Biomedical Strategies for Axonal Regeneration

Abstract

Deficits of the nervous system can be classified into two categories: ‘biochemical’, where replacement of a neurotransmitter like dopamine to a large measure corrects most Parkinsonian motor symptoms, and ‘networking’ deficits, where the connections between two sets of neurons or neurons and muscles are interrupted due to trauma or tumour resection. The underlying theme of all nervous system deficits is the loss of neuronal function. Consequently, the response of the body to an injury or lesion can be classified as being either pro‐regenerative or antiregenerative. Therefore, the goal of all therapies to treat nervous system disorders, ranging from Alzheimer disease to traumatic brain injury, is to foster pro‐regenerative repair mechanisms in nervous tissue. In an attempt to repair such deficits, various biomedical strategies that seek to promote axonal regeneration and plasticity, are being investigated.

Key Concepts:

  • A key difference between the CNS and the PNS is their differential abilities to repair traumatic damage. The PNS has an inherent capability to repair small injuries; the CNS has little or no ability to repair itself.

  • Schwann cells provide an organised matrix facilitating functional regeneration and repair in the PNS.

  • The gold standard in PNS repair using artificial nerve guidance channels is to match or exceed the performance of an autograft.

  • The glial scar in the CNS presents a highly inhibitory and disorganised terrain to regenerating neurites.

  • CNS and PNS repair strategies in the future must include multiple therapies acting synergistically.

Keywords: myelin; glial scar; trophic factors; scaffolds; regeneration

Figure 1.

Diagram of the peripheral nervous system before and after injury, including current repair strategies. (a) Each nerve consists of conduits that are filled with many neurons. Each conduit comprises of sensory neurons and motor neurons ensheathed by Schwann cells. (b) When injury occurs, the proximal end (still connected to the cell body) and the distal end (section removed from the cell body) undergo primary and secondary degeneration, respectively. Inflammatory macrophages enter the injured area, removing cellular debris and releasing chemical signals. Some chemical signals initiate Schwann cell proliferation. Over time, the number of Schwann cells continues to increase, and they produce cell adhesion molecules (CAMs), laminin (LN), fibronectin (FN), nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF) and neurotrophic factor‐3 (NT‐3). Each of these molecules assists in promoting regeneration. (c) Current techniques used to facilitate regeneration include the use of nerve tissue from elsewhere within the patient (autografts). Through the use of immunosuppressive regimens, allografts and xenografts are also being considered. Biomaterial channels are being investigated for their potential to facilitate regeneration. Various material/cellular compositions of the channel wall and cavity are being looked at to maximise regeneration in these channels.

Figure 2.

Diagram of the central nervous system before and after injury, including experimental therapies to promote regeneration. (a) The central nervous system consists of neurons with three main glial support cells. Oligodendrocytes ensheath the neuron's axons, astrocytes provide structural and biochemical support, whereas microglia remain quiescent when injury is not present. (b) When injury occurs, macrophages and microglia move into the damaged space, remove myelin debris and produce signalling chemicals. These chemicals activate astrocytes, producing inhibitory chemicals. Within the myelin debris are proteins that inhibit regeneration, including Nogo proteins and myelin‐associated glycoprotein (MAG). (c) Anatomical intervention is the addition of cellular and/or material implants that facilitate regeneration. (d) Biochemical intervention is the addition of enzymes to remove portions of chondroitin sulfate proteoglycans (CSPGs), antibodies or peptides that mask Nogo proteins, or the infusion of neurotrophins directly or indirectly using gene therapy to promote regeneration.

Figure 3.

Schematic depicting the convergence of various therapeutic strategies to restore complete function after injury to the nervous system. (Reproduced with permission from Aravamudhan and Bellamkonda . © Mary Ann Liebert, Inc.)

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Further Reading

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Saxena, Tarun, Gilbert, Ryan J, Pai, Balakrishna S, and Bellamkonda, Ravi V(Dec 2011) Biomedical Strategies for Axonal Regeneration. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001110.pub2]