A genetic and tissue-engineering approach to improving canine olfactory ensheathing cell transplant for spinal cord injury

  • Jon B M Prager

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Intra-spinal transplantation of olfactory ensheathing cells (OECs) and delivery of chondroitinase ABC (chABC) have separately shown promise as therapies for spinal cord injury (SCI). Efficacy has been demonstrated for both these approaches in trials using dogs with naturally occurring SCI, a model which may represent a means of bridging the gap in translation between laboratory interventions and clinical treatments. However, their individual effect was limited and combination therapy, including a means to increase OEC survival, may improve outcomes.
It was recently demonstrated that OECs can be modified to express chABC (OEC-chABC), providing a combination therapy and novel delivery method of chABC. This thesis builds on that work by testing the functional benefit of this modified OEC transplant in two rodent models of SCI, as well as delivery of OECs within hydrogels to increase cell survival.
We tested the effect of canine OEC-chABC compared to OECs alone on forepaw reaching in an acute incomplete SCI model (dorsal column crush injury), demonstrating greater recovery in OEC-chABC transplanted animals and proof of concept of this therapy. We further tested the effect of canine OEC- chABC on locomotion in a more severe chronic thoracic contusion model, showing no significant behavioural recovery compared to controls in this xenotransplant model with low OEC survival.
We used a chronic cervical dorsal column crush injury in rats to test injection of canine OECs encapsulated in collagen hydrogel, demonstrating an average 7.5-fold increase in surviving OEC number at 2 weeks after transplant. Stiffness matching between implant and host tissue is necessary to reduce inflammatory reaction and prevent iatrogenic damage. Therefore, to facilitate hydrogel delivery on clinics, and to address a knowledge gap in the literature regarding the in vivo stiffness of SCI, we established an intraoperative ultrasound elastography approach to stiffness matching in dogs with natural SCI.
Date of Award12 May 2020
Original languageEnglish
Awarding Institution
  • The University of Bristol
SupervisorNicolas Granger (Supervisor), Liang-Fong Wong (Supervisor), Guillaume Chanoit (Supervisor), John F Tarlton (Supervisor) & Divya M Chari (Supervisor)

Keywords

  • Spinal Cord Injury
  • Olfactory Ensheathing Cell Transplantation
  • Chondroitinase ABC
  • Hydrogel Biomaterial
  • Stiffness Matching

Cite this

A genetic and tissue-engineering approach to improving canine olfactory ensheathing cell transplant for spinal cord injury
Prager, J. B. M. (Author). 12 May 2020

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)