Collagen scaffolds in full- and hemi- resection spinal cord injury models

Abstract

Basic scientific research over the past few decades has shown some light on the complex pathophysiology of SCI and has enhanced our understanding of some of the important factors that contribute to the lack of regeneration following the initial traumatic injury and secondary injury response in the adult spinal cord. These factors include both intrinsic limitations in the regeneration capacity of mature neurons, but also a host of environmental factors which inhibit spontaneous attempts of axon regeneration. These environmental factors include physical barriers to axon regeneration such as fibrous and glial scars as well as molecules which actively inhibit regeneration. Even when these barriers are removed, axons in the central nervous system still require the appropriate stimulatory signals in order for significant regeneration to occur. These signals may include a substrate to provide directional guidance of the extending axon growth cones as well as neurotrophic factors to promote axon growth and survival. Thus, to achieve a clinically meaningful regenerative response following spinal cord injury a combinatorial therapeutic approach is likely necessary. This thesis investigated the use of a porous collagen scaffold with aligned pores to serve as a substrate for axon guidance and a delivery vehicle for select therapeutic agents in both fulland hemi- resection injury models in adult rats. In the hemi-resection injury model, the treatment groups included: a dehydrothermally (DHT) crosslinked scaffold, a carbodiimide (EDAC) crosslinked scaffold, and an EDAC-treated scaffold delivering either soluble Nogo receptor (sNgR), chondroitinase ABC (ChABC), or bone marrow derived mesenchymal stem cells (MSCs). Improvement in hindlimb function over four weeks following injury was seen in the DHT scaffold, EDAC scaffold + ChABC, and EDAC scaffold + MSCs groups, but not in the untreated control group. Immunohistochemical evaluation of the tissue revealed a few regenerating axons reaching the center of the scaffold in the DHT scaffold and EDAC scaffold + ChABC groups at 4 week post injury. Histological evaluation at 4 weeks showed the defect area of all groups to be largely comprised of loosely organized fibrous tissue. Many macrophages were seen surrounding the defect area of all groups; however, there were significantly more macrophages within the defect area of the control group compared to the treatment groups. In the full-resection injury model, at 6 weeks post injury, implanted collagen scaffolds tended to reduce the number of cystic cavities in the defect and to better align the reparative tissue with the long axis of the spinal cord. These results show the potential benefit of collagen scaffolds alone or in combination with select therapeutic agents as a means to modulate the healing response following spinal cord injury.