The long-term objective of this work is the development of new genetically engineered materials to be used in the fabrication of vascular grafts characterized by improving long-term patency. The approach is predicated on the following hypotheses: i). that existing synthetic vascular graft materials - specifically expanded polytetrafluoroethylene (ePTFE) and Dacron - are not optimal, either in terms of surface chemistry or with respect to mechanical properties, ii). that the mechanisms of healing of synthetic grafts are controlled at least in part by cellular interactions with the graft surface or with macromolecules, including plasma proteins or extracellular matrix (ECM) proteins, deposited on that surface, iii). that a measure of control of cellular behavior at the graft surface can be gained by presentation of ligands for specific cell- surface receptors, and iv). that engineered variants of ECM proteins will allow control, both of the key mechanical properties of the graft, and of the presentation of ligands at the graft surface. The project will include: i). microbial expression of artificial genes encoding artificial ECM proteins that incorporate specific cell-binding and crosslinking domains, ii). fabrication and mechanical characterization of crosslinked films prepared from these proteins, iii). determination of the adhesivity of these surfaces with respect to endothelial cells cultured under physiologically relevant shear stresses, and iv). analysis of the behavior of endothelial cell monolayers cultured on artificial extracellular matrices.
|Heilshorn, Sarah C; Liu, Julie C; Tirrell, David A (2005) Cell-binding domain context affects cell behavior on engineered proteins. Biomacromolecules 6:318-23|
|Richman, Gabriel P; Tirrell, David A; Asthagiri, Anand R (2005) Quantitatively distinct requirements for signaling-competent cell spreading on engineered versus natural adhesion ligands. J Control Release 101:3-12|
|Liu, Julie C; Heilshorn, Sarah C; Tirrell, David A (2004) Comparative cell response to artificial extracellular matrix proteins containing the RGD and CS5 cell-binding domains. Biomacromolecules 5:497-504|
|Nowatzki, Paul J; Tirrell, David A (2004) Physical properties of artificial extracellular matrix protein films prepared by isocyanate crosslinking. Biomaterials 25:1261-7|
|Liu, Charles Y; Apuzzo, Michael L J; Tirrell, David A (2003) Engineering of the extracellular matrix: working toward neural stem cell programming and neurorestoration--concept and progress report. Neurosurgery 52:1154-65; discussion 1165-7|
|Welsh, E R; Tirrell, D A (2000) Engineering the extracellular matrix: a novel approach to polymeric biomaterials. I. Control of the physical properties of artificial protein matrices designed to support adhesion of vascular endothelial cells. Biomacromolecules 1:23-30|