Engineering the Future of Restorative Clinical Peripheral Nerve Surgery.

Peripheral nerve injury is a significant clinical challenge, often leading to permanent functional deficits. Standard interventions, such as autologous nerve grafts or distal nerve transfers, require sacrificing healthy nerve tissue and typically result in limited motor or sensory recovery. Nerve regeneration is complex and influenced by several factors: 1) the regenerative capacity of proximal neurons, 2) the ability of axons and support cells to bridge the injury, 3) the capacity of Schwann cells to maintain a supportive environment, and 4) the readiness of target muscles or sensory organs for reinnervation. Emerging bioengineering solutions, including biomaterials, drug delivery systems, fusogens, electrical stimulation devices, and tissue-engineered products, aim to address these challenges. Effective translation of these therapies requires a deep understanding of the physiology and pathology of nerve injury. This article proposes a comprehensive framework for developing restorative strategies that address all four major physiological responses in nerve repair. By implementing this framework, we envision a paradigm shift that could potentially enable full functional recovery for patients, where current approaches offer minimal hope.