Daria Narmoneva, PhD [ View bio ](Biomedical Engineering Department, University of Cincinnati)
Diabetic nonhealing wounds represent a major public health problem. Diabetic wounds are characterized by altered wound microenvironment, unbalanced proteolytic activity, prolonged inflammation, and insufficient neovascularization. The efficacy of conventional therapies is unsatisfactory and often results in recurrence of wounds at characteristically predisposed sites, as a direct consequence of poor wound repair. Skin substitutes based on novel biocomposite materials represent the most promising bioengineering technology today and may offer an exciting new treatment strategy in management of chronic wounds. A new generation of biomaterials—nanofiber-based scaffolds—possesses many properties of an ideal scaffold, including biocompatibility, biodegradability, antibacterial activity, appropriate mechanical properties, and porosity, as well as possibility for the attachment of multiple signals to alter the wound microenvironment and promote healing. The potential advantages of the nanofiber-based, tissue-engineering approaches arise from their ability to more accurately mimic the structure and complex environment of native tissues to promote a better, sustained healing without rejection, as compared to native matrices and allogeneic or xenogeneic grafts. Importantly, the nanofiber microenvironment can be engineered to deliver appropriate environmental cues to influence the behavior of different cell types (i.e., keratinocytes, dermal fibroblasts, and endothelial cells) as well as be used as a stem-cell delivery tool. Nanofibrous scaffolds for wound healing applications can be fabricated via electrospinning or using the self-assembly process. Nanofibers obtained using electrospinning are made from various polymeric materials and usually require surface functionalization (often using native materials such as collagen, elastin, and fibrinogen) and physical or chemical immobilization of bioactive molecules, such as growth factors, to be used as a dermal substitute. These materials have been optimized to promote keratinocyte and fibroblast migration and proliferation, improve reepithelializaion, and decrease bacterial burden; however, the success of the electrospinning-based scaffolds in addressing endothelial dysfunction, excessive proteolytic activity, and impaired neovascularization in diabetic wounds has been limited. On the other hand, several types of the nanofiber hydrogels, including synthetic proteolytically stable self-assembling peptide nanofibers and biomimetic pullulan-collagen hydrogel, have been demonstrated to improve wound healing via stimulation of angiogenesis and attenuation of inflammation. Studies in rodent models of wound healing demonstrate that wound treatment with the nanofiber-based hydrogels resulted in significantly enhanced wound neovascularization, accelerated wound reepithelialization, improved wound morphology, and tissue strength and in some cases showed evidence of regenerative phenotype that was similar to scarless fetal wound healing. Mechanistic studies suggested that the regenerative healing in the nanofiber hydrogel-treated wounds is mediated via integrin-dependent mechanisms and/or stimulation of proangiogenic growth factor expression. In addition, another nanofiber family—poly-nacetyl-glucosamine (sNAG) nanofibers—has been shown to improve wound healing via modulation of the initial inflammatory response and amplification of platelet activation. In summary, recent discoveries and technological advances led to the development of new types of nanofiber-based biomaterials that are able to mimic the native extracellular environment, deliver appropriate signals, and regulate behavior and responses of key cells in the wound milieu, thus opening the road to intelligent design of the next generation of treatment options for chronic diabetic wounds.
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