Programmable hydrogel matrices for oral and maxillofacial organoids: Engineering mechanobiological and biochemical niches to reverse tissue senescence

Jinling Liu, Xiao Wang, Wenting Lu, Tanjun Deng, Shuaiting Wu, Ao Zheng, Hao Shi, Lingyan Cao

Age-related degeneration of oral and maxillofacial tissues, associated with extracellular matrix sclerosis and the senescence-associated secretory phenotype (SASP), poses an escalating challenge in the context of global population aging. Conventional static biomaterials and two-dimensional in vitro culture systems cannot adequately recapitulate this dynamic pathological microenvironment, and animal models are limited by interspecies differences that hinder translational fidelity. Organoid technology can recapitulate key aspects of tissue-specific architecture, cellular heterogeneity, and functional organization, thereby providing physiologically relevant three-dimensional models for aging research and regenerative medicine. These models not only enable disease modeling and pathogenesis studies to investigate senescence mechanisms that are difficult to resolve in conventional in vivo models and support high-throughput screening of anti-aging compounds, but also provide a basis for organoid transplantation in functional tissue regeneration. As an emerging and promising regenerative strategy, organoid-based therapy therefore offers new opportunities for reconstructing aging oral and maxillofacial tissues. However, its clinical potential remains constrained by the lack of programmable matrices capable of dynamically mitigating key features of the senescent microenvironment. This review examines the emergence of programmable hydrogels as tunable active matrices for oral and maxillofacial organoid engineering within senescent microenvironments. We analyze material-based strategies for modulating senescence-associated phenotypes, including mechanobiological approaches, such as tunable stress relaxation to attenuate pathological mechanical memory, and biochemical interventions that target reactive oxygen species via nanozyme catalysis and modulate SASP signaling through spatiotemporal delivery control. We further evaluate the application of these matrices for lineage-specific tissue reconstruction across the dentin–pulp complex, periodontal tissue, temporomandibular joint, salivary gland, and mucosal barrier. Finally, we discuss how integrating spatiotemporal multi-omics, microfluidic organ-on-a-chip platforms, and artificial intelligence-assisted bioprinting may advance organoid engineering, while highlighting key translational barriers related to neurovascularization, safety, standardized manufacturing, and regulatory compliance.