Michael V. Sefton

sefton1University Professor
B.A.Sc. (Toronto), Sc.D. (MIT), P.Eng.
Michael E. Charles Professor of Chemical Engineering
Principal Investigator, Sefton Lab

Room: Donnelly Centre for Cellular and Biomolecular Research 406 | Tel.: 416-978-3088 | Email: michael.sefton@utoronto.ca 

Awards

Engineers Canada Gold Medal, 2014
Professional Engineers Ontario Gold Medal, 2013
R.S. Jane Award, Canadian Society for Chemical Engineering, 2012
Acta Biomaterialia Gold Medal, 2011
Killam Prize, Canada Council for the Arts, 2008
Founders Award, US Society For Biomaterials, 2008
Fellow, Royal Society of Canada
University Professor
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
Clemson Award for Basic Research, Soc. for Biomaterials, 1993
Faculty Teaching Award, 1992
Albright and Wilson America Award, 1989

Memberships

Canadian Society for Chemical Engineering
Canadian 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 Engineering

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 synthesizes 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, tissue culture, genetic engineering (cell transduction with viruses), ELISA, confocal and electron microscopy, histology, RT-PCR, DNA microarrays, mass spectrometry; 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, providing 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 as well.

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 an entire heart or liver 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.

Modular tissue engineering

1. Modular Tissue Engineerin

Modular tissue engineering is illustrated in the Figure. It is based on the porous structure that is created when a column or tube (or an implant site) 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 (e.g., liver cells) are encapsulated in collagen gel rods (~400 mm diameter, aspect ratio 1.5 in current prototype) onto which endothelial cells (e.g., 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 scaleable nature of the modular approach.

Current projects are:

  • Adapt modular tissue engineering for preparing liver tissue for drug testing or to rescue (an animal) after liver failure
  • Adapt modular tissue engineering for treatment of diabetes with embedded pancreatic islets
  • What happens in vivo? How do the modules remodel to generate a chimeric vasculature that consist of both host and donor cells? What is the rate limiting step? What are the roles of hypoxia and inflammation?
  • Exploit microfluidic technologies for exploring the effects of (irregular) flow on module remodeling
  • Exploit modules as an “ink” in bioprinting to create larger structures with complex architectures

2. Biomaterial associated angiogenesis

Therapeutic angiogenesis using growth factors such as VEGF is being explored by many groups in order 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)

Selected Publications

Wells LA, Sefton, MV,  The effect of methacrylic acid in smooth coatings on dTHP1 and HUVEC gene expression,  Biomater. Sci., 2014, DOI: 10.1039/C4BM00159A

OF Khan, D Voice, B Leung, M. V. Sefton. A novel high-speed production process to create modular components for the bottom-up assembly of large scale tissue engineered constructs. Advanced Healthcare Materials. 2014 May 13. Accepted / In Press. Senior Responsible Author.

Ciucurel EC and Sefton MV. Del-1 Overexpression in Endothelial Cells Increases Vascular Density in Tissue-Engineered Implants Containing Endothelial Cells and Adipose-Derived Mesenchymal Stromal Cells. Tissue Eng Part A. 2014 Apr 20(7-8):1235-1252. Senior Responsible Author.

Butler M, Sefton MV, Cotransplantation of Adipose-derived Mesenchymal Stromal Cells and Endothelial Cells in a Modular Construct Drives Vascularization and Fat Development in SCID Mice, Tissue Engineering Part A Vol. 18, No. 15-16, August 2012: 1628-1641. PMID 22655687

Fitzpatrick LE, Lisovsky A, Sefton MV, The expression of sonic hedgehog in diabetic wounds following treatment with poly(methacrylic acid-co-methyl methacrylate) beads., Biomaterials. 2012 Jul;33(21):5297-307PMID: 22541537

Chamberlain MD, Gupta R, Sefton MV: Bone marrow-derived mesenchymal stromal cells enhance chimeric vessel development driven by endothelial cell coated microtissues. Tissue Eng Part A 18, 285-294, 2011

Gupta R, Sefton MV. Application of an endothelialized modular construct for islet transplantation in syngeneic and allogeneic immunosuppressed rat models.Tissue Eng Part A. 2011 Aug;17(15-16):2005-15. Epub 2011 May 16. PubMed PMID: 21449709.

Khan OF, Sefton MV, Perfusion and characterization of an endothelial cell-seeded modular tissue engineered construct formed in a microfluidic remodeling chamber. Biomaterials. 2010 Nov;31(32):8254-61. PMID: 20678792

D. Cheng, M. V. Sefton, Dual Delivery of Placental Growth Factor and Vascular Endothelial Growth Factor from Poly(Hydroxyethyl Methacrylate-Co-Methyl Methacrylate) Microcapsules Containing Doubly Transfected Luciferase-Expressing L929 Cells, Tissue Engineering Part A. 15(8) 1929-1939 (2009)

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]

A. P. McGuigan and M. V. Sefton “Vascularized Organoid Engineered by Modular Assembly Enables Blood Perfusion”, PNAS 103, 11461–11466 (2006).