Improve Burn Wound Healing Research Articles

809 Isotonic Medium Treatment Improves Burn Wound Healing Potential in Larval Zebrafish and Human Skin Explants

809 Isotonic Medium Treatment Improves Burn Wound Healing Potential in Larval Zebrafish and Human Skin Explants

Chitosan-insulin nano-formulations as critical modulators of inflammatory cytokines and Nrf-2 pathway to accelerate burn wound healing

Burn injuries are characterized by prolonged inflammatory phases, neurovascular damage, and hypermetabolism, eventually causing improper tissue regeneration. Insulin has gained considerable attention in normal and diabetic wound healing, yet its role in burn wounds remains poorly understood. In this study, insulin-chitosan nano-formulations (ICNP) were synthesized using a simple and robust mechanism and characterized to monitor specific interactions between insulin and chitosan, and the particles measuring approximately 30 nm in size exhibited mild alterations in the amide I, II, and III bonds of the insulin protein along with impressive insulin loading efficiency of 88.725 ± 0.295% under physiological conditions, and significantly improved burn wound healing in vitro (HEKa cells) and in vivo (murine third-degree burn model). The underlying mechanism behind superior wound closure and tissue remodeling was attributed to significant early phase reduction of pro-inflammatory cytokine IL-6 levels in ICNP-treated mice, while anti-inflammatory cytokine IL-10 levels became markedly elevated, resulting in enhanced re-epithelialization and collagen deposition. Furthermore, treatment of ICNP was associated with unregulated expression of Nrf-2, a key regulator of oxidative stress and inflammation, indicating their molecular crosstalk. These findings highlight the potential of ICNP as a promising therapeutic formulation for burn wound healing, promoting wound closure by modulating inflammatory phases, making it a valuable candidate for further clinical development in burn care.Graphical

Monocytes and T cells incorporated in full skin equivalents to study innate or adaptive immune reactions after burn injury.

Thermal injury often leads to prolonged and excessive inflammation, which hinders the recovery of patients. There is a notable absence of suitable animal-free models for investigating the inflammatory processes following burn injuries, thereby impeding the development of more effective therapies to improve burn wound healing in patients. In this study, we established a human full skin equivalent (FSE) burn wound model and incorporated human peripheral blood-derived monocytes and T cells. Upon infiltration into the FSEs, the monocytes differentiated into macrophages within a span of 7 days. Burn-injured FSEs exhibited macrophages with increased expression of HLA-DR+ and elevated production of IL-8 (CXCL8), in comparison to uninjured FSEs. Among the T cells that actively migrated into the FSEs, the majority were CD4+ and CD25+. These T cells demonstrated augmented expression of markers associated with regulatory T cell, Th1, or Th17 activity, which coincided with significant heightened cytokine production, including IFN-γ, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IP-10 (CXCL10), and TGF-β1. Burn injury did not impact the studied effector T cell subsets or cytokine levels. Collectively, this study represents a significant advancement in the development of an immunocompetent human skin model, specifically tailored for investigating burn-induced innate or adaptive immune reactions at the site of burn injury.

Use of autologous adipose tissue in acute burn wound management: A systematic review

Fat transfer is increasingly used as part of our reconstructive armamentarium to address the challenges encountered in burn wounds and reconstructive surgery. The present systematic review aimed to evaluate the effectiveness of autologous fat transfer for acute burn wound management. A systematic review of the US National Library of Medicine, Cochrane Library, Web of Science, and Embase was conducted on October 15, 2022 (registration number CDR42022369726). A database watch was performed until submission of the manuscript. The review focused on wound healing. All studies reporting fat transfer in adult patients (at least 5 patients reported) with deep 2nd degree burn wounds were included. The database search yielded a total of 720 records and 367 patients were included from 3 studies. A statistically significant improvement in scar texture, scar appearance, and time to healing was reported in one study in the fat transfer group versus control (P<0.001). Similarly, scores for scar color, scar thickness, scar stiffness, and scar regularity increased significantly. The small number of included studies and their heterogeneity did not allow a meta-regression to be performed. This systematic review emphasizes the limited evidence currently available regarding the use of autologous fat transfer to improve burn wound healing in adult patients, even though it seems promising. Future search should focus on randomized controlled trials with a larger number of participants.

Potential therapeutic role of microvesicles derived from mesenchymal stem cells and platelet-rich plasma in murine burn wound healing: scar regulation and antioxidant mechanism.

Microvesicles (MVs) derived from mesenchymal stem cells exhibited an emerging promising therapy in many animal model diseases. Post-burn scars represent one of the significant challenges in wound healing processes. The present study investigated the possible role of MVs derived from mesenchymal stem cells vs. platelet-rich plasma (PRP) in murine burn wound healing. Wistar rats (n = 40) were assigned into four equal groups (control, burn, burn + PRP, burn + MVs). Small-sized burns were induced, morphologically followed for 3 weeks, then rats were sacrificed and skin lesions were analysed biochemically and immunohistochemically. Both MVs and PRP modulated the burn healing process with better results in the MVs group than in PRP. MVs significantly (p < 0.05) accelerated burn wound size healing and dramatically modulated tissue interleukin (IL)-10, IL-6, and hyaluronidase. Both MVs and PRP significantly downregulated gene expression of miRNA203 and alpha smooth muscle actin and immunoblotting analysis of matrix metalloproteinases 3 and transforming growth factor beta compared with the burn group. The immune-staining intensity of tumour necrosis factor alpha was dramatically reversed in the MVs group compared with the burn group, whereas that of connective tissue growth factor, collagen I and III was significantly reduced in both groups. The antioxidant Nrf2 immune-staining intensity had been dramatically enhanced particularly in MVs. Microvesicles derived from mesenchymal stem cells and PRP may improve burn wound healing via regulating scar formation and antioxidant mechanism.

Honey-based Silver Sulfadiazine Microsponge-Loaded Hydrogel: In vitro and In vivo Evaluation for Burn Wound Healing.

Silver sulfadiazine has often been used as a topical antibacterial agent for burn wounds. Aim of this study is to develop silver sulfadiazine-loaded microsponge along with honeyimpelled hydrogel for improved burn wound healing activity. Microsponge were prepared by quasi-emulsion solvent diffusion method. Formulation variables such as concentration of emulsifier and Internal phase volume were optimized by using 32 factorial design. Further, SSD microsponge-based Hydrogel was prepared using carbopol 934 and honey as natural healing agents. In vitro drug release, ex vivo drug deposition, skin irritancy study, and in vivo antibacterial activity were evaluated for optimized hydrogel formulations. The MTT assay was used to determine the safety of the optimized hydrogel using epidermal keratinocyte (HaCaT) cell lines. At the 12th hour, in vitro drug release was found to be 85.11±0.89. An adjusted microspongeloaded hydrogel increased medication retention ability in the epidermal layers when compared to the commercial product. There was also less application time, no skin irritation, low cytotoxicity on dermal cell lines, and better wound contraction. The prepared microsponge-loaded hydrogel can serve as a potential alternative for burn wound as compared to the marketed product.

20(R)-ginsenoside Rg3-loaded polyurethane/marine polysaccharide based nanofiber dressings improved burn wound healing potentials

The management of deep burn injuries is extremely challenging, ascribed to their delayed wound healing rate, susceptibility for bacterial infections, pain, and increased risk of hypertrophic scarring. In our current investigation, a series of composite nanofiber dressings (NFDs) based on polyurethane (PU) and marine polysaccharides (i.e., hydroxypropyl trimethyl ammonium chloride chitosan, HACC and sodium alginate, SA) were accomplished by electrospinning and freeze-drying protocols. The 20(R)-ginsenoside Rg3 (Rg3) was further loaded into these NFDs to inhibit the formation of excessive wound scars. The PU/HACC/SA/Rg3 dressings showed a sandwich-like structure. The Rg3 was encapsulated in the middle layers of these NFDs and slowly released over 30 days. The PU/HACC/SA and PU/HACC/SA/Rg3 composite dressings demonstrated superior wound healing potentials over other NFDs. These dressings also displayed favorable cytocompatibility with keratinocytes and fibroblasts and could dramatically accelerate epidermal wound closure rate following 21 days of the treatment of a deep burn wound animal model. Interestingly, the PU/HACC/SA/Rg3 obviously reduced the excessive scar formation, with a collagen type I/III ratio closer to the normal skin. Overall, this study represented PU/HACC/SA/Rg3 as a promising multifunctional wound dressing, which promoted the regeneration of burn skins and attenuated scar formation.

Effects of Bioactive Compound, Ginsenoside Rb1 on Burn Wounds Healing in Diabetic Rats: Influencing M1 to M2 Phenotypic Trans

Panax notoginseng (P.notoginseng) has been used traditionally to treat traumatic injuries. Ginsenoside Rb1, a key active ingredient derived from P.notoginseng, has received a lot of interest due to its anti-inflammatory, bacteriostatic, and growth-promoting effects on cells. The therapeutic benefits of ginsenoside Rb1 on burn wounds in STZ-induced diabetic rats, as well as the probable underlying processes, were investigated in this work. The skin wound healing effect of ginsenoside Rb1 (0.25 and 0.5% w/w) in a rat model of burn wounds in diabetic rats was observed at various time points after treatment. On days 5 and 19 following treatment, immunohistochemistry and Western blot analysis for Interleukin 1 beta (IL-1β), Tumour necrosis factor-α (TNF-α), Cluster of Differentiation 68 (CD68) and Cluster of Differentiation 163 (CD163) of biological tissues were done. The macroscopic observation was used to track the healing of skin wounds at various periods. The protein expression of CD68 and CD163, which serve as M1 and M2 macrophage markers, was examined in detail. More notably, the ability of ginsenoside Rb1 to alter inflammatory markers (IL-6) and anti-inflammatory markers (IL-10), influence on hydroxyproline and hexosamine was observed. As indicated by increased CD163 (M2) and reduced CD68 (M1) on day 5, ginsenoside Rb1 effectively flips the M1 to M2 phenotypic transition at the right time to improve burn wound healing in diabetic rats. Ginsenoside Rb1 (0.5 % w/w) treatment showed higher tensile strength, anti-inflammatory properties, antioxidant properties, increased tissue hexosamine and hydroxyproline levels. Skin tissue morphology was significantly improved following 19 days of ginsenoside Rb1 (0.5% w/w) therapy, according to hematoxylin-eosin and Masson’s trichrome staining. Furthermore, Ginsenoside Rb1 (0.5% w/w) favoured the inflammatory phase of burn wound healing (IL-6), assisted the proliferation process (IL-10) and had considerably lower expression of IL-1β and TNF-α on the later stage of wound healing. Overall, the data showed that ginsenoside Rb1 (0.5 % w/w) accelerates burn wound healing in diabetic rats through a mechanism that may be linked to the M1 to M2 phenotypic shift.

Advanced multilayer composite dressing with co-delivery of gelsevirine and silk fibroin for burn wound healing

Burn is one of the most common types of injuries worldwide, which remains a clinical challenge due to its progressive exacerbation caused by inflammation and edema that impede the growth and differentiation of fibroblast. To solve this problem, in this study, the anti-inflammatory Gelsvirine (Gs), as a specific STING inhibitor for rheumatoid arthritis pain, is used for inflammation control in burn wound healing. Meanwhile, to improve fibroblast migration, proliferation, and differentiation, the natural protein silk fibroin (SF) was used due to its demonstrated capacity to promote the proliferation of epidermal cells and fibroblasts, facilitate collagen synthesis and further improve wound repair. Through our rational design, a functional dressing for the co-delivery of Gs and SF is developed to improve burn wound healing. A multilayer composite dressing of Polycaprolactone(PCL)/Gs-loaded sodium alginate (SA)/SF-gelatin (Gs@SFD) was prepared using the combination of electrospinning and extrusion method, which contained four layers: PCL-dense barrier layer (to prevent infection), SA-hydrogel layer (to load Gs and keep wound moisture), PCL-loosen support layer (to prevent deformation of bioactive layer and to facilitate Gs release into trauma) and SF/gelatin bioactive layer (to contact with trauma and bioactively induce wound healing). Our data showed that the hydrogel layer realized the sustained release of Gs. As a specific inhibitor of STING signaling pathway, the released Gs inhibited the inflammatory response of macrophages and further reduced the fibroblast damage both in vitro and in vivo. In addition, the bioactive layer promoted cell proliferation, facilitated collagen synthesis, and further improved wound healing in animal model of burn trauma. Therefore, this study provides a novel multilayer composite dressing (Gs@SFD) to facilitate burn wound healing via efficient inflammation control with the sustained release of Gs, and improvement on wound healing due to the bioactive components of silk fibroin, which could serve as a potential therapeutic approach in the future. In addition, our multilayer dressing design provides an advanced drug delivery strategy for burn wound healing.

Metformin Improves Burn Wound Healing by Modulating Microenvironmental Fibroblasts and Macrophages.

Metformin, a biguanide, exerts different functions through various signaling pathways. In order to investigate the function and mechanism of metformin in burn wounds, we established burn rat models, subcutaneously injected metformin to treat the wounds, and observed the morphologies and the expression of collagen I, collagen III, fibronectin, and pro-inflammatory markers. In vitro experiments were performed to investigate the effects of metformin on the proliferation, migration, and collagen I synthesis of the mouse embryonic fibroblast (NIH 3T3) cell line and on the proliferation, apoptosis, and immune response of the mouse mononuclear macrophage (RAW 264.7) cell line. Finally, we studied the regulatory effects of metformin on a co-culture of RAW 264.7/NIH 3T3 cells. We found that 100 mM of metformin reduced dermal thickness, collagen I deposition, and mRNA expression of IL1β and CCL2 in rat burn wounds. In vitro experiments revealed that metformin inhibited the proliferation of NIH 3T3 and RAW 264.7 cells. Metformin attenuated NIH 3T3 cell migration via the AMPK/mTOR pathway and attenuated collagen I synthesis through the TGFβ1/Smad3 pathway. Metformin inhibited the apoptosis of RAW 264.7 cells induced by 10 μg/mL LPS. Metformin downregulated the mRNA expression of IL1β and CCL2 in RAW 264.7 cells under 1 μg/mL LPS induction by inhibiting NF-κB p65 phosphorylation. In a RAW 264.7/NIH 3T3 co-culture, metformin attenuated collagen I synthesis in NIH 3T3 cells by inhibiting RAW 264.7 paracrine secretion of TGF-β1. This provides new evidence related to the development of metformin for potentially improving burn wound healing.

Controlled dual release of dihydrotestosterone and flutamide from polycaprolactone electrospun scaffolds accelerate burn wound healing.

Wound healing is a complex process involving multiple independent and overlapping sequential physiological mechanisms. In addition to cutaneous injury, a severe burn stimulates physiological derangements that induce a systemic hypermetabolic response resulting in impaired wound healing. Topical application of the anti‐androgen drug, flutamide accelerates cutaneous wound healing, whereas paradoxically systemic dihydrotestosterone (DHT) improves burn wound healing. We developed and characterized a PCL scaffold that is capable of controlled release of androgen (DHT) and anti‐androgen (F) individually or together. This study aims to investigate whether local modification of androgen actions has an impact on burn injury wound healing. In a full‐thickness burn wound healing, mouse model, DHT/F‐scaffold showed a significantly faster wound healing compared with F‐scaffold or DHT‐scaffold. Histology analysis confirmed that DHT/F‐scaffold exhibited higher re‐epithelization, cell proliferation, angiogenesis, and collagen deposition. Dual release of DHT and F from PCL scaffolds promoted cell proliferation of human keratinocytes and alters the keratinocyte cell cycle. Lastly, no adverse effects on androgen‐dependent organs, spleen and liver were observed. In conclusion, we demonstrated DHT plus F load PCL scaffolds accelerated burn wound healing when loading alone did not. These findings point to a complex role of androgens in burn wound healing and open novel therapeutic avenues for treating severe burn patients.

615 Evaluation of Topical Off-The-Shelf Therapies to Improve Burn Wound Healing During Prolonged Field Care

IntroductionBurns are common injuries in the battlefield. Given austere environments, prolonged field care (PFC) is often necessary. Delays in surgical debridement create a risk of infection and deranged healing for burn patients. As such, this study attempts to identify the best commercially available off-the-shelf (OTS) dressings with field-deployable potential.MethodsDeep-partial thickness burns (1" diameter) were created on the dorsum of 3 anesthetized pigs utilizing a thermocoupled burn device at 100°C for 15s. Non-surgical debridement was done 1-h post-burn creation and either an OTS dressing or standard-of-care (SOC) treatment (Silver Sulfadiazine) was applied to the wound in order to simulate a PFC environment. OTS dressings were randomized and included irradiated sterile human skin allograft (ISHSA), alloplastic absorbable skin substitute (AASS), and synthetic polyurethane dermal matrix (SPDM). Wounds were serially assessed on post-burn days 3, 7, 14, 21, and 28. Assessments were conducted using a combination of photographs, histology, and quantitative bacteriology. Endpoints included burn wound progression, re-epithelialization, wound contraction, scar elevation index (SEI), and colony forming units (CFU).ResultsNo statistically significant differences in burn wound progression were seen on days 3 and 7 for the ISHSA or SPDM and the SOC. The differences between the AASS and the SOC were statistically significant on both days (p≤0.05). Day 21 re-epithelialization results for the ISHSA, AASS, SPDM and SOC treated wounds were 30%, 85%, 95%, and 78% re-epithelialized, respectively. The difference between the AASS and the SOC was statistically significant (p≤0.05). Results showed that by day 28, wound contraction for the ISHSA, AASS, SPDM and SOC treated wounds were 65%, 80%, 82%, and 78%, respectively. No statistically significant differences in wound contraction were seen for any of the OTS dressings and the SOC. SEI showed no statistically significant difference in scar hypertrophy between the OTS dressings and the SOC on day 28. CFU results showed no statistically significant differences between the OTS dressings and the SOC on days 3 and 7.ConclusionsThree OTS dressings were compared to the SOC for use in the PFC setting. Generally, all the dressings performed well when compared to the SOC in terms of burn wound progression, re-epithelialization, wound contraction, SEI, and CFU. Although significant differences in burn progression and re-epithelialization for burns treated with AASS were seen. In the future, we hope to continue to discover and test various OTS dressings to determine their appropriateness for use in the PFC setting.

Promotion of Burn Wound Healing by Local Application of Adipose-Derived Mesenchymal Stem Cells: An Experimental Study

Background:The burn wound is one of the health problems in the world that affects physical and mental health. Today, adipose-derived mesenchymal stem cells (ADSCs) have received medical attention for their accessibility and the ability to reproduce and repair. The present study was designed to investigate the effect of ADSCs on burn wound healing. Methods : The present experimental study was performed on 36 male Wistar rats divided into 1 control group and 3 experimental groups. The second-degree burns with a radius of 10 mm were induced after anesthesia. ADSCs and Dulbecco's Modified Eagle Medium (DMEM) were injected into the dermis around the burn area in the ADSCs and DMEM groups, respectively. Silver sulfadiazine (SSD) ointment was applied topically once daily as the SSD group. The control group did not receive any treatment. The rats were evaluated for 21 days. Wound healing rate, histopathological parameters, and the number of fibroblasts were evaluated by the immunofluorescence technique and vascular endothelial growth factor and transforming growth factor β (TGF-β) gene expression by reverse transcription-polymerase chain reaction. The results were entered into SPSS software (SPSS Inc) and analyzed with 1-way analysis of variance and repeated measures analysis. Results: The number of fibroblasts, the number of vessels, TGF-β, and VEGF gene expression in the burn area were significantly higher in the ADSCs group than in the SSD, DMEM, and control groups. The results also showed that the amount of inflammation was significantly lower in the ADSCs group compared with the control group (p<0.001). Moreover, the percentage of wound recovery was significantly higher in the ADSCs group compared with other groups (p<0.001). Conclusion: ADSCs accelerate and improve burn wound healing by affecting fibroblasts, keratinocytes, and inflammatory cells as well as increasing the expression of the TGF-β and VEGF genes, and thus increase in angiogenesis.

Accelerated burn wound healing with photobiomodulation therapy involves activation of endogenous latent TGF-β1

The severity of tissue injury in burn wounds from associated inflammatory and immune sequelae presents a significant clinical management challenge. Among various biophysical wound management approaches, low dose biophotonics treatments, termed Photobiomodulation (PBM) therapy, has gained recent attention. One of the PBM molecular mechanisms of PBM treatments involves photoactivation of latent TGF-β1 that is capable of promoting tissue healing and regeneration. This work examined the efficacy of PBM treatments in a full-thickness burn wound healing in C57BL/6 mice. We first optimized the PBM protocol by monitoring tissue surface temperature and histology. We noted this dynamic irradiance surface temperature-monitored PBM protocol improved burn wound healing in mice with elevated TGF-β signaling (phospho-Smad2) and reduced inflammation-associated gene expression. Next, we investigated the roles of individual cell types involved in burn wound healing following PBM treatments and noted discrete effects on epithelieum, fibroblasts, and macrophage functions. These responses appear to be mediated via both TGF-β dependent and independent signaling pathways. Finally, to investigate specific contributions of TGF-β1 signaling in these PBM-burn wound healing, we utilized a chimeric TGF-β1/β3 knock-in (TGF-β1Lβ3/Lβ3) mice. PBM treatments failed to activate the chimeric TGF-β1Lβ3/Lβ3 complex and failed to improve burn wound healing in these mice. These results suggest activation of endogenous latent TGF-β1 following PBM treatments plays a key role in burn wound healing. These mechanistic insights can improve the safety and efficacy of clinical translation of PBM treatments for tissue healing and regeneration.

Accelerated Wound Closure of Deep Partial Thickness Burns with Acellular Fish Skin Graft.

Thermal injuries are caused by exposure to a variety of sources, and split thickness skin grafts are the gold standard treatment for severe burns; however, they may be impossible when there is no donor skin available. Large total body surface area burns leave patients with limited donor site availability and create a need for treatments capable of achieving early and complete coverage that can also retain normal skin function. In this preclinical trial, two cellular and tissue based products (CTPs) are evaluated on twenty-four 5 × 5 deep partial thickness (DPT) burn wounds. Using appropriate pain control methods, DPT burn wounds were created on six anesthetized Yorkshire pigs. Wounds were excised one day post-burn and the bleeding wound beds were subsequently treated with omega-3-rich acellular fish skin graft (FSG) or fetal bovine dermis (FBD). FSG was reapplied after 7 days and wounds healed via secondary intentions. Digital images, non-invasive measurements, and punch biopsies were acquired during rechecks performed on days 7, 14, 21, 28, 45, and 60. Multiple qualitative measurements were also employed, including re-epithelialization, contraction rates, hydration, laser speckle, and trans-epidermal water loss (TEWL). Each treatment produced granulated tissue (GT) that would be receptive to skin grafts, if desired; however, the FSG induced GT 7 days earlier. FSG treatment resulted in faster re-epithelialization and reduced wound size at day 14 compared to FBD (50.2% vs. 23.5% and 93.1% vs. 106.7%, p < 0.005, respectively). No differences in TEWL measurements were observed. The FSG integrated into the wound bed quicker as evidenced by lower hydration values at day 21 (309.7 vs. 2500.4 µS, p < 0.05) and higher blood flow at day 14 (4.9 vs. 3.1 fold change increase over normal skin, p < 0.005). Here we show that FSG integrated faster without increased contraction, resulting in quicker wound closure without skin graft application which suggests FSG improved burn wound healing over FBD.

An Atmospheric Plasma Jet Induces Expression of Wound Healing Genes in Progressive Burn Wounds in a Comb Burn Rat Model: A Pilot Study.

Burn-related injuries are devastating injuries with a high mortality rate that affect people of all ages worldwide. We assessed the effectiveness of plasma jet treatment in altering the expression of genes involved in wound healing in a prospective longitudinal observational animal study. Six male Sprague-Dawley rats weighing 350 g were used, and burn wounds were made by applying a preheated brass comb (100°C) to the back of the rats, resulting in four full-thickness burn wounds separated by three interspaces. A total of 18 burn wounds were induced on three rats. One side of the burn, on each rat received plasma treatment (plasma group), while the other side did not (control group). The interspaces were subjected to the plasma jet for 2 minutes per day until 7 days post-wounding. Plasma treatment significantly decreased the expression of proinflammatory cytokines. Furthermore, an increase in the expression of anti-inflammatory cytokines was observed in the plasma group. We showed that plasma jet treatment could improve burn wound healing by altering the expression of genes involved in the development of wound healing.

Mesenchymal stem cell-based therapy for burn wound healing.

Burns, with their high incidence and mortality rates, have a devastating effect on patients. There are still huge challenges in the management of burns. Mesenchymal stem cells (MSCs), which have multidirectional differentiation potential, have aroused interest in exploring the capacity for treating different intractable diseases due to their strong proliferation, tissue repair, immune tolerance and paracrine abilities, among other features. Currently, several animal studies have shown that MSCs play various roles and have beneficial effects in promoting wound healing, inhibiting burn inflammation and preventing the formation of pathological scars during burn healing process. The substances MSCs secrete can act on peripheral cells and promote burn repair. According to preclinical research, MSC-based treatments can effectively improve burn wound healing and reduce pain. However, due to the small number of patients and the lack of controls, treatment plans and evaluation criteria vary widely, thus limiting the value of these clinical studies. Therefore, to better evaluate the safety and effectiveness of MSC-based burn treatments, standardization of the application scheme and evaluation criteria of MSC therapy in burn treatment is required in the future. In addition, the combination of MSC pretreatment and dressing materials are also conducive to improving the therapeutic effect of MSCs on burns. In this article, we review current animal research and clinical trials based on the use of stem cell therapy for treating burns and discuss the main challenges and coping strategies facing future clinical applications.

Burns in the Elderly: Potential Role of Stem Cells.

Burns in the elderly continue to be a challenge despite advances in burn wound care management. Elderly burn patients continue to have poor outcomes compared to the younger population. This is secondary to changes in the quality of the aged skin, leading to impaired wound healing, aggravated immunologic and inflammatory responses, and age-related comorbidities. Considering the fast-growing elderly population, it is imperative to understand the anatomic, physiologic, and molecular changes of the aging skin and the mechanisms involved in their wound healing process to prevent complications associated with burn wounds. Various studies have shown that stem cell-based therapies improve the rate and quality of wound healing and skin regeneration; however, the focus is on the younger population. In this paper, we start with an anatomical, physiological and molecular dissection of the elderly skin to understand why wound healing is delayed. We then review the potential use of stem cells in elderly burn wounds, as well as the mechanisms by which mesenchymal stem cell (MSCs)-based therapies may impact burn wound healing in the elderly. MSCs improve burn wound healing by stimulating and augmenting growth factor secretion and cell proliferation, and by modulating the impaired elderly immune response. MSCs can be used to expedite healing in superficial partial thickness burns and donor site wounds, improve graft take and prevent graft breakdown.

Simvastatin combined with bone marrow mesenchymal stromal cells (BMSCs) improve burn wound healing by ameliorating angiogenesis through SDF-1α/CXCR4 pathway.

Objective(s):Chemokines are wound mediators that promote angiogenesis during wound healing. We hypothesized that Simvastatin in combination with the bone marrow mesenchymal stromal cells (BMSCs) improve burn wound healing by ameliorating angiogenesis via SDF-1α/CXCR4 pathway.Materials and Methods:Under general anesthesia, deep partial-thickness burns were created on the inter-scapular area of 48 male rats. Study groups were administrated with petroleum jelly (Simvastatin Vehicle), a single dose of intradermal BMSCs (1×106), topical Simvastatin (0.5 mg/kg) daily and combination of BMSCs and Simvastatin for 14 days. In this study, we used MTT assay, in vivo and in vitro wound closure, H&E and Trichorome staining, immunohistochemistry (IHC), real- time PCR, Western blot and tube formation assay.Results:A significant improvement in wound closure percentage, epithelial thickness, collagen remodeling, and up-regulation of stromal cell-derived factor 1 alpha (SDF1α), C-X-C chemokine receptor type 4 (CXCR4), protein kinase B (AKT), and phosphatidylinositol 3- kinase (PI3K), as well as CD31 and vascular endothelial growth factor (VEGF) expression were observed after treatment with simvastatin, BMSCs and combination of them compared to the vehicle group. However, the co-treatment group revealed considerable superiority in examined factors. BMSCs treated with Simvastatin showed the highest viability in the concentration of 0.5 and 1 Nanomolar (nM). Increment in proliferation and capillary vessels formation of BMSCs was observed in the 0.5 nM and 1 nM concentrations of Simvastatin in vitro. Conclusion:Treatment of deep partial-thickness of burns with co-treatment of BMSCs and Simvastatin resulted in improved burn wound healing through up-regulating of SDF-1α/CXCR4 pathway.

Efficacy of erythropoietin-pretreated mesenchymal stem cells in murine burn wound healing: possible in vivo transdifferentiation into keratinocytes.

Stem cells have shown promising potential to treat burn wounds. Erythropoietin was capable of promoting in vitro transdifferentiation of mesenchymal stem cells (MSCs). The aim of the study was to investigate possible role of erythropoietin-pretreated mesenchymal stem cells (EPOa/MSCs) in burn wounds healing and to evaluate its in vivo differentiation into keratinocytes. Forty rats were utilised in this study divided into four groups (n = 10 for each). Control group (I), burn group (II), burn + MSCs, group (III), burn + EPOa/MSCs. 1 × 10⁶ cells were injected locally for each 1 cm² of burn areas. Burn areas were followed-up morphologically. After 21 days of the experiment, the rats were euthanised, skin specimens were assessed biochemically, histologically and immunohistochemically. EPOa/MSCs enhanced significantly (p < 0.05) burn wound vimentin gene expression and level of interleukin (IL)-10 while decreased IL-1 and COX2 as compared to the burn group. Histologically, EPOa/MSCs improved epithelialisation despite stem cells' differentiation into keratinocytes was rarely detected by PKH26 red fluorescence. EPOa/MSCs promoted angiogenesis as detected by significant increase in VEGF and PDGF immunoexpression as compared to burn group. EPOa/MSCs may improve burn wound healing, probably through anti-inflammatory, immunomodulatory and angiogenic action. However, in vivo transdifferentiation into keratinocytes was rarely detected.