Bioengineering Seminar Schedule

Fall 2006

Friday,September 8, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
Herbert H. Lipowsky
Welcome to New Students

Special Seminar
Ramachandra Gullapalli
"Molecular Dynamics Simulations of a Carbocyanine Dye, DiI-C18, in a DPPC Bilayer."

Abstract

Single molecule spectroscopy techniques such as fluorescence correlation spectroscopy (FCS), fluorescence anisotropy, and Forster resonance energy transfer (FRET) can provide molecular-scale insight into lipid dynamics in model and native membranes. In order to provide atomistic-level interpretation of fluorescence readouts of these techniques we performed molecular dynamics simulations of a commonly used fluorescence lipoid dye molecule, DiI-C18, in a model dipalmitoyl-phosphatidylcholine (DPPC) bilayer. DiI-C18 was constructed using GAUSSVIEW and the partial charges were obtained using the quantum chemistry package, GAUSSIAN. The computational chemistry package, GROMACS was used to simulate a DPPC bilayer containing 0 dyes, 2 dyes and 4 dyes for a duration of 40 nanoseconds on the supercomputing cluster, LION-XM. Two schemes of electrostatics, the particle mesh Ewald method (PME method) and the reaction-field method (RF method) were used to define the intermolecular force-field interactions. Post simulation analysis was done subsequently on the dynamics of the dye in the bilayer using customized programs. We present an overview of the simulation process and representative results. Molecular dynamics simulations of fluorescent dyes in combination with experimental techniques such as FCS and fluorescence anisotropy can help determine how well dyes mimic lipids and thus provide valuable insight into the dynamic nature of biomembranes and their constituents.

Friday, September 15, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
Steven J. Schiff
Brush Chair Professor
Neurosurgery/Engineering Science and Mechanics
"Towards a Neural Engineering of Seizure Control in the Brain"

Abstract

Developing more effective strategies which can control patterns of activity in the brain requires that we understand the neuronal ensemble interactions that underlie such activities. I will describe a variety of ways in which we are seeking to understand such interactions sufficiently well to enable us to form computational models that are reflective of the physics which underlies this biology. Such modeling
permits us insight into mechanism, as well a route to the rational design of control algorithms. There are a host of issues surrounding the translation of such control strategies to the intact organism, including the thin film characteristics of deep brain electrode surfaces, the microlesions created from electrode insertion, the cell-type specific lesion threshold, as well as effective real time measurement with simultaneous control signal application. A long term goal to a more effective control strategy is model based control using predictor-corrector strategies, and a framework to carry this out will be presented.

Friday, September 22, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
Jian Cao
Medtronic
"Clinical Challenges of Arrhythmia Discrimination in Implantable Cardiac Devices "

Abstract

Living with heart disease can be frightening and for some it means being at risk for dangerously fast and potentially lethal heart rates. Fortunately, an implantable cardioverter-defibrillators (ICD) can provide protection and life-saving therapy giving patients greater peace of mind to live life. An ICD continuously monitors patient's heart, if a dangerous and potentially lethal heart rate is detected an electrical signal is sent to correct it. The ICD is implanted under patient's skin just below the collar bone. ICDs must discriminate ventricular tachycardia (VT) or ventricular fibrillation (VF) from supraventricular tachycardia (SVT) in order to prevent delivery of inappropriate shock therapies commonly seen in ICD recipients. Ideal discrimination performance remains an unachieved goal despite two decades of evolving technology. First generation ICDs delivered shocks based entirely upon heart rate. A new electrogram morphology-based Wavelet Dynamic Discrimination Algorithm has been developed in Medtronic ICDs to improve arrhythmia discrimination. Morphology discrimination attempts to distinguish VT (with a morphology different from the prevailing ventricular electrogram morphology) from SVT (where the morphology is usually similar or identical to the prevailing rhythm). The clinical needs, design challenges and research methodologies will be discussed. In addition, a novel use of left ventricular rate-sensing electrograms for VF detection in ICDs patients will be presented. The results suggest that VF sensing from a coronary sinus lead is feasible with a standard right ventricular sense amplifier. Finally, clinical challenges of R-wave sensing in Insertable Loop Recorder (ILR) will be discussed. The ILR is an implantable monitoring device designed to monitor and record the heart's electrical activity.

Friday, September 29, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey

Douglas G. Evans, PE
Chief Operating Officer, Kensey Nash Corporation

"Industry Today"

Kensey Nash Corporation (KNC) provides innovative product development and advanced technology for a wide range of medical procedures. Among Kensey Nash’s product offerings is the TriActiv® System, a unique solution to providing protection from embolic debris which can become dislodged during saphenous vein graft interventions. KNC’s flagship product, the Angio-Seal™ Vascular Closure Device, which is now manufactured, marketed and sold worldwide by St. Jude Medical, Inc., our licensing partner, has gained the number one position in the worldwide puncture closure device market.

KNC's orthopaedic products represent the most significant component of our biomaterials business. Along with the VITOSS® Scaffold FOAM™ series of products that we have co-developed with Orthovita, Inc., KNC manufactures several sports medicine products under private label including meniscal repair tacks, anterior cruciate ligament (ACL) screws, soft tissue attachment screws, and trauma implants. We also manufacture for a strategic partner a resorbable growth factor delivery matrix that is commercially available outside the United States.

Kensey Nash has also developed and commercialized products for oral health, wound care and cell research.

Mr. Evans has been a Director of Kensey Nash Corporation since 1995. From 1989 to 1995, he has held several senior positions at Kensey Nash Corporation in product development and engineering. Since March 1995, Mr. Evans has served as Chief Operating Officer of Kensey Nash. From 1986 until he joined Kensey Nash in 1989, Mr. Evans held positions in engineering and business development for several divisions of the General Electric Company. Mr. Evans received a B.S. degree in Engineering Science and a Masters degree in Business Management from Pennsylvania State University and a M.S. degree in Electrical Engineering from the University of Pennsylvania. Mr. Evans is a Registered Professional Engineer in the United States.

Friday, October 6, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
STUDY DAY NO CLASSES

Friday, October 13, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
No Seminar

Friday, October 20, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
No Seminar

Friday, October 27, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
Shuvo Roy
Cleveland Clinic Foundation
"MEMS for Implantable Medical Applications"

Abstract

Recent progress in MEMS (microelectromechanical systems) technology has attracted great attention to its application for biomedical problems, and has spawned a new field of research unto itself, known as BioMEMS. MEMS technology has enabled low-cost, high-functionality microdevices in some commonly used areas, such as inexpensive printer cartridges for ink jet printing and chip-based accelerometers responsible for deployment of automotive airbags.
The characteristics of batch fabrication, miniaturization, and integration with electronics, which are all inherent in MEMS technology, are particularly attractive for the development of next-generation, cost-effective tools for biomedical research and clinical medicine. This awareness in the potential of bioMEMS has resulted in a flurry of research activities, which, in turn, have culminated in some commercialization successes such as microarrays and lab-on-chip in vitro diagnostics. Furthermore, the feasibility of a variety of implantable bioMEMS devices for drug delivery, physiological monitoring, and tissue engineering, has been demonstrated within a research context. However, their translation into the clinical environment has been largely limited.
At the Cleveland Clinic, the BioMEMS Laboratory is developing MEMS for implantable medical applications with a multidisciplinary team comprised of biomedical engineers, basic scientists, and practising clinicians. This talk will present the state of clinical bioMEMS today and will provide examples of on-going research projects at the Cleveland Clinic including the development of microtransducers for intravascular ultrasound (IVUS) imaging, wireless pressure microsensors for in vivo biomechanics, nanoporous membranes for ultrafiltration, and microtextured scaffolds for bone regeneration.

Friday, November 3, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey

Bruce Wheeler
University of Illinois at Urbana-Champaign
"Brain on a Chip: Engineering Form and Function in Cultured Neuronal Networks"

Abstract

We culture embryonic rat hippocampal neurons to learn how small networks of neurons interact and code information. We design the networks by using microlithography to control surface chemistry that in turn controls the initial position of the neurons and strongly influences subsequent growth. The lithography also permits us to guide neurons preferentially to electrodes of a microelectrode array, with a resultant increase in recordability and excitability of the cultured neurons. Geometric control also allows us to begin to investigate the question as to whether the geometric pattern of a neuronal network influences the patterns of its neuroelectric activity. Various neuronal network behaviors can be demonstrated, including propagation of both action potential and synaptically coupled activity, graded activation of networks, convergence of information flow, and elementary learning phenomena. The immediate aim of the research is the creation of a reliable, repeatable, and robust tool for understanding neuronal information processing. Long term the results will assist basic and applied neuroscience including prosthetics and cell based biosensors.

Friday, November 10, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
Ted Lamson
President and CEO, NeoTract, Inc.
"The Emerging Entrepreneur: Tales from the Road"

Abstract

There you are finishing up your bioengineering degree, be it a BS, MS or PhD and you think you have it in you to come up with a great idea, a brilliant idea for a medical device. You are captivated by the excitement of turning a concept into a product that could help millions of patients. Are you prepared to take this on? How do you even get started?

Referencing several "real-life" experiences we will examine various aspects of medical device venture development, from conducting a needs assessment and developing concepts to testing these concepts and ultimately starting a venture. These processes while particularly germane to venture development, are likely applicable to project development in general, whether you are embarking on your first design project as a professional engineer or you are choosing an area of research for your academic future.

Ted Lamson received his PhD in Bioengineering from Penn State University in 1993, and since then has worked in the medical device industry in both large corporations and start-up ventures, from design engineer to CEO.

Friday, November 17, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
Aleksander Popel
Johns Hopkins University
"Systems Biology of Angiogenesis: from Molecules to Therapy"

Abstract

Angiogenesis is the growth of new microvessels from pre-existing vessels. Angiogenesis is important under physiological and pathological conditions (e.g., exercise, cancer, age-related macular degeneration, rheumatoid arthritis, myocardial ischemia, peripheral arterial disease). Over 70 diseases have been identified as angiogenesis dependent. Angiogenesis involves numerous processes such as: cell sensing of oxygen during hypoxia; upregulation of vascular endothelial growth factor (VEGF), and of matrix metalloproteinases (MMPs); extracellular matrix (ECM) proteolysis and release of matrix-binding growth factors; endothelial cell migration, proliferation and differentiation; tubulogenesis or formation of capillary tubes; network morphogenesis or formation of capillary networks; and vessel maturation that involves recruitment of supporting cells such as pericytes and smooth muscle cells. We have developed several molecular-based computational models that will serve as modules in multi-scale integrative models. These include a model of Hypoxia-Inducible Factor HIF1, a transcription factor largely responsible for upregulation of VEGF in hypoxia; a model of interactions of VEGF splice isoforms with their receptors VEGFR1, VEGFR2, Neuropilin-1 and heparan sulfate proteoglycans; and a model of ECM proteolysis by MMPs, specifically MMP2, MMP9 and membrane-type MT1-MMP, in the presence of tissue inhibitors of metalloproteinases (TIMPs). In addition to these molecular-level models, a framework will be described for incorporating these models into multi-scale rule-based models, thus spanning the levels from the molecular to microvascular. Experimental studies that accompany the computational work will also be discussed.

Monday, November 19, 10:00 - 11:00 p.m., Room 210 Hallowell, CG623 Hershey
Walter Lee Murfee III
University of California, San Diego
"Exploring Adult Microvascular Remodeling: Understanding Perivascular Cell Phenotypes, Arterial/Venous Identity, and the Connections with Other Network Systems"

Abstract

Microvascular remodeling is a complex continuum including capillary sprouting, capillary arterialization and arterial/venous (A/V) differentiation. Understanding each of these sub-processes and their interrelationships in part requires the study of cellular phenotypes along arterioles, venules and capillaries during different stages of network remodeling. Until recently, Neuron-Glia Antigen 2 (NG2) had been identified as a marker for vascular pericytes (a subset of perivascular cells elongated along capillaries), yet the distribution of this proteoglycan along the hierarchy of adult networks and its functional role during microvascular remodeling remained unknown. The overall objectives of my previous work were to evaluate the cellular and spatial distribution of NG2 in adult rat microvascular networks and to assess the contribution of NG2 expression to microvascular remodeling. In quiescent microvascular networks, NG2 is expressed by perivascular cells along arterioles and capillaries, but not along venules. Interestingly in remodeling networks, NG2 upregulation along venules is temporally and spatially linked to capillary sprouting. In the context of starting to understand NG2 function, these results implicate NG2 as a marker of activated venules and functional regulator of angiogenesis. More importantly, this work highlights the overlap between the various sub-processes of microvascular remodeling and my long term research interests regarding the functional importance of perivascular cells during angiogenesis, the regulation of A/V phenotype in the adult, and the commonality of cellular signals across multiple tissue remodeling systems. Exploring the molecular and cellular connections between microvascular patterning and other remodeling processes, such as neurogenesis, lymphangiogenesis, and even inflammation, will provide novel insight into the future engineering and therapeutic manipulation of functional vascular networks. As an example of such connections, current work provides direct evidence for lymphatic/blood vessel interactions at the capillary level in adult microvascular networks. These results establish a foundation for investigating the common and independent mechanisms involved in the growth of these two systems and emphasize the need to better understand microvascular remodeling from a more integrative perspective.

Friday, November 24, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey

NO CLASSES THANKSGIVING BREAK

Friday, December 1, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey
Aaron Mulivor
Massachuttes General Hospital
"Shear Mediated Changes in Endothelial Cell Function: Implications in Atherosclerosis"

Abstract

Cardiovascular disease is one of the leading causes of death in humans. Atherosclerosis, a type of cardiovascular disease, occurs when fatty plaques form on the walls of blood vessels, obstruct blood flow and weaken the blood vessel walls. It is interesting that atherosclerotic plaques form predictably at branches and bifurcations almost anywhere in the vasculature. The mechanism of how plaques are formed is well-understood, but there is a gap in the knowledge surrounding the specific reasons why blood vessel bifurcations are more susceptible to plaque formation. Our goal is to quantify changes in the gene and protein expression of endothelial cells as a result of the dynamic forces imparted by blood cells at bifurcations. We have used a combination of lattice boltzmann modeling, microfluidic devices and in vivo models to help us understand the complex relationships between blood vessels, blood cells and blood flow and help us elucidate why bifurcations are the primary location for atherosclerotic plaque formation. A complex understanding of the cell/cell interactions at bifurcations and how they influence the gene and protein expression of the local endothelial cells will help us treat and prevent atherosclerotic plaques in the future.

Friday, December 8, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey

Student Presentations:
Amit Bhatnagar
"Finite Element Analysis of a 3-Dimensional Multiscale Model of Focal Adhesions."

Abstract

Endothelial cell respond to shear forces via many signaling pathways resulting in proliferation, migration, differentiation and apoptosis. These signaling pathways may originate at focal adhesions (FAs) through force-induced changes in integrin-extracellular matrix (ECM) association and through force-induced deformation of the FA complex. To quantify the forces and resulting deformations in FAs we used finite element analysis of fluid dynamics and stress in a solid model of sheared and focally-adhered endothelial cells. 3D microscopy and TIRF microscopy of calcein-stained endothelial cells were used to develop a 3D solid model of the cell and FA, repectively. Integrin forces were calculated from FA stress values and integrin bond densities obtained from the literature. Results of the model suggest that the largest tensile force on an individual integrin molecule is approximately 0.1pN. Thus, the simulation suggests that shear stress does not provide sufficient force to break integrin and ECM bonds or to appreciably affect their association. Instead, the model suggests an alternative hypothesis to explain FA-mediated signaling which involves FA deformation. Specifically, bending of the membrane toward the substrate may increase integrin-ECM bond formation leading to subsequent signaling. This new model highlights the significance of the modulus of the sub-cellular matrix (SCM) in modulating shear effects on endothelial cells.
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Kaushik Chatterjee
"Solution-Phase Interactions of Prekallikrein and Hageman Factor in Material-Induced Plasma Coagulation"

Abstract

A common problem associated with the use of cardiovascular medical devices is that of coagulation/thrombosis. Towards developing hemocomaptible surfaces, it is important to understand the role of the material surface in blood coagulation. This study investigates the interaction between Hageman factor (human FXII) and Prekallikrein, two proteins that are believed to play a major role in activation of the intrinsic pathway of coagulation. Kallikrein generation in protein solutions containing PK with FXII or FXIIa was measured at model hydrophilic and hydrophobic surfaces using a chromogenic substrate. Results suggest that, in contrast to the conventional biochemical theory, cleavage of Prekallikrein to Kallikrein by FXIIa occurs in solution and the material surface does not play an active role in facilitating this reaction. Strongly-adsorbent hydrophobic surfaces inhibit solution-phase molecular interactions by depleting proteins available in solution. Weakly-interacting hydrophilic surfaces are "apparent" activators, not because they are specific for this series of reactions but rather because they do not inhibit solution-phase interactions. ============================================================================================

Chong Haw Kwang
"Liposomal Delivery of SiRNA Against B-Raf Protein in Melanoma"

Abstract

SiRNA are short interfering RNA that has been known to silence the expression of a target protein by providing an anti-sense strand of the mRNA. Liposomes are nanoparticles composing a phospholipid and cholesterol bilayer. The goal here is to characterize the effect of SiRNA against the B-Raf protein delivered via liposomes. B-Raf protein has been shown to play a critical role in the MAPK pathway that regulates cell proliferation and metastatic potential of melanoma.

Friday, December 15, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey

Student Presentations:

Eun Joo Park
"Noninvasive Ultrasound Glucose Sensing and Insulin Delivery"

Abstract

Current management of diabetes often requires painful repetitive blood glucose tests and insulin injections up to 3-4 times each day. As a potential method of noninvasive method for diabetes, transdermal insulin delivery enhanced by ultrasound has been studied. Based on that ultrasonic wavefield can safely permeabilize skin, this research has been proposed to determine the optimal parameters for a cost-effective, noninvasive method to measure blood glucose and deliver insulin. Light-weight "Cymbal" transducer array generates 20 kHz ultrasound with 20 % duty-cycle (200 ms on every 1 sec) and screen printed biosensor is employed to measure the interstitial blood glucose levels.
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Maruti Uppalapati
"Controlling Microtubule Organization: In vitro Spindles"

Abstract

In eukaryotic cells, microtubules are organized by motor proteins into complex structures such as the bipolar mitotic spindle. The purpose of the mitotic spindle is to segregate the replicated chromosomes during cell division. Mitosis is a complex process involving many redundant and antagonist mechanisms to ensure fidelity in segregating chromosomes. Building an in vitro model of the bipolar mitotic spindle will allow effects of individual and combinations of motors can be studied without the interference from other force generating mechanisms, thereby enhancing our understanding of this complex process. We have developed an in vitro model for the spindle, using dielectrophoretic forces to accumulate microtubules and bind them in the right orientation by patterning neutravidin on electrodes.

Monday, December 18, 12:00 - 1:00 p.m., Room 210 Hallowell, CG624E Hershey

Hsin-Hsin Peng
Final Defense
"Intercellular and Intracellular Signaling During Leukocyte-Mediated Melanoma Cell Transdothelial Migration"

Abstract

The goal of this work is to identify key signaling pathways for melanoma-associated host cell responses during metastasis. We have demonstrated that interleukin-8 (IL-8) is up-regulated in polymorphonuclear neutrophils (PMNs) upon co-culturing with melanoma cells. Melanoma cells induce IkB-a degradation in PMNs indicating that NF-kB signaling is active in PMNs. The production of IL-8 in PMNs is NF-kB dependent. We have further identified that interleukin-6 and interleukin-1b from PMN-melanoma co-cultures synergistically contribute to IkB-a degradation and IL-8 synthesis in PMNs. Moreover, attachment of tumor cells to the endothelium has been shown to be critical for cancer metastases. We have demonstrated that contact of melanoma cells to human umbilical vein endothelial cells trigger rapid endothelial [Ca2+]i response through phospholipase C (PLC)-IP3 pathway. Alternation of endothelial adherens junctions following contact of melanoma cells is evidenced by the changes in immunological staining patterns of vascular endothelial (VE)-cadherin. A PLC inhibitor, which is shown to significantly diminish [Ca2+]i response, reduces the occurrence of melanoma cell–induced VE-cadherin reorganization and attenuates melanoma cell transendothelial migration. In addition to experimental approaches, a mathematic model has been established for studying the intracellular dynamics, such as Ca2+ signals. The tool is beneficial for pathway discovery, in addition to biological investigations.