Peripheral nerve regeneration: Experimental strategies and future perspectives

Abstract

Peripheral nerve injuries represent a substantial clinical problem with insufficient or unsatisfactory treatment options. This review summarises all the events occurring after nerve damage at the level of the cell body, the site of injury and the target organ. Various experimental strategies to improve neuronal survival, axonal regeneration and target reinnervation are described including pharmacological approaches and cell-based therapies. Given the complexity of nerve regeneration, further studies are needed to address the biology of nerve injury, to improve the interaction with implantable scaffolds, and to implement cell-based therapies in nerve tissue engineering.

Introduction

The peripheral nervous system (PNS) has an intrinsic ability for repair and regeneration. Injuries are most commonly attributable to direct mechanical trauma, and less frequently, surgical resection secondary to tumour excision. Capacity for regeneration relates to age of patient, mechanism of injury and in particular to the proximity of the injury to the nerve cell body. Distal digital nerve injuries result in sensory loss to a fingertip and will regenerate well, whilst proximal brachial plexus avulsions are functionally devastating with impaired hand sensation, reduced motor function and frequently pain and cold intolerance [1]. Such injuries have a profound and permanent impact on the patient and their ability to perform activities of daily living, as well as preventing return to work.

Currently, the treatment of choice is meticulous microsurgical repair by tensionless epineurial sutures. In the presence of a nerve gap where end-to-end suturing is not possible, autologous nerve grafting remains the gold standard [2]; however, this sacrifices a healthy nerve, requires more extensive surgery and donor nerves are in finite supply. Nerve injuries should be repaired early with delayed repair demonstrated to be significantly detrimental to satisfactory sensory and motor recovery [3], [4]. The principles in clinical treatment for nerve injury have not changed in the last 30 years despite substantially increased understanding of neuropathophysiology, and correspondingly clinical outcomes remain poor [5].

It has become apparent that a purely microsurgical approach to nerve repair will fail to address the complex cellular and molecular events of peripheral nerve regeneration. It is important to recognise that axonal injury has implications for the entire length of the neuron, as well as immediate functional consequences for the brain. Various factors have been implicated in the poor outcome of nerve regeneration: at the site of injury slow, insufficient and misdirected axonal outgrowth; at the target organ atrophy of muscle tissue and failure of reinnervation; in the brain rapid and longstanding cortical reorganisation [6]. Perhaps the single most important factor is the extensive cell death in the innervating neuronal pool [7], [8], since the most fundamental neurobiological prerequisite to regeneration is that neurons are maintained in a viable form.