Research Activities

Current Research Activities
Dr. Rabbany is currently doing research in the field of cellular and tissue engineering as applied to the vascular system. One of the major obstacles in engineering vascularized tissue is induction of endothelial vessel networks. To this end, his research applies engineering principles to the advancements being made in the differentiation of embryonic stem (ES) cells toward engineering vascularized tissue. The focus of the research is to expand pure populations of stem cells in vitro, and influence their cell fate decisions to direct differentiation into vascular cells including functional transplantable endothelial (EC) and smooth muscle (SM) cells. Understanding the mechanistic basis of ES cell differentiation into functional ECs is critical to various aspects of tissue engineering and regenerative medicine. In addition, tissue explants generated by these vascular cells can be introduced in vivo to restore function by augmenting vessel growth, in the ischemic myocardium or limbs of patients after heart attacks or diabetic vascular diseases. The projects range from elucidating the role of physical forces such as cyclic stretch, simulated microgravity, and shear stress on vascular cells and engineering of vascularized constructs. In the past, he has done research in the areas of cardiovascular Mechanics and Biosensors, and cell & receptor biomechanics.

Previous Research Interests:
Nonequilibrium kinetics of antibody-antigen interactions at a solid-liquid interface.
Role of immobilization on antibody function.

The incorporation of biomolecules as recognition elements into optoelectronic devices is becoming an accepted methodology for the fabrication of ultrasensitive detection systems. Biosensors are constructed by immobilizing biomolecules to provide a molecular-level recognition for the compound being detected. A theoretical model is developed to describe the kinetics of antigen binding to immobilized antibodies in flow under nonequilibrium conditions. This area of research utilizes a flow immunoassay which relies on the use of antibodies to detect illegal narcotics or explosives. Antibodies are employed due to their extreme specificity, in order to discriminate drug/explosive molecules among the million of other molecules present in the sample. For example, a cocaine-specific system is presented whereby the anti-cocaine antibody is covalently attached to tiny beads contained in a small column. A fluorescently labeled signal molecule, similar in structure to the cocaine, is bound to the immobilized antibodies, and a continuous flow stream through the column is established. When unlabeled cocaine is injected into the column, it displaces and releases the labeled bound antigen into the flow stream. Fluorescence in the effluent, caused by the presence of the displaced antigen is detected downstream by a fluorimeter. The functional activity of each immobilized antibody is likely to be affected to a different extent depending on the geometry of attachment site on the solid support and the amino acid residue(s) of the antibody molecule used for immobilization. In addition to the physical variables such as flow rate or diffusion, biochemical variables introduced by immobilization include antibody density, steric hindrance, and spatial heterogeneity. Characterization of these parameters will enable manipulation of both the sensors's sensitivity and response time.

Cardiovascular Mechanics
Genesis of intramyocardial pressure. Intracellular pressure, force, and length relations in isolated muscle cells. Mathematical modeling of extravascular forces in the heart. This area of research explores the genesis of intramyocardial pressure (IMP), the positive oscillatory "pressure" measured within the contracting and relaxing walls of the heart. Three generations of mathematical models are developed herein to represent the physical mechanism responsible for the magnitude and distribution of IMP. Model predictions are compared to experimental findings and voluminous literature data. Focusing attention on the muscle cell, intracellular fluid pressure in a contracting isolated skeletal myocyte of the giant barnacle is measured and observed to be dynamically related to shortening, but not to tension in isometric experiments. A mechanistic model of the myocyte, consisting of a fluid-filled cylindrical shell with axially arranged contractile filaments, manifests a positive transmural pressure during shortening, which is attributed to cell distortion. In the myocardium this imposes distortion of the interstitial spaces, thereby altering intramyocardial fluid pressure. Intracellular pressure in the shortening myocyte acts as an internal load, resisting shortening and incurring metabolic costs formerly attributed solely to extracellular load. Transmural pressure developed during shortening is held responsible for cell relengthening during relaxation. Intramyocardial fluid pressure is concluded to be generated by shortening of primarily fluid filled fibers. Therefore, it is caused by an intrinsic wall mechanism, resulting in left ventricular pressure development.Recent efforts are focused on the process(es) of volume regulation within muscle cells. The regulation of cellular volume and its role as a compensatory mechanism for variations in intracellular pressure is being examined.

Cellular Biomechanics

Mechanical forces generated by blood flow have an important effect on vascular pathophysiology. The endothelial cell lining of the cardiovascular system is a highly mutable interface responsive locally to various stimuli such as mechanical stress. The integrity of the endothelial lining of the blood vessels is essential for normal vascular function. Biomechanical forces (i.e., shear stresses) generated by blood flow are important regulators of endothelial function. Expression of vascular specific tyrosine kinases including Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1, flt-1) and Receptor-2 (VEGFR-2, KDR or flk-1) is essential for the survival and functional integrity of endothelial cells. VEGFR-2 is the principal mitogenic receptor for Vascular Endothelial Growth Factor (VEGF) and plays a key role in angiogenesis whereas the role of VEGFR-1 is not clearly understood. In addition, the exact mechanism whereby functional VEGF receptors are expressed on the surface of endothelial cells is not known and is most likely regulated by both growth factors and shear stress. Endothelial cells, serving as a barrier between the vessel and blood, are exposed to shear stress, the tangential component of hemodynamic forces. In this regard, we are currently investigating the potential role of shear stress in the modulation of the surface expression of functional VEGF receptors.