Biomaterial-based strategies for neural modulation in innervated bone regeneration

The nervous system plays a pivotal role in regulating skeletal homeostasis and bone regeneration. However, neural modulation and innervation reconstruction during bone healing have long been underestimated in conventional bone repair strategies. The emerging concept of neuro-bone tissue engineering has therefore gained increasing attention, highlighting nerve-coordinated approaches to bone regeneration. Such materials deliver bioactive cues and provide physical signals to simultaneously promote neural network reconstruction and bone formation, eventually leading to innervated bone regeneration. This review outlines the fundamental mechanisms underlying neural regulation in bone regeneration and focuses on recent advances in biomaterial-based strategies that integrate neural and skeletal repair. Furthermore, current challenges, including issues related to clinical translation, are critically discussed, and future directions for neuromodulatory biomaterial design are proposed. Collectively, these insights offer a rational roadmap for advancing next-generation neuromodulatory strategies in functional bone regeneration and promoting progress in regenerative medicine. STATEMENT OF SIGNIFICANCE: Growing evidence has highlighted neural modulation as a pivotal regulator of bone regenerative outcomes; however, the reconstruction of functional nerve networks remains largely overlooked in many bone tissue engineering approaches. This review synthesizes recent advances in biomaterial-based strategies for innervated bone regeneration. These approaches harness neural signaling to support nerve network reconstruction and functional coordination for promoting bone repair. Furthermore, current challenges, emerging opportunities and translational considerations are critically discussed, offering in-depth perspectives to inform the development of next-generation biomaterials for neuro-bone tissue engineering and advance regenerative medicine.