Bridging the gap: Extracellular matrix-based strategies for peripheral nerve regeneration and neuropathic pain management.

Peripheral neuropathic pain, arising from peripheral nerve injuries, remains a significant clinical challenge because of complex pathophysiology and limited treatment options. Conventional treatments primarily provide symptomatic relief, failing to address underlying nerve damage. The extracellular matrix (ECM) plays a vital role in nerve regeneration by offering structural support and biochemical signals that regulate Schwann cell behaviour, axonal growth and microenvironment remodelling. This review critically examines ECM-based scaffold strategies, focussing on natural proteins such as collagen, laminin and fibronectin and their role in promoting functional nerve recovery. In addition, the role of emerging molecular regulators, including Piezo1 mechanosensitive channels and nuclear transport proteins, is examined for their ability to mediate mechanotransduction and gene regulatory mechanisms critical for nerve regeneration and pain modulation. By integrating biomaterial engineering, mechanical signalling pathways and gene-targeted strategies, this review outlines promising regenerative approaches aimed at restoring nerve function and alleviating chronic pain. These insights may guide the development of next-generation therapies for peripheral nerve repair.