The Physiologic Basis of Molecular Therapeutics for Peripheral Nerve Injury: A Primer
2024; Elsevier BV; Volume: 6; Issue: 5 Linguagem: Inglês
10.1016/j.jhsg.2024.01.017
ISSN2589-5141
AutoresMarie C. Spezia, Christopher J. Dy, David M. Brogan,
Tópico(s)Tissue Engineering and Regenerative Medicine
ResumoPeripheral nerve injuries affect a significant number of patients who experience trauma affecting the hand and upper extremity. Improving unsatisfactory outcomes from repair of these injuries remains a clinical challenge despite advancements in microsurgical repair. Imperfections of the nerve regeneration process, including imprecise reinnervation, distal axon degradation, and muscular atrophy, complicate the repair process. However, the capacity for peripheral nerves to regenerate offers an avenue for therapeutic advancement. Regeneration is a temporally and spatially dynamic process coordinated by Schwann cells and neurons among other cell types. Neurotrophic factors are a primary means of controlling cell growth and differentiation in the repair setting. Sustained axon survival and regrowth and consequently functional outcomes of nerve repair in animal models are improved by the administration of neurotrophic factors, including glial cell-derived neurotrophic factor, nerve growth factor, sterile alpha and TIR motif containing 1, and erythropoietin. Targeted and sustained delivery of neurotrophic factors through gelatin-based nerve conduits, multiluminal conduits, and hydrogels have been shown to enhance the innate roles of these factors to promote expedient and accurate peripheral nerve regeneration in animal models. These delivery methods may help address the practical limitations to clinical use of neurotrophic factors, including systemic side effects and the need for carefully timed, precisely localized release schedules. In addition, tacrolimus has also improved peripheral nerve regrowth in animal models and has recently shown promise in addressing human disease. Ultimately, this realm of adjunct pharmacotherapies provides ample promise to improve patient outcomes and advance the field of peripheral nerve repair. Peripheral nerve injuries affect a significant number of patients who experience trauma affecting the hand and upper extremity. Improving unsatisfactory outcomes from repair of these injuries remains a clinical challenge despite advancements in microsurgical repair. Imperfections of the nerve regeneration process, including imprecise reinnervation, distal axon degradation, and muscular atrophy, complicate the repair process. However, the capacity for peripheral nerves to regenerate offers an avenue for therapeutic advancement. Regeneration is a temporally and spatially dynamic process coordinated by Schwann cells and neurons among other cell types. Neurotrophic factors are a primary means of controlling cell growth and differentiation in the repair setting. Sustained axon survival and regrowth and consequently functional outcomes of nerve repair in animal models are improved by the administration of neurotrophic factors, including glial cell-derived neurotrophic factor, nerve growth factor, sterile alpha and TIR motif containing 1, and erythropoietin. Targeted and sustained delivery of neurotrophic factors through gelatin-based nerve conduits, multiluminal conduits, and hydrogels have been shown to enhance the innate roles of these factors to promote expedient and accurate peripheral nerve regeneration in animal models. These delivery methods may help address the practical limitations to clinical use of neurotrophic factors, including systemic side effects and the need for carefully timed, precisely localized release schedules. In addition, tacrolimus has also improved peripheral nerve regrowth in animal models and has recently shown promise in addressing human disease. Ultimately, this realm of adjunct pharmacotherapies provides ample promise to improve patient outcomes and advance the field of peripheral nerve repair. Advancement in pharmacotherapeutics for hand and upper extremity peripheral nerve injury is critically needed. Approximately 2.3% of all patients with trauma to an extremity experience some form of peripheral nerve injury.1Padovano W.M. Dengler J. Patterson M.M. et al.Incidence of nerve injury after extremity trauma in the United States.Hand. 2022; 17: 615-623Google Scholar Especially in the realm of brachial plexus injuries and other peripheral nerve injuries nearer the ventral root, the slow rate of axonal regeneration can lead to poor outcomes even after prompt and technically proficient microsurgical nerve repair.2Karabeg R. Jakirlic M. Dujso V. Sensory recovery after forearm median and ulnar nerve grafting.Med Arh. 2009; 63: 97-99Google Scholar, 3Ruijs A.C.J. Jaquet J.B. Kalmijn S. Giele H. Hovius S.E.R. 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Skeletal muscle denervation: past, present and future.Int J Mol Sci. 2022; 23: 7489Google Scholar The hallmark difficulties of peripheral nerve repair can be thought of through the lens of three overarching tenants: a struggle to bridge gaps, a tendency for axonal growth along stray paths, and a failure to reconnect vital supply routes between the cell body and distal segment before axonal degeneration and muscle atrophy take hold, thwarting further recovery. Despite improvements in our understanding of nerve pathophysiology and advancements in surgical techniques, persistently poor clinical outcomes after nerve injury create an opportunity to capitalize on the regenerative process using adjunctive pharmacotherapies and molecular treatments. This review will focus on the role of neurotrophic factors and their application as novel therapeutics to promote axonal survival and growth, thereby improving clinical outcomes following peripheral nerve injuries. 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Transcriptional control of peripheral nerve regeneration.Mol Neurobiol. 2023; 60: 329-341Google Scholar Schwann cells are the major glial cell of the peripheral nervous system, a fact underscored by their central role in coordination of peripheral nerve regeneration. Following traumatic nerve injury, denervated SCs switch their phenotype from one dedicated to axonal myelination to one of regenerative capacity within the first 24 hours following injury.8Burnett M.G. Zager E.L. Pathophysiology of peripheral nerve injury: a brief review.Neurosurg Focus. 2004; 16: 1-7Google Scholar In doing so, SCs must first dedifferentiate from the myelinating phenotype and then redifferentiate to the repair phenotype through a series of biochemical and morphological changes that are dependent on the appropriate timing and intensity of neurotrophic factor release among other signals.13Kim H.A. Mindos T. Parkinson D.B. Plastic fantastic: Schwann cells and repair of the peripheral nervous system.Stem Cells Transl Med. 2013; 2: 553-557Google Scholar As part of this repair-focused phenotype, SCs induce demyelination of the damaged nerve and upregulate the expression of genes that promote and guide axonal growth and slow neuronal cell death.14Nocera G. Jacob C. Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury.Cellular and Molecular Life Sciences. 2020; 77: 3977-3989Google Scholar These proregenerative SCs also secret extracellular matrix (ECM) packed with progrowth neurotrophic factors along with cytokines and chemokines to recruit immune cells that also play a role in the regenerative process.12Zhang Y. Zhao Q. Chen Q. Xu L. Yi S. Transcriptional control of peripheral nerve regeneration.Mol Neurobiol. 2023; 60: 329-341Google Scholar Over time, however, growth inhibitory proteins will accumulate in the distal nerve segment, and SCs will lose their regenerative properties.15Ronchi G. Raimondo S. Chronically denervated distal nerve stump inhibits peripheral nerve regeneration.Neural Regen Res. 2017; 12: 739-740Google Scholar, 16Gomez-Sanchez J.A. Pilch K.S. van der Lans M. et al.After nerve injury, lineage tracing shows that myelin and remak Schwann cells elongate extensively and branch to form repair Schwann cells, which shorten radically on temyelination.J Neurosci. 2017; 37: 9086-9099Google Scholar, 17Eggers R. Tannemaat M.R. Ehlert E.M. Verhaagen J. A spatio-temporal analysis of motoneuron survival, axonal regeneration and neurotrophic factor expression after lumbar ventral root avulsion and implantation.Exp Neurol. 2010; 223: 207-220Google Scholar The ability to keep SCs in the repair phenotype sits at the center of therapeutic endeavors to promote the continued production of neurotrophic factors to improve axonal survival and directed outgrowth.18Jessen K.R. Arthur-Farraj P. Repair Schwann cell update: adaptive reprogramming, EMT, and stemness in regenerating nerves.Glia. 2019; 67: 421-437Google Scholar Key to this endeavor would be promoting a proregenerative phenotype across all denervated SCs equally, which makes viral vectors, namely adenoviral vectors, a promising future mode of administration of neurotrophic factors as a complement to surgical repair.19Chan K.Y. Jang M.J. Yoo B.B. et al.Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems.Nat Neurosci. 2017; 20: 1172-1179Google Scholar Neurotrophic factors are proteins released from SCs and other neuron-associated cells, like fibroblasts and macrophages, in the aftermath of peripheral nerve injury to promote neuron survival and function as well as drive the appropriate differentiation of SCs and macrophages.20Skaper S.D. Neurotrophic factors: an overview.Methods Mol Biol. 2018; 1727: 1-17Google Scholar,21Liu X. Duan X. Mechanisms and treatments of peripheral nerve injury.Ann Plast Surg. 2023; 91: 313-318Google Scholar Numerous specific neurotrophic factors or regulators have garnered attention as potential therapeutic targets in nerve regeneration. 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