Enhanced control of both transport properties and surface physiochemical characteristics will be important steps in the development of an effective immunoisolation barrier critical to the success of pancreatic islet cell transplantation. In this proposal, we hypothesize that the cell membrane establishes an important paradigm for the design of a biomimetic immunoisolation barrier with improved performance characteristics because of its capacity to control interfacial mass transport, as well as through its ability to act as a template for more complex structures with other immunoregulatory macromolecules. Specifically, we intend to: 1) Synthesize and characterize a membrane-mimetic, glycosaminoglycan (GAG) containing, glycocalyx for limiting complement activation and macrophage adhesion in the presence of encapsulated xenogeneic islets. In order to limit both complement activation and macrophage adhesion, heparan and chondroitin sulfate will be used as pendant groups on polymerizable phospholipid macromolecules. Alginate-supported lipid membrane assemblies will be produced, polymerized in situ, and both physiochemical and biological properties defined in vitro. 2) Define the transport characteristics of dendrimer based molecular channels. Poly(ethylene oxide) (PEO) dendrimers with macromolecular generations will be synthesized, end-functionalized with a polymerizable moiety, and stably inserted into membrane-mimetic films as artificial transmembrane channels. Diffusivity and mass transfer coefficients will be determined for a range of molecules of varying size and chemical composition. Encapsulated islet cell viability and glucose responsiveness will be defined in vitro. 3) Characterize the physiochemical properties of a biomimetic barrier which influence islet xenograft survival in vivo. Survivability of donor pancreatic islet grafts will be defined in a NOD mouse model using well characterized isograft and xenograft (Porcine yields NOD) models of islet transplantation. Critical endpoints will include capsule stability and biocompatibility, graft survival, and maintenance of euglycemia. The development of an inflammatory response will be analyzed at both cellular and molecular levels utilizing immunohistochemistry, FACS, and PCR based techniques.
| Feng, Xiaoshuang; Chaikof, Elliot L; Absalon, Christelle et al. (2011) Dendritic carrier based on PEG: design and degradation of acid-sensitive dendrimer-like poly(ethylene oxide)s. Macromol Rapid Commun 32:1722-8 |
| Feng, Xiaoshuang; Taton, Daniel; Ibarboure, Emmanuel et al. (2008) Janus-type dendrimer-like poly(ethylene oxide)s. J Am Chem Soc 130:11662-76 |
| Feng, Xiaoshuang; Taton, Daniel; Borsali, Redouane et al. (2006) pH responsiveness of dendrimer-like poly(ethylene oxide)s. J Am Chem Soc 128:11551-62 |
| Feng, Xiao-Shuang; Taton, Daniel; Chaikof, Elliot L et al. (2005) Toward an easy access to dendrimer-like poly(ethylene oxide)s. J Am Chem Soc 127:10956-66 |
