Elastic porous microspheres combined with extracellular matrix hydrogel as injectable composites for the dual-release of bioactive factors to promote tissue regeneration

Abstract Injectable biomaterials have garnered increasing attention for their potential and beneficial applications in minimally invasive surgical procedures and tissue regeneration. Extracellular matrix (ECM) hydrogels and porous synthetic polymer microspheres can be prepared for injectable administration to achieve in situ tissue regeneration. However, the rapid degradation of ECM hydrogels and the poor injectability and biological inertness of most polymeric microspheres limit their pro-regenerative capabilities. Here, we developed a biomaterial system consisting of elastic porous poly(l-lactide-co-ε-caprolactone) (PLCL) microspheres mixed with ECM hydrogels as injectable composites with interleukin-4 (IL-4) and insulin-like growth factor-1 (IGF-1) dual-release functionality. The developed multifunctional composites had favorable injectability and biocompatibility, and regulated the behavior of macrophages and myogenic cells following injection into muscle tissue. The elicited promotive effects on tissue regeneration were evidenced by enhanced neomusle formation, vascularization, and neuralization at 2-months post-implantation in a rat model of volumetric muscle loss. Our developed system provides a promising strategy for engineering bioactive injectable composites that demonstrates desirable properties for clinical use and holds translational potential for application as a minimally invasive and pro-regenerative implant material in multiple types of surgical procedures.