An allogeneic ‘off the shelf’ therapeutic strategy for peripheral nerve tissue engineering using clinical grade human neural stem cells

Abstract

Artificial tissues constructed from therapeutic cells offer a promising approach for improving the treatment of severe peripheral nerve injuries. In this study the effectiveness of using CTX0E03, a conditionally immortalised human neural stem cell line, as a source of allogeneic cells for constructing living artificial nerve repair tissue was tested. CTX0E03 cells were differentiated then combined with collagen to form engineered neural tissue (EngNT-CTX), stable aligned sheets of cellular hydrogel. EngNT-CTX sheets were delivered within collagen tubes to repair a 12 mm sciatic nerve injury model in athymic nude rats. Autologous nerve grafts (autografts) and empty tubes were used for comparison. After 8 weeks functional repair was assessed using electrophysiology. Further, detailed histological and electron microscopic analysis of the repaired nerves was performed. Results indicated that EngNT-CTX supported growth of neurites and vasculature through the injury site and facilitated reinnervation of the target muscle. These findings indicate for the first time that a clinically validated allogeneic neural stem cell line can be used to construct EngNT. This provides a potential ‘off the shelf’ tissue engineering solution for the treatment of nerve injury, overcoming the limitations associated with nerve autografts or the reliance on autologous cells for populating repair constructs.

Developing an In Vitro Model to Screen Drugs for Nerve Regeneration

“…Engineered neural tissue (EngNT) refers to anisotropic cellular hydrogels that have been developed for use in nerve repair to deliver Schwann cells or Schwann cell‐like therapeutic cells to mimic an autograft (Georgiou et al, ; Martens et al, ; Georgiou et al, ; Sanen et al, ; O'Rourke et al, ). This approach, however, also has the potential to be used as a model for pre‐clinical in vitro drug screening as it enables quantification of the regeneration of neurons within an aligned 3D Schwann cell‐seeded collagen gel environment.…”

Strategies for Peripheral Nerve Repair

“…A number of therapeutics for the treatment of PNI have been developed in animal models, including engineered tissues that mimic the regenerative microenvironment found in the nerve autograft and distal nerve segment [73,[79][80][81][82]. However, there are many challenges associated with the clinical translation of these and other therapies with the potential to improve nerve repair outcomes in patients.…”

Somatic Nerve Reconstruction and Reinnervation

“…But after fresh nerve allograft transplantation by Davis et al [18], it was found that the area where it was operated on transplantation could not be fully restored. Considering that the transplanted nerves ended with central necrosis and fibrous scarring, Sunderland believed that using fresh nerve allograft was a failure [19]. At present, it is generally accepted in academia that rejection reaction between graft and recipient is the main factor affecting functional repair.…”