Yuan-cheng B. Fung - US grants

The general objective of this proposal is to develop continuum mechanics in pulmonary physiology, to obtain a better understanding of the mechanical basis of ventilation and perfusion of the lung. Specifically, the following projects will be done: (1) Determination of the elasticity of small pulmonary arteries and veins. (2) Elasticity of pulmonary arterioles and venules. (3) The constitutive equations of pulmonary blood vessel wall. Mathematical representation of the pseudoelastic stress-strain relationship. (4) Interdependence of blood vessels and parenchyma - the tethering of arteries and veins by interalveolar septa. (5) Patency of pulmonary veins under negative pressure, with specific applications to blood flow in zone 2 condition (in which the alveolar gas pressure is smaller than the pressure in the pulmonary artery but larger than that in the vein.) (6) Elasticity of the lung parenchyma. (7) Determination of the material constants of the lung tissue elasticity. (8) Experimental measurement of the distortion of pulmonary alveoli when the parenchymal tissue is subjected to nonuniform anisotropic stress states. (9). The collagen and elastin networks in the interalveolar septa, their experimental determination and theoretical analysis. Thus, by completing this research we will obtain reasonably complete information about the mechanical properties of pulmonary blood vessels and parenchyma, their interdependence and relationship to the microscopic alveolar structure and fibroprotein network in the tissues. With this information the physiological problems of blood flow and stress and strain distribution in the lung, and the stability of the lung will be analyzed.

The dynamics of growth and change in heart, lung, and blood vessels will be studied in response to variations in blood pressure and flow. The aim is to understand the relationship between growth and stress to control health problems and possibly to develop new manufacturing methods for artificial tissues. The study is based on previous results concerning residual stress in tissues and the mechanisms by which these stresses arise. The research is likely to give fundamentally important information about the way in which imposed stress determines the rate of tissue growth.

The goal of this proposal is to improve the understanding of the growth and resorption of blood vessels in response to stresses and strains in the vessel wall. The work includes a) experimental and theoretical work to relate structural and mechanical parameters of the wall to stresses and strains, b) determination of factors that determine growth and resorption, and c) determination of the relationship between stress and growth. The work will provide new fundamental knowledge about the way tissues respond to mechanical intervention. The research strongly depends on advanced engineering techniques to describe tissue characteristics, and should contribute to the developing field of "tissue engineering".

The objective of this research is to gain a better understanding of the dynamic role played by stress and strain on the remodeling and growth of the blood vessels. When blood pressure or flow is increased above the normal, changes occur in the blood vessel lumen, wall thickness, zero- stress state, fine structure of the intima, media and adventitia layers, geometry and dimensions of the endothelial and smooth muscle cells, the mechanical properties of the intima-media and adventitial layers, capillaries, and even branching patterns and total generation numbers. Hence our HYPOTHESIS: Stress and strain are important factors that determine blood vessel structure and function, together with chemical factors. We want to document their influence mathematically, with the following SPECIFIC AIMS: 1) To determine the effects of changing blood shear and blood pressure on the remodeling of the blood vessels and express them in the form of indicial functions. 2) To obtain data on the morphology, histology and experimental mechanics of vessels and use them to calculate the stress and strain distribution and determine the strain energy functions of the intima-media and adventitia layers which change in the remodeling process. 3) To demonstrate the applications of the results by solving some key problems of the heart. The biology of growth and remodeling should be studied at all levels from atoms to the whole animal. The scale of the level chosen for the present study is that of the tissue with a minimum dimension in the mu-m range. In this length scale, our RATIONALE is that the engineering approach is the most efficient, in which questions in physiology and medicine can be converted to boundary - value problems whose solutions can be tested experimentally. In the process, we correct a current deficiency in biomedical science: people really do not know how to compute stress and strain in the tissues of blood vessels. We will make an effort to give biomechanics a firm foundation.

9512778 Schmid-Schoenbein Skeletal muscle represents the largest organ in the body. Normal contraction of muscle fibers depends on an intact blood flow in this organ, especially in the smallest blood vessels known as the microcirculation. The blood flow in the skeletal muscle microcirculation can be adjusted according to the activity of the muscle fibers. Understanding of blood flow in this organ is an essential element in understanding muscle performance and its failure. The overall objective of the PI's research project is to develop an analysis of blood flow in skeletal muscle from a basic point of view at the cellular and molecular level using rigorous physical language. The PI's previous NSF project has served to obtain basic elements of the analysis, including the actual network microanatomy of the vast number of blood vessels in the microcirculation, the biophysical properties of the blood vessels (arteries, capillaries and veins) and the blood fluid, the display of nerves, lymphatics, and other cells in the muscle. This information was integrated into an analysis of blood flow in resting non-contracting skeletal muscle which is based on basic biomechanical principles and implemented in form of a numerical computation on a digital computer by means of highly efficient algorithms. The predictions of the analysis were compared with all suitable experimental results in the skeletal muscle literature. In addition, the PI has carried out additional experiments on blood flow in skeletal muscle to test the analysis in quantitative details. The analysis provides the first time a comprehensive picture of skeletal muscle blood flow with physical precision. While this approach serves to explain a large number of experimental observations in the past, it has also lead to several discoveries including the following: 1) The basis for the specialized relationship between pressure, which drives the blood in skeletal muscle and blood flow, was identified and its physical origin was identified. 2) The identification of the mechanism that leads to cessation of muscle perfusion during pressure pulsations. 3) The identification of a previously undescribed mechanism for lymph flow in skeletal muscle. Recently, evidence has been obtained for a second valve system in the lymphatics of skeletal muscle, in addition to the well-known intralymphatic valve system. This observation provides the first time a comprehensive understanding of the mechanism by which lymphatics transport fluid and cells. 4) The identification of a new membrane function of the cells lining the blood vessels, i.e. the endothelial cells. 5) Analysis that served as the basis in leading to the discovery of a mechanism by which the small arteries in the microcirculation grow (research by the PI's former student Dr. T.C. Skalak at the University of Virginia, Charlottesville). 6) The discovery of a significant influence that circulating white blood cells have on the perfusion of skeletal muscle, especially when these white blood cells are activated. The PI has also identified a mechanism by which endothelial cells project small cytoplasmic extensions into the lumen of the microvessels in the activated state. These observations are important in regards to muscle fatigue. The proposed research serves as a direct expansion of the current analysis. The future analysis is directed at the following: 1) Expansion of the current analysis to the case of contracting muscle. During contraction, the skeletal muscle fibers compress the blood vessels of the microcirculation and therefore strongly influence the blood flow to the organ. 2) Identification of the biomechanical mechanism by which relatively few circulating white blood cells exert a significant influence on the perfusion of muscle microcirculation. 3) To study the influence of cytoplasm extensions on endothelial cells lining blood vessels on perfusion of the muscle microcirculation. The PI will continue to carry out the experiments on skeletal muscle in rats, so that all prev ious information serves as a basis for the future work without uncertainties regarding species differences. ***

The Constitutive Equation of the Tissue Remodeling of Blood Vessels

ABASTRACT (250 words)
The remodeling of blood vessels in human due to high blood pressure is very important to health and has to be understood. The objective of this proposal is to make a more complete plan of biomechanical research to gain a fuller understanding to solve physiological problems. The first step is to describe the spatial distribution of each kind of the bio-molecules in the cell as a tensor. The tensor is a mathematical concept used to describe the geometrical configuration of a system of vectors in a 3-dimentional space and has been used widely. The second step is to determine the relationship between the mechanical stresses acting in the blood vessel wall and the tensors of the bio-molecules in vascular remodeling. This relationship is the Constitutive Equation of the remodeling tissue.

The U.S. Congress has been paying attention to the health of aging population in our country, since baby boomers are getting to retire. Hypertension is one of the major diseases affecting many aging people, since it will cause stroke, heart attack, heart failure, and other complications. The molecular mechanisms of hypertension have been the central theme in biological investigations. However, the connection between the bio-molecules and the mechanical forces is little known, but can be revealed by determining the Constitutive Equation of the remodeling tissue. The importance of this research is to provide a key which is required in the translation of basic science to human benefits. Educational impacts will be achieved by recruiting students to participate in this research.