Reference Heading List by Clinical Area
Note: References were compiled from published literature. Readers are advised to verify all citations and DOIs independently via PubMed or relevant journal databases prior to clinical or academic use. DOIs are not available for publications predating widespread digital indexing (generally pre-1997).
History of Photobiomodulation
The field of PBM originated in the late 1960s with the pioneering work of Hungarian physician Endre Mester, who observed stimulatory effects of ruby laser irradiation on hair regrowth and wound healing in mice. Over subsequent decades, the discipline evolved from ‘biostimulation’ to ‘low-level laser therapy’ (LLLT) and ultimately to the consensus terminology ‘photobiomodulation therapy’ (PBMT), adopted by the World Association for Laser Therapy (WALT) and the American Society for Laser Medicine and Surgery (ASLMS) in 2014.
Abstract:
This paper briefly reviews the authors’ experimental and clinical use of lasers over a 20-year period, during which laser effects on 15 biological systems were studied. Low-energy laser radiation was found to have a stimulating effect on cells, and high-energy radiation had an inhibiting effect. The application of lasers to stimulate wound healing in cases of nonhealing ulcers is recommended.
Abstract:
Quantitative studies of the action of low-power visible monochromatic light on various cells (E. coli, yeasts, HeLa) were performed to find irradiation conditions (wavelength, dose, intensity) conducive to vital activity stimulation. The action spectra of visible light on DNA and RNA synthesis in HeLa cells have maxima near 404, 620, 680, 760, and 830 nm. Growth simulation of E. coli is at a maximum when irradiated at 404, 454, 570, 620, and 750 nm, and biomass accumulation stimulation in yeasts has a maxima at 404, 570, 620, 680, and 760 nm. Absorption of quanta is only a trigger for the rearrangement of cellular metabolism, with photosignal transduction being effected by standard cellular means such as changes in the cAMP level. Respiratory chain components are discussed as primary photoacceptors. It is concluded that «laser biostimulation» is of a photobiological nature, and low-power laser effects can be related to well-known photobiological phenomena.
Description:
This editorial argues for the adoption of “photobiomodulation therapy” as the preferred terminology for the therapeutic use of non-thermal light in medicine. The authors explain that earlier terms such as low-level laser therapy, cold laser, soft laser, photobiostimulation, and laser biostimulation created inconsistency and confusion within both the scientific literature and clinical practice. Although low-level laser therapy had become a widely used and searchable MeSH term, it was considered imprecise because “low-level” lacks a clear scientific definition and “laser” no longer reflects the full range of light sources used, including LEDs and broadband light. Following a terminology consensus meeting held in 2014 under the North American Association for Light Therapy and the World Association for Laser Therapy, photobiomodulation therapy was proposed as a more accurate and scientifically grounded term. The article emphasizes that PBMT involves non-ionizing light sources in the visible and infrared spectrum, acts through endogenous chromophores, and produces photophysical and photochemical effects rather than thermal tissue heating. These effects may contribute to pain reduction, inflammation control, immunomodulation, wound healing, and tissue regeneration. The authors conclude that universal use of the term photobiomodulation therapy would improve clarity, distinguish the field from other forms of phototherapy, support better organization of research, and strengthen acceptance of this therapeutic approach in mainstream medicine.
Abstract:
The use of low levels of visible or near infrared light for reducing pain, inflammation and edema, promoting healing of wounds, deeper tissues and nerves, and preventing cell death and tissue damage has been known for over forty years since the invention of lasers. Despite many reports of positive findings from experiments conducted in vitro, in animal models and in randomized controlled clinical trials, LLLT remains controversial in mainstream medicine. The biochemical mechanisms underlying the positive effects are incompletely understood, and the complexity of rationally choosing amongst a large number of illumination parameters such as wavelength, fluence, power density, pulse structure and treatment timing has led to the publication of a number of negative studies as well as many positive ones. A biphasic dose response has been frequently observed where low levels of light have a much better effect on stimulating and repairing tissues than higher levels of light. The so-called Arndt-Schulz curve is frequently used to describe this biphasic dose response. This review will cover the molecular and cellular mechanisms in LLLT, and describe some of our recent results in vitro and in vivo that provide scientific explanations for this biphasic dose response.
Description:
This editorial describes the transition from the term low-level laser therapy (LLLT) to photobiomodulation therapy (PBMT) and explains why the name change better reflects the scientific and clinical development of the field. Originally discovered by Endre Mester in 1967, LLLT emerged from observations that low-power laser irradiation could stimulate hair growth and improve wound healing without relying on thermal tissue destruction. Over time, research demonstrated that coherent laser light was not essential for these biological effects, as non-coherent light-emitting diodes with comparable parameters could produce similar outcomes. The term “low-level” was also considered imprecise, and the field increasingly recognized that both stimulation and inhibition of biological processes could be therapeutically useful. As a result, the terminology shifted toward photobiomodulation, emphasizing the modulation of biological activity by light rather than the use of a specific device type. The editorial also highlights the growing scientific credibility of PBM, driven by improved understanding of mechanisms such as cytochrome c oxidase activation, mitochondrial signaling, reactive oxygen species, and downstream cellular responses. Hamblin further outlines the expanding range of PBM research, including wound healing, inflammation, oral mucositis, diabetes-related complications, traumatic brain injury, muscle performance, and other emerging clinical applications. Overall, the article presents PBM as a maturing biomedical field moving beyond earlier skepticism toward broader scientific and clinical recognition.
Abstract:
Objectives: Low level light/laser therapy (LLLT) is the direct application of light to stimulate cell responses (photobiomodulation) in order to promote tissue healing, reduce inflammation and induce analgesia. There have been significant studies demonstrating its application and efficacy at many sites within the body and for treatment of a range of musculoskeletal injuries, degenerative diseases and dysfunction, however, its use on oral tissues has, to date, been limited. The purpose of this review is to consider the potential for LLLT in dental and oral applications by providing background information on its mechanism of action and delivery parameters and by drawing parallels with its treatment use in analogous cells and tissues from other sites of the body.
Methods: A literature search on Medline was performed on laser and light treatments in a range of dental/orofacial applications from 2010 to March 2013. The search results were filtered for LLLT relevance. The clinical papers were then arranged to eight broad dental/orofacial categories and reviewed.
Results: The initial search returned 2778 results, when filtered this was reduced to 153. 41 were review papers or editorials, 65 clinical and 47 laboratory studies. Of all the publications, 130 reported a positive effect in terms of pain relief, fast healing or other improvement in symptoms or appearance and 23 reported inconclusive or negative outcomes. Direct application of light as a therapeutic intervention within the oral cavity (rather than photodynamic therapies, which utilize photosensitizing solutions) has thus far received minimal attention. Data from the limited studies that have been performed which relate to the oral cavity indicate that LLLT may be a reliable, safe and novel approach to treating a range of oral and dental disorders and in particular for those which there is an unmet clinical need.
Significance: The potential benefits of LLLT that have been demonstrated in many healthcare fields and include improved healing, reduced inflammation and pain control, which suggest considerable potential for its use in oral tissues.
Keywords: Dental therapy; Low-level laser therapy; Oral disease; Photobiomodulation; Phototherapy.
Description:
This article outlines the historical origins of photobiomodulation through the pioneering work of Endre Mester, M.D. (1903–1984), widely recognized as the “Father of Photobiomodulation.” Following the invention of the laser in 1960 and early medical experiments with ruby lasers, Mester began investigating the biological effects of low-power laser irradiation in the 1960s. Although his initial interest was cancer treatment, his experiments demonstrated that repeated low-power laser exposure did not produce carcinogenic effects in skin. Instead, Mester observed unexpected biological stimulation, including accelerated hair growth in shaved mice and improved wound healing. These findings provided early evidence of a dose-dependent biphasic response, where low-power irradiation produced stimulatory effects while higher doses could inhibit biological activity. Mester later translated these findings into clinical practice, successfully treating difficult-healing skin and mucosal ulcers beginning in 1971. His work demonstrated that low-power laser irradiation could influence inflammation, microcirculation, fibroblast activity, immune responses, and tissue repair. With more than 100 published articles, Mester’s research established the foundation for modern photobiomodulation and opened the field to broader clinical applications in wound healing, pain modulation, inflammation, and emerging neurological and psychiatric indications.
Abstract:
In Russia (formerly USSR) study of biomodulation action (BMA) mechanisms of low-intensity laser irradiation (LILI) began in 1964, immediately after the development of lasers. During the period from 1965 to 1972 several dozens of scientific conferences were held, hundreds of studies were published. Generally, secondary mechanisms and results of LILI effect on patients with various diseases were studied. This data was immediately implemented into practical medicine in the fields of oncology, surgery, dermatology and dentistry, and since 1974 low level laser therapy (LLLT) is included in the standard of state medical care. For 50 years no less than 1000 books were published (monographs, collections, methodical and clinical materials), thousands of researches were carried out. Primary mechanism and patterns of interaction of LILI with acceptors within cells can be represented in the following order: absorption of photon’s energy – emergence of a local temperature gradient – release of Ca2+ from intracellular stores – stimulating Ca2+-dependent processes. Understanding of this process allowed the explanation of all known secondary effects, optimized methods and extremely increased effectiveness of LLLT. Owing to the knowledge of BMA mechanisms of LILI, numerous associated and combined LLLT techniques were developed and are widely used nowadays: locally, on the projection of internal organs, laser acupuncture, reflexology, intracavitary, transdermal and intravenous laser blood illumination, magnetic-laser therapy, laser phoresis, laser-vacuum massage, biomodulation, etc. About 400 000 laser therapeutic devices are used in Russian practical healthcare. Unique, having no analogues in the world devices, are produced – red pulsed laser diodes (wavelength 635 nm, power 5-40 W, pulse duration 100 ns, frequency 10 000 Hz) are designed specially for effective laser therapy.
Keywords: Laser biomodulation; Low-level laser therapy; Mechanisms and methods; Russia.
Mechanism of Action
PBM acts through absorption of photons by endogenous chromophores. The primary intracellular photoreceptor is cytochrome c oxidase (Complex IV of the mitochondrial respiratory chain), which absorbs red and near-infrared (NIR) light. Photon absorption leads to increased mitochondrial membrane potential, enhanced ATP synthesis, transient generation of reactive oxygen species (ROS), nitric oxide (NO) release, and downstream activation of transcription factors including NF-kB, AP-1, and Nrf2. Secondary effects include modulation of inflammatory mediators, increased cell proliferation, and activation of growth factor pathways.
Abstract:
Cytochrome c oxidase is discussed as a possible photoacceptor when cells are irradiated with monochromatic red to near-IR radiation. Four primary action mechanisms are reviewed: changes in the redox properties of the respiratory chain components following photoexcitation of their electronic states, generation of singlet oxygen, localized transient heating of absorbing chromophores, and increased superoxide anion production with subsequent increase in concentration of the product of its dismutation, H2O2. A cascade of reactions connected with alteration in cellular homeostasis parameters (pHi, [Cai], cAMP, Eh, [ATP] and some others) is considered as a photosignal transduction and amplification chain in a cell (secondary mechanisms).
Abstract:
Soon after the discovery of lasers in the 1960s it was realized that laser therapy had the potential to improve wound healing and reduce pain, inflammation and swelling. In recent years the field sometimes known as photobiomodulation has broadened to include light-emitting diodes and other light sources, and the range of wavelengths used now includes many in the red and near infrared. The term «low level laser therapy» or LLLT has become widely recognized and implies the existence of the biphasic dose response or the Arndt-Schulz curve. This review will cover the mechanisms of action of LLLT at a cellular and at a tissular level and will summarize the various light sources and principles of dosimetry that are employed in clinical practice. The range of diseases, injuries, and conditions that can be benefited by LLLT will be summarized with an emphasis on those that have reported randomized controlled clinical trials. Serious life-threatening diseases such as stroke, heart attack, spinal cord injury, and traumatic brain injury may soon be amenable to LLLT therapy.
Abstract:
Photobiomodulation (PBM) also known as low-level laser (or light) therapy (LLLT), has been known for almost 50 years but still has not gained widespread acceptance, largely due to uncertainty about the molecular, cellular, and tissular mechanisms of action. However, in recent years, much knowledge has been gained in this area, which will be summarized in this review. One of the most important chromophores is cytochrome c oxidase (unit IV in the mitochondrial respiratory chain), which contains both heme and copper centers and absorbs light into the near-infra-red region. The leading hypothesis is that the photons dissociate inhibitory nitric oxide from the enzyme, leading to an increase in electron transport, mitochondrial membrane potential and ATP production. Another hypothesis concerns light-sensitive ion channels that can be activated allowing calcium to enter the cell. After the initial photon absorption events, numerous signaling pathways are activated via reactive oxygen species, cyclic AMP, NO and Ca2+, leading to activation of transcription factors. These transcription factors can lead to increased expression of genes related to protein synthesis, cell migration and proliferation, anti-inflammatory signaling, anti-apoptotic proteins, antioxidant enzymes. Stem cells and progenitor cells appear to be particularly susceptible to LLLT.
Keywords: Cytochrome c oxidase; Light sensitive ion channels; Low Level Light Therapy; Mechanism; Mitochondria; Photobiomodulation.
Abstract:
Photobiomodulation (PBM) also known as low-level level laser therapy is the use of red and near-infrared light to stimulate healing, relieve pain, and reduce inflammation. The primary chromophores have been identified as cytochrome c oxidase in mitochondria, and calcium ion channels (possibly mediated by light absorption by opsins). Secondary effects of photon absorption include increases in ATP, a brief burst of reactive oxygen species, an increase in nitric oxide, and modulation of calcium levels. Tertiary effects include activation of a wide range of transcription factors leading to improved cell survival, increased proliferation and migration, and new protein synthesis. There is a pronounced biphasic dose response whereby low levels of light have stimulating effects, while high levels of light have inhibitory effects. It has been found that PBM can produce ROS in normal cells, but when used in oxidatively stressed cells or in animal models of disease, ROS levels are lowered. PBM is able to up-regulate anti-oxidant defenses and reduce oxidative stress. It was shown that PBM can activate NF-kB in normal quiescent cells, however in activated inflammatory cells, inflammatory markers were decreased. One of the most reproducible effects of PBM is an overall reduction in inflammation, which is particularly important for disorders of the joints, traumatic injuries, lung disorders, and in the brain. PBM has been shown to reduce markers of M1 phenotype in activated macrophages. Many reports have shown reductions in reactive nitrogen species and prostaglandins in various animal models. PBM can reduce inflammation in the brain, abdominal fat, wounds, lungs, spinal cord.
Keywords: animal studies; chromophores; clinical trials; inflammation; low-level laser therapy; photobiomodulation.
Abstract:
Mitochondrial signaling is an information channel between the mitochondrial respiratory chain and the nucleus for the transduction signals regarding the functional state of the mitochondria. The present review examines the question whether radiation of visible and near-IR (IR-A) radiation can activate this retrograde-type cellular signaling pathway. Experimental data about modulation of elements of mitochondrial retrograde signaling by the irradiation (mitochondrial membrane potential DeltaPsi(m), reactive oxygen species ROS, Ca(2+), NO, pH(i), fission-fusion homeostasis of mitochondria) are reviewed. The terminal enzyme of the mitochondrial respiratory chain cytochrome c oxidase is considered as the photoacceptor. Functions of cytochrome c oxidase as a signal generator as well as a signal transducer in irradiated cells are outlined.
Abstract:
Currently, light therapies are widely used in both human and veterinarian medicine. The application of light to clinical therapeutics includes: photodynamic therapy, used to kill cancer cells; UVA therapies, used to treat a variety of skin diseases; and photobiomodulation, used to promote cell growth and recovery from injury. Photobiomodu-lation uses light emitting diodes (LEDs) or low energy lasers, which emit light in the visible red to near infrared range. Light in this range penetrates tissue reasonably well, lacks the carcinogenic/mutagenic properties of UV light, and acts on an endogenous photoreceptor which likely acts to initiate light-altered signaling pathways. Although early studies identified mitochondrial cytochrome c oxidase as an endogenous photoreceptor for photobiomodulation, the cellular and molecular mechanisms underlying photobiomodulation have not been clear. Three recent findings provide important new insight. First, nitric oxide has been implicated. Second, cytochrome c oxidase, an enzyme known to reduce oxygen to water at the end of the mitochondrial respiratory chain, has been shown to have a new enzymatic activity–the reduction of nitrite to nitric oxide. This nitrite reductase activity is elevated under hypoxic conditions but also occurs under normoxia. And third, low intensity light enhances nitric oxide synthesis by cytochrome c oxidase without altering its ability to reduce oxygen. From these findings, we propose that cytochrome c oxidase functions in photobiomodulation by producing nitric oxide, a signaling molecule which can then function in both intra- and extracellular signaling pathways. We also propose that the effectiveness of photobiomodulation is under the control of tissue oxygen and nitrite levels.
Abstract:
The purpose of this study is to explore the possibilities for the application of laser therapy in medicine and dentistry by analyzing lasers’ underlying mechanism of action on different cells, with a special focus on stem cells and mechanisms of repair. The interest in the application of laser therapy in medicine and dentistry has remarkably increased in the last decade. There are different types of lasers available and their usage is well defined by different parameters, such as: wavelength, energy density, power output, and duration of radiation. Laser irradiation can induce a photobiomodulatory (PBM) effect on cells and tissues, contributing to a directed modulation of cell behaviors, enhancing the processes of tissue repair. Photobiomodulation (PBM), also known as low-level laser therapy (LLLT), can induce cell proliferation and enhance stem cell differentiation. Laser therapy is a non-invasive method that contributes to pain relief and reduces inflammation, parallel to the enhanced healing and tissue repair processes. The application of these properties was employed and observed in the treatment of various diseases and conditions, such as diabetes, brain injury, spinal cord damage, dermatological conditions, oral irritation, and in different areas of dentistry.
Keywords: laser; low-level laser therapy; photobiomodulation; stem cells; tissue regeneration.
Abstract:
Photobiomodulation (PBM) involves the use of red or near-infrared light at low power densities to produce a beneficial effect on cells or tissues. PBM therapy is used to reduce pain, inflammation, edema, and to regenerate damaged tissues such as wounds, bones, and tendons. The primary site of light absorption in mammalian cells has been identified as the mitochondria and, more specifically, cytochrome c oxidase (CCO). It is hypothesized that inhibitory nitric oxide can be dissociated from CCO, thus restoring electron transport and increasing mitochondrial membrane potential. Another mechanism involves activation of light or heat-gated ion channels. This review will cover the redox signaling that occurs in PBM and examine the difference between healthy and stressed cells, where PBM can have apparently opposite effects. PBM has a marked effect on stem cells, and this is proposed to operate via mitochondrial redox signaling. PBM can act as a preconditioning regimen and can interact with exercise on muscles.
Abstract:
Photobiomodulation (PBM) therapy, a non-thermal light therapy using nonionizing light sources, has shown therapeutic potential across diverse biological processes, including aging and age-associated diseases. In 2023, scientists from the National Institute on Aging (NIA) Intramural and Extramural programs convened a workshop on the topic of PBM to discuss various proposed mechanisms of PBM action, including the stimulation of mitochondrial cytochrome C oxidase, modulation of cell membrane transporters and receptors, and the activation of transforming growth factor-β1. They also reviewed potential therapeutic applications of PBM across a range of conditions, including cardiovascular disease, retinal disease, Parkinson’s disease, and cognitive impairment. Workshop participants largely agreed that PBM holds immense potential as a safe and effective therapeutic approach for a wide range of age-related diseases and cognitive decline. While further research is needed to fully elucidate its mechanisms and optimize treatment protocols, the findings presented at the NIA workshop provide strong evidence for the continued investigation and clinical translation of this promising, inexpensive, safe technology, to aging and age-associated diseases. Here, we review the research presented and discussion held at the meeting. In addition, the text has been updated, where applicable, with recent research findings that have been made since the meeting occurred.
Keywords: Aging and age-associated diseases; Mitochondrial cytochrome C oxidase (CcO); Near-infrared (NIR) Light; Neuroprotection; Non-ionizing light therapy; Non-thermal light therapy; Photobiomodulation therapy; Therapeutic applications of light; Transforming growth factor-β1 (TGF-β1).
Abstract:
Photobiomodulation (PBM) is a procedure that uses light to modulate cellular functions and biological processes. Over the past decades, PBM has gained considerable attention for its potential in various medical applications due to its non-invasive nature and minimal side effects. We conducted a narrative review including articles about photobiomodulation, LED light therapy or low-level laser therapy and their applications on dermatology published over the last 6 years, encompassing research studies, clinical trials, and technological developments. This review highlights the mechanisms of action underlying PBM, including the interaction with cellular chromophores and the activation of intracellular signaling pathways. The evidence from clinical trials and experimental studies to evaluate the efficacy of PBM in clinical practice is summarized with a special emphasis on dermatology. Furthermore, advancements in PBM technology, such as novel light sources and treatment protocols, are discussed in the context of optimizing therapeutic outcomes and improving patient care. This narrative review underscores the promising role of PBM as a non-invasive therapeutic approach with broad clinical applicability. Despite the need for further research to develop standard protocols, PBM holds great potential for addressing a wide range of medical conditions and enhancing patient outcomes in modern healthcare practice.
Keywords: LED; dermatology; laser; photobiomodulation; photodynamic therapy.
Abstract:
Background: Low level light therapy (LLLT) has attracted attention in many clinical fields with a new generation of light-emitting diodes (LEDs) which can irradiate large targets. To pain control, the first main application of LLLT, have been added LED-LLLT in the accelerated healing of wounds, both traumatic and iatrogenic, inflammatory acne and the patient-driven application of skin rejuvenation. Rationale and Applications: The rationale behind LED-LLLT is underpinned by the reported efficacy of LED-LLLT at a cellular and subcellular level, particularly for the 633 nm and 830 nm wavelengths, and evidence for this is presented. Improved blood flow and neovascularization are associated with 830 nm. A large variety of cytokines, chemokines and macromolecules can be induced by LED phototherapy. Among the clinical applications, non-healing wounds can be healed through restoring the collagenesis/collagenase imbalance in such examples, and ‘normal’ wounds heal faster and better. Pain, including postoperative pain, postoperative edema and many types of inflammation can be significantly reduced. Experimental and clinical evidence: Some personal examples of evidence are offered by the first author, including controlled animal models demonstrating the systemic effect of 830 nm LED-LLLT on wound healing and on induced inflammation. Human patients are presented to illustrate the efficacy of LED phototherapy on treatment-resistant inflammatory disorders.
Conclusions: Provided an LED phototherapy system has the correct wavelength for the target cells, delivers an appropriate power density and an adequate energy density, then it will be at least partly, if not significantly, effective. The use of LED-LLLT as an adjunct to conventional surgical or nonsurgical indications is an even more exciting prospect. LED-LLLT is here to stay.
Keywords: Grotthus-Draper law; acne rosacea; dissecting cellulitis; irritant contact dermatitis; nonhealing wound; photochemical cascade; photophysical reaction.
Abstract:
Despite a significant focus on the photochemical and photoelectrical mechanisms underlying photobiomodulation (PBM), its complex functions are yet to be fully elucidated. To date, there has been limited attention to the photophysical aspects of PBM. One effect of photobiomodulation relates to the non-visual phototransduction pathway, which involves mechanotransduction and modulation to cytoskeletal structures, biophotonic signaling, and micro-oscillatory cellular interactions. Herein, we propose a number of mechanisms of PBM that do not depend on cytochrome c oxidase. These include the photophysical aspects of PBM and the interactions with biophotons and mechanotransductive processes. These hypotheses are contingent on the effect of light on ion channels and the cytoskeleton, the production of biophotons, and the properties of light and biological molecules. Specifically, the processes we review are supported by the resonant recognition model (RRM). This previous research demonstrated that protein micro-oscillations act as a signature of their function that can be activated by resonant wavelengths of light. We extend this work by exploring the local oscillatory interactions of proteins and light because they may affect global body circuits and could explain the observed effect of PBM on neuro-cortical electroencephalogram (EEG) oscillations. In particular, since dysrhythmic gamma oscillations are associated with neurodegenerative diseases and pain syndromes, including migraine with aura and fibromyalgia, we suggest that transcranial PBM should target diseases where patients are affected by impaired neural oscillations and aberrant brain wave patterns. This review also highlights examples of disorders potentially treatable with precise wavelengths of light by mimicking protein activity in other tissues, such as the liver, with, for example, Crigler-Najjar syndrome and conditions involving the dysregulation of the cytoskeleton. PBM as a novel therapeutic modality may thus behave as «precision medicine» for the treatment of various neurological diseases and other morbidities. The perspectives presented herein offer a new understanding of the photophysical effects of PBM, which is important when considering the relevance of PBM therapy (PBMt) in clinical applications, including the treatment of diseases and the optimization of health outcomes and performance.
Keywords: mechanotransduction; oscillations; photobiomodulation; photophysical; precision medicine; resonant recognition model.
Description:
This guest editorial examines whether photobiomodulation therapy can be considered cost-effective within modern healthcare systems. Tunér notes that, by the end of 2019, more than 400 randomized placebo-controlled studies on PBM were listed on PubMed, yet questions remain due to variation across medical conditions and inconsistent reporting of treatment parameters. The article argues that policymakers are increasingly interested in nonpharmacological therapies, particularly because of the side effects and costs associated with commonly prescribed pharmaceuticals, but that clinical evidence alone may not be sufficient without economic data. The editorial highlights studies in oncology care showing meaningful cost reductions when PBM was used to prevent or reduce oral mucositis, including reduced costs in patients undergoing hematopoietic stem cell transplantation and in head and neck cancer patients receiving chemoradiation. Tunér also discusses the potential role of PBM in hard-to-heal wounds, especially among elderly and homebound patients, where preliminary Swedish data suggested reduced staff, transportation, and material costs, along with improved ulcer healing. The article emphasizes that successful implementation requires clear professional protocols, appropriate staff training, and practical device design for ambulatory and home-care settings. Overall, the editorial presents PBM as a promising, low-risk, nonpharmacological intervention with potential to reduce healthcare costs, medication use, transportation burden, and patient suffering, while calling for stronger clinical and economic studies to support broader adoption.
Abstract:
Objective: The underlying mechanisms of photobiomodulation (PBM) remain elusive. The most attractive hypotheses revolve around the role of cytochrome c oxidase (CCO) and cellular energetics. Background: No reliable demonstration of any PBM-related light-induced mechanistic effect on CCO has been reported. Studies on PBM have proven to be either nonreproducible, of questionable relevance, or involve wavelengths unlikely to be operative in vivo. The literature reveals very few demonstrable mechanistic light effects of any sort on CCO. Nitric oxide (NO) is involved in a number of the reported light effects on CCO. NO inhibits CCO at high reductive pressures by binding to the heme a3 moiety. This complex is white light labile. Methods: The reported photolability of the heme-NO complex seems to be a prime target for PBM studies, as removal of inhibiting NO from the active site of CCO could restore normal activity to inhibited CCO. Another aspect of CCO-NO chemistry has been revealed that shows intriguing possibilities. Results: A novel nitrite reductase activity of solubilized mitochondria has been demonstrated attributable to CCO. NO production was optimal under hypoxic conditions. It was also found that 590 nm irradiation increased NO production by enhancing NO release. The presence of cellular NO has usually been considered metabolically detrimental, but current thinking has expanded the importance and the physiological roles of NO. Evidence shows that NO production is likely to play a role in cardioprotection and defenses against hypoxic damage. Conclusions: Studies combining PBM and hypoxia also point to a connection between light irradiation, hypoxia protection, and NO production. This leads the authors to the possibility that the intrinsic nature of PBM involves the production of NO. The combination of CCO and hemoglobin/myoglobin NO production with photorelease of NO may constitute the heart of PBM.
Keywords: cytochrome c oxidase; nitric oxide; photobiomodulation.
Description:
This editorial examines the evolving understanding of photobiomodulation therapy mechanisms beyond the traditional cytochrome c oxidase model. Hamblin and Liebert note that, despite more than 50 years of research, thousands of publications, and many successful clinical studies, PBM has not yet become fully mainstream in medicine. One reason is continuing uncertainty regarding its molecular and cellular mechanisms of action, alongside inconsistent treatment parameters and limited large-scale clinical trials. The article reviews the classical hypothesis that red and near-infrared light act primarily through cytochrome c oxidase in the mitochondrial respiratory chain, increasing ATP production, oxygen consumption, mitochondrial membrane potential, and cellular metabolism. However, the authors highlight evidence suggesting that cytochrome c oxidase may not be the only or even always necessary chromophore for PBM effects. Alternative and complementary mechanisms are discussed, including nitric oxide production, structured or exclusion-zone water, changes in water viscosity affecting ATP synthase, transient receptor potential ion channels, opsins, calcium signaling, reactive oxygen species, and direct activation of biomolecules such as latent transforming growth factor beta. The editorial emphasizes that different wavelengths may act through different pathways, with 810 nm light appearing more closely linked to mitochondrial mechanisms, while 980 nm may act through water absorption and heat-sensitive calcium channels. Overall, the article presents PBM as a multi-mechanism biological process in which outcomes depend on wavelength, power density, dose, and tissue context, rather than a therapy explained by a single universal chromophore.
PBM as a Photoceutical
The concept of ‘photoceuticals’ frames PBM as a drug-equivalent intervention–a non-pharmacological agent with dose-dependent, mechanism-specific biological effects. Like pharmaceuticals, PBM exhibits dose-response relationships (including biphasic/Arndt-Schulz behaviour), defined wavelength-activity profiles, and identifiable therapeutic windows. Regulatory and standardisation bodies have increasingly recognised PBM within this framework, supporting its integration into evidence-based clinical protocols.
Abstract:
Objective: The central role of the TGF-β pathway in embryonic development, immune responses, tissue healing, and malignancies is well established. Prior attempts with small molecules, peptides, and regulatory RNAs have failed mainly due to off-target effects in clinical studies. This review outlines the evidence for selectively activating the endogenous, latent transforming growth factor (TGF)-β1 with photobiomodulation (PBM) treatments. Background: Light treatments play a central role in current-directed energy therapeutics in medicine. Therapeutic use of low-dose light treatments has been noted since the 1960s. However, the breadth of treatments and inconsistencies with clinical outcomes have led to much skepticism. This can be primarily attributed to a lack of understanding of the fundamental light-tissue interactions and optimization of clinical treatment protocols. Methods: Recent advances in molecular mechanisms and improved biophotonic device technologies have led to a resurgence of interest in this field. Results: Over the past two decades, our work has focused on outlining a direct molecular mechanism involving PBM-generated redox-mediated activation of endogenous latent TGF-β1. Conclusions: Despite its critical roles in these processes, the complexity and cross talk in this potent growth factor signaling network have prevented the development of directed targeted therapeutics. PBM treatments offer a novel therapeutic and discovery tool in this aspect, especially with the growing evidence for its roles in cancer immunotherapy and stem cell biology.
Keywords: LLLT; cancer immunotherapy; photobiomodulation; stem cells; transforming growth factor-β; wound healing.
Abstract:
Low-intensity light therapy (LILT) appears to be working through newly recognized photoacceptor systems. The mitochondrial electron transport chain has been shown to be photosensitive to red and near-infrared (NIR) light. Although the underlying mechanisms have not yet been clearly elucidated, mitochondrial photostimulation has been shown to increase ATP production and cause transient increases in reactive oxygen species (ROS). In some cells, this process appears to participate in reduction/oxidation (redox) signaling. Redox mechanisms are known to be involved in cellular homeostasis and proliferative control. In plants, photostimulation of the analogous photosynthetic electron transport chain leads to redox signaling known to be integral to cellular function. In gene therapy research, ultraviolet lasers are being used to photostimulate cells through a process that also appears to involve redox signaling. It seems that visible and near visible low-intensity light can be used to modulate cellular physiology in some nonphotosynthetic cells, acting through existing redox mechanisms of cellular physiology. In this manner, LILT may act to promote proliferation and/or cellular homeostasis. Understanding the role of redox state and signaling in LILT may be useful in guiding future therapies, particularly in conditions associated with pro-oxidant conditions.
Description:
This guest editorial discusses whether photobiomodulation should be considered a drug-equivalent therapeutic intervention. Karu notes that photobiomodulation, previously referred to as low-level laser therapy or laser biostimulation, had already been used clinically for more than 40 years, while its cellular and molecular mechanisms had been investigated for more than 30 years. Despite successful use in areas such as chronic wounds, pain management, spinal cord injury, and nervous system disorders, PBM had not yet become part of mainstream medicine. The article highlights several developing clinical applications, including Parkinson’s disease, stem cell stimulation, myocardial infarction, vitiligo, oral mucositis, peripheral nerve repair, depression, anxiety, ischemic stroke, cardiac injury, analgesia, and diabetic wound healing. Karu emphasizes that PBM may be particularly relevant where conventional treatments have limited success or significant side effects. Mechanistically, the editorial focuses on mitochondrial pathways, especially cytochrome c oxidase as a primary photoacceptor for red and near-infrared light. Light absorption by cytochrome c oxidase is described as initiating mitochondrial signaling, gene expression changes, and downstream biological effects, with stronger responses often observed in stressed or diseased cells than in healthy cells. Overall, the article presents PBM as a biologically active intervention with defined dose, wavelength, cellular targets, and therapeutic effects, supporting the argument that it may be appropriate to view photobiomodulation as a drug-equivalent modality rather than simply a physical therapy technique.
Abstract:
Objective: The aim of this study was to review the biological and clinical short-term effects of photoradiation in acute pain from soft-tissue injury.
Background data: It is unclear if and how photoradiation can reduce acute pain.
Methods: Literature search of (i) controlled laboratory trials investigating potential biological mechanisms for pain relief and (ii) randomized placebo-controlled clinical trials which measure outcomes within the first 7 days after acute soft-tissue injury.
Results: There is strong evidence from 19 out of 22 controlled laboratory studies that photoradiation can modulate inflammatory pain by reducing levels of biochemical markers (PGE(2), mRNA Cox 2, IL-1beta, TNFalpha), neutrophil cell influx, oxidative stress, and formation of edema and hemorrhage in a dose-dependent manner (median dose 7.5 J/cm(2), range 0.3-19 J/cm(2)). Four comparisons with non-steroidal anti-inflammatory drugs (NSAIDs) in animal studies found optimal doses of photoradiation and NSAIDs to be equally effective. Seven randomized placebo-controlled trials found no significant results after irradiating only a single point on the skin overlying the site of injury, or after using a total energy dose below 5 Joules. Nine randomized placebo-controlled trials (n = 609) were of acceptable methodological quality, and irradiated three or more points and/or more than 2.5 cm(2) at site of injury or surgical incision, with a total energy of 5.0-19.5 Joules. Results in these nine trials were significantly in favor of photoradiation groups over placebo groups in 15 out of 18 outcome comparisons. Poor and heterogeneous data presentation hampered statistical pooling of continuous data. Categorical data of subjective improvement were homogeneous (Q-value = 7.1) and could be calculated from four trials (n = 379) giving a significant relative risk for improvement of 2.7 (95% confidence interval [CI], 1.8-3.9) in a fixed effects model.
Conclusion: photoradiation can modulate inflammatory processes in a dose-dependent manner and can be titrated to significantly reduce acute inflammatory pain in clinical settings. Further clinical trials with adequate photoradiation doses are needed to precisely estimate the effect size for photoradiation in acute pain.
Abstract:
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and can reduce musculoskeletal pain in spite of the cost of adverse reactions like gastrointestinal ulcers or cardiovascular events. The current study investigates if a safer treatment such as low-level laser therapy (LLLT) could reduce tendinitis inflammation, and whether a possible pathway could be through inhibition of either of the two-cyclooxygenase (COX) isoforms in inflammation. Wistar rats (six animals per group) were injected with saline (control) or collagenase in their Achilles tendons. Then, we treated them with three different doses of IR LLLT (810 nm; 100 mW; 10 s, 30 s and 60 s; 3.57 W cm(-2); 1 J, 3 J, 6 J) at the sites of the injections, or intramuscular diclofenac, a nonselective COX inhibitor/NSAID. We found that LLLT dose of 3 J significantly reduced inflammation through less COX-2-derived gene expression and PGE(2) production, and less edema formation compared to nonirradiated controls. Diclofenac controls exhibited significantly lower PGE(2) cytokine levels at 6 h than collagenase control, but COX isoform 1-derived gene expression and cytokine PGE(2) levels were not affected by treatments. As LLLT seems to act on inflammation through a selective inhibition of the COX-2 isoform in collagenase-induced tendinitis, LLLT may have potential to become a new and safer nondrug alternative to coxibs.
Abstract:
General purpose: To provide background and examine evidence for the therapeutic application of light energy treatments for wound healing.
Target audience: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.
Learning objectives/outcomes: After completing this continuing education activity, you should be better able to:1. Explain the basics of lasers, light-emitting diodes, and light-tissue interactions as they apply to photobiomodulation therapy.2. Summarize the results of the authors’ literature review of the evidence regarding the therapeutic applications of photobiomodulation treatments for wound healing.
Abstract: To provide background and examine evidence for the therapeutic applications of light energy treatments for wound healing.A search was performed in PubMed for peer-reviewed scientific articles published in the last 5 years using the search terms «photobiomodulation therapy» and «low-level laser therapy,» and these terms combined with «wound,» using a «human species» filter. This search yielded 218 articles on photobiomodulation therapy or low-level laser therapy and wounds. Of these, only articles on in vivo wound care using light treatments were specifically included in this review (n = 11).The wound healing effects of low-dose laser treatments were first described over 50 years ago. Various doses ranging from 0.1 to 10 J/cm and wavelengths ranging from 405 to 1,000 nm appear to provide therapeutic benefits for a broad range of chronic wounds. A range of light energy sources from LEDs to lasers have been used and have specific advantages and limitations. There is a lack of consensus on standardized treatment parameters such as wavelengths, dose, and therapeutic outcomes in the reviewed studies, preventing direct comparison and clinical protocol recommendation. An expert opinion based on ongoing research studies and reported literature is offered.Noninvasive, economical, and multipurpose light devices are an attractive tool for wound management. However, there is an urgent need in the wound care community to develop optimal clinical protocols for use based on well-designed, rigorous clinical research studies.
Musculoskeletal Conditions
PBM is one of the most extensively studied non-pharmacological interventions for musculoskeletal disorders. Evidence supports efficacy in tendinopathy, lateral elbow epicondylitis (tennis elbow), Achilles tendinopathy, rotator cuff disorders, low back pain, and fibromyalgia. Proposed mechanisms include modulation of nociceptor activity, reduction of pro-inflammatory cytokines, and promotion of tissue repair in tendons and ligaments.
Abstract:
We investigated if low level laser therapy (LLLT) of the joint capsule can reduce pain in chronic joint disorders. A literature search identified 88 randomised controlled trials, of which 20 trials included patients with chronic joint disorders. Six trials were excluded for not irradiating the joint capsule. Three trials used doses lower than a dose range nominated a priori for reducing inflammation in the joint capsule. These trials found no significant difference between active and placebo treatments. The remaining 11 trials including 565 patients were of acceptable methodological quality with an average PEDro score of 6.9 (range 5-9). In these trials, LLLT within the suggested dose range was administered to the knee, temporomandibular or zygapophyseal joints. The results showed a mean weighted difference in change of pain on VAS of 29.8 mm (95% CI, 18.9 to 40.7) in favour of the active LLLT groups. Global health status improved for more patients in the active LLLT groups ( relative risk of 0.52; 95% CI 0.36 to 0.76). Low level laser therapy with the suggested dose range significantly reduces pain and improves health status in chronic joint disorders, but the heterogeneity in patient samples, treatment procedures and trial design calls for cautious interpretation of the results.
Abstract:
Background: Recent reviews have indicated that low level level laser therapy (LLLT) is ineffective in lateral elbow tendinopathy (LET) without assessing validity of treatment procedures and doses or the influence of prior steroid injections.
Methods: Systematic review with meta-analysis, with primary outcome measures of pain relief and/or global improvement and subgroup analyses of methodological quality, wavelengths and treatment procedures.
Results: 18 randomised placebo-controlled trials (RCTs) were identified with 13 RCTs (730 patients) meeting the criteria for meta-analysis. 12 RCTs satisfied half or more of the methodological criteria. Publication bias was detected by Egger’s graphical test, which showed a negative direction of bias. Ten of the trials included patients with poor prognosis caused by failed steroid injections or other treatment failures, or long symptom duration or severe baseline pain. The weighted mean difference (WMD) for pain relief was 10.2 mm [95% CI: 3.0 to 17.5] and the RR for global improvement was 1.36 [1.16 to 1.60]. Trials which targeted acupuncture points reported negative results, as did trials with wavelengths 820, 830 and 1064 nm. In a subgroup of five trials with 904 nm lasers and one trial with 632 nm wavelength where the lateral elbow tendon insertions were directly irradiated, WMD for pain relief was 17.2 mm [95% CI: 8.5 to 25.9] and 14.0 mm [95% CI: 7.4 to 20.6] respectively, while RR for global pain improvement was only reported for 904 nm at 1.53 [95% CI: 1.28 to 1.83]. LLLT doses in this subgroup ranged between 0.5 and 7.2 Joules. Secondary outcome measures of painfree grip strength, pain pressure threshold, sick leave and follow-up data from 3 to 8 weeks after the end of treatment, showed consistently significant results in favour of the same LLLT subgroup (p < 0.02). No serious side-effects were reported.
Conclusion: LLLT administered with optimal doses of 904 nm and possibly 632 nm wavelengths directly to the lateral elbow tendon insertions, seem to offer short-term pain relief and less disability in LET, both alone and in conjunction with an exercise regimen. This finding contradicts the conclusions of previous reviews which failed to assess treatment procedures, wavelengths and optimal doses.
Abstract:
Background: In recent decades, low-level laser therapy (LLLT) has been widely used to relieve pain caused by different musculoskeletal disorders. Though widely used, its reported therapeutic outcomes are varied and conflicting. Results similarly conflict regarding its usage in patients with nonspecific chronic low back pain (NSCLBP). This study investigated the efficacy of low-level laser therapy (LLLT) for the treatment of NSCLBP by a systematic literature search with meta-analyses on selected studies.
Method: MEDLINE, EMBASE, ISI Web of Science and Cochrane Library were systematically searched from January 2000 to November 2014. Included studies were randomized controlled trials (RCTs) written in English that compared LLLT with placebo treatment in NSCLBP patients. The efficacy effect size was estimated by the weighted mean difference (WMD). Standard random-effects meta-analysis was used, and inconsistency was evaluated by the I-squared index (I(2)).
Results: Of 221 studies, seven RCTs (one triple-blind, four double-blind, one single-blind, one not mentioning blinding, totaling 394 patients) met the criteria for inclusion. Based on five studies, the WMD in visual analog scale (VAS) pain outcome score after treatment was significantly lower in the LLLT group compared with placebo (WMD = -13.57 [95 % CI = -17.42, -9.72], I(2) = 0 %). No significant treatment effect was identified for disability scores or spinal range of motion outcomes.
Conclusions: Our findings indicate that LLLT is an effective method for relieving pain in NSCLBP patients. However, there is still a lack of evidence supporting its effect on function.
Abstract:
Recent studies have explored if phototherapy with low-level laser therapy (LLLT) or narrow-band light-emitting diode therapy (LEDT) can modulate activity-induced skeletal muscle fatigue or subsequently protect against muscle injury. We performed a systematic review with meta-analysis to investigate the effects of phototherapy applied before, during and after exercises. A literature search was performed in Pubmed/Medline database for randomized controlled trials (RCTs) published from 2000 through 2012. Trial quality was assessed with the ten-item PEDro scale. Main outcome measures were selected as: number of repetitions and time until exhaustion for muscle performance, and creatine kinase (CK) activity to evaluate risk for exercise-induced muscle damage. The literature search resulted in 16 RCTs, and three articles were excluded due to poor quality assessment scores. From 13 RCTs with acceptable methodological quality (≥6 of 10 items), 12 RCTs irradiated phototherapy before exercise, and 10 RCTs reported significant improvement for the main outcome measures related to performance. The time until exhaustion increased significantly compared to placebo by 4.12 s (95% CI 1.21-7.02, p < 0.005) and the number of repetitions increased by 5.47 (95% CI 2.35-8.59, p < 0.0006) after phototherapy. Heterogeneity in trial design and results precluded meta-analyses for biochemical markers, but a quantitative analysis showed positive results in 13 out of 16 comparisons. The most significant and consistent results were found with red or infrared wavelengths and phototherapy application before exercises, power outputs between 50 and 200 mW and doses of 5 and 6 J per point (spot). We conclude that phototherapy (with lasers and LEDs) improves muscular performance and accelerate recovery mainly when applied before exercise.
Abstract:
Objective: We used statistical meta-analysis to determine the overall treatment effects of laser phototherapy on tissue repair and pain relief.
Background data: Low-power laser devices were first used as a form of therapy more than 30 years ago. However, their efficacy in reducing pain or promoting tissue repair remains questionable.
Methods: Following a literature search, studies meeting our inclusion criteria were identified and coded. Then, the effect size of laser treatment, that is, Cohen’s d, was calculated from each study using standard meta-analysis procedures.
Results: Thirty-four peer-reviewed papers on tissue repair met our inclusion criteria and were used to calculate 46 treatment effect sizes. Nine peer-reviewed papers on pain control met the inclusion criteria and were used to calculate nine effect sizes. Meta-analysis revealed a positive effect of laser phototherapy on tissue repair (d = +1.81; n = 46) and pain control (d = +1.11; n = 9). The positive effect of treatment on specific indices of tissue repair was evident in the treatment effect sizes determined as follows: collagen formation (d = +2.78), rate of healing (d = +1.57), tensile strength (d = +2.13), time needed for wound closure (d = +0.76), tensile stress (d = +2.65), number and rate of degranulation of mast cells (d = +1.87), and flap survival (d = +1.95). Further, analysis revealed the positive effects of various wavelengths of laser light on tissue repair, with 632.8 nm having the highest treatment effect (d = +2.44) and 780 nm the least (d = 0.60). The overall treatment effect for pain control was positive as well (d = +1.11). The fail-safe number-that is, the number of studies in which laser phototherapy has negative or no effect-needed to nullify the overall outcome of this analysis was 370 for tissue repair and 41 for pain control.
Conclusions: These findings mandate the conclusion that laser phototherapy is a highly effective therapeutic armamentarium for tissue repair and pain relief.
Abstract:
Question: Is low level laser therapy an effective adjuvant intervention for chronic low back pain?
Design: Randomised trial with concealed allocation, blinded assessors and intention-to-treat analysis.
Participants: Sixty-one patients who had low back pain for at least 12 weeks.
Intervention: One group received laser therapy alone, one received laser therapy and exercise, and the third group received placebo laser therapy and exercise. Laser therapy was performed twice a week for 6 weeks.
Outcome measures: Outcomes were pain severity measured using a 10-cm visual analogue scale, lumbar range of motion measured by the Schober Test and maximum active flexion, extension and lateral flexion, and disability measured with the Oswestry Disability Index on admission to the study, after 6 weeks of intervention, and after another 6 weeks of no intervention.
Results: There was no greater effect of laser therapy compared with exercise for any outcome, at either 6 or 12 weeks. There was also no greater effect of laser therapy plus exercise compared with exercise for any outcome at 6 weeks. However, in the laser therapy plus exercise group pain had reduced by 1.8 cm (95% CI 0.1 to 3.3, p = 0.03), lumbar range of movement increased by 0.9 cm (95% CI 0.2 to 1.8, p < 0.01) on the Schober Test and by 15 deg (95% CI 5 to 25, p < 0.01) of active flexion, and disability reduced by 9.4 points (95% CI 2.7 to 16.0, p = 0.03) more than in the exercise group at 12 weeks.
Conclusion: In chronic low back pain low level laser therapy combined with exercise is more beneficial than exercise alone in the long term.
Abstract:
Objectives: Low-level laser therapy (LLLT) is not recommended in major knee osteoarthritis (KOA) treatment guidelines. We investigated whether a LLLT dose-response relationship exists in KOA.
Design: Systematic review and meta-analysis.
Data sources: Eligible articles were identified through PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Physiotherapy Evidence Database and Cochrane Central Register of Controlled Trials on 18 February 2019, reference lists, a book, citations and experts in the field.
Eligibility criteria for selecting studies: We solely included randomised placebo-controlled trials involving participants with KOA according to the American College of Rheumatology and/or Kellgren/Lawrence criteria, in which LLLT was applied to participants’ knee(s). There were no language restrictions.
Data extraction and synthesis: The included trials were synthesised with random effects meta-analyses and subgrouped by dose using the World Association for Laser Therapy treatment recommendations. Cochrane’s risk-of-bias tool was used.
Results: 22 trials (n=1063) were meta-analysed. Risk of bias was insignificant. Overall, pain was significantly reduced by LLLT compared with placebo at the end of therapy (14.23 mm Visual Analogue Scale (VAS; 95% CI 7.31 to 21.14)) and during follow-ups 1-12 weeks later (15.92 mm VAS (95% CI 6.47 to 25.37)). The subgroup analysis revealed that pain was significantly reduced by the recommended LLLT doses compared with placebo at the end of therapy (18.71 mm (95% CI 9.42 to 27.99)) and during follow-ups 2-12 weeks after the end of therapy (23.23 mm VAS (95% CI 10.60 to 35.86)). The pain reduction from the recommended LLLT doses peaked during follow-ups 2-4 weeks after the end of therapy (31.87 mm VAS significantly beyond placebo (95% CI 18.18 to 45.56)). Disability was also statistically significantly reduced by LLLT. No adverse events were reported.
Conclusion: LLLT reduces pain and disability in KOA at 4-8 J with 785-860 nm wavelength and at 1-3 J with 904 nm wavelength per treatment spot.
Prospero registration number: CRD42016035587.
Keywords: knee osteoarthritis; laser therapy; meta-analysis; phototherapy; systematic review.
Abstract:
Articular cartilage is an avascular and aneural connective tissue that is frequently damaged due to trauma or degenerative joint diseases, often resulting in arthritis. Its limited intrinsic capacity for self-renewal poses a significant challenge to effective repair. Hence, the development of regenerative strategies is essential to enhance the poor intrinsic healing of cartilage tissue. Photobiomodulation (PBM) has gained increasing attention as a noninvasive, drug-free, and safe approach. PBM exerts photobiological effects that promote cellular responses and reduce inflammatory conditions, all of which are beneficial for cartilage repair. Nonetheless, the efficacy of PBM varies depending on treatment parameters and treated targets. This review first summarizes PBM parameter-dependent outcomes in cartilage regeneration studies. Reported data indicate frequent use of red lasers (600-660 nm, 0-10 J/cm2), GaAIAs lasers (800-880 nm, 10-50 J/cm2), and Nd:YAG lasers (1064 nm, up to 200 J/cm2) in in vitro, in vivo, and clinical studies. Moreover, PBM in conjunction with cartilage tissue engineering (CTE) has shown synergistic effects, enhancing scaffold-based repair outcomes. This review additionally explores PBM applications within CTE frameworks. The summarized findings aim to inform researchers and physicians by outlining optimized PBM strategies and highlighting PBM’s strong potential in promoting cartilage regeneration, both independently and in combination with CTE.
Keywords: cartilage regeneration; cartilage tissue engineering; photobiomodulation.
Osteoarthritis (OA) & Rheumatoid Arthritis (RA)
Multiple Cochrane reviews and meta-analyses have assessed PBM for OA and RA. Evidence supports short-term pain reduction and improved function in knee OA, and symptom relief in RA. Laser therapy reduces levels of prostaglandin E2, interleukin-1beta, and tumour necrosis factor-alpha in joint tissue, contributing to anti-inflammatory and chondroprotective effects.
Abstract:
Background: Osteoarthritis (OA) affects a large proportion of the population. Low Level Laser Therapy (LLLT) is a light source that generates extremely pure light, of a single wavelength. The effect is not thermal, but rather related to photochemical reactions in the cells. LLLT was introduced as an alternative non-invasive treatment for OA about 20 years ago, but its effectiveness is still controversial.
Objectives: To assess the effectiveness of LLLT in the treatment of OA.
Search strategy: We searched MEDLINE, EMBASE, the Cochrane Musculoskeletal registry, the registry of the Rehabilitation and Related Therapies field and the Cochrane Controlled Trials Register up to January 30, 2004.
Selection criteria: Following an a priori protocol, only controlled clinical trials of LLLT for the treatment of patients with a clinical diagnosis of OA were eligible. Abstracts were excluded unless further data could be obtained from the authors.
Data collection and analysis: Two reviewers independently selected trials and abstracted data using predetermined forms. Heterogeneity was tested with Cochran’s Q test. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed, in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI), where the difference between the treated and control groups was weighted by the inverse of the variance. Standardized mean differences (SMD) were calculated by dividing the difference between treated and control by the baseline variance. SMD were used when different scales were used to measure the same concept (e.g. pain). Dichotomous outcomes were analyzed with odds ratios.
Main results: Seven trials were included, with 184 patients randomized to laser, 161 patients to placebo laser. Treatment duration ranged from 4 to 12 weeks. Pain was assessed by four trials. The pooled estimate (random effects) of three trials showed no effect on pain measured using a scale (SMD: -0.2, 95% CI: -1.0, +0.6), but there was statistically significant heterogeneity (p>0,05). Three of the trials showed no effect and two demonstrated very beneficial effects with laser. In another trial, with no scale-based pain outcome, significantly more patients reported pain relief (yes/no) with laser with an odds ratio of 0.05, (95% CI: 0.0 to 1.56). Only one study found significant results for increased knee range of motion (WMD: -10.62 degrees, 95% CI: -14.07,-7.17). Other outcomes of joint tenderness and strength were not significant. Lower dosage of LLLT was found as effective than higher dosage for reducing pain and improving knee range of motion.
Reviewers’ conclusions: For OA, the results are conflicting in different studies and may depend on the method of application and other features of the LLLT application. Clinicians and researchers should consistently report the characteristics of the LLLT device and the application techniques used. New trials on LLLT should make use of standardized, validated outcomes. Despite some positive findings, this meta-analysis lacked data on how LLLT effectiveness is affected by four important factors: wavelength, treatment duration of LLLT, dosage and site of application over nerves instead of joints. There is clearly a need to investigate the effects of these factors on LLLT effectiveness for OA in randomized controlled clinical trials.
Abstract:
Background: Rheumatoid arthritis (RA) affects a large proportion of the population. Low Level Laser Therapy (LLLT) was introduced as an alternative non-invasive treatment for RA about ten years ago. LLLT is a light source that generates extremely pure light, of a single wavelength. The effect is not thermal, but rather related to photochemical reactions in the cells. The effectiveness of LLLT for rheumatoid arthritis is still controversial. This review is an update of the original review published in October 1998.
Objectives: To assess the effectiveness of LLLT in the treatment of RA.
Search strategy: We initially searched MEDLINE, EMBASE (from 1998), the registries of the Cochrane Musculoskeletal Group and the field of Rehabilitation and Related Therapies as well as the Cochrane Central Register of Controlled Trials (CENTRAL) up to June 2001. This search has now been updated to include articles published up to June 2005.
Selection criteria: Following an a priori protocol, only randomized controlled trials of LLLT for the treatment of patients with a clinical diagnosis of RA were eligible. Abstracts were excluded unless further data could be obtained from the authors.
Data collection and analysis: Two reviewers independently selected trials for inclusion, then extracted data and assessed quality using predetermined forms. Heterogeneity was tested using chi-squared. A fixed effects model was used throughout for continuous variables, except where heterogeneity existed, in which case, a random effects model was used. Results were analyzed as weighted mean differences (WMD) with 95% confidence intervals (CI), where the difference between the treated and control groups was weighted by the inverse of the variance. Dichotomous outcomes were analyzed with relative risks.
Main results: A total of 222 patients were included in the five placebo-controlled trials, with 130 randomized to laser therapy. Relative to a separate control group, LLLT reduced pain by 1.10 points (95% CI: 1.82, 0.39) on visual analogue scale relative to placebo, reduced morning stiffness duration by 27.5 minutes (95%CI: 2.9 to 52 minutes) and increased tip to palm flexibility by 1.3 cm (95% CI: 0.8 to 1.7). Other outcomes such as functional assessment, range of motion and local swelling did not differ between groups. There were no significant differences between subgroups based on LLLT dosage, wavelength, site of application or treatment length. For RA, relative to a control group using the opposite hand, there was no difference observed between the control and treatment hand for morning stiffness duration, and also no significant improvement in pain relief RR 13.00 (95% CI: 0.79 to 214.06). However, only one study was included as using the contralateral limb as control. .
Authors’ conclusions: LLLT could be considered for short-term treatment for relief of pain and morning stiffness for RA patients, particularly since it has few side-effects. Clinicians and researchers should consistently report the characteristics of the LLLT device and the application techniques used. New trials on LLLT should make use of standardized, validated outcomes. Despite some positive findings, this meta-analysis lacked data on how LLLT effectiveness is affected by four important factors: wavelength, treatment duration of LLLT, dosage and site of application over nerves instead of joints. There is clearly a need to investigate the effects of these factors on LLLT effectiveness for RA in randomized controlled clinical trials.
Abstract:
Background: Treatment efficacy of physical agents in osteoarthritis of the knee (OAK) pain has been largely unknown, and this systematic review was aimed at assessing their short-term efficacies for pain relief.
Methods: Systematic review with meta-analysis of efficacy within 1-4 weeks and at follow up at 1-12 weeks after the end of treatment.
Results: 36 randomised placebo-controlled trials (RCTs) were identified with 2434 patients where 1391 patients received active treatment. 33 trials satisfied three or more out of five methodological criteria (Jadad scale). The patient sample had a mean age of 65.1 years and mean baseline pain of 62.9 mm on a 100 mm visual analogue scale (VAS). Within 4 weeks of the commencement of treatment manual acupuncture, static magnets and ultrasound therapies did not offer statistically significant short-term pain relief over placebo. Pulsed electromagnetic fields offered a small reduction in pain of 6.9 mm [95% CI: 2.2 to 11.6] (n = 487). Transcutaneous electrical nerve stimulation (TENS, including interferential currents), electro-acupuncture (EA) and low level laser therapy (LLLT) offered clinically relevant pain relieving effects of 18.8 mm [95% CI: 9.6 to 28.1] (n = 414), 21.9 mm [95% CI: 17.3 to 26.5] (n = 73) and 17.7 mm [95% CI: 8.1 to 27.3] (n = 343) on VAS respectively versus placebo control. In a subgroup analysis of trials with assumed optimal doses, short-term efficacy increased to 22.2 mm [95% CI: 18.1 to 26.3] for TENS, and 24.2 mm [95% CI: 17.3 to 31.3] for LLLT on VAS. Follow-up data up to 12 weeks were sparse, but positive effects seemed to persist for at least 4 weeks after the course of LLLT, EA and TENS treatment was stopped.
Conclusion: TENS, EA and LLLT administered with optimal doses in an intensive 2-4 week treatment regimen, seem to offer clinically relevant short-term pain relief for OAK.
Abstract:
Objectives: Low-level laser therapy (LLLT) is not recommended in major knee osteoarthritis (KOA) treatment guidelines. We investigated whether a LLLT dose-response relationship exists in KOA.
Design: Systematic review and meta-analysis.
Data sources: Eligible articles were identified through PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, Physiotherapy Evidence Database and Cochrane Central Register of Controlled Trials on 18 February 2019, reference lists, a book, citations and experts in the field.
Eligibility criteria for selecting studies: We solely included randomised placebo-controlled trials involving participants with KOA according to the American College of Rheumatology and/or Kellgren/Lawrence criteria, in which LLLT was applied to participants’ knee(s). There were no language restrictions.
Data extraction and synthesis: The included trials were synthesised with random effects meta-analyses and subgrouped by dose using the World Association for Laser Therapy treatment recommendations. Cochrane’s risk-of-bias tool was used.
Results: 22 trials (n=1063) were meta-analysed. Risk of bias was insignificant. Overall, pain was significantly reduced by LLLT compared with placebo at the end of therapy (14.23 mm Visual Analogue Scale (VAS; 95% CI 7.31 to 21.14)) and during follow-ups 1-12 weeks later (15.92 mm VAS (95% CI 6.47 to 25.37)). The subgroup analysis revealed that pain was significantly reduced by the recommended LLLT doses compared with placebo at the end of therapy (18.71 mm (95% CI 9.42 to 27.99)) and during follow-ups 2-12 weeks after the end of therapy (23.23 mm VAS (95% CI 10.60 to 35.86)). The pain reduction from the recommended LLLT doses peaked during follow-ups 2-4 weeks after the end of therapy (31.87 mm VAS significantly beyond placebo (95% CI 18.18 to 45.56)). Disability was also statistically significantly reduced by LLLT. No adverse events were reported.
Conclusion: LLLT reduces pain and disability in KOA at 4-8 J with 785-860 nm wavelength and at 1-3 J with 904 nm wavelength per treatment spot.
Prospero registration number: CRD42016035587.
Keywords: knee osteoarthritis; laser therapy; meta-analysis; phototherapy; systematic review.
Abstract:
Introduction: Inflammation of the synovial membrane plays an important role in the pathophysiology of osteoarthritis (OA). The synovial tissue of patients with initial OA is characterized by infiltration of mononuclear cells and production of proinflammatory cytokines and other mediators of joint injury. The objective was to evaluate the effect of low-level laser therapy (LLLT) operating at 50 mW and 100 mW on joint inflammation in rats induced by papain, through histopathological analysis, differential counts of inflammatory cells (macrophages and neutrophils), as well as gene expression of interleukin 1-beta and 6 (IL-1β and IL-6), and protein expression of tumor necrosis factor alpha (TNFα).
Methods: Male Wistar rats (n = 60) were randomly divided into four groups of 15 animals, namely: a negative control group; an inflammation injury positive control group; a 50 mW LLLT group, subjected to injury and treated with 50 mW LLLT; and a 100 mW LLLT group, subjected to injury and treated with 100 mW LLLT. The animals were subject to joint inflammation (papain solution, 4%) and then treated with LLLT (808 nm, 4 J, 142.4 J/cm(2), spot size 0.028 for both groups). On the day of euthanasia, articular lavage was collected and immediately centrifuged; the supernatant was saved for analysis of expression of TNFα protein by enzyme-linked immunosorbent assay and expression of IL-1β and IL-6 mRNA by real-time polymerase chain reaction. A histologic examination of joint tissue was also performed. For the statistical analysis, analysis of variance with Tukey’s post-hoc test was used for comparisons between each group. All data are expressed as mean values and standard deviation, with P < 0.05.
Results: Laser treatment with 50 mW was more efficient than 100 mW in reducing cellular inflammation, and decreased the expression of IL-1β and IL-6. However, the 100 mW treatment led to a higher reduction of TNFα compared with the 50 mW treatment.
Conclusions: LLLT with 50 mW was more efficient in modulating inflammatory mediators (IL-1β, IL-6) and inflammatory cells (macrophages and neutrophils), which correlated with the histology that showed a reduction in the inflammatory process.
Abstract:
Osteoarthritis is becoming more problematic as the population ages. Recent reports suggest that the benefit of anti-inflammatory drugs is unimpressive and the incidence of side effects is worrying. Low-level laser (light) therapy (LLLT) is an alternative approach with no known side effects and with reports of substantial therapeutic efficacy in osteoarthritis. In this issue of Arthritis Research & Therapy, Alves and colleagues used a rat model of osteoarthritis produced by intra-articular injection of the cartilage-degrading enzyme papain to test 810-nm LLLT. A single application of LLLT produced significant reductions in inflammatory cell infiltration and inflammatory cytokines 24 hours later. A lower laser power was more effective than a higher laser power. However, more work is necessary before the title question can be answered in the affirmative.
Pain Management
PBM is recognised as an effective modality for both acute and chronic pain states. Landmark meta-analyses and RCTs have documented efficacy in neck pain, joint pain, neuropathic pain, and myofascial pain syndrome. Mechanisms of analgesia include suppression of nociceptor sensitisation, modulation of substance P and bradykinin, and upregulation of endogenous opioid pathways.
Abstract:
Background: Neck pain is a common and costly condition for which pharmacological management has limited evidence of efficacy and side-effects. Low-level laser therapy (LLLT) is a relatively uncommon, non-invasive treatment for neck pain, in which non-thermal laser irradiation is applied to sites of pain. We did a systematic review and meta-analysis of randomised controlled trials to assess the efficacy of LLLT in neck pain.
Methods: We searched computerised databases comparing efficacy of LLLT using any wavelength with placebo or with active control in acute or chronic neck pain. Effect size for the primary outcome, pain intensity, was defined as a pooled estimate of mean difference in change in mm on 100 mm visual analogue scale.
Findings: We identified 16 randomised controlled trials including a total of 820 patients. In acute neck pain, results of two trials showed a relative risk (RR) of 1.69 (95% CI 1.22-2.33) for pain improvement of LLLT versus placebo. Five trials of chronic neck pain reporting categorical data showed an RR for pain improvement of 4.05 (2.74-5.98) of LLLT. Patients in 11 trials reporting changes in visual analogue scale had pain intensity reduced by 19.86 mm (10.04-29.68). Seven trials provided follow-up data for 1-22 weeks after completion of treatment, with short-term pain relief persisting in the medium term with a reduction of 22.07 mm (17.42-26.72). Side-effects from LLLT were mild and not different from those of placebo.
Interpretation: We show that LLLT reduces pain immediately after treatment in acute neck pain and up to 22 weeks after completion of treatment in patients with chronic neck pain.
Funding: None.
Abstract:
Objective: Laser phototherapy has been widely used to relieve pain for more than 30 years, but its efficacy remains controversial. To ascertain the overall effect of phototherapy on pain, we aggregated the literature and subjected the studies to statistical meta-analysis.
Methods: Relevant original studies were gathered from every available source and coded. Articles that met preestablished inclusion criteria were subjected to statistical meta-analysis, using Cohen’s d statistic to determine treatment effect sizes.
Results: Fifty-two effect sizes were computed from the 22 articles that met the inclusion criteria. The resulting overall mean effect size was highly significant; d = +0.84 (95% confidence interval = 0.44-1.23). The effect size remained significant even when a high outlying d value was conservatively excluded from the analysis; d = +0.66 (95% confidence interval = 0.46-0.86). The fail-safe number associated with the overall treatment effect, that is, the number of additional studies in which phototherapy has negative or no effect on pain needed to negate the overall large effect size of +0.84, was 348.
Discussion: These findings warrant the conclusion that laser phototherapy effectively relieves pain of various etiologies; making it a valuable addition to contemporary pain management armamentarium.
Abstract:
Pain is the most common reason for physician consultations and the number one reason for missed work or school days is musculoskeletal pain. Pain management is utilized for easing the suffering and improving the Quality of Life of those living with chronic pain. Over the past several decades, physicians have become increasingly willing to prescribe opioids to manage pain. However, the opioid use can cause side effects as poor coordination, sedation, mood swings, depression, and anxiety combined with a dependence on the drugs. In the rehabilitation setting, patients benefit most when their health providers utilize a multimodal approach combining different types of therapies and when patients take on a significant role in optimal management of their own pain. The use of light as a therapeutic alternative form of medicine to manage pain and inflammation has been proposed to fill this void. Photobiomodulation therapy applied in the form of low-intensity Light Amplification by Stimulated Emission of Radiation (LASER) and light-emitting diode (LED) has been shown to reduce inflammation and swelling, promote healing, and reduce pain for an array of musculoskeletal conditions. There is evidence that photobiomodulation therapy reduces pain intensity in non-specific knee pain, osteoarthritis, pain post-total hip arthroplasty, fibromyalgia, temporomandibular diseases, neck pain, and low back pain. Therefore, the purpose of this paper was to present the up-to-dated evidence about the effects of low-intensity LASER and LED (photobiomodulation therapy) on pain control of the most common musculoskeletal conditions. We observed that the photobiomodulation therapy offers a non-invasive, safe, drug-free, and side-effect-free method for pain relief of both acute and chronic musculoskeletal conditions as well as fibromyalgia.
Abstract:
Objective: The efficacy of low-level laser treatment (LLLT) for chronic back pain remains controversial due to insufficient trial data. We aimed to conduct an updated review to determine if LLLT (including laser acupuncture) has specific benefits in chronic non-specific low back pain (CNLBP).
Methods: Electronic databases were searched for randomised trials using sham controls and blinded assessment examining the intervention of LLLT in adults with CNLBP. Primary outcomes were pain and global assessment of improvement with up to short-term follow-up. Secondary outcomes were disability, range of back movement, and adverse effects. A random effects meta-analysis was conducted. Subgroup analyses were based on laser dose, duration of baseline pain, and whether or not laser therapy used an acupuncture approach.
Results: 15 studies were selected involving 1039 participants. At immediate and short-term follow-up there was significant pain reduction of up to WMD (weighted mean difference) -1.40 cm (95% CI -1.91 to -0.88 cm) in favour of laser treatment, occurring in trials using at least 3 Joules (J) per point, with baseline pain <30 months and in non-acupuncture LLLT trials. Global assessment showed a risk ratio of 2.16 (95% CI 1.61 to 2.90) in favour of laser treatment in the same groups only at immediate follow-up.
Conclusions: We demonstrated moderate quality of evidence (GRADE) to support a clinically important benefit in LLLT for CNLBP in the short term, which was only seen following higher laser dose interventions and in participants with a shorter duration of back pain. Rigorously blinded trials using appropriate laser dosage would provide greater certainty around this conclusion.
Keywords: LASER THERAPY, LOW LEVEL; PAIN MANAGEMENT; SYSTEMATIC REVIEWS.
Wound Healing
Wound healing is among the most robustly supported applications of PBM, with evidence spanning acute surgical wounds, chronic ulcers (venous, diabetic, pressure), and burn injuries. PBM accelerates healing through stimulation of fibroblast proliferation, increased collagen synthesis, enhanced angiogenesis, and modulation of inflammatory phases. NASA-sponsored research validated LED-based PBM for wound care in space medicine, contributing to broad clinical adoption.
Abstract:
Objective: The purpose of this study was to assess the effects of hyperbaric oxygen (HBO) and near-infrared light therapy on wound healing.
Background data: Light-emitting diodes (LED), originally developed for NASA plant growth experiments in space show promise for delivering light deep into tissues of the body to promote wound healing and human tissue growth. In this paper, we review and present our new data of LED treatment on cells grown in culture, on ischemic and diabetic wounds in rat models, and on acute and chronic wounds in humans.
Materials and methods: In vitro and in vivo (animal and human) studies utilized a variety of LED wavelength, power intensity, and energy density parameters to begin to identify conditions for each biological tissue that are optimal for biostimulation.
Results: LED produced in vitro increases of cell growth of 140-200% in mouse-derived fibroblasts, rat-derived osteoblasts, and rat-derived skeletal muscle cells, and increases in growth of 155-171% of normal human epithelial cells. Wound size decreased up to 36% in conjunction with HBO in ischemic rat models. LED produced improvement of greater than 40% in musculoskeletal training injuries in Navy SEAL team members, and decreased wound healing time in crew members aboard a U.S. Naval submarine. LED produced a 47% reduction in pain of children suffering from oral mucositis.
Conclusion: We believe that the use of NASA LED for light therapy alone, and in conjunction with hyperbaric oxygen, will greatly enhance the natural wound healing process, and more quickly return the patient to a preinjury/illness level of activity. This work is supported and managed through the NASA Marshall Space Flight Center-SBIR Program.
Abstract:
Objectives: This investigation reviewed experimental studies of laser irradiation of wound healing in mice and rats published from 2003 to August 2008, respectively, to assess putative stimulatory effects of this treatment.
Background: Animal models, including rodents, attempt to reflect human wound healing and associated problems such as dehiscence, ischemia, ulceration, infection, and scarring. They have played a key role in furthering understanding of underlying mechanisms involved in impaired wound healing, and in testing new therapeutic strategies including laser irradiation.
Method: Original research papers investigating effects of laser or monochromatic light therapy on wound healing in mice and rats and published from January 2003 to August 2008 were retrieved from library sources, PubMed and Medline databases, reference lists from retrieved papers, and hand searches of relevant journals. Papers were selected for this review with regard to specific inclusion and exclusion criteria. Studies were critically reviewed in terms of study design, methodology, and appropriateness of laser irradiation parameters.
Results: The literature search identified eight studies in mice and 39 in rats. A variety of wound models were investigated, including acute-wound, impaired-healing, and chronic-wound models. Considerable variation was observed in research design, methodology, and irradiation parameters employed, limiting comparison of research findings between studies. Inadequate reporting of key experimental details, or errors in specification and/or calculation of key irradiation parameters was also found. Evidence from the studies reviewed suggested that use of red or infrared wavelength at a range of dosage parameters (median 4.2 J cm(-2)) results in significant benefits in measured parameters of wound healing. Interestingly, coherence does not seem essential to the photobiomodulatory effects of ‘laser’ phototherapy.
Conclusion: Studies reviewed consistently demonstrated the ability of laser or monochromatic light to photobiomodulate wound healing processes in experimental wounds in rats and mice, and strongly support the case for further controlled research in humans.
Abstract:
Background: Given the recent interest in light-emitting diode (LED) photomodulation and minimally invasive nonablative laser therapies, it is timely to investigate reports that low-level laser therapy (LLLT) may have utility in wound healing.
Objectives: To critically evaluate reported in vitro models and in vivo animal and human studies and to assess the qualitative and quantitative sufficiency of evidence for the efficacy of LLLT in promoting wound healing.
Method: Literature review, 1965 to 2003.
Results: In examining the effects of LLLT on cell cultures in vitro, some articles report an increase in cell proliferation and collagen production using specific and somewhat arbitrary laser settings with the helium neon (HeNe) and gallium arsenide lasers, but none of the available studies address the mechanism, whether photothermal, photochemical, or photomechanical, whereby LLLT may be exerting its effect. Some studies, especially those using HeNe lasers, report improvements in surgical wound healing in a rodent model; however, these results have not been duplicated in animals such as pigs, which have skin that more closely resembles that of humans. In humans, beneficial effects on superficial wound healing found in small case series have not been replicated in larger studies.
Conclusion: To better understand the utility of LLLT in cutaneous wound healing, good clinical studies that correlate cellular effects and biologic processes are needed. Future studies should be well-controlled investigations with rational selection of lasers and treatment parameters. In the absence of such studies, the literature does not appear to support widespread use of LLLT in wound healing at this time. Although applications of high-energy (10-100 W) lasers are well established with significant supportive literature and widespread use, conflicting studies in the literature have limited low-level laser therapy (LLLT) use in the United States to investigational use only. Yet LLLT is used clinically in many other areas, including Canada, Europe, and Asia, for the treatment of various neurologic, chiropractic, dental, and dermatologic disorders. To understand this discrepancy, it is useful to review the studies on LLLT that have, to date, precluded Food and Drug Administration approval of many such technologies in the United States. The fundamental question is whether there is sufficient evidence to support the use of LLLT.
Abstract:
Objective: We tested the hypothesis that LED phototherapy with combined 660-nm and 890-nm light will promote healing of venous ulcers that failed to respond to other forms of treatment.
Background data: A variety of dressings, growth factors, and adjunct therapies are used to treat venous ulcers, but none seems to yield satisfactory results.
Materials and methods: We used a randomized placebo-controlled double-blind study to compare a total of 20 patients divided with 32 chronic ulcers into three groups. In group 1 the ulcers were cleaned, dressed with 1% silver sulfadiazine (SDZ) cream, and treated with placebo phototherapy (<.03 J/cm(-3)) using a Dynatron Solaris 705 phototherapy research device. In group 2 the ulcers were treated similarly but received real phototherapy (3 J/cm(-2)) instead of placebo. In group 3 (controls), the ulcers were simply cleaned and dressed with SDZ without phototherapy. The ulcers were evaluated with digital photography and computer image analysis over 90 d or until full healing was attained.
Results: Ulcers treated with phototherapy healed significantly faster than controls when compared at day 30 (p +/- 0.01), day 60 (p +/- 0.05), and day 90 (p +/- 0.001), and similarly healed faster than the placebo-treated ulcers at days 30 and 90 (p +/- 0.01), but not at day 60. The beneficial effect of phototherapy was more pronounced when the confounding effect of small-sized ulcers was removed from the analysis. Medium- and large-sized ulcers healed significantly faster with treatment (>or=40% rate of healing per month) than placebo or control ulcers (p +/- 0.05).
Conclusion: Phototherapy promotes healing of chronic venous ulcers, particularly large recalcitrant ulcers that do not respond to conventional treatment.
Abstract:
General purpose: To provide background and examine evidence for the therapeutic application of light energy treatments for wound healing.
Target audience: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care.
Learning objectives/outcomes: After completing this continuing education activity, you should be better able to:1. Explain the basics of lasers, light-emitting diodes, and light-tissue interactions as they apply to photobiomodulation therapy.2. Summarize the results of the authors’ literature review of the evidence regarding the therapeutic applications of photobiomodulation treatments for wound healing.
Abstract: To provide background and examine evidence for the therapeutic applications of light energy treatments for wound healing.A search was performed in PubMed for peer-reviewed scientific articles published in the last 5 years using the search terms «photobiomodulation therapy» and «low-level laser therapy,» and these terms combined with «wound,» using a «human species» filter. This search yielded 218 articles on photobiomodulation therapy or low-level laser therapy and wounds. Of these, only articles on in vivo wound care using light treatments were specifically included in this review (n = 11).The wound healing effects of low-dose laser treatments were first described over 50 years ago. Various doses ranging from 0.1 to 10 J/cm and wavelengths ranging from 405 to 1,000 nm appear to provide therapeutic benefits for a broad range of chronic wounds. A range of light energy sources from LEDs to lasers have been used and have specific advantages and limitations. There is a lack of consensus on standardized treatment parameters such as wavelengths, dose, and therapeutic outcomes in the reviewed studies, preventing direct comparison and clinical protocol recommendation. An expert opinion based on ongoing research studies and reported literature is offered.Noninvasive, economical, and multipurpose light devices are an attractive tool for wound management. However, there is an urgent need in the wound care community to develop optimal clinical protocols for use based on well-designed, rigorous clinical research studies.
Abstract:
The fundamental pathophysiologic response for the survival of all organisms is the process of wound healing. Inadequate or lack of healing constitutes the etiopathologic basis of many oral and systemic diseases. Among the numerous efforts to promote wound healing, biophotonics therapies have shown much promise. Advances in photonic technologies and a better understanding of light-tissue interactions, from parallel biophotonics fields such as in vivo optical imaging and optogenetics, are spearheading their popularity in biology and medicine. Use of high-dose lasers and light devices in dermatology, ophthalmology, oncology, and dentistry are now popular for specific clinical applications, such as surgery, skin rejuvenation, ocular and soft tissue recontouring, and antitumor and antimicrobial photodynamic therapy. However, a less well-known clinical application is the therapeutic use of low-dose biophotonics termed photobiomodulation (PBM) therapy, which is aimed at alleviating pain and inflammation, modulating immune responses, and promoting wound healing and tissue regeneration. Despite significant volumes of scientific literature from clinical and laboratory studies noting the phenomenological evidence for this innovative therapy, limited mechanistic insights have prevented rigorous and reproducible PBM clinical protocols. This article briefly reviews current evidence and focuses on gaps in knowledge to identify potential paths forward for clinical translation with PBM therapy with an emphasis on craniofacial wound healing. PBM offers a novel opportunity to examine fundamental nonvisual photobiological processes as well as develop innovative clinical therapies, thereby presenting an opportunity for a paradigm shift from conventional restorative/prosthetic approaches to regenerative modalities in clinical dentistry.
Keywords: ROS; TGF-β; biophotonics; laser; low level light/laser therapy; regeneration.
Abstract:
As an innovative non-antibiotic approach, antimicrobial blue light in the spectrum of 400-470nm has demonstrated its intrinsic antimicrobial properties resulting from the presence of endogenous photosensitizing chromophores in pathogenic microbes and, subsequently, its promise as a counteracter of antibiotic resistance. Since we published our last review of antimicrobial blue light in 2012, there have been a substantial number of new studies reported in this area. Here we provide an updated overview of the findings from the new studies over the past 5 years, including the efficacy of antimicrobial blue light inactivation of different microbes, its mechanism of action, synergism of antimicrobial blue light with other angents, its effect on host cells and tissues, the potential development of resistance to antimicrobial blue light by microbes, and a novel interstitial delivery approach of antimicrobial blue light. The potential new applications of antimicrobial blue light are also discussed.
Keywords: Antibiotic resistance; Antimicrobial blue light; Bacterium; Endogenous photosensitizer; Fungus; Infection; Microbe; Non-antibiotic approach.
Abstract:
Background: In a recent study we showed that blue light inactivates methicillin-resistant Staphylococcus aureus (MRSA) by perturbing, depolarizing, and disrupting its cell membrane.
Purpose: The current study presents visual evidence that the observed biochemical changes also result in cell metabolic changes and structural alteration of the cell membrane.
Methods: Cultures of MRSA were treated with 450 nm pulsed blue light (PBL) at 3 mW/cm2 irradiance, using a sub lethal dose of 2.7 J/cm2 radiant exposure three times at 30-min intervals. Following 24 h incubation at 37 °C, irradiated colonies and control non-irradiated colonies were processed for light and transmission electron microscopy.
Results: The images obtained revealed three major effects of PBL; (1) disruption of MRSA cell membrane, (2) alteration of membrane structure, and (3) disruption of cell replication.
Conclusion: These signs of bacterial inactivation at a dose deliberately selected to be sub-lethal supports our previous finding that rapid depolarization of bacterial cell membrane and disruption of cellular function comprise another mechanism underlying photo-inactivation of bacteria. Further, it affirms the potency of PBL.
Keywords: Electron microscopy; MRSA; Photobiomodulation; Pulsed blue light.
Abstract:
Background: Recent studies evidence that blue-LED-light irradiation can modulate cell responses in the wound healing process within 24 h from treatment. This study aims to investigate blue-light (410–430 nm) photobiomodulation used in a murine wound model within six days post-treatment. Methods: A superficial wound was made in 30 CD1 male mice. The injuries were treated with a blue LED light (20.6 J/cm2), and biopsies were collected at 24, 72, and 144 h. Histology, fluorescence analysis, and advanced microscopy techniques were used. Results: We can observe an increase in the cellular infiltrate response, and in mast-cell density and their degranulation index correlated to the expression of the major histocompatibility complex after 24 h. Furthermore, after six days, the vessel density increases with the expression of the platelet-derived growth factor in the mast cells. Finally, collagen deposition and morphology in the treated wounds appear more similar to unwounded skin. Conclusions: Blue-light photobiomodulation stimulates several cellular processes that are finely coordinated by mast cells, leading to more rapid wound healing and a better-recovered skin morphology.
Abstract:
Objective: To determine effective treatment strategies against bacterial infections of burn wounds with Pseudomonas aeruginosa, we tested different treatment regimens with antibacterial blue light (BL). Background: Infections of burn wounds are serious complications and require effective and pathogen-specific therapy. Hereby, infections caused by P. aeruginosa pose a particular challenge in clinical practice due to its resistance to many antibiotics and topical antiseptics. Methods: LED-based light sources (450-460 nm) with different intensities and treatment times were used. Antibacterial effects against P. aeruginosa were determined by colony-forming unit (CFU) assays, human skin wound models, and fluorescence imaging. Results: In suspension assays, BL (2 h, 40 mW/cm2, 288 J/cm2) reduced bacterial number (>5 log10 CFU/mL). Applying 144 J/cm2, using 40 mW/cm2 for 1 h was more effective (>4 log10 CFU) than using 20 mW/cm2 for 2 h (>1.5 log10 CFU). BL with low irradiance (24 h, 3.5 mW/cm2, 300 J/cm2) only revealed bacterial reduction in thin bacteria-containing medium layers. In infected in vitro skin wounds only BL irradiation (2 h, 40 mW/cm2, 288 J/cm2) exerted a significant antimicrobial efficacy (2.94 log10 CFU/mL). Conclusions: BL treatment may be an effective therapy for P. aeruginosa-infected wounds to avoid radical surgical debridement. However, a significant antibacterial efficacy can only be achieved with higher irradiances and longer treatment times (min. 40 mW/cm2; >1 h), which cannot be easily integrated into regular clinical treatment protocols, for example, during a dressing change. Further studies are necessary to establish BL therapy for infected burns among tissue compatibility and interactions with previous therapeutic agents.
Keywords: Pseudomonas aeruginosa; blue light; burn wound infection; in vitro wound skin model.
Dermatology
In dermatology, PBM has established applications in androgenetic alopecia (hair loss), acne vulgaris, psoriasis, photorejuvenation, and post-procedural recovery. Red and NIR wavelengths stimulate hair follicle stem cells and extend anagen phase, while blue light wavelengths target Propionibacterium acnes in acne treatment. Several PBM devices are cleared by the FDA for hair loss and dermatological indications.
Abstract:
Low-level laser (light) therapy (LLLT) is a fast-growing technology used to treat a multitude of conditions that require stimulation of healing, relief of pain and inflammation, and restoration of function. Although skin is naturally exposed to light more than any other organ, it still responds well to red and near-infrared wavelengths. The photons are absorbed by mitochondrial chromophores in skin cells. Consequently, electron transport, adenosine triphosphate nitric oxide release, blood flow, reactive oxygen species increase, and diverse signaling pathways are activated. Stem cells can be activated, allowing increased tissue repair and healing. In dermatology, LLLT has beneficial effects on wrinkles, acne scars, hypertrophic scars, and healing of burns. LLLT can reduce UV damage both as a treatment and as a prophylactic measure. In pigmentary disorders such as vitiligo, LLLT can increase pigmentation by stimulating melanocyte proliferation and reduce depigmentation by inhibiting autoimmunity. Inflammatory diseases such as psoriasis and acne can also be managed. The noninvasive nature and almost complete absence of side effects encourage further testing in dermatology.
Abstract:
Objective: Alopecia is a common disorder affecting more than half of the population worldwide. Androgenetic alopecia, the most common type, affects 50% of males over the age of 40 and 75% of females over 65. Only two drugs have been approved so far (minoxidil and finasteride) and hair transplant is the other treatment alternative. This review surveys the evidence for low-level laser therapy (LLLT) applied to the scalp as a treatment for hair loss and discusses possible mechanisms of actions.
Methods and materials: Searches of PubMed and Google Scholar were carried out using keywords alopecia, hair loss, LLLT, photobiomodulation.
Results: Studies have shown that LLLT stimulated hair growth in mice subjected to chemotherapy-induced alopecia and also in alopecia areata. Controlled clinical trials demonstrated that LLLT stimulated hair growth in both men and women. Among various mechanisms, the main mechanism is hypothesized to be stimulation of epidermal stem cells in the hair follicle bulge and shifting the follicles into anagen phase.
Conclusion: LLLT for hair growth in both men and women appears to be both safe and effective. The optimum wavelength, coherence and dosimetric parameters remain to be determined.
Keywords: LLLT; alopecia; androgenetic alopecia; hair loss; low level laser (light).
Abstract:
Photobiomodulation (PBM) or low-level laser therapy was discovered over 50 years ago, when Mester in Hungary observed regrowth of hair in mice when irradiated with a ruby laser. At the present time, several different PBM devices are marketed to assist with hair regrowth in alopecia patients. This review covers the three main types of alopecia (androgenetic, areata, and chemotherapy-induced), and discusses the mechanism of action of PBM for each disease. The different devices used (mostly low powered red laser diodes), dosimetry, animal models, and clinical trials are summarized. Criteria for patient selection are outlined. Finally a perspectives section looks forward to the future.
Keywords: alopecia areata; androgenetic alopecia; chemotherapy-induced alopecia; hair follicles; photobiomodulation therapy.
Abstract:
Background: Androgenetic alopecia (AGA) is a condition that affects most people at some point in their life, yet few treatments are available. Use of photobiomodulation is ideal due to the safety profile and lack of serious adverse effects. Therefore, the efficacy of photobiomodulation for AGA therapy was investigated.
Methods: A meta-analysis was used to elucidate treatment efficacy. Additionally, a sub-analysis was performed to determine if the type of device used or if use of lasers versus light emitting diodes (LEDs) significantly impacted results.
Results: Using hair density (hairs/cm2) as a measure of efficacy, the standardized mean difference (SMD) was 1.02 (95% CI: 0.68, 1.36) in favor of treatment over control (15 studies, pooled N = 795, p < .00001). Subgroup analysis comparing comb-style devices versus helmet/hat-style devices did not reveal a significant difference (p = .08). A second subgroup analysis suggested that laser treatment was significantly more effective (p = .009) than a combination of laser/LED treatment although the combination treatment was still significantly better than control treatment.
Discussion: Meta-analysis results suggest that photobiomodulation could be used to effectively treat AGA. Specific device recommendations should be based on use of lasers versus LEDs and not the style (comb/hat/helmet) of the device.
Keywords: AGA; Androgenetic alopecia; LED; laser; photobiomodulation.
Abstract:
It has been reported that skin aging is associated with a downregulation in collagen synthesis and an elevation in matrix metalloproteinase (MMP) expression. This study investigated the potential of light-emitting diode (LED) treatments with a 660 nm sequentially pulsed illumination formula in the photobiomodulation of these molecules. Histological and biochemical changes were first evaluated in a tissue-engineered Human Reconstructed Skin (HRS) model after 11 sham or LED light treatments. LED effects were then assessed in aged/photoaged individuals in a split-face single-blinded study. Results yielded a mean percent difference between LED-treated and non-LED-treated HRS of 31% in levels of type-1 procollagen and of -18% in MMP-1. No histological changes were observed. Furthermore, profilometry quantification revealed that more than 90% of individuals showed a reduction in rhytid depth and surface roughness, and, via a blinded clinical assessment, that 87% experienced a reduction in the Fitzpatrick wrinkling severity score after 12 LED treatments. No adverse events or downtime were reported. Our study showed that LED therapy reversed collagen downregulation and MMP-1 upregulation. This could explain the improvements in skin appearance observed in LED-treated individuals. These findings suggest that LED at 660 nm is a safe and effective collagen-enhancement strategy.
Abstract:
Despite the current treatment options for different types of alopecia, there is a need for more effective management options. Recently, low-level laser therapy (LLLT) was evaluated for stimulating hair growth. Here, we reviewed the current evidence on the LLLT effects with an evidence-based approach, focusing more on randomized controlled studies by critically evaluating them. In order to investigate whether in individuals presenting with hair loss (male pattern hair loss (MPHL), female pattern hair loss (FPHL), alopecia areata (AA), and chemotherapy-induced alopecia (CIA)) LLLT is effective for hair regrowth, several databases including PubMed, Google Scholar, Medline, Embase, and Cochrane Database were searched using the following keywords: Alopecia, Hair loss, Hair growth, Low level laser therapy, Low level light therapy, Low energy laser irradiation, and Photobiomodulation. From the searches, 21 relevant studies were summarized in this review including 2 in vitro, 7 animal, and 12 clinical studies. Among clinical studies, only five were randomized controlled trials (RCTs), which evaluated LLLT effect on male and female pattern hair loss. The RCTs were critically appraised using the created checklist according to the Critical Appraisal for Therapy Articles Worksheet created by the Center of Evidence-Based Medicine, Oxford. The results demonstrated that all the performed RCTs have moderate to high quality of evidence. However, only one out of five studies performed intention-to-treat analysis, and only another study reported the method of randomization and subsequent concealment of allocation clearly; all other studies did not include this very important information in their reports. None of these studies reported the treatment effect of factors such as number needed to treat. Based on this review on all the available evidence about effect of LLLT in alopecia, we found that the FDA-cleared LLLT devices are both safe and effective in patients with MPHL and FPHL who did not respond or were not tolerant to standard treatments. Future randomized controlled trials of LLLT are strongly encouraged to be conducted and reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement to facilitate analysis and comparison.
Keywords: Evidence-based medicine; Hair regrowth; Low-level laser therapy.
Abstract:
Light-emitting diodes (LEDs) are considered to be effective in skin rejuvenation. We investigated the clinical efficacy of LED phototherapy for skin rejuvenation through the comparison with three different treatment parameters and a control, and also examined the LED-induced histological, ultrastructural, and biochemical changes. Seventy-six patients with facial wrinkles were treated with quasimonochromatic LED devices on the right half of their faces. All subjects were randomly divided into four groups treated with either 830nm alone, 633nm alone, a combination of 830 and 633nm, or a sham treatment light, twice a week for four weeks. Serial photography, profilometry, and objective measurements of the skin elasticity and melanin were performed during the treatment period with a three-month follow-up period. The subject’s and investigator’s assessments were double-blinded. Skin specimens were evaluated for the histologic and ultrastructural changes, alteration in the status of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), and the changes in the mRNA levels of IL-1ss, TNF-alpha, ICAM-1, IL-6 and connexin 43 (Cx43), by utilizing specific stains, TEM, immunohistochemistry, and real-time RT-PCR, respectively. In the results, objectively measured data showed significant reductions of wrinkles (maximum: 36%) and increases of skin elasticity (maximum: 19%) compared to baseline on the treated face in the three treatment groups. Histologically, a marked increase in the amount of collagen and elastic fibers in all treatment groups was observed. Ultrastructural examination demonstrated highly activated fibroblasts, surrounded by abundant elastic and collagen fibers. Immunohistochemistry showed an increase of TIMP-1 and 2. RT-PCR results showed the mRNA levels of IL-1ss, TNF-alpha, ICAM-1, and Cx43 increased after LED phototherapy whereas that of IL-6 decreased. This therapy was well-tolerated by all patients with no adverse effects. We concluded that 830 and 633nm LED phototherapy is an effective approach for skin rejuvenation.
Abstract:
Background and objective: Acne vulgaris represents both a challenge to the treating dermatologist and a major concern for the patient. Conventional treatments have proved inconsistent with often unacceptable side effects and high rates of recurrence. Non-thermal, non-laser, phototherapy for acne with a combination of blue and red light has recently attracted attention. The present study was designed to assess the efficacy of this combination phototherapy.
Methods: Twenty-four subjects, Fitzpatrick skin types II-V, with mild to severe symmetric facial acne vulgaris were recruited for the study. Subjects were well matched at baseline in terms of both age and duration of acne. Subjects were treated over eight sessions, two per week 3 days apart, alternating between 415 nm blue light (20 minutes/session, 48 J/cm2) and 633 nm red light (20 minutes/session, 96 J/cm2) from a light-emitting diode (LED)-based therapy system. Patients received a mild microdermabrasion before each session. Acne was assessed at baseline and at weeks 2, 4, 8 and 12.
Results: Twenty-two patients completed the trial. A mean reduction in lesion count was observed at all follow-up points. At the 4-week follow-up, the mean lesion count reduction was significant at 46% (p=0.001). At the 12-week follow-up, the mean lesion count reduction was also significant at 81% (p=0.001). Patient and dermatologist assessments were similar. Severe acne showed a marginally better response than mild acne. Side effects were minimal and transitory. Comedones did not respond as well as inflammatory lesions.
Conclusions: Combination blue and red LED therapy appears to have excellent potential in the treatment of mild to severe acne. Treatment appears to be both pain- and side effect-free.
Abstract:
Acne vulgaris, commonly known as acne, is the most prevalent skin disorder affecting mainly adolescents and young adults, though it can affect people of all ages, making it the most common complaint by patients presenting to a dermatologist. The overactivity of sebaceous glands primarily drives this skin condition due to androgen influence and the presence of Cutibacterium acnes bacteria. Although typically not directly harmful to patient health, acne can be a highly debilitating disease for patients, affecting their self-image and psychosocial well-being. Standard treatments include topical retinoids, benzoyl peroxide, topical antibiotics, and, for more severe cases, systemic antibiotics or isotretinoin, which require prolonged periods of compliance. All these pharmacologic treatments have a risk of side effects ranging from mild ones, like skin irritation and dryness, to severe ones, like depression. Thus, there is a demand for exploring other treatment modalities in treating acne, and laser and light-based therapies have garnered significant interest. This review article will comprehensively assess emerging laser and other light-based therapies that have shown efficacy in treating acne, including the recently FDA-approved 1,726 nm laser.
Keywords: Acne vulgaris; Laser; Light therapy.
Abstract:
Acne vulgaris, a prevalent dermatological disorder, frequently affects individuals’ self-perception and general psychosocial functioning. The growing demand for home-based light therapy devices prompted a systematic review to assess the efficacy of visible light in acne treatment. Overall, 35 studies were included, representing 1185 cases of acne vulgaris (mean age: 23.7 years; sex: 63% female). A total of 69% of the included studies were level 2 evidence. Overall, 92% of patients achieved partial remission of their acne lesions using visible light therapy. Among the patients who experienced a partial remission of their acne, 46% experienced a reduction of 0% to 50% in their acne lesions, while 33% and 12% experienced reductions of 51% to 74% and 75% to 99%, respectively. Notably, blue light emerged as the predominant treatment modality in this context, used in around 64% of the cases. A total of 95% of the patients who were treated with blue light experienced a partial clearance of acne lesions; 44% experienced a reduction of 0% to 50% in their acne lesions, while 42% and 9% experienced reductions of 51% to 74% and 75% to 99%, respectively. Overall, the average total lesion count improved by 43% at week 4 compared to the baseline. The average number of treatment sessions was 22 (range 1-112 sessions). On average, treated patients responded within a period of 4 weeks. Commonly reported side effects included skin irritation and erythema. This review highlights the potential of visible light therapy in acne treatment. Head-to-head studies are needed to compare the efficacy of visible light compared to existing therapies for the treatment of acne.
Keywords: acne vulgaris; blue light; red light; visible light.
Abstract:
Acne vulgaris treatments usually cause sensitivity, teratogenicity and bacterial resistance. Investigations of other therapeutic techniques, such as phototherapy, are highly relevant. Thus, we compared the effectiveness of two Acne vulgaris treatments in adolescents: peeling with salicylic acid (SA) and phototherapy. Teens were randomly divided into: group I, treatment with SA peels (10%) and group II, treatment with phototherapy (blue LED and red laser lights). Photographs were taken before and after ten sessions of each treatment, carried out weekly, and compared. To compare the differences between the treatments, the Student t-test was used. P values < 0.05 were considered significant. Both techniques are effective therapies for the treatment of acne in teenagers since the number of comedones, papules and pustules decreased significantly at the end of the session. However, when the two treatments were compared, phototherapy showed a significant difference in reducing the number of pustules. The combined use of red and blue lights due to their anti-inflammatory and wound-healing properties is a more efficient alternative for treating Acne vulgaris in relation to SA and proves more reliable and without side effects, improving the adolescents’ skin health.
Keywords: Acne vulgaris; phototherapy; salicylic acid; teenagers.
Abstract:
Irradiation with red or near infrared light promotes tissue repair, while treatment with blue light is known to be antimicrobial. Consequently, it is thought that infected wounds could benefit more from combined blue and red/infrared light therapy; but there is a concern that blue light may slow healing. We investigated the effect of blue 470nm light on wound healing, in terms of wound closure, total protein and collagen synthesis, growth factor and cytokines expression, in an in vitro scratch wound model. Human dermal fibroblasts were cultured for 48h until confluent. Then a linear scratch wound was created and irradiated with 3, 5, 10 or 55J/cm(2). Control plates were not irradiated. Following 24h of incubation, cells were fixed and stained for migration and fluorescence analyses and the supernatant collected for quantification of total protein, hydroxyproline, bFGF, IL-6 and IL-10. The results showed that wound closure was similar for groups treated with 3, 5 and 10J/cm(2), with a slight improvement with the 5J/cm(2) dose, and slower closure with 55J/cm(2) p<0.001). Total protein concentration increased after irradiation with 3, 5 and 10J/cm(2), reaching statistical significance at 5J/cm(2) compared to control (p<0.0001). However, hydroxyproline levels did not differ between groups. Similarly, bFGF and IL-10 concentrations did not differ between groups, but IL-6 concentration decreased progressively as fluence increased (p<0.0001). Fluorescence analysis showed viable cells regardless of irradiation fluence. We conclude that irradiation with blue light at low fluence does not impair in vitro wound healing. The significant decrease in IL-6 suggests that 470nm light is anti-inflammatory.
Keywords: Blue light; Fibroblasts; Phototherapy; Scratch; Wound healing.
Description:
This editorial by Hamblin explains that photobiomodulation therapy (PBMT) may have a dual role in treating skin pigmentation disorders by either stimulating repigmentation in vitiligo or reducing hyperpigmentation in conditions such as solar lentigines and melasma. Vitiligo involves autoimmune destruction of melanocytes, and PBMT, particularly with red light such as 632.8 nm, may support repigmentation by stimulating melanocyte stem cells, melanoblast migration, growth factors, and anti-inflammatory/antioxidant effects. Conversely, PBMT using wavelengths such as 660 nm, 630 nm, 940 nm, or 590 nm may reduce excessive melanin production by downregulating MITF, tyrosinase, melanogenesis markers, angiogenic factors, and related cellular pathways. The key message is that PBMT can produce apparently opposite effects—darkening depigmented skin or lightening hyperpigmented areas—depending on the biological context, wavelength, dose, and treatment target, but more research is needed to define optimal parameters.
Abstract:
Light-emitting diode photobiomodulation is the newest category of nonthermal light therapies to find its way to the dermatologic armamentarium. In this article, we briefly review the literature on the development of this technology, its evolution within esthetic and medical dermatology, and provide practical and technical considerations for use in various conditions. This article also focuses on the specific cell-signaling pathways involved and how the mechanisms at play can be put to use to treat a variety of cutaneous problems as a stand-alone application and/or complementary treatment modality or as one of the best photodynamic therapy light source.
Abstract:
Objective: To evaluate the histological effects of a new 675-nm laser device on the skin. Background: Innovative technologies based on physical principles have been proposed in recent years to improve the treatment of aging skin. Laser technology is currently being studied for its potential in skin care treatments. A new 675-nm laser device is being used for the treatment of hyperpigmentation, scars, and various types of wrinkles. Methods: A 42-year-old man underwent a 675-nm RedTouch® laser session for the treatment of aging signs on the neck. Two 2.5-mm biopsies were taken from the treated area and the adjacent area untreated with the laser, 45 days after the procedure. Comparison of the immunohistochemistry findings and assessment of the collagen and elastin fibers were performed by a board-certified dermatopathologist. Results: Skin biopsies revealed histological changes that comprised proliferation of new collagen fibers in the treated area, when compared to that in the untreated areas. Conclusions: Histological analysis suggests that the 675-nm laser has a potential role in stimulating collagen remodeling, with a significant increase in thin and new collagen fibers.
Keywords: 675 nm; collagen; histology; laser.
Abstrakt:
In the last decade, it has been proposed that the sun’s IR-A wavelengths might be deleterious to human skin and that sunscreens, in addition to their desired effect to protect against UV-B and UV-A, should also protect against IR-A (and perhaps even visible light). Several studies showed that NIR may damage skin collagen content via an increase inMMP-1 activity in the same manner as is known for UVR. Unfortunately, the artificial NIR light sources used in such studies were not representative of the solar irradiance. Yet, little has been said about the other side of the coin. This article will focus on key information suggesting that IR-A may be more beneficial than deleterious when the skin is exposed to the appropriate irradiance/dose of IR-A radiation similar to daily sun exposure received by people in real life.IR-A might even precondition the skin–a process called photo prevention–from an evolutionary standpoint since exposure to early morning IR-A wavelengths in sunlight may ready the skin for the coming mid-day deleterious UVR. Consequently IR-A appears to be the solution, not the problem. It does more good than bad for the skin. It is essentially a question of intensity and how we can learn from the sun. © 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: IR-A; Infrared (IR); Irradiance; MMP-1; Photobiomodulation; Photoprevention.
Antibacterial Applications: Blue Light Therapy
Blue light (405-470 nm) exerts direct antimicrobial effects via excitation of endogenous porphyrins within bacterial cells, generating singlet oxygen and other reactive oxygen species that damage bacterial membranes and DNA. Blue light is effective against Gram-positive and Gram-negative organisms including methicillin-resistant Staphylococcus aureus (MRSA), Propionibacterium acnes, Helicobacter pylori, and Candida species. It represents a promising non-antibiotic strategy in the era of antimicrobial resistance.
Abstract:
Blue light, particularly in the wavelength range of 405-470 nm, has attracted increasing attention due to its intrinsic antimicrobial effect without the addition of exogenous photosensitizers. In addition, it is commonly accepted that blue light is much less detrimental to mammalian cells than ultraviolet irradiation, which is another light-based antimicrobial approach being investigated. In this review, we discussed the blue light sensing systems in microbial cells, antimicrobial efficacy of blue light, the mechanism of antimicrobial effect of blue light, the effects of blue light on mammalian cells, and the effects of blue light on wound healing. It has been reported that blue light can regulate multi-cellular behavior involving cell-to-cell communication via blue light receptors in bacteria, and inhibit biofilm formation and subsequently potentiate light inactivation. At higher radiant exposures, blue light exhibits a broad-spectrum antimicrobial effect against both Gram-positive and Gram-negative bacteria. Blue light therapy is a clinically accepted approach for Propionibacterium acnes infections. Clinical trials have also been conducted to investigate the use of blue light for Helicobacter pylori stomach infections and have shown promising results. Studies on blue light inactivation of important wound pathogenic bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa have also been reported. The mechanism of blue light inactivation of P. acnes, H. pylori, and some oral bacteria is proved to be the photo-excitation of intracellular porphyrins and the subsequent production of cytotoxic reactive oxygen species. Although it may be the case that the mechanism of blue light inactivation of wound pathogens (e.g., S. aureus, P. aeruginosa) is the same as that of P. acnes, this hypothesis has not been rigorously tested. Limited and discordant results have been reported regarding the effects of blue light on mammalian cells and wound healing. Under certain wavelengths and radiant exposures, blue light may cause cell dysfunction by the photo-excitation of blue light sensitizing chromophores, including flavins and cytochromes, within mitochondria or/and peroxisomes. Further studies should be performed to optimize the optical parameters (e.g., wavelength, radiant exposure) to ensure effective and safe blue light therapies for infectious disease. In addition, studies are also needed to verify the lack of development of microbial resistance to blue light.
Abstract:
Background: Infections with MRSA remain a growing public health concern, prompting the need to explore alternative treatments instead of the on-going effort to develop stronger drug-based therapies. We studied the effect of 405 nm blue light on two strains of MRSA-US-300 strain of CA-MRSA and the IS853 strain of HA-MRSA-in vitro.
Methods: We cultured and plated each strain, following which bacteria colonies were irradiated with 0, 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 25, 30, 35, 40, 45, 50, 55, or 60 J cm(-2) energy densities-just once-using a Solaris superluminous diode (SLD) device. Specimens were incubated at 35 degrees C for 24 hours. Then, digital images obtained were quantified to obtain colony counts and the aggregate area occupied by bacteria colonies.
Results: Blue light irradiation produced a statistically significant dose-dependent reduction in both the number and the aggregate area of colonies formed by each bacteria strain (P<0.001). Maximum eradication of the US-300 (92.1%) and the IS-853 colonies (93.5%) was achieved within 9.2 and 8.4 minutes of exposure, respectively. The longer the irradiation the more bacteria were eradicated. However, the effect was non-linear as increases of energy densities between 1.0 and 15 J cm(-2) resulted in more bacteria death than similar increases between 15 and 60 J cm(-2).
Conclusion: At low doses, blue light photo-destroys HA-MRSA and CA-MRSA in vitro; raising the prospect that phototherapy may be an effective clinical tool in the on-going effort to stem MRSA infections.
Abstract:
Objective: The purpose of this study was to investigate the effect of wavelength and methicillin-resistant Staphylococcus aureus (MRSA) density on the bactericidal effect of 405 and 470 nm light.
Background data: It is recognized that 405 and 470 nm light-emitting diode (LED) light kill MRSA in standard 5 × 10(6) colony-forming units (CFU)/mL cultures; however, the effect of bacterial density on the bactericidal effect of each wavelength is not known.
Methods: In three experiments, we cultured and plated US300 MRSA at four densities. Then, we irradiated each plate once with either wavelength at 0, 1, 3, 45, 50, 55, 60, and 220 J/cm(2).
Results: Irradiation with either wavelength reduced bacterial colonies at each density (p<0.05). More bacteria were cleared as density increased; however, the proportion of colonies cleared, inversely decreased as density increased–the maximum being 100%, 96%, and 78% for 3 × 10(6), 5 × 10(6), and 7 × 10(6) CFU/mL cultures, respectively. Both wavelengths had similar effects on the sparser 3 × 10(6) and 5 × 10(6) CFU/mL cultures, but in the denser 7 × 10(6) CFU/mL culture, 405 nm light cleared more bacteria at each fluence (p<0.001). To determine the effect of beam penetration, denser 8 × 10(6) and 12 × 10(6) CFU/mL culture plates were irradiated either from the top, the bottom, or both directions. More colonies were eradicated from plates irradiated from top and bottom, than from plates irradiated from top or bottom at the same sum total fluences (p<0.001).
Conclusions: The bactericidal effect of LED blue light is limited more by light penetration of bacterial layers than by bacterial density per se.
Abstract:
Antimicrobial violet-blue light is an emerging technology designed for enhanced clinical decontamination and treatment applications, due to its safety, efficacy and ease of use. This systematized review was designed to compile the current knowledge on the antimicrobial efficacy of 380-480 nm light on a range of health care and food-related pathogens including vegetative bacteria, bacterial endospores, fungi and viruses. Data were compiled from 79 studies, with the majority focussing on wavelengths in the region of 405 nm. Analysis indicated that Gram-positive and Gram-negative vegetative bacteria are the most susceptible organisms, while bacterial endospores, viruses and bacteriophage are the least. Evaluation of the dose required for a 1 log10 reduction of key bacteria compared to population, irradiance and wavelength indicated that microbial titer and light intensity had little effect on the dose of 405 nm light required; however, linear analysis indicated organisms exposed to longer wavelengths of violet-blue light may require greater doses for inactivation. Additional research is required to ensure this technology can be used effectively, including: investigating inactivation of multidrug-resistant organisms, fungi, viruses and protozoa; further knowledge about the photodynamic inactivation mechanism of action; the potential for microbial resistance; and the establishment of a standardized exposure methodology.
Abstract:
The blue wavelengths within the visible light spectrum are intrinisically antimicrobial and can photodynamically inactivate the cells of a wide spectrum of bacteria (Gram positive and negative) and fungi. Furthermore, blue light is equally effective against both drug-sensitive and -resistant members of target species and is less detrimental to mammalian cells than is UV radiation. Blue light is currently used for treating acnes vulgaris and Helicobacter pylori infections; the utility for decontamination and treatment of wound infections is in its infancy. Furthermore, limited studies have been performed on bacterial biofilms, the key growth mode of bacteria involved in clinical infections. Here we report the findings of a multicenter in vitro study performed to assess the antimicrobial activity of 400-nm blue light against bacteria in both planktonic and biofilm growth modes. Blue light was tested against a panel of 34 bacterial isolates (clinical and type strains) comprising Acinetobacter baumannii, Enterobacter cloacae, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Enterococcus faecium, Klebsiella pneumoniae, and Elizabethkingia meningoseptica All planktonic-phase bacteria were susceptible to blue light treatment, with the majority (71%) demonstrating a ≥5-log10 decrease in viability after 15 to 30 min of exposure (54 J/cm(2) to 108 J/cm(2)). Bacterial biofilms were also highly susceptible to blue light, with significant reduction in seeding observed for all isolates at all levels of exposure. These results warrant further investigation of blue light as a novel decontamination strategy for the nosocomial environment, as well as additional wider decontamination applications.
Importance: Blue light shows great promise as a novel decontamination strategy for the nosocomial environment, as well as additional wider decontamination applications (e.g., wound closure during surgery). This warrants further investigation.
Abstract:
Introduction: Several tests are available for assessing the viability of cells; however, there is a dearth of studies comparing the results obtained with each test. We compared the capability of four viability assays (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT), neutral red, trypan blue and live/dead fluorescence), to detect potential toxicity in fibroblasts irradiated with 470nm blue light.
Methods: Cells were irradiated at 3, 55, 110 and 220J/cm(2), incubated for 24h and viability assessed using each test.
Results: MTT assay showed significant decreases in viability when cells were irradiated with 110 and 220J/cm(2) energy fluence (dose) (89% and 57% viable cells, respectively; p<0.0001, compared to control); likewise the trypan blue assay showed 42% and 46% viable cells (p<0.0001). Neutral red assay revealed significant decrease in viability when cells were irradiated with 220J/cm(2) (84% viable cells; p=0.0008, compared to control). The live/dead fluorescence assay was less sensitive, evincing 91% and 95% viable cells after irradiation with 110 and 220J/cm(2) respectively.
Discussion: (1) The four assays differed in their levels of sensitivity to cell viability. (2) The adverse effect of increasing doses seems to manifest as alteration of mitochondrial metabolism, followed by lysosomal dysfunction, membrane disruption and finally loss of cell membrane integrity. (3) Overall, irradiation with 3J/cm(2) or 55J/cm(2) did not adversely affect cell viability. Thus, doses below 110J/cm(2) appear safe.
Keywords: Acetic acid (PubChem CID: 176); Blue light; Calcein-AM (PubChem CID: 4126474); Cell viability; EDTA (Ethylenediaminetetraacetic acid) (PubChem CID: 6049); Ethanol (PubChem CID: 702); Ethidium homodimer (PubChem CID: 12328897); Fibroblasts; Formazan (PubChem CID: 16218671); Live/dead fluorescence; MTT; MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) (PubChem CID: 64965); Methods; Neutral red; Neutral red (PubChem CID: 11105); Phosphate-Buffered Saline (PubChem CID: 24978514); Phototherapy; Trypan blue; Trypan blue (PubChem CID: 9562061).
Green Light Therapy
Green light (515-560 nm) has emerged as a novel PBM modality, primarily investigated for anti-nociceptive and anti-migraine effects. Animal studies demonstrated significant reductions in both acute and chronic pain responses following green light exposure, with proposed mechanisms involving upregulation of endogenous opioid signalling and modulation of trigeminal pain pathways. Early clinical trials show promise for migraine frequency reduction.
Introduction
In the USA, over 100 million patients suffer from chronic pain [36]. On average, 261–300 billion dollars are spent annually to manage pain and 297–336 billion dollars are lost to work nonproductivity [36]. Additionally, the emotional tax from chronic pain has resulted in life altering events ranging from shattering family unity [72] to suicide attempts [26; 29; 32]. Options for treatment of acute, post-operative pain as well as for chronic pain are limited and many drugs are marginally effective [22] and often accompanied by severe side-effects [19]. Non-pharmacological options for the treatment of pain would be highly desirable and advantageous in terms of safety, including lack of tolerance, somnolence, addiction, gastrointestinal disturbances and perhaps other factors such as convenience and cost.
Light therapy has been reported to be useful for multiple medical conditions. For example, light therapy, has been used to control depression [20; 25], to increase daytime circadian stimulation, and to improve sleep quality and mitigate depression in Alzheimer’s disease [21]. Additionally, bright light improved the mood of adolescents taking antidepressants compared to those without light therapy [61]. Exposing patients to bright light of more than 6000 lux significantly improved seasonal affective disorder (SAD), a serious condition with increased risk of suicidality [20; 25]. Pain has sensory, cognitive and affective dimensions [9; 58]. The emotional state of patients significantly influences pain [24]. For example, chronic psychological stress and depression increased pain perception in humans when painful and non-painful heat stimulus were applied to their forearms [76]. A similar response is also reported in rodents. In a model of social defeat, rats demonstrated enhanced nociceptive response to subcutaneous formalin administration [2]. In contrast, elevated emotional status may decrease the perception of pain [46]; general happiness and laughter therapy significantly decreased chronic pain scores in elderly patients [79]. Similar findings were observed in primary care patients who were enrolled in positive psychological intervention programs, which decreased their depression and improved overall functionality, as well as decreased pain perception [42]. It is possible that light therapy may have psychological effects, possibly arising from physiological changes such as increased endogenous opioid release, as shown in this study, which affect pain response or its perception.
Few studies have investigated possible effects of light therapy on pain. A randomized clinical trial investigated the effect of bright light exposure in managing nonspecific back pain where patients received once a week light exposure for 3 weeks reduced pain as assed by the Brief Pain Inventory suggesting an active role for light in controlling pain [43]. Preclinical studies on the possible modulation of pain by light therapy have not been reported. Here, we investigated the effect of light in modulation of acute nociception as well as in a model of chronic neuropathic pain. We found that green light produced antinociceptive and antihyperalgesic effects that involved descending, opioid-sensitive inhibition.
Abstract:
Background: Pharmacological management of migraine can be ineffective for some patients. We previously demonstrated that exposure to green light resulted in antinociception and reversal of thermal and mechanical hypersensitivity in rodent pain models. Given the safety of green light emitting diodes, we evaluated green light as a potential therapy in patients with episodic or chronic migraine.
Material and methods: We recruited (29 total) patients, of whom seven had episodic migraine and 22 had chronic migraine. We used a one-way cross-over design consisting of exposure for 1-2 hours daily to white light emitting diodes for 10 weeks, followed by a 2-week washout period followed by exposure for 1-2 hours daily to green light emitting diodes for 10 weeks. Patients were allowed to continue current therapies and to initiate new treatments as directed by their physicians. Outcomes consisted of patient-reported surveys. The primary outcome measure was the number of headache days per month. Secondary outcome measures included patient-reported changes in the intensity and frequency of the headaches over a two-week period and other quality of life measures including ability to fall and stay asleep, and ability to perform work. Changes in pain medications were obtained to assess potential reduction.
Results: When seven episodic migraine and 22 chronic migraine patients were analyzed as separate cohorts, white light emitting diodes produced no significant change in headache days in either episodic migraine or chronic migraine patients. Combining data from the episodic migraine and chronic migraine groups showed that white light emitting diodes produced a small, but statistically significant reduction in headache days from (days ± SEM) 18.2 ± 1.8 to 16.5 ± 2.01 days. Green light emitting diodes resulted in a significant decrease in headache days from 7.9 ± 1.6 to 2.4 ± 1.1 and from 22.3 ± 1.2 to 9.4 ± 1.6 in episodic migraine and chronic migraine patients, respectively. While some improvement in secondary outcomes was observed with white light emitting diodes, more secondary outcomes with significantly greater magnitude including assessments of quality of life, Short-Form McGill Pain Questionnaire, Headache Impact Test-6, and Five-level version of the EuroQol five-dimensional survey without reported side effects were observed with green light emitting diodes. Conclusions regarding pain medications reduction with green light emitting diode exposure were not possible. No side effects of light therapy were reported. None of the patients in the study reported initiation of new therapies.
Discussion: Green light emitting diodes significantly reduced the number of headache days in people with episodic migraine or chronic migraine. Additionally, green light emitting diodes significantly improved multiple secondary outcome measures including quality of life and intensity and duration of the headache attacks. As no adverse events were reported, green light emitting diodes may provide a treatment option for those patients who prefer non-pharmacological therapies or may be considered in complementing other treatment strategies. Limitations of this study are the small number of patients evaluated. The positive data obtained support implementation of larger clinical trials to determine possible effects of green light emitting diode therapy.This study is registered with clinicaltrials.gov under NCT03677206.
Keywords: Green light; light therapy; migraine; non-pharmacological therapy.
Abstract:
Migraine headache is uniquely exacerbated by light. Using psychophysical assessments in patients with normal eyesight we found that green light exacerbates migraine headache significantly less than white, blue, amber or red lights. To delineate mechanisms, we used electroretinography and visual evoked potential recording in patients, and multi-unit recording of dura- and light-sensitive thalamic neurons in rats to show that green activates cone-driven retinal pathways to a lesser extent than white, blue and red; that thalamic neurons are most responsive to blue and least responsive to green; and that cortical responses to green are significantly smaller than those generated by blue, amber and red lights. These findings suggest that patients’ experience with colour and migraine photophobia could originate in cone-driven retinal pathways, fine-tuned in relay thalamic neurons outside the main visual pathway, and preserved by the cortex. Additionally, the findings provide substrate for the soothing effects of green light.
Keywords: electroretinography; headache; pain; thalamus; visual evoked potential.
Abstract:
Background: Although low-level laser therapy (LLLT) is a widely used noninvasive treatment because of photobiomodulation effects, its application for xerostomia remained uncertain. Tight junctions (TJs), mainly composed of claudins, occludin, and ZO family members, are crucial structures that determine material transport through paracellular pathway in salivary gland epithelial cells. This work aimed to investigate whether LLLT affected salivary secretion through epithelial TJs. Methods: Transepithelial electrical resistance (TER) measurement and paracellular permeability assay were applied to evaluate paracellular permeability in submandibular gland (SMG)-C6 cells after irradiation with 540 nm green light. Immunofluorescence and western blot were used to detect the expression of TJ proteins. Quantitative phosphoproteomics were performed to explore possible intracellular signals. Results: We found that irradiation with 540 nm green light significantly decreased TER values while increased paracellular transport in SMG-C6 cells. 540 nm green light-induced redistribution of claudin-1, -3, and -4, but not occludin or ZO-1. Moreover, above phenomena were abolished by preincubation with capsazepine, an antagonist of transient receptor potential vanilloid subtype 1. Notably, irradiation with 540 nm green light on the skin covering the whole submandibular gland regions promoted salivary secretion and attenuated lymphocytic infiltration in 21-week-old non-obese diabetic mice (n = 5 per group), a xerostomia animal model for Sjögren’s syndrome. Through in-depth bioinformatics analysis and expression verification, ERK1/2 and EphA2 served as potential canonical and noncanonical signals underlying 540 nm green light. Conclusions: Our findings uncovered the novel therapeutic effects of 540 nm green light on xerostomia through regulation on the expression and distribution of TJs.
Keywords: green light; low level laser therapy; salivary secretion; tight junction; xerostomia.
Pre-Conditioning & Sports Performance
Pre-exercise PBM (photobiomodulation pre-conditioning) has demonstrated improvements in muscle performance, delayed fatigue onset, reduced exercise-induced muscle damage, and accelerated recovery. Clinical studies show reduced creatine kinase (CK) and lactate levels, increased peak torque, and faster restoration of strength following PBM applied before or immediately after exercise.
Abstract;
Recent studies have explored if phototherapy with low-level laser therapy (LLLT) or narrow-band light-emitting diode therapy (LEDT) can modulate activity-induced skeletal muscle fatigue or subsequently protect against muscle injury. We performed a systematic review with meta-analysis to investigate the effects of phototherapy applied before, during and after exercises. A literature search was performed in Pubmed/Medline database for randomized controlled trials (RCTs) published from 2000 through 2012. Trial quality was assessed with the ten-item PEDro scale. Main outcome measures were selected as: number of repetitions and time until exhaustion for muscle performance, and creatine kinase (CK) activity to evaluate risk for exercise-induced muscle damage. The literature search resulted in 16 RCTs, and three articles were excluded due to poor quality assessment scores. From 13 RCTs with acceptable methodological quality (≥6 of 10 items), 12 RCTs irradiated phototherapy before exercise, and 10 RCTs reported significant improvement for the main outcome measures related to performance. The time until exhaustion increased significantly compared to placebo by 4.12 s (95% CI 1.21-7.02, p < 0.005) and the number of repetitions increased by 5.47 (95% CI 2.35-8.59, p < 0.0006) after phototherapy. Heterogeneity in trial design and results precluded meta-analyses for biochemical markers, but a quantitative analysis showed positive results in 13 out of 16 comparisons. The most significant and consistent results were found with red or infrared wavelengths and phototherapy application before exercises, power outputs between 50 and 200 mW and doses of 5 and 6 J per point (spot). We conclude that phototherapy (with lasers and LEDs) improves muscular performance and accelerate recovery mainly when applied before exercise.
Abstract:
The use of low level laser (light) therapy (LLLT) has recently expanded to cover areas of medicine that were not previously thought of as the usual applications such as wound healing and inflammatory orthopedic conditions. One of these novel application areas is LLLT for muscle fatigue and muscle injury. Since it is becoming agreed that mitochondria are the principal photoacceptors present inside cells, and it is known that muscle cells are exceptionally rich in mitochondria, this suggests that LLLT should be highly beneficial in muscle injuries. The ability of LLLT to stimulate stem cells and progenitor cells means that muscle satellite cells may respond well to LLLT and help muscle repair. Furthermore the ability of LLLT to reduce inflammation and lessen oxidative stress is also beneficial in cases of muscle fatigue and injury. This review covers the literature relating to LLLT and muscles in both preclinical animal experiments and human clinical studies. Athletes, people with injured muscles, and patients with Duchenne muscular dystrophy may all benefit.
Keywords: ATP; low level laser therapy; mitochondria; muscle fatigue; muscle injury; reactive oxygen species; satellite cells.
Abstract:
Objective: The purpose of this study was to evaluate the effects of light-emitting diodes therapy (LEDT) on quadriceps muscle fatigue by using torque values from the isokinetic dynamometer as an outcome measure.
Background data: Light therapy is considered an innovative way to prevent muscle fatigue. Although positive results have been obtained in animal models and in clinical experiments, no results are available on the effects of this therapeutic modality on human performance studies with isokinetic dynamometry.
Materials and methods: Seventeen healthy and physically active male volunteers were included in a crossover randomized double-blinded placebo-controlled trial. They performed two sessions of an isokinetic fatigue test (30 maximal concentric knee flexion-extension contractions; range of motion, 90 degrees; angular velocity, 180 degrees per second) after LEDT or placebo treatment. Maximal knee extensor muscle isokinetic voluntary contractions were performed before (PRE-MVC) and after (POST-MVC) the fatigue test. LEDT treatment was performed with a multidiode cluster probe (34 red diodes of 660 nm, 10 mW; 35 infrared diodes of 850 nm, 30 mW) at three points of the quadriceps muscle, with a total irradiating dose of 125.1 J.
Results: No differences were observed in the PRE-MVC between LEDT (284.81 ± 4.52 Nm) and placebo (282.65 ± 52.64 Nm) treatments. However, for the POST-MVC, higher torques (p = 0.034) were observed for LEDT (237.68 ± 48.82 Nm) compared with placebo (225.68 ± 44.14 Nm) treatment.
Conclusion: LEDT treatment produced a smaller maximal isometric torque decrease after high-intensity concentric isokinetic exercise, which is consistent with an increase in performance.
Abstract:
The aim of this work was to evaluate the effects of low-level laser therapy (LLLT) on exercise performance, oxidative stress, and muscle status in humans. A randomized double-blind placebo-controlled crossover trial was performed with 22 untrained male volunteers. LLLT (810 nm, 200 mW, 30 J in each site, 30 s of irradiation in each site) using a multi-diode cluster (with five spots – 6 J from each spot) at 12 sites of each lower limb (six in quadriceps, four in hamstrings, and two in gastrocnemius) was performed 5 min before a standardized progressive-intensity running protocol on a motor-drive treadmill until exhaustion. We analyzed exercise performance (VO(2 max), time to exhaustion, aerobic threshold and anaerobic threshold), levels of oxidative damage to lipids and proteins, the activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT), and the markers of muscle damage creatine kinase (CK) and lactate dehydrogenase (LDH). Compared to placebo, active LLLT significantly increased exercise performance (VO(2 max) p = 0.01; time to exhaustion, p = 0.04) without changing the aerobic and anaerobic thresholds. LLLT also decreased post-exercise lipid (p = 0.0001) and protein (p = 0.0230) damages, as well as the activities of SOD (p = 0.0034), CK (p = 0.0001) and LDH (p = 0.0001) enzymes. LLLT application was not able to modulate CAT activity. The use of LLLT before progressive-intensity running exercise increases exercise performance, decreases exercise-induced oxidative stress and muscle damage, suggesting that the modulation of the redox system by LLLT could be related to the delay in skeletal muscle fatigue observed after the use of LLLT.
Abstract:
Background: There is about ten years since the first randomized controlled trial looking for the effects of photobiomodulation therapy using low-level laser therapy and/or light emitting diodes therapy in athletic performance enhancement was published. Since then, the knowledge in this field has increasing exponentially.
Objective: Given the fast advance in clinical interest, research and development in the use of photobiomodulation therapy for athletic performance enhancement and also to accelerate post-exercise recovery, as pioneers in this research field we felt the need to establish recommendations to ensure the correct use of the therapy, and also to guide the further studies in this area looking for the achievement of highest scientific evidence. It is important to highlight that the establishment of both clinical and scientific recommendations in this masterclass article were based on the most recent systematic reviews with meta-analysis and randomized controlled trials published in this field. It is important to stress that the recommendations of this masterclass article are based on most recent systematic reviews with meta-analysis and RCTs published in this research field. Future guidelines must follow the same direction and must be based only at the highest scientific evidence, avoiding overstatements and extrapolations based on animal experiments and case-studies.
Keywords: Light emitting diodes therapy; Low-level laser therapy; Phototherapy; Rehabilitation; Sports.
Abstract:
Recent studies have investigated whether low level laser therapy (LLLT) can optimize human muscle performance in physical exercise. This study tested the effect of LLLT on muscle performance in physical strength training in humans compared with strength training only. The study involved 36 men (20.8±2.2 years old), clinically healthy, with a beginner and/or moderate physical activity training pattern. The subjects were randomly distributed into three groups: TLG (training with LLLT), TG (training only) and CG (control). The training for TG and TLG subjects involved the leg-press exercise with a load equal to 80% of one repetition maximum (1RM) in the leg-press test over 12 consecutive weeks. The LLLT was applied to the quadriceps muscle of both lower limbs of the TLG subjects immediately after the end of each training session. Using an infrared laser device (808 nm) with six diodes of 60 mW each a total energy of 50.4 J of LLLT was administered over 140 s. Muscle strength was assessed using the 1RM leg-press test and the isokinetic dynamometer test. The muscle volume of the thigh of the dominant limb was assessed by thigh perimetry. The TLG subjects showed an increase of 55% in the 1RM leg-press test, which was significantly higher than the increases in the TG subjects (26%, P = 0.033) and in the CG subjects (0.27%, P < 0.001). The TLG was the only group to show an increase in muscle performance in the isokinetic dynamometry test compared with baseline. The increases in thigh perimeter in the TLG subjects and TG subjects were not significantly different (4.52% and 2.75%, respectively; P = 0.775). Strength training associated with LLLT can increase muscle performance compared with strength training only.
Abstract:
The effects of preexercise photobiomodulation therapy (PBMT) to enhance performance, accelerate recovery, and attenuate exercise-induced oxidative stress were still not fully investigated, especially in high-level athletes. The aim of this study was to evaluate the effects of PBMT (using infrared low-level laser therapy) applied before a progressive running test on functional aspects, muscle damage, and inflammatory and oxidative stress markers in high-level soccer players. A randomized, triple-blind, placebo-controlled crossover trial was performed. Twenty-two high-level male soccer players from the same team were recruited and treated with active PBMT and placebo. The order of interventions was randomized. Immediately after the application of active PBMT or placebo, the volunteers performed a standardized high-intensity progressive running test (ergospirometry test) until exhaustion. We analyzed rates of oxygen uptake (VO2 max), time until exhaustion, and aerobic and anaerobic threshold during the intense progressive running test. Creatine kinase (CK) and lactate dehydrogenase (LDH) activities, levels of interleukin-1β (IL-1-β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α), levels of thiobarbituric acid (TBARS) and carbonylated proteins, and catalase (CAT) and superoxide dismutase (SOD) activities were measured before and five minutes after the end of the test. PBMT increased the VO2 max (both relative and absolute values-p < 0.0467 and p < 0.0013, respectively), time until exhaustion (p < 0.0043), time (p < 0.0007) and volume (p < 0.0355) in which anaerobic threshold happened, and volume in which aerobic threshold happened (p < 0.0068). Moreover, PBMT decreased CK (p < 0.0001) and LDH (p < 0.0001) activities. Regarding the cytokines, PBMT decreased only IL-6 (p < 0.0001). Finally, PBMT decreased TBARS (p < 0.0001) and carbonylated protein levels (p < 0.01) and increased SOD (p < 0.0001)and CAT (p < 0.0001) activities. The findings of this study demonstrate that preexercise PBMT acts on different functional aspects and biochemical markers. Moreover, preexercise PBMT seems to play an important antioxidant effect, decreasing exercise-induced oxidative stress and consequently enhancing athletic performance and improving postexercise recovery. This trial is registered with Clinicaltrials.gov NCT03803956.
Dental & Oral Applications
PBM in dentistry has well-documented applications in periodontal therapy, orthodontic pain management, temporomandibular joint (TMJ) disorders, post-extraction healing, aphthous ulcer treatment, and dentine hypersensitivity. PBM reduces post-operative pain, accelerates tooth movement in orthodontics, and serves as an adjunct to scaling and root planing in periodontitis management.
Abstract:
Despite more than 30 years of experience with low level laser therapy (LLLT) or ‘biostimulation’ in dentistry, concerns remain as to its effectiveness as a treatment modality. Controlled clinical studies have demonstrated that while LLLT is effective for some specific applications, it is not a panacea. This paper provides an outline of the biological basis of LLLT and summarizes the findings of controlled clinical studies of the use of LLLT for specific soft tissue applications in dentistry. Areas of controversy where there is a pressing need for further research are identified.
Abstract:
Background and objectives: Although low-level laser therapy (LLLT) has been demonstrated to have a biomodulatory effect on periodontal tissue, no systematic review has exclusively addressed its effectiveness as an adjunct to non-surgical periodontal treatment. This study aimed to evaluate whether an additional benefit exists for the application of LLLT compared with scaling and root planing (SRP) alone.
Material and methods: An extensive search was conducted in the Cochrane Library (Issue 8, 2015), PubMed (1997) and EMBASE (1947) before August 2015 for randomized controlled trials (RCTs). The bias risk was assessed with the Cochrane tool for risk of bias evaluation. A meta-analysis was performed using REVMAN 5.3.
Results: After independent screening of 354 initial records, eight publications (seven RCTs) were included. However, six were rated as ‘having a high risk of bias’ as a result of major methodological weakness in ‘allocation concealment’ and ‘blinding of key personnel’. Meta-analysis showed that LLLT-mediated SRP demonstrated significant short-term benefits over SRP monotherapy in the improvement of the probing pocket depth (p = 0.0009 at 1 mo; p = 0.03 at 2 mo) and the level of interleukin-1β in the gingival crevicular fluid (p = 0.01 at 1 mo). Nevertheless, LLLT failed to show significant additional intermediate-term (3 and 6 mo) effects in terms of clinical parameters and alveolar bone density.
Conclusion: These findings indicated that LLLT showed only short-term additional benefits after conventional SRP. Its long-term effects remain unclear due to substantial methodological weaknesses and an insufficient number of current studies. Future RCTs with better designs and longer follow-up periods are required to assess the effectiveness of LLLT as an adjunctive treatment strategy in patients with periodontal disease.
Keywords: chronic periodontitis; low-level laser therapy; non-surgical periodontal treatment; systematic review.
Abstract:
Background: Despite the large number of publications, there is still controversy among clinicians regarding the application of dental lasers to the treatment of chronic periodontitis. The purpose of this review is to analyze the peer-reviewed research literature to determine the state of the science concerning the application of lasers to common oral soft tissue problems, root surface detoxification, and the treatment of chronic periodontitis.
Methods: A comprehensive computer-based search combined the following databases into one search: Medline, Current Contents, and the Cumulated Index of Nursing and Allied Health. This search also used key words. In addition, hand searches were done for several journals not cataloged in the databases, and the reference lists from published articles were checked. All articles were considered individually to eliminate non-peer-reviewed articles, those dealing with commercial laser technology, and those considered by the author to be purely opinion articles, leaving 278 possible articles.
Results: There is a considerable conflict in results for both laboratory studies and clinical trials, even when using the same laser wavelength. A meaningful comparison between various clinical studies or between laser and conventional therapy is difficult at best and likely impossible at the present. Reasons for this dilemma are several, such as different laser wavelengths; wide variations in laser parameters; insufficient reporting of parameters that, in turn, does not allow calculation of energy density; differences in experimental design, lack of proper controls, and differences in severity of disease and treatment protocols; and measurement of different clinical endpoints.
Conclusions: Based on this review of the literature, there is a great need to develop an evidence-based approach to the use of lasers for the treatment of chronic periodontitis. Simply put, there is insufficient evidence to suggest that any specific wavelength of laser is superior to the traditional modalities of therapy. Current evidence does suggest that use of the Nd:YAG or Er:YAG wavelengths for treatment of chronic periodontitis may be equivalent to scaling and root planing (SRP) with respect to reduction in probing depth and subgingival bacterial populations. However, if gain in clinical attachment level is considered the gold standard for non-surgical periodontal therapy, then the evidence supporting laser-mediated periodontal treatment over traditional therapy is minimal at best. Lastly, there is limited evidence suggesting that lasers used in an adjunctive capacity to SRP may provide some additional benefit.
Abstract:
Objective: The aim of the present study was to assess the effect of low-level laser on the control of pain and the repair of recurring aphthous stomatitis (RAS).
Background: One of the most frequent pathologic conditions in the oral cavity is RAS. This multifactor immunologic inflammatory lesion causes patient discomfort, and treatment is controversial because of its unknown etiology. A number of treatment modalities have been proposed, but none is definitive. Low-level laser treatment (LLLT) has been used for lesions of an inflammatory nature, not as an inhibitor of the process, but for its modulating action and reparative effect on tissues.
Materials and methods: Twenty patients with RAS were divided into one group treated with a topical corticoid agent (n = 5) and another group treated with laser (n = 15). Group I received conventional treatment with triamcinolone acetonide 4 times per day. The patients in Group II received laser treatment with an InGaA1P diode laser with wavelength of 670 nm, 50 mW, 3 J/cm(2) per point in daily sessions (once per day) on consecutive days. Both treatments were applied until the disappearance of the lesions. All patients were evaluated on a daily basis, and the following clinical parameters were determined during each session: pain intensity before and after treatment and clinical measurement of lesion size.
Results: The results revealed that 75% of the patients reported a reduction in pain in the same session after laser treatment, and total regression of the lesion occurred after 4 days. Total regression in the corticoid group was from 5 to 7 days.
Conclusion: The use of LLLT under the conditions administered in the present study demonstrated analgesic and healing effects with regard to RAS.
Abstract:
Objectives: Low level light/laser therapy (LLLT) is the direct application of light to stimulate cell responses (photobiomodulation) in order to promote tissue healing, reduce inflammation and induce analgesia. There have been significant studies demonstrating its application and efficacy at many sites within the body and for treatment of a range of musculoskeletal injuries, degenerative diseases and dysfunction, however, its use on oral tissues has, to date, been limited. The purpose of this review is to consider the potential for LLLT in dental and oral applications by providing background information on its mechanism of action and delivery parameters and by drawing parallels with its treatment use in analogous cells and tissues from other sites of the body.
Methods: A literature search on Medline was performed on laser and light treatments in a range of dental/orofacial applications from 2010 to March 2013. The search results were filtered for LLLT relevance. The clinical papers were then arranged to eight broad dental/orofacial categories and reviewed.
Results: The initial search returned 2778 results, when filtered this was reduced to 153. 41 were review papers or editorials, 65 clinical and 47 laboratory studies. Of all the publications, 130 reported a positive effect in terms of pain relief, fast healing or other improvement in symptoms or appearance and 23 reported inconclusive or negative outcomes. Direct application of light as a therapeutic intervention within the oral cavity (rather than photodynamic therapies, which utilize photosensitizing solutions) has thus far received minimal attention. Data from the limited studies that have been performed which relate to the oral cavity indicate that LLLT may be a reliable, safe and novel approach to treating a range of oral and dental disorders and in particular for those which there is an unmet clinical need.
Significance: The potential benefits of LLLT that have been demonstrated in many healthcare fields and include improved healing, reduced inflammation and pain control, which suggest considerable potential for its use in oral tissues.
Keywords: Dental therapy; Low-level laser therapy; Oral disease; Photobiomodulation; Phototherapy.
Abstract:
Objective: The purpose of this in vivo study was to determine the effect of two low-intensity laser therapy (LILT) protocols on macroscopic and microscopic parameters of experimental tooth movement.
Materials and methods: To induce experimental tooth movement in rats, 40 cN of orthodontic force was applied to the left first molars. Next, a gallium-aluminum-arsenide (Ga-Al-As) diode laser with a wavelength of 830 nm and power output of 100 mW was applied with fluence of 6000 J/cm(2) on the area around the moved tooth. Two different application protocols were used in the experimental groups: one with daily irradiation and another with irradiation during early stages. Macroscopic and microscopic analyses were performed at days 2 and 7 of tooth movement. The amount of tooth movement was measured with a caliper, and tartrate-resistant acid phosphatase and picrosirius staining were used to enable identification of osteoclasts and immature collagen, respectively.
Results: The amount of tooth movement did not differ between the irradiated and nonirradiated groups on days 2 and 7 of the experiment. On day 2, no difference was observed in the number of osteoclasts or the percentage of immature collagen. On day 7, there was an increase in the number of osteoclasts after daily applications of LILT, while two applications produced no significant difference from control. The amount of immature collagen on the tension side significantly increased in the nonirradiated group and when LILT was applied for only 2 d, whereas it was shown to be inhibited by daily LILT applications (p < 0.05).
Conclusion: The tested LILT protocols were unable to accelerate tooth movement. Even though the number of osteoclasts increased when LILT was applied daily, the repair at the tension zone was inhibited.
Abstract:
Introduction: Low level laser therapy (LLLT) also known as photobiomodulation, is a treatment that uses low-level lasers or light-emitting diodes (LEDs) to change cellular function and is a clinically well accepted tool in regenerative medicine and dentistry. Considering the variety of laser, exposure, cells and study types, the exact effects of low level laser therapy seems to be unclear. The aim of this study was to review the data published in the field of the effects of low level laser therapy on proliferation and differentiation of the cells contributing in bone regeneration.
Methods: To access relevant articles, an electronic search in PubMed was conducted from 2001 to April 2014. English language published papers on low level laser therapy were found using the selected keywords .The full texts of potentially suitable articles were obtained for final assessment according to the exclusion and inclusion criteria.
Results: 240 articles were found from 2001 to April 2014. Following the initial screening of titles and abstracts as well as the final screening of full texts, 22 articles completely fulfilled the inclusion criteria of this study. Wavelength used in LLLT irradiation varied between 600 to 1000 nm with an energy density of 0.04-60J/cm(2) . Although almost all studies agreed on getting positive effects from LLLT, some had opposing results.
Conclusion: Low level laser with low-energy density range appears to exert a biostimulatory effect on bone tissue, enhance osteoblastic proliferation and differentiation on cell lines used in in vitro studies. Despite the fact that many researches have been recently done on the effects of LLLT on different cell lines, without knowing the precise mechanism and effects, we are not able to offer a clinical treatment protocol. This paper is a beginning to help further progress and extend practical use of LLLT in future.
Keywords: bone regenerations; cell line; low-level laser therapies.
Oncology – Supportive Care & Oral Mucositis
The most robustly evidenced oncology application of PBM is the prevention and treatment of oral mucositis (OM) induced by chemotherapy and/or radiotherapy. PBM reduces OM severity, shortens duration, and decreases opioid analgesic requirements. Guidelines from MASCC/ISOO now include PBM as a recommended intervention for OM. PBM is also investigated for radiodermatitis, lymphoedema, and peripheral neuropathy secondary to cancer treatments.
Abstract:
Purpose: The purpose of this study is to review the effects of low-level laser therapy (LLLT) in the prevention and treatment of cancer therapy-induced oral mucositis (OM).
Methods: A systematic review and meta-analysis of randomised placebo-controlled trials of LLLT performed during chemotherapy or radiation therapy in head and neck cancer patients.
Results: We found 11 randomised placebo-controlled trials with a total of 415 patients; methodological quality was acceptable at 4.10 (SD ± 0.74) on the 5-point Jadad scale. The relative risk (RR) for developing OM was significantly (p = 0.02) reduced after LLLT compared with placebo LLLT (RR = 2.03 (95% CI, 1.11 to 3.69)). This preventive effect of LLLT improved to RR = 2.72 (95% CI, 1.98 to 3.74) when only trials with adequate doses above 1 J were included. For treatment of OM ulcers, the number of days with OM grade 2 or worse was significantly reduced after LLLT to 4.38 (95% CI, 3.35 to 5.40) days less than placebo LLLT. Oral mucositis severity was also reduced after LLLT with a standardised mean difference of 1.33 (95% CI, 0.68 to 1.98) over placebo LLLT. All studies registered possible side-effects, but they were not significantly different from placebo LLLT.
Conclusions: There is consistent evidence from small high-quality studies that red and infrared LLLT can partly prevent development of cancer therapy-induced OM. LLLT also significantly reduced pain, severity and duration of symptoms in patients with cancer therapy-induced OM.
Abstract:
Introduction: Oral mucositis (OM) is a significant early complication of hematopoietic cell transplantation (HCT). This phase III randomized double-blind placebo-controlled study was designed to compare the ability of 2 different low level GaAlAs diode lasers (650 nm and 780 nm) to prevent oral mucositis in HCT patients conditioned with chemotherapy or chemoradiotherapy.
Materials and methods: Seventy patients were enrolled and randomized into 1 of 3 treatment groups: 650 nm laser, 780 nm laser or placebo. All active laser treatment patients received daily direct laser treatment to the lower labial mucosa, right and left buccal mucosa, lateral and ventral surfaces of the tongue, and floor of mouth with energy densities of 2 J/cm2. Study treatment began on the first day of conditioning and continued through day +2 post HCT. Mucositis and oral pain was measured on days 0, 4, 7, 11, 14, 18, and 21 post HCT.
Results: The 650 nm wavelength reduced the severity of oral mucositis and pain scores. Low level laser therapy was well-tolerated and no adverse events were noted.
Discussion: While these results are encouraging, further study is needed to truly establish the efficacy of this mucositis prevention strategy. Future research needs to determine the effects of modification of laser parameters (e.g., wavelength, fluence, repetition rate of energy delivery, etc.) on the effectiveness of LLE laser to prevent OM.
Abstract:
Purpose of review: Oral mucositis is a common morbid condition associated with chemotherapy or radiotherapy for which there is no standard prophylaxis or treatment. There is increasing evidence that the use of low-level laser can reduced the severity of mucositis associated with chemotherapy or radiation therapy. The purpose of this review is to examine the available evidence for it.
Recent findings: For most approaches commonly used to prevent or treat chemotherapy-associated or radiotherapy-associated oral mucositis, a recent panel of experts could not find sufficient levels of evidence to recommend or suggest their use. As for low-level laser therapy, the results are difficult to assess and compare because of interoperator variability and because clinical trials are difficult to conduct in that field. Nevertheless, there is accumulating evidence in support of low-level laser therapy.
Summary: On the basis of literature data, it is reasonable to conclude that the evidence that low-level laser therapy may be useful in decreasing the severity of chemotherapy-associated or radiotherapy-associated mucositis is substantial, even though there have been few controlled studies in the field of prevention.
Abstract:
Objective: Acute radiodermatitis (RD) is a distressing and painful skin reaction that occurs in 95% of the patients undergoing radiotherapy (RT). The aim of this study was to evaluate the effectiveness of photobiomodulation therapy (PBMT) in the prevention of acute RD in breast cancer (BC) patients undergoing RT.
Methods: This study was a randomized, placebo-controlled trial including 120 BC patients that underwent an identical RT regimen post-lumpectomy. Patients were randomly assigned to the laser therapy (LT) or placebo group, with 60 patients in each group. Laser or placebo treatments were applied 2 days a week, immediately after the RT session, starting at the first day of RT. PBMT was delivered using a class IV MLS® M6 laser that combines two synchronized laser diodes in the infrared range (808-905 nm) with a fixed energy density (4 J/cm2 ). Skin reactions were scored based on the criteria of the Radiation Therapy Oncology Group (RTOG) and the Radiation-Induced Skin Reaction Assessment Scale (RISRAS). The patients completed the Skindex-16 questionnaire to evaluate their quality of life. All the measurements were collected at the first day, at a RT dose of 40 Gray (Gy), and at the end of RT (total dose 66 Gy).
Results: At a RT dose of 40 Gy, there was no significant difference between the groups in the distribution of RTOG grades. However, at the end of RT the severity of the skin reactions significantly differed between the two groups (P = 0.004), with a larger percentage of patients experiencing RTOG grade 2 or higher (e.g., moist desquamation) in the placebo group (30% vs. 6.7%, for the placebo and laser group, resp.). The objective RISRAS score confirmed these results. In addition, the Skindex-16 and RISRAS subjective score demonstrated that the patients’ quality of life was significantly better in the LT than in the control group.
Conclusions: The results of this trial show that PBMT is an effective tool to prevent the development of grade 2 acute RD or higher in BC patients. In addition, it also reduces the patients’ symptoms related to RD. Lasers Surg. Med. © 2018 Wiley Periodicals, Inc.
Keywords: breast cancer; low-level laser therapy; photobiomodulation therapy; radiodermatitis; radiotherapy.
Abstract:
Background: Oral mucositis (OM) is a complication of chemoradiotherapy treatment of head and neck squamous cell carcinoma (HNSCC) patients with no effective therapy. This study was designed to assess the efficacy of preventive low-level laser therapy (LLLT) in reducing the incidence of grade 3-4 OM.
Material and methods: From June 2007 to December 2010, 94 HNSCC patients entered a prospective, randomized, double-blind, placebo-controlled phase III trial. Chemoradiotherapy consisted of conventional radiotherapy plus concurrent cisplatin every 3weeks. A diode InGaAlP (660nm-100mW-1J-4J/cm(2)) was used. OM evaluation was performed by WHO and OMAS scales and quality of life by EORTC questionnaires (QLQ).
Results: A six-fold decrease in the incidence of grades 3-4 OM was detected in the LLLT group compared to the placebo; (6.4% versus 40.5%). LLLT impacted the incidence of grades 3-4 OM to a relative risk ratio of 0.158 (CI 95% 0.050-0.498). After treatment QLQ-C30 showed, differences favoring LLLT in physical, emotional functioning, fatigue, and pain; while the QLQ-H&N35 showed improvements in LLLT arm for pain, swallowing, and trouble with social eating.
Conclusion: Preventive LLLT in HNSCC patients receiving chemoradiotherapy is an effective tool for reducing the incidence of grade 3-4 OM. Efficacy data were corroborated by improvements seen in quality of life.
Keywords: Chemotherapy; Head and neck cancer; Low-level laser therapy; Oral mucositis; Quality of life; Radiotherapy.
Abstract:
Purpose: To systematically review the literature and update the evidence-based clinical practice guidelines for the use of photobiomodulation (PBM), such as laser and other light therapies, for the prevention and/or treatment of oral mucositis (OM).
Methods: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) using PubMed and Web of Science. We followed the MASCC methods for systematic review and guidelines development. The rigorously evaluated evidence for each intervention, in each cancer treatment setting, was assigned a level-of-evidence (LoE). Based on the LoE, one of the following guidelines was determined: Recommendation, Suggestion, or No Guideline Possible.
Results: Recommendations are made for the prevention of OM and related pain with PBM therapy in cancer patients treated with one of the following modalities: hematopoietic stem cell transplantation, head and neck (H&N) radiotherapy (without chemotherapy), and H&N radiotherapy with chemotherapy. For each of these modalities, we recommend 1-2 clinically effective protocols; the clinician should adhere to all parameters of the protocol selected. Due to inadequate evidence, currently, No Guideline Possible for treatment of established OM or for management of chemotherapy-related OM. The reported clinical settings were extremely variable, limiting data integration.
Conclusions: The evidence supports the use of specific settings of PBM therapy for the prevention of OM in specific patient populations. Under these circumstances, PBM is recommended for the prevention of OM. The guidelines are subject to continuous update based on new published data.
Keywords: Cancer; Chemotherapy; Evidence-based; Guidelines; LED; LLLT; Laser therapy; Low-level laser therapy; Oral complications of cancer therapy; Oral mucositis; Pain; Photobiomodulation; Photobiostimulation; Prevention; Radiotherapy; Stomatitis; Treatment.
Abstract:
Background: Photobiomodulation (PBM) therapy is a rapidly growing approach to stimulate healing, reduce pain, increase athletic performance, and improve general wellness.
Objective: Applying PBM therapy over the site of a tumor has been considered to be a contraindication. However, since another growing use of PBM therapy is to mitigate the side effects of cancer therapy, this short review seeks to critically examine the evidence of whether PBM therapy is beneficial or harmful in cancer patients.
Materials and methods: PubMed and Google Scholar were searched.
Results: Although there are a few articles suggesting that PBM therapy can be detrimental in animal models of tumors, there are also many articles that suggest the opposite and that light can directly damage the tumor, can potentiate other cancer therapies, and can stimulate the host immune system. Moreover, there are two clinical trials showing increased survival in cancer patients who received PBM therapy.
Conclusions: PBM therapy may have benefits in cancer patients and should be further investigated.
Keywords: antitumor immune response; cancer; cancer therapy side effects; contraindication; low-level laser therapy; photobiomodulation.
Neurology & Neurodegenerative Diseases
Transcranial PBM (tPBM) applies red and NIR light to the scalp to modulate cortical and subcortical neuronal activity. Research supports neuroprotective and neuroregenerative effects in traumatic brain injury (TBI), stroke, Alzheimer’s disease, Parkinson’s disease, and depression. Proposed mechanisms include increased cytochrome c oxidase activity in metabolically compromised neurons, upregulation of BDNF, anti-apoptotic signalling, and reduction of neuroinflammation.
Abstract:
Photobiomodulation (PBM) describes the use of red or near-infrared light to stimulate, heal, regenerate, and protect tissue that has either been injured, is degenerating, or else is at risk of dying. One of the organ systems of the human body that is most necessary to life, and whose optimum functioning is most worried about by humankind in general, is the brain. The brain suffers from many different disorders that can be classified into three broad groupings: traumatic events (stroke, traumatic brain injury, and global ischemia), degenerative diseases (dementia, Alzheimer’s and Parkinson’s), and psychiatric disorders (depression, anxiety, post traumatic stress disorder). There is some evidence that all these seemingly diverse conditions can be beneficially affected by applying light to the head. There is even the possibility that PBM could be used for cognitive enhancement in normal healthy people. In this transcranial PBM (tPBM) application, near-infrared (NIR) light is often applied to the forehead because of the better penetration (no hair, longer wavelength). Some workers have used lasers, but recently the introduction of inexpensive light emitting diode (LED) arrays has allowed the development of light emitting helmets or «brain caps». This review will cover the mechanisms of action of photobiomodulation to the brain, and summarize some of the key pre-clinical studies and clinical trials that have been undertaken for diverse brain disorders.
Keywords: Alzheimer’s disease; Cognitive enhancement; Ischemic stroke; Low level laser (light) therapy; Major depression; Parkinson’s disease; Photobiomodulation; Traumatic brain injury.
Abstract:
Objective: Two chronic, traumatic brain injury (TBI) cases, where cognition improved following treatment with red and near-infrared light-emitting diodes (LEDs), applied transcranially to forehead and scalp areas, are presented.
Background: Significant benefits have been reported following application of transcranial, low-level laser therapy (LLLT) to humans with acute stroke and mice with acute TBI. These are the first case reports documenting improved cognitive function in chronic, TBI patients treated with transcranial LED.
Methods: Treatments were applied bilaterally and to midline sagittal areas using LED cluster heads [2.1″ diameter, 61 diodes (9 × 633 nm, 52 × 870 nm); 12-15 mW per diode; total power: 500 mW; 22.2 mW/cm(2); 13.3 J/cm(2) at scalp (estimated 0.4 J/cm(2) to cortex)].
Results: Seven years after closed-head TBI from a motor vehicle accident, Patient 1 began transcranial LED treatments. Pre-LED, her ability for sustained attention (computer work) lasted 20 min. After eight weekly LED treatments, her sustained attention time increased to 3 h. The patient performs nightly home treatments (5 years); if she stops treating for more than 2 weeks, she regresses. Patient 2 had a history of closed-head trauma (sports/military, and recent fall), and magnetic resonance imaging showed frontoparietal atrophy. Pre-LED, she was on medical disability for 5 months. After 4 months of nightly LED treatments at home, medical disability discontinued; she returned to working full-time as an executive consultant with an international technology consulting firm. Neuropsychological testing after 9 months of transcranial LED indicated significant improvement (+1, +2SD) in executive function (inhibition, inhibition accuracy) and memory, as well as reduction in post-traumatic stress disorder. If she stops treating for more than 1 week, she regresses. At the time of this report, both patients are continuing treatment.
Conclusions: Transcranial LED may improve cognition, reduce costs in TBI treatment, and be applied at home. Controlled studies are warranted.
Abstract:
This pilot, open-protocol study examined whether scalp application of red and near-infrared (NIR) light-emitting diodes (LED) could improve cognition in patients with chronic, mild traumatic brain injury (mTBI). Application of red/NIR light improves mitochondrial function (especially in hypoxic/compromised cells) promoting increased adenosine triphosphate (ATP) important for cellular metabolism. Nitric oxide is released locally, increasing regional cerebral blood flow. LED therapy is noninvasive, painless, and non-thermal (cleared by the United States Food and Drug Administration [FDA], an insignificant risk device). Eleven chronic, mTBI participants (26-62 years of age, 6 males) with nonpenetrating brain injury and persistent cognitive dysfunction were treated for 18 outpatient sessions (Monday, Wednesday, Friday, for 6 weeks), starting at 10 months to 8 years post- mTBI (motor vehicle accident [MVA] or sports-related; and one participant, improvised explosive device [IED] blast injury). Four had a history of multiple concussions. Each LED cluster head (5.35 cm diameter, 500 mW, 22.2 mW/cm(2)) was applied for 10 min to each of 11 scalp placements (13 J/cm(2)). LEDs were placed on the midline from front-to-back hairline; and bilaterally on frontal, parietal, and temporal areas. Neuropsychological testing was performed pre-LED, and at 1 week, and 1 and 2 months after the 18th treatment. A significant linear trend was observed for the effect of LED treatment over time for the Stroop test for Executive Function, Trial 3 inhibition (p=0.004); Stroop, Trial 4 inhibition switching (p=0.003); California Verbal Learning Test (CVLT)-II, Total Trials 1-5 (p=0.003); and CVLT-II, Long Delay Free Recall (p=0.006). Participants reported improved sleep, and fewer post-traumatic stress disorder (PTSD) symptoms, if present. Participants and family reported better ability to perform social, interpersonal, and occupational functions. These open-protocol data suggest that placebo-controlled studies are warranted.
Keywords: executive function; mTBI; photobiomodulation; treatment for mTBI.
Abstract:
Alzheimer’s and Parkinson’s disease are the two most common neurodegenerative disorders. They develop after a progressive death of many neurons in the brain. Although therapies are available to treat the signs and symptoms of both diseases, the progression of neuronal death remains relentless, and it has proved difficult to slow or stop. Hence, there is a need to develop neuroprotective or disease-modifying treatments that stabilize this degeneration. Red to infrared light therapy (λ = 600-1070 nm), and in particular light in the near infrared (NIr) range, is emerging as a safe and effective therapy that is capable of arresting neuronal death. Previous studies have used NIr to treat tissue stressed by hypoxia, toxic insult, genetic mutation and mitochondrial dysfunction with much success. Here we propose NIr therapy as a neuroprotective or disease-modifying treatment for Alzheimer’s and Parkinson’s patients.
Keywords: amyloid plaques; disease-modifying; neuroprotection; photobiomodulation; tau protein.
Abstract:
Transcranial laser therapy (TLT) was tested for efficacy in a mouse model of Alzheimer’s disease (AD) using a near-infrared energy laser system. TLT is thought to stimulate ATP production, increase mitochondrial activity, and help maintain neuronal function. Studies were performed to determine the effect of TLT in an amyloid-β protein precursor (AβPP) transgenic mouse model. TLT was administered 3 times/week at various doses, starting at 3 months of age, and was compared to a control group (no laser treatment). Treatment was continued for a total of six months. Animals were examined for amyloid load, inflammatory markers, brain amyloid-β (Aβ) levels, plasma Aβ levels, cerebrospinal fluid Aβ levels, soluble AβPP (sAβPP) levels, and behavioral changes. The numbers of Aβ plaques were significantly reduced in the brain with administration of TLT in a dose-dependent fashion. Administration of TLT was associated with a dose-dependent reduction in amyloid load. All TLT doses mitigated the behavioral effects seen with advanced amyloid deposition and reduce the expression of inflammatory markers in the AβPP transgenic mice. All TLT doses produced an increase in sAβPPα and a decrease in CTFβ levels consistent with inhibition of the β-secretase activity. In addition, TLT showed an increase in ATP levels, mitochondrial function, and c-fos suggesting an overall improvement in neurological function. These studies suggest that TLT is a potential candidate for treatment of AD.
Abstract:
Transcranial low-level laser (light) therapy (LLLT) is a new non-invasive approach to treating a range of brain disorders including traumatic brain injury (TBI). We (and others) have shown that applying near-infrared light to the head of animals that have suffered TBI produces improvement in neurological functioning, lessens the size of the brain lesion, reduces neuroinflammation, and stimulates the formation of new neurons. In the present study we used a controlled cortical impact TBI in mice and treated the mice either once (4 h post-TBI, 1-laser), or three daily applications (3-laser) with 810 nm CW laser 36 J/cm(2) at 50 mW/cm(2). Similar to previous studies, the neurological severity score improved in laser-treated mice compared to untreated TBI mice at day 14 and continued to further improve at days 21 and 28 with 3-laser being better than 1-laser. Mice were sacrificed at days 7 and 28 and brains removed for immunofluorescence analysis. Brain-derived neurotrophic factor (BDNF) was significantly upregulated by laser treatment in the dentate gyrus of the hippocampus (DG) and the subventricular zone (SVZ) but not in the perilesional cortex (lesion) at day 7 but not at day 28. Synapsin-1 (a marker for synaptogenesis, the formation of new connections between existing neurons) was significantly upregulated in lesion and SVZ but not DG, at 28 days but not 7 days. The data suggest that the benefit of LLLT to the brain is partly mediated by stimulation of BDNF production, which may in turn encourage synaptogenesis. Moreover the pleiotropic benefits of BDNF in the brain suggest LLLT may have wider applications to neurodegenerative and psychiatric disorders. Neurological Severity Score (NSS) for TBI mice.
Keywords: BDNF; Synapsin-1; neurogenesis; synaptogenesis; transcranial low level light therapy; traumatic brain injury.
Abstract:
Transcranial photobiomodulation (PBM) also known as low level laser therapy (tLLLT) relies on the use of red/NIR light to stimulate, preserve and regenerate cells and tissues. The mechanism of action involves photon absorption in the mitochondria (cytochrome c oxidase), and ion channels in cells leading to activation of signaling pathways, up-regulation of transcription factors, and increased expression of protective genes. We have studied PBM for treating traumatic brain injury (TBI) in mice using a NIR laser spot delivered to the head. Mice had improved memory and learning, increased neuroprogenitor cells in the dentate gyrus and subventricular zone, increased BDNF and more synaptogenesis in the cortex. These highly beneficial effects on the brain suggest that the applications of tLLLT are much broader than at first conceived. Other groups have studied stroke (animal models and clinical trials), Alzheimer’s disease, Parkinson’s disease, depression, and cognitive enhancement in healthy subjects.
Keywords: Alzheimer’s disease; Transcranial photobiomodulation; brain disorders; low level laser therapy; psychiatric diseases; stroke; traumatic brain injury.
Future of Photobiomodulation
The future of PBM encompasses expanding clinical indications, device miniaturisation, wearable and implantable light delivery systems, and integration with digital health platforms. Research frontiers include optimised dosimetry protocols, combination therapies with pharmacological agents and rehabilitation, microbiome modulation, and PBM for systemic conditions via intravenous or transcutaneous blood irradiation. Standardisation of treatment parameters and large-scale RCTs are priorities for advancing evidence-based integration into mainstream medicine.
Abstract:
The fundamental pathophysiologic response for the survival of all organisms is the process of wound healing. Inadequate or lack of healing constitutes the etiopathologic basis of many oral and systemic diseases. Among the numerous efforts to promote wound healing, biophotonics therapies have shown much promise. Advances in photonic technologies and a better understanding of light-tissue interactions, from parallel biophotonics fields such as in vivo optical imaging and optogenetics, are spearheading their popularity in biology and medicine. Use of high-dose lasers and light devices in dermatology, ophthalmology, oncology, and dentistry are now popular for specific clinical applications, such as surgery, skin rejuvenation, ocular and soft tissue recontouring, and antitumor and antimicrobial photodynamic therapy. However, a less well-known clinical application is the therapeutic use of low-dose biophotonics termed photobiomodulation (PBM) therapy, which is aimed at alleviating pain and inflammation, modulating immune responses, and promoting wound healing and tissue regeneration. Despite significant volumes of scientific literature from clinical and laboratory studies noting the phenomenological evidence for this innovative therapy, limited mechanistic insights have prevented rigorous and reproducible PBM clinical protocols. This article briefly reviews current evidence and focuses on gaps in knowledge to identify potential paths forward for clinical translation with PBM therapy with an emphasis on craniofacial wound healing. PBM offers a novel opportunity to examine fundamental nonvisual photobiological processes as well as develop innovative clinical therapies, thereby presenting an opportunity for a paradigm shift from conventional restorative/prosthetic approaches to regenerative modalities in clinical dentistry.
Keywords: ROS; TGF-β; biophotonics; laser; low level light/laser therapy; regeneration.
Abstract:
Photobiomodulation (PBM) describes the use of red or near-infrared (NIR) light to stimulate, heal, and regenerate damaged tissue. Both preconditioning (light delivered to muscles before exercise) and PBM applied after exercise can increase sports performance in athletes. This review covers the effects of PBM on human muscle tissue in clinical trials in volunteers related to sports performance and in athletes. The parameters used were categorized into those with positive effects or no effects on muscle performance and recovery. Randomized controlled trials and case-control studies in both healthy trained and untrained participants, and elite athletes were retrieved from MEDLINE up to 2016. Performance metrics included fatigue, number of repetitions, torque, hypertrophy; measures of muscle damage and recovery such as creatine kinase and delayed onset muscle soreness. Searches retrieved 533 studies, of which 46 were included in the review (n = 1045 participants). Studies used single laser probes, cluster of laser diodes, LED clusters, mixed clusters (lasers and LEDs), and flexible LED arrays. Both red, NIR, and red/NIR mixtures were used. PBM can increase muscle mass gained after training, and decrease inflammation and oxidative stress in muscle biopsies. We raise the question of whether PBM should be permitted in athletic competition by international regulatory authorities.
Keywords: LEDT; LLLT; creatine kinase; delayed onset muscle soreness; fatigue; photobiomodulation.
Abstract:
Background: There is about ten years since the first randomized controlled trial looking for the effects of photobiomodulation therapy using low-level laser therapy and/or light emitting diodes therapy in athletic performance enhancement was published. Since then, the knowledge in this field has increasing exponentially.
Objective: Given the fast advance in clinical interest, research and development in the use of photobiomodulation therapy for athletic performance enhancement and also to accelerate post-exercise recovery, as pioneers in this research field we felt the need to establish recommendations to ensure the correct use of the therapy, and also to guide the further studies in this area looking for the achievement of highest scientific evidence. It is important to highlight that the establishment of both clinical and scientific recommendations in this masterclass article were based on the most recent systematic reviews with meta-analysis and randomized controlled trials published in this field. It is important to stress that the recommendations of this masterclass article are based on most recent systematic reviews with meta-analysis and RCTs published in this research field. Future guidelines must follow the same direction and must be based only at the highest scientific evidence, avoiding overstatements and extrapolations based on animal experiments and case-studies.
Keywords: Light emitting diodes therapy; Low-level laser therapy; Phototherapy; Rehabilitation; Sports.
Abstract:
Purpose: To systematically review the literature and update the evidence-based clinical practice guidelines for the use of photobiomodulation (PBM), such as laser and other light therapies, for the prevention and/or treatment of oral mucositis (OM).
Methods: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) using PubMed and Web of Science. We followed the MASCC methods for systematic review and guidelines development. The rigorously evaluated evidence for each intervention, in each cancer treatment setting, was assigned a level-of-evidence (LoE). Based on the LoE, one of the following guidelines was determined: Recommendation, Suggestion, or No Guideline Possible.
Results: Recommendations are made for the prevention of OM and related pain with PBM therapy in cancer patients treated with one of the following modalities: hematopoietic stem cell transplantation, head and neck (H&N) radiotherapy (without chemotherapy), and H&N radiotherapy with chemotherapy. For each of these modalities, we recommend 1-2 clinically effective protocols; the clinician should adhere to all parameters of the protocol selected. Due to inadequate evidence, currently, No Guideline Possible for treatment of established OM or for management of chemotherapy-related OM. The reported clinical settings were extremely variable, limiting data integration.
Conclusions: The evidence supports the use of specific settings of PBM therapy for the prevention of OM in specific patient populations. Under these circumstances, PBM is recommended for the prevention of OM. The guidelines are subject to continuous update based on new published data.
Keywords: Cancer; Chemotherapy; Evidence-based; Guidelines; LED; LLLT; Laser therapy; Low-level laser therapy; Oral complications of cancer therapy; Oral mucositis; Pain; Photobiomodulation; Photobiostimulation; Prevention; Radiotherapy; Stomatitis; Treatment.