This exploratory study will broaden the existing paradigm on which biomaterials science is based by demonstrating that the cell biology literature can be used to guide development of biomaterial surface modifications that can elicit desired cell behaviors. In this study we aim to identify the main factors important in regulation of endothelial cell recruitment of inflammatory cells. We hypothesize that these factors include the composition of the extracellular matrix (ECM) proteins to which the cells bind, the mechanical properties of the ECM substrate, and the shear stress imparted on the cells by fluid flow. In normal physiology, endothelial cells produce high levels of nitric oxide (NO) and low numbers of Intracellular Adhesion Molecule 1 (ICAM-1) and E-selectin molecules on their surfaces. ICAM-1, and E-selectin are important molecules in the initiation of inflammation because correponding molecules on neutrophils can bind to the endothelial lining of blood vessels through them, and low concentrations of NO lead to up-regulation of one of these. Reduction of inflammation is an important goal of biomaterials science as two of the most prevalent reasons for device failure are acute inflammation and chronic scarring.
Our first aim will be accomplished by comparing the levels of NO, ICAM-1, and E-selectin produced by endothelial cells adhered to Matrigel, laminin-1, collagen IV, collagen III, collagen I, and fibronectin surfaces which have been created either by adsoption or gelation. Experiments will be performed under flow and static conditions. In the second aim, we will measure leukocyte adhesion to endothelial cells cultured on the same substrates also under flow and static conditions. The applications to which this study has direct applicability are vascular grafts and arteriovenous shunts which often lose patency by vascular wall thickening at the edges of the implant that occludes the vessel lumen and decreases blood flow. Eventually we will use the model system developed here to study the usual lack of correlation between in vitro results and in vivo efficacy of biomaterials. Here we use an experimental technique originally developed for intravital microscopy, and this will greatly facilitate such studies by allowing us to use identical experimental measurement techniques in vivo. ? ? ?
| Brower, Jeremy B; Targovnik, Jerome H; Caplan, Michael R et al. (2010) High glucose-mediated loss of cell surface heparan sulfate proteoglycan impairs the endothelial shear stress response. Cytoskeleton (Hoboken) 67:135-41 |
| Caplan, Michael R; Shah, Miti M (2009) Translating biomaterial properties to intracellular signaling. Cell Biochem Biophys 54:1-10 |
