A tissue engineered pancreatic substitute has the potential to provide a less invasive, more physiologic and potentially less costly regulation of blood glucose levels than current treatment methods based on insulin injections or insulin pumps. However, the development of tissue based therapies is hampered by the low availability of donor tissue and/or the need to immunosuppress the transplant recipient. Tissue substitutes based on non-pancreatic cells retrieved from the same patient and engineered for physiologically responsive insulin secretion have the potential to overcome both of these limitations. The long-range goal associated with this research program is to produce the fundamental knowledge and enabling technologies for developing an efficacious and immune acceptable tissue substitute based on such cells. The objective of this application is to engineer a pancreatic substitute consisting of two components: one, based on recombinant hepatic cells and the second, based on recombinant enteroendocrine cells. The central hypothesis is that these two components, in concert, exhibit insulin secretion dynamics closely approximating those of pancreatic islets and can restore normoglycemia more effectively than either component alone. Guided by strong preliminary data, the hypothesis will be addressed by the following three specific aims: 1) develop a pancreatic substitute based on recombinant hepatocytes secreting insulin under transcriptional regulation;2) develop a substitute based on recombinant, insulin-secreting intestinal endocrine cells, which exhibit physiologic responsiveness at the secretion pathway level;3) combine the constructs developed in Aims 1 and 2 to generate a substitute that exhibits appropriate insulin secretion dynamics for in vivo efficacy. The approach is innovative, as it engineers a functional tissue by combining two cell types with each providing a component of the desired functionality. The proposed research is significant, as it will generate new fundamental information on the development of autologous cell therapies for diabetes, which are not limited by tissue availability and immunoreactivity. It is expected that the generated knowledge will produce a significant advancement towards a therapy that is applicable at a clinically relevant scale.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Appel, Michael C
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Georgia Institute of Technology
Engineering (All Types)
Schools of Engineering
United States
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Tiernan, Aubrey R; Sambanis, Athanassios (2017) Bioluminescence tracking of alginate micro-encapsulated cell transplants. J Tissue Eng Regen Med 11:501-508
Tiernan, Aubrey R; Champion, Julie A; Sambanis, Athanassios (2015) Trichostatin A affects the secretion pathways of beta and intestinal endocrine cells. Exp Cell Res 330:212-21
Tiernan, Aubrey R; Thulé, Peter M; Sambanis, Athanassios (2014) Therapeutic effects of a non-? cell bioartificial pancreas in diabetic mice. Transplantation 98:507-13
Thulé, Peter M; Jia, Dingwu; Safley, Susan et al. (2014) Engineered insulin secretion from neuroendocrine cells isolated from human thyroid. World J Surg 38:1251-61
Duncanson, Stephanie; Sambanis, Athanassios (2013) Dual factor delivery of CXCL12 and Exendin-4 for improved survival and function of encapsulated beta cells under hypoxic conditions. Biotechnol Bioeng 110:2292-300
Phelps, Edward A; Headen, Devon M; Taylor, W Robert et al. (2013) Vasculogenic bio-synthetic hydrogel for enhancement of pancreatic islet engraftment and function in type 1 diabetes. Biomaterials 34:4602-11
Sambanis, Athanassios (2012) Encapsulated cell systems: the future of insulin delivery? Ther Deliv 3:1028-32
Thule, Peter M (2012) Mechanisms of current therapies for diabetes mellitus type 2. Adv Physiol Educ 36:275-83
Durvasula, Kiranmai; Thule, Peter M; Sambanis, Athanassios (2012) Combinatorial insulin secretion dynamics of recombinant hepatic and enteroendocrine cells. Biotechnol Bioeng 109:1074-82
Goh, Fernie; Long Jr, Robert; Simpson, Nicholas et al. (2011) Dual perfluorocarbon method to noninvasively monitor dissolved oxygen concentration in tissue engineered constructs in vitro and in vivo. Biotechnol Prog 27:1115-25

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