There are ~ 15 million diagnosed diabetics in the US, 5-10% of whom are type 1 (insulin dependent). Islet transplantation could have a large impact on preventing the degenerative complications of diabetes (here and in developing countries), but the majority of islets (perhaps 60%) in current protocols are lost upon transplantation due to the host response. Our approach (""""""""modular tissue engineering"""""""") enables the creation of uniform, scaleable and most importantly vascularized constructs. It is based on the porous structure that is created when solid objects on to which endothelial cells (EC) are seeded, randomly assemble to fill a space (an implant site or a tube), creating a perfuseable construct. The interstitial gaps among the modules form interconnected channels which are lined by the endothelial cells. The resulting endothelial cell lining enables whole blood to flow around the rods and through these interstitial channels. Current efforts have demonstrated the principle of modular tissue engineering and that blood can be perfused through the channels in vitro. While our long-term objective is to enable islet transplantation to be successful through tissue engineering, we propose now to show the utility of this approach in vivo, with particular emphasis on (a) the assessment of EC thrombogenicity and (b) minimizing the loss of islet viability due to the blood mediated inflammatory response.
Specific aims : (1) Demonstrate that whole blood (without anticoagulant) can be perfused through an EC covered modular construct and assess thrombosis in a canine AV shunt model. Canine EC seeded modular constructs will be inserted in a parallel flow test section within the AV shunt. (3) Restore normoglycemia in diabetic rats using implanted rat EC seeded modules containing embedded pancreatic islets. We expect to ameliorate the adverse local host response through the presence of the transplanted endothelial cells. Rat EC covered modules will be implanted in both the omental pouch and by portal vein infusion (used clinically). We will address these questions: What happens to the EC lined channels once the modules are implanted? Are the vessels functional? Does EC seeding and modular tissue engineering confer an advantage for insulin secretion and diabetes therapy? We will measure thrombogenicity, perfusion, assess remodeling, and measure changes in glycemia. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB006903-02
Application #
7459032
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
2007-07-01
Project End
2010-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$142,884
Indirect Cost
Name
University of Toronto
Department
Type
DUNS #
259999779
City
Toronto
State
ON
Country
Canada
Zip Code
M5 1-S8
Leung, Brendan M; Miyagi, Yasuo; Li, Ren-Ke et al. (2015) Fate of modular cardiac tissue constructs in a syngeneic rat model. J Tissue Eng Regen Med 9:1247-58
Khan, Omar F; Voice, Derek N; Leung, Brendan M et al. (2015) A novel high-speed production process to create modular components for the bottom-up assembly of large-scale tissue-engineered constructs. Adv Healthc Mater 4:113-20
Fitzpatrick, Lindsay E; Lisovsky, Alexandra; Sefton, Michael V (2012) The expression of sonic hedgehog in diabetic wounds following treatment with poly(methacrylic acid-co-methyl methacrylate) beads. Biomaterials 33:5297-307
Butler, Mark J; Sefton, Michael V (2012) Cotransplantation of adipose-derived mesenchymal stromal cells and endothelial cells in a modular construct drives vascularization in SCID/bg mice. Tissue Eng Part A 18:1628-41
Chamberlain, Michael Dean; Gupta, Rohini; Sefton, Michael V (2012) Bone marrow-derived mesenchymal stromal cells enhance chimeric vessel development driven by endothelial cell-coated microtissues. Tissue Eng Part A 18:285-94
Chamberlain, Michael Dean; Gupta, Rohini; Sefton, Michael V (2011) Chimeric vessel tissue engineering driven by endothelialized modules in immunosuppressed Sprague-Dawley rats. Tissue Eng Part A 17:151-60
Cooper, T P; Sefton, M V (2011) Fibronectin coating of collagen modules increases in vivo HUVEC survival and vessel formation in SCID mice. Acta Biomater 7:1072-83
Khan, Omar F; Sefton, Michael V (2011) Endothelial cell behaviour within a microfluidic mimic of the flow channels of a modular tissue engineered construct. Biomed Microdevices 13:69-87
Khan, Omar F; Sefton, Michael V (2011) Endothelialized biomaterials for tissue engineering applications in vivo. Trends Biotechnol 29:379-87
Corstorphine, Lindsay; Sefton, Michael V (2011) Effectiveness factor and diffusion limitations in collagen gel modules containing HepG2 cells. J Tissue Eng Regen Med 5:119-29

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