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 engineering. Cell and molecular studies of the underlying mechanisms provide the basis for developing novel biomimetic materials and blood compatible interfaces. This research has a foundation in macromolecular engineering, which is combined in understanding lessons from Nature, to design and engineer biomaterials derived from principles of self-assembly and biological hierarchical structure.
Biomimetic interface materials: This project area involves the design and synthesis of biomimetic comb-like polymers directed towards improving the blood compatibility and tissue engineering artificial blood vessels. A related project focuses on biomaterials derived from nucleobase-containing monomers. 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.
Cell-selective liposome drug delivery: The goal of this project is to bioengineer new liposome drug delivery systems that selectively targets cell surface molecules expressed at sites of vascular injury and developing restenotic lesions. This is a project area of drug delivery encompassing design, synthesis, and nanoparticle fabrication, followed by in vitro evaluation of targeting specificity to cells, and in vivo evaluations using a rat model. A student will participate on each of these components, but focus on a specific project topic after an initial training period and exposure to the project area.
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.
Orthopedic Tissue Engineering:
Dr. Eben Alsberg is a new Assistant Professor recruited to the Department in August 2005. His research primarily involves orthopedic tissue engineering, and drug delivery for functional tissue regeneration and cancer therapy.
Bone tissue engineering: The student project will address the hypothesis that in tissue engineering bone, regulating cell-biomaterial interactions, controlling polymer degradation, and delivering soluble osteogenic signals may modulate cellular behavior towards tissue regeneration. The specific experiments will involve transplantation of isolated cells on a biodegradable delivery vehicle to create a functional biological replacement tissue without permanent remnants of foreign constituents; and the development of innovative methods to present specific signals to control cell behavior and subsequent tissue formation to guide the process of tissue regeneration. Through temporal and spatial presentation of soluble bioactive factors, mechanical forces, and biomaterial physical/biochemical properties, we will aspire to create microenvironments that regulate cell gene expression and new tissue formation.
Vascular Tissue Engineering
Dr. Horst von Recum is a new Assistant Professor recruited to the Department in January 2005. His 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.
Tissue engineering blood vessels: In this project, the student will examine the differentiation of stem cells, both embryonic and hematopoietic to become the various components of blood vessels. Stem cells show great promise as tissue engineering tools both in their unlimited replication potential and plasticity. Stem cells can be differentiated into circulating endothelial precursors, and it is these cells, which facilitate repair and regeneration of large vascular defects. The student will investigate the use of novel stimuli-responsive polymers designed to allow binding and loading under one condition, and release or expression under another condition. We will examine the use of these polymers as scaffolds for engineered vascular tissue, and as selection substrates in the identification of novel angiogenic factors through a systems biology approach.
Cancer-Targeted Drug Delivery
Dr. Young Jik Kwon is a new Assistant Professor recruited to the Department in August 2005. Dr. Kwon’s research interests are the development of new gene carriers including semi-artificial retroviral vectors and polymeric non-viral carriers for gene therapy, and the synthesis macromolecular nanoparticle drugs which undergo self-disassembly triggered by intracellular stimuli, for drug delivery and cancer immunotherapy.
Degradable polymeric particles as cancer vaccine carriers: In this project, the student will be involved in the preparation and analysis of new biomaterials for drug delivery using synthetic tools and materials characterization, followed by nano- and microfabication to prepare the therapeutic carriers. By delivering antigens in nano- and microparticles that are degradable at lysosomal pH, enhanced major histocompatibility complex class I-directed presentation of antigen-derived peptides by antigen presenting cells can be achieved. This further cascades cytotoxic T lymphocyte (CTL)-mediated immune responses, which are desirable for cancer eradication. The outputs will be confirmed by cell and tissue culture, ex vivo imaging, and quantitative mathematical models. The evidence from ex vivo and in vivo studies shows that the type and magnitude of immune response could be modulated by surface charge and targeting molecules on the carriers, and by acid-degradability of the therapeutic particles.
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.
Development of Contrast Agents for High Resolution Imaging
Dr. Pagel’s research focuses on developing contrast agents to improve tissue imaging in humans.
New MRI agents that detect caspase-3 in mouse models: This project will involve the student in developing a new type of chemical agent that is MRI-observable only after enzymatic activation by caspase-3. The aims include a 3-step chemical synthesis and characterization; in soluto measurement of Michaelis-Menten kinetics of transglutaminase activation of the new agent; in vitro measurement of cell uptake of the MRI agent; and in vivo MRI to monitor the activation of the agent within mouse models. All necessary laboratory techniques and protocols have been established in the PI’s laboratories. The undergraduate student will gain experience with chemical synthesis, biochemical assays, in vitro cell cultures, and in vivo small animal MRI.
Improved assessment of tumor angiogenesis in mouse models of solid tumors: This project will develop a series of chemical agents that can be selectively detected using MRI; the agents will have different sizes, which will be used to measure different vascular permeability characteristics to assess tumor angiogesis and anti-angiogenic therapies. Specific aims include 1) conjugation of chemical agents to biopolymers with different molecular weights; 2) in vivo MRI to monitor the pharmacokinetics of multiple agents within tumor tissues in mouse models; and 3) image analysis and computer modeling to determine vascular permeability values. Undergraduate students will gain experience with biochemical conjugation, in vivo small animal MRI, and image analysis and modeling using Matlab.
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.
