Abstract
In the past few years, there have been many efforts underway to develop effective wound healing treatments for traumatic injuries. In particular, wound‐healing peptides (WHPs) and peptide‐grafted dressings hold great promise for novel therapeutic strategies for wound management. This study reports a topical formulation of a new synthetic WHP (REGRT, REG) embedded in a hyaluronic acid (HA)‐based hydrogel dressing for the enhancement of acute excisional wound repair. The copper‐free click chemistry is utilized to form biocompatible HA hydrogels by cross‐linking dibenzocyclooctyl‐functionalized HA with 4‐arm poly(ethylene glycol) (PEG) azide. The HA hydrogels are grafted with the REG peptide, a functional derivative of erythroid differentiation regulator1, displaying potent cell motility‐stimulating ability, thus sustainably releasing physiologically active peptides for a prolonged period. Combined with the traditional wound healing benefits of HA, the HA hydrogel embedded REG (REG‐HAgel) accelerates re‐epithelialization in skin wound healing, particularly by promoting migration of fibroblasts, keratinocytes, and endothelial cells. REG‐HAgels improve not only rate, but quality of wound healing with higher collagen deposition and more microvascular formation while being nontoxic. The peptide‐grafted HA hydrogel system can be considered as a promising new wound dressing formulation strategy for the treatment of different types of wounds with combinations of various natural and synthetic WHPs.
Highlights
hyaluronic acid (HA) with 4-arm poly(ethylene glycol) (PEG) azide
REG (AES16-2M) is a new synthetic wound healing peptide derived from the functional region of erythroid differentiation regulator1 (Erdr1), a highly conserved autocrine factor regulating stress-related responses.[10]
Excess amounts of active Rac1 and Extracellular signal-regulated kinase (ERK) were observed at REG concentrations above 100 ng mL−1, the rate of cell migration mediated via the Rac1-ERK signaling pathway was rather reduced. This can be attributed to the negative feedback regulation of ERK signaling in normal cells.[16]. These results demonstrated that the REG peptide could accelerate MMP-induced cell migration via activating Rac1-ERK signaling pathways
Summary
REG (AES16-2M) is a new synthetic wound healing peptide derived from the functional region of Erdr, a highly conserved autocrine factor regulating stress-related responses.[10]. REGHAgels achieved maximum cell migration more than twofold higher than REG or HAgels, indicating the peptide and HA acted synergistically to improve migration of fibroblasts Taken together, these in vitro results supported that REG was successfully encapsulated into HAgels and sustainably released as its physiologically active form. By increased hyaluronidase in early wound healing.[21] Many reports consistently demonstrate that degradation of HA hydrogels in vitro or in vivo strongly promotes the release of the payloads due to the increased mesh size of the HA hydrogels.[22] The enhanced fluorescence signal of REG was gradually decreased over time This result suggested that the HAgel-based topical formulations allowed sustained delivery of the REG peptide at the wound site, leading to longer tissue residence time of the peptides maintaining within the therapeutic range
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