School of Biomedical Engineering, Science & Health Systems V 1.0 SD [020308] CARDIOVASCULAR & BIOMECHANICS RESEARCH Faculty/Contact: Ken Barbee, Ph.D, Drexel University PROGRAM OVERVIEWPROGRAM OVERVIEW Central Nervous System trauma imposes a huge cost on our society in terms of healthcare, disability, and yrs of life lost. An understanding of the cellular mechanisms of neural injury will allow us to develop injury-specific tolerance criteria to be used in the design of safer environments and to develop therapeutic strategies that target the underlying mechanisms of injury to improve outcome. We have developed a cell-culture model for neural injury that allows precise control of the mechanical loading parameters critical for determining injury severity. Neural Cell Injury Vascular Tissue Engineering The promise of tissue engineering lies in the prospect of replacing biological tissue that has become dysfunctional because of trauma or disease, with new tissue capable of responding and adapting to environmental stimuli. The ability to sense and respond to mechanical forces to adapt to the changing physical demands on the tissue is of primary importance in tissues that serve a mechanical or structural func- tion. Previous in vivo and in vitro studies suggest that the structural and mechanical properties of blood vessel walls develop in response to the stress history of the tissue. The endothelium mediates vascular tone and structural remodeling in response to changes in blood flow, while the vascular smooth muscle (VSM) cells sense and respond to changes in stress within the vessel wall. Response to Angioplasty: Vascular Smooth Muscle (VSM) Trauma Percutaneous translumenal coronary angioplasty (PTCA, or balloon angioplasty) offers a less invasive alternative to coronary bypass surgery for patients whose coronary vessels have become occluded because of the process of atherosclerosis. The potential of PTCA has not been fully realized, however, because of the high rate of restenosis, which is the rapid re-occlusion of the vessel, resulting from the pathological growth of the vascular smooth muscle (VSM) in response to the trauma of the balloon inflation. Endothelial Mechanotransduction and Atherosclerosis The endothelium plays a crucial role in the detection and transduction of hemodynamic forces, both in the normal physiological regulation of vascular tone and structure, as well as in the initiation and progression of atherosclerosis. The goal of this research is to understand the mechanisms by which endothelial cells sense and respond to their mechanical environment. Our approach has been to examine the distribution of stresses on the cell and within the cell, on ever smaller lengths of scale, to elucidate the relationships between the applied mechanical forces (described on the continuum level) and the elicited molecular scale signaling events.

School of Biomedical Engineering, Science & Health Systems V 1.0 SD [020308] ENDOTHELIAL MECHANOTRANSDUCTION & ATHEROSCLEROSIS The endothelium plays a crucial role in the detection and transduction of hemodynamic forces, both in the normal physiological regulation of vascular tone and structure, as well as in the initiation and progression of atherosclerosis. The goal of this research is to understand the mechanisms by which endothelial cells sense and respond to their mechanical environment. Our approach has been to examine the distribution of stresses on the cell and within the cell, on ever smaller lengths of scale, to elucidate the relationships between the applied mechanical forces (described on the continuum level) and the elicited molecular scale signaling events. The endothelium of blood vessels presents a wavy surface to the flowing blood. The sub-cellular distribution of shear stress depends on the shape and orientation of the cells and their spatial arrangement within the monolayer. By studying the detailed distribution of stress at this scale and the morphological responses that serve to modify the distribution, we can gain insight into the physical mechanisms by which the cell senses its fluid mechanical environment. A rapidly growing body of evidence indicates that endothelial cells discriminate between subtle variations in the exact loading conditions, including differences in temporal and spatial gradients of shear stress, steady and pulsatile laminar flow, and laminar and turbulent flows. While a few studies have carefully isolated the effects of these individual flow characteristics, it is difficult to assess the relative importance of any one parameter. To interpret the relationships between isolated flow characteristics or the integrated effects of combined loading conditions with the biochemical signaling events that mediate the cell response, a full stress analysis of the cell is needed. The microscopic distribution of shear stress acting on the cell surface provides the boundary condition for such an analysis. Experimental and analytical tools are being developed to assess the stress distribution, throughout the cellular structures, that might be involved in mechanotransduction. Faculty/Contact: Ken Barbee, Ph.D., Drexel University Collaborating Researchers: Dov Jaron, Ph.D., Drexel University; Peter Davies, Ph.D., U. of Penn; Donald Buerk, Ph.D., U of Penn; Thomas Tulenko, Ph.D., Lankenau Medical Research Center. Laboratories: Cellular Biomechanics Lab PROJECTONEPAGERPROJECTONEPAGER Figure 1 - The three-dimensional surface topography of an endothelial monolayer aligned by flow in vitro. Figure 2 - Peak calcium activation is dependent on shear stress and onset rate of shear stress (ORSS).

School of Biomedical Engineering, Science & Health Systems V 1.0 SD [020308] RESPONSE TO ANGIOPLASTY: VASCULAR SMOOTH MUSCLE (VSM) TRAUMA Percutaneous translumenal coronary angioplasty (PTCA, or balloon angioplasty) offers a less invasive alternative to coronary bypass surgery for patients whose coronary vessels have become occluded because of the process of atherosclerosis. The potential of PTCA has not been fully realized, however, because of the high rate of restenosis, which is the rapid re- occlusion of the vessel, resulting from the pathological growth of the vascular smooth muscle (VSM) in response to the trauma of the balloon inflation. Despite the recognition of smooth muscle injury as an initiating event in the process of restenosis, there has been no systematic study to determine the mechanical loading conditions required to produce VSM injury and elicit the restenosis response. A cell-culture model was developed to define the loading conditions required to produce VSM injury. The model system allows precise application of a uniform, isotropic strain field at controlled strain rates. Quantification of the mechanical trauma and correlation to the biological response of the cells allows injury tolerance criteria to be developed. The same model is being used to test the efficacy of treatment strategies that target the primary phenomena associated with the injury. Faculty/Contact: Ken Barbee, Ph.D., Drexel University Collaborating Researchers: Edward Macarak, Ph.D., U. of Penn; Paul Weisz, Sc.D h.c., U. of Penn. Laboratories: Cellular Biomechanics Lab Funding Source: Whitaker Grant PROJECTONEPAGERPROJECTONEPAGER

School of Biomedical Engineering, Science & Health Systems V 1.0 SD [020308] NEURAL CELL INJURY Central Nervous System trauma imposes a huge cost on our society in terms of healthcare, disability, and yrs of life lost. An understanding of the cellular mechanisms of neural injury will allow us to develop injury-specific tolerance criteria to be used in the design of safer environments and to develop therapeutic strategies that target the underlying mechanisms of injury to improve outcome. We have developed a cell-culture model for neural injury that allows precise control of the mechanical loading parameters critical for determining injury severity. Cell injury is characterized by a large, transient increase in permeability to macromolecules, the magnitude of which is strongly correlated with the strain rate. Based on our understanding of the mechanism of injury, we have proposed a novel treatment strategy that targets the primary phenomenon of cellular injury – disruption of the plasma membrane. Correlation of the structural response to trauma with biological function dramatically increases the power of this model to establish cell-based injury tolerance criteria and to evaluate the neuroprotective potential of therapeutic treatments prior to use in animal models. Faculty/Contact: Ken Barbee, Ph.D., Drexel University Collaborating Researchers: Joel Horwitz, Ph.D., MCP Hahnemann University. Laboratories: Cellular Biomechanics Lab Funding Source: Synergy Grant PROJECTONEPAGERPROJECTONEPAGER

School of Biomedical Engineering, Science & Health Systems V 1.0 SD [020308] VASCULAR TISSUE ENGINEERING The promise of tissue engineering lies in the prospect of replacing biological tissue that has become dysfunctional because of trauma or disease, with new tissue capable of responding and adapting to environmental stimuli. The ability to sense and respond to mechanical forces to adapt to the changing physical demands on the tissue is of primary importance in tissues that serve a mechanical or structural function. Previous in vivo and in vitro studies suggest that the structural and mechanical properties of blood vessel walls develop in response to the stress history of the tissue. The endothelium mediates vascular tone and structural remodeling in response to changes in blood flow, while the vascular smooth muscle (VSM) cells sense and respond to changes in stress within the vessel wall. These responses are essential to the maintenance of structural integrity and the regulation of blood flow. The central hypothesis of this research is that in normal development, structural relationships in vascular tissue are optimized for efficient sensing and transduction of the mechanical environment by the cells of the vessel wall. To engineer a tissue structure intended to acquire the property of adaptability present in normal tissues, we must first understand the salient features of the interaction of the cells with their surrounding structures that allow appropriate mechanotransduction to occur. The structure and biochemistry of engineered matrices, as well as pre-conditioning with physiological loading regimes, will be analyzed and optimized based on initial functional properties and the acquisition of adaptive behaviors that will allow long-term replacement of biological tissue. Faculty/Contact: Ken Barbee, Ph.D., Drexel University Collaborating Researchers: Michele Marcolongo, Ph.D., Drexel University. Laboratories: Cellular Biomechanics Lab Funding Source: NSF PROJECTONEPAGERPROJECTONEPAGER