Pre-clinical models for examination of human tissue grafts in nerve injury
Sravan Dhulipala, MD1, Gary Lourie, MD2, Debbie Neubauer, MS3, Anne Engemann, PhD3, Erick DeVinney, BS3 and Curt Deister, PhD3
1Wellstar Atlanta Medical Center, Atlanta, GA, 2The Hand and Upper Extremity Center of Georgia, Atlanta, GA, 3AxoGen, Alachua, FL
Introduction: Human tissue products are providing additional clinical opportunities for nerve repair. However, there is still a large amount of additional research needed to improve clinical outcomes. Non-clinical models of nerve injury are important research tools for enabling this improvement. Unfortunately, xenogenic interactions are known complications for the study of human tissues in model systems. Athymic rat models have been used to alleviate xenogenic cross-reactions and allow non-clinical models for human tissue products, including some nerve applications. With the importance of paracrine signaling and macrophages to Wallerian degeneration and nerve repair, the impact of the lack of an adaptive immune system in an athymic model on nerve injury is still unclear. While athymic models should retain normal innate immune system responses, such as macrophages, and should function similar to immune competent models, direct comparisons of athymic and euthymic models are poorly documented in nerve models. This work directly compares a severe nerve crush model in athymic versus euthymic rats in order to ensure athymic rats are an appropriate model in which to investigate the use of human tissue products in nerve repair.
Materials and Methods: Using a modification of a published rat sciatic injury model of severe nerve crush, we examined the differences between athymic and euthymic rats (n=6 per group). Tissues were collected 6 weeks after initial surgery with nerve at the site of injury and distal to injury collected for histology and gastrocnemius wet muscle mas determined. Longitudinal sections with Masson’s trichrome staining were used to evaluate collagen deposition in the injured nerve segment. Transverse sections with osmium post-fix of the distal nerve were used for histomorphometry.
Results: Athymic and euthymic groups showed similar results demonstrating and increased connective tissue to cytoplasm ratio due to injury and decreased muscle mass associated with nerve injury. The overall results were consistent with moderate, long-term nerve trauma as expected for the model.
Conclusions: Nerve repair and injury are broadly similar in athymic and euthymic rat models. Athymic models should not significantly impact nerve injury or repair while minimizing and xenogenic response while studying human tissue products. Future studies will use this athymic, sciatic crush model to investigate the effects of minimally processed human tissue grafts.
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