Among the skin treatments that have been continuously being developed over the three thousand years is the method of utilizing natural or artificial light for improving health and well-being is called phototherapy.1-3 The past several decades have suggested that certain wavelengths from sunlight such as infrared-A, ultraviolet-B, and ultraviolet-A cause negative effects on human skin, thus sunscreens have been developed to block these wavelengths. Although several studies have noted that near-infrared (NIR) wavelengths can damage skin, this effect is barely observed on artificial sources which can barely reach radiant levels comparable to that of the sun. Previous studies even contradict the negative observations indicating positive cell and tissue response upon exposure to appropriate irradiance/dose of NIR.3 Consequently, some studies have also supported the use of ultraviolet -blue wavelength as non-pharmacological prophylaxis.4-8 Phototherapy covers two types of approach: Photobiomodulation (PBM) and Photodynamic therapy (PDT).
PDT is a method of using chemical agents called photosensitizers to cause cellular death upon exposure and activation with certain light wavelengths.9-11 This type of medical utilization of light energy is fairly widespread in procedures for sterilization, disinfection, and purging tissue eradication such as in cases of malignant cancers.12-17 On the opposite end of PDT is PBM, formerly termed as low-level laser therapy (LLLT) because of the prevalent use of laser technology in earlier research endeavors. This alternative technique of invigorating and promoting regeneration on the largest organ of the body has garnered significant attention since the late 1960s due to the invention of lasers.10,18,19 PBM is a procedure by which certain wavelengths of light are used to elicit stimulatory effects on cells and tissues which eventually contributes to health benefits and even tissue regeneration.10-12,20-25 Both PDT and PBM applications, coherent, highly monochromatic, collimated light with higher power densities are preferred. Nevertheless, recent advancements in technology have provided other light sources like broadband lamps and light-emitting diodes (LED) which do not require significant operational knowledge and high energy inputs to be used for PDT and PBM procedures.20 Recent advancements in the field of biomaterials, pharmaceutics, and medical sciences have also started to incorporate PBM and PDT in hopes of advancing therapeutics for skin disease and wound management.
This review will focus on some notable advancements regarding the use of photodynamic therapy and photobiomodulation for dermal wound management and skin tissue regeneration in the past 5 years. For this manuscript, articles published from 2017 to early 2022 were searched in PUBMED using photodynamic therapy, photobiomodulation, skin, wound, and combined therapy as keywords. The selection was narrowed down to include only research articles and exclude review articles. The particular coverage of this article will include several therapeutic approaches combined with either photodynamic therapy or photobiomodulation which uses red to NIR wavelengths. Among the noteworthy approaches that will be covered are the use of PDT for anti-microbial applications; PBM for management of toxin effects; Dual-wavelength Light therapy; the use of PBM with hydrogels; and the combined application of either drug or naturally derived therapeutic agents with PBM (Fig. 1).
Figure 1. Several variations and combinations of PDT and PBM treatments have been investigated for dermal wound management. These include the use of certain wavelength and photosensitizers for antibacterial and PBM function (A); the use of PBM alleviate toxin effects (B); and its synergistic function with drug infusion, hydrogels, and some naturally derived compounds which leads to improved wound healing (C).
As mentioned earlier, disinfection is among the most common application of light energy in the medical field. The use of UV and blue light as germicidal agents have been around since 1870s.26 Recent investigations have now focused on advancing the use of the antimicrobial effect of light through PDT application. A recent study conducted by Petrini et al. attempted to verify the potential of using NIR LED and sodium hypochlorite (NaOCl) for long-term inactivation of
Another more novel application of light energy in the medical field is its utilization as adjuvant therapy after serum therapy following exposure to toxic agents such as snake venom. Several studies have been recently published tackling the positive effects of PBM on tissue exposed to animal poison. Subsequent investigations performed by Pereira Dos Reis et al.31 revealed that LED irradiation (945nm) induced positive effects such as increased mitochondrial metabolism, reduced cytotoxicity, decrease in reactive oxygen species, and nitrogen liberation in activated murine macrophages exposed to bothropstoxin-I (BthTX-I) or bothropstoxin-I (BthTX-II) from
Having established the utility of light energy as an antimicrobial agent and a stimulant for cell growth and tissue development, several studies have tried to investigate the effects of simultaneous irradiation using two wavelengths. A clinical study conducted by Baracho et al. revealed that several sessions of combined 630 nm and 940 nm LED irradiation successfully enhanced the healing of pressure-induced injuries in patients.36 In another study also involving pressure injury, photobiomodulation was carried out using a combined 660 nm + 810 nm continuous laser. Pressure wounds infected with
Another emerging approach with regards to combining dermal wound management methods is the inclusion of routine irradiation in conjunction with the application of hydrogel biomaterials. Bacterial cellulose membrane has garnered much attention in recent years and has been used in a wide array of biomedical applications, particularly for skin tissue.39-42 One fairly recent publication by Brassolatti et al. and Vasconcellos et al. showed that even though the lone application of either photobiomodulation (660 nm) or bacterial nanocellulose membrane resulted in improved healing in second-degree and third-degree burn animal models, combining these two treatments compromised the development of blood vessels and collagen deposition crucial for the reparative phase of wound healing.43,44 This is in contrast to the following studies which involved hydrogels designed for PDT together which PBM. A study conducted by He et al. aimed at investigating the efficacy of using red light on a PDT-based material to simultaneously perform PBM and antibacterial activity.45 For their experiment, they fabricated a catechol motif-modified methacrylated gelatin with mesoporous polydopamine nanoparticles loaded with Chlorin e6 photosensitizer (GelMAc/MPDA@Ce6) which can be used as a wound dressing or coating for other materials. Antibacterial activity was initiated by laser irradiation at 1W cm-2 while PBM stimulation of fibroblasts was achieved with daily irradiation at 100 w cm-2. Their data suggested that both PDT and PBM can be subsequently performed by adjusting irradiation parameters of the hydrogel applied on the wound surface.45 A series of recently published studies by Shanmugapriya et al. showcased the potential of both alginate-based and cellulose-based hydrogels together with laser therapy for wound healing and induction of cancer cell apoptosis. Laser irradiation (635nm) of fucoidan/alginate-polyethylene glycol-gellan gum (Fu/AL-PEG@GGH) hydrogel applied on circular full-thickness skin defect in mice improved fibroblast proliferation and collagen deposition resulting in enhanced wound healing.46 Likewise, Fucoidan/alginate-based gellan gum loaded with carboxymethyl cellulose nanofibrils were also tested together with a 635nm fiber optic laser with comparable results.47 In a follow-up study, Shanmugapriya and his colleagues tried out the effects of using cellulosic materials loaded with nanoemulsion together with low-level laser therapy for skin cancer PDT. A stabilized nanoemulsion (NE) was made by adding Astaxanthin to α-tocopherol which was then incorporated into nanocrystals/cellulose nanofibrils (CNC/CNF). Their hypothesis was proven as astaxanthin acted as a photosensitizer capable of inhibiting cell proliferation and inducing apoptosis in cancer cells while irradiation with 635nm laser stimulated certain factors for differentiation and proliferation in fibroblasts cells.48 These studies substantiate the utility of combining hydrogels with photodynamic therapy or photobiomodulation treatments.
Diabetes is a serious metabolic disease that is often accompanied by pressure wounds that are slow to heal. This illness also contributes to the patient’s susceptibility to infections which could exacerbate wound conditions. Two studies have tried to address this need by examining the combined effects of metformin and PBM using 890nm laser irradiation.49,50 Both investigations found application the combination of intraperitoneal injection of metformin and subsequent PBM treatment on the wounds significantly improved the healing rates of full-thickness skin defects in type 2 diabetic rats. Asghari et al. primarily observed reduction of colony-forming units and improved biomechanical properties of the wound bed treated with PBM and metformin.50 On the other hand Bagheri et al. noted better formation of granulation tissue and increased vascularization in PBM+metformin treatments. He also observed that lone treatments of PBM reduced M2 macrophage while metformin alone increased M2 macrophage. Even so, the data proved that both treatments acted synergistically to improve wound healing in non-genetic diabetic rats.49 In a separate study, co-enzyme Q10 was also tested out together with 904 super-pulsed laser as topical treatments for full-thickness burns in rats. Coenzyme q, also known as ubiquinone is a naturally occurring fat-soluble antioxidant in bacteria and animals.51-54 Yadav et al. found that the dual treatment showed synergism which promoted mitogenesis, re-epithelialization, angiogenesis, collagen deposition, and wound closure.55 Aside from experiments involving known pharmacochemical agents, PBM has also been recently coupled with naturally derived products. Curcumin, the main natural polyphenol found in the rhizome of turmeric plants,56,57 has been also administered with infrared laser (890nm) on tensiometrical wounds in diabetic rats. Data provided by the experiments conducted by Soleimani et al. indicated comparable antibacterial effect and mildly improved biomechanical properties in the early stages leading to accelerated wound healing.58 Last but not the least, medicinal honey was also tested out together with 904nm super pulsed for a similar purpose by the same group who tested PBM with coenzyme Q10. Their finding revealed that the combined treatment resulted in better wound contraction and increased hexosamine, a vital component for extracellular matrix stabilization in the regenerated tissue. The synergistic activity of the medicinal honey and laser irradiation also resulted in: reduced pain and inflammation; decreased expression of COX-2, TNF-α, substance-P receptor, NF-κB, and IL-1β; and fibronectin up-regulation, enhanced cell migration, adhesion. All these observations led to considerable advantage in terms of healing dermal wounds.
Although several decades of investigations have been conducted to elicit mechanisms for regenerative property and establish therapeutic approaches for the application of PDT and PBM, there are still significant gaps and conflicting claims about the utility of these alternative techniques. The current trend in research indicates that photobiomodulation and photodynamic therapy using lasers and LED is here to stay. The current evidence appears to support the idea that phototherapy is not dependent on sole coherence and high energy output but also on selective wavelength application, optimized absorption, and photo-activation to yield desirable physiological effects. The notable combined photodynamic/photobiomodulation therapies discussed above are a testament to the uncharted potential application of light energy in the field of regenerative medicine. As more and more drugs and biomaterials become available, phototherapy would eventually be incorporated in more advanced and effective dermal wound management procedures.
As mentioned earlier, disinfection is among the most common application of light energy in the medical field. The use of UV and blue light as germicidal agents have been around since 1870s.26 Recent investigations have now focused on advancing the use of the antimicrobial effect of light through PDT application. A recent study conducted by Petrini et al. attempted to verify the potential of using NIR LED and sodium hypochlorite (NaOCl) for long-term inactivation of
Another more novel application of light energy in the medical field is its utilization as adjuvant therapy after serum therapy following exposure to toxic agents such as snake venom. Several studies have been recently published tackling the positive effects of PBM on tissue exposed to animal poison. Subsequent investigations performed by Pereira Dos Reis et al.31 revealed that LED irradiation (945nm) induced positive effects such as increased mitochondrial metabolism, reduced cytotoxicity, decrease in reactive oxygen species, and nitrogen liberation in activated murine macrophages exposed to bothropstoxin-I (BthTX-I) or bothropstoxin-I (BthTX-II) from
Having established the utility of light energy as an antimicrobial agent and a stimulant for cell growth and tissue development, several studies have tried to investigate the effects of simultaneous irradiation using two wavelengths. A clinical study conducted by Baracho et al. revealed that several sessions of combined 630 nm and 940 nm LED irradiation successfully enhanced the healing of pressure-induced injuries in patients.36 In another study also involving pressure injury, photobiomodulation was carried out using a combined 660 nm + 810 nm continuous laser. Pressure wounds infected with
Another emerging approach with regards to combining dermal wound management methods is the inclusion of routine irradiation in conjunction with the application of hydrogel biomaterials. Bacterial cellulose membrane has garnered much attention in recent years and has been used in a wide array of biomedical applications, particularly for skin tissue.39-42 One fairly recent publication by Brassolatti et al. and Vasconcellos et al. showed that even though the lone application of either photobiomodulation (660 nm) or bacterial nanocellulose membrane resulted in improved healing in second-degree and third-degree burn animal models, combining these two treatments compromised the development of blood vessels and collagen deposition crucial for the reparative phase of wound healing.43,44 This is in contrast to the following studies which involved hydrogels designed for PDT together which PBM. A study conducted by He et al. aimed at investigating the efficacy of using red light on a PDT-based material to simultaneously perform PBM and antibacterial activity.45 For their experiment, they fabricated a catechol motif-modified methacrylated gelatin with mesoporous polydopamine nanoparticles loaded with Chlorin e6 photosensitizer (GelMAc/MPDA@Ce6) which can be used as a wound dressing or coating for other materials. Antibacterial activity was initiated by laser irradiation at 1W cm-2 while PBM stimulation of fibroblasts was achieved with daily irradiation at 100 w cm-2. Their data suggested that both PDT and PBM can be subsequently performed by adjusting irradiation parameters of the hydrogel applied on the wound surface.45 A series of recently published studies by Shanmugapriya et al. showcased the potential of both alginate-based and cellulose-based hydrogels together with laser therapy for wound healing and induction of cancer cell apoptosis. Laser irradiation (635nm) of fucoidan/alginate-polyethylene glycol-gellan gum (Fu/AL-PEG@GGH) hydrogel applied on circular full-thickness skin defect in mice improved fibroblast proliferation and collagen deposition resulting in enhanced wound healing.46 Likewise, Fucoidan/alginate-based gellan gum loaded with carboxymethyl cellulose nanofibrils were also tested together with a 635nm fiber optic laser with comparable results.47 In a follow-up study, Shanmugapriya and his colleagues tried out the effects of using cellulosic materials loaded with nanoemulsion together with low-level laser therapy for skin cancer PDT. A stabilized nanoemulsion (NE) was made by adding Astaxanthin to α-tocopherol which was then incorporated into nanocrystals/cellulose nanofibrils (CNC/CNF). Their hypothesis was proven as astaxanthin acted as a photosensitizer capable of inhibiting cell proliferation and inducing apoptosis in cancer cells while irradiation with 635nm laser stimulated certain factors for differentiation and proliferation in fibroblasts cells.48 These studies substantiate the utility of combining hydrogels with photodynamic therapy or photobiomodulation treatments.
Diabetes is a serious metabolic disease that is often accompanied by pressure wounds that are slow to heal. This illness also contributes to the patient’s susceptibility to infections which could exacerbate wound conditions. Two studies have tried to address this need by examining the combined effects of metformin and PBM using 890nm laser irradiation.49,50 Both investigations found application the combination of intraperitoneal injection of metformin and subsequent PBM treatment on the wounds significantly improved the healing rates of full-thickness skin defects in type 2 diabetic rats. Asghari et al. primarily observed reduction of colony-forming units and improved biomechanical properties of the wound bed treated with PBM and metformin.50 On the other hand Bagheri et al. noted better formation of granulation tissue and increased vascularization in PBM+metformin treatments. He also observed that lone treatments of PBM reduced M2 macrophage while metformin alone increased M2 macrophage. Even so, the data proved that both treatments acted synergistically to improve wound healing in non-genetic diabetic rats.49 In a separate study, co-enzyme Q10 was also tested out together with 904 super-pulsed laser as topical treatments for full-thickness burns in rats. Coenzyme q, also known as ubiquinone is a naturally occurring fat-soluble antioxidant in bacteria and animals.51-54 Yadav et al. found that the dual treatment showed synergism which promoted mitogenesis, re-epithelialization, angiogenesis, collagen deposition, and wound closure.55 Aside from experiments involving known pharmacochemical agents, PBM has also been recently coupled with naturally derived products. Curcumin, the main natural polyphenol found in the rhizome of turmeric plants,56,57 has been also administered with infrared laser (890nm) on tensiometrical wounds in diabetic rats. Data provided by the experiments conducted by Soleimani et al. indicated comparable antibacterial effect and mildly improved biomechanical properties in the early stages leading to accelerated wound healing.58 Last but not the least, medicinal honey was also tested out together with 904nm super pulsed for a similar purpose by the same group who tested PBM with coenzyme Q10. Their finding revealed that the combined treatment resulted in better wound contraction and increased hexosamine, a vital component for extracellular matrix stabilization in the regenerated tissue. The synergistic activity of the medicinal honey and laser irradiation also resulted in: reduced pain and inflammation; decreased expression of COX-2, TNF-α, substance-P receptor, NF-κB, and IL-1β; and fibronectin up-regulation, enhanced cell migration, adhesion. All these observations led to considerable advantage in terms of healing dermal wounds.
Although several decades of investigations have been conducted to elicit mechanisms for regenerative property and establish therapeutic approaches for the application of PDT and PBM, there are still significant gaps and conflicting claims about the utility of these alternative techniques. The current trend in research indicates that photobiomodulation and photodynamic therapy using lasers and LED is here to stay. The current evidence appears to support the idea that phototherapy is not dependent on sole coherence and high energy output but also on selective wavelength application, optimized absorption, and photo-activation to yield desirable physiological effects. The notable combined photodynamic/photobiomodulation therapies discussed above are a testament to the uncharted potential application of light energy in the field of regenerative medicine. As more and more drugs and biomaterials become available, phototherapy would eventually be incorporated in more advanced and effective dermal wound management procedures.
CrossRef (0) Download (385)
Author ORCID Information Andrew Padalhin |
 |
