Symposium on Valve Mechanics
A Symposium on Valve Mechanics will be held on Thursday, 7 February 2008. The symposium will consist of two sessions, one on Cardiac Valve Mechanics and Flow Dynamics and the other on the Mechanics, Matrix, and Cell Biology of Cardiac Valves and Myocardium. Each session will feature a Keynote Speaker.
Biomechanics of Engineered Heart Valve Tissues
Session 1: Cardiac Valve Mechanics and Flow Dynamics, Keynote Address: Michael S. Sacks Ph.D, University of Pittsburgh, Pittsburgh, PA
On the most basic functional level, heart valves are essentially simple-check valves that serve to prevent retrograde blood flow. This seemingly simple function belies the structural complexity, elegant solid-fluid mechanical interaction, and durability necessary for normal valve function. For example, valves are capable of withstanding 30-40 million cycles per year, resulting in a total of ~3 billion cycles in single lifetime. Passive in nature, heart valves react to the inertial forces exerted by blood flow and local deformations of the valve annulus. Pressure differences operate on the valve leaflets to initiate rapid opening and closure of the valve. In the closed position, the coapted leaflets are exposed to significant transvalvular pressure. In contrast, relatively small pressure gradients are required to initiate an opening or closure event. Functionally the leaflet is required to exhibit diverse properties under varied states and modes of deformation. No valve made from non-living materials has been able to demonstrate comparable functional performance and durability. However, this staggering level of performance can be cut short by aortic valve disease, the most common form being stenosis resulting from calcification. Currently, the treatment of aortic valve disease is usually complete valve replacement. First performed successfully in 1960, surgical replacement of diseased human heart valves by valve prostheses is now commonplace and enhances survival and quality of life for many patients. However, they continue to have significant clinical problems and there is a profound need for new approaches to valve therapies based on sound scientific and engineering principals.
Tissue engineering represents a spectrum of cross-disciplinary technologies aimed toward the repair, replacement, or enhancement of native valve function. Nonwovens fabricated from bioresorbable synthetic polymers (e.g., polyglycolic acid (PGA)) represent one of the earliest, and to date, most ubiquitous biomaterials used as tissue engineering scaffolds. Their amenability to tissue development, however, belies their intricate microstructure and the concomitant complexity of mechanical interactions occurring between scaffold, cellular, and extracellular matrix constituents in an engineered tissue construct. More recent developments have resulting in scaffolds that incorporate viable cells using simultaneous cell electrospraying/polymer fiber electrospinning that exhibit tissue-like behaviors.
Mathematical models that simulate the composite mechanical behavior of the scaffold and the developing tissue could potentially facilitate the design of engineered tissues and mechanical conditioning regimens. Such models could thus play a pivotal role in the design and development of an engineered heart valve. As in many physiological systems, one can approach heart valve biomechanics from a multi-length scale approach, since mechanical stimuli occur and have biological impact at the organ, tissue, and cellular scales. Robust constitutive models provide the fundamental framework for computational modeling of native and engineered heart valve function. The complex multi-modal nature of valvular leaflet deformation warrants a treatment focused on the prediction of response to generalized mechanical stimuli. A complex interaction of constituents influences the structural response of the tissue. Both the polymeric scaffold fibers and the structural proteins (collagen and elastin) react to mechanical stimuli in varied modes to produce a highly nonlinear anisotropic tissue level response that evolves with time. A morphological based constitutive model that considers a broad range of strain and deformation modes is presented.
My overall research focus is characterization and modeling of the structure-function-biomechanics of native and engineered soft tissues, and linking these studies to underlying cell-tissue mechanobiological interactions. In particular, my laboratory has focused on the mechanical behavior and function of the native aortic and mitral heart valves, including the development of the first constitutive (stress-strain) models for these tissues using a structural approach. To acquire the necessary critical experimental data, my laboratory has developed several novel methods to quantify tissue structure and multi-axial mechanical testing techniques. By integrating the resulting experimental data obtained from both techniques, we have developed structural constitutive (stress-strain) models that directly integrate information on tissue composition and structure. These models avoid ambiguities in material characterization, offering insight into the function, structure, and mechanics of tissue components. Recent work includes multi-scale studies of cell/tissue/organ mechanical interactions in native and engineered heart valves. I am particularly interested in determining the local stress environment for heart valve interstitial cells. This work aims to utilize an integrated experimental/multi-scale finite element approach to determine how hemodynamic loading on the valve translates to altered stress states on the valve interstitial cell function and, in-turn, changes in local extra-cellular structure/composition and valve function. My laboratory is also very active in the biomechanics of engineered tissues, and in particular understanding the in-vitro and in-vivo remodeling processes from a functional biomechanical perspective. Our long-term research goal is to develop a rigorous quantitative understanding of the morphological and functional events that occur during both in-vitro development and in-vivo remodeling, and to use this knowledge to improve replacement heart valves for the pediatric population. Specifically, a question fundamental to the successful development of a clinically feasible tissue engineered pulmonary valve (TEPV) is how well does the TEPV functionally match the native pulmonary valve tissue, and what mechanical, structural, and biological factors guide the remodeling process and final outcome. Once these factors are sufficiently well understood, it should then be possible in subsequent studies to optimize cell sourcing, fabrication techniques, and in-vitro conditioning procedures to produce a functioning TEPV designed for long-term in-vivo function. The goal of the current research program is to thus quantify and simulate tissue remodeling events that occur post-implantation, and to understand what primary factors influence the remodeling rate and final tissue state.
Mechanobiology of Aortic Valve Sclerosis
Session 2: Mechanics, Matrix, and Cell Biology of Cardiac Valves and Myocardium, Keynote Address: Craig A. Simmons, Ph.D., University of Toronto, Toronto, Canada
Calcific aortic valve sclerosis is among the most common causes of heart disease and is associated with a 50% increased risk of cardiovascular-related death. Valve dysfunction in aortic sclerosis results directly from pathological remodeling and calcification of the extracellular matrix of the valve leaflets. Notably, calcific lesions occur focally in regions of the leaflets that experience disturbed patterns of blood flow, high bending stresses, and matrix remodeling that may alter matrix stiffness. These spatial correlations suggest that mechanobiological factors contribute to disease susceptibility and progression. Using animal and cell culture models, we are investigating how biomechanical forces regulate the phenotype of valve cells to lead to calcification. In this talk, I will present our recent findings that indicate that the differentiation of aortic valve fibroblasts to distinct pathologic phenotypes is regulated by extrinsic forces, intrinsic cell-generated forces, and paracrine signaling from valve endothelial cells, which themselves are regulated by hemodynamic forces. By elucidating the mechanobiological determinants of valve calcification, we hope to identify potential cellular and molecular targets for the development of new therapies to prevent and treat aortic sclerosis.
Craig A. Simmons is the Canada Research Chair in Mechanobiology and an Assistant Professor at the University of Toronto in the Department of Mechanical & Industrial Engineering, the Faculty of Dentistry, and the Institute of Biomaterials & Biomedical Engineering. He received his Master’s degree from Massachusetts Institute of Technology in 1994 and his Ph.D. from the University of Toronto in 2000 in Mechanical and Biomedical Engineering. He continued his research training with postdoctoral fellowships at the University of Michigan (2000-2002) and the University of Pennsylvania (2002-2004). The goal of his research is to understand how mechanical forces regulate cell function, and to use this knowledge to develop improved therapies to treat or replace diseased tissues. Specific areas of interest include mechanisms of heart valve disease and strategies to regenerate tissues using stem cells. Prof. Simmons recently co-authored “Introductory Biomechanics: From Cells to Organisms,” a textbook for engineering students at the upper undergraduate and graduate levels.
