Since my arrival at the University of Toronto in July 1995, I have developed a polymer and tissue engineering research program that combines fundamental polymer science with drug delivery and guided regeneration.  For neural tissue regeneration, we are focused on nerve fiber (or axonal) guidance. To this end, we have focussed on creating a hollow fiber membrane (HFM) through which axons can regenerate and on defining the haptotactic and chemotactic cues that will promote guidance.

We invented a new and simple method to create reproducible HFMs: by tuning the formulation and rotational speed, we can control wall thickness and morphology. This novel method allows us to design the conduit with the appropriate mechanical and transport properties required for in vivo application.  We have also synthesized biodegradable chitosan nerve guidance channels and have implanted them with growth factors and stem cells in transected spinal cord injury rat models.  We have extensive experience with polymer synthesis, degradation, and 3-D structure creation.  For example, we created a biomimetic scaffold for bone tissue engineering that allowed bone cells (osteoblasts) and bone tissue to regenerate in vivo, throughout the 3-D structure.

To better understand the adhesive cues that are important to axonal guidance, we have investigated surface modification strategies, 2-dimensional patterning and 3-dimensional patterning.  We created surfaces or volumes with alternating regions of adhesion and repulsion, thereby mimicking the guidance pathways observed in vivo. Neurons and neurites were true to the adhesive regions for an extended time.  We found that both adhesive and non-adhesive regions were critical for guidance. Using photochemistry and advanced laser technology, we have demonstrated the first true 3-D patterning methodology which results in biochemical channels of proteins and peptides in which cell and axon migration are guided. 

To gain a better perspective on the role of chemotactic cues for guidance, we prepared well-defined neurotrophic factor concentration gradients in a custom-built diffusion chamber.  We found that a minimum concentration gradient (and not concentration) of neurotrophic factors is required to guide neurites over a maximum distance, thereby addressing some of the ambiguity in the literature.  We investigated the synergistic effect of multiple neurotrophic concentration gradients on guidance and found that lower concentration gradients of multiple factors provide guidance over a longer distance.  We are currently investigating methods to translate this model system to a device having immobilized concentration gradients of neurotrophic factors.

We are also exploring a minimally-invasive, localized drug delivery strategy for treatment of the crushed spinal cord.  This strategy requires the injection of a fast gelling, biodegradable polymer into the sub-arachnoid space.  We demonstrated safety and efficacy of this new technique and showed localized release and efficacy of the growth factors into spinal cord tissue.

We have recently synthesized some novel self-aggregating polymeric nanoparticles for targeted delivery and will begin to study these in animal models.