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"Photobiology is broadly defined to include all biological phenomena involving non-ionizing radiation. It is recognized that photobiological responses are the result of chemical and/or physical changes induced in biological systems by non-ionizing radiation."
(Constitution of the American Society for Photobiology)
Huang Y.Y., Moroz P., Hamblin M.R. Basic Photomedicine. Ying-Ying Huang, Pawel Mroz, and Michael R. Hamblin
Karu, T. Light Coherence: Is this property important for Photomedicine? By Institute of Laser and Information Technologies, Russian Academy of Sciences, Troitsk 142190, Moscow Region, Russian Federation,
Krassovka, Julia, Annika Borgschulze, Benita Sahlender, Tim Lögters, Joachim Windolf, and Vera Grotheer. Blue light irradiation and its beneficial effect on Dupuytren’s fibroblasts. PloS one 14, no. 1 (2019): e0209833.
Dupuytren’s contracture is a fibroproliferative disorder affecting the palmar fascia of the hand. Most affected are the ring fingers, and little fingers of middle-aged men. Symptomatic for this disease is the increased proliferation and differentiation of fibroblasts to myofibroblasts, which is accompanied by an elevated α-SMA expression. The present study evaluated the therapeutic benefit of blue light (λ = 453 nm, 38 mW/cm2, continuous radiance, spot size 10–12 cm2) as well as the molecular mechanism mediating this effect. It could be determined that blue light significantly diminished the induced α-SMA protein expression in both normal palmar fibroblasts and Duypuytren’s fibroblasts. The beneficial effect mediated by this irradiance, radiant exposure and wavelength was associated with an elevated reactive oxygen species generation. Furthermore, the data underlines the potential usefulness of blue light irradiation as a promising therapy option for Dupuytren’s disease, especially for relapse prevention, and may represent a useful strategy to treat further fibrotic diseases, such as keloids, hypertrophic scarring, and scleroderma.
Gibbs, Neil K., Joanne Tye, and Mary Norval. Recent advances in urocanic acid photochemistry, photobiology and photoimmunology. Photochemical & Photobiological Sciences7, no. 6 (2008): 655-667.
Urocanic acid (UCA), produced in the upper layers of mammalian skin, is a major absorber of ultraviolet radiation (UVR). Originally thought to be a ‘natural sunscreen’, studies conducted a quarter of a century ago proposed that UCA may be a chromophore for the immunosuppression that follows exposure to UVR. With its intriguing photochemistry, its role in immunosuppression and skin cancer development, and skin barrier function, UCA continues to be the subject of intense research effort. This review summarises the photochemical, photobiological and photoimmunological findings regarding UCA, published since 1998.
Strickland, F. Basic Photoimmunology. Faith M. Strickland
Department of Internal Medicine, Rheumatology Division
The University of Michigan,
Tadakuma, Takushi. Possible application of the laser in immunobiology. The Keio journal of medicine 42, no. 4 (1993): 180-182.
Agostinis, Patrizia, Kristian Berg, Keith A. Cengel, Thomas H. Foster, Albert W. Girotti, Sandra O. Gollnick, Stephen M. Hahn et al. Photodynamic therapy of cancer: an update. CA: a cancer journal for clinicians 61, no. 4 (2011): 250-281.
Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long‐term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function‐sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment.
Brown, Stanley B., Elizabeth A. Brown, and Ian Walker. The present and future role of photodynamic therapy in cancer treatment. The lancet oncology 5, no. 8 (2004): 497-508.
It is more than 25 years since photodynamic therapy (PDT) was proposed as a useful tool in oncology, but the approach is only now being used more widely in the clinic. The understanding of the biology of PDT has advanced, and efficient, convenient, and inexpensive systems of light delivery are now available. Results from well-controlled, randomised phase III trials are also becoming available, especially for treatment of non-melanoma skin cancer and Barrett’s oesophagus, and improved photosensitising drugs are in development. PDT has several potential advantages over surgery and radiotherapy: it is comparatively non-invasive, it can be targeted accurately, repeated doses can be given without the total-dose limitations associated with radiotherapy, and the healing process results in little or no scarring. PDT can usually be done in an outpatient or day-case setting, is convenient for the patient, and has no side-effects. Two photosensitising drugs, porfirmer sodium and temoporfin, have now been approved for systemic administration, and aminolevulinic acid and methyl aminolevulinate have been approved for topical use. Here, we review current use of PDT in oncology and look at its future potential as more selective photosensitising drugs become available.
Castano, Ana P., Pawel Mroz, and Michael R. Hamblin. Photodynamic therapy and anti-tumour immunity. Nature Reviews Cancer 6, no. 7 (2006): 535.
Photodynamic therapy (PDT) uses non-toxic photosensitizers and harmless visible light in combination with oxygen to produce cytotoxic reactive oxygen species that kill malignant cells by apoptosis and/or necrosis, shut down the tumour microvasculature and stimulate the host immune system. In contrast to surgery, radiotherapy and chemotherapy that are mostly immunosuppressive, PDT causes acute inflammation, expression of heat-shock proteins, invasion and infiltration of the tumour by leukocytes, and might increase the presentation of tumour-derived antigens to T cells.
Dolmans, Dennis EJGJ, Dai Fukumura, and Rakesh K. Jain. Photodynamic therapy for cancer. Nature reviews cancer 3, no. 5 (2003): 380.
Dougherty, Thomas J., Charles J. Gomer, Barbara W. Henderson, Giulio Jori, David Kessel, Mladen Korbelik, Johan Moan, and Qian Peng. Photodynamic therapy. JNCI: Journal of the national cancer institute 90, no. 12 (1998): 889-905.
Photodynamic therapy involves administration of a tumorlocalizing photosensitizing agent, which may require metabolic synthesis (i.e., a prodrug), followed by activation of the agent by light of a specific wavelength. This therapy results in a sequence of photochemical and photobiologic processes that cause irreversible photodamage to tumor tissues. Results from preclinical and clinical studies conducted worldwide over a 25-year period have established photodynamic therapy as a useful treatment approach for some cancers. Since 1993, regulatory approval for photodynamic therapy involving use of a partially purified, commercially available hematoporphyrin derivative compound (Photofrint) in patients with early and advanced stage cancer of the lung, digestive tract, and genitourinary tract has been obtained in Canada, The Netherlands, France, Germany, Japan, and the United States. We have attempted to conduct and present a comprehensive review of this rapidly expanding field. Mechanisms of subcellular and tumor localization of photosensitizing agents, as well as of molecular, cellular, and tumor responses associated with photodynamic therapy, are discussed.
Hamblin, Michael R., and Tayyaba Hasan. Photodynamic therapy: a new antimicrobial approach to infectious disease? Photochemical & Photobiological Sciences 3, no. 5 (2004): 436-450.
Photodynamic therapy (PDT) employs a non-toxic dye, termed a photosensitizer (PS), and low intensity visible light which, in the presence of oxygen, combine to produce cytotoxic species. PDT has the advantage of dual selectivity, in that the PS can be targeted to its destination cell or tissue and, in addition, the illumination can be spatially directed to the lesion. PDT has previously been used to kill pathogenic microorganisms in vitro, but its use to treat infections in animal models or patients has not, as yet, been much developed. It is known that Gram (−) bacteria are resistant to PDT with many commonly used PS that will readily lead to phototoxicity in Gram-(+) species, and that PS bearing a cationic charge or the use of agents that increase the permeability of the outer membrane will increase the efficacy of killing Gram-(−) organisms. All the available evidence suggests that multi-antibiotic resistant strains are as easily killed by PDT as naïve strains, and that bacteria will not readily develop resistance to PDT. Treatment of localized infections with PDT requires selectivity of the PS for microbes over host cells, delivery of the PS into the infected area and the ability to effectively illuminate the lesion. Recently, there have been reports of PDT used to treat infections in selected animal models and some clinical trials: mainly for viral lesions, but also for acne, gastric infection by Helicobacter pylori and brain abcesses. Possible future clinical applications include infections in wounds and burns, rapidly spreading and intractable soft-tissue infections and abscesses, infections in body cavities such as the mouth, ear, nasal sinus, bladder and stomach, and surface infections of the cornea and skin.
Kessel, D. Introduction to Photodynamic Therapy. David Kessel, Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201;
Circadian Effect of Photobiology
Geerdink, Moniek, Thijs J. Walbeek, Domien GM Beersma, Vanja Hommes, and Marijke CM Gordijn. Short blue light pulses (30 min) in the morning support a sleep-advancing protocol in a home setting. Journal of biological rhythms 31, no. 5 (2016): 483-497.
Many people in our modern civilized society sleep later on free days compared to work days. This discrepancy in sleep timing will lead to so-called ‘social jetlag’ on work days with negative consequences for performance and health. Light therapy in the morning is often proposed as the most effective method to advance the circadian rhythm and sleep phase. However, most studies focus on direct effects on the circadian system and not on posttreatment effects on sleep phase and sleep integrity. In this placebo-controlled home study we investigated if blue light, rather than amber light therapy, can phase shift the sleep phase along with the circadian rhythm with preservation of sleep integrity and performance. We selected 42 participants who suffered from ‘social jetlag’ on workdays. Participants were randomly assigned to either high-intensity blue light exposure or amber light exposure (placebo) with similar photopic illuminance. The protocol consisted of 14 baseline days without sleep restrictions, 9 treatment days with either 30-min blue light pulses or 30-min amber light pulses in the morning along with a sleep advancing scheme and 7 posttreatment days without sleep restrictions. Melatonin samples were taken at days 1, 7, 14 (baseline), day 23 (effect treatment), and day 30 (posttreatment). Light exposure was recorded continuously. Sleep was monitored through actigraphy. Performance was measured with a reaction time task. As expected, the phase advance of the melatonin rhythm from day 14 to day 23 was significantly larger in the blue light exposure group, compared to the amber light group (84 min ± 51 (SD) and 48 min ± 47 (SD) respectively; t36= 2.23, p < 0.05). Wake-up time during the posttreatment days was slightly earlier compared to baseline in the blue light group compared to slightly later in the amber light group (–21 min ± 33 (SD) and +12 min ± 33 (SD) respectively; F1,35= 9.20, p < 0.01). The number of sleep bouts was significantly higher in the amber light group compared to the blue light group during sleep in the treatment period (F1,32= 4.40, p < 0.05). Performance was significantly worse compared to baseline at all times during (F1,13= 10.1, p < 0.01) and after amber light treatment (F1,13= 17.1, p < 0.01), while only in the morning during posttreatment in the blue light condition (F1,10= 9.8, p < 0.05). The data support the conclusion that blue light was able to compensate for the sleep integrity reduction and to a large extent for the performance decrement that was observed in the amber light condition, both probably as a consequence of the advancing sleep schedule. This study shows that blue light therapy in the morning, applied in a home setting, supports a sleep advancing protocol by phase advancing the circadian rhythm as well as sleep timing.
Sengupta, A. Melanopsin: A Photopigment Regulating Circadian Photoentrainment May Lead to a Blue Light-Induced Treatment of Diabetes. Anamika Sengupta Center for Teaching and Learning, Ross University School of Medicine, Commonwealth of Dominica, West Indies
Tähkämö, Leena, Timo Partonen, and Anu-Katriina Pesonen. Systematic review of light exposure impact on human circadian rhythm. Chronobiology international 36, no. 2 (2019): 151-170.
Light is necessary for life, and artificial light improves visual performance and safety, but there is an increasing concern of the potential health and environmental impacts of light.
Findings from a number of studies suggest that mistimed light exposure disrupts the circadian rhythm in humans, potentially causing further health impacts. However, a variety of methods has been applied in individual experimental studies of light-induced circadian impacts, including definition of light exposure and outcomes. Thus, a systematic review is needed to synthesize the results. In addition, a review of the scientific evidence on the impacts of light on circadian rhythm is needed for developing an evaluation method of light pollution, i.e., the negative impacts of artificial light, in life cycle assessment (LCA). The current LCA practice does not have a method to evaluate the light pollution, neither in terms of human health nor the ecological impacts. The systematic literature survey was conducted by searching for two concepts: light and circadian rhythm. The circadian rhythm was searched with additional terms of melatonin and rapid-eye-movement (REM) sleep. The literature search resulted to 128 articles which were subjected to a data collection and analysis. Melatonin secretion was studied in 122 articles and REM sleep in 13 articles. The reports on melatonin secretion were divided into studies with specific light exposure (101 reports), usually in a controlled laboratory environment, and studies of prevailing light conditions typical at home or work environments (21 studies). Studies were generally conducted on adults in their twenties or thirties, but only very few studies experimented on children and elderly adults. Surprisingly many studies were conducted with a small sample size: 39 out of 128 studies were conducted with 10 or less subjects. The quality criteria of studies for more profound synthesis were a minimum sample size of 20 subjects and providing details of the light exposure (spectrum or wavelength; illuminance, irradiance or photon density). This resulted to 13 qualified studies on melatonin and 2 studies on REM sleep. Further analysis of these 15 reports indicated that a two-hour exposure to blue light (460 nm) in the evening suppresses melatonin, the maximum melatonin-suppressing effect being achieved at the shortest wavelengths (424 nm, violet). The melatonin concentration recovered rather rapidly, within 15 min from cessation of the exposure, suggesting a short-term or simultaneous impact of light exposure on the melatonin secretion. Melatonin secretion and suppression were reduced with age, but the light-induced circadian phase advance was not impaired with age. Light exposure in the evening, at night and in the morning affected the circadian phase of melatonin levels. In addition, even the longest wavelengths (631 nm, red) and intermittent light exposures induced circadian resetting responses, and exposure to low light levels (5–10 lux) at night when sleeping with eyes closed induced a circadian response. The review enables further development of an evaluation method of light pollution in LCA regarding the light-induced impacts on human circadian system.
Low Level Laser or LED Therapy
Aimbire, F., R. Albertini, M. T. T. Pacheco, H. C. Castro-Faria-Neto, P. S. L. M. Leonardo, V. V. Iversen, R. A. B. Lopes-Martins, and J. M. Bjordal. Low-level laser therapy induces dose-dependent reduction of TNFα levels in acute inflammation. Photomedicine and laser surgery 24, no. 1 (2006): 33-37.
The aim of this study was to investigate if low-level laser therapy (LLLT) can modulate acute inflammation and tumor necrosis factor (TNF α) levels. Background Data: Drug therapy with TNF α -inhibitors has become standard treatment for rheumatoid arthritis, but it is unknown if LLLT can reduce or modulate TNF α levels in inflammatory disorders. Methods: Two controlled animal studies were undertaken, with 35 male Wistar rats randomly divided into five groups each. Rabbit antiserum to ovalbumin was instilled intrabronchially in one of the lobes, followed by the intravenous injection of 10 mg of ovalbumin in 0.5 mL to induce acute lung injury. The first study served to define the time profile of TNF α activity for the first 4 h, while the second study compared three different LLLT doses to a control group and a chlorpromazine group at a timepoint where TNF activity was increased. The rats in LLLT groups were irradiated within 5 min at the site of injury by a 650-nm Ga-Al-As laser. Results: There was a time-lag before TNF α activity increased after BSA injection. TNF α levels increased from 6.9 (95% confidence interval [CI], 5.6–8.2) units/mL in the first 3 h to 62.1 (95% CI, 60.8–63.4) units/mL (p < 0.001) at 4 h. An LLLT dose of 0.11 Joules administered with a power density of 31.3 mW/cm2 in 42 sec significantly reduced TNF α level to 50.2 (95% CI, 49.4–51.0), p < 0.01 units/mL versus control. Chlorpromazine reduced TNF α level to 45.3 (95% CI, 44.0–46.6) units/mL, p < 0.001 versus control. Conclusion: LLLT can reduce TNF α expression after acute immunocomplex lung injury in rats, but LLLT dose appears to be critical for reducing TNF α release.
Bjordal, Jan M., Christian Couppé, Roberta T. Chow, Jan Tunér, and Elisabeth Anne Ljunggren. A systematic review of low level laser therapy with location-specific doses for pain from chronic joint disorders. Australian Journal of Physiotherapy 49, no. 2 (2003): 107-116.
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.
Chung, Hoon, Tianhong Dai, Sulbha K. Sharma, Ying-Ying Huang, James D. Carroll, and Michael R. Hamblin. The nuts and bolts of low-level laser (light) therapy. Annals of biomedical engineering 40, no. 2 (2012): 516-533.
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 tissue 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.
Hamblin M. Mechanisms of Low-Level Light Therapy by Michael R. Hamblin, Department of Dermatology, Harvard Medical School, BAR 414 Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston, MA 02114, firstname.lastname@example.org.
Hashmi, Javad T., Ying‐Ying Huang, Bushra Z. Osmani, Sulbha K. Sharma, Margaret A. Naeser, and Michael R. Hamblin. Role of low‐level laser therapy in neurorehabilitation. Pm&r 2 (2010): S292-S305.
This year marks the 50th anniversary of the discovery of the laser. The development of lasers for medical use, which became known as low-level laser therapy (LLLT) or photobiomodulation, followed in 1967. In recent years, LLLT has become an increasingly mainstream modality, especially in the areas of physical medicine and rehabilitation. At first used mainly for wound healing and pain relief, the medical applications of LLLT have broadened to include diseases such as stroke, myocardial infarction, and degenerative or traumatic brain disorders. This review will cover the mechanisms of LLLT that operate both on a cellular and a tissue level. Mitochondria are thought to be the principal photoreceptors, and increased adenosine triphosphate, reactive oxygen species, intracellular calcium, and release of nitric oxide are the initial events. Activation of transcription factors then leads to expression of many protective, anti-apoptotic, anti-oxidant, and pro-proliferation gene products. Animal studies and human clinical trials of LLLT for indications with relevance to neurology, such as stroke, traumatic brain injury, degenerative brain disease, spinal cord injury, and peripheral nerve regeneration, will be covered.
Karu, Tiina. Photobiology of low-power laser effects. Health phys 56, no. 5 (1989): 691-704.
Quantitative studies have been performed to determine the actions of lowintensity visible monochromatic light on various cells (E-coli. yeasts, He-La Chinese hamster fibroblasts and human lymphocytes); also irradiation conditions (wavelength, dose and intensity) conducive to vital activity stimulation have been examined. Respiratory chain components are discussed as primary photo-acceptors. The possible ways for photo signal transduction and amplification are discussed. It is proposed that enhanced wound heating due to irradiation with low intensity visible laser light (He-Cd. He-Ne and semiconductor Lasers) is due to the increasing Proliferation of cells.
Moghadam, Manijeh Yousefi. Low level laser therapy: a promising adjunct therapeutic modality for pain control after coronary artery bypass graft surgery. The Korean journal of pain 32, no. 1 (2019): 51.
In conclusion, it seems that LLLT can be used as a non-invasive, easily applied, effective, and safe adjunct therapeutic modality for postoperative pain control after CABG surgery. However, further well-design studies are warranted to determine and confirm the potential clinical value of LLLT for postoperative pain management after CABG surgery, as well as its optimal choice of parameters such as power density, wavelength, pulse structure, and influence/timing of the irradiation, which can influence the effectiveness of this therapeutic modality.
Vitoriano, N. A. M., M. I. S. Martins, P. S. Silva, C. A. Martins, H. D. Teixeira, C. B. Miranda, L. M. M. Bezerra, R. M. Montenegro Jr, and J. C. Tatmatsu-Rocha. Evaluation of Low-Level Laser Therapy in Reducing Diabetic Polyneuropathy Related Pain and Sensorimotor Disorders. Lasers Med Sci(2019).
Over the past three decades physicians have used light level laser therapy (LLLT) for the management and the treatment of diabetic peripheral neuropathy and have obtained results that calls for further investigations. This study aimed to investigate the effectiveness of LLLT in treatment of pain symptoms in patients with diabetic polyneuropathy. In this study 60 patients with diabetic peripheral neuropathy were matched based on their sex, age, BMI, type of diabetes, duration of diabetes, and duration of pain, and randomized to case and control groups based on their established scores on the visual analog scale (VAS) and the Toronto clinical scoring system (TCSS). Cases received laser therapy with wavelength of 78 nm and 2.5 j/cm2 two times a week, each time for 5 min, for one month. During the same period, controls received sham laser therapy. Comparing the differences between the two groups’ VAS and TCSS mean scores before the intervention with that of the 2 weeks and 4 weeks after the intervention we were able to see a statistically significant difference between the two groups (P<0.05). On the other hand, when we compared their VAS and TCSS mean scores 4 weeks and 2 weeks after the intervention we did not find any statistically significant difference between the two groups. We achieved the same results when we examined cases’ and controls’ pre and post VAS and TCSS scores independent from each other; no improvement in the assessment based on their 2 and 4 weeks comparisons tests. Laser therapy resulted in improved neuropathy outcomes in diabetic patients who received it relative to the group that received sham therapy, evaluating before and after LLLT assessments. Further studies are needed to test types of lasers, as well as different dosage and exposure levels required in different phase of neuropathic care, so as to obtain reproducible results.
Wang, Wei, Weifeng Jiang, Chuanxi Tang, Xiao Zhang, and Jie Xiang. Clinical efficacy of low-level laser therapy in plantar fasciitis: A systematic review and meta-analysis. Medicine 98, no. 3 (2019): e14088.
This meta-analysis indicates that the LLLT in patients with PF significantly relieves the heel pain and the excellent efficacy lasts for 3 months after treatment.
Walsh, L. J. The current status of low level laser therapy in dentistry, Part 1. Soft tissue applications. Australian dental journal 42, no. 4 (1997): 247-254.
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.