Femke Mathot

General introduction 17 1 NERVE RECONSTRUCTION OPTIONS & SHORTCOMINGS The described process occurs in the first days to weeks after peripheral nerve injury. With a regeneration speed of 1-3mm per day, axon regeneration in proximal nerve injuries can take up to months before the target muscle is reached. 36, 37 The critical time frame for nerve regeneration to occur is 12-18 months after the nerve injury. 38 Delayed regeneration leads to worse or absent functional outcomes, which is attributed to 1) degeneration of synaptic acetylcholine receptors which leads to less receptiveness of muscle fibers for reinnervation, 2) difficulty to recover from muscle denervation atrophy that increases as denervation time extends 39 and 3) deterioration of the endoneurial tubes in the distal nerve stumps, leading to less guidance and less axons that successfully reach the denervated muscle fibers. 40, 41 Maximal nerve regeneration efficiency/speed should be pursued to obtain maximal functional outcomes. Spontaneous successful reinnervation after a peripheral nerve injury depends on the severity of nerve injury, representing the degree of internal disorganization. Neuropraxia, axonotmesis and incomplete nerve lesions have good prospects for axon regeneration when treated conservatively. 38 More extensive lesions or complete transections most often do not spontaneously lead to acceptable outcomes. Therefore, spontaneous nerve regeneration is sometimes awaited in closed, blunt trauma cases, while sharp transection nerve injuries are preferably surgically restored within 72 hours. 38, 42 The severity of the nerve injury, the time elapsed since the injury and the distance between the proximal nerve stump and the target muscle should all be considered when deciding to operate on a peripheral nerve injury. Direct coaptation of both nerve ends by suturing the epineurium is the preferred surgical restoration technique, but only if this can be obtained in a tension-free manner. When this condition cannot be met, one can use nerve grafts (autologous or allogenous) or conduits (natural or synthetic) to bridge the nerve gap. Autografts Nerve autografts are currently used as the gold standard in peripheral nerve repair. 43 They are readily available, provide Schwann Cells and other important neurotrophic factors, contain the desired ultrastructure to guide regenerating axons and are immunologically inert. Unfortunately, autografts require the sacrifice of autologous nerves which are limited available and can result in donor side morbidity like loss of sensation or painful neuroma formation. 44, 45 Especially in big nerve branch injuries or multiple injured nerves, autograft sources fall short to restore all defects, emphasizing the need for autograft substitutes that result in equal functional outcomes. Allografts Efforts to replace the role of autografts have led to the development of allogenous nerve grafts, currently the second-best option in cases with extensive peripheral nerve injuries. 46, 47 To eliminate immune rejection of the allograft, techniques to decellularize the donor nerves have been studied. This decellularization process leads to the loss of Schwann cells