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. Furthermore, these signs can reoccur following external neurolysis, currently the most common surgical treatment, 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. For this reason, we developed a reliable rat model, which 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, known to cause nerve injury in humans. After a three-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 to 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-operatively (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 one week after glue removal, imitating a major clinical challenge. As a comparison, we tested an already published model for generating perineural fibrotic adhesions, which however did not result in significant pathological changes. Taken together, we established an easily reproducible and reliable rat model for peripheral nerve scarring which allows for the effective testing of new therapeutic strategies.