Blue Light Therapy in the Management of Chronic Wounds: A Narrative Review of its Physiological Basis and Clinical Evidence

Chronic wounds are a common problem worldwide. In Australia, it is estimated that 420 000 chronic wounds are managed each year, at an annual cost of approximately 3 billion Australian dollars.¹ Assessment of the underlying etiology is essential to optimize treatment. The most common wounds are pressure ulcers, venous ulcers, diabetic ulcers, and arterial ulcers¹; often, patients present with several such wounds. The average wound duration is 12 to 13 months, and wounds recur in 60% to 70% of patients.² Some chronic wounds are refractory to standard treatment, including offloading, compression, revascularization, skin grafting, and dressings. Malignancy must be excluded, and rarer wound types such as dermatologic and vasculitic wounds require specialized treatment.

One well-established adjunct in the treatment of wounds of various etiologies is phototherapy, that is, the use of light ranging from UV, visible spectrum blue to red, and infrared light to promote wound healing.^3,4 While extensive research supports the use of red or near-infrared light (wavelength 600 nm–1100 nm) for wound healing,^3-5 the use of blue light (wavelength 400 nm–450 nm) has not been as well studied, potentially owing to its proximity to UV light and its associated risks.^5,6 As more alternative therapies are explored, blue light has seen a resurgence in evidence and support. Recently published clinical results on the management of wounds using blue light have been promising, albeit only in a few case series and trials with a low level of evidence. The most prominent publication as of the time of this writing, the Blue Light for Ulcer Reduction (BLUR) study, demonstrated a 33.5% reduction in wound size in the treatment group compared with SOC alone.⁷

To the knowledge of the current authors, this is the first review to consolidate the literature on the physiological basis of blue light therapy and evaluate the published clinical evidence to determine if blue light along with SOC results in improved wound healing compared with SOC alone.

Two searches were conducted in PubMed, Google Scholar, and the Cochrane Library to identify articles for inclusion in this review. The first search used the MeSH headings “blue light”, “photobiomodulation”, “phototherapy”, “wound healing”, and “chronic wounds” and various combinations of those terms in topic, heading, and abstract searches to identify articles that discuss the underlying physiology of blue light therapy. Reference lists of the identified articles were also checked for further studies of interest. The second search used the MeSH headings “blue light”, “photobiomodulation”, “low level light therapy”, “phototherapy”, “wound healing”, “non-healing wounds”, and “chronic wounds” and combinations of those terms in topic, heading, and abstract searches while filtering for primary studies published between January 2010 and July 2022 (n = 69). The reference lists of these articles were also checked for studies that met the selection criteria. Selected studies met the following inclusion criteria: clinical studies that investigated the use of blue light therapy (wavelength 400 nm–450 nm) in the management of chronic, nonhealing wounds. In vitro and animal studies were excluded from the second search. The literature search initially identified 8 clinical trials that met the criteria; however, 2 trials were later excluded owing to light wavelength (400 nm–800 nm) extending beyond the initial criterion.

Abstracts were reviewed for suitability, after which full-text review was done as necessary to address the study questions. Overall, the level of evidence was low, and 5 studies were identified for inclusion in this review: 4 case series and 1 controlled study. No randomized controlled trials have evaluated the use of blue light in wound healing. Identified studies were assessed and evaluated using the National Institutes of Health Study Quality Assessment Tool for Controlled Intervention Studies and for Case Series Studies⁸ to determine internal and external validity (see Appendix 1 and Appendix 2).

Photobiomodulation with blue light

The popularity of phototherapy has waxed and waned in the medical literature. The benefits of sunlight were described for treatment of wounds and skin infections up until the development of pharmacological agents, which rapidly overshadowed the use of phototherapy.⁹ Modern technological advances have resulted in a better understanding of underlying pathophysiology, which led to the development of targeted devices that utilize light. The current applications of phototherapy fall into 3 categories: photothermal, photodynamic, and photobiomodulation. Photothermal and photodynamic phototherapy are both destructive in effect and have been applied in cancer management. In contrast, photobiomodulation acts to stimulate or inhibit biological responses and does not have direct destructive effects.⁹

Photobiomodulation stems from the concept that there are endogenous molecules (chromophores) that absorb photons (light energy), which triggers physical or chemical responses in the surrounding tissue. It is through the actions of chromophores that the proposed benefits of photobiomodulation occur.^3-5 The chromophores targeted and the subsequent effects they produce vary depending on the wavelength, intensity, and fluence (energy over time) of the light used. Blue light photobiomodulation is in the wavelength of 400 nm to 430 nm and has been shown to have a key accepting chromophore in mitochondria known as cytochrome C.^4,5,10-12 PPIX, a component within cytochrome C, is a well-known photosensitive molecule that has been used in the photodynamic treatment of skin cancer¹¹ and is also thought to play a role in the biomodulatory effects of blue light through the role of cytochrome C in cellular respiration and apoptosis, particularly in fibroblasts and keratinocytes.^10,12 Observation of blue light–irradiated fibroblasts demonstrated statistically significant alterations in cytochrome C redox states, with enhanced fibroblast activity at lower doses but inhibitory effects at higher doses.¹² This biphasic result has been echoed in the literature; in fact, photobiomodulation previously was dubbed “low-level light therapy” owing to the better results in wound healing seen at lower doses.^6,10-12 This phenomenon may be associated with the excess production of ROS at higher doses, as observed in cases of PPIX dysregulation and excess endogenous PPIX in the skin resulting in painful, non-blistering photosensitivity caused by ROS formation.¹¹ It is through this mechanism that blue light is also used in photodynamic therapy, with the introduction of exogenous PPIX or its precursor aminolevulinic acid resulting in accumulation of PPIX within cancer cells and the subsequent generation of ROS after photoactivation with blue light.^11,13

Flavins are another key chromophore that have been identified to initiate free radical reactions when excited by light wavelengths less than 500 nm, thus generating ROS.^5,14 Flavin excitation occurs at wavelengths between 400 nm and 500 nm; notably, it is believed that flavin mononucleotide excitation catalyzes the reduction of oxygen, resulting in generation of ROS.^5,14,15 At low concentrations, ROS have important roles in inflammation modulation, angiogenesis, and wound healing; however, it is well understood that at higher concentrations, ROS have significant destructive potential.^16,17

ROS production has been attributed to many of the observed benefits in wound angiogenesis and reepithelialization induced by the proposed effects on various chemical factors and on fibroblasts and keratinocytes, as mentioned previously.^3,5,6,10,12 Photobiomodulation with blue light has been observed to increase local nitric oxide production, which may also be associated with the dose-dependent generation of ROS observed in blue light therapy caused by induction of nitric oxide synthase.^16,18 Interestingly, this localized effect seems to target only stressed or damaged cells under illumination, not healthy tissue.¹⁶ Nitric oxide has well-documented vasodilatory effects on increasing wound bed perfusion, and it is also critical in angiogenesis via VEGF as both a trigger and mediator.^5,19 Indeed, the effects of nitric oxide may have synergistic effects with the stimulation of VEGF via the effects of ROS on hypoxia-inducible factor-1,²⁰ which is critical to the body’s response to hypoxia and plays key roles in regulating the inflammatory and proliferative phases of wound healing by means of redox signaling, with key outcomes of promoting angiogenesis via VEGF.^20,21

In summary, it is believed that through increased local ROS and nitric oxide, improved wound healing occurs as the result of improved local perfusion via angiogenesis, with secondary benefits of improved reepithelialization and reduced inflammation through ROS regulation and signaling.

Light therapy has also been shown to have a bactericidal effect on the illuminated tissue; in fact, some authors have proposed that this is the primary distinction between blue light and other forms of visible light phototherapy.^6,22 Early studies of high-intensity white light demonstrated a dose-dependent effect on bacterial viability.²³ This was attributed to endogenous photosensitizers, or chromophores, within the bacteria that result in a buildup of ROS, which ultimately become lethal to the bacteria.²³ Further analysis demonstrated a greater effect with use of blue light compared with red light, with greater induction of ROS with high-intensity blue light; however, lower fluences of visible light had a proliferative effect on bacteria.²⁴ More recent reviews have confirmed the advantage of blue light, identifying endogenous porphyrins within bacteria that generate ROS through photoexcitation, resulting in membrane and DNA damage; this effect is most profound with blue light irradiation in wavelengths of 400 nm to 415 nm.^25,26 The antimicrobial effects of blue light are independent of bacterial resistance to pharmaceutical agents, demonstrating inhibitory effects on methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa, 2 common skin flora.^26,27 Currently, it is well understood that biofilm compromises wound healing^28-30; thus, it has been proposed that these broad-spectrum antimicrobial effects work synergistically with the effects of photobiomodulation to facilitate wound healing.^6,22,23 Strong evidence exists that blue light therapy has antimicrobial effects on an extremely wide range of bacteria, including many organisms involved in wound infection and biofilm, such as S aureus, Escherichia coli, and Serratia marcescens.^23-27 Of note, blue light has shown promise in the management of acne vulgaris through its antimicrobial properties, with the activity against Cutibacterium acnes deemed a key mechanism of action.³¹

Reservations remain about the use of blue light owing to its proximity to UV light in terms of wavelength and the potential for the DNA damage commonly attributed to UV light.⁵ UV light of shorter wavelengths, specifically, UV-C (100 nm–280 nm) and UV-B (280 nm–315 nm), has an increased propensity to cause damage caused by the absorption of UV energy, thus altering the chemical structure of pyrimidine bases in DNA because the pyrimidine bases have peak absorptions within the UV-C and UV-B range.^32,33 UV-A (wavelength 315 nm–400 nm) is less effective in causing DNA damage in this manner owing to its longer wavelength; however, it can cause DNA damage through the formation of ROS.^32,33 Nevertheless, multiple therapeutic uses for UV light have been well-documented in the literature, particularly for dermatologic conditions for which the immunosuppressive and antiproliferative effects of UV light are useful. UV-B therapy has been most extensively studied in the literature, with targeted UV-B therapy for psoriasis and eczema deemed safe.^34,35 Compared with blue light, UV-B and UV-A have a greater propensity to cause DNA damage, either through direct action on the nucleotide bases or via ROS formation with resultant oxidative damage; however, blue light can cause oxidative DNA damage in a dose-dependent manner.³⁶ Although both UV and blue light therapy have antimicrobial properties, those of UV light and its direct actions on DNA are much more potent, such that UV sterilization is commonplace in medicine and in the food industry.³⁷ The therapeutic effects of UV light and blue light differ primarily in the chromophores targeted, but differences between them may also be related to differing depths of penetration and energy transference. The safe use of blue light requires the use of an easily controlled, precise device that emits a narrow-band wavelength within the visible blue light spectrum at a set fluence and adherence to strict protocols regarding duration of illumination to reach the therapeutic threshold and not extend beyond that into toxicity.

In vitro and animal trials

In a study investigating the effects of blue light on human keratinocytes over a 4-week irradiation period, Denzinger et al³⁸ reported a significant dose- and time-dependent decrease in reepithelialization rates with blue light therapy compared with non-irradiated control group (P ≤.05 at 5 minutes, P ≤.001 at 10 minutes), which was associated with decreased keratinocyte proliferation and limited proinflammatory effects. Wound closure in the control group was 25.57% on day 1, and wound size decreased with increasing duration of treatment, to 20.51% at 1 minute, 7.86% at 5 minutes, and 1.33% at 10 minutes. In another in vitro study exploring the effects of blue light on human skin fibroblasts, Mamalis et al³⁹ reported decreased fibroblast proliferation and migration, as well as increased ROS generation with blue light irradiation (wavelength 400 nm–430 nm) in a dose-dependent manner (dosage ≤ 80 J/cm²) after 24 hours of blue light irradiation when compared to non-irradiated control group. In a study of the effects of blue light on wound healing using a human fibroblast scratch assay, Masson-Meyers et al⁴⁰ reported significantly poorer wound closure and cellular migration rates with blue light irradiation (wavelength 470 nm), most prominently with a dosage above 55 J/cm² (P <.001).

In contrast, in vivo studies in animal models have shown promising evidence supporting the use of blue light in wound healing. In a study investigating the effects of blue light (wavelength 410 nm–435 nm) on the healing process of superficial abrasions in Sprague-Dawley rats, Cicchi et al⁴¹ reported a significant decrease (50% reduction) in inflammatory cell infiltrate (P <.05), fibroblasts (P <.005), and myofibroblasts (P <.05), which was associated with complete regeneration of the epidermal layer, elevated collagen deposition, and increased organization of collagen fiber bundles on histology and immunofluorescence analysis. These findings were based on comparison of treatment and nontreatment groups on day 8 after treatment. In a study investigating the effects of red and blue low-level light therapy on wound healing in Sprague-Dawley rats, Adamskaya et al⁴² similarly reported significant wound area reduction of 50% and increased cellular reepithelialization (as indicated by increased expression of keratin-10 mRNA [associated with keratinocyte differentiation]) after blue light (wavelength 470 nm) irradiation treatment. Neither study assessed or quantified antimicrobial effects or angiogenesis promotion.

Disparity in observations derived from in vitro and in vivo studies can be attributed to mechanisms from different cell lineages associated with wound healing. Heat generation is associated with platelet aggregation and adhesion, resulting in a platelet-mediated hemostatic effect that promotes wound healing.⁴³ The in vivo studies by Cicchi et al⁴¹ and Rossi et al⁴⁴ reported elevated wound site temperatures (maximum surface temperatures of 48.3°C and 49.4°C, respectively) from blue light irradiation as recorded with infrared thermocameras, with both studies reporting favorable outcomes. As mentioned previously, other parameters that affect wound healing include the antimicrobial effects of blue light (wavelength 400 nm–425 nm),^40,45,46 angiogenesis promotion,⁴⁷ and upregulation of intracellular ROS.⁴⁰

Clinical trials

Few clinical trials have investigated the effects of blue light on healing chronic wounds; clinical outcomes are summarized in the Table.^7,48-52 Unfortunately, the level of evidence is poor, predominantly consisting of case series, and is subject to a high degree of bias. Most prominently, the prospective controlled BLUR study conducted by Fraccalvieri et al⁷ investigated the safety and efficacy of blue light phototherapy used in conjunction with SOC on enhancing reepithelialization of chronic wounds. The study population comprised 90 patients with chronic lower extremity wounds of mixed etiologies of greater than 12 months’ duration; 93.3% of patients completed the study. Each patient’s wound area was halved, with half of each wound receiving SOC (control), and the other half receiving blue light irradiation in addition to SOC (treatment). Wound areas were measured via digital imaging over a 10-week period and subsequently analyzed at an independent facility. Secondary end points, such as adverse events and pain, were assessed at weekly clinical visits. Primary study results suggest that blue light (wavelength 410 nm–430 nm) irradiation in addition to SOC resulted in a 33.5% reduction in residual wound area after 10 weeks compared with SOC alone (reduction in initial wound area of 42% and 63%, respectively), with decreased VAS pain scores compared with baseline scores at the beginning of the study. Patients with venous wounds were most responsive to blue light treatment, with wound area reduction of up to 51.1% (P =.007) and significantly reduced VAS pain scores (P <.05) compared with wounds of other etiologies. Despite promising results, limitations of the BLUR study include lack of randomization and masking, resulting in selection and measurement bias, inadequate measurement of secondary outcomes because of study design, and reported conflicts of interest. Assessment of secondary outcomes such as pain and other adverse events were inadequate given the absence of a control group consisting of a separate study population.

Multiple case series have also reported on blue light irradiation for the management of chronic venous ulcers, with promising outcomes. Khoo et al⁴⁸ reported on 2 patients with chronic venous ulcer of the lower extremity who achieved significant reduction in wound size after treatment with blue light irradiation (wavelength 400 nm–430 nm) in addition to SOC. Previous treatment with SOC alone had resulted in recurring, nonhealing wounds of 4 weeks’ duration in 1 patient and 3 weeks’ duration in the other. Case 1 achieved 67% reduction in wound size at week 5 and complete wound closure at week 8 (baseline wound area, 3 cm²), and case 2 achieved 37.8% reduction in wound size at week 3, with complete wound closure at week 6 (baseline wound area of 2 lesions, 13.5 cm² and 10.5 cm²). Both patients’ wound healing was associated with improved functional capacity and decreased patient-reported wound site pain. No wound recurrence was reported at 4-month follow-up. In a different case series, Marchelli et al⁴⁹ investigated the effects of blue light irradiation on lower extremity chronic nonhealing ulcers. Nineteen patients with ulcers of mixed etiology with at least 2 months’ duration that were nonresponsive to SOC received blue light (wavelength 400 nm–430 nm) irradiation in addition to SOC over 10 weeks. Eighty-four percent of patients achieved an average 50% reepithelization within 10 weeks, and treatment was well tolerated, with no reported adverse events. In both case series, wound size was assessed through clinical observation and measurement of lesion dimension and depth, and of the perilesional skin.

Similar outcomes have also been reported with the use of blue light irradiation in the management of nonhealing chronic diabetic ulcers. Nair and Sulong⁵⁰ reported significant reduction in wound size in 5 patients with chronic nonhealing diabetic foot ulcers following adjunct blue light (wavelength 400 nm–430 nm) therapy with SOC over a 10-week period. Wound size was assessed with clinical and photographic observations throughout the treatment period. Complete healing was achieved in 2 cases, and significant wound size reduction of 90%, 94%, and 36% was achieved in 3 cases after 10 weeks. Aliquò et al⁵¹ reported improved wound closure rates in a case series of 11 patients with chronic nonhealing diabetic wounds of various etiologies and of at least 6 months’ duration, after treatment with blue light irradiation (wavelength 400 nm–430 nm) in conjunction with SOC over a 10-week period. Overall, 64% of patients (n = 7) completely recovered during the treatment period, 18% (n = 2) achieved significant reductions in wound size (80% and 90%), and 18% (n = 2) achieved smaller reductions in wound size (30% and 50%). Treatment was well tolerated, with no adverse events reported.

Dini et al⁵² investigated the effects of blue light irradiation (wavelength 400 nm–430 nm) on healing in 20 patients with treatment-resistant wounds of different etiologies (12 venous leg ulcers, 6 vasculitic ulcers, 2 traumatic ulcers) over a 4-week period. Wound area was assessed weekly with digital 3-dimensional imaging, and secondary clinical outcomes were measured weekly in the clinic. Complete wound healing was achieved in 10% of patients, wound bed area reduction was achieved in 80% of patients, and decreased pain scores were achieved in 95% of patients after blue light treatment concurrent with SOC. The average healing rates were highest for traumatic ulcers (0.353 mm/day), with comparable healing rates for venous leg ulcers (0.098 mm/day) and vasculitic ulcers (0.09 mm/day). Treatment was well tolerated, with no adverse events reported.

Clinical evidence suggests that blue light in conjunction with SOC (including dressings and compression) has a real benefit in improving the rate of wound healing. In the studies included in this review, no adverse effects were reported during treatment and the application of blue light was well tolerated. However, long-term follow-up was generally lacking in these studies; thus, long-term side effects and complications are unknown. The physiological basis of improved wound healing appears to be independent of wound etiology, as indicated by the literature, with all common types of chronic leg ulcers demonstrating improved wound healing after blue light therapy. However, as mentioned previously, the quality of the evidence is poor, consisting mostly of case series with observational data and only 1 “controlled” study (with many limitations). All the included studies followed a clearly described protocol and used a specifically engineered device designed to emit a specific wavelength band; however, they lack measures necessary to avoid the introduction of bias.

To the authors’ knowledge, the current review is the first to consolidate the underlying physiology of blue light on tissue and correlate it to clinical applications through an examination of the evidence. Recognizing the mechanisms of action of blue light irradiation, including the role of ROS and the potential for causing harm at higher doses, it is clear why a strict protocol is essential for using a device emitting a precise wavelength spectrum. Both the physiology and evidence suggest that blue light therapy is safe, well tolerated, and effective when used at recommended doses. Higher-quality primary studies are needed, however, particularly trials that involve proper randomization comparing patients receiving SOC with those receiving SOC and blue light therapy with a specific protocol and device. Increased study population size and longer follow-up would also be beneficial to better assess for potential side effects and longer-term complications.

With more robust evidence supporting its use and better long-term safety data, the authors anticipate that blue light will be an attractive option as an adjunct to SOC for wounds. Blue light therapy has clear treatment protocols that are noninvasive, well tolerated, minimally time-consuming, and easily standardized with minimal training. This is in contrast to the current first-line SOC for venous ulcers—compression therapy—which is notoriously inconsistent and heavily dependent on training nurses to properly apply it.⁵³

This review has limitations, mainly owing to its structure as a narrative review. Although efforts were made to be systematic and thorough, there remains the potential introduction of bias from the authors. In addition, the available evidence is limited almost entirely to observational case series.

The current literature indicates that use of blue light photobiomodulation has improved wound healing rates in chronic lower extremity ulcers of various etiologies such as diabetic, venous, and traumatic ulcers, including those refractory to SOC. This review identifies the underlying physiological basis through which blue light affects wound healing regardless of wound etiology and how this relates to the treatment protocols established in the available primary literature. Further directions for study include broadening the scope of wounds addressed, potentially as an adjunct to first-line therapies in all wounds of these common etiologies. There may also be a role in other injuries such as burns, where the promotion of angiogenesis and the antimicrobial properties of blue light will be of benefit.