____________________

Cairo University, NILES

2014-2015

BASIC PHOTOMEDICINE

DR. Moshira Hussein Page 1

 1. Introduction to Photomedicine

 Definition:-
 Photomedicine includes both the study and treatment of diseases caused
by exposure to light and on the other hand the diagnostic and therapeutic
applications of light for detecting and curing disease.
 Light:-
 Light is composed of packets of energy called photons.

 For the purposes of this section, light is defined as non-ionizing

electromagnetic radiation between the wavelengths of 200 nm to about
10000 nm.

 Light energy is capable of causing heating, mechanical effects and chemical

reactions. The transfer of light energy through photon absorption can lead
to many different consequences in photomedicine.

 Moreover, there are many new approaches for using light to see inside the
body to detect and diagnose disease.

 Some of the questions that will be discussed in this section are:-

1. Why do identical photons produce harmful medical effects in some

instances (such as skin cancer), but helpful effects in others (such as
vitamin D production)?

2. Is there any way to control the effects of the light energy in

photomedicine?

3. What light sources are beneficial in photomedicine?

4. What can we do to maximize the beneficial effects, while minimizing the

deleterious effects?

DR. Moshira Hussein Page 2

 2. Diseases Caused by Light
 The precise characteristics (wavelength distribution and intensity) of sunlight
depend on:-
1. Which latitude ‫ خط العرض‬on the earth they inhabit:-
 Sunlight is more intense nearer to the equator.
2. What the time of day is:-
 Sunlight is more intense nearer to midday.
3. What the season of the year is.
 Sunlight is more intense nearer to midsummer.

 The dominant wavelengths in sunlight are shorter at midday, and longer in

morning and evening:-
 This is because the distance through the atmosphere, which the sunlight
must travel to reach the observer, is longer at morning and evening,
because the sun is lower in sky.
 Passing through the atmosphere selectively absorbs ultraviolet and blue
wavelengths, leaving the red.

 Because ultraviolet (UV) light is damaging to the skin, people who live nearer to
the equator tend to have darker skins with more of the protective pigment called
melanin.

 Part of the problem of skin diseases caused by chronic sun exposure has arisen
because:-
1. Fair-skinned people have migrated to countries nearer the equator.
2. The fashion for sunbathing.

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 The two dominant diseases caused by chronic sun exposure are:-
1. Photo-aging (leathery wrinkled skin).
2. Induction of skin cancer:- Both
» The dangerous malignant melanoma.
» The less dangerous non-melanoma skin cancer.
 Harmful acute effects of sun exposure include:-
1. Sun burn.
2. Various photo-dermatoses.
 The interaction of UV light with the skin:-
 Causes a complicated cascade of events that involve:-
1. Cellular damage and repair.
2. Pigmentation changes.
3. Vascular changes.
4. Immune suppression effects.
 UVB wavelengths are absorbed by the nucleic acid bases that tend to have
peaks at 260 nm but these peaks are broad and extend into the biologically
relevant 300-340 nm region received by skin.
 The chemical reaction caused by the UV absorption results in the formation
of several types of DNA lesions, including thymine-thymine dimers.

Schematic depiction of UV-induced DNA lesion formation (T-T dimers).

The adjacent yellow thymine residues become linked together.
The formation of the dimer distorts the DNA.
This distortion is detected by the DNA repair enzymes.

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 Without protection from the sun's rays can cause noticeable changes
to the skin:-
 Changes include:-
1. Freckles.
2. Age spots.
3. Spider veins on the face.
4. Rough and leathery skin.
5. Fine wrinkles that disappear when stretched.
6. Loose skin.
7. Blotchy complexion.
8. Actinic keratoses (thick wart-like, reddish patches of skin).
9. Skin cancer.
10. Photoaging:-
 Definition:-
» Is the term used to describe the type of aging caused by
exposure to the sun's rays.
 The amount of photoaging that develops depends on:-
1. Skin color.
2. History of long-term or intense sun exposure.
♦ People with fair skin with a history of sun exposure develop more
signs of photoaging than those with dark skin.
♦ In the darkest skin:- The signs of photoaging are usually limited to
fine wrinkles, and a mottled complexion.
 Causes:-
 Photo aging occurs over a period of years.
 With repeated exposure to the sun, the skin loses the ability to repair
itself, and the damage accumulates.
 Repeated UV exposure breaks down collagen and impairs the
synthesis of new collagen.
 The sun also attacks elastin.
 Sun-weakened skin ceases to regenerate much earlier than skin
protected from UV rays.
 Skin also becomes loose, wrinkled, and leathery much earlier with
unprotected exposure to sunlight.
 Deep wrinkles, age spots, and leathery skin indicate premature aging
caused by chronic unprotected sun exposure.
 Using sunscreens and limiting sun exposure can mitigate the chronic
adverse effects of sun exposure.

DR. Moshira Hussein Page 5

 Beneficial effect of UV light delivered to the skin during sun exposure:-
 Vitamin D biosynthesis:-
 Mechanism:-
 Due to the conversion of pro-vitamin D3 (7 dehydrocholesterol) to
pre-vitamin D3 by the action of ultraviolet radiation on the skin.
↓↓↓↓
 Previtamin D3 is then thermally converted to vitamin D3 in the skin.
↓↓↓↓
 The vitamin is then transported to the liver on the vitamin D-binding
protein.

 It is thought that there is chronic vitamin D deficiency amongst people who

live in Northern climes, and this could lead to increased occurrence rates of
some cancers.

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 The existence of two opposing good and bad effects of sun exposure created
debates among photobiologists and dermatologists.

 In addition, there are number of rarer diseases characterized by adverse effects

(either acute, chronic or both) suffered by particular individuals exposed to doses
of light that would have no effect on a normal person of similar skin color.

 Many of these diseases are caused by some genetic mutation or

abnormality such as:-
1. Xeroderma pigmentosum:-
» In which the enzymes that repair DNA damage in the skin
caused by UV light are not working properly, leading to early
development of skin cancer.

2. Porphyrias:-
» In which defects in heme biosynthesis lead to levels of
photosensitizing porphyrins being present in the skin.

3. Polymorphic light eruption:-

» Unknown aetiology.
» Leading to rashes on receiving mild sun exposure.

 Secondary photosensitivity disorders involve:-

1. Photosensitizing drugs:-
» Such as some antibiotics and psychoactive compounds.

2. Photosensitizing ingredients in foods:-

» Such as lime, bergamot.

3. Photoallergic reactions:-
» In which a person can become sensitized to an allergen that
is then much worse after sun exposure.

DR. Moshira Hussein Page 7

 3. Photo-protection

 Aim of photo-protection:-
 In order to mitigate the effects of UV damage to the skin received from the
sun, modern practice is to encourage the use of sunscreens.

 Types of topical sunscreen:-

There are two basic types of topical sunscreens: -
1. Absorbers of UV radiation:-
 Chemical sunscreen ingredients such as:-
 Para-amino benzoic acid (PABA).
 Cinnamates.
 Salicylates.
 Benzophenones.
2. Reflectors of UV radiation:-
 Physical sunscreen ingredients such as:-
 Titanium oxide.
 Zinc oxide.
3. Antioxidants:-
 Such as:-
 Vitamins E and C, which do not absorb or reflect UV radiation, but
are believed to enhance the ability of skin cells to repair damage
induced by UV radiation.
 Components of sunscreen:-
 Sunscreens usually consist of a combination of several photoprotective
chemicals.
 Topical sunscreens are marketed as lotions, creams, gels and ointments.
 Degree of protection of sunscreen:-
 Degree of protection of sunscreen is measured as sun protective factor
(SPF).
 Persons who always burn rather than tan:-
 Typically a person with white skin, red or blond hair, and blue or green
eyes are at highest risk for photoaging and skin cancer and should
always use maximum photo-protection.
 Dermatologists strongly recommend a broad-spectrum sunscreen with SPF
of 15 or higher for all skin types.
 SPF is determined in the United States by a guideline accepted by sunscreen
manufacturers and the Food and Drug Administration (FDA).

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 Criteria of effective sunscreen:-
 An effective sunscreen should be Broad-spectrum, providing protection
against both the A and B wavelengths of UV.
 Both UVA and UVB are present in sunlight, and both can cause skin damage.
 The UVB wavelengths are the principal cause of sunburn.
 UVA can penetrate to deeper layers of the skin.
 Since most chemical ingredients of sunscreens are most effective against
either UVA or UVB, many sunscreens are a mixture of UVA and UVB-
absorbing chemicals, or physical blocking agents such as zinc oxide.
 You can check the label to see if a sunscreen provides both UVA and UVB
protection.
 A sunscreen providing only UVB protection is effective against sunburn, but
less effective against the deeper penetrating UVA.
 You can also check the label of a sunscreen product to see if it contains
ingredients that provide broad-spectrum (UVA-UVB) protection, e.g:-
 Oxybenzone.
 Cinnamates (octylmethyl cinnamate and cinoxate).
 Sulisobenzone.
 Salicylates.
 Titanium oxide.
 Zinc oxide.
 Avobenzone.

DR. Moshira Hussein Page 9

 4. Diagnostic Photomedicine

 Introduction:-

 All traditional diagnostic medicine involved light and optics.

 The doctor examines his patient under a bright light or a colored light.
 The doctor uses a hand lens to improve what he could see unaided.

 Then came the advent of various imaging technologies such as X-ray,

computed X-ray tomography, magnetic resonance imaging, positron-
emission tomography, single photon emission computed tomography etc.

 Now things have come full circle with researchers developing optical
imaging technologies relying on visible and near-infrared (NIR) light.

 Principle:-
 Visible light can penetrate into biological tissues.

 Red and NIR light penetrate deeper than green, blue or violet light.

 This phenomenon can be visualized by shining a white flashlight through

hand, observing a red glow on the other side (the blue and green
wavelengths having been absorbed).

 Red light penetrates more because:-

1. It is not strongly absorbed by blood.
2. It tends to scatter more.

Therefore, red or NIR light is generally used to "see" deeper into the body.

 Optical imaging techniques could be cheaper, less invasive and less toxic,
because light is non-ionizing compared with the traditional techniques.

 Tissue is far from transparent to visible and NIR wavelengths when

compared to much shorter wavelengths (X-rays), or to much longer
wavelengths (radiowaves).

 Therefore extra-ordinary measures must be taken to derive useful

diagnostic imaging information from these wavelengths of light.

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  Information may be acquired from:-

1. Photons that are scattered:- e.g.

 Optical coherence tomography
 In vivo confocal microscopy.
 Light scattering spectroscopy
2. Photons that are absorbed:-
 Pulse oximeter for measuring blood oxygenation.
 Diffuse optical tomography.
 Photoacoustic imaging and spectroscopy.

3. Photons that are re-emitted after being absorbed in tissue:-

 Auto-fluorescence imaging.
 In vivo confocal fluorescence microscopy.
 Raman spectroscopy.

Schematic diagram of how scattered, absorbed, or re-emitted photons can be used

to obtain diagnostic information in living tissue.

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 Optical imaging:-

 Optical imaging is capable of producing information on the spatial location

of lesions with varying degrees of resolution.

 By employing spectral analysis, information can be obtained on the identity

and relative concentration of tissue molecular constituents.

 One goal of optical imaging is the "optical biopsy".

 Because optical imaging has the potential to provide the same sub-micron
resolution that is taken for granted in optical microscopy, some
investigators have tried to replicate diagnosis using non-invasive optical
biopsies.

 This is more valuable when one considers that in conditions like Barrett's
esophagus scores of random excisional biopsies may be taken, and in other
anatomical locations such the coronary arteries taking any biopsies is
impossible.

 In practice since tissue is highly opaque the light is often delivered into the
body and diagnostic information is retrieved via fiber optic catheters that
can be inserted into hollow organs via endoscopes and even threaded
through blood vessels.

 Another active area of research in optical diagnostic imaging is the use of

optical contrast agents. These are exogenous chemicals that can act as
optical reporters by such means as high scattering, fluorescence,
phosphorescence, photoacoustic properties, etc.

 Optical imaging is used for:-

 Cancer diagnosis.
 Determination of tissue optical properties for light dosimetry.

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 1. Cancer diagnosis:-
 Optical diagnosis relies on the structural and biochemical differences
between cancer tissue and normal tissue that can be probed with visible
or NIR light.

 Cancerous cells are:-

 More active.
 Reproduce at an abnormally high rate.
 Have larger and more numerous nuclei.

 On the tissue level:-

 Tumors have immature collagen.
 Tumors have network of immature blood vessels due to
angiogenesis, and therefore a higher blood content.

 Exogenous substances that accumulate in tumor tissue can enhance the

optical contrast between tumors and normal surrounding tissue.

 Fluorescent dyes have been developed that can be used to delineate

tumor borders or detect otherwise invisible lesions.

 These fluorescent dyes are chemically attached to some targeting

vehicle that recognizes specific molecules or markers expressed on
tumors.

 Examples of these targeting vehicles are:-

 Monoclonal antibodies.
 Peptide sequences that bind to tumor cell receptors.
 Vitamins such as folic acid, and certain sugars.

 Fluorescent dyes used for diagnosis should:-

 Have Low intrinsic toxicity.
 Be resistant to photo-bleaching.
 Both absorb and emit in the near-infrared spectrum.

 Novel types of optical contrast agents that have attracted attention

include:-
 Quantum dots.
 Gold nano-shells.
 Oxygen sensitive phosphorescent dyes.

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 2. Determination of tissue optical properties for light dosimetry.
 Many diagnostic and therapeutic applications require knowledge of the
light flux through tissue.

 Photons that enter tissue are scattered once or multiple times

until they either escape or are absorbed.

 Computer simulations that track the movement of photons

through biological tissues are based on the absorption and
scattering properties of each specific tissue.

 Absorption and scattering coefficients and anisotropy factors (the

direction in which photons are scattered in tissue) are determined
through a combination of experimental measurements and optical
theory.

Schematic of light propagation in tissue

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  Method used to calculate light propagation in tissue is known as the
Monte-Carlo method because it relies on a very large series of random
scattering events.

 An increasingly popular technique in optical diagnosis is to use 5-

aminolevulinic acid (ALA) to carry out fluorescence detection.

 ALA is a metabolic precursor of the red fluorescent porphyrin,

protoporphyrin IX.

 This means that lesions with high levels of metabolic activity such as
cancers and other areas of inflammation can be easily visualized under
blue light if ALA has been administerd a few hours before by topical
application or even by mouth.

 So far the most successful applications are:-

1. Detecting bladder cancer during cystoscopy.
2. Delineating the infiltration of glioma into the normal brain during
open-skull surgery for brain tumors.
3. In the bronchus or oral cavity for early dysplastic lesions.

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 5. Phototherapy

 Definition:-
 Phototherapy involves the transformation of light energy to chemical,
kinetic or heat energy in order to achieve a desired physiological result.
 Principle:-
 As stated by the First Law of Photobiology, light energy must be absorbed
by an atom or molecule in order to initiate a physical or chemical process.
 Therefore, light that is used for therapeutic applications must be absorbed
by a specific chromophore in the biological tissue.
 The chromophore may be:-
A. Endogenous (naturally occurring in cells or tissue).
B. Exogenous (added to cells or tissue for a therapeutic purpose).

 Light energy is deposited in tissue as the photons are absorbed in the tissue.
 The absorbed energy is converted to heat.
 The body's vascular system removes heat from the treated area over a period
of time.
 However if the heat builds up quickly, such as a large optical power over a
short time, sections of the tissue may boil, vaporize, burn or even explode.
 On the other hand, the same total amount of light applied very slowly to allow
heat dissipation by the vascular system leads primarily to photochemical
reactions.
 Therefore, the rate of application of light is as important as the total amount of
absorbed light.
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 6. Laser Medicine

 Principle:-
 Lasers can cause localized damage by selectively heating dark target matter
(often blood or melanin) while not heating the rest of the skin or tissue.
 Light is absorbed by dark objects, so laser energy can be absorbed by dark
material in the skin (but with much more speed and intensity).
 This dark target matter, or chromophore, can be naturally-occurring or
artificially-introduced.

 Applications:-
1. Dermatology.
2. Surgery.
3. Dentistry.
4. Ophthalmology.
1. Dermatology

 The medical specialty with the largest involvement of lasers is

dermatology.
 The skin is available for light delivery, has many clearly visible markings
upon it and has a high patient demand for aesthetic and cosmetic
improvement.
 This has led to many laser companies developing equipment for
dermatologic applications and the growth of cosmetic laser clinics.

A. Green light:-
o Produced by:-
» Argon (488 nm).
» KTP (532 nm).
» Dye lasers (570 nm).
o Absorbed by:- hemoglobin.
o Used for treatment of vascular lesions e.g.
» Port wine stains.
» Vascular birthmarks.
» Hemangioma.
» Angiofibroma.
» pyogenic granuloma.
» Telangiectases.
» varicose veins.

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 B. Visible and near-infrared lasers:-
o Used for the removal of pigmented lesions e.g.
» Lentigines.
» Nevus of Ota.
» Congenital melanocytic nevi.
» Café-au-lait macules.
» Nevus spilus.
 Laser applications in dermatology:-
1. Hair removal (photoepilation):-
 Melanin:-
o Melanin is the primary chromophore for all hair removal lasers.
o The very broad absorption spectrum of melanin means it absorbs
all wavelengths in the visible and near-infrared.
o Melanin occurs naturally in the skin (it gives skin & hair its color).
o There are two types of melanin in hair:-
1. Eumelanin (which gives hair brown or black color).
2. Pheomelanin (which gives hair blonde or red color).

 Because of the higher absorption of photons of laser light by eumelanin,

black or brown hair is much easier to remove than blond hair.

 Laser works best with dark coarse hair.

Light skin and dark hair are an ideal combination, but new lasers are
now able to target dark black hair even in patients with dark skin.

 Hair removal lasers have been in use since 1997, and the Food and Drug
Administration approved it for "permanent hair reduction."

 Laser hair removal has become extremely popular because of its speed
and efficacy, although some of the efficacy is dependent upon the skill
and experience of the laser operator, and the choice and availability of
different laser technology at the clinic that is performing the procedure.

 Some will need touch-up treatments, especially on large areas, after the
initial set of 3-8 treatments.

 Some people seem to be non-responders; the reasons are not known,

and may in fact be due to the lack of skill on the part of many laser
operators and/or the type of machine and settings they are using.

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2. Tattoo removal:-
 Tattoo removal uses lasers that are "tuned" to the color of ink used in the
tattoo.

 Pulsed laser is thought to fragment the tiny ink particles via photo-thermal
expansion, and these tiny particles can be now be removed from the skin by
macrophage cells, that engulf them, and then migrate to draining lymph nodes.

 The treatment needs to be repeated several times over a course of therapy,

and many different lasers may be used if the tattoo contains different colors of
ink.

Results of laser tattoo removal over a course of treatment. Patients are generally
treated over a period of months (6-20 sessions) with a variety of laser wavelengths
depending on the color of the inks used.

3. Wrinkles and resurfacing:-

 Laser skin resurfacing, called "ablative":-
o Used to involve damaging a large surface of skin with a CW CO2 (10600
nm) laser with the expectation that the new epidermis formed would
have fewer defects.

o Although highly effective, the risk of unwanted side effects was high,
with unwanted thermal damage and scarring.

o The appropriate pulse duration needs to be less than 1 millisecond, the

development of short-pulse, high-peak power, rapidly scanned CW CO2
(10600 nm) and normal mode Er:YAG (2940 nm) lasers provided the
ability to accurately thermally ablate controlled layers of tissue.

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  Non-Ablative rejuvenation;-
o The prototype of non-ablative rejuvenation is:-
» The infrared Nd:YAG CoolTouch laser at 1320 nm with a pulse
duration of 200 microseconds.
» More recently the Smooth Beam diode laser at 1450 nm.
o These lasers produce mild but reproducible improvement in wrinkles
and scars, with histologic evidence of neo-collagenesis 6 months after
treatment.
o The healing time was much shorter than ablative resurfacing.

4. Fractional photothermolysis:-
 Fractional laser is based on the discovery that a large number of very small
lesions (about 100 micron diameter) separated by uninjured skin (lesions are
about 200 micron apart) heal much faster (24 hours compared to 14 days) than
one large lesion that covers exactly the same total area.

 The microscopic thermal injury zones of controlled width, depth, and density
are produced by computer controlled pulsed or scanned lasers.

 For skin resurfacing and wrinkle removal applications where it is desired to

stimulate a wound healing response in the damaged skin and to encourage
new collagen production by dermal fibroblasts, the fractional laser seems to
work very well.

5. Scar removal:-
 Lasrs used for scar removal:-
1. The 585 nm PDL remains the gold standard for the laser treatment of
hypertrophic scars and keloids.
2. Although atrophic scars may best be treated with ablative CO2 (10600
nm) and Er:YAG (2940 nm) lasers.

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 2. Laser Surgery

 Laser surgery is used to:-

1. Cut or destroy tissue that is abnormal or diseased without harming
healthy, normal tissue.
2. Shrink or destroy tumors and lesions.
3. Cauterize (seal) blood vessels to prevent excessive bleeding.

 Advantages of laser surgery:-

1. Bloodless surgery:- laser procedures usually involve less bleeding than
conventional surgery.
2. Reduces the risk of infection:- The heat generated by the laser keeps the
surgical site free of germs.
3. Because a smaller incision is required, laser procedures often take less time
(and cost less money) than traditional surgery.
4. Sealing off blood vessels and nerves reduces bleeding, swelling, scarring,
pain, and the length of the recovery period.
5. Lasers are used to cut, vaporize or coagulate tissues with little or no damage
to surrounding areas.
6. They are also beneficial in reaching inaccessible locations with less trauma,
bleeding and scarring.
7. Surgery with lasers results in reduced post-operative pain and less need for
medication, shorter hospitalization and quicker return to routine activities.
8. Sometimes described as "scalpels of light,":-
Lasers are used alone or with conventional surgical instruments in a diverse
array of procedures that:-
» Improve appearance.
» Relieve pain.
» Restore function.
» Save lives.
 Laser surgery is often standard operating procedure for specialists in:-
1. Cardiology:-
» Laser angioplasty for angina (chest pain).
» Trans-myocardial revascularization.
» Atrial fibrillation.

2. Gastroenterology:-
» Treatment of disorders of the stomach and intestines.
» Fragmentation of gallstones, stomach ulcers .

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 3. Gynecology:-
» Ectopic pregnancy .
» Ovarian cysts.
» Endometriosis.
» Fibroid tumors.
4. Neurosurgery:-
» Brain tumors (malignant and benign).
» Vascular and neural anastamosis.
5. Oncology:-
» Cancerous or non-cancerous tumors that cannot be removed by
traditional surgery.
6. Orthopedics:-
» Treatment of disorders of bones, joints, muscles, ligaments, and
tendons.
7. Otolaryngology:-
» Treatment of disorders of the ears, nose, and throat.
» Stop snoring.
» Remove tonsils.
» Stop nose bleeds.
8. Pulmonary care:-
» Treatment of disorders of the respiratory system.
9. Urology:-
» Treatment of disorders of the urinary tract e.g. laser lithotripsy
» Treatment of the male reproductive system: e.g. non-cancerous
enlargement of the prostate gland.

 Disadvantages of laser surgery:-

o Need well-trained and highly skilled doctor.
o Imprecisely aimed lasers can burn or destroy healthy tissue.

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 3. Dentistry

 Lasers are used by dentists to treat cold and canker sores, gum disease, and
tooth sensitivity or decay.

 Each wavelength has unique effect on dental structures, due to the specific
absorption of that laser energy in the tissue.

 Some lasers are only absorbed by blood and tissue pigments, while others
are only absorbed by water as well as "hard" tissue.

 Lasers produce light energy that can be absorbed by a target tissue, and this
absorption process produces a thermal reaction in that tissue.

 Depending on the instrument's parameters and the optical properties of the

tissue, the temperature will rise and various effects will occur.

 In general, most non-sporulating bacteria, including anaerobes, are

deactivated at temperatures of 50⁰C.

 The inflammatory soft tissue present in periodontal disease can be removed

at 60⁰C.

 Moreover, hemostasis can also be achieved within the same heat 60⁰C.

 Soft tissue excisional or incisional surgery is accomplished at 100⁰C.

 Vaporization of intra- and extra cellular water causes ablation, or removal of

biological tissue.

 The aqueous component of tooth structure and bone boils at 100⁰C, thus
cavity preparation, calculus removal, and osseous contouring can proceed.

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 4. Ophthalmology

 Lasers allow non-invasive treatment of diseases of the eye as well as vision

correction.
 Three important applications of lasers in ophthalmology are illustrated in
Figure:-

1. Vision correction:-
» Utilizes an ultraviolet excimer (193 nm) laser to reshape the cornea in
a process known as laser-assisted in situ keratomileusis (LASIK) by
sculpting the cornea to correct short-sightedness.
2. Selective laser trabeculoplasty:-
» Uses an argon (488 nm) or 810 nm diode laser or Near-infrared Nd-
YAG lasers (1064 nm) to treat glaucoma by thermal injury of the
trabecular meshwork at the corner of the eye.
3. Abnormal retinal blood vessles:-
» Uses Argon lasers (488 nm) to treat abnormal retinal blood vessels
that are common in diabetics.
4. Macular degeneration can also be treated with lasers.
5. Age-related macular degeneration (AMD):-
» Is a disease that results in a breakdown of the macula accompanied
by a loss of central vision.
» "Wet" AMD is characterized by leaky blood vessels.
» Laser photocoagulation is used to seal the blood vessels and restore
vision.
» The procedure performed with a near-infrared Nd-YAG (1064 nm)
laser involves thermal effects and may be accompanied by the
damage of local tissue.

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 7. Ultraviolet Light Therapy

 Definition:-
o Ultraviolet (UV) light is electromagnetic radiation with a wavelength
shorter than that of visible light, but longer than X-rays, in the range 400
nm to 10 nm, and energies from 3 eV to 124 eV.

o It is so named because the spectrum consists of electromagnetic waves

with frequencies higher (wavelengths shorter) than those that humans
identify as the color violet.

 UV light is divided into the following band-pass spectral regions:

o UVC (200-280 nm).
o UVB (280-320 nm).
o UVA2 (320-340 nm).
o UVA1 (340-400 nm)

 Wavelengths lower than 200 nm are highly absorbed by air (chiefly by

oxygen) and can only be used in a vacuum so they are called vacuum UV.

 Nils Ryberg Finsen won the Nobel prize in 1903 for using UV light (then
known as chemical rays) to treat lupus vulgaris (tuberculosis of the skin),
and other skin diseases.

 Narrow band UVB (311 nm) is used for many similar indications to PUVA.

 UV phototherapy is used to treat the following skin conditions:

1. Psoriasis.
2. Polymorphous light eruption.
3. Solar urticarial.
4. Actinic reticuloid.
5. Atopic eczema.
6. Vitiligo.
7. Pruritus.
8. Lichen planus.
9. Early cutaneous T-cell lymphoma.
[Link].
[Link] lichenoides.
[Link] is highly antimicrobial and is under investigation for some superficial
infections.

DR. Moshira Hussein Page 25

 8. Photo-chemotherapy

 Introduction:-
 The first application of psoralen photochemotherapy was in Egypt in 1948
by el Mofty, who used purified 8-methoxypsoralen (8-MOP) plus sunlight
exposure in the treatment of vitiligo (Monem El Mofty, 1948).
 Two young American dermatologists (Aaron Lerner and Thomas Fitzpatrick)
were intrigued by this report, and determined that long wavelength
ultraviolet (320-400 nm, UVA) light was the most efficient for activating 8-
MOP.
 The development of artificial UVA sources enabled the efficient delivery of
these photons to skin containing 8-MOP, and the therapy became known as
PUVA (psoralen and UVA).
 PUVA's major success was in treating psoriasis, an inflammatory skin
disease involving hyperproliferation or skin thickening, and the
development of itchy and scaly lesions or "plaques". This disease is now
known to have an autoimmune component where autoreactive T-cells
attack the bodies' normal skin cells.

 Psoralens:-
 Psoralens are a group of natural furanocoumarins.
 Commercially derived from Ammi majus, a plant found in Egypt.
 They are also present in celery, carrots, parsley, parsnip and other
vegetables.
 It has been known since ancient times that consumption of these foodstuffs
followed by sun exposure can lead to a phototoxic skin reaction similar to
sunburn.
 Psoralens can be taken orally or applied topically.
 8-MOP:-
» The commonest psoralen is 8-methoxypsoralen
» 8-MOP, Methoxsalen, Oxsoralen tablets, Puvapsoralen lotion/paint.
» 8-MOP is also used for bathwater soaks.
 5-MOP:-
» 5-Methoxypsoralen (5-MOP, Bergapten, Psoraderm) is used for very
light-sensitive individuals, or for those with intolerance to 8-MOP.
 Trimethylpsoralen (TMP, Trioxsalen, Tripsor) is used more in bathwater
soaks.

DR. Moshira Hussein Page 26

 Light-source:-

 The light sources used for PUVA tend to be UVA fluorescent tubes made by
Philips.
 They are generally constructed in a whole-body illumination "box".

 There are more specialized light sources designed just to illuminate the hands .

DR. Moshira Hussein Page 27

 Mechanism-of-photochemothrapy:-
 The mechanisms of photo-chemo-therapy are twofold:
A. First:-
 Psoralen molecule has the correct structure and shape to be able to
intercalate between the two strands of DNA in the double helix.
 Upon illumination, induce the formation of covalent inter-strand cross-
linking between opposite nucleic acid strands.
 This DNA damage causes cellular apoptosis via p53 activation in a similar
manner to other well-known DNA damaging agents.
 Because the penetration depth of UVA light into the skin is limited,
PUVA damage is confined to the epidermis, which is often thickened in
the case of psoriasis.
B. Second:-
 There is another different mechanism that operates in addition to the
DNA-cross-linking effect of PUVA.
 This mechanism involves:-
1. The inflammatory process.
2. The alteration of the host immune system.
 Many cytokines are increased in the skin after PUVA and circulating
leucocytes (especially T-cells) tend to be killed

DR. Moshira Hussein Page 28

 Indications:-
 PUVA:-
 Can be used for many different skin disorders:-
1. Vitiligo.
2. Psoriasis.
3. Atopic dermatitis.
4. Atopic eczema.
5. Mycosis fungoides.

 Extracorporeal photopheresis or photochemoimmunotherapy.:-

 A second major application of the combination of psoralen and UVA.
o In this therapy:-
 Psoralens are administered to the patient orally.
 Some blood is withdrawn from the arm and passed through UVA
illuminator, before being re-infused into the arm.
o This treatment is being used for:-
1. Graft-vs-Host Disease (GVHD):-
- GVHD occurs after a bone-marrow transplant.
- Characterized by the T-lymphocytes that were transferred
from donor to host along with the graft, being able then to
attack and destroy normal host tissues.
- The photopheresis treatment can:-
1. Destroy the donor lymphocytes.
2. Sensitize the host immune system.

2. Suppressing allograft rejection, such as in heart transplants.

3. Cutaneous T-cell lymphoma.
4. Sezary syndrome.
5. Pemphigus vulgaris.
6. Atopic dermatitis.

 Side ffects:-
 Major side-effect of long-term use of PUVA:-
1. Skin-cancer (mainly squamous cell carcinoma).

DR. Moshira Hussein Page 29

 9. Low Level Light Therapy (LLLT)

 Definition:-
 LLLT is an emerging medical and veterinary technique in which exposure to
low-level laser light or light emitting diodes might stimulate or inhibit cellular
function, possibly leading to beneficial clinical effects.
 Actions:-
 The use of low levels of visible or NIR light for:-
1. Reducing pain, inflammation and edema.
2. Promote healing of wounds, deeper tissues and nerves.
3. Prevent tissue damage.
 Mechanism of action:-
 Mitochondria are the site for the initial effects of light, specifically the enzyme
cytochrome c oxidase (unit four in the mitochondrial respiratory chain).
 Cytochrome C oxidase absorbs photons and increases its activity leading to:-
1. Increased ATP production.
2. Modulation of reactive oxygen species.
3. Induction of transcription factors.
 Several transcription factors are regulated by changes in cellular redox state:-
1. Redox factor-1 (Ref-1) dependent activator protein-1 (AP-1).
2. Nuclear factor κB (NF-κB).
3. p53.
4. Activating transcription factor/cAMP-response element-binding protein
(ATF/CREB),
5. Hypoxia-inducible factor (HIF)-1α.
6. HIF-like factor.
 Low levels of oxidants appear to stimulate proliferation and differentiation of
some type of cells.
 These effects in turn lead to:-
1. Increased cell proliferation and migration (particularly by fibroblasts).
2. Modulation in the levels of cytokines, growth factors and inflammatory
mediators.
3. Increased tissue oxygenation.
 The results of these biochemical and cellular changes include:-
1. Increased healing in chronic wounds.
2. Improvements in sports injuries and carpal tunnel syndrome.
3. Pain reduction in arthritis and neuropathies.
4. Amelioration of damage after heart attacks, stroke, nerve injury and
retinal toxicity.

DR. Moshira Hussein Page 30

 Figure shows the mechanism and application of LLLT.

1. LLLT for pain relief, inflammation and healing

 LLLT or Biostimulation is a therapeutic modality for pain management).

 Alterations in neuronal activity have been suggested to play a role in pain relief
by laser therapy.
 Biostimulation can be used for pain management in the following conditions:
1. Chronic neck pain.
2. Tendonitis.
3. Chronic joint disorders.
4. Musculoskeletal pain.
5. Chronic pain.
6. Chronic low back pain.
 LLLT can be used for the treatment of patients with inflammatory pathologies:-
1. Carpal tunnel syndrome.
2. Mucositis.
3. Arthritis.
4. Ulceration.

DR. Moshira Hussein Page 31

 LLLT for Wound Healing.
Cells in the wound respond to light induced reactive oxygen species (ROS)
Leading to the expression of growth factors, such as transforming growth
factor beta (TGF), and platelet derived growth factor (PDGF).
Leading to synthesis of more collagen, increased formation of blood vessels,
and less inflammation, all of which increase wound healing.

2. LLLT in the central nervous system

 Low level laser/light therapy (LLLT) for neurological disorders in the central
nervous system (CNS) is currently an experimental concept.
 The broad goals for clinical utilization are:-
1. Prevention and/or repair of damage.
2. Relief of symptoms.
3. Slowing of disease progression.
4. Correction of genetic abnormalities.
 Neurodegenerative diseases:-
o Caused by the deterioration of certain nerve cells (neurons).
o Such as:-
1. Alzheimer's disease.
2. Parkinson's disease.
3. Amyotrophic Lateral Sclerosis.
4. Multiple sclerosis.

All are due to neuronal degeneration in the central nervous system.

DR. Moshira Hussein Page 32

  The chronic, progressive nature of these devastating degenerative diseases has
motivated the search for therapies that could slow down or arrest the
downward course experienced by most patients, and even more desirable
would be a therapy that could actually reverse the neuronal damage.
 Transcranial light therapy is considered to have the potential to accomplish
these goals as depicted.

LLLT for central nervous system (CNS) neurological disorders.

NIR light can penetrate through the skull into the brain, leading to:-
1. Reducing neuronal cell death.
2. Reducing inflammation.
3. Increasing neurogenesis.
The retinal nerves and the spinal cord are classified as part of the
CNS, and light is delivered for similar reasons into the eye or to the
neck or back at the site of the spinal cord lesion.

DR. Moshira Hussein Page 33

 10. Photodynamic Therapy (PDT)

PDT is a treatment for cancer and other diseases characterized by unwanted tissues
or cells (Hamblin et al., 2008). PDT utilizes the combined effect of light, a
photosensitizing dye (i.e. a substance that absorbs visible light) and molecular
oxygen. The dye, harmless in itself, is administered either systemically, locally, or
topically to a patient bearing a lesion (frequently but not always cancer), a few
minutes to a few days ahead of time. The clearance of dye from normal tissue and
the accumulation of dye in tumor tissue enables tumor visualization by fluorescence,
as well as selective treatment. The tumor is illuminated with visible light. The light is
applied at a low energy level and is harmless by itself. The illumination of the lesion
with visible light (usually long wavelength red light), leads in the presence of oxygen
to a transfer of energy from photo-excited dye molecules to oxygen molecules. This
process results in the production of a highly reactive type of oxygen, and
consequently to cell death and tissue destruction.

Most of the reports of applications of PDT for treating clinical disease have been as a
cancer treatment, but in recent years a multitude of different non-malignant
conditions have also been proposed to be amenable to PDT.

10.1. PDT for cancer. It has been known since early in the century that
injection of certain photosensitizing drugs or dyes especially those compounds
derived from the naturally occurring porphyrins, followed by exposure to
sunlight could produce phototoxic reactions that could be severe enough to
cause tissue necrosis. A German physician Friedrich Meyer Betz became highly
photosensitive after injecting himself with 200 mg of hematoporphyrin (Moan
et al., 2003) (Figure 13).

DR. Moshira Hussein Page 34

 Figure 13. (A) Friedrich Meyer Betz before, and (B) after self-injection of
hematoporphyrin, and exposure to sunlight.

The first suggestion that the combination of the tumor-localizing and the
phototoxic properties of porphyrins such as HP and HpD might be exploited to
produce an effective treatment for cancer was reported in 1972 in The Lancet
by Diamond and co-workers (Diamond et al., 1972) from San Francisco. These
authors had originally wondered whether porphyrins might potentiate the
effects of ionizing radiation (X-rays), but having found that this was not the
case, went on to test the hypothesis that HP may serve as a selective
photosensitizing agent to destroy cancer exposed to light. This concept is
depicted in Figure 14.

Figure 14. Schematic depiction of the stages of PDT treatment for a patient with
cancer. Photosensitizer (PS) is injected usually into the bloodstream, and distributes
around the body. After some time, the PS tends to be cleared from normal tissues,
but is retained in cancerous tissue, due to various abnormalities in tumors. This is
thought to be the most advantageous time to deliver light.

They found a marked reduction in tumor volume following light exposure

delivered 24 h after systemic HP administration. Tumor growth was
suppressed for 10-20 days, but regrowth then occurred from viable areas
remaining in deeper regions of the tumor. Histological examination showed
coagulation necrosis in all but the deepest regions of the tumors. Neither HP
alone, nor light alone produced any effect. The authors concluded that PDT
offered a new approach to the treatment of brain tumors and other neoplasms
resistant to other therapies. Since then there have been numerous papers
published on the application of PDT in oncology, and on the number of types of
tumors treated with this procedure (summarized in Table 2).

DR. Moshira Hussein Page 35

 Table 2. List of common tumor types that have been treated by PDT.

One of the most interesting phenomena observed in the PDT treatment of

cancer is the potential to induce strong and long lasting anti-tumor immune
response. It has been known for some years that under certain conditions, PDT
can not only destroy the primary tumor that receives illumination, but also
sensitize the host immune system to recognize and potentially destroy any
remaining tumor cells, whether left at the site of the primary tumor or present
as distant metastases (Figure 15).

DR. Moshira Hussein Page 36

 Figure 15. How the immune system is activated after PDT. When light (hν) is
delivered to PS loaded tumors this induces both apoptotic and necrotic cell death.
These dead and dying tumor cells are phagocytosed by dendritic cells (DC) that have
accumulated owing to the acute inflammatory response triggered by PDT. Stimulated
by cytokines released at the site of inflammation, DCs mature and home to the
regional lymph nodes where they present antigens to the naive T lymphocytes.
Activated lymphocytes become tumor-specific effector T-cells and, attracted by
chemokines, migrate to the tumor and kill the remaining tumor cells.

Successful PDT of tumors growing in immunocompetent syngeneic mice can in

some cases cause a long-term memory anti-tumor immunity, as demonstrated
by a resistance to a rechallenge with the tumor from which they were cured,
but not a different syngeneic tumor (Canti et al., 1994; Hendrzak-Henion et al.,
1999; Korbelik et al., 1999). This effect is not observed when the same tumors
are grown in immunosuppressed mice (Korbelik et al., 1996). Splenocytes
adoptively transferred from immunocompetent mice cured of tumors by PDT
can restore the curative effect of PDT in immunosuppressed animals, and
demonstrate specific lysis of tumor cells growing in vitro in a classical cytotoxic
T lymphocyte assay. Tumor cells killed with PDT in vitro are more effective as
tumor vaccines than the same cells killed by other methods (Gollnick et al.,

DR. Moshira Hussein Page 37

 2002). PDT has effects on cancer cells that make immune activation more likely
in an in vivo tumor treated with PDT. These are the particular mixture of
necrotic and apoptotic cell death caused by PDT, and the fact that necrotic cell
death is more immunogenic compared to apoptotic cell death (Melcher et al.,
1999), which can be immunosuppressive (Voll et al., 1997).

PDT can induce the strong expression of heat shock proteins (especially HSP70)
(Gomer et al., 1996; Korbelik et al., 2005; Mitra et al., 2003) that has been
shown to potentiate immune recognition of tumors. PDT can cause activation
of the transcription factors nuclear factor kappa B (NFκB) (Granville et al.,
2000), and activator protein (AP)-1 (Kick et al., 1996) leading to production of a
large variety of inflammatory mediators including eicosanoids, interleukins (IL)
1, 6, 8 and 10. Neutrophils are an important cell type for the PDT response
(Sun et al., 2002), and if mice are depleted of neutrophils before PDT, the
curative effect is lost (de Vree et al., 1996). Following the initial invasion of
neutrophils into PDT treated tumors there is an increase in mast cells and
macrophages (Krosl et al., 1995). Complement activation is also observed both
in the tumor and serum after PDT (Cecic et al., 2005).

10.2. PDT for ophthalmology. Although PDT was initially designated as an anti-
cancer treatment, probably its most successful clinical application is in
ophthalmology, namely as a treatment of choroidal neovasculature (CNV)
associated with age related macular degeneration (AMD) (Fenton et al., 2006;
Schmidt-Erfurth et al., 2000; van den Bergh et al., 2002a; van den Bergh et al.,
2002b; Wormald et al., 2007). PDT with Verteporfin (Visudyne) was really the
first approved therapy for treating the subfoveal lesions. It was a ground
breaking discovery that has profoundly changed the history of this disease and
saved several hundreds of thousands of eyes from blindness, since 2000. For
PDT of subfoveal CNV, freshly made Verteporfin solution, which is
reconstituted from the lyophilized drug, is intravenously injected over a 10-
minute period. 15 minutes after the start of the perfusion, the excitation light
is applied to the retina from a diode laser at a wavelength of 689 nm. The
fluence rate at the retina is adjusted to be 600 mW/cm2, which is delivered
over 83 seconds giving a fluence of 50 J/cm2.

There are multiple aspects of the selectivity in the angio-occlusion of CNV in

AMD by photodynamic therapy. In the first place there is the selectivity of
vascular damage and the subsequent blood flow stasis. This selectivity is
inherent in the short time interval between the drug injection and the light
application, i.e., 15 minutes after the start of the intravenous injection of the
Visudyne, when the 83 second irradiation takes place, most of the drug that is

DR. Moshira Hussein Page 38

 in the retina is still within the blood vessels, and more specifically, on or in the
endothelial cells lining the CNV, which are to undergo the angioocclusion.
Thus, the main photodynamic effect takes place in the endothelium being
irradiated. A second possible reason for the "selective" vaso-occlusion comes
from the difference in Visudyne retention by vessels. It has been shown that at
the time of irradiation, the retinal capillaries appear to have much less drug in
them than the CNV and choroidal vessels in general. This may well imply a
significant level of protection of the retinal capillaries.

PDT for treating CNV associated with AMD remains now a standard therapy for
patients with recent progression of wet AMD with subfoveal CNV. The
treatment is safe, and has a proven long-term effect, and needs hardly any re-
treatments after the first few years, which put PDT apart from other available
treatments for AMD.

10.3. PDT in dermatology. Mainstream uses for PDT in dermatology include

non-melanoma skin cancer and its precursors such as actinic keratosis, acne,
photorejuvenation and hidradenitis suppurativa. Many other dermatologic
entities have been treated with PDT, and published in the literature. These
include psoriasis, cutaneous T-Cell lymphoma, disseminated actinic
porokeratosis (DSAP), localized scleroderma, and vulval lichen sclerosus,
bacterial infections and verruca vulgaris (Table 3).

Table 3. Dermatologic conditions treated by PDT.

Dermatology is a specialty in which both laser and non-laser light sources are
commonly used clinically for PDT. The fact that the skin is an organ of large
surface area, and in general lesions are relatively superficial but in certain
circumstances can be large, has acted as an impetus for companies to develop
non-coherent lamps and diode arrays that operate in both pulsed and CW
DR. Moshira Hussein Page 39
 modes. Most applications of PDT in dermatology utilize an alternative to
systemic injection of a PS in a process in which a metabolic precursor 5-
aminolevulinic acid (ALA) is administered and the PS protoporphyrin IX (PPIX) is
synthesized in situ in tumors and tissue (Peng et al., 1997). ALA interacts with
the heme biosynthetic pathway shown in Figure 16.

Figure 16. ALA-induced PPIX. Schematic illustrating the interaction of the heme
biosynthesis pathway with exogenous ALA to give intracellular PPIX.
Abbreviations are ALA-D = ALA dehydratase; ALA-S = ALA synthetase; Coprogen III =
coproporphyrinogen III; CPO = coproporphyrinogen oxidase; FCH = ferrochelatase;
HMB = hydroxymethylbilane, PBG-D = porphobilinogren deaminase; protogen III =
protoporphyrinogen; PPO = protoporphyrinogen oxidase; Urogen III =
uroporphyrinogen III; UCS = uroporphyrinogen cosynthase, UGD = uroporphyrinogen
decarboxylase.

Almost all types of cells of the human body, with the exception of mature red
blood cells, are equipped with this metabolic machinery. In the first step of the
pathway, ALA is formed from glycine and succinyl-CoA. The synthesis of ALA by
ALA-synthetase is under feedback regulation by the amount of heme in the
cell. The last step in the pathway is incorporation of iron into PPIX to form
heme catalyzed by the enzyme ferrochelatase, and this is rate-limiting. By
adding exogenous ALA, the feedback inhibition is bypassed, and PPIX will
DR. Moshira Hussein Page 40
 accumulate because of the limited capacity of ferrochelatase to transform PPIX
to heme. Free PPIX is a good PS that effectively causes apoptosis of cells after
illumination. PPIX is initially formed in the mitochondria of cells, but rapidly
diffuses to other intracellular membrane sites.

In vivo, the ALA may be administered orally (van den Boogert et al., 1998),
intravenously (Svanberg et al., 1996), or topically (Calzavara-Pinton, 1995). The
reasons why cancer cells tend to synthesize more PPIX than normal cells, has
been much investigated. Hypotheses include greater expression of heme
biosynthesis enzymes, porphobilinogen deaminase (Gibson et al., 1998),
coproporphyrinogen oxidase (Ortel et al., 1998), or reduced expression of
ferrochelatase (Van Hillegersberg et al., 1992), but increased delivery of ALA to
the tumor may play a role especially in topical applications (Szeimies et al.,
1994).

Based on available literature, it appears that ALA-PDT seems to be a safe and a

suitable alternative for a variety of conditions encountered in dermatology
practice. The technique is effective in patients of all ages and results in clinical
and cosmetic improvement. Visible light sources, in particular lasers and
pulsed lasers can be used to activate the ALA with the added benefit of
improvement in the quality of treated skin.

10.4. PDT for infectious disease. The increasing occurrence of multi-antibiotic

resistant microbes has led to the search for alternative methods of killing
pathogens and treating infections. Photodynamic therapy (PDT) uses the
combination of non-toxic dyes and harmless visible light to produce reactive
oxygen species that can kill mammalian and microbial cells. There were many
reports of photodynamic inactivation (PDI) of various species of bacterial and
fungal cells, as well as viruses, over the years between the discovery of
antimicrobial PDI in 1904 and 1990. In the 1990s it was observed that
fundamental differences in susceptibility to PDT exist between Gram (+) and
Gram (-) bacteria. This was explained by differences in their morphology: the
cytoplasmic membrane in Gram (+) cells is surrounded by a layer of only
peptidoglycan and lipoteichoic acid, which is relatively porous; while Gram (-)
bacteria have a somewhat more intricate, non-porous cell wall structure
consisting of an inner cytoplasmic membrane and an outer membrane, which
are separated by the peptidoglycan-containing periplasm.

It was discovered that in general, neutral or anionic PS molecules are efficiently

bound to and mediate the photodynamic inactivation (PDI) of Gram (+)
bacteria (Malik et al., 1992), but they are not able to photoinactivate Gram
negative bacteria. The latter can be achieved by employing several different
DR. Moshira Hussein Page 41
 techniques. It is possible to use agents that are capable of increasing the
permeability of the cell outer membrane such as polymyxin B nonapeptide
(Nitzan et al., 1992), or EDTA (Bertoloni et al., 1990) together with traditional
PS. Alternatively one can use a PS molecule with an intrinsic positive charge
(Merchat et al., 1996; Minnock et al., 2000), or polycationic PS conjugates
formed from polymers such as polylysine (Hamblin et al., 2002; Lauro et al.,
2002; Rovaldi et al., 2000; Soukos et al., 1998). Several studies have shown that
antibiotic resistant bacteria are as susceptible to PDI as their naive
counterparts (Wainwright et al., 1998; Wilson et al., 1995). The nature of the
PDI-induced damage that involves oxidative modification of vital cellular
constituents, suggests that bacteria will not easily be able to develop
resistance mechanisms, and one study has shown that resistance to PDI does
not occur (Lauro et al., 2002).

The demonstration of efficient PDI of multiple classes of microorganisms,

together with concern about rapidly increasing emergence of antibiotic
resistance amongst pathogenic bacteria, has suggested that PDT may be a
useful tool to combat infectious disease (Hamblin et al., 2004). Nonetheless
there are several limitations. Because the delivery of visible light is almost by
definition a localized process, PDT for infections is likely to be applied
exclusively to localized disease, as opposed to systemic infections such as
bacteremia. The key issues to be addressed with PDT are the effectiveness of
the treatment in destroying sufficient numbers of the disease causing
pathogens; selectivity of the PS for the microbes, thus avoiding an
unacceptable degree of PDT damage to host tissue in the area of infection; and
the avoidance of regrowth of the pathogens from a few survivors in the time
following the treatment.

PDT for infectious disease is likely to be a growing clinical application. With the
increasing international concern about multi-drug resistant bacteria, and the
specter of infectious diseases that have become untreatable by antibiotics
constantly discussed by the popular media, alternative antimicrobial therapies
have become a "hot topic". The rapid bacterial killing typical of PDT and the
unlikelihood of bacteria developing resistance to PDT suggests that PDT should
be at the forefront of new therapies for infectious disease.

10.5. PDT for cardiovascular disease. PDT has been applied in cardiovascular
medicine for two broad indications; treatment of atherosclerosis
(photoangioplasty) and inhibition of restenosis due to intimal hyperplasia after
vascular interventions. Atherosclerosis and its thrombotic complications
(atherothrombosis) are the leading cause of morbidity and mortality in

DR. Moshira Hussein Page 42

 industrialized countries. Atherothrombotic cardiovascular disease is a diffuse
condition involving the coronary arteries, carotid arteries, aorta and peripheral
arteries (Figure 17).

Figure 17. Human vascular system. Atherosclerosis is a systemic disease affecting the
whole body and causing major diseases. Red color indicates arterial vessels, and blue
the venous circulation. Claudication indicates pain arising due to deprivation of the
muscles of blood flow by vascular blockages, usually in the legs.

However, the pathology of the disease and clinical consequences vary in the
different anatomical locations. In patients with atherothrombotic disease,
myocardial ischemia or infarction causes as much as 70% of deaths (Fowkes et
al., 1991). Cerebrovascular disease causes approximately 10% to 17% of deaths
in these patients, and another 10% are caused by ruptured aneurysms or
visceral infarctions. Peripheral arterial disease may be viewed as benign,
because it does not cause direct mortality. Thus symptomatic individuals (i.e.,
those presenting with claudication) have a history of myocardial infarction or

DR. Moshira Hussein Page 43

 stroke in 20% to 30% of cases, and evidence of underlying coronary disease in
50% to 70% of cases.

The main lesion in atherosclerotic disease is called an atherothrombotic plaque

(Stary et al., 1995a, 1995b) (Figure 18).

Figure 18. Schematic diagram of an atherosclerotic plaque. The build-up of the lesion
can eventually lead to arterial obstruction that limits blood flow, or alternatively can
rupture causing catastrophic thrombosis in the coronary arteries. The atherosclerotic
plaque is made of following components: 1) extracellular matrix, including collagen,
proteoglycans, and fibronectin elastic fibers; 2) crystalline cholesterol, cholesteryl
esters, and phospholipids; 3) cells such as monocyte-derived macrophages, T-
lymphocytes, and smooth-muscle cells; 4) thrombotic material with platelets and
fibrin deposition. (Moreno et al., 2004a, 2004b).

Atherosclerosis progresses through lipid core expansion and macrophage

accumulation at the edges of the plaque, leading to fibrous cap rupture. Muller
(Muller et al., 1994) suggested that plaque rupture, superimposed by occlusive
thrombosis, as the underlying mechanism for the majority of sudden cardiac
deaths, particularly in young men. Myocardial infarction (MI) frequently
develops on lesions with pre-existing non-critical stenoses, and attention has
turned to the angiographically non-significant lesions in the last decade;

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 "vulnerable plaque" is used to identify all thrombosis-prone plaques and
plaques with a high probability of undergoing rapid progression, thus
becoming culprit plaques (Naghavi et al., 2003).

The recent renewal of interest in the therapeutic potential of cardiovascular

PDT has been prompted largely by the availability of new agents such as
lutetium texaphyrin (also known as motexafin lutetium or Antrin) with
selective localization, greater PDT efficiency, and minor, self-limited potential
for cutaneous phototoxicity are now available. Photoangioplasty is a term for
the combination of intravenous injection (IV) of PS followed by delivery of
intravascular light by a fiber optic catheter introduced into a blood vessel and
then advanced to the lesion. However, due to the fact that blood will have to
continue to circulate through the vessel during the illumination, and blood is
an efficient optical quencher of light, relatively large fluences have to be
delivered from diffusing tips of several cm in length, necessitating lasers of
considerable power.

A phase I trial of photoangioplasty in intermittent claudication with peripheral

arterial atherosclerosis suggested (Rockson et al., 2000) that the therapy is well
tolerated and has the capacity to invoke a therapeutic response in these
patients. In 90% of vessels treated, intravascular ultrasonography confirmed
measurable improvement in lumen cross-sectional area after Antrin
photoangioplasty. A second phase I trial (Kereiakes et al., 2003) looked at drug
and light dose-escalation of motexafin lutetium (MLu), and far red light
activation (phototherapy) in subjects with coronary artery disease undergoing
percutaneous coronary intervention and stent deployment. The therapeutic
changes were achieved without documented adverse vascular responses or
any treatment limiting phototoxicity.

11. Heliotherapy and Other Visible Light Therapy

11.1. Seasonal affective disorder. While full sunlight is preferred for seasonal
affective disorder, there are a number of products (such as light boxes) using
very intense artificial illumination that are effective for seasonal affective
disorder (Terman et al., 1990) (Figure 19). Newer research indicates that using
a lower intensity of certain wavelengths of light, i.e., the "blue" wavelengths,
may be at least as effective as using 10,000 lux (Wirz-Justice et al., 1993), at
least until one approaches old age, when blue light is no longer more effective
than red or green. The most effective wavelengths of blue light are given as
DR. Moshira Hussein Page 45
 ranging between 460 nm and 485 nm by most sources, with some sources
specifying peak photopigment sensitivity at 479 nm (in mice).

Figure 19. Sun Touch Plus 10,000 lux bright light therapy device.

11.2. Non-seasonal depression. Only recently have clinical studies been

conducted that specifically excluded all patients with any degree of seasonality
(Yamada et al., 1995). Before these studies, there was suspicion that any
depressed patients who benefited from light treatment were really only having
the SAD component of their depression treated. However, light therapy is now
an established treatment for depression, regardless of seasonality (Tuunainen
et al., 2004). One advantage it may have compared with drugs is that results
may appear more quickly; antidepressant drugs typically take several weeks to
reach full effectiveness. Combination of light and medicine has been proven to
be more effective and faster than either alone (Kripke, 1998).

Light therapy has been tested in the following psychiatric disorders:

premenstrual dysphoric disorder (Parry et al., 1989), antepartum postpartum
major depressive disorder, antepartum and postpartum major depressive
disorder, bulimia nervosa (Lam et al., 1994), and adult attention-deficit
disorder.

11.3. Delayed sleep phase syndrome. In the treatment of delayed sleep phase
syndrome (DSPS), the timing of light exposure is critical (Gruber et al., 2007).
The light must be provided as soon after spontaneous awakening as possible to
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 achieve the desired effect, as shown by the phase response curve for light in
humans. Some users have reported success with lights that turn on shortly
before awakening (dawn simulation).

11.4. Jet lag. Light therapy is considered a viable treatment for jet lag (Sack et
al., 2007). Exposure to bright light during the appropriate time periods before,
during and after air travel can reduce the symptoms of jet lag and accelerate
the recalibration of the body clock.

12. Neonatal Jaundice

Neonatal jaundice is a condition that can occur in newborn infants, particularly when
they are born prematurely. Bilirubin levels in the bloodstream of these infants
become elevated, and this can lead to brain damage. Bilirubin is a normal breakdown
product of hemoglobin, so it exists at low levels in all of us. In the bloodstream it is
normally bound to a circulating plasma protein, albumin. If the ratio of bilirubin to
albumin becomes too high, then unbound bilirubin in the bloodstream can enter
tissues of the brain, and this can cause damage. Neonatal jaundice can be treated
with phototherapy. Blue light (450 nm to 500 nm) is applied to the skin of babies in
order to keep the bilirubin concentration at a safe level (Figure 20). Blue light
enhances the excretion of bilirubin, because it photoisomerizes the molecule. The
photoisomer is more readily excreted than the unisomerized form (Maisels, 1990).

DR. Moshira Hussein Page 47

 Figure 20. Neonatal jaundice blue light therapy.

13. Light Sources for Photomedicine

13.1. Lasers. Since the advent of the first laser, scientists and physicians have
been working together to develop medical applications. The specificity of laser
wavelengths, and the precision of fiber optic light delivery, have greatly
enhanced the evolvement of non-invasive surgical techniques. Each laser has
distinct uses depending on the wavelength and power output. The CO2 laser
has an invisible far infrared output (10600 nm) that is strongly absorbed by
water. It is used to make surgical incisions. Fiber optic delivery is not available
for the CO2 laser so it is limited to external procedures. Several lasers emit
invisible NIR light. The neodymnium (1064 nm), erbium (2940 nm) and
holmium (2130 nm) "YAG" lasers are called "non-specific", because the light is
not strongly absorbed by any tissue component. The weak absorption results
in a deep penetration. Short, powerful pulses of NIR light are used in eye
surgery. Several lasers emit light in the visible region. The light from dye laser
(580 nm), KTP laser (532 nm) and argon lasers (488 nm) are absorbed by
melanin and hemoglobin. They are useful for many procedures that require
sealing off blood vessels. A major advantage of lasers is that coherent light can
be easily coupled into flexible fiber optics that allow delivery of light anywhere
in the body via endoscopes or transcutaneous insertion of fibers through
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 needles. Excimer lasers emit invisible UV light. UV light is strongly absorbed by
proteins and DNA. These lasers are often used for hard tissues (Csele, 2004).
Table 4 lists the majority of lasers that have been used for medical
applications. Figure 21 shows photographs of clinical lasers mainly used in
dermatology.

Table 4. Different kinds of lasers that have been used for medical treatments.

DR. Moshira Hussein Page 49

 Figure 21. Assortment of clinical lasers. (A) Q-switched ruby 694 nm made by
Spectrum used for tattoo and pigmented lesion removal; (B) Long-pulse alexandrite
755 nm Candela Gentlelase used for removal of hair and vascular lesions; (C) Diode
laser at 800 nm Luminis LightSheer, used for hair removal and leg vein treatment; (D)
Q-switched Nd:YAG at 1064 nm ConBio Medlite used for removal of black & blue
tattoos and pigmented lesions.

13.2. Lamps and fluorescent tubes.

Broad spectrum lamps are used for some dermatological applications where it
is desired to treat a large area. The spectral output of incandescent lamps is
continuous throughout the infrared, visible and ultraviolet regions with a peak
that depends on the temperature of the bulb. Filters are used to remove
undesired wavelengths that can be either shorter (short-pass or cut-on) or
longer (long-pass or cut-off) than the desired therapeutic range. The lamps
used can be xenon, halogen or tungsten, depending on the wavelength range
and power output desired. The beam is usually focused via parabolic reflectors
and lenses. Lamps operate from 300 nm to 4.8 μm, and reflector types are
offered with 4 coatings: hard dichroic, UV enhanced, gold, and aluminum
(Figure 22A). Infrared heat lamps emitting a broad range of wavelengths
between 1 and 1000 micron can be used to heat tissue according to its water
content (Figure 22B). Narrow band UVB fluorescent tubes (311 nm) are fitted
into cabinets for UVB phototherapy (Figure 22C) in a similar fashion to UVA
tubes for PUVA.

Figure 22. (A) Assortment of bulbs and lamps used in medical phototherapy. (B) Mid-
infrared lamp used as a heat lamp. (C) Narrow band UVB phototherapy cabinet fitted
with Philips TL-01 Narrowband UVB tubes.

13.3. Light emitting diodes (LEDS). Light-emitting diodes are revolutionizing

the whole lighting industry. Their availability in almost any wavelength and
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 with steadily increasing total output power means that light delivery
applications, previously thought to require an expensive laser, can now be
performed at a tiny fraction of the cost (less than 1%) by LEDS compared with
the equivalent laser source. Not surprisingly, LEDs are becoming much more
widely used in medical applications (Barolet, 2008). LEDS have several
differences from lasers however. Firstly the output wavelengths are much less
monochromatic than lasers, with a typical LED having a Full-Width Half-
Maximum of 30 nm compared to 2 nm for a laser. Secondly LED light is non-
coherent, so for LLLT applications where coherence is considered important,
this may be an important difference. Thirdly, the light is non-collimated, and
this makes it very difficult to focus it into a fiber optic cable for endoscopic and
internal applications. On the other hand, it is much easier to illuminate large
areas of the body with LED arrays than it is with lasers, as shown in Figure 23.

Figure 23. Assortment of medical LED devices. (A) Omnilux LED device that can be
fitted with blue, red or near infrared LEDs. (B) Gentle Waves yellow LED device for
skin rejuvenation; (C) Red LED device for PDT of large areas. (D) Red LED device from
Quantum devices.

14. Summary

The human race has evolved to respond to light in both beneficial and harmful
fashions. Although excessive exposure to sunlight (and in particular the UV
component) can be damaging, by and large light exposure is considered beneficial,
and most people like to go outside and feel better when exposed to sunlight. Modern
scientific disciplines such as biomedical optics, photochemistry, photobiology, cell
biology, laser physics, and engineering have all made major contributions to the
development of photomedicine as a fully-fledged division of medical science. Light
can be used to detect and diagnose medical conditions even deep within the body.
The therapeutic uses of light are manifold. UV phototherapy and PUVA treat many
skin diseases, especially those with immune components, and lasers are used in
dermatology, ophthalmology, dentistry and general surgery (among other medical

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specialties). The combination of harmless light with non-toxic photosensitizing dyes is
used in PDT to kill many undesirable cells, including malignant cancer cells and
infectious microorganisms. Photobiomodulation or LLLT is used to stimulate healing,
reduce tissue death, and relieve pain and inflammation. Intense light therapy is used
for many psychiatric disorders. In the coming years we believe that photomedicine
will only continue to grow as many investigational therapies attain regulatory
approval and popular acceptance increases.

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