Photobiomodulation of tissue regeneration: low-power light therapy accelerates wound healing in earthworms.

Diabetes, a highly prevalent disease that affects 9.3% of Americans, often leads to severe complications and slow wound healing. Preclinical studies have suggested that low level light therapy (LLLT) can accelerate wound healing in diabetic subjects, but significant improvements must be made to overcome the absence of persuasive evidence for its clinical use. We demonstrate here that LLLT can be combined with topical Coenzyme Q10 (CoQ10) to heal wounds in diabetic mice significantly faster than LLLT alone, CoQ10 alone, or controls. LLLT followed by topical CoQ10 enhanced wound healing by 68~103% in diabetic mice in the first week and more than 24% in the second week compared with untreated controls. All wounds were fully healed in two weeks following the dual treatment, in contrast to only 50% wounds or a fewer being fully healed for single or sham treatment. The accelerated healing was corroborated by at least 50% higher hydroxyproline levels, and tripling cell proliferation rates in LLLT and CoQ10 treated wounds over controls. The beneficial effects on wound healing were probably attributed to additive enhancement of ATP production by LLLT and CoQ10 treatment. The combination of LLLT and topical CoQ10 is safe and convenient, and merits further clinical study.

Low level light therapy (LLLT) has numerous therapeutic benefits, including improving wound healing, but the precise mechanisms involved are not well established; in particular, the underlying role of cytochrome C oxidase (C-ox) as the primary photoacceptor and the associated biochemical mechanisms still require further investigation. We previously showed the nitric oxide (NO) donating drug nitrosyl-cobinamide (NO-Cbi) enhances wound healing through a cGMP/cGMP-dependent protein kinase/ERK1/2 mechanism. Here, we show that the combination of LLLT and NO-Cbi markedly improves wound healing compared to either treatment alone. LLLT-enhanced wound healing proceeded through an electron transport chain-C-ox-dependent mechanism with a reduction of reactive oxygen species and increased adenosine triphosphate production. C-ox was validated as the primary photoacceptor by three observations: increased oxygen consumption, reduced wound healing in the presence of sodium azide, and disassociation of cyanide, a known C-ox ligand, following LLLT. We conclude that LLLT and NO-Cbi accelerate wound healing through two independent mechanisms, the electron transport chain-C-ox pathway and cGMP signaling, respectively, with both resulting in ERK1/2 activation.

In this study we investigated the effect of repeated low-dose radiation exposure (75 mGy X ray) on skin wound healing in a rat model of diabetes. A skin wound was made on the backs of diabetic and age-matched control rats 60 days after diabetes was induced by a single injection of streptozotocin. Rats with skin wounds were immediately treated with whole-body radiation daily for 5, 10 or 15 days with a 2-day break every 5 days. Wound size was estimated 5, 10 and 15 days after wound formation. Repeated exposure of diabetic rats to low-dose radiation significantly accelerated skin wound healing compared to the nonirradiated diabetic group. Furthermore, low-dose radiation-induced improvement in healing was associated with increases in bone marrow and circulating CD31(+)/CD34(+) stem cells, vessel regeneration and cell proliferation in the wound tissue, and matrix metalloproteinase 2 and 9 expression. Therefore, we conclude that the acceleration of wound healing in diabetic rats by repeated exposure to low-dose radiation is associated with stimulation of bone marrow stem cell proliferation and peripheral mobilization.

Capsaicin/silica-infused polygalacturonic acid/polyvinyl alcohol nano-matrix for enhanced wound healing in skin injuries

Wound healing is a complex sequence of cellular and molecular processes that involves multiple cell types and biochemical mediators. Several growth factors have been identified that regulate tissue repair, including the neurotrophin nerve growth factor (NGF). As non-adenine based purines (NABPs) are known to promote cell proliferation and the release of growth factors, we investigated whether NABPs had an effect on wound healing. Full-thickness, excisional wound healing in healthy BALB/c mice was significantly accelerated by daily topical application of NABPs such as guanosine (50% closure by days 2.5′.8). Co-treatment of wounds with guanosine plus anti-NGF reversed the guanosine-promoted acceleration of wound healing, indicating that this effect of guanosine is mediated, at least in part, by NGF. Selective inhibitors of the NGF-inducible serine/threonine protein kinase (protein kinase N), such as 6-methylmercaptopurine riboside abolished the acceleration of wound healing caused by guanosine, confirming that activation of this enzyme is required for this effect of guanosine. Treatment of genetically diabetic BKS.Cg-m+/+lepr db mice, which display impaired wound healing, with guanosine led to accelerated healing of skin wounds (25% closure by days 2.8′.0). These results provide further confirmation that the NABP-mediated acceleration of cutaneous wound healing is mediated via an NGF-dependent mechanism. Thus, NABPs may offer an alternative and viable approach for the treatment of wounds in a clinical setting.

Smart and bioactive electrospun dressing for accelerating wound healing

Growth factors and cytokines that are secreted by cells play a crucial role in the complex physiological reaction to tissue injury. The ability to spatially and temporally control their actions to maximize regenerative benefits and minimize side effects will help accelerate wound healing and improve tissue regeneration. In this study, the sequential targeted delivery of growth factor/cytokine combinations with regulatory functions on inflammation and tissue regeneration was examined using an internal splint wound healing model. Four examined growth factors and cytokines were effectively incorporated into a novel chitosan-based cryogel, which offered a controlled and sustained release of all factors while maintaining their biological activities. The cryogels incorporated with inflammation modulatory factors (IL-10 and TGF-β) and with wound healing factors (VEGF and FGF) were placed on the wound surface on day 0 and day 3, respectively, after wound initiation. Although wound area gradually decreased in all groups over time, the area in the cryogel group with growth factor/cytokine combinations was significantly reduced starting on day 7 and reached about 10% on day 10, as compared to 60–65% in the control groups. Sequential delivery of inflammation modulatory and wound healing factors enhanced granulation tissue formation, as well as functional neovascularization, leading to regenerative epithelialization. Collectively, the chitosan-based cryogel can serve as a controlled release system for sequential delivery of several growth factors and cytokines to accelerate tissue repair and regeneration.

Heparin-Binding Epidermal Growth Factor–Like Growth Factor as a Critical Mediator of Tissue Repair and Regeneration

Chapter 12 - Acceleration of Wound and Burn Healing by Anti-Gal/α-Gal Nanoparticles Interaction

Identification of a novel fibroblast growth factor receptor-agonistic peptide and its effect on diabetic wound healing.

Polydopamine-doped supramolecular chiral hydrogels for postoperative tumor recurrence inhibition and simultaneously enhanced wound repair

Promising application of pulsed electromagnetic fields on tissue repair and regeneration

Delayed wound healing caused by excessive reactive oxygen species (ROS) remains a considerable challenge. In recent years, metal oxide nanozymes have gained significant attention in biomedical research. However, a comprehensive investigation of Co3O4-based nanozymes for enhancing wound healing and tissue regeneration is lacking. This study focuses on developing a facile synthesis method to produce high-stability and cost-effective Co3O4 nanoflakes (NFs) with promising catalase (CAT)-like activity to regulate the oxidative microenvironment and accelerate wound healing. The closely arranged Co3O4 nanoparticles (NPs) within the NFs structure result in a significantly larger surface area, thereby amplifying the enzymatic activity compared to commercially available Co3O4 NPs. Under physiological conditions, it was observed that Co3O4 NFs efficiently break down hydrogen peroxide (H2O2) without generating harmful radicals (·OH). Moreover, they exhibit excellent compatibility with various cells involved in wound healing, promoting fibroblast growth and protecting cells from oxidative stress. In a rat model, Co3O4 NFs facilitate both the hemostatic and proliferative phases of wound healing, consequently accelerating the process. Overall, the promising results of Co3O4 NFs highlight their potential in promoting wound healing and tissue regeneration.

Wound healing is a dynamic and complex process that contains several sequential phases. However, most of the current drug delivery systems were designed to treat only one certain phase of wound repair, ignoring the fact that every stage plays critical roles in the wound healing process and those critical stages coordinately work to ensure optimal tissue regeneration. Therefore, a delivery system that can precisely meet the requirements of each wound healing stage is desired to enhance tissue regeneration. In this study, an injectable sodium alginate/bioglass (SA/BG) composite hydrogel was used to carry SA microparticles containing a conditioned medium (CM) of cells (SACM). Inside the SACM microparticles, poly(lactic-co-glycolic acid) (PLGA) microspheres containing pirfenidone (PFD) were encapsulated (PLGAPFD). This multilayer injectable hydrogel system (SA/BG-SACM-PLGAPFD) was designed to sequentially deliver bioactive molecules for meeting the bioactivity requirement and timeline of each wound healing stage. First, SA/BG hydrogels could rapidly release BG ionic products in the first 1-3 days to regulate the inflammatory response of the host and initiate the subsequent tissue regeneration. Then, SACM hydrogel microparticles could release CM of RAW 264.7 cells stimulated with BG ionic products in 2-7 days to facilitate the formation of the vascularized granulation tissue. Finally, PLGAPFD microspheres released PFD in 8-20 days to prevent the fibrosis and scar formation in the regenerated skin. Thus, this SA/BG-SACM-PLGAPFD delivery system could restrain host inflammation, accelerate wound healing, and inhibit the fibrosis formation in a diabetic mouse skin damage model, enhancing skin regeneration. As the bioactive components in each layer of the system can be adjusted according to the requirements of different tissue regeneration, this three-layered injectable biomaterial system has a wide application potential in the regenerative medicine field.

Skin wound healing is a tightly orchestrated process between epithelial, dermal, neuronal and vascular cells, all working in concert to restore tissue integrity and skin barrier function. Here, we report the therapeutic regenerative effects of FDA‐approved 4‐aminopyridine (4‐AP) to promote skin wound healing by accelerating re‐epithelialization, wound induced hair neogenesis (WIHN), dermal collagen deposition, angiogenesis, and reinnervation. We demonstrate that 4‐AP enhanced wound closure by promoting keratinocyte proliferation and migration as well as collagen deposition through myofibroblast differentiation. 4‐AP treatment increased both epidermal thickness, as well as the number of hair follicles and blood vessels in healed wounds, suggesting better restoration of skin function and architecture compared to simple wound scar formation. Moreover, 4‐AP enhanced reinnervation of healed wounds by promoting Schwann cell (SC) de‐differentiation and secretion of neuromediators (NGF, SP) associated with regeneration. In‐vitro studies using human cells demonstrated that 4‐AP enhanced proliferation and migration of keratinocytes, and SCs and that 4‐AP enhances cellular interactions between neuronal and non‐neuronal cells to further accelerate wound healing. 4‐AP induced secretion of NGF from both SCs and keratinocytes. 4‐AP enhances many of the key attributes of successful wound healing and is a promising therapeutic adjuvant for skin wound healing and tissue regeneration.