A significant obstacle in islet transplantation is the high rate of primary nonfunction and early islet destruction, which has been observed after intraportal islet infusion, both in animal models and in clinical trials. Substantial evidence now suggests that an acute blood mediated inflammatory injury is largely responsible for the observed functional stunning or destruction of islets and may well amplify subsequent immune reactions. In this proposal, we hypothesize that physiologically relevant anti-coagulant/anti-inflammatory processes establish an important paradigm for the design of a conformal islet encapsulation barrier that is """"""""actively"""""""" anti-inflammatory. Specifically, we plan to fabricate an ultrathin film on the islet surface by a strategy of layer-by-layer (LbL) polymer assembly. Maladaptive inflammatory responses will be modulated by incorporating into the thin film, thrombomodulin (TM) and heparin, as inhibitors of thrombin dependent responses and CD39 as an inhibitor of purinergic mediated (i.e. ATP/ADP) procoagulant/pro-inflammatory pathways. In this manner, the islet cell mass required to achieve euglycemia will be reduced and long-term graft survival enhanced. Specifically, we intend to: (1) Fabricate a biocompatible conformal islet encapsulation barrier of deemed permeability by a strategy of layer-by-layer (LbL) polymer assembly. Porcine and mouse islets will be conformally coated with a polymer film and their short-term function and viability characterized. The ability of a conformal coating to prevent activation of the coagulation cascade and enhance islet engraftment will be defined using established allograft (B 10.BR -> C57/BL6) and xenograft (Porcine -> C57/BL6) models. (2) Determine the complementary effects of surface-bound heparin and thrombomodulin as interactive anti-inflammatory strategies designed to optimize islet engraftment and long-term islet survival. The ability of a TM and heparin containing conformal coating to prevent activation of the pro-inflammatory responses will be determined in vitro and in vivo and the capacity to enhance islet engraftment and long-term survival characterized. (3) Define the capacity of CD39 to abrogate prothrombotic and proinflammatory pathways that contribute to primary islet non-function and late islet destruction. CD39 will be incorporated onto conformally coated islets, either alone or as a component of TM and heparin containing films. The capacity of CD39 to potentiate the anticoagulant/anti-inflammatory properties of a protein C activating polymer coating will be determined. Enhancement of islet engraftment and long-term survival will be investigated.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SRB-G (03))
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Appel, Michael C
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Emory University
Schools of Medicine
United States
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Dydek, E Victoria; Chaikof, Elliot L (2016) Simulated Thrombin Generation in the Presence of Surface-Bound Heparin and Circulating Tissue Factor. Ann Biomed Eng 44:1072-84
Kim, Wookhyun; Haller, Carolyn; Dai, Erbin et al. (2015) Targeted antithrombotic protein micelles. Angew Chem Int Ed Engl 54:1461-5
Krishnamurthy, Venkata R; Sardar, Mohammed Y R; Ying, Yu et al. (2015) Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo. Nat Commun 6:6387
Gagner, Jennifer E; Kim, Wookhyun; Chaikof, Elliot L (2014) Designing protein-based biomaterials for medical applications. Acta Biomater 10:1542-57
Hohmann, Jan David; Wang, Xiaowei; Krajewski, Stefanie et al. (2013) Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding? Blood 121:3067-75
Mets, Joseph M; Wilson, John T; Cui, Wanxing et al. (2013) An automated process for layer-by-layer assembly of polyelectrolyte multilayer thin films on viable cell aggregates. Adv Healthc Mater 2:266-70
Jordan, Sumanas W; Corriere, Matthew A; Vossen, Carla Y et al. (2012) Flow-simulated thrombin generation profiles as a predictor of thrombotic risk among pre-menopausal women. Thromb Haemost 108:258-65
Kim, Wookhyun; Brady, Colin; Chaikof, Elliot L (2012) Amphiphilic protein micelles for targeted in vivo imaging. Acta Biomater 8:2476-82
Naik, Nisarga; Kumar, Vivek; Chaikof, Elliot L et al. (2011) MEMS-assisted spatially homogeneous endothelialization of a high length-to-depth aspect ratio microvascular network. Conf Proc IEEE Eng Med Biol Soc 2011:290-3
Kim, Wookhyun; Xiao, Jiantao; Chaikof, Elliot L (2011) Recombinant amphiphilic protein micelles for drug delivery. Langmuir 27:14329-34

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