Advances in the repair of segmental nerve injuries and trends in reconstruction

Abstract

Despite advances in surgery, the reconstruction of segmental nerve injuries continues to pose challenges. In this review, current neurobiology regarding regeneration across a nerve defect is discussed in detail. Recent findings include the complex roles of nonneuronal cells in nerve defect regeneration, such as the role of the innate immune system in angiogenesis and how Schwann cells migrate within the defect. Clinically, the repair of nerve defects is still best served by using nerve autografts with the exception of small, noncritical sensory nerve defects, which can be repaired using autograft alternatives, such as processed or acellular nerve allografts. Given current clinical limits for when alternatives can be used, advanced solutions to repair nerve defects demonstrated in animals are highlighted. These highlights include alternatives designed with novel topology and materials, delivery of drugs specifically known to accelerate axon growth, and greater attention to the role of the immune system. K E Y W O R D S acellular nerve allograft, autograft, nerve gap, nerve guidance conduit, peripheral nerve 2 | BIOLOGY OF NERVE REGENERATION ACROSS A DEFECT Peripheral nerve is capable of robust regeneration following injury. The molecular and cellular mechanisms have primarily been studied in rodent models. Following injury, neurons and their axons and the nonneuronal cellular environment distal to the injury undergo immediate morphological and molecular changes. Within the axon, there is a rapid influx of ions, principally calcium, as well as a disruption of transport proteins signaling a disruption to homeostasis with its end-organ. This multifactorial injury response from axon damage is rapidly transported to the neuron cell Abbreviations: ANA, acellular nerve allograft; ECM, extracellular matrix; FDA, Food and Drug Administration; FK506, tacrolimus; GDNF, glial cell line-derived neurotrophic factor; GFRα1, glial cell line-derived neurotrophic factor family receptor alpha-1; MRC, Medical Research

Perspective on Schwann Cells Derived from Induced Pluripotent Stem Cells in Peripheral Nerve Tissue Engineering

“…Within the peripheral nerve injury environment are a multitude of intercellular interactions, many of which center around the repair SCs and are essential for axonal regeneration. Repair SCs not only interact closely with the regenerating axon but also with macrophages, neutrophils, endothelial cells, and fibroblasts in and around the nerve bridge [ 10 ]. Interaction takes place through direct contact or indirectly through neurotrophic factor and cytokine release.…”

Restoration of Neurological Function Following Peripheral Nerve Trauma

“…Although the distance across which allografts and conduits induce axon regeneration can be increased by modifying them in various ways, none of those techniques can be used clinically. Therefore, despite their limitations, sensory nerve grafts remain the clinical "gold standard" for repairing peripheral nerves [69,70,166,[220][221][222][223]. The recovery of function across a 12-cm-long nerve gap of a 58-year-old patient, repaired 3.25 years post-trauma, suggests that functional recovery can be established, even when the values of all three injury parameters far exceed those where autografts are effective.…”

“…Axon regeneration is extensive through conduits composed of fibrin [145,153], hydrogel tubes [154], alginate/chitosan polyelectrolyte [155][156][157], poly epsilon-caprolactone [158,159], polyglycolic acid [160], poly(lactic-co-glycolic acid) or silk-based [161][162][163][164]. Conduits composed of decellularized human umbilical artery [165] and muscles [166] are also effective in promoting axon regeneration across nerve gaps.…”

The Role of the IL-4 Signaling Pathway in Traumatic Nerve Injuries

“…6 These suboptimal surgical outcomes are due to factors that limit nerve regeneration: neuronal death following injury, a decreased capacity for neurons to regenerate axons over time, the slow growth of regenerating axons compounded with long distances between lesion site and target, misdirected axonal regrowth to targets, and potentially irreversible chronic denervation-induced muscle atrophy. 7-10 Thus, there is a great need to develop therapies that will enhance nerve regeneration and improve functional recovery following PNI.…”