Tissue engineering therapies for peripheral nerve injuries with short gaps

Todd A Rickett, Purdue University

Abstract

Peripheral nerves are the primary connection between the central nervous system and the rest of the body. As soft tissues, they are easily damaged by trauma, over-exertion, and surgical error, leading to loss of innervation that causes diminished sensation, impaired mobility, and chronic pain. More than 50,000 operations are performed annually to treat these injuries. Stretch injury is the most commonly occurring type of nerve pathology. To better understand nerve functional limits, we strained nerves while recording physical parameters such as force and position. Electrophysiological measurements show the loss of nerve function with diminished action potentials and increased latency at strains greater than 5%. This data illuminates the process of nerve dysfunction and informs the design of therapies for nerve injuries by establishing minimum thresholds for biomaterial mechanical tolerances. Complete transection is the most severe form of nerve peripherally injury. Currently, surgical guidelines recommend suturing discontinuous nerves back together, a process that can induce tissue inflammation and obstruct regenerating axons. Surgical adhesives have been investigated as potential alternatives. We investigated ethyl-cyanoacrylate as an anastomotic agent that is known to have good mechanical properties, a finding reinforced by longitudinal stress analysis. Electrophysiological studies found no acute effects on nerve function, but concerns persist about the chronic toxicity of byproducts of cyanoacrylate degradation when permanently implanted within the body. Bioadhesives of natural origin have been investigated due to their presumably reduced risk profile. Originally developed as hemostatic agents, fibrin based glues have been used clinically for peripheral nerve coaptation, but risk dehiscence and pathogenicity. We modified chitosan, an established bioadhesive, with 4-azidobenzoic acid to produce a photo-cross-linkable Az-chitosan hydrogel. This hydrogel polymerizes rapidly under UV light and performs comparably to existing fibrin adhesives in ex vivo mechanical tests on severed peripheral nerves. Neural cells were found to attach and proliferate readily on and within these experimental gels. Further experiments reinforced the Az-chitosan matrix with a semi-interpenetrating network of polyethylene glycol (PEG) chains of varying lengths with distinct functional groups. Of note, peripheral nerves anastomosed by 2000 Da PEG with terminal hydroxyl groups tolerated significantly more force than nerves anastomosed with a commercial fibrin glue. The ultimate aim of this research project is to develop a new technique for stabilizing primary nerve repairs. Using chitosan bioadhesives, this therapy could potentially reduce the need for invasive sutures in peripheral neurosurgeries and improve functional outcomes. These findings have applications in treating many types of nerve injuries, and could offer hope to thousands living with disabilities.

Degree

Ph.D.

Advisors

Shi, Purdue University.

Subject Area

Neurosciences|Biomedical engineering

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