremity and better orienta-
tion. Injection area is prepared and made sterile,
and anatomical landmarks is marked with a ster-
ile marking pen. Extensor hallucis longus tendon
is marked, and by gentle plantar-dorsal flexion,
the head of the first metatarsal and base of the
proximal phalanx is identified and marked
(Fig. 27.10). By applying dorsiflexion, joint cap-
sule on the dorsal aspect is loosened, and the
needle is inserted from the medial side in an
oblique fashion (Fig. 27.11). After penetrating
the joint capsule, the first syringe containing
local anesthetic is infused, and low resistance of
joint to fluid is confirmed; then without removing
the needle, the second syringe containing cortico-
steroid is infused after confirming the position of
the needle in the joint.
Fig. 27.11 Medial-sided joint penetration showing the
entry point

[Link] Sesamoid Injection

The patient is placed supine, and the injection
site is prepared sterile with anatomical landmarks
drawn by sterile marking pen. Medial and lateral
sesamoids, the plantar surface of the metatarsal
head, and the tendon are identified (Fig. 27.12).
The (1) MTP joint is plantarflexed, and the space
between metatarsal and sesamoids is widened.
From the proximal site of medial sesamoid, a
needle is penetrated in an oblique fashion and
advanced distally under the metatarsal area
(Fig. 27.13). After penetrating the joint capsule,
the first syringe containing local anesthetic is
infused, and low resistance of joint to fluid is
confirmed; then without removing the needle, the
second syringe containing corticosteroid is
infused after confirming the position of the nee-
dle in the joint.

Fig. 27.10 Skin marking of the EHL tendon and meta-

tarsal and phalangeal surfaces is easier with gentle motion
of the MTP joint
220 T. K. Ulku and B. Bayram

27.5.6 Aftercare

After the injection the patient is observed for

15 min for development of any early symptoms.
Depending on the injected agent, if no contrain-
dication is present, icing for 15 min may be help-
ful. After, the patient is informed about relative
rest, low activity for the first 24–48 h, and warned
about red flags for complications such as redness,
swelling, or drainage from the injection zone.

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