Enhancing peripheral nerve regeneration with rehabilitation and biomaterial-driven drug delivery strategies

Peripheral nerve injury (PNI) is a common problem worldwide. PNI can lead to loss of sensory and motor functions, chronic neuropathic pain, and mental health issues, significantly impacting the patients' quality of life. Recent studies revealed that, beyond the topical injury site at peripheral nerves, PNIs can also induce dysfunctions in the central nervous system by causing maladaptive plasticity, which will result in exaggeration and exacerbation of the pathological condition caused by the primary injuries. The typical therapy strategies for traumatic PNI treatment are using sutures, nerve autografts, or conduits in cases requiring surgical intervention as well as applying physical-based rehabilitation to facilitate functional recovery. However, the functional restoration is generally unsatisfactory due to insufficient regeneration and long-lasting maladaptive neuroplasticity in the nervous system. In this review, we summarized various neurotrophic factors and neuroprotective agents that have been extensively studied as adjuvant therapies to enhance recovery efficiency after PNIs in the last two decades. Particularly, with the rapid development of biomaterials and bioengineering, controllable drug delivery techniques have shown great potential to maintain the drug bioactivity and, consequently, prolonging the therapeutic effects. Additionally, we explored the virus-based gene delivery technique, which has been used to transduce neural cells for enhancing nerve regeneration. Finally, we discussed current challenges, including inadequate motor function restoration, poorly defined rehabilitation protocols, unresolved chronic inflammation, and limited understanding of macrophage dynamics. We also offered perspectives on integrating various approaches to develop effective and comprehensive treatment strategies for PNIs.