Engineering Polymers to Control Cell Fate

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Our overarching goal is to engineer polymers to control cell fate. Using innovative biomaterials science and engineering strategies, we are tackling some of the biggest questions in cell biology. For example, for decades cells have been cultured in tissue culture polystyrene plates – hard, plastic surfaces – that poorly mimic how cells grow, divide, differentiate in vivo. The consequence is that in vitro studies are poor predictors of in vivo outcomes, whether to understand fundamental phenomena or screening assays. Thus, while significant advances have been achieved with traditional 2D cell culture, the problem is significant advances have also been missed. The community has recognized the need to grow cells in a more biomimetic environment – one that mimics the chemical, physical, mechanical properties of normal tissue – so that we can recapitulate cell growth in the laboratory. The key question is how to grow tissues in the lab. Our underlying goal is to design polymeric hydrogel scaffolds in which to guide cell growth and differentiation in order to create tissue mimetics in the laboratory. The innovation is in the polymer science – the outcome is in the cellular response. This platform strategy can be adapted for multiple cell types; herein, we will focus primarily on cells of the central nervous system and investigate the intimate role of the extracellular matrix with neurons and glia to create biomimetic neural tissues. At the same time, we propose to tackle another big challenge in stem cell biology using bioengineering strategies – that is, how to ensure cell survival and integration after transplantation. Stem cells are typically injected in saline and typically die and disperse soon afterwards. For the central nervous system, cells need to integrate into the neural circuitry and for this they need to survive. Delivering cells in a microenvironment that promotes survival addresses this key challenge. Our underlying goal is to design an injectable delivery system with such a defined microenvironment. Affinity-based release is an emerging approach to achieve controlled release of bioactive molecules, but has been primarily explored with heparin-based materials where the protein-heparin interaction controls release and is inherently limited to heparin-binding growth factors. In order to design a platform strategy for controlled affinity release, we propose to take advantage of non-covalent, specific interactions to modulate the release of bioactive proteins. By controlling the rate constants of association/dissociation, this “Velcro-like” system enables controlled release of proteins. We propose to control the simultaneous release of two bioactive factors, at different rates - something that has not been previously explored – with the ultimate goal of enhancing cell survival. This innovative strategy is broadly applicable to multiple materials and proteins and will be tested with two factors that influence retinal stem cell survival and a hydrogel, which itself has a pro-survival effect on the cells suspended within. We are engineering solutions to biological questions using advanced polymer science. In this proposal, we both advance knowledge and train high quality personnel in key areas of strength for Canada. My record of HQP training is exceptional – the 115 HQP trained in my laboratory have gone on to pursue leadership positions in academia, industry and government. We publish in high impact journals, patent new inventions, present at international conferences, collaborate with world leaders in academia and industry, and provide advice to government.