Abstract
Cranio-maxillofacial bone defects resulting from trauma, tumors, infection, or congenital malformations not only severely impair patients' physiological functions, but also impose a profound psychological burden, constituting a major public health issue that affects overall health and quality of life. Conventional reconstructive approaches, including autologous grafting and allogeneic implantation, can partially restore tissue morphology; however, limitations, such as donor-site morbidity, immune rejection, and long-term resorption prevent the achievement of true biological functional reconstruction. These challenges are particularly pronounced in the repair of complex and large-scale bone defects. The underlying cause lies in the insufficient understanding of the complex cellular behaviors, signaling networks, and material-host interactions involved in bone regeneration, which hampers precise regulation of the repair process. Therefore, the development of new theories, technologies, and materials grounded in mechanistic insights has become a key strategic direction in cranio-maxillofacial bone regeneration research. Supported by the National Natural Science Foundation of China, the Beijing Natural Science Foundation, and National and Provincial Major Talent Programs, our research group has addressed critical clinical challenges in cranio-maxillofacial bone defect repair by proposing an innovative concept of "regulating cell fate, designing intelligent biomaterials, and achieving functional reconstruction". Centered on this key scientific question, we have systematically carried out a full-chain research strategy spanning "fundamental theory-technological breakthroughs-product translation", overcoming multiple bottlenecks and achieving a series of original outcomes. (1) At the level of fundamental theory, we elucidated the epigenetic and ubiquitination regulatory networks governing skeletal stem cell fate determination, and precisely defined functional stem cell subpopulations using single-cell technologies. We also pioneered apoptotic vesicles as a new paradigm for cell-free therapy and clarified their functional diversity. (2) In terms of technological breakthroughs, we established 4D printing technologies with dynamically tunable morphology and function, developed metal surface engineering strategies that integrate controllable degradation with biofunctional regulation, and built artificial intelligence-driven intelligent design and manufacturing platforms. (3) Regarding translational applications, we developed a series of apoptotic vesicle-based biotherapeutics, smart responsive bone-repair scaffolds, and next-generation biofunctionalized biodegradable metal implants. Collectively, these achievements have advanced the fundamental theory of regenerative medicine, overcome key technological barriers, established new clinical strategies for cranio-maxillofacial tissue defect repair, and significantly enhanced core competitiveness in this field.