ABSTRACT Vaginal defects resulting from surgical resection, congenital anomalies, or pelvic exenteration significantly impair reproductive functions and sexual health. Reconstructive surgery for full‐thickness vaginal defects remains challenging by fibrotic scarring and inadequate restoration of native tissue architecture. To address this, we engineered a novel recombinant fusion peptide linking a collagen‐binding domain (CBD, heptapeptide TKKTLRT) to human β‐defensin‐3 (hBD‐3) using E. coli Origami (DE3). Recombinant CBD‐hBD‐3 promoted fibroblast proliferation and upregulated the expression of pro‐angiogenic genes, while suppressing macrophage polarization toward a pro‐inflammatory phenotype. Then, we fabricated CBD‐hBD‐3‐functionalized collagen scaffolds (hCM) that enabled sustained local release of the peptide. In a rat model of full‐thickness vaginal injury, hCM implantation significantly accelerated re‐epithelialization, supported smooth muscle regeneration, enhanced vascularization, and attenuated fibrotic remodeling by reducing disorganized collagen deposition. Notably, hCM promoted epithelial repair through an EMT‐associated process without inducing fibrosis, a balance that may be attributed to the concomitant upregulation of endogenous TGF‐β inhibitors. In addition, CBD‐hBD‐3 competitively bound CD36 to disrupt the pro‐fibrotic thrombospondin‐1(TSP‐1)‐CD36‐TGF‐β axis, preventing fibroblast transition into an inflammatory phenotype. This work presents a multifunctional yet simple biomaterial strategy that actively reprograms fibroblast fate and disrupts core fibrotic pathways, offering a promising therapeutic collagen‐based platform for scar‐reduced tissue defect regeneration.
Li et al. (Fri,) studied this question.