Multifunctional copper phosphate-modified carbonate apatite honeycomb plug-in scaffolds for preventive tissue regeneration of medication-related osteonecrosis of the jaw

Medication-related osteonecrosis of the jaw (MRONJ) remains a serious complication in patients receiving antiresorptive agents. MRONJ prevention measures rely on procedural caution and prophylactic antibiotics but fail to address multifactorial pathogenesis, including impaired angiogenesis, infection, and delayed tissue repair. In this study, we developed a multifunctional scaffold to promote concurrent regeneration of soft and hard oral tissues and prevent MRONJ onset. The material consisted of a carbonate apatite (CAp) base for osteoconductivity and bioresorbability and featured a honeycomb (HC) structure to enhance tissue ingrowth. Its surface was modified with copper phosphate (CuP) for rapid antibacterial and proangiogenic functionality. Additionally, the cylindrical plug-in geometry enabled easy insertion into the extraction sockets with positional stability and mechanical support for gingival and alveolar bone healing. In vitro, Cu-modified CAp HC (CuP/CAp HC) plugs with 340 ppm Cu exhibited complete bactericidal effect against methicillin-resistant staphylococcus aureus and oral streptococci while maintaining the viability of human mesenchymal stem cells (hMSCs) and endothelial cells (HUVECs). The plugs also enhanced the osteogenic differentiation and mineralization of hMSCs and promoted growth and NO production in HUVECs. In vivo, conventional CAp granules and CAp HC plugs induced the hallmark MRONJ lesions, whereas CuP/CAp HC plugs suppressed these pathologies and promoted bone regeneration and gingival closure. Thus, the CuP/CAp HC plugs enable MRONJ prevention and oral tissue regeneration that are unattainable with conventional materials. This study underscores the therapeutic potential of a structurally and functionally engineered biomaterial for addressing the complex pathophysiology of MRONJ. • Biomaterial to address causes of medication-related osteonecrosis of the jaw (MRONJ). • Use of osteoconductive and bioresorbable carbonate apatite as base material • Antibacterial and angiogenic functions conferred by copper phosphate modification. • Soft and hard tissue regeneration promoted by honeycomb structure and plug-in form. • In vivo regeneration of bone and gingiva with MRONJ prevention