The Potential Clinical Utility of Novel Methods for Peripheral Nerve Regeneration: Where Are We Now?

Shimon Rochkind; Yuval Shapira; Zvi Nevo


Future Neurology. 2014;9(2):105-107. 

Traumatic injury of the PNS represents a major cause of morbidity and disability, which subsequently causes a substantial economic and social burden in a global perspective. In previous studies, peripheral nerve injuries have been estimated to affect 2.8% of all trauma patients, many of whom acquire life-long disability, resulting in an incidence of between 13 and 23 per 100,000 individuals a year (in developed countries).[1]

Although axons in the PNS harbor the potential of axonal regeneration, recovery of severe peripheral nerve injury is often unsatisfactory. This undesirable outcome is believed to be related to the process of axonal attrition and misdirection following nerve injury with anatomical disruption of the nerve tissue.[2]

In recent years, many research advancements and understanding of the process involved in peripheral nerve regeneration allowed for the development of novel therapies that significantly improve patient's outcome. The treatment of traumatic transection of peripheral nerves primarily consists of surgical intervention and anastomosis, either in the acute phase or during the chronic phase.[3,4] The gold standard autograft repair of the damaged peripheral nerve is far from being optimal and often disappointing.[5] An alternative to the use of grafts is the interposition of an artificial nerve scaffold.[6–8] Most repair scaffolds consist of a hollow tube made of polymeric materials (e.g., silicone), biologic materials (e.g., collagen), chitosan or biodegradable polymers.[5–10] The use of nerve guidance channels, sutured in between the proximal and distal nerve stumps, has been actively pursued in order to obtain better regenerative results and obviate the need for the additional surgical intervention. Since fewer epineural sutures are required for entubulation repair (since the nerve stumps are placed into the ends of the tube as opposed to simply abutting against the autograft), it is expected to cause less surgical trauma and diminish the potential of neuroma formation due to fibrosis. Moreover, guidance channels (or tubes) assist in directing axons from the proximal to the distal stump without interference from imperfectly aligned degenerating fascicles of the nerve graft or the closely apposed distal stump.[11] There are several hollow nerve tubes, currently available for clinical use, which are applied mostly for repair of small-diameter nerves with nerve defects up to 3 cm.[9] These nerve tubes are made of different biomaterials and, therefore, differ in physical properties. The ideal properties for a nerve tube are biodegradability, permeability, to be flexible but noncollapsible, simple to handle and suture, transparent and also must be capable of being sterilized without compromising the physical properties.

Of particular interest is the decellularized and sterile extracellular matrix processed from human peripheral nerve tissue. This allograft developed for the reconstruction of peripheral nerve preserves the essential structure of the extracellular matrix, while cleansing away cellular and noncellular debris.[12]

Guidance channels minimize the infiltration of fibrous scar tissue, which can hinder axonal regeneration, while at the same time maximize the accumulation of soluble factors produced by the nerve stumps and may also act as scaffolds for different filling materials, which can support regeneration. A recently developed filling material includes Guiding Regenerative Gel, which is a novel biocompatible gel for recovery of peripheral nerve with massive loss defect.[13] It is composed of a complex of substances comprising transparent, highly viscous gel that is almost impermeable to liquids and gasses, flexible, elastic, malleable and adaptable to various shapes and formats. The gel resembles the extracellular matrix and was found to support 3D growth and differentiation of various cell types including embryonic and adult stem cells in culture, neuronal precursor cells and neuronal accompanying cells.

In peripheral nerve injury, axonal regeneration is dependent on de-differentiated and proliferating Schwann cells, which provide intimate and essential support to neurons and guide elongating axons. Unfortunately, denervated Schwann cells progressively lose their ability to express regeneration-assisting genes and in effect become 'turned off'. This loss of vitality and functionality in distal Schwann cells directly translates to poor behavioral recovery.[14] Therefore, cell therapy is expected to aid functional recovery by improving the supportive environment for regenerating axons in the PNS and it has created exciting new avenues for the treatment of various nerve injuries.[6,15]

Despite refined microsurgical methods, only 40–70% of adults regain functional activity after complete transection and reconstruction of a major peripheral nerve. Therefore, innovative regenerative therapies for injured peripheral nerve that simultaneously potentiate axonal regeneration, promote selective target reinnervation and modulate central reorganization are needed.[16]

A technique of brief electrical stimulation of proximal nerve stump immediately following surgical repair of a transected peripheral nerve, greatly accelerates axon outgrowth.[17] Electrical stimulation was demonstrated to enhance the regeneration of injured peripheral nerves by accelerated axon growth across the injury site.

Considerable interest exists in the potential therapeutic value of low-power laser irradiation (laser phototherapy) for peripheral nerve recovery and preservation of denervated muscle. Animal studies on peripheral nerve injury model showed that laser phototherapy decreases scar tissue formation at the injury site, decreases degeneration in corresponding motor neurons of the spinal cord and significantly increases axonal growth and myelinization.[18] The restoration of the injured peripheral nerve prevents the progression of the muscle atrophy process, and makes functional restoration possible. However, restoring functions in the severe cases or long-term peripheral nerve injury is still difficult as progressive muscle atrophy starts shortly after nerve injury. For this reason, therapeutic solutions can lessen muscle degeneration during the period of nerve recovery, thereby increasing the chances of early recuperation of functional motor activity. It was found that in early stages of muscle atrophy, laser phototherapy may preserve the denervated muscle by maintaining creatine kinase activity and the amount of acetylcholine receptors.[19,20]

The development of artificial peripheral nerve and methodology for stimulation and enhancement of nerve regeneration is an ongoing process that demands close collaboration between the fields of tissue engineering, neuroscience and peripheral nerve surgery.