A novel experimental rat model of peripheral nerve scarring: reliably mimicking post-surgical complications and recurring adhesions

Abstract

Inflammation, fibrosis and perineural adhesions with the surrounding tissue are common pathological processes following nerve injury and surgical interventions on peripheral nerves in human patients. These features can reoccur following external neurolysis, currently the most common surgical treatment for peripheral nerve scarring, thus leading to renewed nerve function impairment and chronic pain. To enable a successful evaluation of new therapeutic approaches, it is crucial to use a reproducible animal model that mimics the main clinical symptoms occurring in human patients. However, a clinically relevant model combining both histological and functional alterations has not been published to date. We therefore developed a reliable rat model that exhibits the essential pathological processes of peripheral nerve scarring. In our study, we present a novel method for the induction of nerve scarring by applying glutaraldehyde-containing glue that is known to cause nerve injury in humans. After a 3-week contact period with the sciatic nerve in female Sprague Dawley rats, we could demonstrate severe intra- and perineural scarring that resulted in grade 3 adhesions and major impairments in the electrophysiological peak amplitude compared with sham control (P=0.0478). Immunohistochemical analysis of the nerve structure revealed vigorous nerve inflammation and recruitment of T cells and macrophages. Also, distinct nerve degeneration was determined by immunostaining. These pathological alterations were further reflected in significant functional deficiencies, as determined by the analysis of relevant gait parameters as well as the quantification of the sciatic functional index starting at week 1 post-operation (P<0.01). Moreover, with this model we could, for the first time, demonstrate not only the primary formation, but also the recurrence, of severe adhesions 1 week after glue removal, imitating a major clinical challenge. As a comparison, we tested a published model for generating perineural fibrotic adhesions, which did not result in significant pathological changes. Taken together, we established an easily reproducible and reliable rat model for peripheral nerve scarring that allows for the effective testing of new therapeutic strategies.

Alginate and its application to tissue engineering

“…The endothelial ancestor cells were properly transplanted on the vehicles that are created from RGDalginate. This supports the cell migration and adhesion and the incorporated gels of alginate releases VEGF to facilities the distribution of the cell [88][89][90].…”

Adipose-Derived Mesenchymal Stem Cells Applied in Fibrin Glue Stimulate Peripheral Nerve Regeneration

“…The rate and degree of nerve fiber de- and regeneration after damage is a complex process associated with inflammation, adhesion, regulation of neurotrophic factors, neurotransmitter synthesis and release, formation of the nerve growth cone, neuron survival, growth of axons and myelination, and many other factors (38, 39). At the same time, immune reactions taking place in the injury area cause the expression of pro-inflammatory transmitters around the damaged tissue and contribute to the development of scar tissue, nerve fibrosis (40), neuromas, and hyperplasia which impact on nerve damage and on conduction restoration after injury (41).…”

Niclosamide Targets Inflammatory and Profibrotic Pathways in Amyotrophic Lateral Sclerosis

“…Most interestingly, our in vivo results demonstrate that niclosamide relieves ALS-related pathological features in spinal cord, sciatic nerve and skeletal muscle of hFUS mice. Central and peripheral nerve pathology with in ammation and brosis is a major harmful mechanism contributing to degeneration [21,61]. In ALS, neuronal regeneration and axonal growth may be limited by a hostile environment characterized by extensive gliosis and aberrant remodeling of ECM components [8].…”