Eggshell-Templated Mn-Doped Hydroxyapatite Composite Scaffold: Coupling ROS Scavenging with Piezo1 Activation for Bone Regeneration

Abstract The treatment of critical-sized bone defects remains challenging due to immune microenvironment dysregulation characterized by excessive ROS, persistent inflammation, and apoptosis, which impede tissue regeneration. Conventional biomaterials often overlook the unique structure and composition of natural materials. Here, we utilize waste eggshells not only as a cheap calcium source but also as a biogenic template providing a hierarchical porous structure and natural trace elements. Based on this template, we synthesize manganese-doped eggshell-derived hydroxyapatite (Mn-EHA) and construct a biodegradable porous composite scaffold (PHMs) from polycaprolactone and Mn-EHA. The scaffold enables sustained Mn2+ release, effectively scavenging endogenous ROS, remodeling the redox microenvironment, and inducing macrophage polarization toward an anti-inflammatory phenotype. Meanwhile, Mn-EHA nanoparticles enhance mechanical properties and provide local mechanical stimulation, activating the mechanosensitive Piezo1 channel and triggering Ca2+ influx to upregulate osteogenic signaling. In a rat calvarial defect model, PHMs alleviate inflammation and promote angiogenesis and new bone formation. Collectively, this study establishes a biotemplate-doping synergy strategy that transforms waste eggshells into a high-performance biomaterial for treating inflammation-related bone defects.