Extracellular Matrix-Mimicking Dual-Network Hydrogel With Microenvironment Remodeling to Enhance Vascularized Skeletal Muscle Regeneration Following Volumetric Muscle Loss

Background: Volumetric muscle loss (VML) significantly impairs the inherent regenerative ability of skeletal muscle, causing dysfunction and scar tissue formation. Current treatments are limited to functional muscle transplantation, posing many complications and incomplete functional recovery. Methods: To simulate the extracellular matrix microenvironment and promote vascularized muscle regeneration, we developed a bioactive composite hydrogel with the angiogenic and myogenic effect of strontium ions (Sr2+) and collagen type I (COL I), polyvinyl alcohol (PVA)/tannic acid (TA)/COL I/Sr2+ (PTCS). The physical properties of PTCS were characterized, including the mechanical properties, degradation, and release behavior. The in vitro influences of PTCS on C2C12 myoblasts and human umbilical vein endothelial cells (HUVECs) were evaluated via Cell Counting Kit-8, Live/Dead staining, wound healing, myotube differentiation, and Transwell assays. In addition, PTCS was implanted in the rat VML model and assessed for its effect on muscle regeneration in vivo. Results: The modulus of PTCS was similar to that of native rat muscle, and the degradation matched the muscle regeneration timeline. Controlled release of Sr2+ and COL I created a favorable microenvironment for vascular and muscular regeneration. PTCS facilitated the proliferation, migration, and differentiation of C2C12 myoblasts and enhanced the migration and invasion of HUVECs. Furthermore, the therapeutic effects of PTCS in vivo demonstrated a promoted vascular-specific marker CD31 expression, muscle fibers regeneration, and a decreased fibrosis area. Conclusions: These findings demonstrated that PTCS was a promising implantable biomimetic scaffold in skeletal muscle tissue engineering, and Sr2+ had a synergistic effect with COL I in muscle regeneration.