Biodegradable and electroactive cryogel microspheres for neurovascularized bone regeneration

Abstract

Bone regeneration is a complex and dynamic biological process involving vascularization, neurogenesis, and osteogenesis. Inspired by the piezoelectric properties of natural bone, this study develops an innovative dual-electroactive cryogel microsphere system that uniquely integrates conductive polymers, bioactive ion release, and piezoelectric materials to support neurovascularized bone regeneration. These injectable and biodegradable microspheres, composed of whitlockite, poly(3,4-ethylenedioxythiophene), and gelatin methacrylate, are designed to enhance electrical output and sustain bioactive ion release. In vitro analyses demonstrate that these dual-electroactive microspheres synergistically promote angiogenesis, lymphogenesis, neurogenesis, and osteogenesis by combining bioelectric and biochemical cues. Transcriptomic analysis highlights the activation of key signaling pathways, including MAPK-ERK1/2, PI3K-AKT, and HIF-1, underlying these regenerative processes. In vivo evaluations using a rat calvarial defect model confirm accelerated bone repair, with the microspheres recreating bioelectric microenvironments and facilitating bioactive ion delivery. This study presents a minimally invasive strategy for advancing bone tissue engineering and enhancing bone regeneration.