Clinical Effect of Photobiomodulation on Wound Healing of Diabetic Foot Ulcers: Does Skin Color Needs to Be Considered?

Diabetic foot ulcers (DFUs) are one of the most common complications of diabetes. DFUs impede patients' quality of life and are known to be unresponsive to conventional therapy. Photobiomodulation (PBM) is a pain-free, noninvasive treatment method that has been shown to promote chronic wound healing and has been successfully used for the treatment of DFUs. Since skin tone and color can affect the way light interacts with tissue, studies should take this into consideration when determining protocols for the use of PBM. This review is aimed at critically evaluating data of existing studies conducted to evaluate the clinical effect of PBM on DFUs, taking skin color into consideration. A literature search was conducted and resulted in articles on cell studies, animal studies, and clinical trials. Only 13 clinical trials and 2 clinical case studies were adopted and used in this review. All the clinical trials adopted for this review show evidence that PBM together with conventional treatment results in an increased healing rate of DFUs; however, only one study adjusted their protocol according to skin color. There are not enough studies conducted on people of color to determine the safety and efficacy of PBM therapy in such ethnic groups. Future randomized, placebo-controlled clinical trials are necessary on PBM and DFUs and should take skin color into consideration.


Diabetes Mellitus (DM)
. DM is a universal widespread metabolic disease in which a person has high-blood glucose. There are two types of DM: type I, known as "insulin independent diabetes", which results from the body's inability to produce and secrete insulin and type II, known as "noninsulin-dependent diabetes", which results from the inability of the cells to respond to the insulin produced by the body [1]. According to the International Diabetes Federation (IDF), there are 536.6 million adults aged 20-79 years living with DM globally (24 million in Africa), a figure which is predicted to increase to 696 million (10.2% of the population) by 2030, and 783.2 million (12.2%) by 2045 [2]. Globally, DM is among the top 10 causes of death [2]. People living with DM are at increased risk of developing various life-threatening complications, including chronic diabetic foot ulcers (DFUs), leading to an increased need for medical care, a reduced quality of life, and undue financial and psychological stress.

Diabetic Foot Ulcers (DFUs).
People with DM are subjected to foot complications that develop due to long periods of hyperglycaemia. Diabetic foot neuropathy and peripheral vascular disease are two of the main causes of severe diabetic foot complications. The concurrent occurrence of diabetic foot complications leads to ulcerations [3]. The highly causative factor of DFUs is peripheral neuropathy (sensory, motor, and autonomic). Sensory neuropathy leads to patients experiencing a loss of protective sensation which results in susceptibility to physical and thermal trauma, and thus increased risk of ulceration [4]. Plantar pressure and friction that result from limited joint mobility and foot deformity caused by diabetes also causes foot ulcerations. This friction and increased pressure cause breakdown of the skin and lead to increased risk of infections, blister formation, callus formation, and ulcerations, and in severe cases, necessitates amputation [5]. Diabetic foot and lower limb complications affect 40 to 60 million people globally with DM and it is the principal cause of morbidity in diabetic patients [6]. It is estimated that the lifetime risk for developing a DFU is as high as 25%, with a global prevalence of 6.3% [7,8].

Classification of Diabetic Foot Ulcers (DFUs).
Taking size and depth into consideration, DFUs can be classified as mild (superficial), moderate (deeper), and severe (systemic signs). However, in 1976, Meggitt-Wagner designed a classification system for DFUs, and this classification has been used over the years to date. This classification system is based on wound depth and tissue viability. There are six classifications from this system and ulcers are graded on a scale from 0 to 5. Grade 0 describes a preulcerative or postulcerative site; grade 1 describes a superficial ulcer; grade 2 describes ulcers which penetrate the tendon or joint capsule; grade 3 describes ulcers which involve deeper tissues; grade 4 describes ulcers that involve gangrene of the forefoot; and grade 5 includes whole foot gangrene involving more than two thirds of the foot [9].
1.4. Diabetic Ulceration Management. The management and care of DFUs pose an increasing socioeconomic burden owing to repeated hospital admissions, lengthy treatment plans, and the risk of amputations, incurring extensive healthcare costs [8]. A conventional holistic treatment approach is used to treat DFUs involving an interdisciplinary team of healthcare professionals, as well as the patients and caregivers. This treatment approach includes debridement, cleaning and dressing of the wound, and in some cases, antibiotic therapy and pain management [10]. Debridement involves the removal of dead, necrotic tissue, or foreign material from and around a wound to expose healthy tissue and is part of the standard of care for DFUs [11]. There are different methods of debridement, including sharp/surgical, biological, autolytic, biochemical, and osmotic debridement. Wound dressings are applied to the wounds to clean, cover, and protect the wound from the external environment, to protect the wound from infection, and to promote healing. Wound dressings should provide a moist environment as well as remove excess exudate. There are different types of wound dressings each with their own unique properties available for the management of DFUs, including hydrogels, hydrocolloids, alginates, foam, silverinduced dressings, growth factor-impregnated dressings, and silicon-impregnated atraumatic dressings, and each dressing is suitable for different wound conditions [12]. Part of the treatment approach for DFUs also includes offloading for pressure redistribution and relief in pressure areas of the foot. Offloading results in tissue trauma prevention and facilitation of wound healing [13].
Despite having all these treatments in place, only a 50% healing rate is achieved, and the global risk for recurrence stands at 50% [8,14]. There is a need for the development of alternative, safe, efficient treatments for DFUs. A new adjunct treatment known as photobiomodulation (PBM) for DFUs has emerged and involves the use of lowpowered light at specific wavelengths. With efficient intervention and treatment of DFUs, lower limb amputations can be avoided, thus reducing the socioeconomic burden and improving the quality of life of patients.
1.5. Photobiomodulation (PBM). PBM, formally referred to as low-level laser therapy, involves the use of light, typically from lasers or light emitting diodes (LEDs), usually within the visible red and/or near infrared (NIR) electromagnetic spectrum to stimulate healing. PBM is a therapeutic, noninvasive modality that aids in the relief of pain and the reduction of inflammation [15]. PBM has been shown to positively affect the three principal phases of healing, namely, inflammation, proliferation, and maturation in both acute and chronic wounds [16,17]. A systematic review of PBM for DFUs reported that the therapy has significant potential to become a portable, minimally invasive, easyto-use, and cost-effective treatment modality for DFUs [18].
Research suggests that the effects of PBM are photochemical and photobiological rather than thermal [19]. The physical properties of skin, including chemical, optical, mechanical, and the concentration, and distribution of components that makes up the tissue (such as melanin) affect the interaction of light with tissue [20]. When light comes into contact with skin, there are four possible outcomes, namely, reflection, scattering, absorption, and transmission [21]. During reflection, approximately 30% of the photons bounce off the skin, and there is no light-tissue interaction [22]. Some of the light that does pass through gets scattered within the tissue; longer wavelengths have a deeper penetration while shorter wavelengths are scattered more [23]. During absorption, the photons are absorbed by chromophores in the tissue. During transmission, the light passes straight through the tissue unhindered, without interacting with the tissue. Both absorption and scattering are dependent on wavelength. Wavelengths < 600 nm are absorbed mainly by melanin and hemoglobin, and wavelengths > 1,200 nm are absorbed by water [21,24]. There is a so-called "optical window" which refers to the optimum wavelengths to use in PBM and where effective tissue penetration and tissue-light interaction are maximized. This lies between 600-1,070 nm. Wavelengths between 600-700 nm are used to treat superficial tissue as their penetration depth is less, and longer wavelengths between 780-950 nm are used to treat deeper tissues as they penetrate further into tissue [21].
One of the proposed mechanisms of action involves the absorption of photons by mitochondrial cytochrome c oxidase (COX). This enzyme forms part of the mitochondrial electron transport chain and transports electrons from cytochrome c to molecular oxygen. It has been shown that PBM at 660 nm increases the activity of cytochrome c oxidase in irradiated isolated mitochondria, leading to an increase in adenosine triphosphate (ATP) [25]. There is also an increase in intracellular reactive oxygen species (ROS), which is an important messenger for cell signalling pathways and gene transcription. Another theory explains how inhibitory nitric oxide (NO) binds to COX and is photodissociated, freeing the copper and heme centers of COX which can then bind to oxygen [26].
During PBM, the light (photon) energy must be absorbed by the skin and reach subcutaneous tissue. Absorption of this photon energy may be affected by skin color [19], and treatment protocols may need to be adjusted accordingly. The study conducted by Joensen et al., [19] on the thermal effect of a class 3B laser (200 mW; 810 nm) on different skin types within the therapeutic dose showed a consistent thermal effect of laser irradiation, which was strictly 2 Journal of Diabetes Research limited to the area of irradiation, and that the heat induced was strongly related to skin color. On the contrary, Sithole [27]   The following keyword search strategy was used: "Photobiomodulation AND Diabetes mellitus," "Photobiomodulation AND diabetic wound healing," "Photobiomodulation AND diabetic ulcers," "low level laser therapy AND Diabetes mellitus," "Effects of LLLT on diabetic wound," "low level laser therapy AND diabetic wound healing," "Chronic diabetic wounds," and "low level laser therapy AND diabetic ulcers". Only data from articles written in English were included. Articles not written in English were excluded. The search resulted in cell studies, animal studies, and human studies. Only thirteen clinical trials and two clinical case studies were adopted and used in this review. This article was not intended to be a systematic review or metaanalysis but as a "narrative overview".

Results and Discussion
Thirteen clinical trials and two clinical case studies were included, and a summary of the studies can be seen in Table 1. The clinical studies all show a similar pattern when it comes to healing of diabetic ulcers or general wounds with PBM. Kazemi-Khoo [29] conducted a clinical case study on the treatment of DFUs with PBM. This study included type 2 diabetic patients (four males with a mean age of 63 years and three females with a mean age of 61 years) with Braden Scale type II and III diabetic ulcers that presented with an average of 6.5 months. The PBM intervention included PBM of the ulcer bed with red light (wavelength 660 nm) and wound margins with infrared light (wavelength 980 nm). There was also intravenous laser irradiation with red light (wavelength 655 nm) and laser acupuncture with an infrared diode laser (wavelength not provided) for LI-11, LI-4, SP-6, PC-6, ST-36, and GB-34 points. Irradiation took place every other day for 10 to 15 sessions (route 1) then continued twice weekly till there was complete recovery (route 2). Complete wound closure took an average of 19 sessions: route 1 with an average of 15 sessions and route 2 with an average of 10 sessions. All cases achieved complete recovery after approximately six months. No side effects were reported by patients, and there was no ulcer relapse at the 6-month follow-up [29]. The author did not report on the skin color nor race of participants; however, based on the images used in the article, we can assume that the participants were of a lighter skin color. Limiting factors of this study included limited information on methodology and contradictory information on the laser parameters in the abstract and methodology section of the manuscript (abstract indicates intravenous PBM was done at a wavelength of 650 nm and power of 1.5 mW, while the methodology section indicates 655 nm with 2 mW). Also, no controls were included. Saltmarche [30] conducted a prospective comparative clinical trial aimed at testing the effectiveness of PBM in wound healing combined with the Extendicare Wound Prevention and Management Program, a program consisting of a multidisciplinary team of clinicians with an interest and expertise in wounds. The study comprised of 21 open wounds and four "at risk" closed areas. The study was not conducted exclusively on DFUs, and also included pressure wounds and venous wounds. Fifty-seven percent of the wounds were chronic (present for more than three months) and 42.9% of the wounds were acute (present for less than three months). Saltmarche [30] used a laser cluster (wavelength 785 nm). In the first week, the intervention was performed daily for five days, and thereafter, three times weekly up to week 9 or until complete wound closure was observed. The results showed that 61.9% of the open wounds treated with PBM improved and attained >50% wound closure. Nine of the wounds (42.8%) achieved 100% closure and 14.3% of the wounds indicated some improvement, with 23.8% showing no change. This clinical trial showed that there were no differences in healing times between the chronic and the acute wounds. No PBM adverse side effects were noted [30]. There was no reporting on participant skin color or race; however, it was mentioned that for patients with dark skin the dose around the wound periphery was increased by 50%, as melanin absorbs photons and less energy is delivered to the underlying tissue. Limiting factors of this study include the way the results were presented. The researcher did not separate and report on the results of the various ulcer types. These ulcers have different etiologies and could respond differently to PBM. Nonetheless, the author did take skin color into consideration and adjusted the protocol accordingly.   conventional wound care (dressings with wet There was a significant reduction in ulcer size in both groups at 4 and 8 weeks with no significant differences between the groups. Group I had a baseline ulcer size (cm 2 ) of 10:2 ± 5:6, with ulcer sizes of 7:1 ± 1:5 and 3:7 ± 1:2 after 4 and 8 weeks, respectively, while group II had a baseline ulcer size (cm 2 ) 6 Journal of Diabetes Research

Journal of Diabetes Research
A double-blinded, randomized, placebo-controlled trial was conducted by Minatel et al. [31]. This study tested the hypothesis that combined 660 nm and 890 nm PBM using superluminous diodes would promote healing of diabetic leg ulcers that did not respond to other treatment modalities.
The study was carried out on 14 patients with a total of 23 diabetic leg ulcers. Group one had 10 ulcers and group two had 13 ulcers. All patients received conventional therapy twice a week. Group one received conventional therapy and placebo phototherapy (<1.0 J/cm 2 ). Group two received conventional therapy together with PBM at 660 nm. Ulcer size was measured on days 0, 15, 30, 45, 60, 75, and 90. The results showed that the mean ulcer healing and granulation rates were higher in group two than in group one. At 30 days, group two had 56% more granulation tissue and a 72% faster healing rate, while the ulcers in group one worsened. By day 90, 58.3% of group two had fully healed ulcers, while only one ulcer was fully healed in the placebo group. Overall, 75% of ulcers in group two achieved 90-100% healing, while none of the ulcers in group two (with the exception of one ulcer) attained >90% healing. No side effects were experienced by the patients in this study [31]. Race nor skin color of the participants was indicated. Other limiting factors for this study included a small sample size and the fact that ulcers in the placebo group were exposed to some red light (660 nm) which could not be avoided due to the blinding nature of the study.
In a randomized clinical trial, Kaviani et al. [32] explored the effect of PBM on chronic diabetic foot wound healing. This study included 23 patients with Wagner grade I and II DFUs of an average of 10 months. In this double-blinded, randomized clinical trial, 10 patients were treated with placebo and 13 patients were treated with PBM at 685 nm. Patients were simultaneously treated with conventional therapy. This trial was set to take place over 20 weeks or until there was complete wound closure. Kaviani et al. [32] noted that the size of the ulcers in the PBM group had significantly decreased at week 4. At week 20, it was noted that 8 of 13 ulcers (66.6%) had complete wound closure in the PBM group, and only 3 of 9 ulcers (38.4%) had complete wound healing in the placebo group. This was not significantly higher than the placebo group, despite the mean time of complete healing being 11 weeks in the PBM group compared to 14 weeks in the placebo group. During the course of the study, two patients from the placebo group were hospitalized and underwent limb amputation, while one patient from the PBM group was hospitalized for infection treatment (no amputation required) [32]. This study provides evidence that PBM can accelerate wound healing in DFUs and shortens the time needed to achieve complete wound healing. Limiting factors include not reporting on the skin color/race of participants; however, the images used indicate that lighter skinned patients participated in this trial, and a small sample number.
Kajagar et al. [33] conducted a study similar to Kaviani et al. [32] whereby they evaluated the efficacy of PBM using a multidiode cluster probe (wavelengths not provided) on wound healing in patients with chronic DFUs. This was a randomized-controlled clinical trial that involved 68 patients with type 2 DM who presented with Wagner grade I foot ulcers for an average of 4 weeks. Patients were randomized into two groups of 34 each. The first group was treated with PBM and conventional therapy, and the second group (control) was only treated with conventional therapy. Kajagar et al. [33] noted that there was significant wound reduction in group one, which received both PBM and conventional therapy, as compared to group two, which only received conventional therapy. The mean reduction in ulcer size was 1043:20 ± 266:62 mm in the PBM-treated group compared to 322:44 ± 85:84 mm in the control group, which was clinically significant. The researchers did not mention participant skin color/race, though from a photograph provided in the article, some participants may have been skin type III or IV; however, this is based on assumptions and not facts provided for in the article.
Feitosa et al. [34] conducted a clinical trial aimed at evaluating the effects of PBM on diabetic ulcers. This was a randomized-controlled clinical study that involved 16 patients with type 2 DM. Eight patients were included in the control group and the other eight were exposed to PBM (wavelength 632.8 nm). This study was designed to detect pain and ulcer size before and after PBM on day 30 of follow-up. At the end of 30 days, the control group displayed no significant decrease in wound size; the patients still experienced pain and one patient required amputation. The average wound area (cm 2 ) before treatments in the control group was 2:55 ± 0:77, which increased to 8:43 ± 1:84 after 30 days. In the study group, a significant decrease in wound size was noted and patients reported an improvement in pain. The average wound area (cm 2 ) before treatments in the PBM group was 7:98 ± 2:06, which decreased to 2:39 ± 1:26 after 30 days [34]. Skin color nor race of participants was mentioned in this study. Photographs supplied in the article suggest skin types III and less; however, this is again based on assumptions.
Ortíz et al. [35] conducted a randomized-controlled clinical trial on twenty-eight participants comparing the effects of PBM (9 participants), high-voltage-pulsed current (HVPC; 9 participants) and standard wound care (10 participants) on the healing of DFUs localized on the distal leg or feet. Ulcers classified as category I or II according to the Wagner classification system were included. Ulcers were treated for 16 weeks, and DFUs in the control group were treated daily with conventional treatment. The HVPC participants were treated with an electrical simulator and standard wound care. The PBM group was treated with a semiconductor laser diode at 685 nm and standard care. The results showed that the control group achieved 66% healing, the PBM group achieved 77.7% healing, and the HVPC group achieved 80% healing. The authors did not find any differences between the three intervention groups (p = 0:087), with no significant differences for abnormal protective sensations between the PBM and the HVPC group (p > 0:52). The authors concluded that there were no additional effects of PBM or HVPC to the standard wound care on healing of DFUs. The study did not mention race nor skin color of the participants.
de Carvalho et al. [36] conducted a clinical case study to evaluate the effects of PBM alone and associated with 8 Journal of Diabetes Research Calendula officinalis oil in treating DFUs. This was an experimental, randomized, controlled, and prospective interventional clinical case study that involved 32 patients of both genders with type 2 DM and aged 40-70 years old. Ulcers were located on the foot or in the medial or distal third of the leg and were between 1 and 5 cm in size. This study was designed to detect pain, wound size, ankle-brachial index (ABI), and Doppler readings. The participants were divided into four groups: group 1 was the control and received conventional standard treatment, group 2 received PBM (658 nm), group 3 received essential fatty acids (EFA; C. officinalis), and group 4 received PBM together with EFA. The results showed no significant difference within the groups with regards to the ABI and Doppler readings; the data remained consistent till the end of the study. The PBM group (group 2) and the PBM together with essential oils (group 4) reported a significant reduction in both wound area and pain, showing that PBM has analgesic effects [36]. Since there was no reported significance in group 3 in wound size or pain, it can be assumed that the results observed in group 4 are largely due to PBM. The skin color nor race of the participants was not mentioned in this study. Mathur et al., [37] investigated the efficacy of PBM for the treatment of DFUs in a tertiary care center. This randomized controlled trial included a total of 30 patients with type 2 DM that presented with Wagner grade I foot ulcers for more than 6 weeks. The control group consisting of 15 patients who were treated with conventional treatment only. The study group was treated with PBM (wavelength 660 ± 20 nm) along with conventional therapy. The results showed that the PBM group had a significant reduction in wound size just after 2 weeks compared to the control group. The reduction in ulcer area was 37 ± 9% (30-50% wound area reduction observed in 75% of patients) in the PBM group compared to 15 ± 5:4% in the control group (80% of wounds showed a wound area reduction of <20%). The study group also showed increased granulation tissue. The results show significant benefits in patients treated with PBM over patients not treated with PBM. No adverse events and side effects were reported [36]. Skin color nor race of participants was mentioned in this study, though from a photograph provided in the article some participants may have had dark skin tones; however, this is based on assumptions and not facts provided for in the article.
A double-blinded, randomized study was conducted by Frangež et al. [38] on 60 patients which examined the influence of PBM with LEDs on chronic diabetic wound healing. Patients were randomized into an active (LED, 625 nm, 660 nm, and 850 nm) group (30 patients) or a control (placebo) group (30 patients). Results showed that after both the fourth and eighth week, the LED group had a remarkable improvement in wound bed granulation as well as a reduction in fibrin and eschar. After eight weeks, the mean wound surface was 56% of the starting wound surface in the LED group and 65% in the control group; there was a slight, although insignificant, faster reduction in wound surface area in the LED group. The patients in this study did not experience any side effects [38]. The race nor skin color of the participants was mentioned in this study.
Tantawy et al. [39] conducted a randomized controlled trial comparing the use of PBM at two different wavelengths in the management of DFUs. The clinical trial took place at the outpatient clinic of the Faculty of Physical Science at Cairo University for three months. Sixty-five participants were enrolled with ages ranging from 45 to 60 years, and with DFUs classified as grade I and II (Wagner Scale). Participants were randomly assigned to two groups; group I (33 participants) received PBM using a helium-neon laser and conventional wound care and group II (32 participants) received PBM at a wavelength of 904 nm and conventional care. Ulcer area was calculated from impressions on cellophane paper to graph paper. The two groups had similar baseline characteristics; however, after 4 and 8 weeks, there was a significant reduction in ulcer size (surface area) in both groups, with no significant differences between the two groups. The researchers did not mention the race nor participant skin color.
The study by Priyadarshini et al. [40] was a randomized controlled trial that consisted of 100 patients with Wagner grade I and II DFUs. The control group was treated with conventional therapy only, while the study group was treated with PBM (wavelength 660 nm) daily for 15 days. The ulcer size, grade, and culture status were assessed on day 1 and day 15. After 15 days, the study group showed improvement and healing; the ulcer size reduced and so was the grade as compared to the control group. The mean wound area at the start of the study in the control group was 19:09 ± 15:03 and 13:74 ± 11:88 in the PBM group. After treatment for 15 days, the mean wound area in the control group was 18:80 ± 17:70 compared to 3:97 ± 5:41 in the PBM group. At the start of the study, on day 1, 29 patients had grade II ulcers and 21 patients had grade I ulcers in the PBM group. At the end of the study, on day 15, there were no grade II ulcers; of the 29 grade II ulcers, 28 (96.6%) improved to grade I and one ulcer was completely healed. Of the 21 grade I ulcers, seven (33.33%) remained in grade I and 14 (66.67%) were completely healed. At the start of the study, on day 1 in the control group, 26 ulcers were classified as grade II and 24 as grade I. At the end of the study, on day 15, 23 (88.46%) grade II ulcers remained, and three ulcers (11.53%) improved to grade I. None of the grade I ulcers healed completely, and they all remained in grade I. In the PBM group, 31 patients had bacterial growth on day 1, of which 10 still had positive bacterial cultures at the end of 15 days. In the control group, 34 patients had bacterial growth on day 1, of which 29 still had positive bacterial cultures at the end of 15 days. This study concluded that PBM is a painless, cost-effective procedure that accelerates wound healing. No adverse events and side effects were reported [40]. Skin color nor race of participants was mentioned, though from a photograph provided in the article some participants may have had dark skin tones; however, this is based on assumptions and not facts provided for in the article.
de Alencar Fonseca Santos et al. [41] conducted a clinical trial to evaluate the effect of PBM on tissue repair processes in chronic DFUs. This was a randomized clinical trial with qualitative and quantitative prospective experimental methods. 9 Journal of Diabetes Research The clinical trial was carried out on 18 patients, with noninfected chronic DFUs. The patients were randomly divided into two groups: the control and the PBM group. The control group was treated with conventional treatment and the PBM group was treated with conventional treatment and PBM (660 nm). The pressure ulcer scale (PUSH) for healing was used to observe the tissue repair process weekly and it looked at the area of the wound, the exudate quantity, and the appearance of the wound bed. Higher PUSH scores indicated no ulcer improvement and lower PUSH scores indicated improvement in the healing of the wound. Pain intensity was analysed weekly using the visual analogue scale (VAS). de Alencar Fonseca Santos et al. [41] noted that the PBM group had a significant increase in tissue repair index as compared with the control group. The average final area in the control group was 1.63 cm 2 , while the average final area in the PBM group was 0.32cm 2 . There were no differences in the PUSH scale. It was concluded that the PBM group had an effective response in the tissue repair process in a short period of time. The skin color nor race of participants was not mentioned in this study.
Vitoriano et al. [42] conducted a prospective comparative clinical trial on laser and LED influence on tissue repair and improvement of neuropathic symptoms during the treatment of diabetic ulcers. This study consisted of twelve patients who were randomized in two groups; one group was treated with a GaAIAs laser (wavelength 830 nm) and the other group was treated with LED (wavelength 850 nm). The study took place over a period of 6 months, with sessions twice a week and patients were observed at the end of the 10 th session. Both groups showed a significant reduction in wound size at the end of treatments as compared to the start of the study. The results showed that the laser group had 81% wound reduction size by the 10 th session as compared to the LED group which had 62% wound size reduction. Although participants in the laser group had a significant wound size reduction as compared to the LED group, both treatments resulted in a decreased score of neuropathic signs and symptoms. There were no side effects noted in this study [40]. The skin color nor race of participants was not mentioned.
A clinical case study was done by de Alencar Fonseca Santos et al. [41] on self-administered PBM on diabetic leg ulcers. This case study was performed on an 84-year-old Chinese woman who had type 2 DM for 32 years and presented with diabetic complications such as neuropathy, vascular disease, eye disease, and leg ulcers. The leg ulcers had been present for 3 weeks and the biggest leg ulcer had a diameter of 1 cm. The B-cure laser pro device (808 nm) was used by the patient at home and was applied twice daily for 15 min. The results showed that after a week of treatment the smallest ulcer dried and crusted, while the larger ulcer significantly improved. All ulcers were completely healed after 30 days of treatment. There were no side effects mentioned in this case study [41]. The study supported the home use of PBM for the self-treatment of DFUs.

Conclusion
Conventional therapy alongside the use of PBM has shown significant efficacy as treatment modalities for diabetic ulcers. PBM seems to be an efficient, viable, painless method of treating DFUs. The available studies on the use of PBM for diabetic wounds encourage further investigation. There are not enough properly designed, randomized, placebo-controlled clinical trials on a larger group to determine the safety and efficacy of PBM, especially taking skin color into consideration. More randomized clinical trials with variable doses and treatment protocols for different wounds on patients of a specific, darker skin color (or animal studies) should be carried out so as to determine if skin color does affect PBM treatments. However, the studies that have been published show great promise for this therapy. Most studies conducted thus far on PBM do not mention the skin color nor race of patients, which should be considered due to varying photon absorbencies by melanin. Only one of the studies evaluated in this review took skin color into consideration and adjusted the dose accordingly. However, despite these potential shortfalls, all the studies showed an improvement in the healing rate of DFUs treated with either red or NIR light. More studies on the healing of DFUs with PBM must be done and these studies should focus on the skin types/colors.

Data Availability
All articles used in this review are available from the respective journals concerned.

Conflicts of Interest
The authors declare that there is no conflict of interest regarding the publication of this article.