ISSN 2473-4799
DERMATOLOGY
Open Journal
PUBLISHERS
Review
Photobiomodulation in Cells’ Repair
Yvona Zivic, HP, PgDp1,2*
1
Health Practitioner, Phototherapy, Naturopathic and Hair Clinician, Sorbonne Université, Paris, France
Cosmetic Medicine, University of South Wales, United Kingdom
2
*
Corresponding author
Yvona Zivic, HP, PgDp
Health Practitioner, Phototherapy, Naturopathic and Hair Clinician, Sorbonne Université, Paris, France; E-mail:
[email protected]
Article information
Received: June 18th, 2019; Revised: May 14th, 2020; Accepted: June 1st, 2020; Published: June 2nd, 2020
Cite this article
Zivic Y. Photobiomodulation in cells’ repair. Dermatol Open J. 2020; 5(1): 12-25. doi: 10.17140/DRMTOJ-5-141
ABSTRACT
Photobiomodulation is a non-invasive treatment modality acting at different biological levels through the non-thermal transfer
of photons to the living matter via a photoelectric effect, inducing photochemical reactions in treated cells. The objective of
this article is to review the literature on Photobiomodulation, its different fields of application and mechanisms of action, for
establishing a comprehensive summary of evidence. The search strategy initially run searches in scientific databases MEDLINE,
PubMed, EMBASE and Cochrane registries from 1990 up to March 2020, with entries Photobiomodulation, LLLT-LEDT, PDT,
Photobiology, Cytochrome c Oxidase. Selection criteria was based on preferably inclusion of randomized clinical trials (RCTs),
systematic reviews (SR) and studies providing qualitative and quantitative data with the best consistency, in a field where heterogeneity of light parameters is often a difficulty to comparison of findings. Publised expert opinions were also considered. A total
of 80 publications were reviewed out of a thousand obtained from databases, among which were retained 9 RCTs, 6 systematic
reviews, 3 meta-analysis and 2 case-reports. Differences were found in treatment parameters as wavelength, dosage, energy output,
treatment length, performances of light-sources, quantity of diodes and single power of these, which may explain the paucity
of high-level body of evidence in Cochrane databases. However, numerous state-of-the- art researches are also found, led by
dedicated research teams paving the way to standardized methods of evaluation and comprehension of light-biological-tissues
interaction and optimization of outcomes in a promising field.
Keywords
PhotoBioModulation; Low-Level-Laser-Therapy (LLLT); Light emitting diodes (LED); Biophotons-mitochondria;
Adenosine-triphosphate (ATP); Inflammation-pain-skin rejuvenation; Photo dynamic therapy (PDT); Photobiology.
INTRODUCTION
hotobiomodulation (PBM) is defined as the use of low-level-lasers or light-emitting-diodes (LED) of low-intensity and
non-ionizing radiation, emitting visible light from 400 nm to 700
nm and near-infrared (NIR) from 700 nm to 1100 nm in the electromagnetic spectrum, aiming at a biostimulation of exposed tissues.1,2 PBM has mostly been studied for pain reduction, mitigation
of inflammation and stimulation of wound healing. In the settings
of a dermatological or aesthetic medicine practice, PBM has also
demonstrated to be a useful tool, assisting practitioners to better address adverse events and recovery time in the aftermath of
surgical and non-surgical procedures. Potential side-effects of any
intervention, even when minor and temporary, remain anxiogenic
for both patient and practitioner, when they can be significantly
improved with PBM. These therapeutic effects of photonic en-
P
ergy have been applied since the beginning of humanity with the
use of sunlight, as a photomedicine, for the treatment of a variety
of diseases and skin disorders.3 With the progress of sciences and
technologies, a more comprehensive understanding of the nature
of light, its interaction with matter and particularly with biological tissues, improving wound healing, was achieved.4 The decoding of the mechanisms of action of PBM, revealed the role of
the cytochrome-c-oxidase as photo-acceptor (CCO) but also the
importance of interfacial water layers (IWL) interacting with photons and participating in adenosine-triphosphate (ATP) upregulation.5,6 National Aeronautics and Space Administration (NASA),
US Navy and UK military, with their own therapeutic experiments
in the 1990s, demonstrated faster recovery post-injuries, enhanced
wound healing, angiogenesis and cytoprotection.7,8 Since three
decades, research has demonstrated the efficacy, tolerability and
high safety profile of low-level-light-therapies—light-emitting-
cc Copyright 2020 by Zivic Y. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows
to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited.
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diodes-therapies (LLLT-LEDT), alone or in combined protocols,
in numerous domains which will be reviewed, as dermatology,
rheumatology, sports medicine, gynecology, dentistry, oncology
and infectiology.9 Supporting tissues to self-repair, energizing cells’
metabolism for a faster return to homeostasis, this non-invasive,
non-ablative, biostimulative therapy has also shown that cohesion
was not an absolute requirement for PBM, introducing the labelling of LLLT.10
THE NATURE OF LIGHT
Light
Light is a periodic phenomenon, characterized by its frequency (ν)
defined into Hertz (Hz), periodicity (T) and wavelength (λ) measured by meter and nanometer (nm) and, the interplay between
these parameters participating in the manifestation of light.11 The
contact between light and matter generates interaction. Light is
absorbed, reflected, deviated or emitted by matter. Absorption
occurs when matter retains light without emitting it back, usually
transforming light energy into thermal energy; scattering when
light is absorbed and re-emitted; reflection when light bounces
back on a planar surface with a straightforward, predictable trajectory or multiple trajectories on uneven surface; deviation or refraction when light crosses different propagation mediums and,
emission when excited atoms land back from higher orbital levels
to their basal level producing radiation in quantifiable emission or
luminescence in the visible or non-visible spectrum.4,12 Additional
properties of the electromagnetic waves are polarization and interference. Hence, light is a wave constituted of a herd of particles or
photons behaving wave-like, defined also as light quanta.13 Light is
carried into waves comprising perpendicular electric and magnetic
fields in motion and superposition. Although extremely fast, the
speed of light (c) is not infinite, it is considered a universal constant: c=299,792 458 m/s in vacuum, with differences according
to the medium it travels.14
to 1 millimeter and frequency beneath 400 THz (Figure 1). The
sources, as lasers, emitting light with a sole wavelength and optical frequency are monochromatic, whereas sources emitting with
more than one wavelength and frequency are polychromatic, as is
the sun.15
Interaction Light and Matter
Light interacts with matter by phenomena of absorption, scattering, reflection or refraction. When applied to biological tissues,
rays of light constituted of trillions of photons will interact in regard to the optical qualities of the recipient. This communication
is the response of biological tissues. The settings and parameters
of all light-devices appreciate this response of biological tissues
to the light stimuli for optimizing their therapeutic effects. PBM
focuses on light absorption by biological tissues, interplay between
the photon and its target, also called chromophore or receptor,
capturing the energy of light.16
COHERENCE VS NON-COHERENCE
Distinct Interactions
In 1917, Einstein initiated the concept of monochromatic light
in which all photons were to be aligned in a row, leading to the
creation of the first laser source in 1960 and later the development
of non-coherent light-sources too (Figure 2).2,17 Two technologies
appeared: the high frequency thermal lasers, applying to targeted
chromophores a higher energy than their repairing capacity and,
the low frequency non-thermal LLLT or LEDs-sources, applying
to chromophores energy levels optimizing cells’ repairing capacities18 Photobiomodulation was born.
Figure 2. Effects of Coherent 632,8 nm Red Light (A) and Non-coherent
633 nm Red Light (B) on the Integration of Thymidine Radio-marked in
Culture of Cells: Coherence is Not Essential to Biostimulation, Karu et al18
Light Spectrum
The various radiations of the electromagnetic spectrum are differentiated according to their wavelength.1 A smaller segment of
this field is observed when white light passes through a prism and
refracts separated colored components, known as the light spectrum, constituted of a range from 400 nm to 700 nm of different
wavelengths of light visible to the human eye. Infrared (IR) corresponds to wavelengths above the 700 nm nominal edge of red up
Figure 1. The Segment of Visible Light in the Electromagnetic Spectrum
Light interacts with human multi-layered and heterogeneous biological tissues through an array of mechanisms. Depending on the thermal or non-thermal character of light-tissue interaction, the effects induced are either photophysical, photochemical
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or photobiomodulative.18-20
Lasers
The thermal effects of coherent lasers characterized by their
monochromaticity and single wavelength, produce, depending on
the degree and duration of the heating of tissues, either hyperthermia (41-44°), coagulation (50-100°), vaporization (100°) or the
melting of tissues (above 300°), thoroughly described by Ansari et
al.4 These thermal modifications, also influenced by the distribution of temperature in targeted tissues, result into different applications from dermatological surgery, ophthalmology, odontology,
gynecology, gastroenterology, arthroscopy with the use of endoscopes, angioplasty and radiological monitoring.4
Low-Level-Light and LED
The non-thermal effects of LLLT and LEDs are related to the
biophysiological properties of wavelengths, defined as the distance
between two consecutive peaks, the chromophore they target and
their depth of penetration. Mester et al9 demonstrated in 1973 in
a study on murines, that He-Neon laser emitting in red 632,8nm
had visible effects on cytochromes, accelerating wound healing,
evidenced by following studies.11 NASA experimented the influence of light on astronauts’ metabolism, weakened in space in the
absence of gravity, evidencing improved wound healing post minor injuries7 and leading to the equippement of its spaceships with
LED panels.8
Low Level Lasers are non-thermal lasers, known as soft
lasers, emitting a coherent, monochromatic polarized light penetrating deeply into tissues, ranging from 400nm to 800nm and
900nm to 940nm for Near-Infrared (NIR).2 As a comparison,
the Helium Neon laser (He-Neon), emitting red at 632nm, has a
power output between 1 and 25 milliwatts, whereas the Nd:YAG
(neodymium-doped yttrium aluminum garnet) laser, used in cataract surgery, delivers up to 10 watts. Low-Level-Lasers have a significant lower power output requiring longer treatment sessions,
ranging in minutes rather than seconds yet, energizing tissues they
penetrate rather than cutting or burning them.20
Light emitting diodes (LEDs) are electroluminescent
diodes producing narrow-band light through the motion of electrons in high-efficiency semi-conducting materials as germanium
(Ge) or gallium (Ga) resulting into a specific colored component
or wavelength of red (633 nm), yellow (590 nm), blue (415 nm)
and their combinations in the visible spectrum. Therapeutic LEDs
(247 nm-1300 nm) are non-coherent, monochromatic lights, transferred to tissues for absorption through a photoelectric effect in a
non-thermal fashion.19,21,22 The infrared wavelengths are absorbed
by cell membranes inducing photophysical reactions.21,23 Up to
date, the therapeutic properties are evidenced for a portion of this
scale, although research in luminotherapy is found back to the 19th
century when Finsen (1903) demonstrated that red light increases
the metabolic level of cells’ mitochondria.3 His intensive research
on the activity of red light on smallpox and measles, published
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ology and led to the establishment of the first sanatoriums across
Europe treating tuberculosis with sunlight.3 Since then, the therapeutic capacities of light have been studied in many fields of medicine. A multi-center research initiated by the Institute of Cellular
and Integrative Neurosciences in Strasbourg, France, led by Tsai
et al (CNRS)24 studied the role of the photopigments melanopsin, encoded by OPN4 gene, on sleep control patterns in humans.
Light reaching human eye transmits to the brain two types of information, a visual one analyzed by retinal rods and cones photoreceptors and, a non-image-forming one regulated by melanopsin
able to detect the intensity and quality of the light emission.24 Haltaufderhyde et al25 demonstrated that photons absorbed through
opsins are converted into a cellular response by phototransduction. The authors observed in cell culture that OPN1-SW, OPN2,
OPN3 and OPN5 were also expressed at epidermal level in melanocytes and keratinocytes.25 In cultured primary human epidermal
melanocytes (HEMs) and primary human keratinocytes (KERs),
the authors found opsin receptors, suggesting that they may function as epidermal photoreceptors, which is of interest when considering the application of PBM to the skin (Figure 3).25
Figure 3. Thermal and Non-thermal Photo-effects of Lasers and LEDs
MECHANISMS OF ACTION
The Mitochondrial Respiratory Chain
Cellular respiration is achieved via the glycolysis and the citric acid
cycles, producing the essential energy-carrier adenosine triphosphate (ATP).26 An additional pathway also generates ATP via the
respiratory electron transport chain and its redox reactions during
the aerobic glucose catabolism.26 Karu et al5 demonstrated that the
mitochondrial protein cytochrome c oxidase (CCO), a terminal enzyme in this mitochondrial respiration in charge of molecular oxygen reduction and ultimately ATP synthesis, was a photo-active acceptor. This major finding enlightened how much communication
between the extra-cellular matrix and other cells was fundamental
for cells’ integrity, growth and differentiation.27 By catching the
stimuli of light through the CCO enzyme, cells respond through
a signaling pathway, matching together as key and keyhole.5,22 In
vegetable kingdom, this transformation of light,or photosynthesis, into photochemical energy triggering biochemical modifications is a process well-documented.28 Karu et al18 demonstrated,
while evaluating the effects of wavelengths in the optical band
570 nm-650 nm on deoxyribonucleic acid (DNA) and ribonucleic
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acid (RNA,) that light coherence was not an absolute necessity for
igniting a biostimulative activity. The authors showed that similar results can be achieved with non-coherent LED-sources.18 The
mitochondria within cells is receptive to visible light, inducing a
photochemical response via the CCO or a photophysical response
when stimulated by NIR (Figure 2).23,29 This photoactivation is also
related to the redox-sensitive status of the photoreceptor: damaged cells with lower redox potential are more sensitive to light
stimuli.23 In many studies, the repairing and rejuvenating outcomes
obtained with LEDT are related to the mitochondria, the CCO
and the ATP upregulation,10 as well as the synthesis in the cytosol
of the nicotinamide adenine dinucleotide reduced form (NADH).6
The use of appropriate wavelengths, pulsed wave (PW) or continuous wave (CW) modes generated a different impact on the reduction of free radicals, a higher tissues stimulation was observed with
pulsed modes in specific contexts. This was also described by Barol
et al30 in a case-control study on limited cutaneous systemic sclerosis where significant improvement of osteo-articular symptoms
severity was reported in cases treated with (PW) mode at 940nm
LLLT, while the augmentation of microcirculation and catabolism
may also have participated in the in situ calcinosis and overall functional improvement.30 Better and faster wound healing with (PW)
was also reported with 810 nm diode laser at 10 Hz, evidencing a
significant decrease of inflammation, increase of cellular proliferation, epithelization, neovascularization, enhanced CCO and ATP
performance.31
The benefits of LLLT-LEDs could be comprehended as
a mitochondrial therapy, care and micronutrition, mitochondrial
protection from dysfunction, oxidative stress and molecular degradation and, a photo prophylaxis too.26,32,33
Adenosine Triphosphate Production
Adenosine triphosphate production represents the core energy
supply to cellular activity, an inner currency for cells’ exchanges
synthesized under aerobic conditions in the mitochondria, the
organelles containing the respiratory electron transport chain. As
seen above, CCO being the end enzyme of the electron transport
chain, it combines oxygen and NADH for hydrogen ions synthesis.6 The hydrogen ions once increased in number, diffuse out of
the matrix space, participating into the phosphorylation of adenosine diphosphate (ADP) into ATP.34 However, this respiration
is compromised when mitochondria start generating nitric oxide
(NO), binding to the CCO in place of oxygen, resulting into less
ATP and more oxidative stress and, potentially more inflammation. He et al34 described that PBM helps recover the binding of
CCO with oxygen inducing quantifiable changes in the mitochondrial membrane potential (MMP) and in the ATP content. Therefore, the primary mechanism of action of PBM takes place within
the mitochondria, the CCO absorbing the emitted light and water
achieving less density, more fluidity.5,34 A resonance takes place between cells and light wavelengths, inducing metabolic processes of
repair and regeneration. It is now established that at DNA level,
cells emit biophotons, which may explain their affinity with light.34
The interest of LLLT and LEDT lies in this capacity to increase
MMP and ATP synthesis in various types of cells, protecting them
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from oxidative stress, modulating reactive oxygen species (ROS)
production, in a dose-dependent way.10 More recently, Sommer6
suggested that the causal relation between CCO, as a primary
photo-acceptor, and the extra-ATP synthesis was not necessarily
the only hypothesis in red-to-NIR (R-NIR) exposure. The author
evaluated that two more aspects have to be considered in the ATP
synthesis: the mitochondrial inner membrane and the role of the
CCO in reducing molecular oxygen to water. For Sommers, the interaction light-tissues between photons and interfacial water layers
(IWL) was causal to ATP upregulation in R-NIR therapies (Figure
4).6
Figure 4. Schematic Representation of a Mitochondrion
Dosing the Stimulation
Dosimetry is to phototherapy what dosage is to medicine; it depends of the anciency, the depth and the surface of the target. It
also depends of the physiological or pathological condition of the
tissues. Karu et al5,35 described that PBM induces a higher stimulation in weaker, stressed or damaged cells, up to the maximum of
their biological activity. As is the case for all energy-based therapies, setting the parameters acknowledging this dose-response is
primordial for optimizing patient-centered outcomes.35 Biostimulation and cellular effects are modulated by critical parameters: the
power density or irradiance or intensity measured in mW/cm2, the
energy density or fluence, dose or radiant exposure measured in J/
cm2 and the treatment/irradiation time in seconds.36 Biostimulation is supported by an equation between intensity, surface, total
irradiation time and energy density, if not, the result is absence
of biostimulation. A similar rule was reported with lasers: under
4 mW, no biological effect was observed, whatever the irradiation
time.37 A physiological response can be initiated with a minimal irradiance. On the contrary, a too long exposure with low irradiance
will not induce the expected physiological effect, while a too long
exposure with too high irradiance may inhibit PBM benefits or
lead to cells’ exhaustion. The World Association for Laster Therapy (WALT) has provided dosage recommendations in LLLT.38
Treatment frequency, intervals between sessions and correct coverage of the treatment target are also parameters to be considered
as light can be reflected, refracted or scattered depending on the
treated tissues.4,12 The relationship between these parameters is
usually adopted with the equation described by Jagdeo et al.29
Power density (W/cm2)×time (seconds)=fluence (J/cm2)
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Dosing the stimulation is particularly of prime essence in
photo dynamic therapy (PDT) where irradiance source, total light
dose and power output in milliwatt, are game changers in treatment protocols and performance.38,39
FIELDS OF APPLICATION
Cells respond to the biostimulation of light during and post PBM,
through cellular and molecular mechanisms seen above, particularly with oxygen re-binding with CCO, enhancing cellular respiration and augmentation of ATP synthesis. Restoring the respiratory
electron transport chain is essential in the context of inflammatory reactions as an impaired cells’ repiration, when NO is also increased and competing with oxygen, endangers the innate immune
system and homeostasis.29,34
Dermatology
Non-coherent wavelengths of LLLT-LED-sources applied in
PBM target chromophores as the CCO or the endogenous protoporphyrin, as a monotherapy for skin conditions and diseases
or associated to systemic or topical therapies. These light-sources
have a modulating action on the intrinsic cellular activity, either inhibiting or stimulating it and a biphasic dose-dependent response,
demonstrated in wound healing and mitigation of inflammation.40
The applications in dermatology are vast and thoroughly studied
by authors as Pelletier.41 Recently, Jagdeo et al39 performed a systematic review of 31 RCTs studying dermatological conditions
treated with LED-PBM. According to criteria of the Oxford Centre for Evidence-based Medicine-Levels of Evidence,42 the authors
attributed a grade B of recommendation for the Food and Drug
Administration (FDA)-approved treatment of Acne vulgaris, Herpes complex and zoster and, a grade C of recommendation for
skin rejuvenation with LED-PBM. Non-FDA-cleared LED procedures were attributed a grade B of recommendation for the treatment of acute wound healing, grade C for psoriasis and grade D
for atopic dermatitis, chronic wound healing, oral mucositis and
radiation dermatitis.39
Dermatological conditions are characterized by the suffering of cells depleted from the energy necessary for self-repair.
It is particularly the case in the healing of wounds and ischemic tissues lacking trophicity, ulcers or compressed nerves. PBM may be
comprehended as an energy supplementation improving DNA and
RNA synthesis, as well as cells’ adhesion. Wound healing is maybe
the most widely spread application of PBM in dermatology, its
effects having been demonstrated at all stages of the healing process.7-9,43,44 A normal wound healing undergoes three distinct phases. At first inflammatory signs in tissues, secretions from lymph
and blood vessels, followed by coagulation by thrombokinases activation and fibrin production start the exudation and detersion
phase of wound healing. Increased capillary permeability brings
antibodies, leucocytes and macrophages towards the wounded
area.45 Stimulated fibroblasts generate from approximatively Day 4
a muco-polysaccharides matrix for collagen fibers synthesis necessary in the gradual restoration of the wound from the inside out. In
this proliferative phase, neo-angiogenesis assures nutrition to growing tissues. Approximatively from Day 6, myofibroblasts contract
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to progressively close the wound borders; less irrigated, granulation tissues become tighter and ultimately form scar tissues in this
differentiation phase which will stop with the re-epithelialization
by migration of epidermal cells at wound surface.45 Studies have
also shown that PBM improves post-operative wound healing at
the first stages.46 NASA7,8 experimental studies monitoring injuries
in spaceships reported wound healing improved by 50% in cases
receiving LED treatments compared to those not treated. Similarly,
the Naval Special Warfare (Norfolk, USA)7 evaluated wound healing in the conditions of submarines where there is no light, lower
oxygen and higher CO2 levels, concluding in 50% improvement
of muscularskeletal injuries in cases treated with LLLT-LEDs 670
nm, 720 nm and 880 nm. Accelerated healing of burn injuries and
systemic effect of PBM were also observed on mice models.43 In
a preliminary study Min et al44 evaluated the faster healing of ischemic wounds and recalcitrant diabetic ulcers, reporting increased
fibroblasts proliferation, growth factors synthesis, collagen production and angiogenesis. without neoplastic transformation, tissues’ growth stops once the wound is healed. The treatment of
ophthalmic herpes zoster with PBM was evaluated by Park et al47 in
a pilot study on 28 individuals all receiving antiviral agents and half
receiving 830 nm LED-PBM additionally. The authors concluded
in significantly faster healing and lower mean visual analogue scale
(VAS) scores in the group who received LED-therapy compared
to control groups. Kleinpenning et al48 evaluated the treatment of
inflammatory skin diseases as psoriasis and atopic dermatitis in a
double-blind, randomized comparative study between red and blue
wavelengths activity targeting the endogenous photosensitizer protoporphyrin IX. Clinical improvement of psoriasis erythematous
plaques was observed in both groups yet, was significantly higher
with blue light therapy.48 Comprehensive studies have also evaluated the treatment of acne with blue-red therapies, particularly
with pulsed wavelengths.49,50 Tsoukas et al51 described the activity
of red light in inflammatory processes of acne modulating cytokine release from macrophages while blue light, once absorbed at
a peak of 415 nm by the natural porphyrins secreted by Propionibacterium acnes colonizing sebaceous glands, was releasing singlet
oxygen and ROS with significant bactericidal action.52-54 With the
emergence of bacterial resistance to antibiotics, blue-red therapy is
estimated a safe and efficient tool for treating inflamed lesions in
mild to moderate acne.49 Many studies have also demonstrated the
accelerated healing of edema, erythema and inflammation postsurgical and non-surgical aesthetic procedures as intense pulsed
light (IPL) and fractional lasers.55,56
The stimulation of the mitochondria has also substantial effects on the aging process, increasing collagen production
and decreasing collagenase activity. Boisnic et al57 observed in a
hospital-setting study the repairing action of LEDs on connective
tissues, directly stimulating the metabolic activity of dermal fibroblasts, inducting new dermal papilla, with synthesis of endogenous
collagen and elastin. Fouque-Parachini et al58 demonstrated in an in
vivo study assessed by vivascope confocal microscopy, the benefits
of a LED-source (Triwings®, Biophoton) on skin rejuvenation at
epidermal and basal layers, improving lentigos and stimulating neocollagenesis. The authors findings demonstrated cells’ membranes
repolarization, modification of the free-water/bound-water ratio,
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improvement of microcirculation, emergence and increase of vascularized dermal papillae count and, tissular hydration resulting in
an overall rejuvenation of the skin. The authors also observed decrease and homogenization of melanin in treated areas.58
Barolet59 and Weiss et al60 described a photo prophylaxis
role of LLLT-LED therapies in prevention of post-inflammatory
hyperpigmentation, solar lentigines and ultraviolet (UV)-induced
erythema, concomitant to proper use of broad-spectrum sun care.
In a prospective, randomized, placebo-controlled, double-blinded,
split-face clinical study Lee et al61 evaluated with histologic, ultrastructural, profilometric and biochemical analysis the effects of
633 nm and 830 nm LEDT on skin rejuvenation. Their findings
demonstrated significant reduction of wrinkles, activation of fibroblasts and increase of collagen and elastin, also observed in a
study of Calderhead et al.23
Another major application of monochromatic lights in
dermatology is the treatment with photo dynamic therapy (PDT)
of non-melanoma skin cancer (NMSC) and cancerization fields,
particularly superficial basal cell carcinoma (sBCC) and in-situ
squamous cell carcinoma (in-SCC) not exceeding 2 mm thickness
according to the international guidelines.62 The therapeutic fundaments of topical PDT for NMSC imply a photosensitizer-precursor of protoporphyrin IX (PpIX), light in the absorption spectrum of the photosensitizer and oxygen.63 More recently, Alam64
described the conversion of lipophilic methyl-aminolevulinate
(MAL) or 5-aminolevulinic acid (5-ALA) into photoactive porphyrins at lesion site once exposed to light at 37 J/cm2, as advised by
the industry leader.65 MAL-PDT is reported for good neoplastic
cells selectivity, tissue penetration and intracellular PpIX accumulation in a diffuse uptake fashion. PDT induces a type II photooxidation generating ROS affecting cells’ membranes, improving
dermic echogenicity and reducing lesional vascularization.66 PDT
is also applied to non-malignant skin diseases and pre-cancerous
lesions, experiments are proposed with lower-irradiance red wavelengths for lessening the pain in actinic keratosis67 and for treating
acne and infections.53,54,68 Researchers are also working on the incorporation of light for PDT in a novel fabric.69
Since paradoxical hair growth has been observed postlaser and IPL-assisted hair reduction, researchers investigated the
use of light to promote hair growth.70 Trelles et al71 first described
in 1984 hair re-growth in alopecia areata cases treated with an
HeNe laser at 632,8 nm and 4 J/cm2 weekly, while daily application
resulted in cells’ exhaustion and hair thinning, evidencing the biphasic dose-dependent response in PBM.40 The authors described
hair shafts showing increased keratin number in medulla at microscopic analysis.71 In a systematic review of LLLT at R-NIR 635 nm
and 810 nm in adult androgenic alopecia, the authors described
that the upregulation of ATP production may reverse bulbs miniaturization and maintain hair follicles longer in their anagen phase.72
In a double-blinded randomized controlled trial (RCT), Lanzafame et al73 evaluated the efficacy and safety of 655 nm LLLT-LED
vs placebo in 47 females with androgenic alopecia. Their findings
showed a change in hair count over baseline of 100.3-53.4 (N=24)
(p<0.0001) in the treated cases group and a percentage of hair in-
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creased by 11.05-48.30 (N=18) in placebo controls while 48.0717.61 (N=24) (p<0.001) in the treated cases, with an overall hair
growth over the study time increased by 37% in the treatment
group.73 The stimulative activity of LLLT-LED on epidermal stem
cells in hair follicle bulges when applied at 90 mW/cm2 R-NIR is
estimated to down regulate inflammatory mediators and to shift
hair follicles into the anagen phase, enhancing also hair tensile
strength and scalp health.74 In another recent study, Buscone et al75
provided evidence that OPN2 and OPN3 are expressed in human
hair follicle and interact with blue light at 453 nm resulting in hair
growth ex vivo. Further research is required in this application, with
well-controlled studies. However, LLLT-LED therapies for male
and female androgenic alopecia are FDA-approved since 2007 on a
safety basis, they may also represent a promising prospective solution for other forms of non-cicatricial alopecia.76
Body contouring with the application of LLLT as a
non-invasive modality has also been evaluated in a retrospective
study entailing 689 individuals, concluding in significant mean circumferential reduction recorded at different measurement points
with 3.27 in. (p<0,0001) and overall mean reduction of 5.17 in.
(p<0,0001) not related to fluid loss, demonstrating adipocytes’
apoptosis and influence of LLLT on systemic lipid metabolism.77
Rheumatology,Traumatology and Sports Therapies
PBM for the management of acute and chronic pains has been
thoroughly evidenced since decades in scientific literature.78 Efficacy, tolerability and safety of treatments require appropriate
wavelengths in the optical window between 633 nm and 905 nm in
R-NIR and appropriate intensity on elected anatomical site. Beneficial treatment of musculoskeletal pains, orthopedic injuries and
post-surgical conditions, in humans and animals, is largely reported
in literature.78-82
Particularly, Konstantinović et al83 in a double-blind, randomized, placebo-controlled study on 60 individuals with acute
neck pain with radiculopathy treated with 905 nm LLLT, demonstrated statistically significant pain reduction on VAS measurement
in cases against controls (p=0.003, accounting high effect size
d=0.92). The mechanism of action of PBM in pain control entails
the anti-inflammatory activity of R-NIR wavelengths decreasing
also edema, the blockade of the nociceptor transfer along A and
C fibers and the mitigation of neurotransmitters.78 Overall good
reduction of pain induced by masseter muscle fatigue and tinnitus
condition have also been reported,84 making PBM a cost-effective
and evidence-based therapeutic modality in chronic and acute pain.
In sports medicine, PBM for the treatment of injuryrelated pain has demonstrated significant reduction of all-pain, enhanced tissues’ repair and faster recovery, by improvement of inflammation, micro-circulation and tissues’ oxygenation85,86 PBM in
tendinopathy, golfer or tennis elbow and injuries influencing knee
or wrist mobility and ankle stability, impacting the return-to-play
of athletes has demonstrated significant results.87 Additionally, by
increasing mitochondrial respiration and ATP production mediated by MMP at muscle levels, PBM is considered a preventive
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measure for muscle conditioning prior to physical performance,
in men and women.88,89 In a systematic review with meta-analysis,
Leal-Junior et al,87 evaluated 12 RCTs in which LLL-LED therapies
where applied in the course of exercise with 50 to 200 mW, 5J
per spot. Findings demonstrated significant improvement of athletes’ performance up by 5.47 (95 % CI 2.35-8.59, p<0.0006) and
increase of time until exhaustion up by 4.12 (95 % CI 1.21-7.02,
p<0.005) against placebo. The authors reported that the improvement of muscle metabolism was dose-dependent and they evaluated a time-response of 3-6 h,87 confirmed in other studies.10,40
PBM is an evidence-based therapeutic option for optimizing the
return-to-play of athletes.87
Neurology
Hamblin90 first reviewed the interest of transcranial-photobiomodulation (t-PBM) in brain disorders, including trauma, degenerative diseases and psychiatric disorders and, the existing evidence
on light applied to the prefrontal cortex. The global aging of the
population and the augmentation of lifespan may involve higher
occurrence rates of neurodegenerative diseases as dementia, Alzheimer or Parkinson, burdening public health policies. Hamblin90
also initiated a current of thoughts for future hypothesis of research on t-PBM, focusing on neurodevelopmental disorders as
autism and depression and, how attention bias and ischemia risk
can be improved. The question of light penetration to the cerebral
cortex has been addressed by many researchers, the debate being
still on in regard of optimal light-source, laser or non-coherent
LED, wavelength range and power density for achieving the best
biological effects.91,92 The outcomes observed in these studies have
enlightened significant improvement of cognitive function in individuals with long-standing traumatic brain injury, which unfortunately, faded away once treatment was stopped. Furthermore,
Gordon et al93 have discussed that the effects of PBM were not
restricted to the sole area illuminated and that a remote, indirect
benefit is to be explored in the future. The interest of t-PBM on
healthy individuals as a cognitive capacity improvement light-therapy, enhancing capacity to stay focused, is also in the pipeline of
research.90,94
A few authors have described a mood-enhancement and
regulation of sleep patterns effect following PBM, it is known
that pro-inflammatory cytokines participate to mood disorders.
In a recent review, Askalsky et al95 consider that t-PBM in range
of 808-835 nm NIR at higher powers outputs could be a novel
neuromodulating strategy for major depressive disorders (MDD).
In previous research, the mechanism of action of t-PBM was estimated to stimulate the respiratory chain and ATP production at
the mitochondrion as well as the regional blood circulation.96 Current knowledge stimulates further research, evidencing if coherent
lights are mandatory or if non-coherent lights can be a more practical and cost-effective alternative. Also, demonstrating if (PW)
mode would be superior to (CW) mode as anti-depressor application of t-PBM.90,95
Bensadoun et al102 have also thoroughly described the relieving effects of PBM in mucositis reduction. A research followed
in 2017 by a clinical trial for establishing a treatment protocol reducing chemo and radio-induced oral mucositis in children applied
LLLT-LED 635 nm (Oncolase) every other day at doses of 4 J/
cm2 in a sweeping fashion in cheeks, tongue dorsum, lateral and
belly, palate, superior and inferior gums.103 The findings demonstrated significant reduction in recovery time, in pain and inflammation associated to the condition and no aggravation towards a
higher grade of mucositis.103 Improvement of quality of life was
also assessed with the recovery of chew and swallow capacity.
Gynecology
The gynecological internal applications of lasers originated from
applications in cancerology as described above and from applications in odontology as will be reviewed below.
PBM in gynecology can be applied with LED or laser
sources, internally and externally according to the indication, for
alleviating inflammation, sanitizing the tissues, enhancing the healing of gynecological and obstetrical wounds,104 improving functional disorders of the vulvar-vaginal and uro-genital regions105
and, decreasing low-grade inflammation and endometriosis-related
pelvic pain.106 PBM alone or combined to other therapies is reported in the treatment of genital cutaneous diseases as lichen, herpes
or eczema.107 Lanzafame et al108 recently discussed the application of PBM for relieving genitourinary syndrome in menopausal
women, concluding in high efficacy and tolerability of this option.
Morphological and physiological changes occurring in menopausal
women, particularly with the decrease of intra-mucous microcirculation leading to vaginal dryness, lack of trophicity, atrophy and
irritation are syndromes well-treated with PBM with intravaginal
probes and external light-exposure. Red and NIR have showed
interesting effect by stimulating collagen production109 and angiogenesis.110
Dentistry
Oncology
Photo dynamic therapy has a strongly evidenced background in
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the treatment of superficial skin cancers but has also limitations
in the capacity of light to penetrate tissues deeply, depending on
the elected photosensitizers and in-situ dosimetry.97 Expanding this
therapeutic modality from superficial to deep-seated diseases and
malignant tumors has raised interest in research in the past years.
Scientific reflections have focused on different light-sources for
exciting a mono-photosensitizer, two-photon photosensitizers or
conjugated with nanosystems for achieving synergetic action.98,99
Research evolves towards a NIR-activated PDT allowing deeper
tissues penetration with longer wavelengths and less off-targeting
or normal tissues damaging.98 This interstitial PDT challenges
scientists with barriers to overcome as the non-homogeneity and
three dimensions (3D) shape particular to solid tumors.100 Clinical
translation requires this new modality to be approved and light and
photosensitizers parameters to be consolidated in well-designed
trials before expanding treatment options.101
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The LLLT-LEDT have been reported since three decades in Rus18
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sian111 and Japanese112 scientific literature in fields of dentistry and
oral diseases, for hard and soft tissues, triggering biochemical exchanges for the healing of wounds in the oral cavity, the reduction
of pain with endorphins‘release, the enhancement of bone and
nerves repair after oral surgery.113 In a systematic review Shukla
et al114 analyzed findings of 13 studies in which LLLT-LED was
applied in temporomandibular (TMD) or craniomandibular disorders. The reduction of pain in individuals suffering from TMD
was effective in the majority of these studies, with the hypothesis proposed of modulation of inflammation at the TMD joint
capsule.115 However, the discrepancies in trials standards call further research for consensus on light dosage. PDT with toluidine
blue patch has also been described as a useful tool for disrupting
the adherence of bacterial biofilms at root canal.116,117 As seen in
previous chapter Dermatology, the stimulative action of PBM on
fibroblasts was mainly evidenced with cultured dermal fibroblasts
yet, it is estimated that similar analgesic, anti-inflammatory and regenerative effects on buccal and gingival fibroblasts is possible in
reason of their close response profile. PBM is a relevant option for
optimizing wound healing, alleviating pain, as trigeminal neuralgia
or in TMD and repairing tissues by biostimulation.118
Infectiology
We have seen in the treatment of acne and cutaneous superficial or
deep-seated malignant lesions, the antibacterial and anticarcinoma
activity triggered by PDT with ROS and singlet oxygen generation.52-54
Another field of application of the antimicrobial effect
of visible violet-blue light at 405-470 nm has been researched for
the decontamination of hospitals and healthcare premises.68,119 Disinfection policies for risk control of hospital-acquired infections
are a major public health concern, aggravating with antimicrobial
resistance.120 Therefore, PDT has been explored as an alternative
solution with demonstrated efficacy on bacteria and fungi but also
on viruses.121,122 Gram-positive, sensible to major photosensitizers,
respond to anionic types, while Gram-negative bacteria to cationic
photosensitizer.123 Viruses also have shown sensitivity to PDT, according to their nucleic acid and capsid type, whereas fungi require
higher doses of light and photosensitizer.124,125 The photodisinfection of environmental surfaces with blue light is also of interest
in clinical practice for sanitizing and reducing the risk of pathogens proliferation, in adjunction of asepsis rules, by application of
LEDs on facial and body areas immediately after aesthetic procedures, when not contraindicated.126
Addressing the field of photobiomodulation, the blue
light hazards shall be mentioned. Blue wavelengths are shorter yet,
intense, while retinal tissues are rich in chromophores. The retinal
mitochondria are susceptible to potential photochemical damage
in case of prolonged and unprotected exposure,127 which implies
proper knowledge and training of healthcare professionals for
adopting preventive measures against this public concern.
Interest of Photobiomodulation in Acute Pulmonary Disorder
trum demonstrated substantial antimicrobial activity and capacity
to inactivate certain viruses. This could possibly be of interest in
the fight for jugulating pandemics, a fortiori in viruses having host
pathways replicating in humans.128
Photobiomodulation has also a potential role in the prevention of respiratory complications in coronavirus disease-2019
(COVID-19) pandemic through its capacity to modulate the inflammatory response in individuals. A recent review of Enwemeka
et al129 evaluated the evidence-based data on the effects of PBM
concluding that light-therapies at 660 nm may alleviate pulmonary
inflammation, down regulate pro-inflammatory and pro-fibrotic
cytokines, reduce collagen deposits in murine lungs and improve
airways edema.130,131 Furthermore, a protective role on cardiomyocytes from hypoxia with R-NIR wavelengths has also been demonstrated supporting that PBM, when individuals are in need for
extra mitochondrial ATP, may play an important role, improving
also cutaneous manifestations.132
Finally, in the prevention of infectious diseases, the respect of individual’s microbiome is a principle now largely integrated and, the interaction light-microbiome recently researched
by Libert et al133 may have a natural role for maintaining individual’s
integrity towards a better health.
CONCLUSION
The efficacy of PBM is not always easy to understand, particularly
when the outcomes of this therapy have sometimes a certain latency. However, PBM and more specifically LEDT may be considered
as an homeopathic counterpart, assisting aesthetic interventions,
inducing a regeneration, rejuvenation and foremost, a repair at organelles, cells and organs levels with a dynamic flux of biophotons.134 A better understanding of the life of underlying tissues,
their interplay with light and the mechanisms of action of PBM at
cellular level will enable clinicians to define parameters optimizing
benefits of light therapies. There is also the necessity for rigorous
methodology, randomized controlled clinical trials enabling further research to achieve higher statistical power and overpass any
further controversy in a very promising therapeutic modality with
arrays of indications, deeply revolutionizing healing concepts and
healthcare professions.
FUNDING
This work has not received any financial support. The author was
alone involved in writing and editing this article.
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