Cell-based therapies provide a novel approach to treating chronic diseases. Recapitulating a damaged organ's function by secreting hormones or other factors is dependent upon successful engraftment of transplanted cells. Engraftment of the transplanted cells requires that cells survive the initial hypoxic environment following transplantation, connect with the host vasculature for exchange of nutrients and waste products and also deliver secreted factors into the circulation. Doing this requires creating an environment that promotes long term function of the transplanted cells. If the cell supply is limited, approaches to expand the transplant graft in vivo may also be important. We propose to address the hypothesis that micro-porous polymer scaffolds capable of delivering biologically active peptides can create a microenvironment to promote cell engraftment, survival and proliferation. A classic paradigm for cell-based therapy is islet transplantation for treatment of type 1 diabetes in which destruction of insulin-secreting beta cells in the pancreas results in hyperglycemia and its complications. Recent trials have provided proof of concept that islet transplantation can be efficacious, yet problems remain. To address these problems, we are proposing to transplant islets on microporous scaffolds capable of releasing proteins that can influence the host tissue (e.g., vascularization) or enhance the functionality of the transplanted islets. These factors will condition the microenvironment to promote islet engraftment, survival, and function. We have recently shown that microporous scaffolds can serve as a platform for islet transplantation.
The Specific Aims are as follows. (i) 1) To investigate the hypothesis that the scaffold architecture, as defined by porosity, pore size, and stability, will influence islet engraftment and function. (ii) To address the hypothesis that use of a polymer scaffold to deliver angiogenic factors will improve islet survival and function post-transplantation in a murine model of diabetes. (iii) To test the hypothesis that polymer scaffolds delivering factors that inhibit islet cell death and/or increase islet cell mass post-transplantation will enhance islet engraftment and function. (iv) To determine whether delivering a combination of growth factors that affect different processes (e.g., angiogenesis and islet cell survival and/or proliferation) is more efficacious than delivering a single factor. These studies have the potential to substantially advance cell therapies for islet transplantation.

Public Health Relevance

Transplantation of islets or, ultimately, insulin-secreting cells from other sources represents a potential cure for diabetes, which results from destruction of insulin-secreting cells by the immune system. To enhance cell replacement therapy for diabetes, we are developing scaffolds for transplantation of islets or insulin-secreting cells into peritoneal fat. These scaffolds provide a support for cell growth and can deliver proteins which will be to enhance cell survival and function following islet transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB009910-03
Application #
8274742
Study Section
Biomaterials and Biointerfaces Study Section (BMBI)
Program Officer
Hunziker, Rosemarie
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$349,439
Indirect Cost
$113,675
Name
Northwestern University at Chicago
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Hlavaty, K A; Gibly, R F; Zhang, X et al. (2014) Enhancing human islet transplantation by localized release of trophic factors from PLG scaffolds. Am J Transplant 14:1523-32
Boehler, R M; Kuo, R; Shin, S et al. (2014) Lentivirus delivery of IL-10 to promote and sustain macrophage polarization towards an anti-inflammatory phenotype. Biotechnol Bioeng 111:1210-21
Bryant, Jane; Hlavaty, Kelan A; Zhang, Xiaomin et al. (2014) Nanoparticle delivery of donor antigens for transplant tolerance in allogeneic islet transplantation. Biomaterials 35:8887-94
Gower, R Michael; Boehler, Ryan M; Azarin, Samira M et al. (2014) Modulation of leukocyte infiltration and phenotype in microporous tissue engineering scaffolds via vector induced IL-10 expression. Biomaterials 35:2024-31
Graham, John G; Zhang, Xiaomin; Goodman, Ashley et al. (2013) PLG scaffold delivered antigen-specific regulatory T cells induce systemic tolerance in autoimmune diabetes. Tissue Eng Part A 19:1465-75
Yap, Woon Teck; Salvay, David M; Silliman, Michael A et al. (2013) Collagen IV-modified scaffolds improve islet survival and function and reduce time to euglycemia. Tissue Eng Part A 19:2361-72
Boehler, R M; Shin, S; Fast, A G et al. (2013) A PLG/HAp composite scaffold for lentivirus delivery. Biomaterials 34:5431-8
Gibly, Romie F; Zhang, Xiaomin; Lowe Jr, William L et al. (2013) Porous scaffolds support extrahepatic human islet transplantation, engraftment, and function in mice. Cell Transplant 22:811-9
Boehler, Ryan M; Graham, John G; Shea, Lonnie D (2011) Tissue engineering tools for modulation of the immune response. Biotechniques 51:239-40, 242, 244 passim
Gibly, R F; Graham, J G; Luo, X et al. (2011) Advancing islet transplantation: from engraftment to the immune response. Diabetologia 54:2494-505

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