Application of Temporally Controlled Release Systems in Periodontal Tissue Regeneration: From Material Design to...

Periodontitis, a chronic inflammatory disease driven by plaque biofilm, is a leading cause of tooth loss in adults worldwide. Effective treatment requires not only infection and inflammation control but, more critically, functional regeneration of the periodontal ligament, cementum, and alveolar bone. Periodontal regeneration, however, is a highly ordered, multi-stage biological cascade involving temporally coordinated phases of blood clot formation, inflammatory regulation, tissue formation, and remodeling. Conventional single-drug or mixed-delivery strategies cannot distinguish the distinct demands of each healing phase and fail to replicate this natural rhythm. Sequential controlled-release systems address this gap by delivering multiple bioactive agents (antimicrobials, immunomodulators, and growth factors) in a programmed order tailored to the healing cascade, enabling precise modulation of the periodontal microenvironment and orderly tissue regeneration. This review systematically summarizes advances in these systems, classifying material platforms into four categories: (1) diffusion-barrier and degradation-kinetics systems, including multilayer films, core-shell fibers, porous microspheres, and microneedle arrays; (2) stimuli-responsive systems triggered by pH, matrix metalloproteinases, reactive oxygen species, or exogenous physical stimuli; (3) cell and extracellular vesicle-based systems exploiting the inflammatory tropism of M2 macrophage-derived exosomes for targeted immune reprogramming; and (4) asymmetric structural designs achieving spatiotemporal coordination of physical and biochemical signals through hierarchical architectures. These systems follow an anti-infection/anti-inflammation first, osteogenesis later therapeutic logic, circumventing temporal antagonism among bioactive factors. However, significant challenges hinder clinical translation, including individualized prediction of release kinetics, long-term biocompatibility of carrier materials, material retention under dynamic oral conditions, translational limitations of animal models, and precise regulation of complex factor networks. Future progress will likely depend on multi-responsive and logic-gated systems, deeper integration of biotechnology and immunomodulation, personalized precision medicine, AI-driven material design, and robust clinical translational research.