Teresa A. Murray - US grants

1261495
Murray

The number of bioengineering degree programs in the United States has skyrocketed over the past decade. There are more than 70 ABET accredited undergraduate Biomedical Engineering/Bioengineering programs, and this is expected to exceed 100 within the next few years. Likewise, the range of new devices and technologies in the healthcare field has increased dramatically. While the products and services that Biomedical Engineers design and implement are intended to improve health and well-being, they can also create a range of social and ethical dilemmas, especially for leading-edge technologies. As an example, potential difficulties stem from implantable or wearable sensors that can store and transmit personal health information which emergency care providers could electronically access. Yet, this same information might also be accessed by insurance companies or identity thieves. A device that could save people's lives could also be the gateway to harm them. Additionally, public policy has an effect on the funding for innovation and on the laws that regulate it. Thus, students would benefit from exposure to the process of the public policy debate.

Biomedical Engineering (BME) students today are only a few years away from becoming a part of the process driving the development of new biomedical technologies. It is imperative that this generation of engineers be well-equipped to identify potential social and ethical issues that may arise from their inventions. It is equally important that they learn how public policy impacts their work and how to effectively engage with policy makers and the general public to ensure that conditions for innovation are optimized for the benefit of all. Most BME academic programs include ethics and social impact of medical devices only as integrated components in a selected course or courses, and few programs cover public policy. In 2005, AEMB determined to fill in the gaps by hosting an intensive educational ethics session for students during the Biomedical Engineering Society (BMES) Annual Meeting, a leading national conference. Today, AEMB sponsors three sessions at the BMES Annual Meeting, including ethics, public policy and societal impacts. Funding from this grant will be used to (1) provide matching travel grants to students to attend the conference and these three sessions, and (2) to produce professional video recordings of each session for free use by schools and student groups. Students receiving these grants will participate in all three sessions. After they return home, they will facilitate training sessions at their schools using videos and other materials from these sessions. Other student leaders and faculty that attend these sessions will be asked to host sessions at their campuses, as well. Furthermore, AEMB will contact each US BME program chair to request that they use the session materials. This should promote wide use of the content.

Intellectual Merit
This set of sessions is a new model for broadening the knowledge and skills of these important topics and for improving student involvement in their profession. Other societies will hopefully recognize the merits of this approach and use it as a template for exposing undergraduate and graduate students in other disciplines to these same problems. Furthermore, this method of educating students via a combination of presentations and discussions is known to be an effective educational approach. The students and faculty participants will be encouraged to use this approach when they run their own sessions and thus promote the increased use of active learning methods in BME education.

Broader Impacts
It is expected that student participants will routinely consider ethics, public policy, and societal impact issues during the process of device and technology design and implementation; this will further improve technologies available to society. As they bring this knowledge to their communities they will also increase awareness in the wider society of the important consequences of both good and poor engineering design and practice. AEMB leadership is encouraging all faculty advisors to bring students from underrepresented groups to the conference and our session by applying for FASEB MARC Mentor/Student travel grants. Also, because many local AEMB student leaders are women, this travel grant program will ensure that women are well-represented. Additionally, the professionally recorded videos of each session and other materials will be available free of charge so that any school or student organization can present their content to students. Potentially, this can reach students in every BME program in the country.

DESCRIPTION (provided by applicant): Glial cells greatly outnumber neurons in the brain and have active roles in development, modulation of neurotransmission, health and disease. Yet, relatively little is known about glial cells compared to neurons. What is known about glial cells i derived largely from studies of dissociated cells or live brain slices. Yet these methods have not elucidated phenomena such as the nuanced dynamics between astrocytes and neurons in the living brain. Multiphoton fluorescence microscopy can facilitate studies in the living, intact mouse brain (in vivo), but only when the cells are less than ~0.5-mm below the brain surface. Thus, most glial cells cannot be observed in vivo. Thin optical fibers have been implanted in the mouse brain that can reach great depths to visualize fluorescently labeled cell bodies without disrupting much brain tissue. However, they cannot resolve fine membrane processes of glial cells as they interact with neurons. This would be useful information to study normal development and aging, or the effects of drug use, neurodegeneration, or injury. More recently, endoscopes have been miniaturized for in vivo studies in mouse brain. The high-resolution version is implanted in a glass sheath and can resolve fine cellular processes when used with a multiphoton microscope. Yet, it's 1800-um diameter is markedly wider than fiber optics, which are on the order of 300-um in overall diameter. Therefore, it displaces over 25 times more brain tissue than fibers and requires brain tissue removal prior to implantation. Thus, these have limited applications and should not be implanted very deep into the brain. This project will develop an implantable, 350-um diameter lens to use with multiphoton fluorescence microscopy that is thin, like an optical fiber, and has high resolution to observe fine cellular processes in vivo. It will have the best attributes of optical fibers and miniaturized endoscopes without their drawbacks. To demonstrate its utility, a long version of the lens will be implanted deeply enough to observe adult-born glial cells in vivo over a period of three months. This will offer a major improvement over the current method of using brain slices for short-term studies. The slice study observations are highly dependent on technique and have produced conflicting estimates of migration rates. In another test of its ability, a small port for injection of a calcium-sensitie dye will be incorporated with the implant. The dye will be injected at later time points to observe the release of calcium inside glial cells. Calcium release is one measure of glial function and may provide important clues to their modulation of neuron function. This tool is expected to have numerous other uses because of the expansion of fluorescent labeling tools, including promoter-directed expression of fluorescent proteins in mice that could label subpopulations of glial cells, and the ability to image the same brain region over hours, days or months. PUBLIC HEALTH RELEVANCE: This project will create a tool for researchers to discover how glial cells in the brain function and how they are involved in aging and disorders, such as Alzheimer's and Parkinson's diseases. A tiny glass lens with needle-like diameter will be implanted in the brain of laboratory mice that have a fluorescent dye (or protein) in their glial cells. Using a microscope to look into the lens, researchers will be able to record the numbers and shapes of the cells by illuminating the fluorescent dye and determine if there are major changes in aging or certain diseases, and if potential treatments return them to a normal state.

? DESCRIPTION (provided by applicant): This project will provide high-content data that will be used for both basic and preclinical research. BASIC RESEARCH ASPECT: We will use a novel method of high-resolution, subcortical, in vivo imaging to fill critical gaps in knowledge about th dynamics of diffuse traumatic brain injury at a cellular level in subcortical white matter in live mice over a 60-day period post-injury. This knowledge will give us new insights into understanding the progressive degeneration that happens after TBI and for optimizing therapeutic windows for future combination drug therapy. We will obtain these images in live mice using a permanently implanted microlens positioned over a subcortical white matter tract and periodically image through this lens using a multiphoton microscope. We will reveal previously unseen spatio-temporal dynamics of axon degeneration, microglia infiltration and activation, and microvascular changes with cellular resolution in this region. PRECLINICAL ASPECT: We will also use 3 key outcomes from our observations to evaluate the efficacy of a drug which is now in preclinical trials. This drug, minocycline, is an FDA-approved antibiotic that has reduced axonal loss and microglial activation when given in a single dose within a few hours of experimental traumatic brain injury in mice. We hypothesize that a dose given 3 days post-injury will have the same therapeutic benefits of significantly (1) reducing axonal loss and (2) reducing microglial activation. We further hypothesize that minocycline will result in significant improvement in microcirculation rates. Widening the therapeutic window for this promising drug will better position it for translation to the clinic.

PI: DeCoster, Mark A.
Proposal Number: 1547693

One type of Biomanufacturing involves placing cells together in both two dimensions (2D) and three dimensions (3D). To better approximate what happens in the body in both healthy and diseased tissues, the growth of cells, as well as cell death must be understood. Much like pruning the limbs of a tree without killing it, the investigators of this project will use a controlled, natural process called apoptosis to prune groups of cells in both 2D and 3D environments to improve the function of the overall construct. These studies could enhance our understanding of how to control normal cell formations into tissues and how to control disease processes such as cancer. The containers for the cells to be studied in this project will include bioreactors generated using 3D printers.

The technological components of this project seek to address the challenges of generating and shaping assemblies of cells in both 2D and 3D environments. The project aims to understand the growth processes of both normal and cancer cells, with the goal of achieving better biomanufacturing strategies and insight into tumor growth. Beyond just growth, the investigators of this EAGER award will also apply apoptotic stimuli to cells using two types of high-aspect ratio structures (HARS), to prune away cells in a controlled manner. To facilitate imaging into thicker (>0.5 mm) 3D cell assemblies in this project, gradient index (GRIN) lenses combined with multi-photon microscopy will be used. The HARS materials used in this project include a hollow, non-degradable halloysite, and a novel, biodegradable biocomposite containing copper. Both HARS materials scale from the nano-dimension in diameter to the micro-dimension in length. The experiments carried out in this project will utilize bioreactors generated using 3D printers and functional outputs from the bioreactors will include detection of glutamate and pH dynamics using a fast-growing glioma cell line and slower growing (normal) astrocyte primary culture model to compare cellular outputs with growth before and after the pruning process of apoptosis. To better approximate dynamic processes in the brain, microglia will also be added to model recovery after apoptosis. A foundry of 3D printed bioreactors generated for the project will be established in the form of bioreactor images, .stl files, and animations, and will be tested for integration with commercially available millifluidic devices to detect, for example, chemical changes occurring in the bioreactors over time. Results from this project are anticipated to impact future biomanufacturing strategies and educational materials considering the increasing availability of 3D-printing technology and design software.

Proposal No: 1643343 -
PI: Murray, Teresa

NSF has made an award in support of travel for undergraduate students to attend the AEMB (Alpha Eta Mu Beta, the National Biomedical Engineering Honor Society) Annual Meeting and MINDS (Mentoring for INnovation Design Solutions) Workshop being held in Minneapolis, MN, Oct. 5-8, 2016, at the same time as the Biomedical Engineering Society (BMES) 2016 Annual Meeting. Students, preferably junior undergraduates, will be recruited through over 40 AEMB chapters. Students applying for the workshop will identify an unmet need for a biomedical device or technology (innovation) and its potential impact. Awardees will be selected based on the quality and novelty of the design idea and their potential impact. Workshop participants will be assigned to teams consisting of approximately 4 students and a team mentor. The teams will work together while at the workshop to identify design considerations, use online sources and upload ideas and considerations to their own collaboration site. The teams will be encouraged to meet virtually for up to 6 months after the workshop ends to further refine their innovation. This highly innovative workshop format will build necessary engineering design skills including 5 key considerations that are not usually stressed in coursework projects: i) market considerations for commercialization, 2) establishing methods for testing the product, 3) quality control requirements for production, 4) regulatory strategy, and 5) evaluating prospects for intellectual property protection. Students will learn how to effectively communicate with teammates and mentors who are from other schools and organizations using collaborative online tools. The proposal also includes detailed assessment plans, including surveys at the end of the workshop and at the end of the projects. Videos and written promotions will be evaluated to determine level of understanding of the 5 key design considerations. The program is expected to develop a core group of engineers who will better understand the importance of considering human needs before attempting design devices and who will be better equipped to work in the increasingly virtual environment that requires communication between distant facilities and customers. Key elements of the workshop are expected to be adopted by BME programs. A white paper describing the workshop organization and outcomes will be produced.

Non-technical Description
Twelve researchers across three institutions in three states (Louisiana, Arkansas, and Alabama) will collaborate on this brain research, and develop a foundation for the region as a hub for interdisciplinary, collaborative research activity in the neurosciences. This work will focus on understanding the initiation of epileptic brain seizures and longer-term impacts on brain function such as memory. Epileptic seizures directly impact roughly 1% of humans, and have indirect impacts on loved ones and caregivers as well as economic impacts on society. Epilepsy has been called a ?window to brain function? because the condition impairs different brain functions depending on the location of the seizure in the brain and the impacted network of neurons, and because it provides a unique opportunity to study an impaired brain?s function over time and space. The project will develop minimally invasive implantable sensors that can be used for monitoring before, during, and for several months following seizure events. Researchers will relate changes occurring during seizure events with those observed in the intervals between events. The project includes hiring four new faculty, design and purchase of equipment, development of new undergraduate and graduate courses, recruitment and training of a diverse student population to better reflect the regional community, and new student research and workforce opportunities.

Technical Description
The activities of the team across three institutions (Louisiana Tech University, the University of Arkansas, and the University of Alabama) are organized under four thrust areas that focus on recording and analysis of electrical activity, magnetic activity, neurochemical and optical signals, and memory function of the brain. A series of coordinated and synergistic investigations will be conducted using innovative methods and tools designed to probe brain function at the molecular, cellular, and macro levels in epileptic rats and human subjects. Patients with focal epilepsy, during their presurgical evaluation, will undergo implantation of intracranial electroencephalographic (iEEG) electrodes for subsequent long-term (days) recording and monitoring of their spontaneous seizures. Non-invasive magnetoencephalographic (MEG) imaging is also used to provide important complementary information on the electromagnetic activity of the brain. This collaboration will advance research and also result in the creation of unique databases of human and animal data from the participating institutions.

This award will fund the 2017 MINDS (Mentoring for Innovative Design Solutions) Workshop organized by Alpha Eta Mu Beta, the National Biomedical Engineering Honors Society. The workshop will be held October 11-14 in Phoenix, AZ, in parallel with the BMES 2017 Annual Meeting. This will allow the students selected for the MINDS Scholar Program to also participate in the BMES Annual Meeting. The MINDS Scholar Program is an innovative approach that provides students with the opportunity to collaborate and network with peers and mentors across the country for a 5-month period, while building necessary engineering design skills, including three key considerations that are not usually stressed in coursework projects. The three key considerations are: (1) market considerations for commercialization (unmet need, size of market reimbursement potential, etc.), (2) regulatory strategy, and (3) evaluating prospects for intellectual property protection. The program begins with an initial workshop where students meet their team members, drawn from other universities across the US, and mentors. The team then selects a central design idea that will be developed over the subsequent 5 months. Students will be selected through a competitive process, with junior undergraduates preferred. Students will then work with their teams and mentors to develop a design solution that takes into account issues such as market evaluation, intellectual property issues, and regulation. Subject matter experts will provide support to the teams during this 5 month design period. Teams will be encouraged to submit their designs to various design contests, investment opportunities, and grant programs. This program will develop a core group of engineers who will better understand the importance of considering human needs before attempting to design devices, and who will be more likely to engage in a variety of activities that improve the human condition. Moreover, the participants will learn how to assess human needs and will effectively use the key design considerations that are of paramount importance for successful translation of ideas to the marketplace so that they can truly help people. Additionally, the collaborative and long-distance communication skills that they develop in this project will better equip them to work in an environment that is increasingly dependent on communication between distant facilities and customers.


The majority of design courses in the US, particularly in biomedical engineering programs, do not have sufficient time to provide students with a strong experience in the non-technical aspects that are key to design success: market potential, intellectual property, and regulation. This program will provide seven teams of three students, selected through a competitive process from across the US, with key experience related to real world design processes for medical systems. It will also provide students with significant experience in working on a geographically separated team and with peers from varied backgrounds, both of which are strongly valued by industry.

The 2019 MINDS (Mentoring for Innovative Design Solutions) Workshop organized by Alpha Eta Mu Beta, the National Biomedical Engineering Honors Society, will be held in parallel with the Biomedical Engineering Society (BMES) Annual Meeting on October 17-20, 2019 in Philadelphia, PA. This award will support student travel to the MINDS Workshop and BMES Annual Meeting. The MINDS Scholar Program provides students with the opportunity to collaborate and network with peers and mentors from across the country for a 5-month period, while building necessary engineering design skills. The students would also learn about design considerations that are not usually stressed in coursework projects: (1) market considerations for commercialization, (2) regulatory strategy, and (3) evaluating prospects for intellectual property protection.

Students will be selected through a competitive process, with junior undergraduates preferred. Students will then work with their teams and mentors to develop a design solution, and subject matter experts will provide support to the teams during this five-month design period. Teams will be encouraged to submit their designs to various design contests, investment opportunities, and grant programs. This program will develop a core group of engineers who will better understand the importance of considering human needs before attempting to design devices. Additionally, the collaborative and long-distance communication skills that students will develop in this project will better equip them to work in an environment that is increasingly dependent on communication between distant facilities and customers.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

PROJECT SUMMARY For most traumatic brain injuries (TBI), the moment that an impact occurs, there is surprisingly little apparent damage. Yet, within minutes of impact, endogenous responses in the brain amplify and perpetuate the damage manifold. This cascade of responses is called secondary injury, and it is thought that this process can lead to long-term neurological problems. Our goal is to quickly mitigate some of the contributing elements of secondary injury to reduce long-term damage and neurological impairments. We will use a unique combination of drugs, including noninvasive delivery of one drug to the brain using a recently-developed co-polymer, poly (lactide-co-glycolide)-graft-polyethylenimine (PgP) as a nanocarrier. Morphological, physiological, chemical, and behavioral markers of secondary injury will be recorded at several time points up to one month after experimental TBI in mice to determine if the drug combination reduces secondary injury at an earlier time point than either drug alone, and if it maintains this reduction through one month after injury. We will use a unique multimodal system to monitor effects comprised of a newly developed microwire biosensor for glutamate (GLU) and ?-aminobutyric acid (GABA) with a modified micro-prism implant to correlate the dynamics of GLU and GABA signaling and ongoing secondary cellular damage by observing the same cells over time. Our highly sensitive and selective GLU and GABA microbiosensor will be used to evaluate the effect of treatment on reducing excitotoxicity by measuring extracellular concentrations and release dynamics in the cortex, in real time, at 5 time points after TBI versus preinjury baseline. At the same time points, high-resolution multiphoton microscopy through a permanently-implanted, modified prism will be used to facilitate a vertical view of cortical layers 3-6, to monitor development of varicosities (swellings) on dendrites and axons, axonal undulations and retraction bulbs, and the disappearance of axons. Furthermore, by viewing the same cells over time, we will compare the ability of the drugs to resolve dendritic and axonal varicosities on cells exhibiting damage in previous imaging sessions. Therapeutic effects will also be evaluated using standard behavioral tests for motor coordination, exploration, and memory, and by using established assays and antibody staining and cytokine assays for molecular biomarkers of secondary injury. By comparing the results from our novel combination of optical imaging and real-time glutamate and GABA signaling with the results from well-established behavioral and molecular biomarker tests at matched time points, we will demonstrate the utility of this longitudinal, optical- biosensor system to quantify secondary damage and its resolution. Notably, this longitudinal approach will require fewer animals because each animal serves as its own control, reducing variability, and each is used at multiple time points. In addition, optical-biosensor data from injured, vehicle-treated mice will provide new insights for better understanding the cascade of secondary injury and neural degeneration after TBI. Furthermore, this new optical-biosensor system will become a valuable tool for evaluating other drugs and for optimizing therapeutic windows.

Water pollution is a widespread problem. According to a recent Gallup Poll, ground and drinking water pollution are Americans' top environmental concerns. Some of the most serious pollutants include pesticides and heavy metals, such as lead and arsenic. These substances not only get into our drinking water, but their accumulation in plants and animals can make food unsafe in many communities, adversely affecting human health. Yet, bodies of water are often tested only once a year due to manual collection procedures and large, costly equipment to measure pollutants. This project will create small, printable sensors to simultaneously measure toxic heavy metals and pesticides on-site to enable widespread environmental surveillance in bodies of water, and to measure levels of heavy metals in human populations. The project will recruit and train a diverse workforce to design, test, and produce these new types of sensors. Through collaborations at four universities, the project will leverage the unique skills and facilities at Boise State University, Louisiana Tech University, the University of Alabama at Birmingham, and the University of Arkansas for Medical Sciences to produce and test the sensors. In addition to traditional K-12 outreach activities and recruitment to increase diversity in science, technology, engineering, and mathematics (STEM), this project has developed a novel, hybrid pre-mentoring research experience (PRE Program) to recruit and train underrepresented minority students that will enhance training and increase retention. The PRE Program will be run by the University of Arkansas at Pine Bluff, an HBCU institution. Students will engage in learning and professional development activities for several months prior to working in one of the other four universities for a summer research experience, gaining essential knowledge and experience to ensure success in a STEM career. Furthermore, the project leadership will work with economic development teams to establish manufacturing capabilities to commercialize the sensors for large global markets and to employ project trainees, which will amplify investment in this project. The sensors have the potential to enable a future convergence with the Internet of Things, artificial intelligence, and consumer cell phone apps to provide widespread surveillance and analysis of environmental toxins in water and in human populations. This convergence will create new research and commercialization opportunities contributing to the sustainability of the project beyond the life of the award.<br/><br/>The project will advance chemical and materials engineering, sensor design, environmental research, and human safety. Our research will produce databases of eco-friendly, printable sensor inks for microelectronic devices and functionalized photonic carbon dots for detection of toxic chemicals, as well as electronic and photonic sensor detection methods for multianalyte measurements. Using this fundamental research, the project team will design and optimize economical, multianalyte, eco-friendly sensors that avoid or use only a minute amount of precious metals. The project will develop non-invasive, human HM sensors for on-site use in the home and in community screening clinics. Sensors will be deployed to areas with toxic spills or persistent leakage to evaluate initial exposure and monitor exposure over time, and to gage the progress of remediation procedures. This research project will (1) provide a fundamental understanding of the emergent electrochemical properties of nanocomposite network coatings (NNCs) that avoid or use only minute amounts of precious metals versus Si-based sensors; (2) discover catalytic effects of NNC inks and their sensing mechanisms; (3) develop optimal jet printing parameters for NNC inks; (4) explore novel dopant and functionalization methods for luminescent carbon dot (CD) sensors, including upcycling of papermill and plastics industry waste; (5) learn how the electronic energy gap shifts between functionalized CDs and specific heavy metals; and (6) optimize sensing parameters for multianalyte detection for printed ink and CD sensors. These economical sensors will enable wider use and more frequent monitoring of toxic chemicals which will facilitate a greater understanding of the impact of human activity in the environment and how to minimize the spread of toxic chemicals to humans.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.