Hydrogel-based nerve conduit systems with integrated therapeutic cargo and controlled delivery strategies for peripheral nerve regeneration: a systematic preclinical review

Peripheral nerve injuries (PNIs) with nerve gaps remain a major clinical challenge. Although autologous nerve grafting is considered the gold standard for repair, its use is limited by donor-site morbidity and limited graft availability. Recent advances in tissue engineering have led to the development of hydrogel-based nerve conduits that better mimic the natural environment for nerve regeneration. To systematically review preclinical studies using hydrogels, biologic therapies, and delivery systems for peripheral nerve repair, and evaluate their effects on nerve regeneration and functional recovery compared with autografts. A systematic search of PubMed, Web of Science, and Embase was conducted through March 2026 in accordance with PRISMA guidelines. Studies were included if they used hydrogel-based systems incorporating therapeutic agents and engineered delivery strategies in rat sciatic nerve defect models (10–15 mm) with an autograft comparator. Fourteen studies met the inclusion criteria and were analyzed qualitatively . Included studies demonstrated a consistent trend toward improved functional, electrophysiological, and histological outcomes with advanced hydrogel systems. Growth factor–based therapies were most common, often delivered via controlled, carrier-assisted, or stimuli-responsive mechanisms. Functional recovery, assessed primarily by sciatic functional index, improved substantially across studies and frequently approached autograft performance. Conductive and stimuli-responsive hydrogels further enhanced regeneration by integrating bioelectrical and dynamic release mechanisms. Multimodal delivery systems combining multiple strategies showed the most robust outcomes. Despite this, complete equivalence to autografts was not universally achieved. Notably, non-hydrogel approaches leveraging structural and electroactive design also demonstrated comparable regenerative potential. Combining hydrogel scaffolds with therapeutic biologics and controlled delivery systems may improve peripheral nerve regeneration and functional recovery in preclinical studies. While these approaches enhance outcomes and may approach the performance of autografts, further optimization and translational validation are required.