Nerve regeneration

Nervous system injuries affect over 90,000 people every year, though function recovery is not guaranteed in most cases [1]. It is estimated that spinal cord injuries alone reach 10,000 each year [2]. As a result of this high incidence of nervous system injuries, nerve regeneration and repair, a subfield of neural tissue engineering, is becoming a rapidly growing field dedicated to the discovery of new ways to recover nerve functionality after injury. The nervous system is divided into two parts: the central nervous system, which consists of the brain and spinal cord, and the peripheral nervous system, which consists of cranial and spinal nerves along with their associated ganglia. While the peripheral nervous system has an intrinsic ability for repair and regeneration, the central nervous system is for the most part incapable of self-repair and regeneration. There is currently no treatment for recovering human nerve function after injury to the central nervous system [3]. In addition, multiple attempts at nerve re-growth across the PNS-CNS transition have not been successful [3]. There is simply not enough knowledge yet about regeneration in the central nervous system. And although the peripheral nervous system has the capability for regeneration, much research still needs to be done to optimize the environment for maximum regrowth potential.

Peripheral Nervous System Regeneration
Injury to the peripheral nervous system immediately elicits the migration of phagocytic cells, Schwann cells, and macrophages to the lesion site in order to clear away debris such as damaged tissue. When a nerve axon is severed, the end still attached to the cell body is labeled the proximal segment, while the other end is called the distal segment. After injury, the proximal end swells and experiences some retrograde degeneration, but once the debris is cleared, it begins to sprout axons and the presence of growth cones can be detected. The proximal axons are able to regrow as long as the cell body is intact, and they have made contact with the neurolemmocytes in the endoneurial channel. Human axon growth rates can reach 2 mm/day in small nerves and 5 mm/day in large nerves [3]. The distal segment, however, experiences Wallerian degeneration within hours of the injury; the axons and myelin degenerate, but the endoneurium remains. In the later stages of regeneration the remaining endoneurial tube directs axon growth back to the correct targets. During Wallerian degeneration, Schwann cells grow in ordered columns along the endoneurial tube, creating a band of Bungner (boB) that protects and preserves the endoneurial channel. Also, macrophages and Schwann cells release neurotrophic factors that enhance re-growth.

Central Nervous System Regeneration
Unlike peripheral nervous system injury, injury to the central nervous system is not followed by extensive regeneration. It is limited by the inhibitory influences of the glial and extracellular environment. The hostile, non-permissible growth environment is in part created by the migration of myelin-associated inhibitors, astrocytes, oligodendrocytes, oligodendrocyte precursors, and microglia. Slower degeneration of the distal segment than that which occurs in the peripheral nervous system also contributes to the inhibitory environment because inhibitory myelin and axonal debris are not cleared away as quickly. All these factors contribute to the formation of what is known as a glial scar, which axons cannot grow across. The proximal segment attempts to regenerate after injury, but its growth is hindered by the environment. It is important to note that central nervous system axons have been proven to regrow in permissible environments; therefore, the primary problem to central nervous system axonal regeneration is crossing or eliminating the inhibitory lesion site. [3]

Autologous Nerve Grafting
Currently, autologous nerve grafting or a nerve autograft is known as the gold standard for clinical treatments used to repair large lesion gaps in the peripheral nervous system. Nerve segments are taken from another part of the body, the donor site, and inserted into the lesion to provide endoneurial tubes for axonal regeneration across the gap. However, this is not a perfect treatment; often the final outcome is only limited function recovery. Also, partial deinnervation is frequently experienced at the donor site and multiple surgeries are required to harvest the tissue and implant it.

Allografts and Xenografts
Variations on the nerve autograft include the allograft and the xenograft. In allografts, the tissue for the graft is taken from another person, the donor, and implanted in the recipient. Xenografts involve taking donor tissue from another species. Allografts and xenografts have the same disadvantages as autografts, but in addition, tissue rejection from immune responses must also be taken into account. Often immunosuppression is required with these grafts. Disease transmission also becomes a factor when introducing tissue from another person or animal. Overall, allografts and xenografts do not match the quality of outcomes seen with autografts, but they are necessary when there is a lack of autologous nerve tissue.

Nerve Guidance Conduit
Because of the limited functionality received from autografts, the current gold standard for nerve regeneration and repair, recent neural tissue engineering research has focused on the development of bioartificial nerve guidance conduits in order to guide axonal regrowth. The creation of artificial nerve conduits is also known as entubulation because the nerve ends and intervening gap are enclosed within a tube composed of biological or synthetic materials [4].