M. V. Sefton
B.A.Sc. (Toronto), Sc.D. (MIT), P.Eng. University Professor and Michael E. Charles Professor of Chemical Engineering
Room: Donnelly Centre for Cellular and Biomolecular Research 406
Tel.: 416-978-3088
Email: michael.sefton@utoronto.ca
Web Site: http://www.ibbme.utoronto.ca/faculty/core/sefton.htm
Awards
Acta Biomaterialia Gold Medal, 2011Killam Prize, Canada Council for the Arts, 2008
Founders Award, US Society For Biomaterials, 2008
Fellow, Royal Society of Canada
University Professor
Albright and Wilson America Award, 1989
Faculty Teaching Award, 1992
Clemson Award for Basic Research, Soc. for Biomaterials, 1993
Fellow, Chemical Institute of Canada
Fellow, Biomaterials Science and Engineering
Fellow, American Institute of Medical and Biological Engineering
Fellow, AIChE
Century of Achievement, CSChE, 1999
Memberships
Canadian Society for Chemical EngineeringCanadian Biomaterials Society
Society for Biomaterials, USA
American Institute of Chemical Engineers
Professional Engineers of Ontario
Controlled Release Society
American Inst. of Medical and Biological Engineering
Research Interest
Biomaterials and Biomedical EngineeringThe central theme is that biomaterials and biomaterial based devices (eg cell microcapsules, tissue engineering scaffolds) are agonists of biological responses. These responses include thrombosis (“clotting”), inflammation, Immune responses, matrix remodelling, angiogenesis, wound healing; ie, 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 PhD 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 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
Modular tissue engineering is illustrated in Figure 1. It 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 (Fig. 1a). 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 (Fig 1b). 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 scaleable nature of the modular approach.
Current projects are:
- Adapt modular tissue engineering for preparing cardiac muscle
- Adapt modular tissue engineering for preparing fat for breast reconstructive surgery
- Adapt modular tissue engineering for treatment of diabetes with embedded pancreatic islets What happens in vivo? How do the transplanted EC connect to the host vasculature after intraperitoneal implantation? After hepatic vein infusion?
- What limits EC survival after transplantation? Is it apoptosis? Immune response?
- Exploit microfluidic technologies for exploring the effects of (irregular) flow on endothelial cell phenotype
- Characterize the modular constructs and especially endothelial cell thrombogenicity with modules prepared from these materials
- Prepare and characterize biodegradable versions of these materials
- Explore the utility of preparing sheets of cardiac or skeletal muscle using photolithography
Therapeutic angiogenesis using growth factors such as VEGF is being explored 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)
Upon implantation, tissue-engineered constructs trigger an inflammatory response, characterized by the accumulation of inflammatory cells, such as neutrophils and macrophages. Local remodelling of the environment forms a fibrotic capsule which walls off and isolates the implant from the rest of the body. Because the construct’s intended therapeutic effect can be diminished by the tissue response, there exists a need to control this process. One possible target for control is a group of enzymes known as matrix metalloproteinases (MMPs). MMPs degrade extracellular matrix (ECM) and both facilitate inflammatory cell migration and local implant environment remodelling.
Remodelling within the tissue construct also changes the structure and function of what was created outside the body, even if there had been no inflammatory response. These same enzymes also influence this internal restructuring. Thus while we have some ability to control and influence the construct before it is implanted, after implantation it is remodelled and to date we have limited understanding of the underlying biological processes.
Rimon Therapeutics, our collaborators, have prepared MMP-sequestering biomaterial beads (another Theramer™, see the angiogenic bead project above) that reduce MMP levels and function in vitro. They also inhibit the degradation of subcutaneously implanted gelatin tubes in vivo. We hypothesize that the use of an MMP-sequestering biomaterial alters the tissue response to an implant by lowering the amount of MMPs in vivo, which alters the level of ECM degradation and remodelling.
- Characterize the remodelling/wound healing dynamics in a porous scaffold and explore the effects of MMP inhibition
- Characterize the effects of MMP inhibition on the foreign body response to a biomaterial implant
- Explore the effects of MMP inhibition on non-matrix targets such as chemokines
Selected Publications
S. Lahooti, M.V. Sefton, “Microencapsulation of Normal and Transfected L929 Fibroblasts in a HEMA-MMA Copolymer”, Tiss. Eng., 6, 139-149 (2000).Sefton, M.V., Gemmell, C.H., Gorbet, M.B., "What Really is Blood Compatibility?", J. Biomat., Sci. Polymer Edn., 11, pp. 1165-1182 (2001).
M.V. Sefton , "Perspective on Hemocompatibility Testing", J. Biomed. Mater. Res. 55, pp. 445-446 (2001).
M.V.Sefton, A. Sawyer, M.Gorbet, J.P.Black, E. Cheng, C.Gemmell, E. Cooper-Pottinger, "Does Surface Chemistry Affect Thrombogenicity of Surface Modified Polymers?" J. Biomed . Mater. Res. 55, 447-459 (2001).
M.B. Gorbet and M.V. Sefton, "Material-induced Tissue Factor expression but not CD11b upregulation depends on the presence of platelets", J.Biomed.Mater.Res., 67, pp. 792-800 (2003).
M.B. Gorbet and M.V. Sefton, "Biomaterial associated thrombosis: roles of coagulation factors, complement, platelets and leukocytes, Biomaterials, 25, pp.5681-5703 (2004). [republished as one of best 25 papers published in Biomaterials from 1980-2004, in The Biomaterials Silver Jubilee Compendium, ed D.F. Williams, Elsevier, 2005]
P. Xu and M.V. Sefton, "Expression of Matrix Metalloproteinase -2 and -9 in Exudates Associated with Polydimethyl Siloxane and Gelatin tubes Implanted in Mice", J. Biomed. Mater. Res., 71A, pp.226-232 (2004).
K. Jones, M.V. Sefton and R. Gorczynski, “In Vivo Recognition by the Host Adaptive Immune System of Microencapsulated Xenogeneic Cells”, Transplantation, 78(10), pp.1454-1462 (2004)
M.B. Gorbet, and M.V. Sefton, “Complement inhibition reduces material-induced leukocyte activation with PEG modified polystyrene beads (Tentagel™) but not polystyrene beads”, J. Biomed. Mater. Res.: Part A 74A, 511-522 (2005).
A.Khademhosseini, M.H. May, and M.V. Sefton, “Conformal Coating of Mammalian Cells Immobilized onto Magnetically Driven Beads”, Tissue Engineering, 11, 1797-1806. (2005)
A. Sosnik and M.V. Sefton, Semi-synthetic collagen/poloxamine matrices for Tissue Engineering, Biomaterials, 26, 7425-7435 (2005)
A. Sosnik A. and M.V. Sefton, Methylation of poloxamine for enhanced cell adhesion, Biomacromolecules, 7, 331-338 (2006).
A. P. McGuigan and M. V. Sefton “Vascularized Organoid Engineered by Modular Assembly Enables Blood Perfusion”, PNAS 103, 11461–11466 (2006).
K. S. Jones, M. V. Sefton and R.M. Gorczynski , Suppressed splenocyte proliferation following a xenogeneic skin graft due to implanted biomaterials., Transplantation. 82, 415-421 (2006).
M. She, A. P. McGuigan and M. V. Sefton, Tissue factor and thrombomodulin expression on endothelial cell seeded collagen modules for tissue engineering, J. Biomed Mater. Res 80, 497-504 (2007)
A. P. McGuigan and M. V. Sefton, Design and fabrication of sub-mm sized modules containing encapsulated cells for modular tissue engineering, Tissue Engineering 13(5): 1069-1078 (2007)
A. P. McGuigan and M. V. Sefton, Design criteria for a modular tissue-engineered construct, Tissue Engineering 13(5): 1079-1089 (2007)
M. J. Butler and M.V. Sefton A poly(butyl methacrylate-co-methacrylic acid) tissue engineering scaffold with proangiogenic potential in vivo, J. Biomed. Mater. Res. 82A: 265-273 (2007)
A. P. McGuigan and M. V. Sefton, The influence of biomaterials on endothelial cell thrombogenicity, Biomaterials 28:2547-2571(2007)
B. M. Leung and M. V. Sefton, A Modular Tissue Engineering Construct Containing Smooth Muscle Cells and Endothelial Cells , Ann. Biomed. Eng. 35, 2039-2049 (2007)
J.N. Vallbacka and M. V. Sefton, Microencapsulation of VEGF-secreting cells: vascularization for tissue engineering, Tissue Engineering, 13: 2259-2269 (2007)
A. A. Eckhaus, J. S. Fish, G. Skarja, J. L. Semple and M. V. Sefton, A Preliminary Study of the Effect of Poly(methacrylic acid-co-methyl methacrylate) Beads on Angiogenesis in Rodent Skin Grafts and the Quality of the Panniculus Carnosus, Plastic and Reconstructive Surgery (in press)
M. Surzyn, J. Symes, J. A. Medin and M. V. Sefton,IL-10 Secretion Increases Signal Persistence of HEMA-MMA Microencapsulated Luciferase-Modified CHO Fibroblasts in Mice, Tissue Engineering (in press)
D. Cheng, C. Lo and M. V. Sefton, Effect of mouse VEGF164 on the viability of HEMA-MMA microencapsulated cells in vivo: bioluminescence imaging, J. Biomed Mater. Res. (in press)