The goals of this application are to improve the functionality (insulin secretion rate and pattern) and to expand the life-span of immunoprotected pancreatic islets. The low functionality (less than 15% of the insulin release rate of native islets in pancreas) required a large number of islets within the implant, which causes complications in surgery and discomfort for patients. The limited life-span of the islets in a biohybrid artificial pancreas (BAP) may require frequent cell reseeding and cause further supply problems in islet transplantation. Improved islet functionality and prolonged life-span will minimize the volume of the BAP by reducing the number of islets needed for diabetic patients to achieve normoglycaemia and reduce probes associated with islet supply. It is hypothesized in this research that 1) my mimicking facilitated oxygen transport in avascular tissues, the immunoprotected islets release a higher amount of insulin, recover their intrinsic biphasic release pattern, and prolong their life-span, and 2) insulinotropic agents further promote insulin secretion from islets. Based on these hypotheses, a new BAP system will be designed which contains the water-soluble polymeric conjugates of oxygen carriers (or oxygen binding vesicles) and islet stimulants of sulfonylurea compounds and glucagon-like insulinotropic peptide-1 with entrapped islets in the BAP. The research examines their effects on islet viability, the amount of insulin secretion, the insulin release profile, and the life-span of immunoprotected pancreatic islets. Especially, the combined synergy effects of both hypotheses will be emphasized. The successful results in improving functionality and life-span of islets entrapped in an immunoprotected membrane can be applied in the delivery of micro-encapsulated therapeutic cells and to the miniaturization of a BAP. In addition, the approaches proposed in this research will provide a potential solution to the shortage problem of human cell or tissue sources.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056884-02
Application #
6350743
Study Section
Special Emphasis Panel (ZRG1-SSS-W (21))
Program Officer
Arreaza-Rubin, Guillermo
Project Start
2000-03-01
Project End
2004-01-31
Budget Start
2001-02-01
Budget End
2002-01-31
Support Year
2
Fiscal Year
2001
Total Cost
$233,649
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Nadithe, Venkatareddy; Mishra, Deepa; Bae, You Han (2012) Poly(ethylene glycol) cross-linked hemoglobin with antioxidant enzymes protects pancreatic islets from hypoxic and free radical stress and extends islet functionality. Biotechnol Bioeng 109:2392-401
Nadithe, Venkatareddy; Bae, You Han (2011) Hemoglobin conjugates with antioxidant enzymes (hemoglobin-superoxide dismutase-catalase) via poly(ethylene glycol) crosslinker for protection of pancreatic beta RINm5F cells in hypoxia. Tissue Eng Part A 17:2453-62
Nadithe, Venkatareddy; Bae, You Han (2010) Synthesis and characterization of hemoglobin conjugates with antioxidant enzymes via poly(ethylene glycol) cross-linker (Hb-SOD-CAT) for protection from free radical stress. Int J Biol Macromol 47:603-13
Kang, Han Chang; Bae, You Han (2009) Transfection of insulin-secreting cell line and rat islets by functional polymeric gene vector. Biomaterials 30:2837-45
Kang, Han Chang; Bae, You Han (2009) Transfection of rat pancreatic islet tissue by polymeric gene vectors. Diabetes Technol Ther 11:443-9
Kang, Han Chang; Bae, You Han (2006) Polymeric gene transfection on insulin-secreting cells: sulfonylurea receptor-mediation and transfection medium effect. Pharm Res 23:1797-808
Kim, Sungwon; Wan Kim, Sung; Bae, You Han (2005) Synthesis, bioactivity and specificity of glucagon-like peptide-1 (7-37)/polymer conjugate to isolated rat islets. Biomaterials 26:3597-606
Kim, Yong Yeon; Chae, Su Young; Kim, Sungwon et al. (2005) Improved phenotype of rat islets in a macrocapsule by co-encapsulation with cross-linked Hb. J Biomater Sci Polym Ed 16:1521-35
Kang, Han Chang; Kim, Sungwon; Lee, Minhyung et al. (2005) Polymeric gene carrier for insulin secreting cells: poly(L-lysine)-g-sulfonylurea for receptor mediated transfection. J Control Release 105:164-76
Kang, Han Chang; Lee, Minhyung; Bae, You Han (2005) Polymeric gene carriers. Crit Rev Eukaryot Gene Expr 15:317-42

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