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EDITED BY
Maurizio Delvecchio,
University of L'Aquila, Italy

REVIEWED BY
Yuzhen Wang,
People's Liberation Army General Hospital,
China
Maria Guadalupe Moreno Treviño,
University of Monterrey, Mexico

*CORRESPONDENCE

Quentin Perrier

<figure><img src="image_2.png" /></figure>

qperrier@chu-grenoble.fr

RECEIVED 28 September 2023

ACCEPTED 26 February 2024

PUBLISHED 19 March 2024

CITATION

Perrier Q, Moro C and Lablanche S (2024)
Diabetes in spotlight: current
knowledge and perspectives of
photobiomodulation utilization.
*Front. Endocrinol.* **15**:1303638.
doi: 10.3389/fendo.2024.1303638

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© 2024 Perrier, Moro and Lablanche. This is an
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which does not comply with these terms.

Diabetes in spotlight: current
knowledge and perspectives of
photobiomodulation utilization

Quentin Perrier¹*, Cécile Moro² and Sandrine Lablanche³

¹Univ. Grenoble Alpes, INSERM U1055, Pharmacy Department, Grenoble Alpes University Hospital, Laboratory of Fundamental and Applied Bioenergetics, Grenoble, France, ²Univ. Grenoble Alpes, CEA-Leti, Clinatec, Grenoble, France, ³Univ. Grenoble Alpes, INSERM U1055, Diabetology and Endocrinology Department, Grenoble Alpes University Hospital, Laboratory of Fundamental and Applied Bioenergetics, Grenoble, France

**Introduction:** Diabetes is a global health concern characterized by chronic hyperglycemia resulting from insulinopenia and/or insulin resistance. The rising prevalence of diabetes and its associated complications (ulcers, periodontitis, healing of bone defect, neuropathy, retinopathy, cardiopathy and nephropathy) necessitate innovative therapeutic approaches. Photobiomodulation (PBM), involves exposing tissues and cells to low-energy light radiation, leading to biological effects, largely via mitochondrial activation.

**Methods:** This review evaluates preclinical and clinical studies exploring the potential of PBM in diabetes and its complications, as well as all clinical trials, both planned and completed, available on [ClinicalTrials](https://ClinicalTrials.gov) database.

**Results:** This review highlights the variability in PBM parameters across studies, hindering consensus on optimal protocols. Standardization of treatment parameters and rigorous clinical trials are needed to unlock PBM's full therapeutic potential. 87 clinical trials were identified that investigated PBM in diabetes mellitus (with 5,837 patients planned to be treated with PBM). Clinical trials assessing PBM effects on diabetic neuropathy revealed pain reduction and potential quality of life improvement. Studies focusing on wound healing indicated encouraging results, with PBM enhancing angiogenesis, fibroblast proliferation, and collagen density. PBM's impact on diabetic retinopathy remains inconclusive however, requiring further investigation. In glycemic control, PBM exhibits positive effects on metabolic parameters, including glucose tolerance and insulin resistance.

**Conclusion:** Clinical studies have reported PBM-induced reductions in fasting and postprandial glycemia without an increased hypoglycemic risk. This impact of PBM may be related to its effects on the beta cells and islets in the pancreas. Notwithstanding challenges, PBM emerges as a promising adjunctive therapy for managing diabetic neuropathy, wound healing, and glycemic control. Further investigation into its impact on diabetic retinopathy and muscle recovery is warranted.

KEYWORDS

photobiomodulation, diabetes, neuropathy, wound healing, periodontitis, retinopathy, glycemic control
# 1 Introduction

Diabetes is characterized by chronic hyperglycemia due to insulinopenia [type 1 diabetes (T1D)] and/or insulin resistance [type 2 diabetes (T2D)]. The International Diabetes Federation reported 537 million of potential cases of diabetes across the world in 2021 with an increment planned for 2045 at 783 million of potential cases (1). As a result, diabetes caused 6.7 million of death in 2021 (1) and led to USD 966 billion health expenditures (1) partially due to numerous complications related to diabetes disease (2) such as macrovascular complication (ischemic cardiomyopathy, stroke and arteriopathy) (2–5) and microvascular complications: 1) retinopathy, diabetes is the first cause of non-traumatic blindness (6), 2) nephropathy, diabetes is the first cause of dialysis, 3) amputation and 4) neuropathy (7, 8) leading to foot ulceration and exposing patient to a risk of lower limb amputation [diabetes is the first cause of non-traumatic amputation (9)]. Finally, patients living with diabetes are also exposed to a risk of periodontitis (10). Altogether, diabetic complications alter quality of life (11, 12). These complications can be prevented through optimal glycemic control and could be managed with some medicines (13, 14). However, despite optimal medical management, prevention of diabetic complications remains a challenge and additional treatment remains mandatory.

Light was used as potential of treatment since the ancient Egypt. The biological reaction to light and its therapeutic applications are not new. For example, the beneficial effect of light on neonatal jaundice, discovered in the 1950s, made phototherapy (with blue light with a wavelength between 420-490 nm) the main modality for its treatment (15). Another example, the effects of light on mood, demonstrated in the 80s, made it possible to propose light therapy as a treatment for seasonal affective disorders, and it has recently been shown to have an effect comparable to antidepressants in episodes major depression (16).

Photobiomodulation therapy (PBM), formerly called “Low level laser therapy”, is a phototherapy based on the exposure of tissues and cells to non-ionizing and very weak light radiation with a wavelength generally ranging from red (between 600-700 nm) to the near infrared (between 700-1400 nm) and resulting in biological effects following its absorption by endogenous chromophores. Historically, PBM was first described by Endre Mester in 1968 who observed faster hair regrowth in rodents exposed to a low-energy laser with a wavelength of 694 nm (17, 18). In the same years, it was also developed by the National Aeronautics and Spatial Administration (NASA) to accelerate the healing and regeneration of muscle cells in astronauts (19). For the past decades, biomedical research relating to PBM has been constantly increasing, indicating a growing interest in its therapeutic potential. Interest in PBM has also been linked to technical developments in illumination technology, with the improvement of LEDs, which are cheaper, safer and give off less heat than lasers (20). Depending on the targeted use, and the illumination device, PBM can be brought along white light, to have the full spectrum of wavelength as a natural light, or along LED to obtain mainly a light targeted around a wavelength, or a laser to deliver only a define wavelength. At the

beginning of the 2000s, the use of PBM in aesthetics (hair regrowth, wrinkle reduction) and sports recovery helped to democratize its use. Photobiomodulation is now used to help heal damaged tissues, improve immune response, reduce inflammation, and was recommended to prevent or treat certain side effects of treatments such as chemotherapy and radiotherapy (mucositis and radiodermatitis). In 2010, the first clinical authorization was reached as therapeutics for pain in conditions such as osteoarthritis. Since the 2020s, based on successful preclinical researches, various clinical trials have been initiated to evaluate PBM as a treatment to slow down neurodegenerative diseases, such as Alzheimer's or Parkinson's diseases (21, 22). Over the past three years (2020–2022), approximately 850 articles per year have been published and referenced in MEDLINE.

The main mechanism of action involves the mitochondria (23), possessing photo-acceptors sensitive to the lengths used with PBM. Briefly, PBM has been reported to activate non-mitochondrial cellular functions (light/heat-gated ion channels) and restore mitochondrial function (through interfacial water and/or activation of cytochrome C oxidase), resulting in a short-term increase adenosine triphosphate (ATP) energy production in body cells and increased production of NO. This process leads to long-term effects, with the expression of various stimulatory and protective genes. The main biological effects highlighted in preclinical and clinical studies are an anti-inflammatory, analgesic action, an increase in blood circulation, angiogenesis, and a healing/ regeneration and tissue proliferation action (24–26). Given these effects, the potential therapeutic applications are numerous. PBM is already used in certain medical disciplines. It is part, for example, of the recommendations for the prevention of mucositis in patients treated by radiotherapy.

The use of PBM in the context of neurodegenerative diseases, and in particular Parkinson's disease, is currently being studied and is the subject of clinical trials. PBM could represent an innovative therapeutic solution, to slow down the neurodegenerative process. The preclinical results in this direction are very encouraging, and clinical data should be published soon due to ongoing clinical trials. The metabolic syndrome in neurodegenerative diseases, and in particular Parkinson's disease, are well established (21, 22). The observed effect of PBM on cellular metabolism, inflammatory and scarring processes is a lead that may indicate an interest of PBM in the regulation of phenomena related to metabolic syndromes, such as diabetes.

In the present work, the purpose is to review the clinical studies using PBM and conducted in the field of the treatment of diabetes and diabetic complications.

# 2 Materials and methods

Identification was made regarding:

- Pre-clinical (animal study) and clinical data available until 23 May 2023

- Clinical trials available on clinicaltrials.gov (27) until 23 May 2023
## 2.1 Searching strategy and selection criteria of papers

A MEDLINE research was conducted via PubMed using the search terms: [(Photobiomodulation) or (Low-level laser therapy) or (Near-infrared therapy)] AND (diabetes or diabetic or T1D or T2D) AND (1900/01/01:2023/05/23[edat]). In addition, references from cited papers were investigated. For each paper, the following parameters were recorded: 1st author, year of publication, model used (including the number of patients in clinical trials), wavelength, light source (LED or laser), mode of administration (continuous or pulsed), PBM parameters (power density in mW/cm², time per exposure, energy density in J/cm², frequency, sites), and the study's conclusion. The data were analyzed both collectively and individually, considering different diabetes conditions such as retinopathy, ulcers, and periodontitis. In the case of clinical trial papers, it was specified whether they were randomized clinical trials (RCTs), pre-post interventional trials (Pre-Post ITV) or observational studies.

## 2.2 Searching strategy for clinical trials and classification

The screening of the ClinicalTrials database (27) was conducted using three terms: photobiomodulation, low-level laser therapy and near-infrared therapy. Only trials related to diabetes were considered eligible, and studies employing methods other than PBM were excluded (Figure 1). For each included trial, the following parameters were recorded: starting date, country of the sponsor, expected number of enrolled patients, and enrolment status (not yet recruiting, recruiting, enrolling by invitation, active, suspended, terminated, completed, withdrawn, or unknown). Regarding clinical trials published in the Medline database, the following parameters were recorded: country of the sponsor and number of enrolled patients. All these trials were classified as completed.

## 3 Results

Following Medline research, 124 articles met the search criteria. 170 different exposure times were studied and varied widely, with 35% of the studies (60/168) having exposure times (for one session) of less than a minute and 35% (59/168) exceeding 5 min (Figure 2). Laser was the predominant light source investigated in 80% of the studies (Figure 2), and continuous exposure was the primary mode of administration (84% of studies, Figure 2). The power density values ranged from 1 mW/cm² to 8.32 W/cm², whereas the energy density ranged from 0.03 to 420 J/cm². These studies investigated various wavelengths ranging from 425 to 1064 nm, with 82% of studies between 600 and 900 nm, and six studies exploring multiple wavelengths applying simultaneously (Figure 2). It should be noted that

these parameters were not fully described or available in 37 studies (29%).

<figure><img src="image_3.png" /><figcaption>FIGURE 1 Flow chart for selection of clinical trials. PBM: photobiomodulation.</figcaption></figure>

## 3.1 Clinical trials in humans

42 trials were identified in ClinicalTrial database (27), and 56 articles were found in Medline. After removing duplicate trials, 87 were conducted or planned (Figure 2). These trials included 5,837 patients (see Table 1 for details). The top three countries planning to conduct trials on PBM and diabetes were the United States (n = 19), Brazil (n = 18), and India (n = 10, Figure 3). 50% of publications were by completely independent teams (n = 21 articles). Regarding diabetic neuropathies, two teams each published three studies: Burke et al. (28–30), and Arun G et al. (31–33). Regarding diabetes chronic periodontitis, three teams each published 2-3 studies: Chava et al. (34, 35), Haaki et al. (36, 37), and Obradovic et al. (38–40). Regarding performance and functionality during or after exercise in patient with diabetes Ferraresi et al. (41–43). published three studies. Finally, two teams have published on neuropathic pain and diabetic ulcers: Arisawa et al. (44, 45), and Schindl et al. (46–48).

## 3.2 Impact of PBM on diabetic neuropathy

A total of 23 studies were conducted, including 5 on preclinical models- (49–53) and 18 in humans (28–33, 46, 54–63) (Table 2).
<figure><img src="image_4.png" /><figcaption>FIGURE 2</figcaption></figure>

Global PBM parameters. The data from both preclinical and clinical studies are presented. (A) Repartition of time exposure to PBM. (B) Repartition of source of light uses. (C) repartition of the mode of illumination uses. (D) Repartition of wavelength uses.

<table><caption>TABLE 1 Number of patients treated in clinical trials with PBM for diabetes condition.</caption><thead><tr><td>Status of studies</td><td>Number of studies</td><td>Expected number of participants</td></tr></thead><tbody><tr><td>Active, not recruiting</td><td>1</td><td>80</td></tr><tr><td>Completed</td><td>66</td><td>4954</td></tr><tr><td>Not yet recruiting</td><td>2</td><td>160</td></tr><tr><td>Recruiting</td><td>5</td><td>300</td></tr><tr><td>Suspended</td><td>1</td><td>60</td></tr><tr><td>Terminated</td><td>4</td><td>75</td></tr><tr><td>Unknown status</td><td>6</td><td>208</td></tr><tr><td>Withdrawn</td><td>2</td><td>0</td></tr><tr><td>Total</td><td>87</td><td>5837</td></tr></tbody></table>

These numbers of participant represent the expected enrolment for trial not already completed.

### 3.2.1 Pain investigation

Among 14 studies investigating pain, 11 reported a decrease in pain after PBM, with 4 studies conducted on preclinical models and 7 on clinical subjects. In clinical trials, pain was evaluated using a visual analogic scale (VAS), either alone or in combination with other pain assessment scores with a follow-up period ranging from 4 to 90 days. For pre-post interventional trials (n = 3), the VAS scores decreased by an average of 2.3 to 5.2 points after PBM. In RCTs (n = 4), the VAS scores decreased more in the PBM group than in the control group (0 to 3 points vs. 3 to 5 points after 10 days) (44, 54), and the VAS scores at the end of the follow-up period were lower in the PBM group than in the control group (6.9-7.9 vs. 5.9-5.3) (33, 56).

### 3.2.2 QoL investigation

Four studies investigated the effect of PBM on QoL. Two studies reported a positive impact of PBM on QoL associated with a decrease in pain (44, 54). Conversely, 2 studies did not report an impact of PBM on QoL but in these 2 studies PBM did not induced a decrease in pain (58, 59). The first study (58) used the highest
<figure><img src="image_5.png" /><figcaption>FIGURE 3</figcaption></figure>

Repartition around the world of clinical trials about PBM and diabetes.87 trials have been conducted or are planned, 43 in America, 26 in Asia, 12 in Europe, 5 in Africa, and 1 in Oceania.

<table><caption>TABLE 2 Effects of PBM on diabetic neuropathy.</caption><thead><tr><td>Author/ Year</td><td>Model</td><td>Wave (nm)</td><td>Light</td><td>PBM parameters</td><td>Conclusions</td></tr></thead><tbody><tr><td>Vieira 2022 (49)</td><td>Lewis rat Streptozotocin induced</td><td>904</td><td>Continuous laser</td><td>7W/cm², 29sec, 203J/cm²<br>Frequency: once a day<br>Site: 1, dorsal, direct contact</td><td>↓ pain<br>↓ cytokines (TNFα, IL-1β, IL-10)<br>No effect on metabolic parameters</td></tr><tr><td>Rocha 2021 (50)</td><td>Wistar rat Streptozotocin induced</td><td>904</td><td>Continuous laser</td><td>340mW/cm², 18sec, 6,23J/cm²<br>Frequency: once a day, for 10 days<br>Site: on sciatic nerve routes, direct contact</td><td>Restore fusion/fission<br>mitochondria dynamic</td></tr><tr><td>Vieira 2019 (51)</td><td>Lewis rat Streptozotocin induced</td><td>904</td><td>Continuous laser</td><td>7W/cm², 29sec, 203J/cm²<br>Frequency: once a day for 8 days<br>Sites: 4 points, direct contact</td><td>↓ pain</td></tr><tr><td>Abdel-Wahhab 2018 (52)</td><td>Albinos rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>30sec, 90J*<br>Frequency: 3 times a week for 8 weeks<br>Sites: 3 points</td><td>↓ pain<br>↓ PGE2, TNFα, IL1β, IL10</td></tr><tr><td>da Silva Oliveira 2018 (53)</td><td>C57BL6 mice Streptozotocin induced</td><td>660</td><td>Continuous laser</td><td>107mW/cm², 15sec, 1.6J/cm²<br>Frequency: once a day, for 21 days<br>Site: 1, plantar hind paw, direct contact</td><td>↓ pain<br>Prevent myelin degenerescence<br>↓ loss of C fiber</td></tr><tr><td>Rastogi 2021 (54)</td><td>Human, n = 38 Diabetes RCT<sup>T</sup></td><td>890</td><td>LED Unknown</td><td>30min, 58.5J/cm²/min<br>Frequency: 3 times a week, for 12 weeks<br>Sites: 4, plantar foot x2, posterior & anterior distal leg</td><td>↓ pain (VAS decrease of 5.3 vs. 3 at 3 months)<br>↑ QoL (Norfolk-QoL DN 8 vs. 12 at 3 months)<br>No effect on cutaneous reinnervation</td></tr><tr><td>Anju 2020 (31)</td><td>Human, n = 50 T2D Pre-Post ITV<sup>a</sup></td><td>632.8</td><td>Continuous laser</td><td>5.7mW/cm², 9min, 3.1J/cm²<br>Frequency: once a day, for 10 days<br>Sites: 2, plantar and dorsal foot</td><td>↓ vibration perception threshold<br>↓ neurone specific enolase</td></tr><tr><td>da Silva Leal 2020 (44)</td><td>Human, n = 30 T2D RCT<sup>†</sup></td><td>660</td><td>Continuous laser</td><td>1.66mW/cm², 30min, 3J/cm²<br>Frequency: once a day, for 10 days, 20 days washout and start 2 times more<br>Site: 1, radial artery region, direct contact</td><td>↓ pain<br>VAS: no change vs. decrease of 3 points<br>LANSS: no change vs. decrease of 3 points<br>Pain detect questionnaire: no change vs. decrease of 5 points<br>↑ QoL (SF-36, all parameters increase)</td></tr><tr><td>Anju 2019 (32)</td><td>Human, n = 40 T2D Pre-Post ITV<sup>a</sup></td><td>632.8</td><td>Continuous laser</td><td>5.7mW/cm², 9min, 3.1J/cm²<br>Frequency: once a day, for 10 days<br>Sites: 2, plantar and dorsal foot</td><td>↑ Mg and Vitamin D</td></tr><tr><td>Kumar 2015 (55)</td><td>Human, n = 19 T2D Pre-Post ITV<sup>a</sup></td><td>660 + 850</td><td>Continuous laser</td><td>5.7mW/cm², 9min, 3.1J/cm²<br>Frequency: once a day, for 10 days<br>Sites: 2, plantar and dorsal foot, direct contact</td><td>↓ pain (VAS: decrease of 5.2 points after 10 days)</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 2 Continued</caption><thead><tr><th>Author/ Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusions</th></tr></thead><tbody><tr><td>Bashiri 2013 (56)</td><td>Human, n = 60 T1D &amp; T2D RCT†</td><td>780</td><td>Continuous laser</td><td>8.3mW/cm², 5min, 2.5J/cm²<br>Frequency: 2 times a week, for 4 weeks<br>Site: unknown</td><td>↓ vibration perception threshold<br>↑ microcirculation<br>↓ pain (VAS: score of 7.9 vs. 5.9 for PBM after 4 weeks)</td></tr><tr><td>Yamany 2012 (33)</td><td>Human, n = 30 T2D RCT†</td><td>850</td><td>Continuous laser</td><td>6.3mW/cm², 15min, 5.7J/cm²<br>Frequency: 3 times a week, for 4 weeks<br>Sites: 2, plantar surface of foot, lombo-sacral area, 30cm above the area</td><td>↓ pain (VAS: score of 6.9 vs. 5.3 for PBM after 4 weeks)<br>↑ microcirculation<br>↑ sural nerve conduction<br>No effect on peroneal nerve</td></tr><tr><td>Khamesh 2011 (57)</td><td>Human, n = 27 T2D Pre-Post ITV†</td><td>800</td><td>Continuous laser</td><td>1W*<br>Frequency: 10 sessions<br>Sites: 6 paravertebral points, 4 on sciatic nerve routes</td><td>↑ neuronal potential amplitude</td></tr><tr><td>Swisloki 2010 (58)</td><td>Human, n = 121 Diabetes RCT†</td><td>870</td><td>Continuous laser</td><td>25W*, 10J/cm²<br>Frequency: 10 sessions<br>Sites: 6 paravertebral points and 4 on sciatic nerve routes</td><td>↑ neuronal potential amplitude</td></tr><tr><td>Lavery 2008 (59)</td><td>Human, n = 60 Diabetes RCTº</td><td>890</td><td>Continuous LED</td><td>350W*, 7min, 1800J*<br>Frequency: Once a day, 4 days<br>Sites: 16 on each foot</td><td>Restauration sensation<br>No effect on pain (VAS, PQAS)<br>No effect on quality of life (SF-36)</td></tr><tr><td>Arnall 2006 (60)</td><td>Human, n = 22 T1D &amp; T2D RCT (for foot)†</td><td>880 + 650</td><td>Pulsed LED</td><td>40min, 1,3J/cm²/min<br>Frequency: once a day, for 90 days<br>Sites: 4, plantar foot x2, medial &amp; lateral side of the calf</td><td>No effect on pain (VAS)<br>No effect on QoL (Neuro QoL)<br>No effect on peripheral sensation</td></tr><tr><td>Harkless 2006 (28)</td><td>Human, n = 979 Diabetes Pre-Post ITVº</td><td>890</td><td>Pulsed laser</td><td>30min<br>Frequency: 3 times a week, for 8 weeks<br>Sites: 2, volar and dorsum of foot</td><td>↑ mechanical sensation<br>↓ perception threshold<br>↑ peripheral protective sensation</td></tr><tr><td>Cliff 2005 (61)</td><td>Human, n = 70 Diabetes RCTº</td><td>890</td><td>Continuous laser</td><td>Unknown</td><td>↓ pain (VAS: decrease of 4.8 points)<br>↑ foot sensation</td></tr><tr><td>DeLellis 2005 (29)</td><td>Human, n = 790 T2D Pre-Post ITVº</td><td>890</td><td>Pulsed laser</td><td>30min, 58.5J/cm²/min<br>Frequency: 3 times a week, for 4 weeks<br>Sites: 4, plantar foot x2, posterior &amp; anterior distal leg</td><td>No effect on sensation</td></tr><tr><td>Leonard 2004 (62)</td><td>Human, n = 27 T1D &amp; T2D Pre-Post ITVº</td><td>890</td><td>Continuous laser</td><td>No detail</td><td>↓ sensitivity impairment<br>Restauration protective sensation</td></tr><tr><td>Zinman 2004 (63)</td><td>Human, n = 50 Diabetes RCT†</td><td>905</td><td>Continuous laser</td><td>40min, 50J/cm²<br>Frequency: 3 times a week, for 4 weeks<br>Sites: 4, inferior member</td><td>↓ pain (VAS: decrease of 2.3 points after 4 weeks)<br>↓ place without sensation<br>Restauration protective sensation</td></tr><tr><td>Kochman 2002 (30)</td><td>Human, n = 49 T1D &amp; T2D Pre-Post ITV†</td><td>Unknown</td><td>Continuous laser</td><td>60mW*, 5min<br>Frequency: 2 times a week, for 4 weeks<br>Sites: 2 painful sites, direct contact</td><td>No effect on pain (p = 0.07) (VAS)</td></tr><tr><td>Schindl 2002 (46)</td><td>Human, n = 30 Diabetes RCTº</td><td>632.8</td><td>Continuous laser</td><td>30min<br>Sites: 4, Posterior &amp; anterior tibia, dorsal &amp; ventral foot</td><td>↓ sensitive impairment<br>↑ neural function (hot/cold discrimination)</td></tr><tr><td></td><td></td><td></td><td></td><td>30J/cm²<br>Frequency: Once<br>Site: 1</td><td>↑ microcirculation</td></tr></tbody></table>

T: no other treatment for pain, †: treatments for pain are permitted, but must be balanced and not change during the course of the study (i.e. amitryptilin, gabapentin, tramadol), °: no information provided about other treatment during the study, IL, Interleukin; LANSS, Leeds assessment of neuropathy symptoms and signs; LED, Light emitting diode; PBM, photobiomodulation; PQAS, Pain qualities assessment scale; Pre-Post ITV, Pre-post interventional trial; QoL, Quality of life; RCT, randomized controlled trial; T1D, Type 1 diabetes; T2D, Type 2 diabetes; TNF, Tumor necrosis factor; VAS, Visual analogic scale. *Surface of PBM not reported.

↑, increase; ↓, decrease.
power (350W), and the second study (59) used the longest exposure time (40 min) and application frequency (once a day for 90 days).

## 3.3 Impact of PBM on diabetic retinopathy

A total of 6 studies were conducted, including 4 studies on preclinical models (64–67) and 2 studies in humans (68, 69) (Table 3). Preclinical studies consistently reported a positive effect of PBM on retinal structure associated with a decrease in oxidative stress. In clinical studies focusing on macular oedema, findings were divergent regarding improvement of visual acuity between the two identified studies (68, 69). However, no side effects were reported in either study.

## 3.4 Impact of PBM on glucose metabolism in T2D

A total of 9 studies were conducted, with 8 studies conducted on preclinical models (70–78) and one study in humans (79) (Table 4). The preclinical studies consistently reported positive effects of PBM on metabolic parameters with an improvement in glucose tolerance [with a glucose tolerance test area under the curve (GTT AUC) decreasing by 12–28%], a decrease in insulin resistance [with a 22% decrease in homeostatic model assessment of insulin resistance (HOMA-IR (70)) and a 10% decrease in insulin tolerance test (ITT) AUC (72)] and a decrease in fasting glycemia. PBM also showed positive effects on lipid profiles with a reduction in free fatty acid,

triglycerides and cholesterol levels. In the clinical study (79), PBM applied on eight muscles in patients with T2D resulted in a decrease in glycemia (fasting and 1h post-prandial glucose) observed 30 min to 12 h after PBM treatment. This decrease was evidenced by a reduction in the GTT AUC by 37% and a reduction of 1h postprandial glucose by 16%. Importantly, no additive effect of hypoglycemic treatment was observed and no hypoglycemia were reported.

## 3.5 Impact of PBM on exercises and muscles in T2D

A total of 7 studies were conducted, including 3 studies on preclinical models (41, 80, 81) and 4 studies in humans (42, 43, 82, 83) (Table 5). In preclinical models, PBM has been demonstrated to have a positive impact on biochemical parameters, such as a decrease in oxidative stress and an increase in antioxidant activity. However, in clinical studies focusing on muscular performance and functionality during or after exercise, PBM has failed to show any improvement. No significant effects on the muscular performance were observed.

## 3.6 Impact of PBM on healing process

### 3.6.1 Wound healing

A total of 44 studies were conducted to evaluate impact of PBM on wound healing, including 31 studies on preclinical

<table><caption>TABLE 3 Effect of PBM on diabetic retinopathy.</caption><thead><tr><td>Author/ Year</td><td>Model</td><td>Wave (nm)</td><td>Light</td><td>PBM parameters</td><td>Conclusions</td></tr></thead><tbody><tr><td>Ahmed 2021 (64)</td><td>Wistar rat Streptozotocin induced</td><td>670</td><td>Continuous laser</td><td>5mW/cm², 90sec, 0.9J/cm²<br>Frequency: 2 times a week, for 6 weeks<br>Sites: 2, each eye, directly in eye</td><td>Improve structure of inner nuclear layer and retinal pigmented epithelium<br>↓ anatomical abnormalities</td></tr><tr><td>Cheng 2018 (65)</td><td>C57BL/6J mice Streptozotocin induced</td><td>670</td><td>Continuous LED</td><td>25mW/cm², 240sec, 6J/cm²<br>Frequency: once a day, for 8 months<br>Site: 1, back of the animal</td><td>↓ degenerescence of retinal capillaries<br>↓ albumin accumulation in the inner nuclear and in the outer plexiform layers of the retina<br>Preservation of spatial frequency threshold contrast sensitivity</td></tr><tr><td>Saliba 2015 (66)</td><td>C57BL/6J mice Streptozotocin induced</td><td>670</td><td>Continuous LED</td><td>20mW/cm², 240sec, 5J/cm²<br>Frequency: once a day, for 10 weeks<br>Site: Total body</td><td>↓ superoxyde in retina<br>↓ abnormalities induced in leukostasis<br>No effect on contrast sensitivity</td></tr><tr><td>Tang 2013 (67)</td><td>Lewis rat Streptozotocin induced</td><td>670</td><td>Continuous LED</td><td>25mW/cm², 240sec, 6J/cm²<br>Frequency: once a day, for 10 weeks<br>Site: total body</td><td>↓ diabetes induced abnormality of retinal function and abnormalities of electroretinograms<br>↓ retinal ganglion cell death<br>Inhibited leukostasis</td></tr><tr><td>Shen 2020 (68)</td><td>Human, n = 21 Diabetes Pre-Post ITV†</td><td>670</td><td>Continuous LED</td><td>25-100-200mW/cm², 90sec, 2.25-9-18J/cm²<br>Frequency: 12 sessions over 5 weeks<br>Site: fundus contact lens</td><td>↓ central macular thickness (100 and 200>25)<br>No effect on visual acuity<br>No adverse event</td></tr><tr><td>Eells 2017 (69)</td><td>Human, n = 10 Diabetes RCT‡</td><td>670</td><td>Unknown</td><td>45mW/cm², 100sec, 4.5J/cm²<br>Frequency: 3 consecutive days per week, for 8 weeks<br>Sites: 2, each eye, directly in eye</td><td>↓ central retinal thickness<br>↑ visual acuity (+ 6 letters)</td></tr></tbody></table>

<footnote>†: PBM in addition to the best standard of care, at the investigator discretion choice, LED, Light emitting diode; Pre-post interventional trial; RCT, Randomized controlled trial. ↑, increase; ↓, decrease.</footnote>
<table><caption>TABLE 4 Effect of PBM on glucose metabolism in T2D.</caption><thead><tr><th>Author/ Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusions</th></tr></thead><tbody><tr><td>Min 2022 (70)</td><td>Diabetic Goto Kakizaki rat</td><td>630</td><td>Continuous LED</td><td>3.7mW/cm², 600sec, 2.22J/cm²<br>Frequency: 1 session<br>Site: intra-duodenal</td><td>No effect</td></tr><tr><td></td><td></td><td>630 + 850</td><td>Continuous LED</td><td>32.72mW/cm², 100sec, 3.6J/cm²<br>Frequency: 1 session<br>Site: intra-duodenal</td><td>↓ glucose intolerance at 4 weeks (↓GTT AUC about 14.5%)<br>↓ insulin resistance only at 1 week (↓HOMA-IR about 22%)<br>↑ expression of insulin in beta cells</td></tr><tr><td>Bonifacio 2021 (71)</td><td>C57BL/6 mice High fat diet</td><td>808</td><td>Continuous laser</td><td>3.57W/cm², 8sec, 30J/cm²<br>Frequency: 3 times a week, for 4 weeks<br>Site: 1, direct contact with skin in pancreas region</td><td>No effect on glucose tolerance (GTT)<br>No effect on insulin resistance (ITT)<br>No effect on fasting glycemia<br>No effect on body weight<br>No effect on pancreas morphology<br>No effect on adiposity tissue<br>No effect on pancreas morphology</td></tr><tr><td>Gong 2021 (72)</td><td>C57BL/6 mice High fat diet and mice C57BLK5 diabetic</td><td>635</td><td>Continuous laser</td><td>72.1mW/cm², 10min, 43.3J/cm²<br>Frequency: once a day, for 10 weeks<br>Sites: 2, direct contact with skin</td><td>↓ glucose intolerance (↓GTT AUC about 12%)<br>↑ insulin sensitivity (↓ITT AUC about 10%)<br>↓ fed glycemia (500 vs. 280mg/dL)<br>↓ fasted glycemia (490 vs. 200mg/dL)<br>↑ glycogen in muscle<br>↓ ectopic fat in muscle<br>↓ triglycerides and free fatty acid</td></tr><tr><td>Gong 2020 (73)</td><td>C57BL/6 mice High fat diet</td><td>635</td><td>Continuous laser</td><td>72.1mW/cm², 10min, 43.3J/cm²<br>Frequency: once a day, for 10 weeks<br>Site: abdomen, direct contact with skin</td><td>↓ triglycerides, plasmatic FFA<br>↑ relative oxygen species</td></tr><tr><td>Guo 2020 (74)</td><td>C57BL/6 mice High fat diet</td><td>635</td><td>Continuous laser</td><td>72.1mW/cm², 10min, 43.3J/cm²<br>Frequency: once a day, for 8 weeks<br>Site: abdomen, direct contact with skin</td><td>↓ glucose intolerance (GTT)<br>↑ insulin sensitivity (ITT)<br>Protect against obesity (weight similar to control)<br>Protect against hyperglycemia (glycemia similar to control)<br>↓ weight, glycemia, triglycerides, cholesterol, insulinemia<br>↓ hepatic steatosis</td></tr><tr><td>Silva 2020 (76)</td><td>Swiss albinos mice High fat diet</td><td>630</td><td>Continuous LED</td><td>779.53mW/cm², 40sec, 31.18J/cm²<br>Frequency: 5 days per week, for 4 weeks<br>Sites: 5, direct contact with skin</td><td>↓ glucose intolerance (↓GTT AUC about 28%)<br>↓ fasting hyperinsulinemia (↓insulin concentration by 3)</td></tr><tr><td>Silva 2018 (77)</td><td>Swiss albinos mice High fat diet</td><td>780</td><td>Continuous laser</td><td>259mW/cm², 40sec, 10J/cm²<br>Frequency: 5 days per week, for 4 weeks<br>Sites: 5, direct contact with skin</td><td>↓ glucose intolerance (↓GTT AUC about 16%)<br>No effect on insulin resistance (HOMA-IR)<br>↓ fatty mass epididymal<br>↓ total cholesterol<br>↑ insulin signaling pathway</td></tr><tr><td>Yoshimura 2016 (78)</td><td>C57BL/6 mice High fat diet</td><td>843</td><td>Continuous LED</td><td>19mW/cm², 300sec, 5.7J/cm²<br>Frequency: day 1, 3, 7, 10, 14 and 21<br>Site: abdomen, direct contact with skin</td><td>↓ glycemia (98 vs. 118 mg/dL for non-treated group)<br>No effect on weight<br>↓ abdominal fatty infiltration</td></tr><tr><td>Scontri 2023 (79)</td><td>Human, n = 10 T2D RCT†</td><td>830</td><td>Continuous LED</td><td>114.28mW/cm², 50 or 120sec, 5.71 or 13.71J/cm²<br>Frequency: One session and 7 days of washout<br>Sites: 8, muscles, in contact with skin</td><td>Effect only with 5.71J/cm²<br>↓ post prandial glycaemia (30 min to 12h after PBM)<br>Better effect on glycemic control than hypoglycemic treatments<br>↓ GTT AUG around 37%<br>Faster glucose decay post prandial (16%, -60 vs. -70mg/dL/h)<br>No additive effect with hypoglycemic treatments</td></tr></tbody></table>

<footnote>†: PBM in addition to the best standard of care, at the investigator discretion choice, AUC, Area under the curve; FFA, Free fatty acid; GTT, glucose tolerance test; HOMA-IR, Homeostasis model assessment insulin resistance; ITT, insulin tolerance test; LED, Light emitting diode; PBM, photobiomodulation; RCT, randomized controlled trial; T2D, Type 2 diabetes.
↑, increase; ↓, decrease.</footnote>
<table><caption>TABLE 5 Effect of PBM on exercise and muscle in T2D.</caption><thead><tr><th>Author/ Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusions</th></tr></thead><tbody><tr><td>da Silva Tonetto 2023 (80)</td><td>Wistar rat Streptozotocin and diet induced</td><td>660</td><td>Continuous laser</td><td>571mW/cm², 36.75sec, 21J/cm²<br>Frequency: 5 days per week, for 6 weeks<br>Sites: 2, medium and laterally of gastrocnemius</td><td>↓ oxidative activity<br>↑ antioxidative activity (↑super oxide dismutase)</td></tr><tr><td>de Oliveira 2019 (41)</td><td>Wistar rat Streptozotocin induced</td><td>660</td><td>Continuous laser</td><td>250mW/cm², 16sec, 2J/cm²<br>Frequency: 3 times a week, for 3 weeks<br>Site: 1, dorsal</td><td>No effect on glucose concentration<br>No effect on muscle parameters if PBM was not associated with exercise</td></tr><tr><td>Frigerò 2018 (81)</td><td>Wistar rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>107.1mW/cm², 44sec, 4.71J/cm²<br>Frequency: 1/session of exercise<br>Sites: 3, gastrocnemius</td><td>↓ oxidative stress (↓ lactate, ↓ catalase, ↑ supe oxide dismutase)<br>↑ VO₂ max and speed of run</td></tr><tr><td>Linares 2022 (42)</td><td>Humain, n = 13<br>DT2<br>RCTT</td><td>850</td><td>Continuous LED</td><td>375mW/cm², 140 to 1120 sec, 52.5-420J/cm²<br>Frequency: 1/session of exercise<br>Sites: 7, oblique and rectus abdomen, quadriceps femoris, triceps, hamstrings bilateral</td><td>↓ glycemia and lactate 15min after PBM<br>Improvement of cardiac parameters</td></tr><tr><td>Gobbi 2021 (82)</td><td>Humain, n = 17<br>DT2<br>RCTT</td><td>620</td><td>Continuous LED</td><td>52.86mW/cm², 96sec, 5.074J/cm²<br>Frequency: once a day, for 3 days<br>Sites: 4, ankle flexor and extensor bilaterally</td><td>No impact on muscular performance<br>No impact on muscular functionality</td></tr><tr><td></td><td></td><td>940</td><td>Continuous LED</td><td>33.7mW/cm², 106sec, 3.572J/cm²<br>Frequency: once a day, for 3 days<br>Sites: 4, ankle flexor and extensor bilaterally</td><td>No impact on muscular performance<br>No impact on muscular functionality</td></tr><tr><td></td><td></td><td>620<br>+<br>940</td><td>Continuous LED</td><td>Same parameters of 2 others</td><td>No impact on muscular performance<br>No impact on muscular functionality</td></tr><tr><td>Milan-Mattos 2020 (43)</td><td>Humain, n = 7<br>T2D<br>RCTT</td><td>850</td><td>Continuous LED</td><td>375mW/cm², 40sec, 15J/cm² ou 80sec, 30J/cm²<br>Frequency: 1/session of exercise<br>Sites: 2, quadriceps and triceps bilaterally</td><td>No impact on baroreflex during or after exercise<br>No impact of PBM on cardiovascular autonomic control</td></tr><tr><td>Francisco 2019 (83)</td><td>Humain, n = 16<br>T2D<br>RCTT</td><td>850</td><td>Continuous LED</td><td>375mW/cm², 40sec, 15J/cm²<br>Frequency: 1/session of exercise<br>Sites: 2, quadriceps and triceps bilaterally</td><td>No impact of PBM on lactate concentration<br>No impact on cardiopulmonary and hemodynamic adjustments</td></tr></tbody></table>

T, no other treatment for pain; σ, no information provided about other treatment during the study; LED, light emitting diode; PBM, photobiomodulation; RCT, Randomized controlled trial; T2D, Type 2 diabetes.

↑, increase; ↓, decrease.

models (84–114) and 13 studies on humans (45, 47, 48, 115–124) (Table 6). In preclinical models, PBM had a predominantly positive effect on wound healing in 94% of studies. PBM improved various aspects of wound healing, including collagen density, fibroblast proliferation, angiogenesis, granulation tissue formation, and epithelialization. These effects were often accompanied by a decrease inflammatory marker. Only one study, which poorly described PBM parameters, did not report a positive effect of PBM (104). Most studies utilized wavelengths in the red to near-infrared spectrum, whereas studies investigating green wavelengths did not report positive effects of PBM (84, 94). In clinical studies, the majority (92%) reported a positive effect of PBM on chronic ulcers healing. Among the 12 RCTs, there was an increase in wound closure ranging from 15% to 47.3% in the control group compared to 37% to 90.8% in the PBM group. Consequently, the PBM groups had smaller wound areas compared to the control groups, with measurements of 2.39 cm² vs. 8.43 cm² (120), indicating a decrease in wound area of approximately 3.2 cm² vs. 10.4 cm² (122). The only study that did not report a positive effect of PBM utilized the shortest

exposure time (less than one second) (121). Two studies specified that PBM did not have any reported side effects (115, 117) while other studies did not explicitly mention it.

## 3.6.2 Healing of bone defect

A total of 16 studies were conducted to evaluate impact of PBM on healing of bone defect, with 15 studies conducted on preclinical models (125–139) and one study in humans (140) (Table 7). Among these studies, only one preclinical study did not report a positive impact of PBM on bone repair. This study used the highest power among all studies, with a dosage of 369.4J/cm². In addition to the effect of PBM on bone repair, several studies reported an increase in bone vascularization and a decrease in inflammation.

## 3.6.3 Chronic periodontitis

A total of 16 studies were conducted to evaluate the impact of PBM on chronic periodontitis in humans (34–40, 141–149) (Table 8).

■ Effect on healing process

The effects of PBM were evaluated using the following measures:
<table><caption>TABLE 6 Effect of PBM on wound healing and ulcer.</caption><thead><tr><td>Author/Year</td><td>Model</td><td>Wave (nm)</td><td>Light</td><td>PBM parameters</td><td>Conclusion</td></tr></thead><tbody><tr><td rowspan="3">Dungel 2023 (84)</td><td rowspan="3">C57BL diabetic mice</td><td rowspan="3">629</td><td rowspan="3">Pulsed LED</td><td>40mW/cm², 360sec, 14.4J/cm²<br>Frequency: day 0 and 1<br>Site: near to the wound</td><td>↑ wound closure<br>↑ angiogenesis</td></tr><tr><td>40mW/cm², 360sec, 14.4J/cm²<br>Frequency: day 0 and 1<br>Site: near to the wound</td><td>↑ wound closure<br>↑ angiogenesis</td></tr><tr><td>40mW/cm², 360sec, 14.4J/cm²<br>Frequency: day 0 and 1<br>Site: near to the wound</td><td>No effect</td></tr><tr><td>Ebrahimpour-Malekshah 2023 (85)</td><td>Wistar rat<br>Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>20mW/cm², 200sec, 1.08J/cm²<br>Frequency: once a day, for 14 days<br>Sites: 9, direct contact</td><td>↑ granulation tissue formation<br>↓ neutrophils, ↑ macrophages<br>↑ fibroblasts<br>↑ vascularization (VEGF)</td></tr><tr><td>Mehrvar 2021 (86)</td><td>Diabetic mice</td><td>670</td><td>Continuous LED</td><td>60mW/cm², 90sec, 4.5J/cm²<br>Frequency: 5 days per week, for 2 weeks<br>Site: 1, next to the wound</td><td>↓ wound area<br>↓ oxidative stress<br>↑ Red-Ox ratio</td></tr><tr><td>Ahmadi 2020 (87)</td><td>Wistar rat<br>Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>1mW/cm², 200sec, 0.2J/cm²<br>Frequency: once a day, for 14 sessions<br>Sites: 9, next to the wound</td><td>↑ wound healing<br>↓ inflammation (neutrophils)<br>↑ fibroblasts<br>↑ vascular length</td></tr><tr><td>Bagheri 2020 (88)</td><td>Wistar rat<br>Streptozotocin induced</td><td>890</td><td>Continuous laser</td><td>1mW/cm², 300sec, 0.324J/cm²<br>Frequency: once a day, for 7 days<br>Site: 1, next to the wound</td><td>↓ inflammation (macrophages, neutrophiles)<br>↑ fibroblast</td></tr><tr><td>Kouhkeil 2019 (89)</td><td>Rat<br>Streptozotocin induced</td><td>890</td><td>Continuous laser</td><td>1.08mW/cm², 200sec, 0.2J/cm²<br>Frequency: 6 days per week, for 2 weeks<br>Site: 1, next to the wound</td><td>↓ mast cells<br>↓ CFU<br>↑ wound strength</td></tr><tr><td rowspan="2">Fekrazad 2018 (90)</td><td rowspan="2">Wistar rat<br>Streptozotocin induced</td><td rowspan="2">660</td><td rowspan="2">Continuous laser</td><td>30mW*, 33sec, 2J/cm²<br>Frequency: every 2 days, for 10 days<br>Site: near to the wound</td><td>No effect</td></tr><tr><td>200mW*, 5sec, 2J/cm²<br>Frequency: every 2 days, for 10 days<br>Site: near to the wound</td><td>No effect</td></tr><tr><td></td><td></td><td>660 + 810</td><td>Continuous laser</td><td>Same parameters</td><td>↓ TGF-β1</td></tr><tr><td>Asghari 2017 (91)</td><td>Wistar rat<br>Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>0.324J/cm²<br>Frequency: 6 days per week, for 2 weeks<br>Site: 12, next to the wound</td><td>↑ wound healing<br>↓ CFU</td></tr><tr><td>Leite 2017 (92)</td><td>Wistar rat<br>Alloxan induced</td><td>660</td><td>Continuous laser</td><td>1W/cm², 9 or 130sec, 10 or 140J/cm²<br>Frequency: once a day, for 3 days<br>Site: 1, next to the wound</td><td>140J/cm² > 10J/cm²<br>↑ wound healing<br>↑ mast cells number, VEGF, FGF, neovascularization<br>↓ leukocytes number</td></tr><tr><td>Fahimipour 2016 (93)</td><td>Albinos mice<br>Streptozotocin induced</td><td>632.8</td><td>Continuous laser</td><td>250mW/cm², 16sec, 4J/cm²<br>Frequency: once a day, for 14 days</td><td>632.8 > 830 to improve healing<br>↑ density of collagen fibers</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 6 Continued</caption><thead><tr><th>Author/Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusion</th></tr></thead><tbody><tr><td></td><td></td><td></td><td></td><td>days<br>Sites: 2, next to the wound</td><td>↑ number of fibroblasts<br>↑ neovascularization</td></tr><tr><td></td><td></td><td>830</td><td>Continuous laser</td><td>250mW/cm², 16sec, 4J/cm²<br>Frequency: once a day, for 14 days<br>Sites: 2, next to the wound</td><td>=</td></tr><tr><td>Fekrazad 2015 (94)</td><td>Wistar rat Streptozotocin induced</td><td>425</td><td>Continuous laser</td><td>55mW/cm², 36sec, 2J/cm²<br>Frequency: day 0, 1, 2, 4, 6, 8<br>Site: 1, next to the wound</td><td>Red &amp; Blue &amp; green<br>↑ wound healing</td></tr><tr><td></td><td></td><td>532</td><td>Continuous laser</td><td>50mW/cm², 40sec, 2J/cm²<br>Frequency: day 0, 1, 2, 4, 6, 8<br>Site: 1, next to the wound</td><td>=</td></tr><tr><td></td><td></td><td>630</td><td>Continuous laser</td><td>50mW/cm², 40sec, 2J/cm²<br>Frequency: day 0, 1, 2, 4, 6, 8<br>Site: 1, next to the wound</td><td>=</td></tr><tr><td>Dancáková 2014 (95)</td><td>SD rat Streptozotocin induced</td><td>810</td><td>Continuous laser</td><td>30mW/cm², 30sec, 0.9J/cm²<br>Frequency: once a day, for 7 days<br>Site: 1, next to the wound</td><td>↑ wound healing<br>↑ wound tensile &amp; strength<br>↑ granulation tissue</td></tr><tr><td>Aparecida da Silva 2013 (96)</td><td>Wistar rat Streptozotocin induced</td><td>660</td><td>Continuous laser</td><td>1.43W/cm², 80sec, 4J/cm²<br>Frequency: one session<br>Site: 1, next to the wound</td><td>↑ collagen density<br>↓ MMP2 and MMP9</td></tr><tr><td>Fathabadie 2013 (97)</td><td>Wistar rat Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>1.08mW/cm², 200sec, 0.2J/cm²<br>Frequency: once a day, for 6 days<br>Sites: 18, next to the wound</td><td>↑ mast cells</td></tr><tr><td>Firat 2013 (98)</td><td>Wistar rat Streptozotocin induced</td><td>940</td><td>Continuous laser</td><td>1.1W/cm², 9sec, 10J/cm²<br>Frequency: every 2 days, for 7 days<br>Site: 1, next to the wound</td><td>↓ inflammation<br>↑ collagen synthesis<br>↑ fibroblasts</td></tr><tr><td>Dadpay 2012 (99)</td><td>Wistar rat Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>1.08mW/cm², 30 or 300sec, 0.03 or 0.2J/cm²<br>Frequency: 6 days per week, for 2 weeks<br>Sites: 18, next to the wound</td><td>↑ Enhancing maximum stress and elastic modulus</td></tr><tr><td>Park 2012 (100)</td><td>SD rat Streptozotocin induced</td><td>980</td><td>Continuous laser</td><td>232.5mW/cm², 60sec, 13.95J/cm²<br>Frequency: once a day, for 14 days<br>Site: 1, next to the wound</td><td>↓ inflammation cells infiltration<br>↑ number of fibroblasts<br>↑ wound healing</td></tr><tr><td>Hegde 2011 (101)</td><td>Swiss Albino mice Streptozotocin induced</td><td>632.8</td><td>Continuous laser</td><td>4.02mW/cm², 255 to 1277sec, 1 to 5J/cm²<br>Frequency: once<br>Site: 1, next to the wound</td><td>The best = 3J/cm²<br>↑ wound healing<br>↑ collagen synthesis</td></tr><tr><td>Peplow 2011 (102)</td><td>Diabetic mice</td><td>660</td><td>Continuous laser</td><td>233-313mW/cm², 20sec, 2J*<br>116-156mW/cm², 40 sec, 2J*<br>58-78mW/cm², 80sec, 2J*<br>Frequency: once a day, for 7 days<br>Site: 1, next to the wound</td><td>Same effects between puissance<br>↑ wound healing<br>↑ epithelialization, granulation</td></tr><tr><td>Akyol 2010 (104)</td><td>Wistar rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>100mW/cm², 20sec, 2J/cm²<br>Frequency: every 2 day, for 8 days<br>Site: 1, next to the wound</td><td>↑ wound healing<br>No effect on inflammation<br>No effect on epithelialization</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 6 Continued</caption><thead><tr><td>Author/Year</td><td>Model</td><td>Wave (nm)</td><td>Light</td><td>PBM parameters</td><td>Conclusion</td></tr></thead><tbody><tr><td>Carvalho 2010 (103)</td><td>Wistar rat Alloxan induced</td><td>660</td><td>Continuous laser</td><td>166mW/cm², 24sec, 4J/cm² Frequency: unknown Site: 1, next to the wound</td><td>↑ fiber of collagen ↓ macrophages</td></tr><tr><td>Chung 2010 (105)</td><td>Diabetic mice</td><td>660</td><td>Continuous laser</td><td>10sec -> 1J*, 20sec -> 1.6J*, 40sec -> 3.2J* Frequency: once a day, for 7 days Site: 1, next to the wound</td><td>Best one = 1.6J/day ↑ wound healing</td></tr><tr><td>Santos 2010 (106)</td><td>Wistar rat Streptozotocin induced</td><td>660</td><td>Continuous laser</td><td>30mW* -> 2,5J/cm² Frequency: once a day, for 8 days Sites: 16, next to the wound</td><td>790 better than 660 ↑ angiogenesis</td></tr><tr><td></td><td></td><td>790</td><td>Continuous laser</td><td>40mW* -> 2,5J/cm² Frequency: once a day, for 8 days Site: 16, next to the wound</td><td></td></tr><tr><td>Al-Watban 2009 (107)</td><td>SD rat Streptozotocin induced</td><td>532</td><td>Continuous laser</td><td>20.4mW/cm², 290 to 1470sec, 5 to 30J/cm² Frequency: 3 times per week</td><td>Best = Laser 633 ↑ wound healing</td></tr><tr><td></td><td></td><td>633</td><td>Continuous laser</td><td>15.56mW/cm², 322 to 1932sec, 5 to 30J/cm² Frequency: 3 times per week</td><td></td></tr><tr><td></td><td></td><td>810</td><td>Continuous laser</td><td>22.2mW/cm², 225 to 1350sec, 5 to 30J/cm² Frequency: 3 times per week</td><td></td></tr><tr><td></td><td></td><td>980</td><td>Continuous laser</td><td>22.2mW/cm², 225 to 1350sec, 5 to 30J/cm² Frequency: 3 times per week</td><td></td></tr><tr><td></td><td></td><td>1060</td><td>Continuous laser</td><td>66.37mW/cm², 75 to 450sec, 5 to 30J/cm² Frequency: 3 times per week</td><td></td></tr><tr><td></td><td></td><td>510-872</td><td>Continuous LED</td><td>13.6mW/cm², 367 to 2206sec, 5 to 30J/cm² Frequency: 3 times per week This was a polychromatous LED</td><td></td></tr><tr><td>Güngörmüş 2009 (108)</td><td>Wistar rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>10J/cm² Frequency: every 2 days for 8 days Site: unknown</td><td>↑ wound healing</td></tr><tr><td>Maiya 2009 (109)</td><td>Wistar rat Alloxan induced</td><td>632.8</td><td>Continuous laser</td><td>10mW/cm², 3 to 27min, 3 to 9J/cm² Frequency: 5 days per week until wound healing Site: 1, next to the wound</td><td>3 to 7J/cm²: ↑ epithelialization, tissue granulation ↑ wound healing 8-9J/cm²: ↓ reparative process</td></tr><tr><td>Carvalho 2006 (110)</td><td>Wistar rat Alloxan induced</td><td>632.8</td><td>Continuous laser</td><td>200mW/cm², 60sec, 4J/cm² Frequency: once a day, for 14 days Site: 1, next to the wound</td><td>↑ fiber of collagen</td></tr><tr><td>Rabelo 2006 (111)</td><td>Wistar rat Streptozotocin induced</td><td>632.8</td><td>Continuous laser</td><td>588mW/cm², 17sec, 10J/cm² Frequency: once a day, for 15 days Site: 1, next to the wound</td><td>↓ wound area ↓ local inflammation ↓ inflammatory cells</td></tr><tr><td>Maiya 2005 (112)</td><td>Wistar rat Alloxan induced</td><td>632.8</td><td>Continuous laser</td><td>4.8J/cm² Frequency: 5 days per week</td><td>↑ collagen ↑ fibroblastic and capillary proliferation ↑ granulation tissue formation, vascularization, epithelialization</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 6 Continued</caption><thead><tr><td>Author/Year</td><td>Model</td><td>Wave (nm)</td><td>Light</td><td>PBM parameters</td><td>Conclusion</td></tr></thead><tbody><tr><td>Byrnes 2004 (113)</td><td>Purina sand rat chow 5L09 DT2 model</td><td>632.8</td><td>Continuous laser</td><td>until wound healing<br/>Site: 1, next to the wound<br/>16mW/cm², 250sec, 4J/cm²<br/>Frequency: once a day, for 3 days<br/>Site: 1, next to the wound</td><td>↑ wound closure<br/>↑ collagen, bFGF<br/>↑ neovascularization</td></tr><tr><td>Reddy 2001 (114)</td><td>SD rat Streptozotocin induced</td><td>632.8</td><td>Continuous laser</td><td>1J/cm²<br/>Frequency: once a day, for 5 days<br/>Site: 1, next to the wound</td><td>↑ collagen<br/>↑ maximum strain<br/>↑ toughness</td></tr><tr><td>Haze 2022 (115)</td><td>Human, n = 20 Diabetes RCT†</td><td>808</td><td>Continuous laser</td><td>138mW/cm², 8min, 1.1J/cm²<br/>Frequency: once a day, for 12 weeks<br/>Site: next to the wounds</td><td>↓ wound area (12.5 vs. 1.5cm²)<br/>↑ wound closure (49.4 vs. 97.3%)<br/>No side effects link to PBM</td></tr><tr><td>Vitoriano 2019 (116)</td><td>Human, n = 12 Diabetes RCT† (for 2 sources of light)</td><td>850</td><td>Continuous LED</td><td>240mW/cm², 22sec, 14.64J/cm²<br/>Frequency: 2 times a week, for 5 weeks<br/>Sites: 6, next to the wound</td><td>Laser seems better than LED<br/>↓ wound area (1.45 to 0.64 vs 1.76 to 0.36cm²)</td></tr><tr><td></td><td></td><td>830</td><td>Laser</td><td>250mW/cm², 28sec, 15.48J/cm²<br/>Frequency: 2 times a week, for 5 weeks<br/>Sites: 3, next to the wound</td><td></td></tr><tr><td>de Alencar Fonseca Santos 2018 (45)</td><td>Human, n = 18 Diabetes RCT†</td><td>660</td><td>Continuous laser</td><td>490mW/cm², 13sec, 6J/cm²<br/>Frequency: every 2 days, for 4 weeks<br/>Site: 1, next to the wound</td><td>↑ wound healing index<br/>↑ pressure ulcer scale for healing<br/>No effect on pain (VAS)</td></tr><tr><td>Frangez 2018 (117)</td><td>Human, n = 60 Diabetes RCT†</td><td>625 (24%)<br/>660 (71%)<br/>850 (5%)</td><td>Pulsed LED</td><td>5min, 2.4J/cm²<br/>Frequency: 3 times a week, for 8 weeks<br/>Site: 1, next to the wound</td><td>↑ Falanga score (score of healing)<br/>No effect on size</td></tr><tr><td>Ruh 2018 (118)</td><td>Human, n = 8 Diabetes Pre-Post ITV†</td><td>660</td><td>Continuous laser</td><td>167mW/cm², 12sec, 2J/cm²<br/>Frequency: once a day for 12 days<br/>Site: 1, next to the wound</td><td>↓ wound size (data not shown)<br/>↓ TNFα, ↑TGFβ, ↑VEGF<br/>No effect on IL6</td></tr><tr><td>Mathur 2017 (119)</td><td>Human, n = 30 T2D RCT†</td><td>660</td><td>Continuous laser</td><td>50mW/cm², 60sec, 3J/cm²<br/>Frequency: once a day, for 15 days<br/>Sites: 5-8, above the wound</td><td>↑ wound closure (15% vs. 37%)<br/>No side effects</td></tr><tr><td>Carvalho 2016 (120)</td><td>Human, n = 32 DT2 RCT†</td><td>658</td><td>Continuous laser</td><td>50mW/cm², 80sec, 4J/cm²<br/>Frequency: 3 times a week, for 4 weeks<br/>Site: 1, next to the wound</td><td>↓ wound area (8.43 vs. 2.39cm²)<br/>↓ pain (VAS: 4.8 vs 1.9)<br/>↑ neovascularization</td></tr><tr><td>Sandoval Ortiz 2014 (121)</td><td>Human, n = 9 Diabetes RCT†</td><td>685</td><td>Continuous laser</td><td>-11mW/cm², 0.14-0.18sec, 1.5-2J/cm²<br/>Frequency: Unknown<br/>Sites: multiple along the edges of the ulcer and in the wound bed, next to the wound</td><td>No effect on wound healing<br/>No effect on protective sensation<br/>No effect on QoL (EQ-5D)</td></tr><tr><td>Kajagar 2012 (122)</td><td>Human, n = 68 T2D RCT†</td><td>660 + 850</td><td>Pulsed LED</td><td>60mW*, 2-4J/cm²<br/>Frequency: once a day, for 15 days<br/>Site: 1, above the wound</td><td>↓ ulcer area (decrease of 32 vs. 104cm²)</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 6 Continued</caption><thead><tr><th>Author/Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusion</th></tr></thead><tbody><tr><td>Kaviani 2011 (123)</td><td>Human, n = 23 T2D RCT†</td><td>685</td><td>Continuous laser</td><td>50mW/cm², 200sec, 10J/cm² Frequency: 6 days per week, at least 2 weeks Site: 1, next to the wound</td><td>↑ wound closure (47.3% vs 73.7% after 4 weeks) ↑ wound healing (non-ischemic wound)</td></tr><tr><td>Minatel 2009 (124)</td><td>Human, n = 14 Diabetes RCT†</td><td>890 + 660</td><td>Continuous LED</td><td>100mW/cm², 30sec, 3J/cm² Frequency: 2 times a week, for 3 months Site: 1, next to the wound</td><td>↑ granulation ↑ wound closure (43.3% vs. 90.8%)</td></tr><tr><td>Schindl 1999 (47)</td><td>Human, n = 8 Diabetes Descriptive†</td><td>632.8</td><td>Continuous laser</td><td>30mW*, 30J/cm² Frequency: 3 times a week until wound healing Site: unknown</td><td>100% of closure of chronic ulcers after 32 to 130 sessions</td></tr><tr><td>Schindl 1998 (48)</td><td>Human, n = 30 Diabetes RCT†</td><td>632.8</td><td>Continuous laser</td><td>10mW/cm², 50min, 30J/cm² Frequency: 1 time Site: 1, skin surface</td><td>↑ skin temperature ↑ microcirculation in patient with microangiopathy</td></tr></tbody></table>

<table><caption>TABLE 7 Effect of PBM on healing of bone defect.</caption><thead><tr><th>Author/Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusions</th></tr></thead><tbody><tr><td>Dalirsani 2021 (125)</td><td>Wistar rat Streptozotocin induced</td><td>660</td><td>Continuous laser</td><td>76.4mW/cm², 24sec, 7.2J/cm² Frequency: once a day, for 14 days Site: 1, direct contact</td><td>↑ bone formation ↓ inflammation ↑ vascularization</td></tr><tr><td></td><td></td><td>802</td><td>Continuous laser</td><td>127.32mW/cm², 14sec, 7J/cm² Frequency: once a day, for 14 days Site: 1, direct contact</td><td>↓ inflammation ↑ vascularization</td></tr><tr><td>Lee 2021 (126)</td><td>Wistar rat Streptozotocin induced</td><td>660</td><td>Continuous laser</td><td>2.42mW/cm², 1652sec, 4J/cm² Frequency: once a day, for 12 weeks Site: 1, near to the bone defect place</td><td>↑ bone formation ↑ bone fracture healing No effect on osteogenic factor</td></tr><tr><td>Diker 2019 (127)</td><td>SD rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>3.5W/cm², 22sec, 78.5J/cm² Frequency: once a day, for 3 days Site: 1, direct contact</td><td>↑ bone formation ↑ osteoblasts</td></tr><tr><td>Gomes 2018 (128)</td><td>Wistar rat Streptozotocin induced</td><td>780</td><td>Continuous laser</td><td>16W/cm², 10, 20 or 40sec, 160, 320 or 640J/cm² Frequency: every 2 days, for 21 days Site: 1, direct contact</td><td>Only or 640J/cm²: Better maintenance of periodontal tissue subjected to a force</td></tr><tr><td>Mostafavinia 2018 (129)</td><td>Wistar rat Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>1.5W/cm², 1300sec, 1.5J/cm² Frequency: 3 times a week, for 4 weeks Sites: 3, direct contact</td><td>↑ bone formation ↑ bone cortical volume ↑ bone trabecular volume ↑ osteoblasts and osteocytes</td></tr><tr><td>Mostafavinia 2017 (130)</td><td>Wistar rat Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>8.32W/cm², 1300sec, 1.5J/cm² Frequency: 3 times a week, for 4 weeks Sites: 3, direct contact</td><td>↑ bone density</td></tr><tr><td>Yildirimturk 2017 (131)</td><td>SD rat Streptozotocin induced</td><td>820</td><td>Continuous laser</td><td>0.5W/cm², 32sec, 16J/cm² Frequency: 3 times a week, for 4 weeks Site: 1, tibiae, direct contact</td><td>↑ bone formation ↑ vascularization No effect of osteoblast quantity</td></tr></tbody></table>

(Continued)

<footnote>†: PBM in addition to the standard wound care (rising, cleaning, drying), CFU, colony forming unit; FGF, fibroblast growth factor; LED, Light emitting diode; MMP, Matrix metalloproteinases; PBM, Photobiomodulation; Pre-Post ITV, Pre-post interventional trial; QoL, Quality of life; Rat SD, Rat Sprague Dawley; RCT, Randomized controlled trial; T2D, Type 2 diabetes; TGF, Transforming Growth factor; TNF, Tumor necrosis factor; VAS, Visual analog scale; VEGF, Vascular endothelial growth factor. *Surface of PBM not reported.
↑, increase; ↓, decrease; =, equal/same.</footnote>
<table><caption>TABLE 7 Continued</caption><thead><tr><td>Author/Year</td><td>Model</td><td>Wave (nm)</td><td>Light</td><td>PBM parameters</td><td>Conclusions</td></tr></thead><tbody><tr><td>Patrocinio Silva 2016 (132)</td><td>Wistar rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>3.57W/cm², 33sec, 120J/cm² Frequency: 3 times a week, for 8 weeks Site: 1, direct contact</td><td>↑ bone density<br/>↑ bone mineral content stiffness<br/>↑ cortical tibia area</td></tr><tr><td>Magri 2015 (133)</td><td>Wistar rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>3.57mW/cm², 8 or 16 or 33sec, 30, 60 or 120J/cm² Frequency: 3 times a week, for 4 weeks Sites: 2, direct contact</td><td>↑ bone formation<br/>No histological effect</td></tr><tr><td>Nascimento 2015 (134)</td><td>Wistar rat Alloxan induced</td><td>780</td><td>Continuous laser</td><td>1.75W/cm², 10sec, 17.5J/cm² Frequency: every 2 days, for 7 days Site: 1, direct contact</td><td>↑ bone formation<br/>↓ inflammation<br/>↑ alkaline phosphatase</td></tr><tr><td>Patrocinio Silva 2014 (135)</td><td>Wistar rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>3.57W/cm², 33sec, 120J/cm² Frequency: 3 times a week, for 6 weeks Sites: 4, direct contact</td><td>↑ bone density<br/>↑ cortical area<br/>↑ values of fracture force<br/>↑ osteogenic potential</td></tr><tr><td>Akyol 2010 (136)</td><td>Wistar rat Streptozotocin induced</td><td>808</td><td>Continuous laser</td><td>100mW/cm², 20sec, 2J/cm² Frequency: every 2 days, for 7 days Site: 1, right distal epiphysis</td><td>↑ bone repair<br/>↑ substantia spongia formation<br/>No effect on union bone marrow</td></tr><tr><td>Abdi 2009 (137)</td><td>Wistar rat Alloxan induced</td><td>780</td><td>Continuous laser</td><td>318mW/cm², 1166sec, 369,4J/cm² Frequency: 3 times a week, for 6 weeks Sites: 2, direct contact</td><td>No effect on bone repair</td></tr><tr><td>Bayat 2009 (138)</td><td>Wistar rat Streptozotocin induced</td><td>632.8</td><td>Continuous laser</td><td>3.17mW/cm², 90 or 1200sec, 88.6 or 382.2J/cm² Frequency: once a day, for 14 days Sites: 4, direct contact</td><td>↑ bone density<br/>↑ bone lamella meshwork<br/>↑ maximum force and load at the break<br/>↓ bend stiffness</td></tr><tr><td>Javadieh 2009 (139)</td><td>Wistar rat Streptozotocin induced</td><td>890</td><td>Pulsed laser</td><td>265 or 530sec, 5 or 10J/cm² Frequency: 3 times a week, for 6 weeks Sites: 2, direct contact</td><td>↑ bone repair<br/>↑ bending stiffness<br/>↑ maximum force</td></tr><tr><td>Attia 2023 (140)</td><td>Human, n = 40 T2D RCT<sup>a</sup></td><td>808</td><td>Continuous laser</td><td>125mW/cm², 1.23min, 0.15J/cm² Frequency: 2 times, pre and post implantation Sites: 6, direct contact</td><td>↑ bone repair and density<br/>↑ bone structure</td></tr></tbody></table>

1) gingival index represents inflammation of the gingival tissue (150),

2) the plaque index, which represents the presence of supragingival plaque on all four tooth surfaces (151).

Among the clinical studies, 11 were RCTs, 3 were RCTs specifically focused on pockets treated with PBM, and two were Pre-Post ITV. The results were heterogeneous, with a decrease in the plaque index observed in 50% of the studies, a decrease in the gingival index in 80% of the studies, a reduction in bleeding in 66% of the studies, a decrease in probing depth in 50% of the studies, and improvements in clinical attachment levels in 29% of the studies.

■ Effect on bacterial population

Two studies investigated the effect of PBM on reducing the bacterial population at periodontitis sites, but the results were contradictory.

## 3.7 Others utilization described in diabetes mellitus

### 3.7.1 Erectile function

In a preclinical study, Yang et al. (152) reported a positive impact of PBM on erectile function two weeks after PBM exposure. This suggests a potential therapeutic effect of PBM on improving erectile function (Table 9).

### 3.7.2 Ischemia reperfusion injury

Asghari et al. (153) conducted a preclinical study and demonstrated a protective effect of PBM against ischemia/ reperfusion injury in the diabetic kidney. They observed a decrease in tubular epithelial necrosis, polymorphonuclear cells in the outer medulla, cellular oedema, tubular dilatation, hyaline casts, and medullary congestion. These findings indicate the potential of

<footnote>ª: no information provided about other treatment during the study. Rat SD, Rat Sprague Dawley; RCT, Randomized controlled trial; T2D, Type 2 diabetes.</footnote>

<footnote>↑, increase; ↓, decrease.</footnote>
<table><caption>TABLE 8 Effect of PBM on chronic diabetes periodontitis.</caption><thead><tr><td>Author/ Year</td><td>Model</td><td>Wave (nm)</td><td>Light</td><td>PBM parameters</td><td>Conclusions</td></tr></thead><tbody><tr><td>Kamatham 2022 (34)</td><td>Human, n = 60 T2D RCT<sup>T</sup></td><td>650</td><td>Continuous laser</td><td>0.4W*, Frequency: 1 session Site: 1/tooth, in contact with gingival tissue</td><td>↓ inflammation ↓ calprotectin No effect on probing depth, clinical attachment level</td></tr><tr><td>Pulivarthi 2022 (35)</td><td>Human, n = 30 T2D RCT<sup>†</sup></td><td>650</td><td>Continuous laser</td><td>0.8W/cm<sup>2</sup>, 15sec, 12J/cm<sup>2</sup> Frequency: once a day, for 8 weeks Sites: 3, in contact with gingival tissue</td><td>No effect on TNFα No effect on bleeding index, probing depth, clinical attachment level</td></tr><tr><td>Mrasori 2021 (141)</td><td>Human, n = 80 T2D RCT<sup>†</sup></td><td>660</td><td>Continuous laser</td><td>10mW*, 8min Frequency: 5 days per week, for 3 months Sites: 5, in contact with gingival tissue</td><td>↓ IL6</td></tr><tr><td>Soi 2021 (142)</td><td>Human, n = 44 T2D RCT<sup>†</sup></td><td>940</td><td>Pulsed laser</td><td>0.8W*, 15sec, 24J* Frequency: unknown Sites: 2/tooth, into the periodontal pocket</td><td>No effect of adjunction of PBM to SRP (scaling and root planning)</td></tr><tr><td>Koçak 2020 (36)</td><td>Human, n = 60 T2D RCT<sup>†</sup></td><td>940</td><td>Pulsed laser</td><td>1.061W/cm<sup>2</sup>, 20sec Frequency: 1 session Sites: 2/tooth, intra periodontal pocket</td><td>No effect on bacteria level (P.gingivalis, T.forsythia, T.denticola)</td></tr><tr><td>Özberk 2020 (143)</td><td>Human, n = 22 T2D RCT<sup>†</sup></td><td>980</td><td>Continuous laser</td><td>33mW/cm<sup>2</sup>, 15sec, 0.5J/cm<sup>2</sup> Frequency: day 0, 1, 3 and 7 Sites: 2/tooth, in contact with maxilla and mandibula</td><td>↓ probing depth (2.9 vs. 2.6 mm) ↓ clinical attachment level (3.0 vs. 2.8 mm) No effect on plaque index and gingival index</td></tr><tr><td>Castro dos Santos 2019 (144)</td><td>Human, n = 24 T2D RCT<sup>†</sup> (on pocket)</td><td>660</td><td>Continuous laser</td><td>1.1W/cm<sup>2</sup>, 20sec, 22J/cm<sup>2</sup> Frequency: 1 session Sites: 2, buccal and lingual</td><td>No effect on probing depth, clinical attachment level</td></tr><tr><td>Chandra 2019 (145)</td><td>Human, n = 40 T2D RCT<sup>†</sup></td><td>808</td><td>Continuous laser</td><td>1.5-1.8W/cm<sup>2</sup>, time in second Frequency: 1 session Site: 1, intra periodontal pocket</td><td>↓ plaque index (1.56 vs. 1.26) ↓ gingival index (1.56 vs. 1.04) ↓ probing depth (2.63 vs. 1.80) ↓ clinical attachment level (7.50 vs. 6.65) ↓ bacteria level (35% more reduction with PBM)</td></tr><tr><td>Dengizek Eltas 2019 (146)</td><td>Human, n = 40 T2D RCT<sup>†</sup></td><td>810</td><td>Continuous laser</td><td>1W*, 15-20sec Frequency: once a day Sites: 3/tooth</td><td>↓ gingival index (0.91 vs. 0.58) ↓ bleeding on probing (31.7 vs. 24.7%) ↓ probing depth (2.99 vs. 2.77mm) No effect on plaque index, clinical attachment level and inflammation (CRP)</td></tr><tr><td>Li 2018 (147)</td><td>Human, n = 80 T2D RCT<sup>†</sup></td><td>Unknown</td><td>Unknown</td><td>Unknown</td><td>↓level of TNF, IL-1, LPS Increase leptin</td></tr><tr><td>Demirturk-Gocgun 2017 (148)</td><td>Human, n = 22 T2D RCT<sup>†</sup> (on pocket)</td><td>808</td><td>Continuous laser</td><td>0.89W/cm<sup>2</sup>, 5sec, 4.46J/cm<sup>2</sup> Frequency: Day 1, 2 and 7 Sites: 4, in contact with gingival tissue</td><td>No effect on bleeding of probing, probing depth, clinical attachment level, plaque index</td></tr><tr><td>Koçak 2016 (37)</td><td>Human, n = 60 T2D RCT<sup>†</sup></td><td>940</td><td>Pulsed laser</td><td>1.061W/cm<sup>2</sup>, 20sec Frequency: 1 session Sites: 2/tooth, intra periodontal pocket</td><td>↓ VCAM No effect on IL1/6/8/ICAM</td></tr><tr><td>Javed 2015 (149)</td><td>Human, n = 22 T2D RCT<sup>†</sup> (on pocket)</td><td>1064</td><td>Pulsed laser</td><td>1430W/cm<sup>2</sup>, 60 to 120sec (depending on the accessibility of the pocket), 240-480J* Frequency: unknown Site: 1/tooth, into the periodontal pocket</td><td>↓ plaque index (6.4 vs. 1.5) at 1 month, not 3 months ↓ bleeding probing (5.5 vs. 2.1) at 1 month, not 3 months</td></tr><tr><td>Obradović 2013 (38)</td><td>Human, n = 300 T1D, T2D RCT<sup>†</sup></td><td>670</td><td>Continuous laser</td><td>2mW/cm<sup>2</sup>, 16min, 2J/cm<sup>2</sup> Frequency: once a day for 5 days Site: 1, in contact with gingival tissue</td><td>↓ alteration of periodontium (histologic description)</td></tr><tr><td>Obradović 2012 (39)</td><td>Human, n = 200 T1D, T2D</td><td>670</td><td>Continuous laser</td><td>5mW*, 14min Frequency: once a day, for 5 days Site: 1, in contact with the jaws</td><td>↓ gingival index (0.31 vs. 0.16) ↓ inflammation ↑ cytomorphometric parameters</td></tr></tbody></table>

(Continued)
<table><caption>TABLE 8 Continued</caption><thead><tr><th>Author/ Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusions</th></tr></thead><tbody><tr><td></td><td>RCT†<br>(on pocket)</td><td></td><td></td><td></td><td></td></tr><tr><td>Obradović<br>2011 (40)</td><td>Human, n =<br>150<br>T1D, T2D<br>Pre-Post ITV†</td><td>Unknown</td><td>Unknown</td><td>5mW*<br>Frequency: for 5 days<br>Site: only right site of the jaw</td><td>↓ gingival index (data not available)<br>↓ nuclei areal</td></tr></tbody></table>

T: no other treatment for pain, †: PBM in addition to non-surgical periodontal treatment (i.e. scaling and root planning, ultrasonic periodontal debridement), CRP: C reactive protein, ICAM: Intercellular adhesion molecule, IL: Interleukin, LPS: lipopolysaccharide, PBM: photobiomodulation, Pre-post ITV: Pre-post interventional trial, RCT: Randomized controlled trial, SRP: scaling and root planning, T1D: Type 1 diabetes, T2D: Type 2 diabetes, TNF: Tumor necrosis factor, VCAM: Vascular cell adhesion molecule, *Surface of PBM not reported.
↑, increase; ↓, decrease.

PBM in mitigating kidney injury associated with ischemia/ reperfusion (Table 9).

### 3.7.3 Facial nerve palsy

Aghemohamdi et al. (154) demonstrated the positive impact of PBM in patients with T2D who experienced facial nerve palsy. After 12 sessions of PBM, 60% of the patients showed recovery on electromyogram without any reported side effects. However, the investigation of QoL outcomes were not investigated in this study (Table 9).

## 4 Discussion

This review shows a clear interest in the use of PBM in diabetes, both at preclinical (70 studies) and clinical level [56 studies out of 88 clinical trials identified by clinicaltrials.gov (27)]. However, the therapeutic effect of PBM is variable, with inconsistent illumination parameters that are not standardized across studies.

Regarding clinical trials, PBM has generated interest across various fields, with 2,573 clinical trials identified on clinicaltrials.gov (27). Although 42 clinical trials related to PBM in diabetes were found on clinicaltrials.gov (27), an additional 46 studies were identified through the Medline bibliographic search. Since PBM is not considered as a

drug, the reporting of trials in the global clinical trials database is not consistent. Moreover, in some cases, trials may be reported directly to national registries, as seen in many studies conducted in Brazil. Another important point to note is that among the 67 completed trials, only 56 were published, indicating a significant publication bias (16%), which is likely underestimated. Moreover, quality of clinical trials must be upgraded, as there is heterogeneity in the number of patients included, in the presence of a control group and in the parameters used. Furthermore, in terms of clinical publications, few teams have conducted more than one study, amplifying the heterogeneity of the PBM parameters used.

Currently, there is no consensus on the optimal PBM parameters to achieve biological or clinical effects. In terms of light sources, some studies have reported superior effects with coherent laser light (155, 156). However, a recent review found no difference in efficacy between LEDs and laser sources, with LEDs being more cost-effective. In the context of diabetes and wound healing, two studies compared lasers and LEDs. Al-Watban et al. (107) reported a better efficacy of a 633 nm laser compared to LEDs with polychromatic light for ulcer healing, may be due to dilution of the effect as the irradiance was comparable for both. Vitoriano et al. (116) reported a greater reduction in ulcer size with an 830 nm laser compared to 850 nm LEDs (with comparable irradiance). Despite these two studies favoring lasers, numerous studies in the field of diabetes have reported positive effects of LED-based PBM. However,

<table><caption>TABLE 9 Effect of PBM on other complications.</caption><thead><tr><th>Author/ Year</th><th>Model</th><th>Wave (nm)</th><th>Light</th><th>PBM parameters</th><th>Conclusions</th></tr></thead><tbody><tr><td>Yang 2023 (152)</td><td>SD rat Streptozotocin induced</td><td>808</td><td>Laser</td><td>4J/cm²<br>Frequency: for 2 weeks<br>Site: Unknown</td><td>↑ erectile function<br>↑ mitochondrial function and morphology<br>↓ oxidative stress</td></tr><tr><td>Asghari 2016 (153)</td><td>Wistar rat Streptozotocin induced</td><td>685</td><td>Continuous laser</td><td>53.6mW/cm², 60sec, 3.2J/cm²<br>Frequency: H0, H1, H2<br>Sites: 6, direct contact with skin</td><td>↓ ischemia-reperfusion injury<br>↓ plasma creatinine<br>↓ tubular dilatation, glomerular atrophy<br>↑ glutathione, superoxide dismutase and catalase</td></tr><tr><td>Aghamohamdi 2020 (154)</td><td>Human, n = 30 Diabetes Pre-Post ITV†</td><td>830</td><td>Pulsed laser</td><td>334mW*, 60sec, 16J/cm²<br>Frequency: 3 times a week, for 4 weeks<br>Sites: 9, pathway of facial nerve, direct skin contact</td><td>Recovery in electromyogram in diabetic patient with Bell's palsy</td></tr><tr><td></td><td></td><td>980</td><td>Pulsed LED</td><td>9min, 5J/cm²<br>Frequency: 3 times a week, for 4 weeks<br>Sites: 9, pathway of facial nerve, direct skin contact</td><td></td></tr></tbody></table>

<footnote>†: PBM in addition to the best standard of care, LED, Light emitting diode; Pre-Post ITV, Pre-post interventional trial. *Surface of PBM not reported.
↑, increase; ↓, decrease.</footnote>
the choice between laser and LED was a technologic choice and could be
led by the accuracy of wavelength search, the availability of the device
and energetic consumption. It is important to note that the principle of
PBM is based on the Arndt-Schultz law (20), which describes a biphasic
response. A dose that is too low will produce no effect while a dose that
is too high can be toxic and induce mitochondrial permeabilization and
apoptosis through activation of caspases (157). This biphasic response to
PBM was reflected in two studies on ulcer healing in diabetes. Hedge
et al. (101) tested a 632.8 nm laser with different irradiances ranging
from 1 to 5 J/cm². While irradiances of 1 and 5 J/cm² resulted in poorer
and slower wound healing, an irradiance of 3 J/cm² appeared to be
optimal for improving and accelerating wound healing. Maiya et al.
(109) tested a 632.8 nm laser with different irradiances ranging from 3 to
9 J/cm². Irradiances between 3 and 7 J/cm² had a positive effect on
healing, including increased epithelialization, tissue granulation, and
accelerated wound healing; whereas irradiances of 8 and 9 J/cm²
hindered the healing process. To date, there is no consensus on the
power or optimal irradiance to be applied, and the wavelength applied is
another parameter of interest that lacks consensus and may depend on
the target tissue. Red and near-infrared light correspond to the
absorption wavelengths of cytochrome c oxidase in the mitochondria
(23). Green light, on the other hand, is rarely used and not very effective
in inducing biological changes as it was not in the specter of absorption
of cytochrome c oxidase. Two studies compared blue, green, and red
wavelengths in diabetes. Dungel et al. (84) reported that blue light (470
nm) had no effect on wound healing, whereas green (540 nm) and red
(629 nm) light accelerated wound healing. Fekrazad et al. (94) reported
no effect of blue (425 nm) and green (532 nm) light, whereas red light
(630 nm) promoted wound healing. Another study (93) reported that a
632.8 nm laser is more effective than an 830 nm laser for wound healing.
Given these findings, it is logical that the most commonly used
wavelengths (80 studies) fall within the red and near-infrared range
(600-810 nm). In any case, numerous articles have shown that the effect
of PBM depends on various parameters: wavelength, fluence (J/cm²),
total energy received (J), pulsed or continuous emission mode ...
Moreover, the absorption characteristics of the tissue, as well as the
delivery mode, and the frequency of use of the PBM (number of
applications, treatment schedule etc.) add complexity. It is now
necessary to standardize PBM parameters, and to precise them into
papers; in order to be reproducible and identify effective
application methods.

The first experiment to investigate the effect of PBM on healing
showed promising results (17, 18). Extensive research has been
conducted in this field, with several preclinical and clinical reviews
reporting positive effects of PBM on wound healing (158), healing of
bone defect (159), and periodontitis (160). In a specific population of
patients with diabetes, the results regarding these healing processes
were encouraging. Numerous preclinical studies have focused on
ulcer and wound healing, demonstrating the beneficial effects of
PBM. These effects include improved angiogenesis and associated
trophic factors, increased fibroblasts, reduced inflammation,
increased collagen quantity, and even a reduction in colony-
forming units (CFU). Clinically, these results were supported by a
significant reduction in wound area (by a factor of 3.5 to 8.2) and
increased wound closure (ranging from 22% to 47.9%), which may be
associated with reduced pain. Wound healing issues in patients with

diabetes significantly impact their QoL (161). However, only one
study (121) has examined the impact of PBM on the QoL of patients
with diabetes and ulcers and did not demonstrate any beneficial
effects of PBM on QoL. Overall, the data on wound healing are
encouraging. The ideal parameters may involve repeated exposure
over several weeks, at multiple sites as close as possible to the lesion,
with a fluence between 1 and 10 J/cm², continuous illumination using
LED or laser, and a wavelength ranging from 660 to 830 nm. In
wound healing, PBM appeared as a sage approach to enhance healing
process in addition to wound standard of care.

Regarding healing of bone defect, 94% of preclinical studies showed positive results (improved vascularization, increased osteoblasts and osteocytes, reduced inflammation, increased bone volumes, and enhanced bone density). Clinically, only one study (140) has been conducted, demonstrating improved bone repair, density, and structure after dental implant insertion with one session of PBM before and after implantation. However, conclusions cannot be drawn from a single clinical study, but the promising results from preclinical and clinical studies should motivate further clinical trials to determine the optimal parameters for PBM.

To date, only clinical studies have investigated the effects of
PBM on periodontitis, yielding heterogeneous results due to
variations in the applied parameters. The exposure periods ranged
from a single session to several days or even weeks. Among studies
that examined the gingival index, plaque index, and clinical
attachment level, 75% reported improvements in at least one of
these parameters. Four studies reported negative results: one had
the highest fluence (144), one had the highest exposure frequency
[once a day for 8 weeks (35)], one had poorly described illumination
parameters and a wavelength beyond the infrared range (142), and
one had four PBM exposure sites (148), whereas most studies
reported one to two exposure sites. Finally, the ideal parameters
could involve a single exposure or exposure over 2 to 3 days, on one
to two sites in direct contact with gingival tissue or intra-pocket,
with a fluence of 1 to a few J/cm², continuous or pulsed laser
illumination, and a wavelength range of 650 to 1064 nm. These data
have been supported by previous results on *in vitro* model (162)
reporting positive response of fibroblasts to the PBM in diabetic
hypoxic wounded models. Even if three teams published several
studies, the lack of rigorous methodology and the heterogeneity of
PBM parameters, did not allowed to identify leader in this field.
Moreover, due to the wide variability in illumination parameters
and obtained results, definitive conclusions regarding the
therapeutic effects of PBM on periodontitis cannot be formally
drawn. Further clinical trials are required to establish clearer
conclusions and defined optimal PBM parameters to use PBM as
an added therapy for diabetes chronic periodontitis management.

Regarding neuropathy, five preclinical studies reported a positive
effect of PBM on pain, leading to a decrease in cytokines and
improvement in mitochondrial parameters. Clinically, in 77% of the
studies, a 2-5 points reduction on the VAS was observed for pain. Out
of the studies that considered the impact of PBM on QoL (24%), two
studies reported no effect (58, 59) (similarly, no effect on pain was
observed), while two studies reported a 4-point improvement in
Norfolk Quality of Life-Diabetic Neuropathy (54) and SF-36 scores
on all these parameters (44). No adverse effects of PBM were reported
in any of the studies. Two teams have been identified in this field. Unfortunately, studies of Burka et al. (28–30), lack methodological rigor and a description of the PBM parameters used. On the other hand, Arun G et al. (31–33), succeeded in demonstrating in their three studies (with the same PBM parameters used) an improvement of vibration perception threshold, decrease of pain, improvement of microcirculation and biological parameters. These benefits were observable as early as 10 days after daily PBM with 2 lasers (632.8 nm and 660 nm + 880 nm) over 9 min (3.1 J/cm² of fluence) on the plantar and dorsal surfaces of the feet. These parameters should therefore serve as a basis for future clinical trials aimed at defining whether MBP will be used instead of or in addition to current pharmacological treatments.

For diabetic retinopathy, only a few studies have been conducted in this field. Four preclinical studies reported promising results on the effect of PBM, showing histological improvements in the retina. However, clinically, only two studies reported a reduction in central macular thickness, with (69) or without (68) an improvement in vision. Therefore, it is not possible to conclude whether PBM must be used. Clinical trials must be conducted to demonstrate PBM safety in use and its efficacy as a complementary or alternative therapy to current therapeutic options.

PBM is also gaining popularity among its potential benefits for post-physical activity recovery, this fact was still a source of debate (163, 164). In the context of T2D, a limited number of studies (n = 7) have been conducted. The results of 3 preclinical studies reported positive effects of PBM on oxidative stress, antioxidant activity, and muscular parameters. However, clinically (n = 4), no study reported improvements in performance or muscle functionality. Only one study (42) reported a benefit in terms of lactate concentration and cardiac parameters. Based on these findings, it can be concluded that the current parameters used for PBM do not provide benefits for post-exercise muscle recovery in patients with T2D.

Lastly, since diabetes is a metabolic disease characterized by an imbalance in glycemic control, PBM has also been investigated in this field. Preclinical results have shown promising results, with 83% of the studies that examined glucose tolerance possibly due to a direct impact of PBM on islet insulin secretion capability and insulin resistance reporting an improvement in these parameters. The only negative study (71) applied the highest power (3.57 W/ cm²) for the shortest period (8 seconds). Preclinical studies have also demonstrated beneficial effects of PBM on lipid profiles, including reduced ectopic fat in muscle, triglycerides, and free fatty acids. Additionally, a small-scale clinical study (79) (n = 10) reported beneficial effects of PBM, including a 37% reduction in post-meal AUC for glucose and approximately 16% faster postprandial glucose decay. No adverse effects were reported with PBM, and there was no increased risk of hypoglycemia when PBM was combined with hypoglycemic treatments. Overall, these findings support the potential of PBM in improving glycemic control in patients with type 2 diabetes. Further clinical trials with larger sample sizes are warranted to determine the optimal parameters for PBM as an additional therapy in the therapeutic arsenal, helping to improve patients’ glycemic control.

Moreover, the effect of PBM on glucose intolerance could be lead to the action of PBM on beta cells and islets.

Liebman et al. (165) reported improvement of insulin secretion of beta cells and glucagon of alpha cells associated with a rise of calcium activity. Irani et al. (166) demonstrated that PBM could improve insulin secretion of rat pancreatic islets with poor insulin secretion. Huang et al. (167) investigated the effects of PBM on pig islets, which are being explored as a potential source of islets for xenotransplantation. However, they did not observe any significant positive or negative effects on glucose-stimulated insulin secretion. Further research is needed to explore the potential of PBM to enhance islet function for transplantation purposes, even if Asghari et al. (153) reported protector effect of PBM on ischemia-reperfusion injury in diabetic kidney of rats.

# 5 Conclusion

Overall, this review highlights the growing interest in PBM as a potential therapeutic approach for various aspects of diabetes. This study emphasizes the potential of PBM as a valuable approach for managing wound healing issues and neuropathic pain in diabetic patients in both preclinical and clinical studies. The potential benefits of PBM in healing of bone defect and glycemic control show promise. In retinopathy, the small number of studies make it impossible to draw any conclusion. In periodontitis, more extensive clinical trials are warranted to establish the optimal parameters and protocols for PBM. Likewise, the current evidence does not support the use of PBM for muscle recovery after physical exercise.

# Author contributions

QP: Writing – original draft, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

CM: Writing – review & editing, Validation, Supervision, Funding acquisition. SL: Writing – review & editing, Validation, Supervision, Funding acquisition, Conceptualization.

# Funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was funded by the "Région Auvergne-Rhône-Alpes", the Edmond J.Safra Foundation, the "Fond de Dotation-Clinatec" and its sponsors, CEA, UGA, CHUGA.

# Acknowledgments

We thank J. Mitrofanis for his proofreading of English.

# Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated

organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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