biomedical engineering meng projects 2013-2014€¦ · biomedical engineering meng projects...
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Biomedical Engineering MEng Projects 2013-2014 Professor Jonathan Butcher and Jack Thompson projects:
1). Optimization of gene delivery for cardiovascular applications.
The best way to understand biological phenomena is through conducting gain and loss of function experiments. Achieving these experiments requires the ability to add DNA into cells to increase expression of a protein, or to add interfering RNA to reduce (knock-down) expression of the protein. We collaborate with a molecular biologist that has made several novel DNA plasmids to enhance the expression of proteins important in valve disease. The objective of this project is to optimize the delivery of these plasmids into live cells. We will explore electroporation, virus, and chemical based methods in both adult, embryonic, and stem cell sources. We will test the effects of gaining and losing this protein at embryonic and adult stages, and the potential effects of mechanical stimulation. Students working on this project will gain valuable expertise in molecular biology, plasmid purification, and cloning. A background in cell biology, molecular biology or biochemistry is helpful in this project.
Contact information: [email protected]
2). Design of an ex vivo/in vivo bioreactor for cardiovascular implants
Typical bioreactors for tissue engineered cardiovascular tissues simulate in vivo mechanical conditions on a bench. These are often bulky devices with expensive control systems to replicate internal environments, and are not capable of using actual blood as the fluid medium. Our goal in this project is to design a bioreactor system that itself could be implanted in a body cavity and condition a tissue prior to its eventual use in its intended position. This innovation would remove much of the time and cost associated with current approaches, but has significant design challenges. Students will explore the role of immune/inflammatory response to biomaterials, and depending on project progression build a prototype using 3D printing technology. Interested students should have experience in mechanical engineering design, electrical engineering, and/or computer science. Some knowledge of biology is helpful but not required. This project is best suited for a team of independently motivated students with minimally-overlapping skill sets.
Contact information: [email protected]
3). BioHaptix 2013/2014 Project Proposal – Version 22 June 2013 Background: BioHaptix is currently engaged in the commercialization of a real-time soft tissue characterization device that utilizes technology developed in Professor Jonathan Butcher’s Lab (see http://cornell.flintbox.com/public/project/21610/ ). BioHaptix has identified a number of promising applications including biomedical tissue research, in-vivo assessment of meat quality in cattle, and the early assessment of preterm birth risk in pregnant women.
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Opportunity: As with any early-stage business, there are a number of near term priorities for BioHaptix. One of these involves the refinement and advancement of a prototype demonstrating the technology. This prototype consists of 3 main elements: 1) Base Unit 2) PC Application 3) Probe Materials and Methods: The main areas of refinement for each of the prototype elements are as follows:
1) Base Unit: Additional programming of the firmware loaded into the Arduino microcontroller to improve robustness and increase automaticity. The Arduino is at the heart of the Base Unit and controls all other functions and subsystems within the Base Unit and also communicates with the PC application and Probe. An ideal candidate for this activity is someone with a strong programming background with specific experience in the creation of firmware to control and direct hardware elements. 2) PC Application: Additional programming (Visual Basic 6 or VB6) to increase automaticity and improve data post processing and visualization. An ideal candidate for this activity is someone with strong VB6 background with some experience in parsing, summarizing, and analyzing large amounts of data. 3) Probe: Mechanical and electrical updates to the functionalized electrode tip design to improve ease of use and optimize it for use in the assessment of meat quality in live cattle. An ideal candidate for this activity is someone with a solid mechanical design background with some experience in basic electrical design (specifically flex circuits). Criteria for Success: For each activity success would be defined as follows: 1) Base Unit: a. Reduced overall test cycle time. b. Demonstrated ability both receive inputs and send commands (switch electrode pairs) to the probe. c. Improvement management of subroutines associated with pressure controller and other aspects of the base unit. 2) PC Application: a. Reduced overall test cycle time. b. Tighter integration and communication with the Arduino, Data Acquisition System (DAQ), and Arbitrary Wave Generator (AWQ) in the Base Unit. c. Improved visualization and post processing of the resultant data. 3) Probe: a. Fabrication of successful testing of new probe design optimized for use in live cattle. b. Improved ergonomics and ease of use (particularly with the attachment and detachment of the probe tip). c. Demonstration of successful integration of Probe with Base Unit.
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Professor Cynthia Reinhart-King projects:
1). Measuring Cellular Traction Stresses in Response to Dynamic Changes in Substrate Stiffness: Reinhart-King Lab Statement of the Problem: Cardiovascular disease is the number one cause of death worldwide and atherosclerosis is recognized as the underlying pathology. Previously, the Reinhart-King Lab has shown that age-related stiffening of the arterial wall increases endothelial cell contractility contributing to endothelial dysfunction and increased lipid permeability. These previous studies relied on end-point analysis evaluating endothelial cell behavior on hydrogel substrates of increasing stiffnesses. The goal of this project is to measure endothelial cell behavior using a dynamic model that more closes mimics the natural arterial stiffening that occurs with age. A hyaluronic acid hydrogel capable of sequential cross-linking to increase substrate stiffness will be used and the resulting cellular traction forces will be measured. Goals for MEng Project:
1. Learn aseptic technique, cell culture, hydrogel synthesis, and traction force microscopy. 2. Practice making hydrogel substrates and seeding cells onto them. 3. Determine the cross-linking exposure limits for endothelial cell viability using a live/dead assay. 4. Dynamically stiffen the hydrogel substrates and measure cellular traction forces. Requirements for Position:
Applicants should have at least 6 months laboratory experience. Cell culture experience and previous coursework in cell biology preferred. Must commit to working 10-15hours / week minimum on the project. Submit resume/CV to Marsha Lampi ([email protected]).
References:
1. Huynh J, et al. (2011) Sci Transl Med. 3(122):112-122. 2. Guvendiren M and Burdick JA. (2012) Nat Commun. 3(792):1-9.
2). Design of bioengineered model of a carotid bifurcation and investigation of endothelial cell shape in response to flow: Reinhart-King Lab Statement of the Problem: Atherosclerosis, or plaque development in arteries, is the number one cause of death in our society.1 For plaque progression to take place, cholesterol must permeate endothelial cells which line the blood vessels. These cells are subjected to disturbed fluid shear stress which is thought to affect cell shape and therefore cholesterol permeability. While in vitro systems have been created to model endothelial cell permeability, a system which takes into account the effect of fluid shear stress at vessel bifurcations remains to be created. Here, we will adapt a current 3D microvessel model to create a bifurcated channel system and investigate the effect of different shear stress levels on the shape of endothelial cells. Goals for MEng Project:
1. Learn aseptic technique, cell culture, and collagen scaffold synthesis.
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2. Adapt current model to create bifurcated channel.
3. Seed endothelial cells onto scaffold and implement fluid shear.
4. Analyze cell shape using ImageJ.
Requirements for Position: Applicants should have at least 6 months laboratory experience. Cell culture experience and previous coursework in cell biology preferred. Must commit to working 10-15hours / week minimum on the project. Submit resume/CV to Cynthia Reinhart-King ([email protected]). References: 1. Glass, C.K. and Witztum, J.L. (2001). “Atherosclerosis : The Road Ahead Review,” Cell, 104(4):503–516.
3). Project: Age dependent changes in heterogeneity of Extracellular Matrix (ECM) in blood vessels
The role played by the stiffness of the matrix within blood vessels in regulating the permeability of the endothelium has recently been highlighted and found to be critical in the progression of atherosclerosis. The project offered proposes to extend the findings by investigating the micro/meso-scopic local changes in the architecture of intimal ECM brought about by age or high-fat diet.
Goals:
1. Learn mice surgery and handling 2. Tissue staining and preparation for microscopy. 3. Confocal imaging 4. Scoring, quantification of image-data This project is collaborative with Dr. Nishimura.
Interested students should send their CV to Saumendra Bajpai ([email protected]) in the Reinhart-King Lab.
Reference:
J. Huynh, N. Nishimura, K. Rana, J. M. Peloquin, J. P. Califano, C. R. Montague, M. R. King, C. B. Schaffer, C. A. Reinhart-King, Age-Related Intimal Stiffening Enhances Endothelial Permeability and Leukocyte Transmigration. Sci. Transl. Med. 3, 112ra122 (2011).
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4). Understanding the effects of extracellular matrix heterogeneity on tumor cell invasion – Reinhart-King Lab
Statement of the Problem:
Since tumor cell invasion is both first discernible step of metastasis and the basis for histopathological diagnosis of metastatic cancer, the invasive potential of tumor cells is of significant clinical relevance. While the molecular and cellular mechanisms of tumor invasion are increasingly understood, it remains to be determined how structural, mechanical, and biochemical heterogeneity in the stromal extracellular matrix (ECM) influences invasion. Here, we will develop an in vitro tumor invasion model to directly study how biophysical and biochemical properties of the ECM affect cancer cell invasion.
Goals for Project:
1. Learn aseptic technique, cell culture, and microscopy techniques 2. Develop in vitro tumor invasion model 3. Study tumor cell invasion as a function of ECM structure, mechanics, and biochemical
composition Requirements for Position:
Applicants should have at least 6 months of laboratory experience. Cell culture experience and previous coursework in cell biology preferred. Applicants must commit to working 10-15 hours per week minimum on the project. Submit resume/CV to Shawn Carey ([email protected]).
5). Metastatic Cell Isolation from 3D Collagen Microenvironments: Reinhart-King Lab
Description of Project:
It is commonly understood that the genomic makeup of cancer cells within a tumor is largely heterogeneous, and may condition a subpopulation of cells for metastasis.1 There exists a current need to investigate the specific biophysical changes occurring in cancer cells which promotes their invasion through resident stroma tissue. It has been shown that the expression of key proteins, from lamins to neurotrophic factors, changes in the onset of a variety of cancers2,3 but the dynamics of this expression during invasion is still not well understood. This project aims to successfully isolate invasive cells from an established 3D collagen model, in order to propagate and further characterize this sub-population. A key novelty of this project includes engineering a method for isolation of invading cancer cells, and subsequent analysis using staining and protein expression assays (time permitting).
Goals for MEng Project:
1) Learn cell spheroid and 3D collagen embedding protocols. 2) Successfully isolate invading cells from collagen matrix. 3) Expand isolated invading cell sub-population. 4) If time permits, characterize unique structural changes in invading cells through techniques such
as immunostaining and PCR techniques.
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Requirements for Position:
Student should have prior laboratory and cell culture experience. Applicants with background knowledge in cell biology are preferred. A commitment of at least 8-10 hours/week is expected. Submit resume/CV to Alex McGregor ([email protected]) and Turi Alcoser ([email protected]), cc’ing Dr. Cynthia Reinhart-King ([email protected]).
References:
1. Gerlinger M. and Swanton C., et. Al. (2012) N Eng. J Med. 366(10):883-892. 2. Zwerger M., Ho C.Y., and Lammerding J. (2011) Annu Rev Biomed Eng. 13:397-428 3. Dolle L. and Hondermark H. (2003) Oncogene. 22(36):5592-601
Professor Claudia Fischbach project:
No projects being offered this year.
Professor Christopher Hernandez projects:
1). Title: Orthopaedic Surgical Equipment
Project Duration: 1-2 semester
Introduction
One common failure mode of orthopaedic implants is implant loosening associated with micromotion. Micromotion at the implant interface causes mechanical damage to the neighboring tissue, leading to local bone loss. When enough bone surrounding the implant is lost, the implant is no longer secured in the bone and the implant fails.
Description
In this project the student will design and manufacture a number of implants and loading fixtures to be used in animal experiments. Implant design includes CAD drawings of parts that may be manufactured in a reasonable time frame. Additionally the student will be involved in preparation and performing surgical interventions on animals and interacting with local animal care and use ethical committees. Students working on this project must have substantial mechanical design experience, such as gained in most undergraduate mechanical engineering degree programs.
Contact information: [email protected]
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2). Title: Genomic Library Design
Project Duration: 2 semesters
Two Projects: 1 primary engineering, 1 primary biology
Introduction
The Hernandez Research Group is actively developing novel devices for sorting and fractionating complex microbial communities.
Description
In this project the student will develop genomic libraries for the analysis of genomic backgrounds of organisms selected using the devices. The proposed work includes the design of microfluidic devices to perform the selection methodology and DNA/RNA analysis of the selected organisms. The student must have experience with microbiology/molecular biology at the level of introductory undergraduate coursework.
Contact information: [email protected]
Professor Michael Shuler projects:
1). Title: Lab on a Chip Projects
The “Dual –flow Lab –on-a-Chip” (Dual—flow Rocker Chip) is a device that was designed to help us study the interactive cellular responses to chemicals that could be potentially ingested. This device is a 3-dimensional dynamic physiological model that should provide us with more interactive toxicity data than the 2D in vitro models. This is done by culturing human cell lines in interconnected chambers and represents a physiologically based pharmacokinetic (PBPK) model of the whole body.
Basically, two independent fluidic channel networks can be linked indirectly by a gastrointestinal cell layer and enables us to mimic digestion, diffusion and distribution. Other cellular chambers are then incorporated into this device and are able to communicate with the GI chamber through these fluid channels. This feature allows us to study the effects of potentially ingested materials.
This device can be extremely valuable in the field as well as in the laboratory. It can provide crude as well as detailed toxicity assessments. The importance of obtaining a crude assessment would be for individuals on survival expeditions or in emergency situations.
A couple of project ideas are (but are not limited to):
1. To test and modify the present “Dual-flow Rocker Chip” so that it will be more comparable to a human’s physiology.
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2. To test cells with a variety of matrices to establish the best 3-dimensional differentiated morphology
3. To perform various toxicity studies in the “Dual-flow Rocker Chip” 4. To develop a cell freezing process for the “Dual-flow Rocker Chip” that can be used directly.
This will make field toxicity studies easier to perform. 5. To develop electronic and optical means for taking real time readings on the Chip
Contact information: Paula Miller ([email protected])
2). Title: In Vivo and In Vitro Models to Understand Adipokine Signaling For Biomedical Engineers Description: The goal of this project is to understand the role of adipokines in human physiology and investigate how in vitro models can be used to study cell-to-cell signaling interactions. Adipokines or adipocytokines (Greek adipo-, fat; cyto-, cell; and -kinos, movement) are cytokines (cell-to-cell signaling proteins) secreted by adipose tissue. It was only recently discovered that the adipose tissue was recognized as an active endocrine organ involved in many physiological processes. Our focus is on metabolic processes that are influenced by the presence of adipokines. Adipokine dysregulation patterns are often implicated in the pathogenesis of obesity, the metabolic syndrome, insulin resistance, type 2 diabetes, cardiovascular disease and even cancer. Activities: The student will navigate a research experience across both clinical and in vitro methods and incorporate them in their engineering design. The student will have access to human specimens and nucleic acids for their projects e.g. adipose tissue, liver, aortic valves, mononuclear cells, DNA, RNA, Proteins (circulating peptides in plasma and or serum), microRNA, among others.
The student will 1. Be introduced to the concepts of adipokine physiology and obesity 2. Identify clinical parameters that can be further studied and modulated in vitro 3. Write a research plan on adipokine physiology that includes the identification of the
clinical problem, and possible research approaches to find a solution 4. Develop expertise in cell and molecular biology and genetics techniques, systems and
software 5. Explore engineering options and possibilities to develop screening tools 6. Will get ready to present their research work in at least one scientific meeting 7. The final project is to write the conclusion of their work as compared to similar published
options. Requirements:
1. Ability to commit 3 credit hours (at least 12 hours/week) for both semesters. 2. Participate in weekly lab meetings 3. Present progress report weekly (10 minute power point)
One group 3 to 5 participants Must adhere to a dress policy Contact information: Magnolia Ariza-Nieto ([email protected])
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Professor Abraham Stroock project: Will be submitting project shortly
Professors Schaffer-Nishimura Lab Projects:
Our combined labs use advanced optical microscopy to study the biology of several different disease models in the living animal. Many aspects of disease and injury involve the interaction many tissue and cell types, so are best studied in the complete organism. In order to be able to analyze structure and cell dynamics in the whole animal, we need to develop novel imaging instrumentation and optical techniques. http://www.bme.cornell.edu/schafferlab http://nishimura.research.engineering.cornell.edu 1) Title: Design and construction of advanced nonlinear microscopes Nonlinear microscopy provides an approach to look deep into live tissue with micrometer resolution to study cellular dynamics and potentially to diagnose disease and guide treatment. For example, in two-photon excited fluorescence microscopy, an infrared femtosecond laser pulse is tightly focused into a sample where structures of interest are labeled with a fluorescent dye. Fluorescence cannot be directly excited by infrared light, so fluorescence is produced only at the laser focus, where the laser intensity is high enough to excite the dye through the simultaneous absorption of two laser photons. To form an image, the fluorescence intensity is then recorded while the position of the laser focus is scanned throughout the sample in three dimensions. Nonlinear microscopy is especially well suited to imaging deep within scattering specimens because light that is scattered en route to the detector still contributes to image formation and does not produce an unwanted background. This project will focus on developing next-generation nonlinear imaging tools that will be used for in vivo studies of healthy and disease state cellular physiology. For example, we are designing two-photon microscopes that detect dozens of fluorescence channels and have multiple excitation lasers, all multiplexed. We are exploring the use of other nonlinear optical effects to produce image contrast as well as identifying the utility of already demonstrated contrast mechanisms for in vivo imaging. Students involved with this project will gain a detailed understanding of linear and nonlinear optics, in electronics and optics design, in the construction of electronic and optical systems, and in live animal imaging. Contact: Chris Schaffer ([email protected]) and Nozomi Nishimura ([email protected]) 2) Imaging pathology in brain due to high-fat and high-sodium diets Recent research has demonstrated that high-fat and high-salt diets can cause brain pathology after only several weeks in rodents. The pathology includes clots, hemorrhages and abnormalities in the brain blood vessels. Such lesions could be linked to loss of cognitive function and increased risk of developing dementia. Until now, these findings have been studied in post-mortem histology. Using in vivo imaging in mice with chronically implanted cranial windows we hope to study the earliest changes in the brain due to these dietary challenges. Hypothetical changes include alterations in blood flow, increases in
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inflammation, and degradation of microvasculature. Eventually, these changes will likely lead to clots and bleeding. This study seeks to understand how nutrition and lifestyle could lead to changes in cognition through damage to the brain microvasculature. Contact: Nozomi Nishimura ([email protected]) and Chris Schaffer ([email protected]) 3) Three-dimensional mapping of the topology of microvascular networks Surprisingly, the topology of the microvascular network (arterioles, capillaries, and venules) remains unknown for many vascular beds. This lack of knowledge is largely due to the difficulty associated with mapping three-dimensional structures using traditional techniques. However, the structure of the microvasculature can change dramatically with age and disease. In the two systems we intend to study here, knowledge of the three-dimensional architecture of the microvasculature is critical for understanding the biology in both the normal and disease states. Our goal is to label, image, map and analyze the microvascular geometry and topology of several different organ systems. One possible strategy is a specialized tissue processing approach (e.g. Clarity – http://www.nature.com/news/see-through-brains-clarify-connections-1.12768), followed by immunohistology or other labeling and two-photon excited fluorescence microscopy to map fluorescently labeled structures, such as blood vessels, deep into the tissue specimen. We are particularly interested in the microvasculature of the heart and the aging brain. Both of these organs are highly susceptible to ischemic injury due to insufficient blood flow, so that understanding the topology of and changes in microvasculature may provide important information in the study of neurodegenerative and cardiovascular diseases. Contact: Chris Schaffer ([email protected]) and Nozomi Nishimura ([email protected]) 4) Fluid flow and Abeta drainage in Alzheimer’s disease brains Alzheimer’s disease is the leading cause of dementia in the elderly and although some recent therapeutics modestly slow progression of the disease, there is no cure. Alzheimer’s disease is caused by the dysfunction of neurons in the brain likely due, in part, to the toxic effects of aggregates of a small peptide, amyloid-beta, which eventually accumulates into dense plaques scattered throughout the brain. The brain has no lymphatic system, but it has been speculated that the motion of interstitial fluid provides some of the functions covered by lymphatic vessels in other organs. It is thought that clearance of some waste products, such as amyloid-beta, is partially accomplished via convective transport by the flow of this interstitial fluid. Although amyloid-beta processing and clearance has been studied with genetic and molecular tools extensively, mechanical processes such as fluid flow are less studied. In this study we want to manipulate the fluid flow in the brains of mouse models of Alzheimer’s disease to see if this alters the deposition of amyloid-beta in the brain. We propose to implant catheters that infuse fluid slowly over time and compare the amyloid-beta plaque formation in control and infused animals. This would represent a new approach to treating a disease in which molecular tools have failed. Contact: Nozomi Nishimura ([email protected]) and Bill Olbricht ([email protected]) 5) Light emitting neurons for brain-machine interfaces Next generation brain-machine interfaces (BMIs) will require high fidelity recording of the activity of large ensembles of neurons, while maintaining specificity for single neurons. The goal is to develop a long lasting, mechanically and functionally robust solution for BMI. Such a BMI should reliably function in active people who may encounter physical trauma or health challenges. In addition, for a lifetime of
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functionality, the interface should allow for cognitive flexibility. Such technologies would benefit users of prosthetic devices such as amputees, as well as patients with nervous system damage such as spinal cord injury patients, among others. We propose a novel combination of optogenetic technologies, optical engineering and algorithm innovation to develop an entirely new modality for recording brain activity that could be useable for long-term human applications. The proposed scheme would also enable mapping of brain activity in animals during complex behaviors and could be an important technical innovation for neuroscience research. The technology is based on a genetically-encoded bioluminescent calcium reporter that emits light when neurons are active. The light will scatter through the brain tissue and will be detected at the skull outside of the brain. We will engineer versions of this reporter that use different wavelengths to enable mapping of the activity of a population of neurons. Importantly, this technique is expected to be scalable and would avoid the tissue damage caused by implanted electrodes, potentially enabling robust neural prostheses for humans. Contact: Nozomi Nishimura ([email protected]) and Chris Schaffer ([email protected]) 6) Imaging the formation of atherosclerotic lesions in vivo Inflammation, turbulent blood flow and mechanical properties of the vessel can influence the likelihood of the development of an atherosclerotic plaque. However, the dynamics of plaque formation, inflammatory cell invasion and rupture have been difficult to study because reduced model systems do not capture the such complex events involving many cell types. The goal of this project is to develop imaging techniques based on multiphoton microscopy to image the formation of atherosclerotic plaques, in vivo. One option is based on a GRIN lens, a thin, fiber-like lens that can be inserted into the vessels of a mouse in order to image the inside surface of an artery. We hope to be able to track the invasion of macrophages into active plaque as well as see the dynamics of plaque rupture. The development of this imaging technique would provide a novel tool for understanding how plaques form, grow and eventually cause vessel clotting when they rupture. Contact: Nozomi Nishimura ([email protected]) Collaborators: Prof. Cindy Reinhart King and Prof. Chris Xu Professor Daniel Fletcher project (Vet College) project:
Title: High fidelity dog and cat simulators for veterinary training
Training of veterinary students in the area of emergency and critical care medicine poses many practical and ethical challenges. Although didactic lectures have traditionally been used to teach the concepts of the management of these types of cases, it is often difficult to allow students to transfer that knowledge into practice in a clinical training environment due to the time sensitive nature of the diagnostic and treatment decisions that must be made. In human medicine, high fidelity simulators have been developed to address this deficit in clinical training. These devices provide feedback of many types, including pulses, heart sounds, lung sounds, input to clinical monitors, and responses to physical interventions that allow the development of realistic, timely clinical scenarios for training without risk to an actual patient. Such devices are programmable, and can be used to simulate a multitude of clinical scenarios and procedures. Numerous studies have been published showing enhanced and accelerated clinical competence among medical students trained with these simulators when compared to students trained with the didactic approach. However, these technologies have not successfully been adapted for training of veterinary students in the context of the types of clinical diseases common in veterinary species.
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Dr. Dan Fletcher, an Emergency and Critical Care Medicine specialist at Cornell's College of Veterinary Medicine, has a PhD in Biomedical Engineering and is interested in developing a cost-effective simulator for clinical training of veterinary students. The project includes development of open-source, cross-platform control software, as well development of interfaces to microcontrollers, sensors, and actuators within the mannequin. The end product will be made available for use at veterinary training facilities around the world.
Contact information: Daniel Fletcher ([email protected])
Professor David Putnam Projects:
Will be submitting project shortly
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Figure 1. Stretching cells to measure nuclear stiffness. (A) Schematic overview of nuclear deformations during applied substrate strain for cells with stiff and soft nuclei. (B). Lamin A/C-deficient (Lmna–/–) cells have softer nuclei that deform more under the same applied membrane strain.
Figure 2. Schematic illustration of a microfluidic based strain device. Reducing the pressure in the hollow side channels results in increasing strain in the silicone membrane spanning the central chamber.
Professor Jan Lammerding Projects: 1. Design of a “cell stretcher” to measure the biophysical properties of cells and the cell nucleus. Mutations in nuclear envelope proteins such as lamins cause a large number of human diseases, including muscular dystrophy and dilated cardiomyopathies. The mechanism by which mutations in these proteins can cause muscle-specific defects remains unclear, but recent findings from our laboratory have indicated that the mutations may render the nucleus more fragile, thereby resulting in progressive cell death in tissues exposed to repetitive mechanical strain such as muscle. The goal of this project is to design a new and improved microscope mounted device to apply uniaxial strain to cells plated on elastic silicone membranes (a “cell stretcher”). In normal cells, the nucleus is 2-10× stiffer than the surrounding cytoplasm, so that the nucleus only deforms very little during strain application (see the images for the fluorescently labeled nucleus of a Lmna+/+ wild-type cell below); in contrast, mutations that cause muscular dystrophy result in softer, more deformable nuclei, as seen in the lamin A/C-deficient Lmna–/– cells. The new cell stretcher device should allow precise control over the applied strain and can be combined with micropatterning and contact printing of extracellular matrix proteins to further improve the experimental procedures. Applications for this device include screening cells from patients with muscular dystrophies to test whether these cells have impaired nuclear mechanics, and also the study of diverse human cancer cells, which may be characterized by more deformable nuclei. We are also considering building a miniature cell stretcher, which is based on the principle of stretching a thin silicone membrane suspended between two microfluidic channels by reducing the pressure in the channels (Fig. 2) Students joining this project will learn design and fabrication techniques, advanced optical microscopy, computer-aided imaging and image analysis, and cell culture techniques. Background in mechanical engineering and design as well as some cell biology are all useful for this project, and experience with cell culture is a plus.
Contact information: Jan Lammerding ([email protected])
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2. Designing a microfluidic device for high throughput measurements of cellular mechanics. In many biological processes, the ability of cells to deform and squeeze through narrow openings is a critical and often rate limiting step. For cancer cells, it has been shown that invading/metastasizing cells can pass through pores as small as 3µm, but smaller pore sizes will result in the cell nucleus getting stuck. Some immune cells, faced with similar obstacles, have evolved highly flexible and lobulated nuclei to facilitate passage through the endothelial cell layer in blood vessels and through dense tissue spaces. In our lab, we have previously shown that modifications in nuclear stiffness can have dramatic effects of the ability of cells to pass though narrow constrictions. The aim of this project is to develop novel microfluidic devices that will enable measurement of the deformability of hundreds of single cells per minute and directly probe their ability to pass through microscopic pores. The devices will consist of small channels with precisely defined constrictions through which cells are perfused or induced to migrate along a chemotactic gradient. Advanced designs could include additional microfluidic valves and pressure gauges as well as devices to sort heterogeneous populations of cancer cells based on their deformability. Students involved in this project will learn microfabrication techniques, cell culture techniques, using these devices on a microscope, and image analysis techniques and approaches. A background in mechanical engineering, some fluid mechanics, microfabrication, and cell culture is a big plus, but not absolutely required. Contact information: Jan Lammerding ([email protected])
3. Optimizing experimental techniques to probe the physical connection between the nucleus and the cytoskeleton.
Many cell biology textbooks depict the nucleus as an isolated structure in the middle of the cell, acting as a passive compartment to hold the cell’s genomic information. Recent findings show that the nucleus is physically coupled to the surrounding cytoskeleton through a number of specialized nuclear envelope proteins, and that disrupting this connection can cause severe defects in cytoskeletal organization, cell migration, and polarization, resulting in severe muscular dystrophies in humans and mouse models of the disease. In my laboratory, we have been working on novel biophysical techniques to probe the force transmitted between the nucleus and the cytoskeleton and to compare the effect of different mutations associated with the human diseases. These experiments include a
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microneedle manipulation assay in which a microneedle is used to apply precisely controlled localized strain to the cytoskeleton and induced nuclear and cytoskeletal deformations are imaged. We have also been working on additional techniques to directly measure the forces transmitted across the nuclear envelope in intact cells and isolated nuclei. Students joining this project will learn basic and advanced cell culture techniques and microscopy skills, and are also encouraged to acquire new microfabrication and contact printing techniques to further optimize existing techniques and to study the effect of specific nuclear envelope protein mutations. Basic knowledge of cell culture techniques is required, and additional experience with microscopy is a plus. Contact information: Jan Lammerding ([email protected])
4. Development of an in vitro muscle regeneration model using a combination of microfluidics and micropatterning
In our laboratory, we study how mutations in proteins of the cell nucleus can result in human diseases such as muscular dystrophy. One especially fascinating problem is to determine how the physical structure and organization of biological cells can modulate the cell’s function and how changes in the cell’s organization, for example, caused by a mutation in a structural protein, can interfere with normal cellular function and result in disease. We are particularly interested in “LINC” complex proteins, which physically link the nucleus to the cytoskeleton. This connection is critical for transmitting forces between the nucleus and the surrounding cytoskeleton and is likely to play an important role in moving and anchoring the nuclei of muscle cells to neuromuscular junctions, i.e., the sites where the muscle cell and nerve meet (Fig. 1, top).The long-term goal of this project is to study the physical connections between the cell nucleus and the rest of the cell, and how mutations in proteins involved in these connections cause muscular dystrophy. During muscle development and regeneration, small muscle cells (myoblasts) fuse together and form a multi-nucleated elongated “giant” cell called a myotube. Initially, the nuclei are located in the center of the myotube. During maturation of these myotubes, the nuclei move to the periphery. A subset of nuclei, termed synaptic nuclei, are positioned near the neuromuscular junction. We hypothesize that mutations associated with muscle diseases result in defects in this maturation process. Since this process is difficult to study in humans or animals and biopsies taken from patients and mouse models do not allow visualizing the time-course of the process, we want to implement an in vitro model system that allows us to recapitulate the muscle regeneration and maturation process in a cell culture dish and image it step-by-step under a microscope. This system will then enable us to conduct detailed studies on the effect of specific mutations associated with muscular dystrophies on nuclear positioning in muscle cells and compare the results between mutant and normal cells.
The goal of this project is to use soft lithography to create microfluidics and microfabricated polydimethylsiloxane (PDMS) stamps to deposit molecules that promote cell adhesion in well-defined
Figure 1: Top, schematic representation of the neuromuscular junction. Synaptic nuclei are represented in dark blue. Bottom, device to be built with local delivery of agrin.
nerve cell
muscle cell
synaptic nuclei
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patterns onto glass slides, resulting in the formation of regularly shaped myotubes on these striation patterns (Fig. 2, bottom). We will combine these patterns with a microfluidic system to deliver agrin to localized sections of the myotubes. Agrin is normally secreted by neurons as they begin to form neuromuscular junctions, inducing the aggregation of muscle nuclei at those sites in normal cells. We will use this microfluidic system to compare the movement and positioning of muscle nuclei in normal cells, as well as in cells that have mutations in LINC complex proteins
Students involved in this project will learn microfabrication and microfluidic techniques, cell culture techniques, using these devices on a microscope, and image analysis techniques and approaches. A background in mechanical engineering, some fluid mechanics, microfabrication, and cell culture is a big plus, but not absolutely required. Contact information: Jan Lammerding ([email protected])
Industrial Projects offered by Professor Jonathan Black projects:
Note: These are brief descriptive titles. Full descriptions are available on request. Initial expressions of interest should include order of preference (if more than one is selected) and c.v. (one page, including undergraduate course and GPA). Teams will be selected and charged by September 6.
PROJECT 1: Project Title: Reproducible Assembly-Disassembly of Ceramic-Metal Modular Interfaces for Total Hip Replacements
Sponsor: CeramTec GmbH, Ger. Contact: Dr. Robert Streicher
Problem statement:
Replacement of the hip and knee joint has become increasingly successful, with non-revision rates routinely exceeding 95% at ten years post implantation for most patient groups. A continuing process of evolutionary modification, driven by clinical and economic requirements, has transformed earlier designs that contained only a few parts, into more elaborate multi component assemblies. A common pairing is the use of a high strength ceramic femoral head on a cobalt-chromium or titanium alloy trunnion/stem. Careful design of the interface provides optimal stress distribution and protects the strong but brittle head from fracture under load. This interface is altered by deformation during assembly, which is currently done manually during surgical insertion. There is a pressing need to design an assembly-disassembly tool for this ceramic-metal interface in order to render it more durable and reusable.
This project will examine the mechanical requirements and designs utilized in such interfaces in contemporary joint replacement designs, and devise one or more design approaches to meeting assembly-disassembly requirements.
Project field: Problem and application analysis, material and process design, in vitro testing, biomaterials (orthopaedic)
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Team requirements: This is a team project for 3-4 people with various engineering backgrounds. This would be a good project for a mechanical engineer and/or materials scientist with some industrial design experience. SolidWorks experience a definite plus!
PROJECT 2: Project Title: Implantable Long Bone Segmental Replacement Sponsor: Seraph Robotics, Ithaca, NY Contact: Adam Tow [email protected]
Problem statement:
It has long been a surgical practice to use vascularized segments of the human tibia to provide live structural supports in repair of congenital, developmental or trauma related major bone defects in the skeleton (see: Malizos KN et al., Free Vascularized Fibular Grafts for Reconstruction of Skeletal Grafts, J Am Acad Orthop Sur, 12(5):360-9, 2004). Unfortunately this procedure leaves a major critical size (= will not heal) defect in the fibular shaft and may require additional surgery to stabilize the ankle joint.
This design project will build on a prior study that defined design parameters for 3D (additively) printable materials, usable for in vitro laboratory studies, which possess the mechanical properties of cancellous and cortical bone. The result will be a thorough material redesign to render the materials usable as permanent implants as well as design of an implantable segmental long bone replacement system utilizing this new materials system.
Project field: Problem and application analysis, device design, in vitro testing, biomechanics/biomaterials (orthopaedic),
Team requirements: This is a team project for 3-5 people with various engineering and (possibly) biological backgrounds. It is essential that one or more members either have FEA experience or will be taking a course in analysis in the Fall ’13 Semester. Knowledge of SolidWorks™ and any 3D printing experience would be extremely valuable; mechanical (materials) testing knowledge also useful.
PROJECT 3: Project Title: Non-Articulating Approaches to Functional Restoration of the Temporomandibular Joint
Sponsor: TMJ Association, Milwaukee, WI Contact: Terrie Cowley [email protected]
Problem statement:
Disorders of the temporomandibular joint (jaw joint or TMJ; positioned bilaterally between the maxilla and the mandible) and associated musculature and nerve processes affect 10 million US patients acutely or chronically. Temporomandibular Joint Disorders (TMJDs) are a complex and poorly understood set of conditions characterized by pain in the jaw joint and surrounding tissues and limitation in jaw movements. Injury and other conditions that routinely affect other joints in the body, such as arthritis, also can affect the temporomandibular joint. One or both joints may be involved and, depending
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on the severity, can affect a person's ability to speak, eat, chew, swallow, make facial expressions, and even breathe. Also included under the heading of TMJD are conditions involving the jaw muscles. These may accompany the jaw joint problems or occur independently and are often confused with jaw joint disability because they produce similar signs and symptoms.* TMJD is frequently accompanied by a confusing array of painful and debilitating conditions (comorbidities) in other parts of the body.
Research and treatment to date have focused on pharmacological alleviation of pain and mechanical restoration of joint structure. An initial design study identified biological restoration or replacement of the TMJ disc as a promising approach to definitive treatment. However, this has proven difficult to achieve. This team’s effort will take advantage of the particular mechanics of the TMJ and focus on functional replacement of the full joint using non-articulating designs that minimize particulate debris release.
Project field: Problem and application analysis, device design, in vitro testing, biomechanics/biomaterials (orthopaedic), animal studies (surgery, neurophysiology)
Team requirements: This is a team project for 3-5 people with various engineering and (possibly) biological backgrounds. It is essential that one or more members either have FEA experience or will be taking a course in analysis in the Fall ’13 Semester.
* Adapted from: Sponsor’s web site: http://www.tmj.org/site/content/tmjd-basics
PROJECT 4: Project Title: “Wild Card” Design Competition
Sponsor: To be determined Contact: Later
Problem statement:
Not all good ideas come out of Professor’s heads! This is an opportunity to propose an approach to an unsolved problem in clinical application of biomaterials to problems of disability and disease in the human musculoskeletal system. If you have an idea in this area and are of an adventurous nature, prepare a submission.
Details: Prepare a write up of 200-300 words, with at least 5 references, describing the clinical problem (unmet need), contemporary (historical) approaches to the problem and some possible conceptual approaches (no details, please!) to a possible engineering solution. Please submit these to Professor Black as soon as possible but absolutely no later than August 31st, 2013. He will select the most promising submission, as quickly as possible, and select interested students to form a team suitable for achieving a design solution within the constraints of the MEng program. If the project is suitable and has commercial potential, he will also seek an industrial sponsor
Project field: Problem and application analysis, device design, in vitro testing, biomechanics/biomaterials (orthopaedic),
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Team requirements: This is will be a team project for 3-5 people with various engineering and (possibly) biological backgrounds. Team members will be selected with backgrounds to suit the proposed problem.
PROFESSOR BLACK’S Contact Information:
Office: 406 Weill Office hours: By arrangement; but no appointment required for Tuesdays 8-10am, when Prof. Black is in Ithaca (Schedule posted outside of his office) Email: [email protected] Biographical info: http://www.bme.cornell.edu/people/profile.cfm?netid=jb2245
Jack Thompson ([email protected]) Projects:
1). Welch Allyn Concussion Screener Problem statement, Area of investigation, Un-met clinical need, etc.
Welch Allyn currently manufactures diagnostic medical equipment for worldwide clinical applications. Many of our products support physical assessments of patients. This project would entail developing an innovative handheld or tabletop system to screen for concussion for athletic, emergency personnel, or military teams. The device would likely be a video or image processing device that a patient can look into, that can perform pupil recognition, eye tracking and or basic cognitive assessments vs. stimulus. This could be pc based or on a tablet. The team would have opportunity to understand market competitive analysis, intellectual property and patent analysis, image processing vs. stimulus, as well as design of a product that can help where no product currently exists in wide market use. Outputs of the design team would be product design and a basic functional prototype device. Project field:
A) Hardware B) Device development C) Theoretical analysis D) In vivo or in vitro experiments
Students can expect to create a design and prototype medical device. The prototype will be designed, built, and tested on human subjects. The project will likely include study of video capture, processing, SW, and concussion detection techniques. Criteria for success or key milestones The first milestone is a review of the marketplace including market size, growth, market shares, and a competitive analysis of existing products. This should include an interview with an appropriate clinician. Then there will be a comprehensive review of current technologies and their shortcomings. That will be followed by a brief patent search for prior art held by competitors. One (or possibly two) technology(s) with the highest probability of success will be chosen as the basis for the design of a
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prototype device. The project team will choose the design direction to pursue. The final report will include a comparison of the prototype to the theoretical model and a recommendation for further development.
Other relevant materials or resources needed for the project. The students will need time to manufacture a prototype. The prototype can be PC or tablet based. Skills students will learn during the project if they are not already inherent. Students will explore marketing research, competitive analysis, intellectual property analysis, FDA classification, creative problem solving, computer model simulation, use of specific laboratory equipment, product design, CAD drawing, estimation of production costs, estimation of sales volumes, design review, and successfully working on a team.
Contact: Jack Thompson ([email protected]) 2). Welch Allyn Spinal Immobilization Board
Problem statement, Area of investigation, Un-met clinical need, etc.
Welch Allyn currently manufactures diagnostic medical equipment for worldwide clinical applications. Many of our products are used in emergency medicine. This project would entail developing an innovative spinal immobilization system that would be functional but allow more comfortable transport and stabilization. Currently the spinal immobilization boards that are utilized are antiquated and painfully uncomfortable. Patients are secured on rigid boards for hours at a time. This causes great discomfort and pressure sores for immobilized patients. Outputs of the design team would be product design and a basic functional prototype device. The device may also include a disposable design to prevent cross contamination or to maximize comfort. Project field:
A) Hardware B) Device development C) Theoretical analysis D) In vivo or in vitro experiments
Students can expect to create a design and prototype medical device. The prototype will be designed, built, and tested on human subjects. The project will likely include the study of emergency medicine techniques, spinal physiology, immobilization techniques, infection control, pneumatic technologies, and different biocompatible materials.
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Criteria for success or key milestones The first milestone is a review of the marketplace including market size, growth, market shares, and a competitive analysis of existing products. This should include an interview with an appropriate clinician. Then there will be a comprehensive review of current technologies and their shortcomings. That will be followed by a brief patent search for prior art held by competitors. One (or possibly two) technology(s) with the highest probability of success will be chosen as the basis for the design of a prototype device. The project team will choose the design direction to pursue. The final report will include a comparison of the prototype to the theoretical model and a recommendation for further development.
Other relevant materials or resources needed for the project. The students will need time to manufacture a prototype. The prototype will be tested and demonstrated by the team and emergency transport personnel. The prototype should be compatible with existing ambulance hardware and systems. Skills students will learn during the project if they are not already inherent. Students will explore marketing research, competitive analysis, intellectual property analysis, FDA classification, creative problem solving, computer model simulation, use of specific laboratory equipment, product design, CAD drawing, estimation of production costs, estimation of sales volumes, design review, and successfully working on a team. Contact: Jack Thompson ([email protected])
Professor Lawrence Bonassar Projects:
1). Surgical Device Design to Study Ankle Post-Traumatic Osteoarthritis Approximately one in every 10,000 people sprain their ankle each day. This number increases by at least 5-fold in young athletes and military personnel, with ankle sprain representing the single most common athletic injury. At least half of sprains result in damage to the articular cartilage of the ankle and over 50% of these lead to irreversible joint damage, or osteoarthritis (OA).
A collaborative team including members of the Fortier Lab (College of Veterinary Medicine), the Bonassar Lab (BME/MAE) and Weill Cornell NYC/Hospital for Special Surgery are currently developing a pre-clinical large animal model to study ankle Post-traumatic osteoarthritis (PTOA). The aim of this study is to better understand the early pathophysiology of OA and to evaluate therapeutic interventions to stop the progression from cartilage trauma to end-stage OA.
Our model involves delivering an intraoperative impact injury to equine articular cartilage using a custom made, spring-loaded impacting device. Immediately following impact injury, we will perform live-cell imaging via an arthroscopically-adapted multiphoton microscope. This will allow us to monitor and characterize changes to the extracellular matrix as well as determine chondrocyte viability.
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Students who join the team will be tasked with designing and executing a mounting/holding apparatus that will facilitate the intraoperative use of our impacting and imaging devices. Depending on the students’ interest and background, additional opportunities exist, including optimization of in vivo stress/strain data collection and analysis, and creation of a positional recording system for study samples.
This project is well suited for 1-2 students who have a background in mechanical design, including CAD and experience in machining. Familiarity with mechanical testing, Labview and Matlab software is also desirable. Interested students should forward a copy of a resume and unofficial transcript to Prof Bonassar,
Contact: Prof. L.J. Bonassar Email: [email protected] Phone: 5-9381 Office: 149 Weill Hall
2). Mechanical Analysis of Cartilage from Human Tracheomalacia Patients
Tracheomalacia is a softening of cartilage rings in the trachea that affects neonates, victims of smoke inhalation, and patients requiring prolonged intubation. If left untreated, this condition can lead to airway constriction and spontaneous collapse of the trachea, which is potentially fatal. Little is known about the mechanistic causes of this disease, and the only current treatment is partial resection of the trachea.
The goal of this project is to characterize the mechanical performance of tracheal cartilage obtained from partial surgical resections. This characterization will include analysis of the mechanical performance and biochemical composition of tracheal cartilage and screening the tissue for markers of inflammatory cytokines and proteinases typically associated with cartilage degradation.
The project is part of an ongoing collaboration between the laboratories of Prof, Bonassar in the Department of Biomedical Engineering, Dr, Jon Cheetham in the College of Veterinary Medicine, and Dr. Subroto Paul, a cardiothoracic surgeon from Weill Cornell Medical College. Work will take place primarily in Prof, Bonassar’s laboratory, with frequent consultation with Dr, Cheetham and Paul.
Students participating in the project will be developing and executing protocols for mechanical testing of tracheal tissue, performing biochemical analysis to measure their collagen and proteoglycan content, and assisting in the performance of histology and immunohistochemistry to assess tissue structure,
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This project is well suited for 1-2 students with a solid foundation of coursework in mechanics, some laboratory experience with mechanical testing, and basic laboratory chemistry skills. Facility with programming in Matlab is preferred. Interested students should send a copy of a resume and unofficial transcript to Prof. Bonassar.
Contact: Prof. L.J. Bonassar Email: [email protected] Phone: 5-9381 Office: 149 Weill Hall
3). Assessing the Effects of Impact Injury on Cartilage Frictional Properties
Knee joint trauma associated with ligament and meniscus tears is invariably associated with damage to articular cartilage. The damage to cartilage results from mechanical disruption of the tissue, cell death, and joint inflammation. Collectively, all of these phenomena put the joint at high risk for subsequent osteoarthritis. Although many factors in change in the joint after injury, damage is thought to be associated with loss of critical lubricants from the cartilage surface and degradation of these lubricants in synovial fluid.
The goal of this project is to characterize the changes in cartilage frictional properties. This characterization includes measuring cartilage friction coefficients using a custom tribometer and measuring the shedding of wear particles from the cartilage surface. These studies will also assess the extent to which supplementation of cartilage with lubricant from synovial fluid can restore normal frictional behavior and prevent shedding of wear particles.
This project is part of an ongoing collaboration between the laboratory of Prof, Bonassar in the Department of Biomedical Engineering, Dr. Lisa Fortier of the College of Veterinary Medicine, and scientists at Fidia Farmaceuti in Venice, Italy. Work will take place primarily in the Bonassar lab with consultations from Dr. Fortier and Fidia.
This project is well suited for 1-2 students with a solid foundation of coursework in mechanics, some laboratory experience with mechanical testing, and basic laboratory chemistry skills. Facility with programming in Matlab is preferred. Interested students should send a copy of a resume and unofficial transcript to Prof. Bonassar.
Contact: Prof. L.J. Bonassar Email: [email protected] Phone: 5-9381 Office: 149 Weill Hall
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4). Development of a Co-Culture Bioreactor for Anchoring Tissue Engineered Meniscus
In the knee joint, the meniscus connects to the tibial plateau at the horns, acts as a shock absorber, and lubricates and protects the articular cartilage. Meniscus damage is one of the most common intra-articular knee injuries. Due to the partially avascular nature of the meniscus, healing of deep tissue injuries is limited. Current treatments for total meniscus replacement require total meniscectomy followed by allograft transplant, which results in joint degeneration and is limited by supply and donor geometry. The preferred surgical approach for meniscus transplantation is fixation with osteochondral plugs. Studies have shown that proper fixation of the meniscus is essential to the restoration of health knee biomechanics. In native menisci there is a bone to fibrocartilage gradient at the attachment sites, which is difficult to mimic in vitro. Dr. Bonassar’s lab has established a method to create an anatomically accurate tissue engineered (TE) meniscus, however a fixation technique has yet to be established.
The goal of this project is to create a bioreactor for meniscus culture that accommodates anchoring the meniscus construct to bone. The design will need to two chambers in which different types of media can be applied to either the bone or meniscus construct. Depending on the progress of the project there is potential to expand studies to evaluate constructs cultured in the chamber using histology and biochemical analysis.
This project is a collaboration between Dr. Bonassar in the department of biomedical engineering and Dr. Scott Rodeo at the Hospital for Special Surgery. Project work will be conducted in Dr. Bonassar’s lab with consultation with Dr. Scott Rodeo.
This project is well suited for 1-2 students who have a background in mechanical design, including CAD and experience in machining. Familiarity with mechanical testing, Labview and Matlab software is also desirable. Interested students should send a copy of a resume and unofficial transcript to Prof. Bonassar.
Contact: Prof. L.J. Bonassar Email: [email protected] Phone: 5-9381 Office: 149 Weill Hall
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5). Development of Injectable Biomaterials for the Repair of Dura The dura mater is a layer of tissue encasing the brain and spinal cord. It serves mainly as a barrier, protecting the brain, spinal cord and cerebrospinal fluid (CNF). In order to surgically treat many neurological conditions, doctors must often cut the dura to reach the spinal cord or brain. If left unrepaired, a defect in the dura can allow CNF leakage and further neurological damage as well as the risk of infection and other complications. As such, there is a clinical need for methods to repair the dura.
We have developed a crosslinkable collagen gel formulation that has been used successfully in intervertebral disc repair. The gel is injectable, and has been shown to inhibit the progress of disc degeneration. Furthermore, our collagen gel formulation can be delivered to an in vivo model with little immune response observed from the body. Our success with this collagen gel has prompted us to consider its use as a dura sealant.
A collaborative team including members of the Härtl Lab (Weill Cornell NYC/Hospital for Special Surgery), and the Bonassar Lab (BME/MAE) are currently expanding our neurological repair efforts to include repair of the spinal dura. The goal of this project is to assess the ability of our crosslinked collagen gel formulations to seal defects in a spinal dura model.
A proposed model has been used by research groups in the development of commercially available spinal dura sealants. Defects made in a collagen-based casing are then sealed with the substance to be tested. Once the substance has finished polymerizing, the casing is placed under pressure to assess repair ability. Students would be: validating the model and testing different gel formulations as well as established dura sealants.
This project is well suited for a student who is familiar with mechanical testing, fundamental biochemistry, as well as data analysis in Excel and MATLAB. Interested students should forward a copy of a resume and unofficial transcript to Professor Bonassar:
Contact: Prof. L.J. Bonassar Email: [email protected] Phone: 5-9381 Office: 149 Weill Hall
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Professor Peter Doerschuk projects:
1). Real-time MRI biofeedback of speech articulation Real-time MRI (rtMRI) involves rapid, continuous acquisition of one or several anatomical slices, in combination with an iterative image reconstruction algorithm. rtMRI was initially developed for imaging joint and heart diseases; the Cornell Speech Imaging Group (SIG)—a collaboration between Weill Cornell Medical College, Cornell BME, and the Cornell Phonetics Lab—is extending its use for basic and applied research on the control of vocal organs during speech. The combination of temporal resolution and spatial coverage offered by rtMRI provide a wealth of information about the time-varying geometry of the vocal tract during speech. By extracting relevant anatomical features from successive images, rtMRI allows for kinematics of vocal organs such as the tongue, lips, jaw, and soft palate to be studied with a combination of temporal resolution and spatial coverage that has previously been unavailable. By implementing a fast image reconstruction algorithm, video images of articulation can be used in a clinical context for articulation therapy. GOAL: Develop a software system for analysis of reconstructed images, feature extraction, and video replay of articulation images. Fields: Software engineering (especially Matlab, Python, C/C++) and/or Image processing; background in BME, ECE, and/or CS Key milestone #1: Develop software in Matlab for robust detection of anatomical edges and volumes in MRI images, constrained by anatomical and kinematic models of the vocal tract and speech motor control. Key milestone #2: Develop a software system to enable user visualization of relevant image features in combination with controllable playback for clinical use. This is a project for 2 students. The tasks involved are the following: 1. Develop and optimize speaker-adaptive robust edge-detection algorithms in Matlab for extracting anatomical features of sagittal and coronal vocal tract slices. Current algorithms in use are prone to error due to variation in image contrast. We are looking for a student to develop creative solutions, such as:
• Algorithms appropriately constrained by physiology and kinematics. • Specialized contrast enhancement and image filtering. • Functional parameterization of image features. • Speaker/image-adaptive algorithms.
2. Develop Matlab and C code (using OpenMP compiler directives) for end-user visualization and playback of acquired images immediately after reconstruction. This would allow a clinician to use rtMRI images as biofeedback for articulation therapy: a patient in a scanner (perhaps with dysarthria or apraxia) could observe where they positioned their tongue in attempting to make a sound, and the clinician could provide visual feedback-based instructions regarding how to alter their articulation. Sponsors: Sam Tilsen (Cornell Linguistics), Peter Doerschuk (BME and ECE) Contact: Sam Tilsen ([email protected]), Peter Doerschuk ([email protected]) Website: http://conf.ling.cornell.edu/plab/SIG.html
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2). Electron microscopy Overview: Electron microscopy is a critically important method for 3-D visualization of nanoscale biological machines such as ribosomes and viruses. Electron microscopy of snap-frozen specimens, so-called cryoEM, provides fundamentally tomographic projection information. Therefore, the process of computing a 3-D image of the biological object is similar to the process used to compute a 3-D image of a patient in a medical x-ray computed tomography scanner. However, the cryoEM problem is more challenging because the signal to noise ratio is lower, the orientation of the tomographic projections is not known, and the microscope measures the tomographic projections modified by a so-called Contrast Transfer Function, which is a linear system with zeros in the spatial frequency band of interest. With graduate students and collaborators at The Scripps Research Institute, Peter Doerschuk has developed a variety of algorithms and parallel software implementations of the algorithms for a variety of specific cryoEM problems. One of the outputs of this activity is a Matlab (http://www.mathworks.com/) program (about 5000 lines) about which there has been a lot of interest. But our collaborators would prefer a python/scipy (http://www.python.org/, http://www.scipy.org/) program because it would be open source and have better opportunities for the development of distributed-memory parallel versions. The goal of the project is to do a careful translation from Matlab to python/scipy. As a part of the project, you will come to understand the tomography ideas and the statistical ideas that underlie the algorithm. Contact information: Peter Doerschuk ([email protected]).
Professor Harold Craighead projects:
No projects being offered this year.
Professor Jesse Goldberg project:
1). Large-scale population neural recordings in motor circuits of singing birds Advisor: Jesse H. Goldberg, MD, PhD, Department of Neurobiology and Behavior
Problem statement: Brains are extremely complex electrical circuits. To understand the neural basis of behavior, it is necessary to record the electrical activity in brain circuits of freely behaving animals. Songbirds provide a model system for studying how neural circuits produce complex motor sequences. To this end, we have recently developed techniques to record the activity of single neurons in freely moving, singing birds, and have discovered brain pathways required for vocal babbling. To get more detailed into insight into information processing inside of these pathways, we need to scale up our recording technologies to record simultaneously from tens and even hundreds of neurons at the same time. To do this in small animals requires new technology. When we record the tiny electrical currents generated by single neurons in the brain, we filter, amplify and digitize them before we can begin to analyze how the signals contribute to behavior. The goal of this project is to implement these processes in parallel on a lightweight, miniaturized, low power, low noise device that can be comfortably carried by a singing bird.
Project field: Electrical engineering, systems neuroscience, digital signal processing, data analysis and animal behavior.
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Benchmarks for progress: The overarching goal is to design and build a lightweight recording system that will allow us to record simultaneously from hundreds of neurons in small, freely behaving animals. A first step is to use existing technologies to test the recording capabilities of commercially available electrodes that allow for population neural recording (e.g. http://www.neuronexustech.com). This will require learning small animal neurosurgical, recording and signal processing techniques commonly employed in the lab. A next step will be to build a miniaturized, lightweight device where signals recorded from these electrodes can be filtered, amplified, multiplexed and digitized, incorporating recently developed microchips suited to this purpose (e.g. http://www.intantech.com). Next, we will test the ability of this device to record and process signals in freely moving, singing birds. Success on this front will open up a variety of new projects in the lab, providing opportunities for data analysis and experimental design.
Other relevant materials or resources needed for the project: This project involves collaboration between Jesse Goldberg in the Department of Neurobiology and Behavior and Chris Schaffer in BME. An ideal background for this project would be strengths in electrical engineering, digital signal processing, CAD, and a passion for ‘tinkering’ and building new things, as well as an interest in learning more neuroscience. We envision a team of two students working closely with the PI on this project.
Contact information: Jesse H. Goldberg ([email protected])
2). Millisecond timescale sculpting of motor behavior in the mouse Advisor: Jesse H. Goldberg, MD, PhD, Department of Neurobiology and Behavior
Problem statement: Transgenic mice offer a powerful model system to study the neural mechanisms of motor learning because specific classes of brain cells can be recorded and optogenetically manipulated during behavior. However, the behavior of laboratory mice is not ideal for experimental study. Mice are laborious to train in conventional stimulus-response learning paradigms and they exhibit limited flexibility in acquiring novel motor skills. An exception is that mice spontaneously learn (without training) to reach through bars to grasp food for consumption. Reaching and grasping are natural yet extremely complex learned behaviors that consist of coordinated sequences of micro-movements, all of which occur in fractions of a second. Presently, the kinematics of this reach-and-grasp sequence are poorly understood because mouse reaching has historically been studied crudely and with subjective human assessments of performance. Recent technologies such as fast computing and imaging systems set the stage for a revolution in our ability to study reaching in mice. These technologies will pave the way for neurophysiological and optogenetic studies into the neural mechanisms of complex motor sequence generation. Such studies are of fundamental importance because the same brain structures implicated in mouse reaching are also associated with Parkinson’s, Huntington’s and Tourette’s disorders in humans.
Project field: Animal behavior experiments, systems neuroscience, electrical engineering, digital signal processing and data analysis.
Benchmarks for progress: In this project, we will build a novel, automated and high throughput system for the study of mouse reaching. First, cages will be designed with slits that entice mice to reach for their food. An automated, mechanized system will be built that will detect paw traversals through the slits and trigger food pellet placement to identified positions. Next, a fast imaging and analysis system will be built to monitor—with millisecond resolution—the kinematics of paw trajectories during reaches. Finally, real
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time analysis of paw trajectories will enable pellet placement and availability to be made contingent on the kinematics of the current trajectory. This real-time analysis will bring motor learning under experimental control. The final product should be a user-friendly integrated hardware and software system that interfaces directly with the mouse home environment. The ultimate goal is to scale up operations to several (>10) training boxes running simultaneously for high throughput analysis of mouse motor learning.
Other relevant materials or resources needed for the project: This project involves a collaboration between Jesse Goldberg in the Department of Neurobiology and Behavior and Chris Schaffer in BME. An ideal background for this project would be strengths in computer programming (Matlab, Labview), digital signal processing, and a passion for ‘tinkering’ and building new things. We envision a team of two students working closely with the PI on this project.
Contact information: Jesse H. Goldberg ([email protected])
Professor William Olbricht Projects: No projects this year.
Professor Tracy Stokol Projects:
No projects being offered this year.
Professor Steven Adie Projects:
1) Title: Several projects in optical coherence elastography
Optical coherence elastography (OCE) is a new biomedical imaging technique to improve upon the ancient practice of diagnosing diseased tissue (e.g. tumors) by manual palpation. OCE is an example of a class of elastography techniques that can generate images based on the mechanical properties of tissue. Other examples include ultrasound elastography and magnetic resonance elastography (MRE). Elastography works by mechanically perturbing/exciting the sample and measuring the resulting displacements with an imaging system. These displacements can then be utilized to deduce the underlying viscoelastic mechanical properties of the sample. OCE can provide higher resolution and displacement sensitivity, than its ultrasound or MR counterparts by leveraging the high-resolution and exquisite phase-sensitivity of an optical coherence tomography (OCT) system. Recent work in OCE is beginning to explore tissue mechanical properties through dynamic/harmonic excitation in the audio frequency regime. One promising line of research is mechanical spectroscopy – measurement of the frequency dependent mechanical response. Like other methods of spectroscopy, there is a potential for rich information, but this area of OCE is largely unexplored. Several projects are offered, including:
• Design and testing of viscoelastic phantoms for calibrating an OCE system • Novel mechanical excitation schemes, e.g. acoustic radiation force of focused ultrasound • Dynamic OCE and mechanical spectroscopy of various types of tissue • Mathematical modelling to extract quantitative mechanical properties from OCE datasets
Contact information: Steven Adie ([email protected])
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2) Title: Bio-chamber for longitudinal OCT imaging of 3D cell culture
Imaging of cell populations in vitro is becoming increasingly important to isolate and study the factors influencing the behavior of both normal and pathological cells. In particular, the dimensionality of the matrix, whether 2D or 3D, in which cells are cultured has been found to influence on their behavior, e.g. whether or not cancerous cells they manifest malignant behavior. Recent developments in computed imaging techniques for optical coherence tomography (OCT) offer the promise of 3D cellular-resolution tomography without traditional depth-of-field limitations or detrimental effects of optical aberrations. This volumetric imaging capability can be exploited to track the long-term behavior and migration of cells in three-dimensions.
The aim of this project is to adapt existing solutions for cell culture microscopy to OCT imaging, and demonstrate long-term viability of populations of cells in 3D cell culture.
Contact information: Steven Adie ([email protected])
Drs. David Lipson and Hayan Dayoub Projects:
1). Project Title: Portable Surgical Stereoscope Sponsor(s)- Hayan Dayoub MD, hd274 Contact: David Lipson, dl324 or Warren Zipfel, wrz2
Problem statement, Area of investigation, Un-met clinical need, etc.
Surgical microscopes are essential devices for the performance of microsurgery, neurosurgery, (examples: connecting small vessels, removing deep seated tumors). However they are bulky, heavy, and expensive, not-sterile, and time consuming to set up. Designing a small portable device that achieves the same objectives of a microscope would allow for expanding the clinical applications of microsurgery.
Project field:
A) Software – -Control Schemes, Blue-tooth or equiv. to Smartphone B) Device development- Stereo Imaging and Visualization. C) Biochemical process D) Theoretical analysis E) In vivo or in vitro experiments F) Microfabrication or nanotechnology G) Other- -Mechanical design, Optical design, H) Is this a Team project (Y/N) Y How many students ____2-3____? I) What background should student have: ME, AEP ECE
Please indicate the relevant technological field(s) in order to help the student understand where they will develop expertise. Optics/Stereoscopy Video capture and transmission
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Device position control (voice or electronic activation of movement) The two basic functions of a microscope are: illumination and magnification of a target. Modern surgical microscopes offer added functions: 1- The ability to move in space and look at a target from multiple angles. 2- Record a procedure for educational and record keeping purposes. 3- Interface with image navigation systems to localize a lesion. 4- Use fluorescence to differentiate normal from abnormal tissue, or to illuminate vessels.
Criteria for success or key milestones A) successful outcome would be designing a device that is
1- able perform the functions of a surgical microscope ( illuminate and magnify a target) 2- allows for video capture and transmission to a monitor or recording device 3- can be mounted to a surgical bed 4- can be moved in space on command
B) Proof of principle prototype mountable on a stereotaxic patient head frame.
Other relevant materials or resources needed for the project. Exposure to neurosurgical environment at Guthrie in Sayer, PA pending approval to enter hospital.
Warren Zipfel 255-0663 David Lipson 255-7683
Drs. David Lipson and William Frayer Projects:
1). Project Title: Automated Cycler for Peritoneal Dialysis Sponsor(s): Dr. William Frayer
Contact: Dr. Meubarak
Problem statement, Area of investigation, Un-met clinical need, etc.
Patients with renal failure in developing nations face the cost burden of disposables used in hemocytometers. The current practice in Tanzania is the use of peritoneal dialysis (PD), which uses the patient’s intestine as the dialysis membrane. Their PD unit requires the doctor to come visit the patient in the hospital every 4 hours, and therefore he wants to automate this system. This design team would create a cycler unit that can switch valves on and off, starting and stopping the dialystate fluid. Students will begin by understanding PD, and then develop an automated cycler machine for the PD equipment taking into account the local resources. Project field:
A) Software B) Device development C) Biochemical process D) Theoretical analysis E) In vivo or in vitro experiments F) Microfabrication or nanotechnology G) Other- describe
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H) Is this a Team project (Y/N) How many students ___3-4_____ I) What background should student have: ME, CBE, ECE, ? ________?
Please indicate the relevant technological field(s) in order to help the student understand where they will develop expertise. Understanding of dialysis, mechanical and electrical valve design, product development for the developing world.
Criteria for success or key milestones Please estimate what would constitute a successful outcome and any interim steps or objectives that might help clarify the path the student needs to follow. What deliverables do you wish ?
Demonstrate understanding of current peritoneal dialysis, Brainstorm cycler designs, How the product fits local constraints, Final prototype
Other relevant materials or resources needed for the project. Please identify resources or contacts the student will need to secure or other faculty or people that will be helpful during the project. Resource of Tanzanian doctor specialist in dialysis: Dr. Meubarak, [email protected], 0713755596
Dr. David Lipson Projects:
1). Project Title: Left Ventricular Assist Device Improvements Sponsor(s); Lowell Macadam( CEO, Verizon, gift) and Doctors at Weill Cornell & Columbia Medical Schools Contact: David Lipson, dl324, 607-255-7683
Problem statement, Area of investigation, Un-met clinical need, etc.
Left Ventricular Assist Device (LVADs) are mechanical circulatory pumps that are used to partially or completely replace the function of a failing heart. While a new living heart is better, there are about 3,500 heart transplants were performed annually. The vast majority of these are performed in the United States (2,000-2,300 annually). About 800,000 people have a Class IV heart defect indicating a new organ (Wikipedia). Consequently, LVADs are the only interim option for many.
We propose developing a improved catheter to supply more blood from the pump, in a smaller area. Computer modeling will be used to pick the better range of designs, and several prototype cannulas will be fabricated and tested.
Project field:
J) Software – computer model of a new catheter-optimization K) Device development - prototype of actual catheter L) In vivo or in vitro experiments - flow bench modeling M) Microfabrication or nanotechnology
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N) Other- describe Assessment of Clinical needs and technical options
O) Is this a Team project (Y) How many students ___2-3_____? P) What background should student have: ME, CBE, ECE, BME
Please indicate the relevant technological field(s) in order to help the student understand where they will develop expertise.
1)Mechanical design in Solid Works or equivalent. 2) Poiseuille flow models in non-circular geometries. 3) Flow measurement 4) Molding, extrusion, or related. Criteria for success or key milestones
1) Develop calculations and estimates for flow improvement. 2) Assess fabrications schemes for prototyping catheters. 3) Develop computer model of flow, and optimize catheter design. 4) Complete final report and supply pre-clinical prototypes.
Other relevant materials or resources needed for the project. Background literature will be supplied, and Dr. David Farrar, VP , Thoratec, will collaborate with the team.
Experience with fluid flow modeling software, and bench flow studies is helpful, but not required.
Drs. David Lipson and Jenghwa Chang Projects:
1). Project Title: Tumor motion reconstruction by projecting the contours on the MIP CT onto the 4D CT Sponsor(s):
Jenghwa Chang, Ph.D., Associate Professor and Director of Centralized Treatment Planning, Department of Radiation Oncology, NewYork-Presbyterian Hospital/Weill Cornell Medical College
Contact:
525 E 68 St, Box 575, New York, NY 10065 TEL: (646)-317-8301, Fax: (212) 746-8850 Email: [email protected] And Dr. David Lipson ([email protected])
Problem statement, Area of investigation, Un-met clinical need, etc.
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Breathing motion is a major source of dose delivery error for radiotherapy of lung tumors. To manage the tumor motion, it is a standard practice that a lung cancer patient receives a four-dimensional (4D) CT scan during the treatment simulation consisting of cross-sectional CINE images of the tumor, which can be further processed to construct the volumetric images for different breathing phases, or the MIP (maximal intensity projection) images of all breathing phases. For non-gated treatment, the tumor is usually contoured by the radiation oncologist on the MIP images for radiotherapy planning. However, the MIP images lack the temporal information of the tumor location that can be used to analyze the potential radiation delivery errors due to tumor motion.
This project is a continuation of last year’s project titled “Personalized motion phantom for radiotherapy.” The hypothesis of this project is that the trajectory of tumor motion can be reconstructed by projecting the tumor contours on the MIP images onto the CT scans of different breathing phases. In this project we will continue the code development for identifying the tumor location for each breathing phase, and modeling its movement for the full breathing cycle. The currently developed software requires the CT scan of each breathing phase be manually generated from the CINE scan using commercially available software. We would like to be able to perform the reconstruction of tumor trajectory directly from the CINE scan. In addition, the algorithm for projecting the tumor contours onto the CT scans of different breathing phases needs much improvement.
The output of the proposed software can be used to guide the motion phantom to evaluate the accuracy of the motion management technique before the treatment. Potential delivery errors can be identified and corrected during the planning stage. It can also be used to test new motion management techniques that are being developed.
Project field:
E) Software X F) Device development G) Biochemical process H) Theoretical analysis I) In vivo or in vitro experiments J) Microfabrication or nanotechnology K) Other- describe L) Is this a Team project (Y/N) N How many students ________? M) What background should student have: ME, CBE, ECE, ? ECE
The goal of this project is to continue the software development of last year’s project titled “Personalized motion phantom for radiotherapy,” specifically, to complete the code development for identifying the tumor location for each breathing phase, and modeling the tumor trajectory for the full breathing cycle. The relevant technological field(s) required includes:
(1) Programming using C++ and Matlab. (2) Curve fitting and optimization. (3) Image segmentation. (4) Medical image processing in DICOM (Digital Imaging and Communications in Medicine)
format. (5) Motion modeling of a moving object.
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Criteria for success or key milestones
The students will be expected to
(1) Get familiar with the existing codes in the first month. (2) Finish the final flow chart before the end of month 3. (3) Preliminary results at the end of month 6. (4) Submit abstracts to AAPM conference in month 7. (5) Deliver the final product by the end of month 9. (6) Write the report and prepare manuscript.
The final product should be able to
(1) Import the CINE images of a patient. (2) Derive the CT images of different breathing phases from the CINE CT. (3) Identify for each breathing phase the lung tumor position from contours on the MIP images. (4) Reconstruct the moving path of the tumor.
Other relevant materials or resources needed for the project.
The Department of Radiation Oncology will fund the cost for the software development tools. Participation of faculty members familiar with image processing and motion modeling will greatly improve the chance of success for the proposed project.
2). Project Title: Personalized Prediction of Radiotherapy Outcome for Lung Cancer Patients using Artificial Neural Network (ANN) Sponsor(s): Jenghwa Chang, Ph.D., Associate Professor and Director of Centralized Treatment Planning, Department of Radiation Oncology, NewYork-Presbyterian Hospital/Weill Cornell Medical College
Contact: 525 E 68 St, Box 575, New York, NY 10065 TEL: (646)-317-8301, Fax: (212) 746-8850 Email: [email protected]
And David Lipson ([email protected])
Problem statement, Area of investigation, Un-met clinical need, etc.
Lung cancer (both small cell and non-small cell) is the second most common cancer and the leading cause of cancer death in both men and women. Treatment of lung cancers includes surgery, radiation therapy (RT) and chemotherapy. RT uses high-energy rays (such as x-rays) or particles to kill cancer cells. Since radiation also causes severe complications to the normal tissues, treatments are carefully planned to deliver the radiation dose to the tumor while sparing the surrounding normal tissues as much as possible.
Although RT has been used to treat lung diseases for almost a century, the capability for predicting the outcomes is still lacking as most available metrics for predicting the outcomes has a large uncertainty (i.e., large confidence interval). For example, mean survival based on histology and stage is the most common information provided to the patients but the large confidence interval renders this metric not very informative.
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In this project we propose to build an artificial neural network (ANN) for predicting the treatment outcomes of lung RT patients, particularly, the life expectancy based on the personal physiology and pathological evaluations performed before the treatment. The main hypothesis of this study is that prediction based on personal physiological and pathological conditions can significantly reduce the confidence interval of the mean survival prediction and thus provide more accurate life expectancy information to the patients.
The ANN will be trained in a supervised mode based on the clinical outcome data that are already available in our department. In addition to histology and stage, personal data including sex, age, surgery, chemotherapy, smoking history… will also be included in the training data to personalize the prediction. The accuracy of the ANN will be evaluated using cross validation. Receiver operating characteristic (ROC) of the ANN will be determined based on the sensitivity and specificity of different decision-making thresholds.
This is the first step of our efforts toward building a general outcome predictor for the RT patients in the Radiation Oncology Department. If this project is successful, we plan to extend its functions to predicting the outcomes for other treatment complications and for other sites.
Project field:
N) Software Matlab and ROOT O) Device development P) Biochemical process Q) Theoretical analysis R) In vivo or in vitro experiments S) Microfabrication or nanotechnology T) Other- describe U) Is this a Team project (Y/N) N How many students ________? V) What background should student have: ME, CBE, ECE, ? ECE
The goal of this project is to build an ANN to predict the treatment outcome for lung RT patients, particularly the life expectancy using the physiological, pathological and treatment data acquired before the treatment. The relevant technological field(s) required includes:
(6) Programming language: C++ (7) ROOT package with Neural Network package using C++ (8) Cross validation. (9) ROC curve.
Criteria for success or key milestones
The students will be expected to
(7) Get familiar with the background knowledge (Neural Network, cross validation and ROC curve) in the first month.
(8) Finish the flow chart of the ANN before the end of month 2. (9) Finish programming of ANN before the end of month 4.
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(10) Preliminary results at the end of month 6. (11) Submit abstracts to AAPM conference in month 7. (12) Deliver the final product by the end of month 9. (13) Write the report and prepare manuscript.
The final product should be able to
(5) Import the physiological, pathological and treatment data of a patient. (6) Predict the life expectancy of the patient after receiving RT.
Other relevant materials or resources needed for the project.
The Department of Radiation Oncology will fund the cost for the software development tools. Participation of faculty members familiar with image processing and motion modeling will greatly improve the chance of success for the proposed project.