Neuro-bone tissue engineering: Multiple potential translational strategies between nerve and bone

Numerous tissue regeneration paradigms show evident neurological dependence, including mammalian fingertip, skin, and bone regeneration. The mature skeleton is innervated by an abundant nervous system that infiltrates the developing axial and appendicular bones and maintains the stability of the systemic skeletal system by controlling blood flow, regulating bone metabolism, secreting neurotransmitters, and regulating stem cell behavior. In recent years, neurotization in tissue-engineered bone has been considered as a promising strategy to effectively overcome the challenge of vascularization and innervation regeneration in the central zone of "critical-sized bone defects" that conventional tissue-engineered scaffolds are unable to handle, however, further validation is needed in relevant clinical applications. Therefore, this study reviews the mechanisms by which the nervous system regulates bone metabolism and regeneration through a variety of neurogenic or non-neurogenic factors, as well as the recent progress and design strategies of neuralized tissue-engineered bone, to provide new ideas for further studies on subsequent neural bone tissue engineering. STATEMENT OF SIGNIFICANCE: The interaction of nerve and bone tissue during skeletal development and repair has attracted widespread attention, with emerging evidences highlighting the regulation of bone metabolism and regeneration by the nervous system, but the underlying mechanisms have not been elucidated. Thus, further applications of neuro-bone tissue engineering still needs careful consideration. In this review, we summarize the numerous neurogenic and non-neurogenic factors which are involved in bone repair and regeneration, and further explore the current status of their application and biomaterial design in neuro-bone tissue engineering, and finally discuss the challenge and prospective for neuro-bone tissue engineering to facilitate its further development.