Designing In-situ Gels for Periodontal Repair: A Review of Sustained Release Strategies, Advanced Manufacturing Approaches, and Bio-Fabrication.

Periodontitis is a chronic biofilm-mediated inflammatory disease that progressively destroys the gingiva, periodontal ligament, and alveolar bone. Although scaling and root planing remain the cornerstone of care, incomplete pocket access, rapid microbial recolonization, and the limited residence time of many conventional local formulations can reduce therapeutic effectiveness. The development of in-situ gelling drug delivery systems, administered as low-viscosity liquids that transform within periodontal pockets into mucoadhesive gels, improves retention, prolongs drug contact time, provides sustained site-specific release, and reduces systemic exposure. In this review, we summarize the rationale for localized therapy in the context of periodontal disease and outline the design space of periodontal in-situ gels. Additionally, thermosensitive, pHresponsive, ion-activated, solvent exchange, enzymatically crosslinked, photosensitive, and multi-responsive platforms are compared. The polymer selection and concentration govern injectability, gelation trigger and time, mechanical integrity, biodegradation, and diffusion-controlled release behavior, with commonly used matrices including chitosan, poloxamers, carbomers, sodium alginate, gellan gum, carrageenan, HPMC, and Eudragit-based systems. We highlight representative formulations delivering antimicrobials, antiseptics, and anti-inflammatory agents, as well as herbal extract-loaded gels. Key evaluation parameters relevant to periodontal pockets are also discussed, together with translational considerations reflected in patents, early clinical investigations, and marketed products. Future directions that integrate multifunctional responsiveness with regenerative cues, including growth factor- or cell-compatible gels and advanced manufacturing approaches such as 3D bioprinting and in-situ bio-fabrication, aimed at personalized periodontal tissue repair and durable control of inflammation are urgently needed.