Vascular Endothelial Growth Factor-Recruiting Nanofiber Bandages Promote Multifunctional Skin Regeneration via Improved Angiogenesis and Immunomodulation

Abstract

Tissue injury leads to gradients of chemoattractants, which drive multiple processes for tissue repair, including the inflammatory response as well as endogenous cell recruitment. However, a limited time window for the gradients of chemoattractants as well as their poor stability at the injury site may not translate into healthy tissue repair. Consequently, intelligent multifunctional scaffolds with the capability to stabilize injury-induced cytokines and chemokines hold great promise for tissue repair. Vascular endothelial growth factor (VEGF) plays a significant role in wound healing by promoting angiogenesis. The overarching objective of this research was to develop intelligent multifunctional scaffolds with the capability to endogenously recruit VEGF and promote wound healing via angiogenic and immunomodulatory dual functions. Prominin-1-derived peptide (PR1P) was encapsulated into electrospun poly(L-lactide-coglycolide)/gelatin (P/G)-based bandages. The sustained release of PR1P recruited VEGF in situ, thereby stabilizing the protein concentration peak in vivo and affording a reparative microenvironment with an adequate angiogenic ability at the wound site. Meanwhile, PR1P-recruited VEGF-induced macrophage reprogramming towards M2-like phenotypes further conferred immunomodulatory functions to the bandages. These dual functions of proangiogenesis and immunomodulation formed a cascade amplification, which regulated matrix metalloproteinases (MMP-9) as well as inflammatory factors (nuclear factor (NF)-κb, tumor necrosis factor (TNF)-α) in the wound microenvironment via the VEGF/macrophages/microenvironment axis. Consequently, the bandages realized multifunctional regeneration in splinted excisional wounds in rats, with or without diabetes, affording a higher skin appendage neogenesis, sensory function, and collagen remodeling. Conclusively, our approach encompassing in situ recruitment of VEGF at the injury site with the capability to promote immunomodulation-mediated tissue repair affords a promising avenue for scarless wound regeneration, which may also have implications for other tissue engineering disciplines.

Graphical Abstract

References

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Funding

National Natural Science Foundation of China(NSFC32050410286); Science and Technology Innovation Plan Of Shanghai Science and Technology Commission(No.20DZ2253700); Japan Society for the Promotion of Science(JP21F21353); Sino German Science Foundation Research Exchange Center(M-0263); Science and Technology Commission of Shanghai Municipality (20DZ2254900)