Engineering an Injectable Scaffold with Enhanced ECM Mimicry for Cell Delivery and Tissue Regeneration

The development of biomimetic scaffolds that emulate the extracellular matrix (ECM) is critical for advancing cell-based therapies and tissue regeneration. This study reports the formulation of CHyCoGel, a novel injectable, ECM-mimetic hydrogel scaffold composed of chitosan, hyaluronic acid, chondroitin sulfate, and an amphiphilic stabilizer. CHyCoGel addresses key limitations of existing scaffolds, offering improved structural uniformity, injectability, and <i>in situ</i> gelation suitable for cell encapsulation and minimally invasive delivery. Primary dermal fibroblasts (PDFs) isolated from neonatal rat skin were grafted into CHyCoGel, which supported high cell viability, well-organized cytoskeletal structures, and modulation of genes involved in tissue remodeling, including α-SMA, fibronectin, Col1A1, and TGF-β. <i>In vivo</i> application of PDF-loaded CHyCoGel significantly enhanced wound healing, epithelialization, and the regeneration of skin appendages. Notably, CHyCoGel promoted angiogenesis by upregulating VEGF and facilitated balanced ECM remodeling through enhanced type I collagen expression with reduced total collagen accumulation. These findings highlight CHyCoGel's potential as a cytocompatible, bioactive scaffold capable of directing reparative cellular behavior and promoting structurally and functionally integrated tissue regeneration, particularly in chronic and complex wound settings.