Evolution of Biological Hydroxyapatite Modification Strategy: Anti-Inflammation Approach Rescues the Calcium-NOD-Like Receptor-Inflammation Axis-Mediated Periodontal Redevelopment Failure.

Abstract

Periodontal regenerative medicine is currently undergoing a paradigm shift from dissecting the healing process toward utilization of the developmental program. Biological hydroxyapatite (BHA), a major component of guided tissue regeneration, has long been optimized for inducing multidirectional differentiation of periodontal ligament cells (PDLCs). However, this approach runs counter to the redevelopment strategy. Thus, the conventional BHA should evolve to induce the redevelopment process of periodontal tissue. In this study, histopathological changes and immune microenvironment characteristics of the periodontal developmental process, natural healing process (Blank group), and BHA-mediated healing process (BHA group) were compared to evaluate the main manifestations of BHA-mediated periodontal "developmental engineering" outcome. Our results suggested that neither the Blank nor BHA group could recur key events in periodontal development. The implantation of BHA led to pro-inflammatory immune microenvironment and an unstable blood fibrin clot structure, which facilitated the invasion of outer gingival fibroblasts, consequently disrupting redevelopmental events. High-throughput chip technology was further used to explore the underlying mechanism of immune activation, revealing that the calcium-NOD-like receptor-inflammation axis signaling axis promoted the activation of pro-inflammatory immune response that contributed to redevelopment failure. An immunomodulatory cytokine interleukin 4 (IL4)-modified BHA was used to further validate the efficacy of developmental engineering strategy. IL4 could partially rescued the redevelopment failure through immunosuppression. This study presented an innovative strategy for the development of advanced periodontal regenerative materials and offered a potential approach for the application of development-inspired periodontal tissue engineering strategies. It represented a marked advancement in the development of regenerative medicine and propelled the clinical organ restoration forward.