Background: The paper contains a mini-review of perspective techniques for the diabetic foot and different internal diseases treatment, prevention and rehabilitation by low-intense lasers and light-emitting diodes. The mechanisms of the general and specific influences of the irradiation are discussed. The latter are determined by the photo induced biochemical reactions while the former are produced by local intensification of the blood microcirculation and related physiological effects. The technical characteristics of the biomedical engineered units and the results of the treatments are presented. The specific mechanisms of the curating influence of different wave frequencies are discussed.

Keywords: diabetic foot treatment, blood microcirculation, low-level laser therapy, light-emitting diodes

During the centuries optical radiation has been used for the therapeutic heating of surface tissues and curation of a wide set of diseases. Mostly the infrared (IR) radiation in combination with visible light (VL) of different intensities and wavelengths has been used for treatment of local skin problems, infectious diseases, skeletal, muscular and respiratory diseases, wound healing and growth stimulation.^1–3 In the prevalent cases the VL or combination of VL with IR treatment produce an enhancement in blood circulation, normalizes metabolic processes, strengthens the body's defense systems, stimulates reparative processes, and promotes the wound healing.^4–7 Expositions to VL with red/IR wavelengths improve the blood circulation in the tissues, enhance the regeneration of damaged tissues, normalizes the water balance, increase the rate of redox reactions, has a pronounced vasodilating, anti-inflammatory, analgesic, and lymph-depleting effects.^1–7 IR radiation of the wavelengths λ=0.76-400mcm penetrates into the surface tissues to a depth h~2-3cm, influences the skin thermo receptors and after 2-3minutes of the exposition causes local hyperemia accompanied by the increased blood flow and heat transfer, tissue metabolism, oxidative processes and reduce the water content in the tissues. It was shown that it is the removal of the vascular spasm and the intensification of microcirculation that underlies the therapeutic effect of VL and IR radiation in skin diseases.^6,7

During the last decades high attention has been paid to the therapeutic use of non-destructive and non-toxic low-level laser therapy^7,8 (LLLT) and light-emitting diodes^9,10 (LED). Such treatments produce moderate changes in the temperature of the irradiated tissues below the temperature range of skin thermo receptors and evoke noticeable therapeutic effect due to photochemical and photophysical mechanisms.^1,2,11,12 The mechanisms of the action of photons are associated with cellular and sub cellular receptors, where the photo induced increase/ decrease in their activity leads to a series of reactions at different scales.¹³ For example, the cellular chromophores like cytochrome C oxidase and photoactive porphyrins are responsible for the effect with absorption peaks in the near IR. Due to such mechanisms the irradiation of LEDs activates the synthesis of elastin and collagen by the cells, causes an increase of the growth factors, the remodeling of extracellular matrix, and enhanced microcirculation.^14–17 The latter is associated with activation of the mitochondrial respiration. The increase in the blood vessel diameter after the LED irradiation is confirmed by MRI,¹⁸ and the increase in the blood flow velocity has been confirmed by the Doppler velocimetry and capillarography.¹⁹ The activated synthesis of collagen and the release of growth factors provide a healing effect in bones, skin, cartilage, tendons and ligaments.²⁰ Noticeable activation of blood microcirculation promotes the rise of tissue metabolism and faster recovering after the inflammatory diseases of the skin, in the case of diabetes,^17,21 wound healing,^3,5,13,20 and pain reduction.²²

The very first mention on the heliotherapy can be found in the manuscripts of Hippocrates, but the phototherapy as a science began to form only in the 19^th century, after the discovery by the British scientists J. Down and R. Blount (1877) of the therapeutic properties of ultraviolet (UV) radiation. In 1903, Danish physiotherapist N. Finsen was awarded the Nobel Prize in Physiology and Medicine for the development and widespread introduction of treatment methods, especially autoimmune and skin diseases, with the help of focused VL irradiation. Subsequently, in a large number of experimental studies, it was shown that blue light changes the biochemical composition of blood, improves the functioning of the heart and lungs, stimulates the immune system, and has an antimicrobial effect. At the beginning of the 20th century, before the discovery of antibiotics, blue light lamps were widely used in dentistry for the treatment of gum inflammation, as well as for anesthesia.^1,2 At the cellular level, blue light stimulates ATP synthesis, regulates metabolism, improves the function of external respiration, oxygen delivery and utilization in cells, and improves the conduction of nerve impulses.^1,2 As a result, at the level of the blood circulation system, a decrease in blood viscosity, strengthening of the vessel walls, improvement of microcirculation, and an increase in blood flow velocity in the main vessels are observed. The absorption of photons by endogenous photo sensitizers leads to the appearance of photodynamic effects, such as the destruction of bilirubin and elimination from the body in the form of non-toxic products. Selective absorption of blue light by low-density lipids leads to their destruction and reduction of their level in the blood. This triggers the genetic mechanism of regulation of lipid metabolism, which leads to the destruction of atherosclerotic plaques.^1,2 Red VL and IR irradiation improves blood microcirculation in small vessels, increases the rate of redox reactions, enhances the regeneration of damaged tissues, normalizes the water balance of cells, has a pronounced vasodilating, anti-inflammatory, analgesic, lymphatic drainage and anti-oedema actions, increases local and general immunity. IR radiation with a wavelength of λ=0.76–40µm penetrates into the tissues to a depth of h=2–3cm, affects the skin thermo receptors, and after 2–3minutes, causes hyperemia on the irradiated part of the body, accompanied by the increased blood flow and heat transfer, tissue metabolism, and oxidative processes and reducing the water content in the tissues. Stronger tissue heating causes the breakdown of some protein molecules with the release of biologically active substances, which leads to a generalized vascular reaction in the body, resulting in an increase in heartbeat and sweating. Infrared irradiation of large areas of the body of the animal provides a good therapeutic effect in chronic inflammatory processes and reduces the pain response. It was shown that it is the removal of vascular spasm and the intensification of microcirculation that underlies the therapeutic effect of VL radiation in skin diseases.^23,24

Low-intensity optical radiation accelerates wound healing, has anti- inflammatory and analgesic effects, including as a post-operative analgesic, has a protective effect on cells, and prevents their death from cytotoxic factors.^7,25–29 Intensification of the microcirculation system under the action of VL+IR can be a key mechanism for wound healing³⁰ and pain reduction.³¹ The cyto protective effect of LLLs of different wavelengths and radiation doses on the cells in culture has been shown in a number of works, including cells treated with cyanide poisons,³² tetrodotoxin,³³ MPP+ and rotenone.³⁴ The cyto protective effect of LLLs and a decrease in apoptosis was recorded in neurons treated with beta-amyloids.^35,36 Despite the good reproducibility of many of the effects of LLLS on the cells in vitro, on the human body, domestic and experimental animals in vivo, the mechanisms of action at the cellular level are not entirely clear.³⁷ Recently, a lot of attention has been paid to the therapeutic use of non-destructive and non-toxic influence of LLLs and LEDs. Starting from the work,³⁸ in which the possibility of accelerating muscle regeneration and wound healing under the influence of a ruby laser with an intensity of J= 1 J/cm² was shown and confirmed,^39,40 the VL treatment in combination with IR is widely used in medical care all over the world. LED in vivo irradiation has a pronounced analgesic and anti-inflammatory effect, activates the body's protective reactions, normalizes water metabolism and increases the intensity of metabolism. It is important that LED radiation does not cause thermal damage to the tissues and contributes to the withdrawal of active radicals. Currently, the low-level optical radiation is determined by^41,42 the power of J=10^-3–10^-1 W, with a wavelength λ =300–10600 nm, frequency from f=0 (continuous) to f=5 kHz, a pulse duration t=1–500 ms, inter pulse interval t=1–500 ms, total exposure time T=10–3000 s, intensity j=0.01–10 W/cm², and total dose D=0.01–100 J/cm². Inert gases such as helium-neon (632.8 nm), argon (488 and 514nm) and krypton (521, 530, 568 and 647nm), as well as a ruby laser (694nm), semiconductor laser diodes from gallium arsenide (GaAs; 904 nm), aluminum-gallium arsenide (GaAlAs; 820 and 830 nm)⁴³ are used as a body for the lasers. Such wide variations in the treatment parameters make it difficult to standardize the experimental conditions, as well as the development, validation and implementation of appropriate therapeutic techniques.^44,45 Due to low intensity of the applied radiation and insignificant increase in the temperature of the irradiated biological object (below temperature changes to which tissue thermo receptors or the corresponding molecular receptors of cells are sensitive), that is, the practical absence of thermal effects, and the involvement of photochemical and photophysical mechanisms of action mostly.^41,46 In recent years, there has been an increasing interest in the therapeutic use of non-invasive methods, with almost no negative after-effects and contraindications, including the LEDs.^6,10,11 In this case, the mechanisms of photon action are associated with cellular and sub cellular receptors, the photo induced increase or decrease in the activity of which leads to a cascade of reactions at the cellular and tissue, and then at the organism level.¹³ A brief review of reproducible results of LED therapy is given in Table 1 & 2. According to Planck’s theory, the photons of a long-wave have less energy than the photons of a short-wave range of optical radiation E=hc / λ, where h is the Plank constant, c is the light speed in vacuum.

Therefore, LED- irradiation of skin activates the synthesis of collagen and elastin in cells, causes an increase in the content of growth factors, the formation of extracellular matrix, increased microcirculation^{11,14,15,42,50–56} The latter effect is associated with the activation of the mitochondrial respiratory chain due to photo biomodulatory effects of VL. An increase in the lumen of blood vessels after the irradiation has been confirmed by tomography,³¹ and an increase in blood flow velocity has been approved by the Doppler flowmetry and capillary chromatography.⁵⁶ An increase in the intensity of microcirculation leads to changes in the systemic circulation in the closed blood circulation system. Synthesis of collagen and the presence of growth factors provide a healing effect.⁵⁷ Activation of microcirculation contributes to increased tissue metabolism and improvement in inflammatory skin diseases, diabetes,^55,58 wound healing and pain reduction,³¹ provides rejuvenating and smoothing effect, which is confirmed by measuring the elastic modulus of the skin before and after exposure to LED in red and IR ranges.⁵⁰ The analgesic, anti- inflammatory, and vasodilating effects of AOIs have also been noted with intravenous blood irradiation with LLEL.⁵⁶ It was also noted relaxation of the MMC of the arteries by improving cellular respiration and removal of vascular spasm, improving the rheological properties of blood, normalizing the ratio of coagulation and anticoagulation systems.

Modern biomedical engineering units for phototherapy

Phototherapy is successfully used in complex medical treatment of diabetic foot, angiopathy of the lower

extremities, cerebral palsy, injuries, burns, frostbite, trophic ulcers and wounds. The basis of the therapeutic effect of light is its ability:^1,2,7,27,42

1. To normalize the work of the regulatory systems of the human body (immune, endocrine and central nervous).
2. To increase the microcirculation of blood and lymph, to increase the elasticity of the blood vessel walls, to normalize the rheological parameters of blood and its oxygen transport function.
3. The anti-inflammatory, anti-oedema, healing, analgesic, radio protective and photo reactivating effects;
4. To accelerate the process of tissue regeneration.
5. To stimulate the formation of ATP in mitochondria that increases the bioenergetic potential of cells;
6. To accelerate metabolic processes.

The final result of in vivo exposure of human body or its local regions to IR and VL is an increase in its resistance and an extension of the limits of adaptation, i.e. body resistance to various diseases and negative external factors. VL has neither contraindications or negative side effects and can be used for the treatment and prevention of the most common human diseases.

Diabetic foot treatment

The above mentioned properties of the IR and VL radiation have been used for the treatment and prevention of diabetic foot syndrome, since any pathological process starts with a non-specific phase, namely, a violation of the microcirculation of the blood and lymph. To ensure effective uniform irradiation of the lower limbs of the patient, the following biomedical engineered units have been designed (Figure 1).⁵⁹ Six small printed circuit boards with eighteen LEDs mounted on them are located in each section on the base and the rear wall. One small board is placed on the front wall of the section. On each side wall of the section there are three large printed circuit boards, each containing thirty-six LEDs. The printed circuit boards with LEDs on the base and the back wall are covered with transparent polycarbonate plates of 5 mm thick, which are fixed to the support posts, that allows patients weighing up to 120 kg to stand on the base of the chamber. The printed circuit boards on the side walls are protected by 2mm thick transparent polycarbonate plates.

Figure 1 The biophotonic device Barva-CDC for the diabetic foot treatment: A – general view of the unit with UV light turned on, B – feet location in the unit with IR+red light turned on.

All printed circuit boards are electrically interconnected in parallel, and connected to the power supply unit MPB-2S/500, which is powered from 220V, 50Hz and has an output voltage of 15 V DC 5A. The power supply is outside the device and is located in a separate case for maximum safety when using the device. The technical parameters of one of the modifications of the unit are given in Table 3. The acceptable colors for the treatment procedures are: IR (λ=940nm), red ( λ=630nm), yellow ( λ=595nm), green ( λ=525nm), blue ( λ=470nm), and violet (405nm). The following combinations have been approved after the clinical testing: IR+red, IR+green, IR+blue, IR+red+yellow+ green+blue+violet.⁴²

Treatment of the internal diseases

This type of photonic applicators have been designed for prevention, treatment and rehabilitation of the most common human diseases: myocardial infarction, stroke, hypertension, hypotension, influenza, tuberculosis, pneumonia, bronchitis, asthma, gastric ulcer and duodenal ulcer, osteochondrosis, vascular dystonia, neuralgia, sinusitis, otitis media, arthritis, arthrosis, allergies, prostatitis, andexitis, injuries, burns, frostbite, and others needed local heating and activation of local tissues and their microcirculation. Several types of the applicators can be helpful (Figure 2). The units designed for local applications are composed of 24LEDs (Figure 2A) while the units for the distributed purposes have 120LEDs (Figure 2B). The pulsed control unit MPB-2S/80 ensures the operation of the unit in continuous, pulsed or scanning modes. The scanning is performed according to the modulation frequency of the luminous flux. Also the unit can be used for dosing of the phototherapeutic procedure according to the duration of the irradiation. The main technical parameters of the unit MPB-2S/80 are given in the Table 4. The first unit can be used for local treatment of small local areas 10x12cm, while others are applicable for the treatment of back, high and low extremities. High therapeutic effect of both units have been shown during the detailed clinical trials.⁴² The same combinations of the colors for activation of the photo induced reactions in the cells and tissues with IR radiation for local heating and intensification of the microcirculation have been chosen (see §5.1).

Figure 2 Combined applicators for biophotonic therapy of local (A) and distributed (B) areas of the body.

Treatment of neurological diseases

Therapeutic influence on the head needs a delicate approach. Special phototherapeutic units for the prevention and treatment of neurological diseases caused by acute or chronic cerebro vascular accident, Alzheimer's disease, Parkinson's disease, meningitis, herpes viral encephalitis, migraine, epilepsy and other brain diseases have been elaborated (Figure 3A). Such diseases are difficult to treat with drugs or other physiotherapeutic procedures. The proposed treatment cannot substitute the drug therapy prescribed, and can be used as a complimentary measure that can enhance the main treatment and accelerate the recovery. The photon units Barva- CNS are manufactured as a hat that can be adjusted to any size of the head (Figure 3A) or neck (Figure 3B). Its application allows reducing the duration of treatment of neurological diseases by 2-3 times depending on its severity, and significantly increases the efficiency of drug therapy. The first type of unit (Figure 3A) is designed for the problems caused by acute or chronic insufficient cerebro vascular blood circulation. They can also be used for treatment of the skin and hair problems like alopecia and others. The units contain 228 or 240 LEDs depending on their type and size. The most efficient combinations of colors with IR radiation are the same as in §5.1. The second type of unit (Figure 3B) is designed for the prevention and treatment of otolaryngological (sore throats, pharyngitis, laryngitis) and neurological diseases (neck osteochondrosis, etc.). The technical characteristics are similar to those presented in Table 3. The restoration of blood microcirculation in the ischemic zone allows elimination the cause of the pathology development and ensuring rapid recovery.

Figure 3 The photon units Barva-CNS for applications on head (A) and neck (B) with red color VL irradiation.

The valuable database of the experimental data on positive therapeutic effect of the IR and VL irradiation in strengthening the organism, prevention and treatment of many internal diseases like stroke, myocardial infarction, hypertension, pneumonia, bronchitis, asthma, ulcers, osteochondrosis, neuralgia, sinusitis, arthritis, arthrosis, injuries, burns and others stimulates the deeper data analysis and classification, understanding the mechanisms of the therapeutic effects. Among them, the intensification of local microcirculation in the irradiated tissues and the photo induced biochemical reactions with active participation of cellular chromophores like cytochrome C oxidase and photoactive porphyrins.^1,2,7,27,42 the main therapeutic mechanism is connected with fast restoration of blood microcirculation in the ischemic zone, that promotes elimination the cause of the problem/disease development and ensures rapid recovery. The applied IR+VL treatment does not substitute the individual drug therapy prescribed by a doctor, but can be used as a complimentary synergetic measure that enhances the treatment, preventive or rehabilitation measures, and accelerate the general recovery and improvement of the organism.

None.

Author declares that there is no conflicts of interest.

1. Karu T. Low Power Laser Therapy, Ch.48. Biomedical Photonics Handbook. CRC Press; 2003.
2. Mester E, Mester AF, Mester A. The biomedical effects of laser application. Lasers Surg Med. 1985;5:31–39.
3. Conlan MJ, Rapley JW, Cobb CM. Biostimulation of wound healing by low-energy laser irradiation. A review. J Clin Periodontol. 1996;23:492–496.
4. Machadoa AF, Micheletti JK, Vanderlei FM, et al. Effect of low-level laser therapy (LLLT) and light-emitting diodes (LEDT) applied during combined training on performance and post-exercise recovery: protocol for a randomized placebo-controlled trial. Brazilian J Physical Therapy. 2017; 21(4):296–304.
5. Yoshino F, Yoshida A. Effects of blue-light irradiation during dental treatment. Japan Dental Sci Review. 2018;54:160–168.
6. Geronemus R, Weiss RA, Weiss MA, et al. Non-ablative LED photomodulation – light activated fibroblast stimulation clinical trial. Lasers Surg. Med. 200;32(Suppl.15):22.
7. Karu T. Photobiology of low-power laser effects. Health Phys. 1989;56:691–704.
8. Wu CS, Hu SC, Lan CC, et al. Low-energy helium-neon laser therapy induces repigmentation and improves the abnormalities of cutaneous microcirculation in segmental-type vitiligo lesions. J Med Sci. 2008;24:180–189.
9. Campos GRS, de Moura KMB, Barbosa AM, et al. Light emitting diode (LED) therapy reduces local pathological changes induced by Bothrops asper snake venom. Toxicon. 2018;152:95-102.
10. McDaniel DH, Newman J, Geronemus R, et al. Non-ablative nonthermal LED photomodulation – a multicenter clinical photoaging trial. Lasers Surg. Med. 2003. 32(Suppl 15):37.
11. Weiss RA, McDaniel DH, Geronemus RG. Review of nonablative photorejuvenation: reversal of the aging effects of the sun and environmental damage using laser and light sources. Semin Cutan Med Surg. 2003;22:93–116.
12. Schindl A, Schindl M, Pernerstorfer-Schon H, et al. Low-intensity laser therapy: a review. J Invest Med. 2000;48:312–326.
13. Posten W, Wrone DA, Dover JS, et al. Low-Level Laser therapy for wound healing: mechanism and efficacy. Dermatol Surg. 2005; 31:334–340.
14. Karu T. Primary and secondary mechanisms of action of visible to near-IR radiation on cells. J Photochem Photobiol B. 1999;49:1–17.
15. Weiss RA, McDaniel DH, Geronemus RG, et al. Clinical experience with light emitting diode (LED) photomodulation. Dermatol Surg. 2005;31:1199–1205.
16. Whelan HT, Connelly JF, Hodgson BD, et al. NASA light-emitting diodes for the prevention of oral mucositis in pediatric bone marrow transplant patients. J Clin Laser Med Surg. 2002;20:319–324.
17. Whelan HT, Buchman EV, Dhokalia A, et al. Effect of NASA light-emitting diode irradiation on molecular changes for wound healing in diabetic mice. J Clin Laser Med Surg. 2003;21:67–74.
18. Schaffer M, Bonel H, Sroka R. Effects of 780nm diode laser irradiation on blood microcirculation: preliminary findings on time-dependent T1-weighted contrast-enhanced magnetic resonance imaging (MRI). J Photochem Photobiol B. 2000;54:55–60.
19. Mikhaylov VA. The use of Intravenous Laser Blood Irradiation (ILBI) at 630–640nm to prevent vascular diseases and to increase life expectancy. Laser Ther. 2015;24:15–26.
20. Abergel RP, Lyons RF, Castel JC, et al. Biostimulation of wound healing by lasers: experimental approaches in animal models and in fibroblast cultures. J Dermatol Surg Oncol. 1987;13:127–133.
21. Wong-Riley MTT, Bai X, Buchmann E, et al. Light-emitting diode treatment reverses the effect of TTX on cytochrome oxidase in neurons. Neuro Report. 2001;12:3033–3037.
22. Gale GD, Rothbart PJ, Li Y. Infrared therapy for chronic low back pain: A randomized, controlled trial. Pain Res Manag. 2006; 11:193–196.
23. Barton JK, Hammer DX, Prefer TJ, et al. Simultaneous irradiation and imaging of blood vessels during pulsed laser delivery. Lasers Surg Med. 1999;24:236–243.
24. De Abreu Chaves ME, de Araújo AR, Piancastelli ACC, et al. Effects of low-power light therapy on wound healing: LASER x LED. An Bras Dermatol. 2014;89:616–623.
25. Agha-Hosseini F, Moslemi E, Mirzaii-Dizgah I. Comparative evaluation of low-level laser and CO2 laser in treatment of patients with oral lichen planus. Int J Oral Maxillofac Surg. 2012;41:1265–1269.
26. Freddo AL, Rodrigo SM, Massotti FP, et al. Effect of low-level laser therapy after implantation of poly-L-lactic/polyglycolic acid in the femurs of rats. Lasers Med Sci. 2009;24:721–728.
27. Chervinsky LS. Primary mechanism of action of optical radiation on living organisms. Int J Biosen Bioelectron. 2018;4(4):204.
28. Pinheiro AL. Advances and perspectives on tissue repair and healing. Photomed Laser Surg. 2010;27:833–836.
29. Tsai SR, Yin R, Huanga YY, et al. Low-level light therapy potentiatesNPe6-mediated photodynamic therapyin a human osteosarcoma cell line viaincreased ATP. Photodiagn Photodyn Therapy. 2015;12:123–130.
30. Scardina GA, Carini F, Noto F, et al. Microcirculation in the healing of surgical wounds in the oral cavity. Int J Oral Maxillofac Surg. 2013; 42:31–35.
31. Schaffer M, Bonel H, Sroka R. Effects of 780nm diode laser irradiation on blood microcirculation: preliminary findings on time-dependent T1-weighted contrast-enhanced magnetic resonance imaging (MRI). J Photochem. Photobiol B. 2000;54:55–60.
32. Liang HL, Whelan HT, Eells JT, et al. Photobiomodulation partially rescues visual cortical neurons from cyanide-inducedapoptosis. Neuroscience. 2006;139:639–649.
33. Wong-Riley MT, Liang HL, Eells JT, et al. Photobiomodulation directly benefits primary neurons functionally inactivatedby toxins: role of cytochrome C oxidase. J Biol Chem. 2005; 280:4761–4771.
34. Ying R, Liang HL, Whelan HT, et al. Pretreatment with near-infrared light via light-emitting diode provides added benefitagainst rotenone- and MPP+ induced neurotoxicity. Brain Res. 2008; 1243:167–173.
35. Zhang L, Xing D, Zhu D, Chen Q. Low-power laser irradiation inhibiting Abeta25-35-induced PC12 cell apoptosis via PKCactivation. Cell Physiol Biochem. 2008; 22:215–222.
36. Zhang H, Wu S, Xing D. Inhibition of Abeta(25-35)-inducedcell apoptosis by low-power-laser-irradiation (LPLI) throughpromoting Akt-dependent YAP cytoplasmic translocation. Cell Signal. 2012; 24:224–232.
37. Philipp CM, Berlien HP. The future of biophotonics in medicine–A proposal. Medical Laser Applic. 2006;21:115–122.
38. Mester E, Spiry T, Szende B, et al. Effect of laser rays on wound healing. Am J Surg. 1971;122:32–35.
39. Mester E, Korenyi-Both A, Spiry T, et al. The effect of laser irradiation on the regeneration of muscle fibers (preliminary report). Exp Chirurg. 1975;8:258–262.
40. Mester E, Mester AF, Mester A. The biomedical effects of laser application. Lasers Surg. Med. 1985;5:31–39.
41. Schindl A, Schindl M, Pernerstorfer-Schon H, et al. Low-intensity laser therapy: a review. J Invest Med. 2000;48:312–326.
42. Kizilova NN, Korobov AM. Mechanisms of the influence of low intense optical radiation on the microcirculatory system: A review. Photobiol Photomed. 2016;1:79–93.
43. Basford JR. Low intensity laser therapy: still not an established clinical tool. Lasers Surg Med. 1995;16:331–342.
44. Bouma MG, Buurman WA, van den Wildenberg FA. Low energy laser irradiation fails to modulate the inflammatory function of human monocytes and endothelial cells. Lasers Surg Med. 1996;19:207–215.
45. Rood PA, Haas AF, Graves PJ, et al. Low-energy helium neon laser irradiation does not alter human keratinocyte differentiation. J Invest Dermatol. 1992;99:445–448.
46. Conlan MJ, Rapley JW, Cobb CM. Biostimulation of wound healing by low-energy laser irradiation. A review. J Clin Periodontol. 1996; 23:492–496.
47. http://healingtools.tripod.com/PT.html
48. Niemz MH. Laser – Tissue Interactions: Fundamentals and Applications. Berlin; 1996.
49. Valvano JW. Tissue thermal properties and perfusion. In: Welch AJ, van Gemert MJC. Optical-Thermal Response of Laser-Irradiated Tissue. NY, 1995.
50. Lee SY, Park KH, Choi JW, et al A prospective, randomized, placebo-controlled, double-blinded, and split-face clinical study on LED phototherapy for skin rejuvenation: Clinical, profilometric, histologic, ultrastructural, and biochemical evaluations and comparison of three different treatment settings. J Photochem Photobiol B. 2007;88:51–67.
51. Russell BA, Kellett N, Reilly LR. A study to determine the efficacy of combination LED light therapy (633nm and 830nm) in facial skin rejuvenation. J Cosmet Laser Ther. 2005;7:196–200.
52. Weiss RA, Weiss MA, Geronemus RG, et al. A novel non-thermal non-ablative full panel LED photomodulation device for reversal of photoaging: digital microscopic and clinical results in various skin types. J Drugs Dermatol. 2004;3:605–610.
53. Weiss RA, McDaniel DH, Geronemus RG, et al. Clinical trial of a novel non-thermal LED array for reversal of photoaging: clinical, histologic, and surface profilometric results. Lasers Surg Med. 2005;36:85– 91.
54. Whelan HT, Connelly JF, Hodgson BD, et al. NASA light-emitting diodes for the prevention of oral mucositis in pediatric bone marrow transplant patients. J Clin Laser Med Surg. 2002;20:319–324.
55. Whelan HT, Buchman EV, Dhokalia A, et al. Effect of NASA light-emitting diode irradiation on molecular changes for wound healing in diabetic mice. J Clin Laser Med Surg. 2003;21:67–74.
56. Shvetsky FM, Musikhin LV, Smolnikov PV, et al. Effects of intravenous laser blood irradiation on systemic microcirculation. In: Abstracts of 13th European Medical Laser Association Congress. 2008;S16.
57. Abergel RP, Lyons RF, Castel JC, et al. Biostimulation of wound healing by lasers: experimental approaches in animal models and in fibroblast cultures. J Dermatol Surg Oncol. 1987;13:127–133.
58. Wong-Riley MTT, Bai X, Buchmann E, et al. Light-emitting diode treatment reverses the effect of TTX on cytochrome oxidase in neurons. Neuro Report. 2001;12:3033–3037.
59. Laser and Health.