Emerging Cosmetic and Medical Applications of LED Technology - Caerwyn Ash White Paper

Emerging Cosmetic and Medical Applications of LED Technology

Dr Caerwyn Ash

euroLED 2013

Birmingham NEC


Dr Caerwyn Ash

Abstract

The rapid development of high brightness light emitting diodes (LED) makes feasible the use of LED,

among other light sources (such as laser, intense pulse light and other incoherent light systems) currently

used for cosmetic and medical treatment. Recent research into the comparison dosimetry of LED compared

with laser and IPL devices are to be discussed and the relationship of wavelength and treatment modality

explained.

This is a general review on current and emerging LED applications in cosmetic and medical treatments such

as wound healing, Neonatal jaundice, Acne, Inflammation, rejuvenating aged skin, skin cancer PDT,

circadian rhythm disorders, and human diagnostics. In-vitro and in-vivo (animal and human) studies utilized

a variety of LED wavelengths, power intensity, and energy density parameters to begin to identify

conditions for each biological tissue that are optimal for biostimulation. LED is safe, non-thermal, non-toxic

and non-invasive, and to date, without side effects have been reported in published literature.

LED light sources for medical application are much more economical than using laser sources, highly

durable and thus are less-expensive in the long term. Their compact and light design and the resulting lower

weight make the use of LED systems simpler than current laser systems. While many of the wavelength

segments are not yet available in traditional and semiconductor laser, wavelengths generated from LEDs have covered partial ultraviolet, near infrared, and almost all the visible bands. This work predicts LED

technology will become a leading technology in medicine and aesthetic therapy. In such a growing and

unsaturated market, the enviable succession of professional salon based light technology is transitioning into

consumer markets, bringing with it many emerging launch opportunities. A brief discussion will provide

technical information on these devices.

Keywords: LED, Skin, medicine, bioluminescence, photochemistry, PDT Cancer, Cytochrome C Oxidase,

Light-Tissue Interaction.

Contact Details: Caerwyn Ash

Research Scientist

E: [email protected]

M: 07790 160659

An experienced technologist with over 8 years experience of photonic based technologies. A key research scientist at CILT (CyDen Institute of Light Therapy), who was responsible for the development of skin

tone meter and optical safety of products sold through Boots (UK) and Proctor & Gamble. He has a PhD in

medical physics and deep understanding of the key aspects of all elements of light tissue interaction.

Application and understanding of his findings are respected worldwide, and such research is being heavily

relied upon in the development and production of consumer products. Such innovative clinical applications

of light based products are far-reaching and ever increasing to include the treatment of hair removal, acne,

skin rejuvenation, cellulite reduction, and wound healing. Caerwyn is a regular contributor to influential

journal publications and maintains a high collaborative relationship with academia. Caerwyn pursues

active research into cellular effects of LED, Intense Pulsed Light (IPL) and laser technology for a variety

of cosmetic and medical conditions.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

1.0 Introduction

The biomedical applications of Low Level Light Therapy

(LLLT), so far, reach from accelerated wound healing

processes (1) to nerve tissue recovery (2), including

strategies to counteract the severe biological imbalances

experienced by astronauts in microgravity (e.g. muscle and

bone atrophy). The primary importance of intensity

thresholds has been verified in-vitro and in-vivo in different

biosystems as fibroblasts, keratinocytes, osteoblasts,

neurons, retinal receptor cells, heart cells, sperm, and,

recently, in cultured nanobacteria.

Phototherapy, from the Greek words meaning treatment with light, has been a valid phototherapy modality since at least the days of the ancient Egyptians, when the sun was

used in that the Ancient Greeks later termed heliotherapy.

Natural light is a double edge sword when it comes to our

health. The ultraviolet (UV) rays present in sunlight can also

damage DNA in exposed skin, which can lead to skin

cancer. They can also damage eyes leading to cataracts. On

the other hand, sunlight also has enormous therapeutic

benefits, having long been used for example to treat

psoriasis and other skin disorders. Phototherapy is, in its

broadest sense, the use of light for any kind of surgical or

nonsurgical treatment, but it is the non-thermal and non-

traumatic therapeutic application of light which is now

accepted as the working definition of phototherapy. A

medical application of solar therapy was later rediscovered

by Niels Ryberg Finsen, a Danish physician and scientist

who won in 1903 the Nobel Prize in Physiology or Medicine

in recognition of his contribution to the treatment of

diseases, notably lupus vulgaris. Since then phototherapy

involving the use of an artificial irradiation source has

expanded our knowledge and understanding of human

biology. Research into light therapy stems back to the 19th

century, the Italian scientist Fubini demonstrated that red

light had a specific effect on mitochondria, increasing their

metabolic rate.

A new lease of life was given to light therapy by the

successful development of the first ruby laser in 1960,

followed in the next 4 years by the argon, Nd:YAG and CO2

lasers. The introduction of light-emitting diode (LED)

devices has reduced many of the concerns formerly

associated with lasers, such as expense, safety concerns, and

the need for trained personnel to operate them. In the past

few years, LED based systems have been successfully

applied in an increasingly large number of fields, and three

major wavelengths have emerged with a good

photobiological basis and proven clinical utility, blue around

415 nm, red 633 nm and near infrared 830 nm. Each has its

own specific cellular target or targets and biological action

spectrum and reaction, but it has become even clearer that no

single wavelength can accomplish everything and

combination LED therapy has proved necessary for greatest

efficacy.

LEDs have become the new favourite in the field of medical treatment and phototherapy. Today, LEDs not only thrive in the field of low intensity photo rejuvenation; but

are also used for the treatments of rhinitis, arthritis, jaundice,

joint/tissue inflammation, skin abnormality, and for the

relief of stress, seasonal affective disorder, as well as

biological clock disorders. LED photomodulation is the

newest category of non-thermal light therapies to find its

way to the dermatologic armamentarium and will be the

focus of this review. Initial work in this area was mainly

developed by National Aeronautics and Space

Administration (NASA). NASA research came about as a

result of the effects noted when light of a specific

wavelength was shown to accelerate plant growth. Because

of the deficient level of wound healing experienced by

astronauts in zero-gravity space conditions and Navy Seals

in submarines under high atmospheric pressure, NASA

investigated the use of LED therapy in wound healing and

obtained positive results.

This new generation of LEDs was some orders of magnitude more powerful than its predecessors, capable of

delivering a much less divergent beam of quasi

monochromatic light, only a few nanometres either side of

the rated wavelength, yet still comparatively inexpensive.

The selectivity of LEDs allows the development of phototherapy treatments using wavelengths with positive

effects. The use of LED phototherapy is now applied to

many thousands of people worldwide each day for various

medical conditions. As a consequence of brighter LEDs of specific wavelengths treatment modalities that werent possible previously are now possible due to technological

advancement in LED.

Non-invasive therapies for skin disease and skin

rejuvenation are being used increasingly at a high rate,

especially in Western countries, where relatively high

disposable incomes are combined with the desire for an ideal

appearance fostered by societal pressures. This article will

examine and attempt to justify the use of LEDs from photo biological principles, looking at the benefits of LEDs a phototherapeutic source, the importance of wavelength, the

targets for LED phototherapy including cellular action

spectra, a discussion on appropriate intensity, and finally a

brief overview illustrating the range of current practical

applications in the clinical field.

2.0 Mechanism of Action

In the same way that plants use chlorophyll to convert

sunlight into plant tissue, LEDs can trigger natural intracellular photo biochemical reactions. To have any effect

on a living biological system, LED emitted photons must be

absorbed by a molecular chromophore or photo acceptor.

Light, at appropriate doses and wavelengths, is absorbed by

chromophores such as porphyrins, flavins, and other light

absorbing entities within the mitochondria and cell

membranes of cells. A growing body of evidence suggests

that photomodulation mechanism is ascribed to the

activation of mitochondrial respiratory chain components

resulting in the initiation of a cascade of cellular reactions. It

has been postulated that photo acceptors in the red to NIR

region are the terminal enzyme of the respiratory chain

cytochrome c oxidase with 2 copper elements. The first

absorption peak is in the red spectrum and the second peak

in the NIR range.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

Seventy-five years ago, Otto Warburg, a German

biochemist, was given a Nobel Prize for his ingenious work

unmasking the enzyme responsible for the critical steps of

cell respiration, especially cytochrome oxidase governing

the last reaction in this process. Two chemical quirks are

exploited: carbon monoxide (CO) that can block respiration

by binding to cytochrome oxidase in place of oxygen, and a

flash of light that can displace it, allowing oxygen to bind

again.

The mechanisms of low level laser therapy (LLLT) are

complex, but essentially rely upon the absorption of

particular visible red and near infrared wave lengths in

photoreceptors within sub-cellular components, particularly

the electron transport (respiratory) chain within the

membranes of mitochondria [3, 4]. The absorption of light

by the respiratory chain components causes a short-term

activation of the respiratory chain, and oxidation of the

NADH pool. This stimulation of oxidative phosphorylation

leads to changes in the redox status of both the mitochondria

and the cytoplasm of the cell. The electron transport chain is

able to provide increased levels of promotive force to the

cell, through increased supply of Adenosine triphosphate

(ATP), as well as an increase in the electrical potential of the

mitochondria membrane, alkalization of the cytoplasm, and

activation of nucleic acid synthesis [5]. Because ATP is the

"energy currency" for a cell, LLLT has a potent action that

results in stimulation of the normal functions of the cell.

The primary means for photomodulated upregulation of cell

activity by LED is the activation of energy switching

mechanisms in mitochondria, the energy source for cellular

activity. Cytochrome molecules are believed to be

responsible for the light absorption in mitochondria.

Cytochromes are synthesized from protoporphyrin IX and

absorb wavelengths of light from 562 nm to 600 nm. It is

believed that LED light absorption causes conformational

changes in antenna molecules within the mitochondrial

membrane. Proton translocation initiates a pump, which

ultimately leads to energy for conversion of ADP to ATP.

This essentially recharges the cell battery and provides more energy for cellular activity.

Nowadays, it has been reported that cells often use CO and,

to an even greater extent, nitric oxide (NO) binding to

cytochrome oxidase to hinder cell respiration. Mitochondria

harbour an enzyme that synthesizes NO. So why would cells

go out of their way to produce NO right next to the

respiratory enzymes? Evolution crafted cytochrome oxidase

to bind not only to oxygen but also to NO. One effect of

slowing respiration in some locations is to divert oxygen

elsewhere in cells and tissues, preventing oxygen sinking to

dangerously low levels. Respiration is about generating

energy but also about generating feedback that allows a cell

to monitor and respond to its environment. When respiration

is blocked, chemical signals in the form of free radicals or

reactive oxygen species are generated. Free radicals had a

bad reputation, but now they can be considered signals. The

activity of many proteins, or transcription factors, depends,

at least in part, on free radicals (6). These include many

proteins such as those involved in the p53 cell signalling

pathway. Further, to bring free radical leak under control,

there is a cross-talk, known as retrograde response, between

the mitochondria and genes in the nucleus for which we are

just beginning to explore the mechanism at play. If we can

better modulate this signalling, we might be able to

influence the life or death of cells in many pathologies as it

is more and more demonstrated in its anti-aging effects on

collagen metabolism.

A recent discovery has revealed that NO eliminates the

LLLT induced increase in the number of cells attached to the

glass matrix, supposedly by way of binding NO to

cytochrome C oxidase. Cells use NO to regulate respiratory

chain processes, resulting in a change in cell metabolism. In

turn, in LED exposed cells like fibroblasts increased ATP

production, modulation of reactive oxygen species (such as

singlet oxygen species), reduction and prevention of

apoptosis, stimulation of angiogenesis, increase of blood

flow, and induction of transcription factors are observed.

These signal transduction pathways lead to increased cell

proliferation and migration (particularly by fibroblasts),

modulation in levels of cytokines (eg, interleukins, tumour

necrosis factor), growth factors and inflammatory mediators,

and increases in anti-apoptotic proteins (7). The photo

dissociation theory incriminating NO as one of the main

players suggests that during an inflammatory process, for

example, cytochrome C oxidase is clogged up by NO. LED

therapy would photo dissociate NO or bump it to the

extracellular matrix for oxygen to bind back again to

cytochrome C oxidase and resume respiratory chain activity.

Understanding the mechanisms of cutaneous LED induced

specific cell signalling pathway modulation will assist in the

future design of novel devices with tailored parameters even

for the treatment of degenerative pathologies of the skin.

Figure 1: the ATP Cycle and the influence of light on the

respiratory chain

Since wavelength is the most important factor in any type of

photo-therapy, the specification of the device must consider

which wavelengths are most effective of producing the

desired effects within living tissues. The effect of visible red

light on the local vasculature is also well recognized. The

red light will bring more oxygen and nutrients into the area,

further helping to reduce inflammation and enhance the

wound repair process. Corazza et al [7] have compared the

blood vessels proliferation effects of laser and LEDs


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

illumination on wounds induced in rats. The results have

shown that the proliferations of blood vessels in all

irradiated groups are superior in comparison to those of the

control group, which indicates that both LED and laser

based therapy have demonstrated expressive results in

angiogenesis.

Light at a wavelength of 830 nm (near infrared) is absorbed

in the cellular membrane rather than in cellular organelles,

which remain the target when using light in the visible

spectrum. Irradiation at 830 nm leads to accelerated

fibroblast-myofibroblast transformation and mast-cell

degranulation. In addition, chemotaxis and phagocytic

activity of leucocytes and macrophages is enhanced through

cellular stimulation by this wavelength [8, 9].

Figure 2: Absorption characteristics of human skin

(Melanin, Oxyhaemoglobin, Porphyrin and Water)

3.0 Optimal LED Parameters

The question is no longer whether it has biological effects

but rather what the optimal light parameters are for different

uses. Biological effects depend on the parameters of the

irradiation such as wavelength, dose (fluence), intensity

(power density or irradiance), irradiation time (treatment

time), continuous wave or pulsed mode, and for the latter,

pulsing patterns. In addition, clinically, such factors as the

frequency, intervals between treatments and total number of

treatments are to be considered. The prerequisites for

effective LED clinical response are discussed hereafter.

Light is predominately measured in wavelength and is

expressed in units of nanometres (nm). Different

wavelengths have different chromophore absorption

characteristics can have various effects on tissue.

In general the longer the wavelength, the deeper photons

penetrate into tissue. Depending on the type of tissue, the

penetration depth is less than 1 mm at 400 nm, 0.5 to 2 mm

at 514 nm, 1 to 6 mm at 630 nm, and maximal at 700 to 900

nm (10). The various cell and tissue types in the body have

their own unique light absorption characteristics, each

absorbing light at specific wavelengths. For best effects, the

wavelength used should allow for optimal penetration of

light in the targeted cells or tissue.

3.1 Wavelength

The first law of photobiology, states that only energy which

is absorbed in a target can produce a photochemical or photo

physical reaction. However, any such reaction is not an

automatic consequence of energy absorption. It may be

simply converted into heat, or re-emitted at a different

wavelength (fluorescence). The prime arbitrator of this no absorption, no reaction is not the output power on the incident photons, but their wavelength, and this comprises

two important considerations: wavelength specificity of the

target, or the target chromophore; and the depth of the target.

Based on these two considerations, the wavelength must not

only be appropriate for the chosen chromophore, but it must

also penetrate deeply enough to reach enough of the target

chromophores with a high enough photon density to induce

the desired reaction (11). Penetration of light into living

tissue is, however, extremely important in phototherapy, and

very frequently displays characteristics which are often in

discord with results produced by mathematical models. The

different wavebands, visible light and invisible infrared

light, have different primary mechanisms. Absorption of

visible light photons at appropriate levels induces a

photochemical reaction, and a primary photochemical

cascade occurs within the cell, usually instigated by the

mitochondria, the adenosine triphosphate producing power

houses of the cell. Infrared photons, on the other hand, are

primarily involved in photo physical reactions which occur

in the cell membrane, changing the rotational and vibrational

characteristics of the membrane molecules. Through

subsequent activation of the various membrane-located

transport mechanisms, such as the Na++/Ca++ and

Na++/K++ pumps and changes in the cell permeability,

changes occur in the chemical and osmotic balance in the

cytosol, finally resulting in the induction of a secondary

chemical cascade which gives more or less the same

endpoint as the visible light photons, namely cellular

activation or proliferation. Wavelength is thus probably the

single most important consideration in phototherapy,

because without absorption, there can be no reaction.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

Table 1: Effect of different wavelengths on biostimulation (12)

Table 1: Literature based summary of the phototherapeutic wavelength specific efficacy in raising the action potentials of specific

cells

Table 1 shows in the left hand column a selection of

investigated wavelengths, in increasing length from the top,

and along the top of the table can be found the most

important cellular targets. These cells can be sub grouped

into 4 types. The first three subgroups are concerned with

the wound healing process. Subgroup 1 consists of mast

cells, neutrophils and macrophages, which are associated

with the inflammatory stage of wound healing; subgroup 2

consists of fibroblasts, associated with the proliferative

stage; and subgroup 3 are the transformational cells

associated with the remodelling stage. In subgroup 4 can be

found epidermal keratinocytes, which, when photo activated,

are an extremely important source of cytokines and other

chemokines which can descend into the dermis and are

involved in either proinflammatory or anti-inflammatory

reactions. From the various wavelengths reported, two are

notable for their effect on raising the action potential of

target cells, but they do so in different ways. Visible red at

633 nm has been reported to have profound effects on

fibroblasts, inducing fibroplasia with increased numbers of

highly active mitochondria. Near IR 830 nm, on the other

hand, has some apparent effects on fibroblasts, but profound

effects on all three of the inflammatory stage cells. Both

visible red and near IR wavelengths photo modulate the

mechanisms of epidermal keratinocytes, producing an

increased amount of interleukins such as IL1, 2, and 6 and

also tumour necrosis factor alpha (TNF). Both IR and visible

red light are well associated with increased local blood flow

post irradiation. This is important when considering that this

not only increases the flow of nutrients and oxygen into the

treated area, but also provides a gradient between areas of

low and high oxygen tension which can act as highways for the wound healing cells into the target area, particularly

those associated with the inflammatory stage of wound

healing. In the case of visible red light the main target is the

respiratory chain of the mitochondrion in the fibroblast, and

specifically cytochrome C oxidase. In the process, in which

copper ions play an important role, it translocate protons,

helping to establish a chemiosmotic potential that the ATP

synthase then uses to synthesize ATP. One of the major

peaks in the absorption spectrum of cytochrome C oxidase is

in the visible yellow, but bearing in mind the poor

penetration of yellow light in living human tissue. It is not

possible for yellow light to reach deeply enough into the

reticular dermis to affect the activity of fibroblasts in that

zone so the yellow waveband is not ideal for any

phototherapeutic application involving fibroblasts. Another

major peak in the cytochrome C oxidase absorption

spectrum is around 633 nm, and that wavelength does offer

much deeper penetration, and thus potentially greater

applications in phototherapy involving fibroblast activity,

such as wound healing and even skin rejuvenation.

3.2 Fluence and Irradiance Wavelength as already argued will determine both the target,

and the depths at which the desired targets can be reached,

but the photon intensity will help to ensure that treatment is

successfully achieved with the selected wavelength or

sequential wavelengths to get the desired clinical result. The

Arndt-Schulz law states that there is only a narrow window

of opportunity where you can actually activate a cellular

response using precise sets of parameters, i.e. the fluence or


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

dose. The challenge remains to find the appropriate

combinations of LED treatment time and irradiance to

achieve optimal target tissue effects. Fluence or dose is,

indicated in Joules per cm2.

In practice, if light intensity (irradiance) is lower than the

physiological threshold value for a given target, it does not

produce photo stimulatory effects even when irradiation time

is extended. It should be cautioned, however, that an

excessive dose of radiation can be detrimental. Thus, at

proper doses of light there can be a stimulation of growth,

but at high doses an excessive amount of singlet oxygen may

be produced, and its chemical action can be detrimental to

cells. This is another reason for determining an action

spectrum.

Fig 3: The biphasic dose response in of a positive response

with sufficient illumination for a measurable reaction,

however excessive dose can be detrimental. A narrow

margin occurs for effective treatment

4.0 Clinical Literature

In our laboratory we perform many dose response

experiments to firstly understand the mechanism of action

and to understand the limits of the dose response. The

magnitude of the bio stimulation effect depends on the

physiological condition of the cells and tissues at the

moment of irradiation. Compromised cells and tissues

respond more readily than healthy cells or tissues to energy

transfers that occur between LED emitted photons and the

receptive chromophores. For instance, light would only

stimulate cell proliferation if the cells are growing poorly at

the time of the irradiation. Cell conditions are to be

considered because light exposures would restore and

stimulate pro-collagen production, energizing the cell to its

own maximal biological potential. This may explain the

variability in results in different studies.

Figure 4: Laboratory collaboration for wound healing.

4.1 Wound Healing

The need to care for a population with chronic wounds is a

growing challenge that requires innovative approaches.

Laser light have been widely acclaimed to speed wound

healing of ischemic, hypoxic, and infected wounds (13).

Lasers provide low energy stimulation of tissues that results

in increased cellular activity during wound healing (14, 15).

LED photo modulation has an effect on human skin that is

non-thermal and most likely mediated by mitochondrial

cytochrome light absorption. This leads to increased cellular

metabolic activity by targeted cells, such as increased

collagen synthesis by fibroblasts. The second phase of

wound healing involves proliferation, with the formation of

granulation tissue as a result of new blood vessel growth.

This angiogenesis combined with the deposition of new

connective tissue requires successful degradation of the

wound matrix by macrophages.

Tissue repair and healing of injured skin are complex

processes that involve a dynamic series of events including

coagulation, inflammation, granulation tissue formation,

wound contraction and tissue remodelling (16).

Photomodulation with light in the red to the near infrared

range (630-1000 nm) has been shown to accelerate wound

healing, improve recovery from ischemic injury, and

attenuate degeneration in the injured optic nerve. Low

fluence of photo irradiation at the cellular level can generate

significant biological effects including cellular proliferation

and the release of growth factors from cells.

Erdle et al (17) have evaluated the wound healing effect of

670 nm LED light on incisions and burn injuries in hairless

mice and suggested that red light exposure may be helpful in

postoperative wound repair. Their results show that while

not so effective for burn injuries, 670 nm LED red light

sources do accelerate healing in skin of hairless mice with

incisions.

Desmet et al (18) have also studied the use of near infrared

light treatment in various in vitro and in vivo models to

determine the effect of near infrared LED light treatment on

physiologic and pathologic processes. Their research found

that the light treatment stimulates the photo acceptor

cytochrome oxidase, which results in increased energy

metabolism and production,


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

Trelles and Allone (19) have studied 10 subjects regarding

the effects of a LED phototherapy system on enhancing

wound healing following the combination of eyelid surgery

and laser ablative resurfacing. After the surgery, one-half of

each subjects face was treated with the red LED therapy (20 min, 96 J/cm

2, 633 nm), the other half of each subjects face

being the non-irradiated control. Erythema, edema, bruising,

and days to healing were independently evaluated from the

clinical photography. The 633 nm LED therapy treated side

is superior to the non-irradiated control by a factor of two to

three in all instances.

Early work involving LED mainly focused on the wound

healing properties on skin lesions. Visible/NIR LED light

treatments at various wavelengths have been shown to

increase significantly cell growth in a diversity of cell lines,

including murine fibroblasts, rat osteoblasts, rat skeletal

muscle cells, and normal human epithelial cells. Decrease in

wound size and acceleration of wound closure also has been

demonstrated in various in vivo models, including toads,

mice, rats, guinea pigs, and swine (20, 21). Accelerated

healing and greater amounts of epithelialization for wound

closure of skin grafts have been demonstrated in human

studies (22, 23). The literature also shows that LED therapy

is known to positively support and speeds up healing of

chronic leg ulcers: diabetic, venous, arterial pressure. It is

important to keep in mind that to optimize healing of

necrotic wounded skin, it may be useful to work closer to the

near infrared spectrum as an increase in metalloproteinases

(MMP-1) production accelerates wound remodelling. Mast

cells, neutrophils, and macrophages are the first cells to

respond to a wound, and that these cells respond best to 830

nm light. In contrast, fibroblasts, which are involved later,

respond better to 633nm light. The suggestion has been

made that it might be better to irradiate first with 830nm

light, followed by 633nm light, and then again with 833 nm

light to activate the myofibroblasts.

Figure 5: 15 years old wound on a diabetic male (aged 46),

previously had 8 skin grafts over 15 years. Image shows

12% closure after 7 weeks as the keratinocytes migrate from

the edges of the wound.

4.2 Inflammation

The phases of wound healing and the cells involved must be

understood in order to appreciate the important role of

inflammation in these processes. In the inflammatory phase,

leukocytes peak, monocytes transform into phagocytes and

mast cells peak and degranulate. This response initiates the

migration of more macrophage cells and fibroblasts to the

target stimulated by chemotactic signals from pre-existing

fibroblasts, leukocytes and macrophages. At the start of the

proliferation phase macrophages gradually decrease and the

number of fibroblasts peak then start to drop off. At the end

of the proliferation phase two transitional events occur: the

differentiation of active fibroblasts into myofibroblasts and

the differentiation of active fibroblasts into dormant

fibrocytes. The role of the myofibroblasts is to position

themselves on collagen fibres and exert a longitudinal force

on them, tightening and aligning them. Red light at 633 nm

has been shown to make mast cells preferentially

degranulate. Mast cells are present in the dermis, located

near blood vessels. The stimulation given by their fast-acting

proallergenic granules is seen by the surrounding tissue as

inflammation, so the wound healing process is triggered

without any thermal damage.

The inflammatory response from 633 nm is a controlled

short lived phase, which transcends through to the

proliferation phase, together with the creation of

neovascularization and the increase of local blood and

lymphatic vessel flow. Lymphatic drainage is important in

transporting leukocytes and lymphocytes into the target area

and maintaining homeostasis of the treated skin. An

increased blood supply raises the oxygen tension in the

target area, creating cellular gradients and ensuring that the

connection between the papillary dermis and the basement

membrane of the dermal epidermal junction and the

basement membrane is supported.

Fibroblasts are essential in achieving the desired effect in the

dermis during the second and third phases following the

inflammatory reaction caused by mediated mast cell

degranulation. The fibroblast is multifunctional, not only

synthesizing collagen and elastin, but also regulating the

homeostasis of the ground substance and maintaining

collagen fibres.

Free radicals are known to cause subclinical inflammation.

Inflammation can happen in a number of ways. It can be the

result of the oxidation of enzymes produced by the bodys defence mechanism in response to exposure to trauma such

as sunlight (photodamage) or chemicals. LED therapy brings

a new treatment alternative for such lesions possibly by

counteracting inflammatory mediators. A series of recent

studies have demonstrated the anti-inflammatory potential of

LED. A study conducted in arachidonic acid treated human

gingival fibroblast suggests that 635 nm irradiation inhibits

PGE 2 synthesis like COX inhibitor and thus may be a

useful anti-inflammatory tool.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

4.3 Acne vulgaris

Acne vulgaris is an exceedingly common chronic disease of

the sebaceous gland and follicle, affecting approximately 40

million U.S. adolescents and 25 million adults (24) and

accounts for over 30% of annual dermatology visits. It is the

current consensus that acne is a multifactor disease which

involves four primary events; follicular hypercornification,

increased sebum secretion, colonization by the gram positive

bacterium, Propionibacterium acnes (P. acnes), and

inflammation (25). The rise in antibiotic resistance threatens

to reduce the future usefulness of the current mainstay of

therapy.

Acne often improves after exposure to sunlight or artificially

produced solar radiation. P. acnes produces porphyrins (26)

which absorb light energy at the near ultraviolet (UV) and

blue light spectrum. Irradiation of P. acnes colonies with

blue visible light leads to photoexcitation of bacterial

porphyrins, singlet oxygen production and eventually

bacterial destruction (27). In-vivo it has been shown that

acne may be treated successfully with blue visible light

phototherapy

Papageorgiou et al (28) have evaluated the effectiveness of

blue light (peak at 415 nm) and a mixed blue and red light

(peaks at 415 and 660 nm) in acne treatments. Their study

randomly assigned 107 patients with mild to moderate acne

in four treatment groups to be treated with blue light, mixed

blue and red light, cool white light, and 5% benzoyl

peroxide cream, respectively. Subjects in the phototherapy

groups received irradiation 15 min daily from portable light

sources. After 12 weeks of active treatment, the combined

blue/red light group achieved a mean improvement of 76%

in inflammatory lesions, significantly superior to that in all

other groups. The final mean improvement by using bluered light is 58%, still better than that in the other groups.

The author has just reported a significant study using 414

nm LEDs in combination with a proprietary cream for clearing acne vulgaris. In a study of 39 adults with mild-to-

moderate facial inflammatory acne were recruited. Subjects

were randomly assigned to blue light therapy (n=31) or

control (n=8). Subjects were well matched at baseline in

terms of age, sex and duration of acne. Severity of cyclic

breakouts, improvement in skin appearance, clarity,

radiance, tone, texture, smoothness and subject satisfaction

was recorded at 1, 2, 3, 4, 6, 8, 12 weeks.

Inflammatory lesion counts reduced by 64% in treatment

group and 4% in controls. The reduction was most observed

in the first 3 weeks after start of treatment. Treatment is pain

and side effect-free. Home-use blue light therapy improves

inflammatory facial acne three weeks after first treatment

with no serious adverse effects. The blue light device offers

a valuable alternative to antibiotics and potentially irritating

topical treatments. The onset of the effect was observable at

week 3, and maximal between weeks 8 and 12. Blue light

phototherapy using a narrowband LED light source appears

to be a safe and effective additional therapy for mild to

moderate acne (29).

4.4 Skin Rejuvenation

Over time, skin gradually displays the effects of aging. The

collagen in the skin begins to break down and results in fine

lines and then deeper grooves on the skin surface. Factors

like sun, gravity, and hormones can speed up the aging

process. The treatment of aging skin has always been a very

popular topic.

Lubart et al (30) propose a photo rejuvenation mechanism

based on light-induced reactive oxygen species (ROS)

formation. They irradiate collagen in-vitro with a broadband

of visible light (400800 nm, 2472 J/cm2) and have found that the irradiated collagen results in the formation of

hydroxyl radicals. These researchers suggest that visible

light at the energy doses used for skin rejuvenation (2030 J/cm

2) produces high amounts of ROS, which destroy old

collagen fibres, encouraging the formation of new ones.

While at inner depths of the skin, where the light intensity is

much weaker, low amounts of ROS are formed, which are

well known to stimulate fibroblast production. Trelles (31)

have suggested that LED therapy represents a potential

approach in anti-aging prevention. He has proposed to apply

prevention to subjects in their very early 20s before the appearance of fine lines. The prevention can be achieved via

irradiating low level photo energy with specific wavelengths

that, based on the photo biological findings, can stimulate

both epidermal and dermal cells. He has also reported that

the LEDs from the NASA Space Medicine Program can

enhance action potentials of the skin cells and increases in

local blood and lymphatic flow in a non-invasive, a thermal

manner. His conclusion is that LED-based systems can be

less-expensive but clinically useful light source against

photo aging.

Figure 6: Possible mechanism of actions for LLLTs effects on skin rejuvenation. LLLT aids skin rejuvenation through

increasing collagen production and decreasing collagen

degradation. Increase in collagen production occurs by

LLLTs increasing effects on PDGF and fibroblast production, which happens through decreasing apoptosis and

increasing vascular perfusion and bFGF and TGF- expressions. Decrease in IL-6 and increase in TIMPs, which

in turn reduce MMPs, aid in reduction of collagen

degradation. (Figure courtesy of Wellman Center for

Photomedicine.)


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

Using a variety of LED light sources in the visible to NIR

regions of the spectrum, in vitro studies have revealed that

LED can trigger skin collagen synthesis with concurrent

reduction in MMP. A significant increase in collagen

production after LED treatment has been shown in various

experiments, including fibroblasts cultures, third-degree

burn animal models, and human blister fluids, and skin

biopsies.

4.5 Sunburn prevention LLLT for Photo protection

Results from our own laboratory testing suggest that LED

660 nm treatment before UV exposure provides significant

protection against UV-B induced erythema. The induction of

cellular resistance to UV insults may possibly be explained

by the induction of a state a natural resistance to the skin

(possibly via the p53 cell signalling pathways) without the

drawbacks and limitations of traditional sunscreens.

It is widely accepted that the UV range (400 nm) exposure is

responsible for almost all damaging photo induced effects on

human skin (32, 33, 34). Some proposed mechanisms for

UV induced skin damage are collagen breakdown, formation

of free radicals, inhibition of DNA repair, and inhibition of

the immune system. Existing solutions to prevent UV

induced damaging effects are based on minimizing the

amount of UV irradiation that reaches the skin, which is

achieved by either avoidance of sun exposure or use of

sunscreens. However, sometimes sun avoidance might be

hard to implement, especially for the people involved in

outdoor occupations or leisure activities. In contrast, the

photo protective efficacy of topical sunscreens has

limitations as well, which include decreased efficacy after

water exposure or perspiration, spectral limitations, possible

toxic effects of nanoparticles that are contained by most

sunscreens (35), user allergies, and compliance. It has

recently been suggested that infrared (IR) exposure might

have protective effects against UV induced skin damage

mainly by triggering protective/repair responses to UV

irradiation. In the natural environment, visible and IR solar

wavelengths predominate in the morning, and UVB and

UVA are maximal around noon, which suggests that

mammals already possess a natural mechanism that, in

reaction to morning IR radiation, prepares the skin for

upcoming potentially damaging UV radiation at noon (36).

However, opposing views also exist, such as Krutmann and

Schroeders study demonstrating IR induced disturbance of the electron flow of the mitochondrial electron transport

chain, which leads to inadequate energy production in

dermal fibroblasts (37) Schroeder et als report is another example stating that IR alters the collagen equilibrium of the

dermal extracellular matrix (ECM) by leading to an

increased expression of the collagen degrading enzyme

MMP-1, and by decreasing the de novo synthesis of the

collagen itself (38). As previously mentioned, the same light

source may have opposite effects on the same tissue,

depending on the parameters used, and these conflicting

views are probably due to the biphasic effects of light.

Menezes et al demonstrated that non-coherent NIR (700-

2000 nm) generated a strong cellular defence against solar

UV cytotoxicity in the absence of rising skin temperature,

and it was assumed to be a long lasting (at least 24 h) and

cumulative phenomenon (39). Following this study, Frank et

al proposed that IR irradiation prepares cells to resist UVB

UVB induced damage by affecting the mitochondrial

apoptotic pathway (40). IR pre-irradiation of human

fibroblasts was shown to inhibit UVB activation of caspase-

9 and -3, partially release cytochrome C and

Smac/DIABLO, decrease proapoptotic proteins (ie, Bax),

and increase anti apoptotic proteins (ie, Bcl-2 or Bcl-xL).

The results suggested that IR inhibited UVB induced

apoptosis by modulating the Bcl-2/Bax balance, pointing to

a role of p53, a sensor of gene integrity involved in cell

apoptosis and repair mechanisms. In a further study, Frank

et al studied more specifically the role of the p53 cell

signalling pathway in the prevention of UVB toxicity. The

response to IR irradiation was shown to be p53 dependent,

which further suggests that IR irradiation prepares cells to

resist and/or to repair further UVB-induced DNA damage.

Finally, the IR induction of defence mechanisms was

supported by Applegate et al, who reported that the

protective protein, ferritin, normally involved in skin repair

(scavenger of Fe2 otherwise available for oxidative

reactions) was induced by IR radiation (41). In an in vitro

study, it was reported that an increase in dermal fibroblast

procollagen secretion reduces MMP or collagenase

production after non thermal non coherent deep red visible

LED exposures (660 nm, sequential pulsing mode). These

results correlated with significant clinical improvement of

rhytids in-vivo. In a subsequent in-vivo pilot study, effect of

this wavelength in 3 healthy subjects using a minimal

erythema dose method adapted from sunscreen sun

protection factor (SPF) determination has been investigated.

The results showed that LED therapy was effective,

achieving a significant response in the reduction of the

erythema induced by UVB. Following this pilot study, a

further investigation has been performed to find out in-vivo

aspects of this phenomenon. Effects of non-thermal non

coherent 660 nm LED pulsed treatments in providing

enhanced skin resistance before upcoming UV damage were

investigated in a group of subjects with normal fair skin and

patients presenting with polymorphous light eruption.

Results suggested that LED based therapy before UV

exposure provided significant dose related protection against

UVB induced erythema. A significant reduction in UVB

induced erythema reaction was observed in at least one

occasion in 85% of subjects as well as in the patients

suffering from polymorphous light eruption. Furthermore, an

SPF 15 like effect and a reduction in post inflammatory

hyperpigmentation were observed. An in vitro study by Yu

et al revealed that HeNe laser irradiation stimulated an

increase in nerve growth factor (NGF) release from cultured

keratinocytes and its gene expression (42). NGF is a major

paracrine maintenance factor for melanocyte survival in skin

(43). It was shown that NGF can protect melanocytes from

UV induced apoptosis by upregulating Bcl-2 levels in the

cells (44). Therefore, an increase in NGF production induced

by HeNe laser treatment may provide another explanation

for the photo protective effects of LLLT.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

4.6 Scar Prevention

Hypertrophic scars and keloids can form after surgery,

trauma, or acne and are characterized by fibroblastic

proliferation and excess collagen deposition. An imbalance

between rates of collagen biosynthesis and degradation

superimposed on the individuals genetic predisposition have been implicated in the pathogenesis of these scar types.

It has recently been proposed that interleukin (IL)-6

signalling pathways play a central role in this process and

thus, that IL-6 pathway inhibition could be a promising

therapeutic target for scar prevention. As LED therapy has

been shown to decrease IL-6 mRNA levels, it may

potentially be preventing aberrant healing.

4.7 Photodynamic Therapy (PDT)

PDT can best be defined as the use of light to activate a

photosensitive medication that is applied to the skin prior to

treatment. The PDT light source has a direct influence on

treatment efficacy. Red light (630 nm) has been used for

many years in combination with a sensitizer (levulinic acid)

for photodynamic therapy (PDT). When exposed to light of

the proper wavelength, the sensitizer produces an activated

oxygen species, singlet oxygen, which oxidizes the plasma

membrane of targeted cells. Due to a lower metabolic rate,

there is less sensitizer in the adjacent normal tissue, hence a

lesser reaction. One of the absorption peaks of the metabolic

product of levulinic acid, protoporphyrin absorbs strongly at

630 nm. Nowadays, the importance of treatment parameters

of this light source is unfortunately greatly underestimated.

High-end LED devices meet this challenge and can be used

as the light source of choice for PDT.

4.8 Rheumatoid arthritis

McDonald has conducted a study in which she instructed 60

female rheumatoid arthritis patients to place their hands into

a box to be exposed in blue light for up to 15 min (45). Most

subjects have experienced a pain relief after the exposure.

McDonald has concluded that the pain relief is due to the

blue light and the length of time exposed. The longer the

exposure is, the greater the chance of pain relief. While the

light source used in this 1982 study is not specified, there is

no reason to rule out that blue light LED will have similar

treatment effect. Hart and Malak have patented a therapeutic

light source for the treatment of arthritis or joint

inflammation. The device includes a set of 350 to 1000 nm

LEDs and fibre optic connections for treating and reducing inflammation and edema both internal and external, to joints,

muscles, nerves, and skin tissues of the subject. The device

can be worn in contact with the skin and surrounding the

areas of inflammation, edema, neural, and muscular damage

over short and long periods of time.

4.9 Neonatal Jaundice

UV phototherapy has been used for decades in the

management of common skin diseases (46). However, there

are side effects associated with UV deleterious effects as

well as several contraindications, including the long-term

management of children and young adults and patients

receiving topical or systemic immunosuppressive drugs. The

primary effectors of UV phototherapy in the treatment of

various skin conditions bear similarities with some of those

associated with blue LEDs and IR phototherapy with LEDs,

including singlet oxygen production and modulation of

interleukins (47, 48). This provides a unique opportunity to

explore the use of LED in skin conditions where UV therapy

is used without the downside of inherent side effects. This

approach has been termed UV free therapy.

Figure x: tradition UV phototherapy for neonatal jaundice

Our solution of flexible LEDs incorporated into fabric to

provide comfortable treatment to infant, without any UV eye

risk to the infant. The blanket or baby grow suit may also

have continuous bilirubin measurement and will turn off the

UV phototherapy when normal bilirubin levels are sustained.

This is an attractive solution as the infant wont have to endure painful blood tests, and better monitoring of infant

than relying on nurses. Without the need of the sick baby

being in an incubator the infant can be wrapped in the

blanket and greater direct bonding and interaction between

mother and baby.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

4.10 Psoriasis

Typically UVA is used to treat Psoriasis, Atopic Dermatitis

and Uricaria pigmentosa. Although a visible LED and laser

diode have been used to treat acne and facial rejuvenation, to

our knowledge there are no reports of UV LED based

phototherapy with adequate reporting of results. Most

hospitals use large arrays of florescent tubes to treat the

whole body. These are highly inefficient typically

consuming 3.5-5KW electricity, costly and difficult to

maintain, requiring several meters of floor space. Irradiation

of health tissue is difficult to avoid when using large area

irradiation. Medical workers are also exposed to UV

irradiation while operating the system. Considerable heat

generated is uncomfortable during treatment while standing.

LEDs provide a significant reduction in running costs, Improved Lifetime and no toxic compounds and only treat

body areas affected. Treatment performed at work, home, or

at night.

Figure X:

4.11 Herpes simplex virus (HSV)

HSV is chronic and lasts ones entire life. The exposure of the host to several kinds of physical or emotional stresses

such as fever, exposure to UV light, and immune

suppression causes virus reactivation and migration through

sensory nerves to skin and mucosa, localizing particularly on

the basal epithelium of the lips and the perioral area (49).

Although several antiviral drugs such as acyclovir and

valacyclovir are used to control recurrent herpes outbreaks,

only limited reduction in the lesions healing time has been observed. Although mechanism of action is still not clear, an

indirect effect of LLLT on cellular and hormonal

components of the immune system involved in antiviral

responses rather than a direct virus-inactivating effect was

proposed (50). Activation and proliferation of lymphocytes

(51, 52, 53, 54) and macrophages (55), as well as the

synthesis and expression of cytokines (56, 57) after low

intensities of red and NIR light, have been reported by

several investigators.

4.12 Hypertrophic Scars and Keloids

Hypertrophic scars and keloids are benign skin tumours that

usually form after surgery, trauma, or acne and are difficult

to eradicate. Fibroblastic proliferation and excess collagen

deposits are the 2 main characteristics, and imbalance

between rates of collagen biosynthesis and degradation

superimposed on the individuals genetic predisposition has been implicated in their pathogenesis. It has recently been

proposed that poor regulation of IL-6 signalling pathways

and TGF expression have a significant role in this process,

and thus inhibition of the IL-6 pathway and/or TGF

expression could be a potential therapeutic target. Based on

the reports demonstrating the role of LLLT in decreasing IL-

6 mRNA levels and modulation of PDGF, TGF, ILs such as

IL-13 and IL-15, and MMPs, which are also associated with

abnormal wound healing, it was proposed to be an

alternative therapy to existing treatment options. The use of

LLLT as a prophylactic method to alter the wound healing

process to avoid or attenuate the formation of hypertrophic

scars or keloids has been investigated by Barolet and

Boucher in 3 case studies, where after scar revision by

surgery or CO2 laser ablation on bilateral areas, a single scar

was treated daily by the patient at home with 805 nm NIR-

LED at 30 mW/cm2 and 27 J/cm

2.

4.13 Diagnostics

The biggest use of the multi wavelength monochromatic

properties of LED is for tissue diagnostics. LEDs have been

used for decades for quantifying blood oxygenation in-vivo

by absorption of oxygenated and deoxygenated haemoglobin

on both side of the isobastic point.

Skin tone is a continuous shade from Albino to dark Afro-

Caribbean, the author published work on the optimum

wavelength and the results on 220 subjects to quantify skin

tone into 6 categories (58, 59). The same technology

previously described can also be used to quantify bilirubin

in-vivo.

Its been shown that fresh fibroblasts in which are key in the process of wound healing fluoresce under certain near UV

wavelengths, this may be used to optimise treatment for

wound care and skin rejuvenation as illuminating fresh

fibroblasts may be detrimental in their transformation stages

optimising the best time for treatment.

A long-term ambition from many global companies to

produce an in-vivo blood glucose meter for diabetic for

monitoring of their blood glucose levels. Patients with type 1

diabetes test their blood glucose by pricking their fingertip

and self-injecting insulin, an alternative to this technique

particularly for paediatric cases is an ideal goal.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

5.0 Discussion

LEDs are based on semiconductor technology, just like

computer processors, and are increasing in brightness,

energy efficiency, and longevity at a pace reminiscent of the

evolution of computer processors.

Basic science is elucidating some of the mechanisms at

tissue, cellular and subcellular levels, proving what

clinicians and therapists have already found in patients. The

combination of one LED wavelength with another, used

sequentially, has appeared as the best and most effective

approach. LED therapy may be used as a standalone light

therapy, but has very interesting effects when used in an

adjunctive manner to improve and speed up the already good

results achieved with other light sources, or conventional

surgery. There is no doubt that LED phototherapy, when

used based on the solid photobiological precepts of

appropriate wavelength, target and photon intensity, is a

safe, flexible, effective and comparatively inexpensive

modality, very welcome in this era of ever-spiralling costs

for both practitioners and patients.

Besides being used for the treatments of rhinitis, arthritis,

jaundice, etc. LEDs are used for the relief of stress, seasonal affective disorder, and biological clock disorders; not to

mention that LEDs are thriving in the field of low intensity photo rejuvenation. The LED based PDT has even been

expanded to cancer treatments. LEDs allow the adjustment of light intensity. They have the ability to produce high light

levels with low radiant heat output and maintain useful light

output for years. LED based systems can provide a

homogenous light dose in optimal intensity.

It is inevitable that one day a body suit for astronauts and

submariners can provide visible and UV for vitamin D

synthesis in situations of light is limited or restricted. This

paper does not cover UV bacteria decontamination or teeth

whitening, which are currently large markets both

domestically in the UK and globally.

6.0 Conclusion

Phototherapy has definitely arrived in the clinical field for

the treatment of inflammatory acne, wound healing, skin

rejuvenation, and the treatment of pain. LLLT appears to

have a wide range of applications in dermatology, especially

in indications where stimulation of healing, reduction of

inflammation, reduction of cell death, and skin rejuvenation

are required. The introduction of LED array based devices

has simplified the application to large areas of skin.

It is difficult for lasers to produce the efficient wavelength

combination optimal for wound healing. The size of wounds

that may be treated by the small beam width of laser is also

limited. In contrast, LEDs allow the control of spectral composition and can be arranged in flat arrays of all sizes for

the treatment of small or large areas. LEDs offer an effective alternative to conventional light sources also for

the following reasons:

1. Using LED array light source for medical devices is much more economical than using IPL or laser

sources. LEDs are highly durable and thus are less expensive in the long term. Their compact and light

design and the resulting lower weight make the use

of LED systems simpler.

2. Solid-state high efficiency LED is safer to use than the traditional gas laser. The energy level of LED is

low. When used in medical treatment, LED based

systems do not need a high voltage power supply as

required in laser based ones. When required, LED

based devices are more easily to be made self-

contained. They can be continuously operated with

a battery pack for a longer period. For any medical

treatment equipment, especially those used in the

remote areas where no modern utilities are readily

available, this is an attractive feature.

3. While many of the wavelength segments are not yet available in semiconductor laser, wavelengths

generated from LEDs have covered partial ultraviolet, near infrared, and almost all the visible

bands.

4. LEDs produce less heat than high pressure lamps and thus the hyperthermic effects that can be

induced by high-intensity light sources are avoided.

As a result, LEDs can be placed in a closer range from the treatment areas than other light sources so

there will be less distance to diminish the intensity

required. This accounts for more energy saving.

5. Their relatively narrow emission spectrum of LED systems can be optimally tuned so as to correspond

to the treatment requirement and thus eliminates

wavelengths not needed for the therapy. As a result,

the irradiation time required for treatment is much

shorter than with incoherent light sources. The

studies reviewed in this paper indicate that LEDs have opened up new prospects as an effective light

source of phototherapy and medical treatment

These manufacturers may also develop new patent

technology to produce new products that can boost the LED

industry. All these lead to lower LED costs and more LED

varieties. Therefore, LED based applications, along with

phototherapy, are setting out for a superior outlook in the

years to come as LED becomes more qualified to replace its

more energy demanding counterparts.

LED is safe, non-thermal, non-toxic and non-invasive, and

to date, no side effects have been reported in published

literature. Caution must be emphasized especially for

epileptic and photophobic patients especially if LEDs are pulsed.

On the basis of sound photobiology principles, scientific and

clinical studies conducted so far have shown promising

results. The application of LEDs has ushered in a new and exciting era in phototherapy, and offers a versatile and

inexpensive therapeutic modality either as a standalone

therapy or in combination with reactive drug compounds.

Phototherapy, whether using low intensity radiation of the

proper wavelength from a laser, an LED, or a filtered

incandescent lamp, can be beneficial in a number of clinical

situations, from pain remission to wound healing.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

Unfortunately, the absence of this type of phototherapy from

the mainstream of medicine makes it currently unavailable

to many patients who would benefit from it.

Phototherapy has been found to accelerate wound healing

and reduce pain, possibly by stimulating oxidative

phosphorylation in mitochondria and modulating

inflammatory responses. By influencing the biological

function of a variety of cell types, it is able to exert a range

of several beneficial effects upon inflammation and healing.

Phototherapy exerts marked effects upon cells in all phases

on wound healing, but particularly so during the

proliferative phase. There is good evidence that the

enhanced cell metabolic functions seen after phototherapy

are the result of activation of photoreceptors within the

electron transport chain of mitochondria. The effect is

specific for wavelength, and cannot be gained efficiently

with normal, non-coherent, non-polarized light sources, such

as LEDs.

7.0 Future Work

Andrei Sommer et al used 670 nm to improve the uptake of

chemotherapeutic drugs into human cancer cells in vitro.

Light increases cell volume by absorption of IR in

membrane, this increase in volume makes the cells breathe in surrounding water. Traditional chemotherapeutic drugs rely on drugs entering cells by diffusing across the bilayer

lipid structure of the cell membrane. The drawback to this

process is that its relatively slow. This new process is a potentially powerful delivery system for chemotherapy

drugs that can pull chemotherapy drugs into a cell faster than

they would normally penetrate.

Future research should focus on investigating specific cell

signalling pathways involved to better understand the

mechanisms at play, search for cellular activation threshold

of targeted chromophores, as well as study its effectiveness

in treating a variety of cutaneous problems as a stand-alone

application and/or complementary treatment modality or as

one of the best PDT light source.

8.0 References

1. Mester, E.; Mester, A. F.; Mester, A. Lasers Surg. Med. 1985, 5, 31. 2. Wollman, Y.; Rochkind, S. Neurol. Res. 1998, 20, 470.

3. Karu TI. Photobiology of low-power laser effects. Hlth Phys

1989:56:691-704. 4. Karu TI. Photobiology of low-power laser therapy. London: Harwood

Academic Publishers. 1989.

5. Yu W, Naim JO, Lanzafame RJ. Effects of photostimulation on wound healing in diabetic mice. Lasers Surg Med 1997:20:5663. 6. Barolet D, Light-Emitting Diodes (LEDs) in Dermatology

7. Photobiomodulation on the Angiogenesis of Skin Wounds in Rats Using Different Light Sources

8. Osanai T, Shiroto C, Mikami Y (1990) Measurement of Ga ALA diode

laser action on phagocytic activity of human neutrophils as a possible therapeutic dosimetry determinant. Laser Th er 2:123134 9. Dima VF, Suzuko K, Liu Q (1997) Eff ects of GaALAs diode laser on

serum opsonic activity assessed by neutrophil-associated

chemiluminescence. Laser Th er 9:153158 10. Ash C, Effect of Wavelength and Beam Width on Penetration in Light-

Tissue Interaction using Computational Methods, Laser Europe 2013, Manchester UK

11. Ash C, Effect of Wavelength and Beam Width on Penetration in Light-

Tissue Interaction using Computational Methods, Laser Europe 2013, Manchester UK

12. Laakso EL, Richardson CR, Cramond T. Factors affecting low level

laser therapy. Aust J Physio 1993:39:95-99. 13. Conlan, MJ., Rapley, J.W., and Cobb, C.M. (1996). Biostimulation of

wound healing by low-energy laser irradiation. J. Clin. Periodont. 23, 492496. 14. Beauvoit, B., Kitai, T., and Chance, B. (1994). Correlation between the

light scattering and the mitochondrial content of normal tissues and

transplantable rodent tumors. Biophys. 67, 25012510. 15. Beauvoit, B., Evans, S.M., Jenkins, T.W., Miller, E.E., and Chance B.

(1995). Contribution of the mitochondrial compartment to the optical

properties of the rat liver: a theoretical and practical approach. Anal. Biochem. 226, 167174. 16. Karukonda S, Corcoran Flynn T, Boh E, McBurney E, Russo G,

Millikan L (2000) The effects of drugs on wound healing: part 1. Int J Dermatol 39:250257 17. BRANDON J. ERDLE, Effects of Continuous-Wave (670-nm) Red

Light on Wound Healing Dermatol Surg 2008;34:320325 18. Desmet

19. Trelles and Allone Combined Nonablative Skin Rejuvenation with the

595m and 1450-nm Lasers 20 Manteifel V, Bakeeva L, Karu T. Ultrastructural changes in chondriome

of human lymphocytes after irradiation with He-Ne laser: Appearance of

giant mitochondria. J Photochem Photobiol B. 1997;38:25- 30. 21. Bolton P, Young S, Dyson M. Macrophage responsiveness to light

therapy: A dose response study. Laser Ther. 1990;2:101-106. 22. Funk JO, Kruse A, Kirchner H. Cytokine production after heliumneon

laser irradiation in cultures of human peripheral blood mononuclear cells. J

Photochem Photobiol B. 1992;16:347-355. 23. Yu HS, Chang KL, Yu CL, et al. Low-energy helium-neon laser

irradiation stimulates interleukin-1 alpha and interleukin-8 release from

cultured human keratinocytes. J Invest Dermatol. 1996;107:593-596. 24. Leyden JJ. Acne vulgaris is a multifactorial disease. J Am Acad

Dermatol 2003;49 (3 Suppl):S199.

25. Charakida A, Seaton ED, Charakida M, et al. Phototherapy in the treatment of acne vulgaris: What is its role? Am J Clin Dermatol

2004;5:211216. 26. Melo TB. Uptake of protoporphyrin and violet light photodestruction of Propionibacterium acnes. Z Naturforch C 1987; 42: 1238.

27. McGinley KJ, Webster GF, Leyden JJ. Facial follicular porphyrin

fluorescence. Correlation with age and density of Propionibacterium acnes. Br J Dermatol 1980; 102: 43741.

28. Papageorgiou P, Katasambas A, Chu A. Phototherapy with blue (415

nm) and red (660 nm) light in the treatment of acne vulgaris. Br J Dermatol. 2000;142:973 978. 29. Ash C, Home Use Efficacy and Safety Study for Mild to Moderate Acne

using High Intensity 414nm Solid State Diode Arrays, Laser Europe 2013, Manchester UK

30. A Reasonable Mechanism for Visible Light Induced Skin Rejuvenation

- Rachel Lubart et al 31. Trelles and Allone Combined Nonablative Skin Rejuvenation with the

595nm and 1450nm Lasers

32. Sinha RP, Hder DP. UV-induced DNA damage and repair: A review. Photochem Photobiol Sci. 2002;1:225-236.


Dr Caerwyn Ash

euroLED 2013

Birmingham NEC

33. Calles C, Schneider M, Macaluso F, et al. Infrared A radiation

influences the skin fibroblast transcriptome: Mechanisms and consequences. J Invest Dermatol. 2010;130:1524-1536.

34. Schroeder P, Calles C, Benesova T, et al. Photoprotection beyond

ultraviolet radiationEffective sun protection has to include protection against infrared A radiation-induced skin damage. Skin Pharmacol Physiol.

2010;23:15-17.

35. Kimura E, Kawano Y, Todo H, et al. Measurement of skin permeation/ penetration of nanoparticles for their safety evaluation. Biol Pharm Bull.

2012;35:1476-1486.

36. Barolet D, Boucher A. LED photoprevention: Reduced MED response following multiple LED exposures. Lasers Surg Med. 2008;40:106-112.

37. Krutmann J, Schroeder P. Role of mitochondria in photoaging of human

skin: The defective powerhouse model. J Investig Dermatol Symp Proc. 2009;14:44-49.

38. Schroeder P, Calles C, Benesova T, et al. Photoprotection beyond

ultraviolet radiationEffective sun protection has to include protection against infrared A radiation-induced skin damage. Skin Pharmacol Physiol.

2010;23:15-17.

39. Menezes S, coulomb B, Lebreton C, et al. Non-coherent near infrared radiation protects normal human dermal fibroblasts from solar ultraviolet

toxicity. J Invest Dermatol. 1998;111:629-633.

40. Frank S, Oliver L, Lebreton-De Coster C, et al. Infrared radiation affects the mitochondrial pathway of apoptosis in human fibroblasts. J Invest

Dermatol. 2004;123:823-831. 41. Applegate LA, Scaletta C, Panizzon R, et al. Induction of the putative

protective protein ferritin by infrared radiation: Implications in skin repair.

Int J Mol Med. 2000;5:247-251. 42. Yu HS, Wu CS, Yu CL, et al. Helium-neon laser irradiation stimulates

migration and proliferation in melanocytes and induces repigmentation in

segmental-type vitiligo. J Invest Dermatol. 2003;120:56-64. 43. Yaar M, Grossman K, Eller M, et al. Evidence for nerve growth factor

mediated paracrine effects in human epidermis. J Cell Biol. 1991;115: 821-

828.

44. Zhai S, Yaar M, Doyle SM, et al. Nerve growth factor rescues pigment

cells from ultraviolet-induced apoptosis by upregulating BCL-2 levels. Exp

Cell Res. 1996;224:335-343. 45. Effect of visible lightwaves on arthritis pain: A controlled study.

McDonald, Sharon F. International Journal of Biosocial Research, Vol

3(2), 1982, 49-54. 46. Krutmann J, Hnigsmann H, Elmets CA, et al: Dermatological

Phototherapy and Photodiagnostic Methods. New York, Springer, 2001

47. Morita A, Werfel T, Stege H, et al: Evidence that singlet oxygen-induced human T helper cell apoptosis is the basic mechanism of

ultraviolet-A radiation phototherapy. J Exp Med 17:1763-1768, 1997

48. Kramer M, Sachsenmaier C, Herrlich P, et al: UV irradiation-induced interleukin-1 and basic fibroblast growth factor synthesis and release

mediate part of the UV response. J Biol Chem 268:6734-6741, 1993

49. de Paula Eduardo C, Bezinelli LM, de Paula Eduardo F, et al. Prevention of recurrent herpes labialis outbreaks through low-intensity laser

therapy: A clinical protocol with 3-year follow-up. Lasers Med Sci.

2012;27:1077-1083. 50. Krner R, Bahmer F, Wigand R. The effect of infrared laser rays on

herpes simplex virus and the functions of human immunocompetent cells.

Hautarzt. 1989;40:350-354. 51. Inoue K, Nishioka J, Hukuda S. Altered lymphocyte proliferation by

low dosage laser irradiation. Clin Exp Rheumatol. 1989;7:521-523.

52. Yu W, Chi LH, Naim JO, et al. Improvement of host response to sepsis by photobiomodulation. Lasers Surg Med. 1997;21:262-268.

53. Schindl L, Schindl M, Polo L, et al. Effects of low power laser-

irradiation on differential blood count and body temperature in endotoxinpreimmunized rabbits. Life Sci. 1997;60:1669-1677.

54. Manteifel V, Bakeeva L, Karu T. Ultrastructural changes in chondriome

of human lymphocytes after irradiation with He-Ne laser: Appearance of giant mitochondria. J Photochem Photobiol B. 1997;38:25- 30.

55. Bolton P, Young S, Dyson M. Macrophage responsiveness to light

therapy: A dose response study. Laser Ther. 1990;2:101-106. 56. Funk JO, Kruse A, Kirchner H. Cytokine production after helium neon

laser irradiation in cultures of human peripheral blood mononuclear cells. J

Photochem Photobiol B. 1992;16:347-355. 57. Yu HS, Chang KL, Yu CL, et al. Low-energy helium-neon laser

irradiation stimulates interleukin-1 alpha and interleukin-8 release from

cultured human keratinocytes. J Invest Dermatol. 1996;107:593-596. 58. Ash C, Town G, Clement M, Bjerring P, Kiernan M, Optimum Choice

of Irradiation Wavelength for Skin Colour Determination using Skin Reflectance Measurements. Presented at 31th Annual Conference,

American Society for Laser Medicine and Surgery Dallas, Texas, USA.

2011

59. Ash C, Town G, Bjerring P, Evaluation of a Commercial Fitzpatrick

Skin Type Classification Device and the Correlation Between Fitzpatrick Skin Type and Skin Colour, Abstract O.46. Presented at Laser Europe 2010

Congress, La Pineda, Taragonna, Spain, 2010.

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