modules in vivo
liver modules in vitro
modules in vivo
wound bed treated with MAA beads
subq injection of MAA beads

Research Interests

The central theme is that biomaterials and biomaterial based devices (e.g. cell microcapsules, tissue engineering scaffolds) are agonists of biological responses. These responses include thrombosis ("clotting"), inflammation, immune responses, matrix remodelling, angiogenesis, wound healing; i.e., all aspects of a host response to an implanted material or device. The material is an agonist, much like small molecule drugs; however, the materials are 3-dimensional objects acting across an interface so that the mechanism of action is more complex and our understanding of what is happening is more rudimentary than it is for small molecules. Hence, our challenge is to translate what is known about biological mechanisms with small molecule agonists into a picture of what is occurring with the biomaterial. Depending on the problem, the lab synthesises new polymers, formulates existing polymers into novel forms, assesses surface chemistry and structure, studies cell-material interactions in cell culture and/or conducts in vivo experiments in animals (mice, rats and occasionally dogs and pigs). Most of the responses of interest are only evident in vivo and so the in vivo studies are typically key in many projects at the Masters and Ph.D. levels. In current projects, we use XPS spectroscopy, flow cytometry, genetic engineering, zymography, ELISA, confocal and electron microscopy, histology, RT-PCR, DNA microarrays; more generally we use whatever method is needed to answer a particular research question. The University of Toronto has one of the largest health science complexes in North America and a very strong engineering/physical sciences infrastructure so we get ready access to any method or expertise, required.

Special emphasis is given to Tissue Engineering and Regenerative Medicine and particular applications are described below. These problems often involve exploiting chemical or biomedical engineering principles, making them natural vehicles for chemical or biomedical engineering students to build on their interests in biology and biomedical applications. Nonetheless, some students in the lab don't have an engineering background; the lab has a strong biological focus and this makes for a good learning environment for life science students.

Although these problems have a significant biomedical orientation (making them suitable as thesis projects for non-engineering students), the difficulties that arise generally necessitate the use of well established engineering approaches. Hence a student in this area will have the background to handle difficult problems not only in biomedical engineering but in other areas also.

Many of these projects relate to Tissue Engineering. We have a novel strategy for creating scaffolds using modular components that are then vascularised by endothelial cell (EC) seeding. Growing a capillary bed is a critical step towards growing large tissue structures such as entire heart since diffusion limitations require cells to be within one hundred microns of a blood supply. In the past there have been projects on blood compatibility and on cell microencapsulation. These projects have been retired.

1. Modular Tissue Engineering

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Modular tissue engineering is based on the porous structure that is created when a column or tube is packed, randomly, with solid objects (here, short cylindrical rods). In a very much larger scale, such packed columns are standard pieces of chemical engineering process equipment. Because of the narrow channels in such columns, mass transfer coefficients are relatively high, making them efficient separating devices. We have adapted this geometry for tissue engineering. Functional cells (eg cardiomyocytes, liver, fat cells) are encapsulated in collagen gel rods (~400 mm diameter, aspect ratio 1.5 in current prototype) on to which endothelial cells (eg., HUVEC) are seeded. These collagen modules (containing cells) are then randomly packed into the construct. The interstitial gaps among the rods form interconnected channels which become lined by the endothelial cells. The resulting endothelial cell lining enables whole blood to percolate around the rods and through these interstitial channels. Current efforts have demonstrated the principle of modular tissue engineering in vitro and have, for example, elicited the design rules underscoring the scalable nature of the modular approach.

Current and future projects address the following questions: Does modular tissue engineering benefit the treatment of diabetes with embedded pancreatic islets or pancreatic precursors? What happens in vivo? How do the transplanted endothelial cells connect to the host vasculature after intraperitoneal implantation? How do we adapt modular tissue engineering for preparing liver tissue? What limits endothelial cells survival after transplantation? Is it apoptosis? Immune response? Can we enhance endothelial cells survival by genetically modifying the cells? How do we exploit microfluidic technologies for exploring the mechanism of remodeling?

2. Biomaterial associated angiogenesis

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Therapeutic angiogenesis using growth factors such as VEGF is being explored by others to enhance perfusion in ischemic limbs and hearts as well as in engineered tissues and in chronic wound care. Surprisingly beads made from a methacrylic acid (MAA) copolymer caused new blood vessels to grow without any exogenous growth factors. These new vessels were functional in that they saved a full thickness rat skin graft from necrosis, while a skin graft placed over control beads without MAA died due to the absence of the polymer associated angiogenesis. How these beads cause blood vessels to grow is a mystery that remains to be solved: we have some clues but not enough to tell a good story. This copolymer is the first example of a therapeutic polymer (Theramer™), a polymer that has therapeutic effects but without any immobilized, entrapped or released pharmacological agent. Current and future projects are: Understand the molecular basis of biomaterial associated angiogenesis Delineating the benefits of biomaterial associated angiogenesis in skin and other wound healing scenarios Create biomaterial scaffolds or degradable materials with angiogenic characteristics Characterize vessel structure and flow in biomaterial associated angiogenesis Create new Theramers™ with novel biological properties (eg apoptosis induction)