Grant: RFA- DK-08-001 Title: Functionalized, Nanoscale Coatings for Islet Encapsulation PI: Cherie Stabler Project Summary While clinical islet transplantation (CIT) has shown promise for the treatment of Type 1 diabetes, it is dampened by the impaired function and loss of islets following implantation. This loss is attributed to strong inflammatory and immunological response to the transplant, primarily due to cell surface inflammatory proteins and antigens. In this proposal, we seek to minimize detrimental host responses that lead to islet engraftment failure by encapsulating the islets in novel nanoscale biomaterial layers. By developing stable capsules on the order of 1000-fold smaller than standard practices via controlled covalent linking of individual polymers layers on the islet surface, void volumes are dramatically reduced and nutritional transport and glucose sensing is unaffected. Nanoscale layers not only serve as a means to immunocamouflage the implant, but also have tremendous potential to optimize the composition, structure, thickness, and function of these layers on the nanometer level. Once fabricated, these nanoscale layers serve as ideal platforms for the tethering of functional agents, proteins or markers capable of dynamically interacting at the implant-host interface. Therefore, the inert biomaterial layer can be converted to a bioactive surface capable of actively altering the localized implant environment. In this proposal, we seek to tether active immunomodulatory proteins/enzymes, anti-inflammatory agents, and/or engraftment- enhancing nanoparticles to the nanolayer surface. The design of effective strategies to build tailored nano-layers on the islet surface capable of expressing active pro- engraftment agents could significantly improve transplant efficacy and long-term stability. The public health implications of this research are that this approach may provide a means to dramatically improve current clinical islet transplantation results, by reducing or completely eliminating the need for immunosuppressive therapy and improving long- term implant function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
NIH Director’s New Innovator Awards (DP2)
Project #
1DP2DK083096-01
Application #
7613679
Study Section
Special Emphasis Panel (ZDK1-GRB-B (O1))
Program Officer
Appel, Michael C
Project Start
2008-09-30
Project End
2013-06-30
Budget Start
2008-09-30
Budget End
2013-06-30
Support Year
1
Fiscal Year
2008
Total Cost
$2,295,000
Indirect Cost
Name
University of Miami School of Medicine
Department
Surgery
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Giraldo, Jaime A; Molano, R Damaris; Rengifo, Hernán R et al. (2017) The impact of cell surface PEGylation and short-course immunotherapy on islet graft survival in an allogeneic murine model. Acta Biomater 49:272-283
Yang, E Y; Kronenfeld, J P; Gattás-Asfura, K M et al. (2015) Engineering an ""infectious"" T(reg) biomimetic through chemoselective tethering of TGF-?1 to PEG brush surfaces. Biomaterials 67:20-31
Weaver, Jessica D; Stabler, Cherie L (2015) Antioxidant cerium oxide nanoparticle hydrogels for cellular encapsulation. Acta Biomater 16:136-44
Rengifo, Hernán R; Giraldo, Jaime A; Labrada, Irayme et al. (2014) Long-term survival of allograft murine islets coated via covalently stabilized polymers. Adv Healthc Mater 3:1061-70
Pileggi, Antonello; Ricordi, Camillo (2013) A new home for pancreatic islet transplants: the bone marrow. Diabetes 62:3333-5
Gattás-Asfura, Kerim M; Stabler, Cherie L (2013) Bioorthogonal layer-by-layer encapsulation of pancreatic islets via hyperbranched polymers. ACS Appl Mater Interfaces 5:9964-74
Coronel, Maria M; Stabler, Cherie L (2013) Engineering a local microenvironment for pancreatic islet replacement. Curr Opin Biotechnol 24:900-8
Pileggi, Antonello; Xu, Xiumin; Tan, Jianming et al. (2013) Mesenchymal stromal (stem) cells to improve solid organ transplant outcome: lessons from the initial clinical trials. Curr Opin Organ Transplant 18:672-81
Pedraza, Eileen; Coronel, Maria M; Fraker, Christopher A et al. (2012) Preventing hypoxia-induced cell death in beta cells and islets via hydrolytically activated, oxygen-generating biomaterials. Proc Natl Acad Sci U S A 109:4245-50
Pileggi, Antonello (2012) Mesenchymal stem cells for the treatment of diabetes. Diabetes 61:1355-6

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