Charles Taylor, Ph.D. Stanford Mechanical Engineering Surgery Phil Tsao, Ph.D. Stanford Medicine Ken Jansen Rensselaer

2. Background Cardiovascular Disease is the leading cause of death in U.S. and developed countries. Will be the leading cause of death in developing world by 2010. Cardiovascular Disease responsible for over $300 Billion in direct and indirect health care costs in U.S. – annually. Cardiovascular Device Industry in U.S. has revenues of approx. $5 Billion - annually. Despite support for basic and applied research programs targeted at CV disease by NIH, NSF, American Heart Association, Whitaker Foundation (single scale), strong need for support for the development of multiscale technologies applicable to CV device design.

3. Application Goals Develop multiscale model including: the effect of the transport, residence time and accumulation of lipoproteins, the interaction between atherogenic agents and the artery wall, blood clotting phenomena and biocompatibility of medical devices response of the artery wall to hemodynamic forces on macroscopic (cardiovascular system) and microscopic (cellular) levels. Develop a computational framework combining a multiphase model for blood, system-to-cellular deformable models for blood vessels and models for the mass transport between the vessel wall and blood stream Apply multiscale biological insights to devise new clinical devices to therapeutically alter the course of abnormal processes (e.g. congenital and adult cardiovascular disease)

4. Multiscale Modeling Needs: Mechanics & Vascular Biology Diameter of blood vessels modulated by blood flow and wall shear stress Thickness and structure of blood vessels modulated by tensile stress and wall strain Cca is common carotid artery, AVF is arterial-veinus Fistula. Middle picture is vein and artery sewn together. Result is high flow and vessel response is to increase diameter and length (not just a bulging hose whose thickness would be reduced but a growth-response). UPSHOT surface forces control size of blood vessels Building Blocks: F fibers, E Elastin, M Matrix, C smooth muscle cell which align circumfrentially to carry hoop stresses (largest) about 100 constituents in humans.Cca is common carotid artery, AVF is arterial-veinus Fistula. Middle picture is vein and artery sewn together. Result is high flow and vessel response is to increase diameter and length (not just a bulging hose whose thickness would be reduced but a growth-response). UPSHOT surface forces control size of blood vessels Building Blocks: F fibers, E Elastin, M Matrix, C smooth muscle cell which align circumfrentially to carry hoop stresses (largest) about 100 constituents in humans.

5. Mechanics & Vascular Biology: Shear Stress Atomic Force Microscropy Scanning Electron Micrograph of fissures that develop in the interelastic lamina the start of the breaing, remodeling, rebuilding process that lead to vessel response.Atomic Force Microscropy Scanning Electron Micrograph of fissures that develop in the interelastic lamina the start of the breaing, remodeling, rebuilding process that lead to vessel response.

6. Cells are cultured onto silicone membrane. Membrane subjected to cyclic strain. Assay determines expression of critical protein Smad6 for varius strain percentages. Cusom M.R. coil for placement in pig, then invivo, then an MR image that it produced with black markers whose position is tracked to give inVivo strain.Cells are cultured onto silicone membrane. Membrane subjected to cyclic strain. Assay determines expression of critical protein Smad6 for varius strain percentages. Cusom M.R. coil for placement in pig, then invivo, then an MR image that it produced with black markers whose position is tracked to give inVivo strain.

7. Multiscale Analysis Needed for Design of Devices Coarctation is pre-existing stenosis (stenosis is a progressive disease)Coarctation is pre-existing stenosis (stenosis is a progressive disease)

8. Cardiovascular Device Application Team Domain Experts: C. Taylor, C. Zarins, and P. Tsao Multiscale Engineering Experts K. Jansen, T.J.R. Hughes, C. Taylor Validation Experts: C. Taylor, C. Zarins Industries Involved: Medtronic and Guidant University validation:Cardiovascular Biomechanics Laboratory (Stanford) Taylor and Tsao have significant experimental programs funded by NIH to support validation studies. C. Taylor is engaged in discussions with Medtronic and Guidant at V.P. level to solicit their participation in ERC. Current status: Reasonably mature modeling of single phase continuum fluid flow with ongoing development (ITR) of continuum vessel models is capable of depicting the mechanical environment but strong need for modeling of multiphase mass transport to the vessel wall, the biological response within the vessel walls and at the fluid/vessel interface before disease progression can be predicted.