Lithium as a neuroregenerative modulator in peripheral nerve repair: Mechanistic insights and bioengineered delivery strategies: A systematic review

Abstract

nbsp;Introduction: Peripheral nerve injuries (PNIs) remain a major clinical challenge with limited functional recovery despite advances in microsurgery. Lithium has emerged as a neuroactive agent with effects on neuronal survival, Schwann cell function, axonal regeneration, and remyelination. This review evaluates evidence on Lithium in peripheral nerve regeneration, focusing on bioengineered delivery approaches. Methods: A PRISMA-guided systematic review was performed using PubMed, Scopus, and Web of Science up to April 2026. Studies addressing Lithium in peripheral nerve regeneration, Schwann cell biology, neuroprotection, remyelination, and biomaterial-based delivery systems were included. Data were synthesized qualitatively with emphasis on experimental and translational findings. Results: Preclinical studies suggest Lithium enhances peripheral nerve regeneration via modulation of glycogen synthase kinase-3β (GSK-3β), activation of pro-survival pathways, autophagy induction, and effects on Schwann cell proliferation and myelination. Most evidence comes from in vitro and animal models, showing improved axonal regrowth, remyelination, and functional recovery. Some supporting data derive from central nervous system models and were interpreted with caution due to inherent differences in regenerative capacity between the central and peripheral nervous systems. Newer studies indicate that Lithium-loaded biomaterials, including hydrogels, nerve conduits, adhesive polymers, and nanostructured systems, may enable localized delivery with reduced systemic toxicity. Conclusions: Lithium appears to be a promising adjunct in peripheral nerve repair, especially when delivered through bioengineered local systems. However, current evidence is largely preclinical, and translation is limited by a narrow therapeutic window and systemic toxicity. Further studies are needed to clarify safety and clinical applicability.