Integrating Cells, Biomaterials, and Advanced Engineering for Next-Generation Peripheral Nerve Repair

BACKGROUND: Peripheral nerve injuries (PNIs) disrupt sensory and motor circuits, affecting millions worldwide and often resulting in lasting functional deficits. Autologous nerve grafting remains the surgical benchmark for segmental defects, yet limited graft length, donor site morbidity, and inconsistent outcomes - particularly in long (>30 mm) or proximal lesions - underscore the need for engineered alternatives. Although parallel strategies seek to enhance autograft outcomes (e.g., polyethylene glycol fusion, growth factor sleeves, post-repair electrical stimulation), this review focuses specifically on engineered replacements. Over the past decade, convergent advances in cell biology, biomaterials science, and biofabrication have produced tissue-engineered conduits intended to serve as effective alternatives to autografts. Unlike previous reviews that address these domains separately, this work treats cells, biomaterials, and advanced engineering as a unified design problem, benchmarking outcomes with standardized quantitative metrics across both short-gap rodent and long-gap large-animal models and articulating specific design-readiness targets as a translational framework. SUMMARY: This review synthesizes the past decade (2015-2025) of progress, identified through a structured narrative search of PubMed, Google Scholar, Web of Science, and Scopus (160 articles included), in three domains: (1) cell-based therapies, including Schwann cells, mesenchymal stem cells, induced pluripotent stem cell (iPSC)-derived glia, neural stem/progenitor cells, and olfactory ensheathing cells (OECs), emphasizing their roles in neurotrophic support, immunomodulation, and remyelination; (2) biomaterial scaffolds, spanning natural polymers, synthetic polymers, and hybrid composites, with design parameters tailored to mimic native nerve microarchitecture and degradation timelines; and (3) integrated strategies that couple living cells with architecturally and biochemically instructive scaffolds, including pre-seeded conduits, injectable hydrogel systems, conductive/electroactive designs, and three-dimensional bioprinted constructs. Functional outcomes are evaluated across short-gap (≤15 mm) rodent and long-gap (≥30 mm) large-animal models using motor metrics (Sciatic Functional Index [SFI], compound muscle action potential, nerve conduction velocity) and, where reported, sensory assessments (von Frey thresholds, two-point discrimination), enabling cross-study benchmarking against quantitative scaffold design-readiness criteria. KEY MESSAGES: Well-designed, cell-seeded conduits consistently achieve ≥85% of motor functional recovery compared to autografts in rodent models of ≤15 mm nerve gaps, with certain platforms nearing equivalence in 20-30 mm defects in large animals; sensory recovery, though less frequently reported, shows parallel trends in studies employing standardized sensory testing. Persistent barriers - including rapid vascularization of long grafts, acidic degradation by-products from synthetic polyesters, mitigation of fibrotic by-products, donor-to-donor cell variability, and scalable good manufacturing practice-compliant manufacturing of combination products - remain central to translation. Clinical translation is promising for cell-seeded biodegradable conduits in digital nerve repairs (≤30 mm gaps), with future prospects for obstetric brachial plexus injuries and longer term horizons for iPSC-based, patient-specific grafts. A next-generation framework integrating optimized biomaterials, function-tuned cells, and advanced fabrication - guided by the quantitative design criteria codified here - will enable predictable, high-quality repair of complex PNIs.