The purpose of this study was to permit bone marrow mesenchymal stem cells (BMSCs) to reach their full potential in the treatment of chronic wounds. A biocompatible multifunctional crosslinker based temperature sensitive hydrogel was developed to deliver BMSCs, which improve the chronic inflammation microenvironments of wounds. A detailed in vitro investigation found that the hydrogel is suitable for BMSC encapsulation and can promote BMSC secretion of TGF-β1 and bFGF. In vivo, full-thickness skin defects were made on the backs of db/db mice to mimic diabetic ulcers. It was revealed that the hydrogel can inhibit pro-inflammatory M1 macrophage expression. After hydrogel association with BMSCs treated the wound, significantly greater wound contraction was observed in the hydrogel + BMSCs group. Histology and immunohistochemistry results confirmed that this treatment contributed to the rapid healing of diabetic skin wounds by promoting granulation tissue formation, angiogenesis, extracellular matrix secretion, wound contraction and re-epithelialization. These results show that a hydrogel laden with BMSCs may be a promising therapeutic strategy for the management of diabetic ulcers.

Chronic wounds, such as pressure ulcers, vascular ulcers and diabetic foot ulcers (DFUs), often stay in a state of pathological inflammation and suffer from persistent infection, excess inflammation, and hypoxia, thus they are difficult to be healed. Nitric oxide (NO) plays a critical role in the regulation of various wound healing processes, including inflammatory response, cell proliferation, collagen formation, antimicrobial action and angiogenesis. The important role of NO in wound healing attracts intensive research focus on NO-based wound healing therapy. However, the application of NO gas therapy needs to resolve the intrinsic shortcomings of gas therapy, such as short storage and release times as well as temporal and spatial uncontrollability of the release mode. So far, various types of NO donors, including organic nitrates (RONO₂), nitrites (RONO), S-nitrosothiols (RSNOs), nitrosamines, N-diazeniumdiolates (NONOates), and metal–NO complexes, have been developed to solidify gaseous NO and they were further encapsulated in or conjugated onto a variety of biomaterial vectors to develop NO delivery systems. NO synthetic enzyme mimics to catalyze the production and release of NO from L-arginine have also been developed. This paper reviews recent advances of NO donors, biomaterial vectors, thus-formed NO delivery systems, as well as recently emerged NO synthetic enzyme mimics. Furthermore, this review also summarizes the functions of NO releasing biomaterials that would benefit chronic wound healing, including antibacterial properties and the promotion of angiogenesis, as well as the convenient combination of light/thermal induced NO release with light/thermal therapies, and the prospects for future developing trends in this area.

Skin wound healing is a complicated process that involves a variety of cells and cytokines. Fibroblasts play an important role in this process and participate in transformation into myofibroblasts, the synthesis of extracellular matrix (ECM) and fibers, and the secretion of a variety of growth factors. This study assessed the effects of peptide Ser-Ile-Lys-Val-Ala-Val (SIKVAV)--modified chitosan hydrogels on skin wound healing. We investigated the capability of peptide SIKVAV to promote cell proliferation and migration, the synthesis of collagen, and the secretion of a variety of growth factors using fibroblasts in vitro. We also treated skin wounds established in mice using peptide SIKVAV-modified chitosan hydrogels. Hematoxylin and eosin staining showed that peptide-modified chitosan hydrogels enhanced the reepithelialization of wounds compared with negative and positive controls. Masson’s trichrome staining demonstrated that more collagen fibers were deposited in the wounds treated with peptide-modified chitosan hydrogels compared with the negative and positive controls. Immunohistochemistry revealed that the peptide-modified chitosan hydrogels promoted angiogenesis in the skin wound. Taken together, these results suggest that peptide SIKVAV-modified chitosan hydrogels may be useful in wound dressing and the treatment of skin wounds.

Angiogenesis and re-epithelialization are critical factors in skin wound healing. Growth factors and stem cells have demonstrated their active roles in promoting these two processes. Peptides show similar effects with growth factors with lower cost and controllable properties. Here we report a biomimetic fragment of the laminin –Ser-Ile-Lys-Val-Ala-Val (SIKVAV)-conjugated chitosan hydrogel that can promote skin regeneration. In vitro we found that this peptide-conjugated hydrogel significantly promoted BMSC adhesion and proliferation. In vivo, this hydrogel accelerated wound contraction. The subcutaneous implantation test and H&E staining results revealed that the peptide-modified chitosan hydrogel dramatically led to the formation of new blood vessels. Moreover, Masson staining showed that many newborn collagen fibers appeared in the peptide hydrogel group, while only a few newborn collagen fibers were found in control and chitosan hydrogel groups. The peptide chitosan hydrogel also re-epithelialized quickly, while the control and chitosan hydrogel took more time to complete. These results suggest that the SIKVAV peptide is an effective motif to significantly improve the function of chitosan in angiogenesis and re-epithelialization of skin.

Background: The use of keratinocytes derived from induced pluripotent stem cells (iPSCs-KCs) may represent a novel cell therapy strategy for burn treatment. There is growing evidence that extracellular vesicles, including exosomes, are primary mediators of the benefits of stem cell therapy. Herein, we thus explored the effects of exosomes produced by iPSCs-derived keratinocytes (iPSCs-KCs-Exos) in a model of deep second-degree burn wound healing and evaluated the mechanistic basis for the observed activity. Methods: iPSCs-KCs-Exos were isolated from conditioned medium of iPSCs-KCs and verified by electron micrograph and size distribution. Next, iPSCs-KCs-Exos were injected subcutaneously around wound sites, and its efficacy was evaluated by measuring wound closure areas, histological examination, and immunohistochemistry staining. The effects of iPSCs-KCs-Exos on proliferation and migration of keratinocytes and endothelial cells in vitro were assessed by EdU staining, wound healing assays, and transwell assay. Then, high-throughput microRNA sequencing was used to explore the underlying mechanisms. We assessed the roles of miR-762 in iPSCs-KCs-Exos-induced regulation of keratinocytes and endothelial cells migration. Furthermore, the target gene which mediated the biological effects of miR-762 in keratinocytes and endothelial cells was also been detected. Results: The analysis revealed that iPSCs-KCs-Exos application to the burn wound drove the acceleration of wound closure, with more robust angiogenesis and re-epithelialization being evident. Such iPSCs-KCs-Exos treatment effectively enhanced endothelial cell and keratinocyte migration in vitro. Moreover, the enrichment of miR-762 was detected in iPSCs-KCs-Exos and was found to target promyelocytic leukemia (PML) as a means of regulating cell migration through a mechanism tie to integrin beta1 (ITGB1). Conclusion: These results thus provide a foundation for the further study of iPSCs-KCs-Exos as novel cell-free treatments for deep second-degree burns. Graphical