RESEARCH EXPERIENCE FOR UNDERGRADUATES (REU)
Undergraduate Research
IN BIOMEDICAL ENGINEERING 2007
REU Research Areas
The REU program focuses on research in the major thrust areas of the Department of Biomedical Engineering. Examples of research projects that are designed for the 10-week REU program are listed below.
Biomaterials, Tissue Engineering, and Drug Delivery
Cardiovascular Biomaterials and Vascular Engineering
Dr. Marchant's research is concerned with biomimetic materials and vascular tissue engineering. Cell and molecular studies of the underlying mechanisms provide the basis for developing biomimetic materials and blood compatible interfaces. This research has a foundation in understanding and exploiting lessons from Nature to design and engineer biomaterials derived from principles of self-assembly and biological hierarchical structure. Project areas include cardiovascular biomaterials, vascular tissue engineering, and project concerned with understanding the mechanisms of infection on biomaterials.
Vascular tissue engineering project area is concerned vascular tissue engineering small diameter arterial replacement. The research is based on the hypothesis is that endothelial cell (EC) function can be controlled by utilizing peptides with high affinity and specificity for EC surface receptors in a biomimetic polymer that will also suppress platelet adhesion and thrombosis, and that an adventitial/medial peptide-bearing degradable polymer scaffold system will encourage smooth muscle cell (SMC) incorporation and healing. The research involves synthetic and biopolymer synthesis and characterization of biomimetic constructs, cell culture studies using either human endothelial cells or smooth muscle cells, and hemodynamic flow studies.
The Biomimetic interface materials project area involves the design and synthesis of biomimetic comb-like polymers directed towards improving the blood compatibility and tissue engineering artificial blood vessels. The projects are based on the hypothesis that controlled spatial placement of oligosaccharides and/or cell adhesion peptides on a biomaterial will facilitate programmed biological responses that minimize non-specific interactions, and enhance selective cell interactions. The multi-component, non-covalent biomimetic self-assemblies provide enhanced interfacial biocompatibility and biological function. Students may focus on either the biomimetic design, synthesis, and analysis of the self-assembling materials using spectroscopic techniques and AFM with in vitro evaluations of blood compatibility using microscopy techniques, or on the tissue engineering aspects, by focusing on protein and endothelial cell interactions with the materials, which involves cell culture studies.
Staphylococcus epidermidis infections can be a significant complication involving blood-contacting biomaterials. In this project area we explore targeting the bacteria using binding ligands on gold nano particles as a route for treating device infections. The research involves peptide synthesis and characterization, peptide-modified nanoparticles, optical and electron microscopies and atomic force microscopy.
Nanoscale Orthopedic Biomaterials:
Dr. Eppell’s research involves nanoscale self-assembly and structure-function relationships in connective tissues. A parallel research thrust involves technique development for probing biological systems at the nanoscale.
Mechanical properties of mineralized collagen gels: The student will learn how to make synthetic collagen fibrils starting with collagen monomers, and to then mineralize the fibrils. They will then learn how to uniaxially press the mineralized gel and dehydrate the material using a cold press. The student may also attempt to improve the mechanical properties of collagen gels by orienting the fibrils and crosslinking them to achieve a biomimetic construct. The degree of crosslinking will be determined using IR spectroscopy, while fibril morphology will be assayed using polarization light microscopy and Scanning electron microscopy (SEM), with changes in mechanical properties assayed using a dynamic mechanical analyzer.
Computer simulation of collagen fibril self-assembly: The student will use Matlab to create a model of a collagen molecule and compute the interaction energy between two molecules as a function of the relative displacement and angle between the two molecules. The student will build an interaction profile based on Coulombic interactions, van der Waals interactions, and an effective medium theory to handle hydrophobic interactions. The project draws on topics of electrostatics, solvation forces, programming in Matlab, and protein structure.
Calibration of near field nanoscale electrostatic measurements: This project focuses on developing atomic force spectroscopy so that electrostatic fields around nanoscale objects can be measured. The student will use current protocols to measure the electrostatic field around 50 nm diameter polystyrene spheres. This will involve learning some organic chemistry, how to image a sample by AFM, how to use a 100 MHz digitizing board to collect high bandwidth AFM data, and some computer programming skills to assist in data analysis.
Alsberg Stem Cell and Engineered Novel Therapeutics (ASCENT) Lab:
Dr. Eben Alsberg is an Assistant Professor in the Departments of Biomedical Engineering and Orthopaedic Surgery. His laboratory focuses on engineering functional biologic replacements to repair damaged or diseased tissues in the body. We use the complex signals that are implicated in tissue morphogenesis, repair, and homeostasis as a template for the development of innovative biomaterials for tissue regeneration. Through the precise temporal and spatial presentation of soluble bioactive factors, mechanical forces, and biomaterial physical and biochemical properties, we aspire to create microenvironments that regulate cell gene expression and new tissue formation.
Examples of student projects in his lab include engineering and characterizing new biomaterial systems and cellular microenvironments, studying stem cell interactions with biomaterials, controlling delivery of growth factors, genetic material, and cells, and understanding the role of mechanics in modulating cell behavior.
Development of multifunctional nanoparticles for targeted drug delivery:
Nanoparticle platforms carrying therapeutic and diagnostic payload, and surface-modified by cell-selective ligands are an effective way to achieve site-targeted delivery and release of bioactive agents to various pathologic sites while avoiding non-specific uptake and systemic side effects. The Integrative Nanomedicine Engineering and Technology (INET) laboratory lead by Dr. Sen Gupta uses this approach for developing targeted drug delivery platforms for vascular and cancer pathologies. The research involves synthesis and characterization of novel polymers, development of nanoparticles therefrom, surface-modification of nanoparticles with disease-specific 'homing' ligands, formulation of drugs in the nanoparticle, and study of cell-targeting and drug delivery using microscopy techniques.
Image Guided Drug Delivery
Dr. Agata Exner's research focuses on image guided drug delivery. A major thrust of our laboratory is to utilize advancements in drug delivery, nanotechnology and biomedical imaging to advance the field of cancer therapy with the long term goal to minimize the burden of treatment on the patient. To achieve this goal we have focused on three treatment areas - local drug delivery, targeted multifunctional nanoparticles and focused hyperthermia. These approaches have great potential for maximizing the treatment directly at the tumor site while minimizing systemic side effects. However, they have not been widely accepted as part of the mainstream cancer management because they have not yet shown adequate benefit over the gold standards (surgical resection, radiation and systemic chemotherapy). Our primary research focus is engineering polymer implants for image-guided intratumoral chemotherapy. We are investigating the use of ultrasound for noninvasive characterization and modulation of drug delivery from these implants, and assessing their efficacy in vivo as a stand-alone system and as an adjuvant to image-guided ablation. We are also developing a mathematical model of in situ-forming drug delivery systems to serve as a tool for future selection of optimal formulation parameters for a specific application. This research will advance the field of on-demand drug release from implantable devices and increase benefits of local drug therapy by enhancing drug retention and distribution. Another research direction is the development of nanoparticles for cancer detection and treatment. We are striving to build a platform technology for multifunctional, ultrasound-aided nanoparticles which will expand the use of ultrasound contrast agents in novel applications. These particles will possess a combined vascular and cellular targeting strategy unique targeting to reduce nonspecific binding. Finally, we are engineering a thermosensitizer and associated delivery system for improved hyperthermia tumor treatment. Within the scope of this project we are evaluating a bioactive polymer as a thermosensitizer specific to cancer cells and determining the mechanism of action of its bioactivity. We are also developing a carrier vehicle for delivery and monitoring of active agent with ultrasound. This research will broaden the impact of sensitizing molecules in cancer therapy and establish new approach to strengthen the use of hyperthermia in cancer treatment.
Vascular Tissue Engineering
Dr. Horst von Recum's research includes tissue-engineered epithelia; pre-vascularized polymer scaffolds for tissue engineering; directed stem cell differentiation; and novel stimuli responsive biomaterials for gene and drug delivery.
Controlled Delivery of Molecules and Cells - Our research group is examining the creation of novel polymeric platforms for drug delivery and tissue engineering. Student projects could be on the following topics:
1) Drug Delivery: Polymers which can be loaded with drug and refilled at a later time. Delivery of Chemotherapeutic Agents, Proteins for HIV Therapy, Antibiotics , DNA and siRNA. Degradable polymers which are capable of in situ polymerization or gelation.
2) Tissue Engineering: Polymers which can present biomolecules, and are available for remodeling or refilling at a later time. Cellular models using embryonic stem cells to generate mature cells which are difficult to proliferate in culture. Differentiation into Endothelial Cells, Cardiomyocytes, Motor Neurons
Computational and Experimental Mechanobiology
Dr. Knothe-Tate studies the effects of forces on cells and cellular structures, and transport at different length scales from tissue to cells. Two areas are suitable for REU projects are:
Cytoskeletal conformation in health and disease The student will apply currently established protocols to investigate the conformation of the osteocyte skeleton in health and disease. Changes in the cytoskeleton, in response to the application of dilatational (e.g. compressive) and deviatoric (e.g. shear) stresses, will be investigated to determine the potential role of the cytoskeleton in adapting to dynamic mechanical and physiological environments. This project incorporates fundamentals of cellular mechanics with those of cell biology, empowering the student to apply state of the art methods in a multidisciplinary fashion.
Network modeling of biotransport in brains and bones: The project provides the student with the opportunity to apply computational modeling algorithms to understand transport of endogenous (e.g. nutrients and cytokines) and exogenous (e.g. drugs) transport through a student defined system, organ or tissue. These methods are currently being implemented to study transport through brain and bone tissue in healthy and pathological states. Designed for the student with mathematical or computational "flair", this project affords the opportunity to apply theoretical techniques to patient care scenarios.
Biomedical Imaging and Sensing
Electrochemical and Optical Biosensors
Dr. Gratzl is interested in cost-effective diagnostic devices, measurements of cellular neurotransmitter and cancer cell drug resistance.
A BioMEMS platform for acute cellular transport and communication. The student project will involve developing a BioMEMS platform for neurotransmitter monitoring at PC12 cells and at cells derived from the nervous system, and testing different aspects of the approach. Examples include: oxygen metabolism at macrophages; simultaneous monitoring of oxygen and nitric oxide at macrophages; chloride and bicarbonate transport at cystic fibrosis related cell patterns before and after genetic treatment; and dopamine release at single PC12 cells. The student will gain experience with MEMS technology and wet laboratory practice, and experience with optical and electrochemical instrumentation, The student will develop skills for designing electronic circuits, experiments involving live cell preparations, write and implement software to control instruments, and analyze data with statistical methodologies.
Biomedical Image Analysis:
Dr. Wilson’s research concerns biomedical image analysis including image registration, image segmentation, and image measurements. Application areas include interventional MRI and vascular MRI and in vivo cellular and molecular imaging.
Vascular image analysis (VIA): In this project, the student will be involved in developing the VIA computer program for visualization and image analysis of human blood vessel disease. MR images will be displayed with or without registration, noise reduction filtering, and coil sensitivity correction. Window-level values will be changed and stored so as to enable identical displays for multiple operators in a tissue analysis study. Tissue will be manually typed from multiple MR images using an interface where multiple, registered, images are visible side-by-side. A cursor will be linked to all images so that one can compare the MR signal for different morphological features. Various measurements will be exported into a spreadsheet, with data saved in an open format such that all the parameters can be easily identified. VIA will enable comparisons of the image analysis results. Expert versus expert comparisons of contours and tissue typing will be possible with statistical analysis. We will compare contours and tissue typing results imported from computer algorithms with those from experts. Visual comparisons will be possible, including comparisons to typed, registered histology images.
In vivo assessment of pneumonia using bioluminescent imaging: This project concerns assessing bacterial pneumonia infection non-invasively. The REU student will label bacteria with luciferase and use bioluminescent imaging techniques. The idea is to compare wild type and knockout mice, which have been modified to omit a protein thought to be important for neutrophil adhesion and movement. Serial in vivo studies will greatly aid the analysis. We will compare results from mice knockouts and wild types to see if there is a tendency for spreading of infection. The student also will participate in the imaging experiments and develop an image analysis method.
Magnetic Resonance Imaging and Spectroscopy of Cardiovascular System
Dr. Xin Yu’s laboratory is devoted to the integrative study of the cardiovascular system. The focus of research in my laboratory is to develop magnetic resonance imaging (MRI) and spectroscopy (MRS) techniques for phenotypic characterization of cardiovascular diseases in both humans and animal models, and to apply these techniques to elucidate the structure-function and energy-function relationships in diseased hearts. We are interested in both basic science and translational clinical research that combines the state-of-the-art NMR technology with molecular biology approaches to explore the mechanisms of myocardial remodeling in diseased hearts. Currently, we are investigating the myocardial remodeling processes in genetically manipulated mouse models, muscular dystrophy and diabetes in particular.
Biophotonics, Optical Biomedical Imaging, Optical Coherence Tomography
Dr. Rollins is interested in the application of advanced optics and photonics technologies for imaging and characterization of biological samples, and early disease and monitoring of therapy. The technique of optical coherence tomography (OCT) is the primary basis of this research.
Imaging probe for clinical optical coherence tomography (OCT): This project will involve the REU student in the design and construction of a compact optical scanning probe for clinical imaging using a gradient index relay lens. The experiments will include optical design, probe fabrication, and integration with clinical OCT imaging instrumentation. Applications include imaging in clinical dermatology and oral cavity.
In vivo confocal microspectroscopic imaging: This will involve modification of an in vivo confocal microscope to enable differential absorption microspectroscopic imaging and fluorescence microscopy. The project will include specification and integration of optical sources, cameras and filters with the existing instrument, and customization of control and data acquisition software. Applications of this instrument will be imaging cell infiltration of the cornea.
Integrated electronics for real-time optical coherence tomography (OCT): Improvement and integration of signal processing electronic for real-time OCT imaging instrument. This project will involve specification, design, simulation, fabrication, testing, and integration of signal processing electronics, including a frequency-tracking bandpass filter. A second component of this work involves development of a software package for viewing, processing, and analyzing OCT images and image streams to be used by researchers and clinical collaborators, including non-technical users. The project will involve integration of existing software, development of new software, and interfacing with users to specify functional and interface needs. These improvements will impact all of our clinical and scientific projects using real-time OCT imaging.
Neural Engineering and Rehabilitation
Neural Engineering:
Dr. Durand works in the area of neural engineering, which is at the interface between engineering and neuroscience, and combines computational neuroscience, engineering and electrophysiology to solve problems in the central nervous system (seizures in patients with epilepsy) and peripheral nervous system (neural Interfacing).
Neural Interfacing In the peripheral nervous system: Novel nerve electrodes are being developed capable of stimulating and recording neuronal activity selectively. This methodology is applied to the hypoglossal nerve to restore potency in the airways in patients with obstructive sleep apnea and to design neural prostheses for patients with spinal cord injury. An REU student on this project will participate in designing a tool for installing nerve electrode. The student will work in a team, which includes a clinical and faculty collaborators, to design and test a tool to be used in surgery. The student will develop skills in the relevant areas of neural engineering, biomechanics, and biomaterials.
Computer simulations of both neurons and volume conductors are used in conjunction with experiments for the quantitative analysis of neural systems and to design new electrodes for interfacing with the nervous system. 3-dimensional reconstruction of nerve cross sections. The student will work on software imaging alongside several researchers in the neural engineering center to reconstruct the anatomy of peripheral nerve and determine how fascicles branch within the nerve. The student will work with histological slides and new software designed to reconstruct volumes for cross sections and will develop skills in bio-computation and software engineering.
Neuroprosthesis For Coordinated Arm and Hand Function:
Dr. Kirsch is interested in restoring arm and hand movement function to individuals with paralysis arising from spinal cord injury and other neurological conditions through the use of neuroprostheses based on functional electrical stimulation. The research tools employed include musculoskeletal biomechanical measurements, mathematical modeling and simulation, and tests of control concepts with neuroprostheses users. REU Students will have opportunities to learn how to measure human motor performance using state-of-the-art 3D video systems and 3D force measurement transducers. They will also learn how to record muscle activity and witness the involvement of biomedical engineers in the rehabilitation environment.
Command source evaluation for arm-hand neuroprosthesis. Functional electrical stimulation can produce muscle contractions that generate desired movements, but an interface through which the user instructs the system on what movement is desired must be developed. Students will investigate different possible command sources such as eye movements, head movements, voice commands, and EEG signals using a robotic simulation of a paralyzed arm. Different signal processing techniques will be employed and information transfer will be computed to evaluate each command source.
Model-based development of FES controller algorithms. Musculoskeletal modeling is a technique that uses mathematical descriptions of the skeleton, the joints, and the muscles to create a “virtual arm“ or a “virtual leg“ that can be used to perform simulations of movements of interest. The musculoskeletal model can be used as a proxy for an actual human subject, allowing simulations to replace tedious and perhaps risky procedures in the early evaluation of a new neuroprosthesis. Students will take anatomical measurements obtained from the literature, from experimental measurements, and from MR images, to obtain accurate measurements of model parameters. The model will then be used to develop feedback controllers for the arm and the leg that could be implemented in actual human subjects to restore function.
Motor Function Restoration with Neural Prostheses, Control of Orthotic and Prosthetic Systems:
Dr. Peckham is interested in development of special sensor mechanisms for the detection of physiological events.
Development of sensor systems for detection of physiological events: Restoration of functional control of the paralyzed nervous system with neuroprostheses requires the analysis in real time of physiological events, such as foot to floor contact, or grasp force to sense contact pressure. The development of sensor systems that detect such events enables testing in clinical subjects the control algorithms to be used in more complex and clinically acceptable implanted systems. Furthermore, these sensor systems employ technologies that will be used in more complex implantable devices.
Analysis of command control techniques for neuroprostheses: The interface between the disabled person and the neuroprosthesis is one of the most complex challenges in the development of neuroprostheses. An effective command control interface requires that the control be natural and unobtrusive. Several alternative command control interfaces with a range of complexity are under development, including physical sensing of joint position, myoelectric activity, and cortical signals. Undergraduate projects in this area are to identify signal source and signal processing techniques to provide a command signal with the characteristics that enable an effective interface to the neuroprosthesis.
Brain-computer interfacing:
Dr. Dawn Taylor’s primary area of research is in brain interfacing. Brain activity can be used to drive a variety of assistive technologies by thought. Using brain signals in real time to direct the actions of an assistive device has the potential to benefit severely paralyzed individuals as well as advance our understanding of how the brain works. The REU student will be involved in using invasive and non-invasive brain recording techniques such as intracortical microelectrodes, brain surface recordings, and scalp surface recordings. These different types of brain signals will be applied to the control of customized computer software, assistive robotics, and neuroprostheses designed to restore arm and hand function in people with spinal cord injuries. One aspect of this work for a student to focus on is to assist in developing ways to utilize brain signals more effectively, by retraining the brain to convey the desired action of the assistive device. This requires the development of appropriate training environments and adaptive decoding algorithms that can track changes in brain pattern generation over time. Direct brain control of both physical and virtual reality objects will be used to evaluate decoding algorithms and retraining methods as well as identify different control strategies that map command information from the brain to each specific device function.
Neural Engineering, Neural Prostheses & Sensory Neurophysiology for Organ Function
Dr. Gustafson is interested in the areas of neural engineering and neural prostheses. His research interests focus on understanding the systems-level neurophysiology and neural control of pelvic functions, and using this information to design and develop neural prostheses that interface with native spinal neural circuitry and restore physiologic function. Lower urinary tract dysfunction can have a devastating clinical impact. Therefore his efforts include developmental and pre-clinical studies to translate research advances into clinical implementation at the earliest opportunity.
High frequency waveforms for blocking neural activity. High frequency waveforms can be used to completely block nerve fibers. This technology can be applied to stop unwanted muscle spasms, improve organ function or stop pain. We are conducting in vivo experiments and in vitro analysis of electrode designs for implantation in humans. REU students will work with a team of graduate students, engineers, nurses and physicians to design, fabricate and test electrodes for implantation in humans. Students will learn the basics of neural stimulation and electrode materials. Students will have opportunities to observe surgical procedures, be exposed to commercialization activities and cadaver evaluations may result from a successful project.
Project: Effect of Substrate Stiffness and Drug Elution on Cortical Response to Implanted Devices
PI: Dr. Jeff Capadona
Location: Most of the work will be conducted at the L. Stokes Cleveland VA Medical Center, but some aspects of the project will be completed in the Neural Engineering Center in Wickenden.
Project Summary: Electrodes that can be safely placed in the brain and function for more than 20 years offer new opportunities for the management and rehabilitation of many previously incurable conditions, such as spinal cord injury, Parkinson’s disease, epilepsy, and limb amputation, just to name a few. For an electrode to survive decades in the brain it requires the tissue response and inflammation to be as minimal as possible. This project utilizes our recently developed mechanically dynamic polymer nanocomposites (see Science 2008, 319(5868); 1370-1374), to looks at the relationship between device stiffness, administration of anti-inflammatory agents, and tissue response. Initial studies will being with the re-engineering of our current dynamic materials to include the elution of neuro-protective anti-inflammatory agents. Once established, these materials will be evaluated for their improved biocompatibility in a model neural-interfacing system, including both in vitro and in vivo systems.
