2014 Research Symposium

The first-ever iBME symposium was held on April 21-22, 2014 at the UT Conference Center in downtown Knoxville.  The two-day event focused on the breadth and depth of biomedical research taking place amongst institute faculty. The symposium highlighted a multitude of research topics in order to stimulate discussion amongst those in attendance. Topics included neuro-rehabilitation; medical imaging; cellular, molecular, tissue engineering; bioinformatics; biomechanics; sensing technology; and industry relationships.

 

Student Poster Winners

Thank you to all of those who participated in the student poster session. We would like to extend our congratulations to the winners of the 2014 iBME Symposium Student Poster Competition.

1st place – TrueMotion, A Multi-Axial Continuous Passive Motion Device for the Elbow

Authors: Amber Sproul, Christine Hurst, Kim Phan, and Molly Young

2nd place – Development of Iron Nanoparticles for Brain Cancer

Authors: Julie E. King, Hien-Yoong Hah, Charles E. Johnson, Jacqueline A. Johnson, Michelle D. Pawel, Adam J. Rondinone, Kellye C. Kirkbride, and Todd D. Giorgio

3rd place – Development of a Single-vector Based Estrogen-Responsive Bioluminescent Yeast Bioreporter

Authors: Alexandra Lynn, Alexandra Rogers, Shivani Patel, Enolia Marr, Tingting Xu, Dan Close, Steve Ripp, and Gary Sayler

 

Day 1 Agenda – April 21, 2014

Introductory Remarks

Mohamed Mahfouz PhD (Director, Institute of Biomedical Engineering)

Wayne Davis PhD (Dean, College of Engineering)

Taylor Eighmy PhD (Vice Chancellor for Research and Engagement)

James Neutens PhD (Dean, Graduate School of Medicine)

Jim Thompson DVM PhD (Dean, College of Veterinary Medicine)

 

iBME Strategic Plan

Discussion Lead: Mohamed Mahfouz PhD (Director, Institute of Biomedical Engineering)

Discussion Panel: Wayne Davis PhD (Dean, College of Engineering), Taylor Eighmy PhD (Vice Chancellor for Research and Engagement), James Neutens PhD (Dean, Graduate School of Medicine), Jim Thompson DVM PhD (Dean, College of Veterinary Medicine), Randy Sessler MBA (VP of Strategic Planning & Business Development, Zimmer Orthopedics), Robert Davis MD MPH (Governor’s Chair, UTHSC-ORNL Center in Biomedical Informatics)

 

Biomedical Engineering PhD and Master’s Program

Eric Boder PhD (Academic Director, Institute of Biomedical Engineering)

 

Engineering Approaches to Neuro-rehabilitation

Eric Wade PhD (Core Faculty, iBME)

Changes in population demographics have led to more people aging into and with disability, placing an increasing burden on society. Unfortunately, there is a lack of evidence explaining determinants of outcomes after treatments for disabling diseases. For instance, after a stroke, it remains unknown how a person’s physical state interacts with rehabilitation practice variables to determine the efficacy of the intervention. The targeted use of assistive technologies with disabled populations is key to bridging this knowledge gap, but will require: technical expertise to develop computational tools to help researchers interpret clinically relevant physiological data; and a practical understanding of the needs of end users (patients and clinicians) necessary to translate research outcomes to practice. This talk will highlight computationally grounded approaches to monitoring and intervening in the recovery process for people with disabilities.

 

Engineering Autobioluminescence for Biomedical Surveillance: From Bacteria to Whole Animals

Tingting Xu PhD (Post-Doc, Center for Environmental Biotechnology)

The use of bioluminescent and fluorescent imaging as an optical technique has increased steadily in recent years due to the continuous advancement of imaging hardware such as the IVIS series of imaging systems offered by PerkinElmer. Concurrent with these advances has been the introduction of new fluorescent imaging markers that significantly improve detection ability in living systems. However, despite these advances, relatively few new bioluminescent systems have been introduced, and none that have been capable of functioning without the exogenous application of a chemical substrate. To overcome this deficiency, we have pioneered an alternative approach that allows for the autonomous production of bioluminescent signal from human cells and whole animals (zebrafish) through expression of the bacterial luciferase (lux) gene cassette. The resulting autobioluminescent phenotype can be genetically programmed to continuously produce light, to trigger light production in response to cellular signals, or to inhibit light production in response to changes in cellular health. This expression system can either complement existing fluorescent and bioluminescent systems or, when used independently, can provide a simplified, more economical, and more informative approach for the acquisition of bioluminescent data, while utilizing existing detection hardware and protocols.

 

Wearable Body Sensors for Real-Life Real-Time Patient Monitoring

Bashir Morshed PhD (Affiliate Faculty, iBME)

With the infusion of smart phones and ubiquitous wireless connectivity in our daily lives, wearable body sensors (WBS) are the emerging trend for physiological data recording, monitoring and contextual interpretation with a multitude of applications extending from critical clinical needs to regular monitoring of individual physical activities. Embedded systems are suitable technologies to develop WBS devices; but many challenges must be resolved for this translational research that will be the focus of this talk. To provide neurologists and psychologists with solutions for real-life, real-time monitoring capability of neurological disorder patients including autism, epilepsy, Alzheimer’s, and TBI patients, our lab strives to develop wearable devices to record neurological signals (EEG) along with co-sensed multimodal physiological data (e.g. ECG, HRV, GSR). We have prototyped a minimalistic ambulatory device (NeuroMonitor) for 2-channel referential or bipolar montage EEG data recording for classroom engagement monitoring of autistic children. Towards a reconfigurable and scalable solution, we are exploring a WBS architecture containing Lego-like modules of wired smart sensing nodes and wireless passive physiological sensors, a bio-inspired model founded on human nervous system.

 

Preclinical Imaging in a World Void of Large Corporate Players

Discussion Lead: Jens Gregor PhD (Core Faculty, iBME)

Not too many years ago, neither GE, Siemens nor Philips had a preclinical division. Back then, it was possible obtain NIH funding to develop a new instrument. Then followed a period of 10-12 years where one might have argued that scanners built and sold by these large corporations were missing features and capabilities, but it was almost futile to propose building a device from scratch. Today, the situation has reversed back to the way it was with only small companies left in the market. This may imply that NIH once again is receptive to preclinical instrumentation proposals that target local needs. One thing that hasn’t changed is the requirement that the work must have potential for translation impact.

Discussion Panel: Dustin Osborne PhD (Core Faculty, iBME), Ham Bozdogan PhD (Affiliate Faculty, iBME), Mohamed Mahfouz PhD (Core Faculty, iBME), Jackie Johnson PhD (Core Faculty, iBME)

 

A Novel Computer-aided Detection of Breast Cancer: Stalking the Serial Killer

Ham Bozdogan PhD (Affiliate Faculty, iBME)

Breast cancer is the second-leading cause of death among women worldwide, killing nearly half a million women every year. Radiologists still miss up to 30 percent of breast lesions in mammograms. What can data mining do? In this talk we present a new data mining technology to study a computer-aided detection (CAD) of breast cancer by introducing and developing a novel and flexible supervised classification method called, Probabilistic Kernel Discriminant Analysis (PKDA), to classify the signs of disease on the resulting digital radiographic images (i.e., mammograms) in order to help the decision making process for the radiologists. Mammography screening programs are worldwide adopted to reveal possible signs of breast cancer on asymptomatic patients at an early stage, especially when the chance of survival is highest. PKDA model is based on kernel machines that exploit Bayesian derivation of classification problem using different kernel functions with model selection criterion based on the information-theoretic measure of complexity (ICOMP) index of this author that allows robust statistical inference in the kernel feature space. An experimental case study on a real data set consisting of two breast cancer groups (“Benign”/”Malignant”) which is composed by n = 1269 Italian patients on p = 132 continuous features has been analyzed in detail.  The efficiency and robustness of our approach is presented and compared as an alternative tool to the usual Support Vector Machines (SVMs) used in Computer System Detection (CAD) of breast tumors. According to our criterion, the best-kernelized mapping is with the ERBF kernel function with a tuning parameter c = 2.602 which corresponds also to the lowest validation error rate of 37.97% with a gain of 14.64% over the usual Fisher Discriminant Analysis (FDA). Such a result elucidates the current inferential problems in the classical statistical data mining and it shows that our approach is a first step toward the specification of a robust classification model for breast cancer detection.

 

Nanoscience in Imaging

Jackie Johnson PhD (Core Faculty, iBME)

Glass ceramics consist of a glass matrix, which contain nanoparticles. This offers a unique solution to imaging. The material acts as a scintillator (i.e., it emits visible light when exposed to x-rays) or as a storage phosphor (i.e., electron-hole pairs are created and stored until they are later released by exposure to a laser beam), depending on the thermal processing used. The glass ceramic is inexpensive and easy to form so it can be manufactured in any shape or size.

Freestanding iron nanoparticles are being synthesized and characterized at UTSI, Vanderbilt University and Oak Ridge National laboratory. Applications in medicine include identification of tumor margins, magnetic resonance imaging and nanoparticle-assisted hyperthermia.

 

A Multi-Disciplinary Approach to Improved Trauma Care

Stephanie TerMaath PhD (Affiliate Faculty, iBME)

The Systems Modeling and Simulation Working Group encompasses a diverse range of expertise and facilities, spanning scales from the cellular level to detailed 3D physiology modeling to clinical team training. This lightening talk will summarize how the team is integrating their vast capabilities to improve the quality of trauma care.

 

Novel Imaging Compounds and the Future of Molecular Imaging

Discussion Lead: Dustin Osborne PhD (Core Faculty, iBME)

New agents for molecular imaging have been slow to market and those that have have been FDA-cleared have often experienced setbacks with regard to insurance reimbursement making them dead on arrival. New compounds and efforts by a number of imaging groups may open some new doors, especially for PET/CT imaging that may lead to improved clinical adoptions and reimbursement of novel imaging agents for nuclear medicine.

Discussion Participants: Jens Gregor PhD (Core Faculty, iBME), Karen Hasty PhD (Director of Basic Orthopaedic Research, UTHSC/ Campbell Clinic), Ham Bozdogan PhD (Affiliate Faculty, iBME), Jonathan Wall PhD (Core Faculty, iBME)

 

Biowireless Technologies: A New Frontier for 21st Century Medicine

Mohamed Mahfouz PhD (Core Faculty, iBME)

The wireless community has recently seen a large increase in the research being conducted that pertains to medical applications. A few example applications include remote patient monitoring; vital sign detection; wireless implantable devices for endoscopy, pacemakers, brain computer interface; intra-cranial pressure implant; and hyperthermia for treating breast and prostate cancer. Bioinstrumentation is one of the fastest growing industries, providing numerous solutions from clinical equipment to life-sustaining medical implants. Advancements in sensor technologies and innovation in computerization have spawned a vast amount of new devices for numerous applications. Recently, the introduction of reliable low-cost, low-power wireless technologies has given rise to a new generation of medical devices, which can be connected through pervasive wireless sensor networks

This talk provides an overview of smart bioinstruments highlighting examples from industry and academia. Smart bioinstruments are broken down into various applications including diagnostics, surgical, in vivo, remote patient monitoring, and indoor positioning. Each of these applications has unique requirements and constraints related to power, sensor performance, wireless transmitter and receiver front-ends, and antenna. This talk focuses on application driven design and provides an expanded discussion beyond implantable devices to wireless systems designed for diagnostic, remote patient monitoring, surgical, and positioning/tracking applications.

 

Interactive Debriefing App (IDA)

Xueping Li PhD (Core Faculty, iBME; Co-Lead, HITS)

The rapid growth of simulation in healthcare has challenged traditional paradigms of hospital-based education and training. Simulation provides an active learning environment for healthcare providers to experience clinical situations and use cognitive, effective, and psychomotor skills. As one of the most important features of simulation-based education, video briefing plays a critical role in synergizing, strengthening, and transferring learning from healthcare experiential learning. According to a survey conducted by SimVentures of approximately 900 healthcare educators, 94 percent of those who use advanced patient simulators felt that “the ability to capture high quality simulation videos that run clearly and smoothly” is important. Only 38 percent of those who capture some type of data, however, are estimated to be capturing “video” data. The proposed IDA is to improve the efficiency and effectiveness of healthcare education, engage learners in discussion, collaboration, and active experimental learning.

 

Numerical Simulations for Biomedical Applications

Kidambi Sreenivas PhD (Research Professor, SimCenter at UTC)

The talk will cover some of the simulations involving biomedical applications that have been carried out at the SimCenter at the University of Tennessee at Chattanooga.  Examples presented will include shape optimization of arterial stents and oscillatory flow through the respiratory passages.  Another example (with potential biomedical applications) that will be included is the numerical simulation of the passage of electromagnetic waves through different materials.

 

Keynote Presentation: How Innovation Challenges the Established Paradigms of Healthcare Protocols and Improve Patient Outcomes

Randy Sessler MBA (VP of Strategic Planning & Business Development, Zimmer Orthopedics)

This discussion will provide a summary overview of the Affordable Care Act, and one of its goals of shifting the U.S. Healthcare Payment Model from a “Fee-For-Service” to “Quality Driven Outcomes.”  The strategic ramifications and opportunities created for new technologies being utilized by U.S. Healthcare Providers and Medical Device Firms competing in this new “Quality Driven Outcomes” environment.  Along with one of Zimmer’s strategic responses focused on the acquisition of Knee Creations’ Subchondroplasty Procedure, which is an example of new innovation challenging the established paradigms of healthcare protocols and improving patient outcomes.

 

Microfabricating the Human Body on a Chip

Discussion Lead: Steve Ripp PhD (Affiliate Faculty, iBME)

Over the past 20 years drug discovery has transitioned away from whole animal, in vivo screening and focused instead on the use of cultured mammalian cells and in vitro target-based assays that are better tailored to the demands of high-throughput screening. Unfortunately, since that transition occurred, drug discovery has remained stagnant with approximately 30 new drug approvals per year despite R&D investments that have more than doubled during that period. Significant criticism has been levied against the in vitro screening strategy as a root cause of drug discovery’s high attrition rates due to its inability to adequately reveal the molecular complexities of a drug’s action (i.e., biology is not a single cell). Conversely, in vivo screens probe molecular interactions extraordinarily well since they embody all of the collaborative biological parts of a whole animal, but are too costly, time consuming, and ethically questionable to routinely implement. A potential solution to drug discovery’s dilemma is organ-on-chip technology that attempts to recreate the human body on a microfabricated platform by engineering 3D organ structures, tissue/tissue interfaces, and vasculature within a physiologically relevant chemical and mechanical microfluidics environment. Such in vitro microsystems may better represent the complexities of in vivo systems and ultimately enable cheaper, higher throughput, and more informative drug discovery and drive the development of new disease models.

Discussion Participants: Stacy Stephenson MD (Assistant Professor, Department of Surgery, Graduate School of Medicine), Eric Boder PhD (Core Faculty, iBME), Xiaopeng Zhao PhD (Core Faculty, iBME), Steve Abel PhD (Core Faculty, iBME), Lloyd Davis PhD (Professor, Center for Laser Applications, UTSI)

 

Vascularization of Tissue Engineered Constructs

Stacy Stephenson MD (Assistant Professor, Department of Surgery, Graduate School of Medicine)

Creation of clinically useful tissue engineered constructs is currently limited by the inability to adequately vascularize these constructs. Vascularization of tissue-engineered constructs can be accomplished by extrinsic vascularization, vessel ingrowth in vivo, or intrinsic vascularization, formation of a vascular network in vitro. These two vascularization strategies have been approached in a multitude of ways including material functionalization, microfabrication, endothelial cell seeding, and in vivo vascularization systems.

Intrinsic vascularization shortens the time required for creation of a functional vascular network by forming connections between the vascular supply of surrounding tissue and the preformed microvascular network.  Formation of a vascular network in vitro requires a cellular source. The pluripotent adipose tissue-derived stem cells (ADSCs) provide an excellent cellular source for tissue-engineered constructs because of their abundance and easy isolation. The differentiation of ADSCs into endothelial cells has been reported for human tissue with demonstration of their functional capacity to form tubular networks in vitro. Thus, ADSCs are an ideal cellular source for intrinsic vascularization of tissue-engineered constructs.

 

Single-molecule Fluorescence in Micro-/nano-fluidic Devices & Femtosecond Laser Microfabrication

Lloyd Davis PhD (Center for Laser Applications, UTSI)

This talk presents an overview of several projects in biomedical optics. Discussion will include implementation of real-time control for trapping or recycling of a single biomolecule in a nanochannel, for 3-dimensional trapping and tracking of a fluorescent nanoparticle undergoing Brownian diffusion, and for sorting of mammalian cells for directed evolution of new fluorescent proteins. Use of our femtosecond laser for machining microfluidic devices will also be discussed.

 

Inference of Transcription-translation Dynamics Through Stochastic Fluctuations in Protein Expression

Chris Cox PhD (Core Faculty, iBME)

At the cellular level, gene expression is a stochastic process owing to the discrete nature of transcript and protein populations and the burstiness of transcription and translation process. Stochastic fluctuations in protein levels can be observed directly at the single-cell level using GFP-tagged proteins and characterized in terms of noise magnitude and frequency. Through modeling, analysis, and simulation, it is possible to infer a certain aspects of other underlying transcription and translations processes from the observed protein fluctuations. This talk will briefly review the noise analysis techniques used to make these inferences and demonstrate their use to make inferences about transcription dynamics at the genome level.

 

Cell Signaling: An Opportunity for Computational and Experimental Collaboration

Discussion Lead: Steve Abel PhD (Core Faculty, iBME)

Cells have the ability to detect and respond to environmental stimuli by means of biochemical signaling networks. These networks involve many interacting components, and understanding their behavior typically requires a systems biology perspective. This talk will discuss how computational modeling of signal transduction pathways can be paired with experimental studies to give insight inaccessible to either approach alone. Focus will be on an example motivated by our interest in T cell activation but pertinent to many cellular processes: the activation of the small GTPase Ras by the guanine nucleotide exchange factor SOS. Recent single-molecule experimental measurements have provided detailed insight into the allosteric control of SOS catalytic activity, and using computational methods, we have probed the implications for the behavior of the larger Ras activation network, which can include a bistable response to an input signal. The talk will conclude by identifying open problems involving cell signaling that can potentially be addressed by pairing computational and experimental expertise from within iBME. Examples include aberrant signaling in cancer cells, cellular consequences of off-target drug interactions, and the response of cells to mechanical stimuli.

Discussion Participants: Steve Ripp PhD (Affiliate Faculty, iBME), Eric Boder PhD (Core Faculty, iBME), Seung Baek PhD (Core Faculty, iBME), Lloyd Davis PhD (Center for Laser Applications, UTSI)

 

Prion-like, Autocatalytic Refolding and Aggregation of a Prototypical Viral Fusion Protein

Eric Boder PhD (Core Faculty, iBME)

Influenza hemagglutinin is a prototypical viral membrane fusion protein that induces lipid bilayer fusion following a large, irreversible, environmentally-triggered conformational change.  We have observed autocatalytic behavior in the conformational change, resulting in aggregation of the protein on the cell surface.  The striking similarity of this phenomenon to amyloidogenic species raises a number of questions regarding the possible role of amyloid-like properties in viral fusion proteins function and presents the potential for further functional and imaging studies to explore this behavior.

 

Combinatorial Algorithms for Biomarker Discovery

Mike Langston PhD (Core Faculty, iBME)

We will discuss the use of innovative algorithmic methods and powerful computational technologies in the analysis of high-throughput biological data. Efficient combinatorial search remains a core concern in the quest to identify important latent signatures and structures. We will concentrate on the use of novel techniques for handling noisy data, machine learning, and the role that methylation may play in the pursuit of biological markers relevant to human health.

 

Elucidating and Harnessing Cellular Metabolisms for Biotechnological and Biomedical Applications

Cong Trinh PhD (Core Faculty, iBME)

The current technology of strain engineering involves engineering each desirable strain in many trial-and-error strain optimization cycles. To engineer new desirable strains to produce other target molecules, the entire process must be repeated, which is laborious and expensive. To overcome this limitation, our lab explores innovative approaches based on the constraints-based metabolic network modeling and statistical analysis to rapidly design and build modular microbial cell factories that can efficiently produce target molecules from exchangeable biological parts in a predictable and reproducible plug-and-play fashion. These approaches can be applied for developing optimal pathways for efficient combinatorial biosynthesis of secondary metabolites and can be further extended to identify targets for drug development.

 

 

Day 2 Agenda – April 22, 2014

Gaps in Cancer Detection and Treatment

Discussion Lead: Tim Sparer PhD (Associate Professor, Microbiology)

The “War on Cancer” was initiated with Richard Nixon’s signing of the National Cancer Act in 1971. In the forty-plus years, a few battles have been won (i.e. childhood leukemias) but the cancer still remains the second leading cause of death in the US. Cancer is a complex disease that initiates with a mistake in cell cycle control genes, involves the vascularization and growth factors in the tumor microenvironment, and in many cases the metastasis and growth to a distant organ. Synergy between cell biologists, biochemists, and engineering is essential for the detection, diagnosis, and treatment of cancers. Areas of synergy include:

Biosensors for earlier detection – Novel biomarkers and the ability to process multiple markers from a single sample will allow for a more sensitive and specific diagnosis.

In vitro organotypic cultures (i.e. 3D cultures) – The reconstruction of the tumor microenvironment is important for drug treatments testing in a complex tissue environment.

Improved imaging – It is not usually the primary tumor kills the patient, but the metastasis to distant organs that leads to a patient’s death.  With improved imaging, a more thorough evaluation of available treatment options for metastatic cancers will be possible.

Drug delivery systems – The goal of any cancer treatment is to target the cancer cells while minimizing the damage to surrounding tissues. Currently the side effects of toxic anticancer drugs contribute to the morbidity of cancers. These delivery systems can include novel targeted lipids, nanoparticles, and/or polymers.

Novel anti-tumor/anti metastatic drugs – With the phase-in of personalized medicine, anti-cancer treatments are becoming more specific.  At the same time additional developing new “tools in the tool chest” will be important for making personalized medicine even more “personalized.”

Discussion Participants: Seung Baek PhD (Core Faculty, iBME), John Bell MD (Professor, Surgical Oncology, Graduate School of Medicine), Steve Abel PhD (Core Faculty, iBME), Jackie Johnson PhD (Core Faculty, iBME)

 

Computational Modeling and Simulation of Changes in Healthcare Delivery and Payment Models

Mallikarjun Shankar PhD (Computational Sciences and Engineering, Oak Ridge National Laboratory)

A fundamental shift in national healthcare from fee-for-service to value-driven payments is taking place. The Patient Protection and Affordable Care Act (ACA) promises a sea-change in cost-control and quality improvement by shifting incentives and payments to “value” and “quality”, instead of paying for physician visits. Addressing the dynamics of this change, we describe a large-scale high-fidelity model for the constituent actors in the US healthcare eco-system. The model supports scenario-driven and prospective investigations of cost and quality outcomes regionally and nationally, and allows us to anticipate and respond to the dynamics of new payment models.

 

Polymer Materials for Biomedical Application

Vera Bocharova PhD (Department of Chemistry)

At the beginning of my talk I will give a general overview of iBME-relevant research interests of our group, including imaging, biopreservation and stimuli-responsive polymers. The latter will be the specific focus of our current presentation. Stimuli-responsive polymers are the center of many studies related to the development of materials and concepts in a broad-range of applications including biomedicine, smart coatings, self-healing systems, etc. Those polymers are capable of switching physical properties (such as optical, electrical, magnetic, wettability, permeability, etc.) upon application of the different external signals including pH, temperature, electric field, etc. Since many biochemical reactions result in pH or temperature changes, stimuli-responsive materials have found their biomedical application as drug-delivery devices, sensing systems, actuators, etc. The general aspects of the different types of stimuli that can be used for biomedical applications will be reviewed mainly for the case of hydrogels. Example of a system that recognizes more than one stimulus will be presented. Besides the typical response to temperature and pH, a system which reacts to biochemical stimulus will be discussed.

 

Use of Equine Molar Stem Cell Tissue in the Treatment of Refractory Equine Musculoskeletal Injuries

Ray Wasielewski MD (Core Faculty, iBME)

The pulps of unerupted 3rd molar tissues in humans have been shown to contain considerable numbers of stem cells.  Similarly, equine molar stem cell tissue contains considerable amounts of mesenchymal stem cells.  We have treated 10 horses with significant musculoskeletal osteoarthritis and tendon injuries.  All but one animal responded to this therapeutic as demonstrated by reduction in lameness.  Currently a blinded control clinical trial is being conducted to better document the efficacy of this treatment. Mammalian musculoskeletal injuries and other conditions may benefit from use of this minimally manipulated tissue product.

 

In vivo Biomechanics of the Human Body

Richard Komistek PhD (Core Faculty, iBME)

The objective of this study was to use both an inverse and forward solution mathematical models of the human body to gain a better understanding of present day implant failure modes and to derive future implant designs that may lead to greater implant longevity. Initially, an inverse dynamic model that uses in vivo motions as input, predicting the in vivo contact forces, areas and stresses for subjects not having an implants compared to those subjects having implants. Then, a forward solution model, using muscle force temporal profiles as input, predicting both the implant motion and bearing surface mechanics was derived and utilized. The results from the inverse model compared very well with telemetric implants. In vivo contact stresses varied considerably for different implant types. Varying shapes and interactions using the forward solution model lead to future implant designs exceeding the maximum force available in the quadriceps muscles required to produce deep flexion maneuvers. The model is also very sensitive to ligament changes, patellofemoral interactions and movement of the femoral head within the acetabulum. Using a mathematical model, it has been shown that in vivo contact areas, forces and stresses can be derived computationally.

 

Wireless Insertable Cameras and Wearable Sensors

Jindong Tan PhD (Core Faculty, iBME)

This talk discusses a novel wireless surgical camera system (sCam) to enhance and improve surgical procedures for single incision laparoscopic surgery (SILS) and natural orifice translumenal endoscopic surgery (NOTES). sCam can be inserted into a body cavity via the incision for the operation instrument or natural orifice, which will eliminate the need for dedicated incisions for laparoscopic cameras and the share use of an incision for surgical instruments. This talk discusses the research challenges and designs of insertable camera systems in locomotion mechanisms for the motion control of the camera system inside the body cavity, which include anchoring and manipulating (translational and rotational motion) the camera system. This talk also discusses research on wireless wearable sensors and their applications in our group.

 

ABT Molecular Imaging, Dose On Demand Production of PET Radiopharmaceuticals

Mark Haig Khachaturian PhD (Vice President of Research & Development, ABT Molecular Imaging, Inc.)

Positron emission tomography (PET) is the fastest growing segment of medical imaging worldwide.  In the United States, since PET came into clinical acceptance, the installed base of PET scanners has grown from less than 100 in 1995 to over 2,400 in 2012.  PET imaging is dependent upon access to a short-lived radioisotope, which for many years inhibited the growth of PET.  The advent of commercial distribution of these radioisotopes in the mid-90s created both availability and lower cost, which significantly fueled widespread adoption of PET imaging in the U.S, Western Europe and Japan.  The emerging world (~85% of the world’s population) does not have ready access to these radioisotopes; therefore PET is rarely available in these markets.  ABT Molecular Imaging, Inc. (ABT) solves this problem.  After six years of development and over $20 million of investment, the low cost, easy to use Biomarker Generator (BG) makes PET radiopharmaceuticals where they are needed and when they are needed.  The “Dose on Demand(tm)” BG dramatically simplifies the production process and know-how required, as well as reduces the investment required by healthcare institutions to introduce state-of-the-art molecular imaging diagnostics to their healthcare programs.  This presentation will provide an overview of the ABT Molecular Imaging Biomarker Generator.

 

Digital Health, a New Healthcare Era

Discussion Lead: Emam Abdel Fatah PhD (Core Faculty, iBME)

With increased healthcare cost, aging patient population, and growth in chronic conditions; the demand for innovative methodologies to achieve on-demand high quality healthcare have risen. The idea of pervasive computing was first put forward as a paradigm shift from the traditional human-desktop interaction computing model. In pervasive computing, communication and networking resources are embedded within the physical environment allowing individuals to perform required activity anywhere and anytime thereby creating a user-centric environment. The smart device and communication revolutions have provided the needed infrastructure for expanding the pervasive computing concept and integrating it in many aspects of daily activities. Pervasive computing has the power to create a patient-centric environment through the use a set of sensing and communication technologies designed to seamlessly integrate health education, interventions, and monitoring technology into our everyday lives, regardless of space and time.

Discussion Participants: Russell Langdon MD (Affiliate Faculty, iBME), Mitch Goldman MD (Core Faculty, iBME), Eric Wade PhD (Core Faculty, iBME), Mohamed Mahfouz PhD (Core Faculty, iBME)

 

Theranostic Nanosomes for Early Osteoarthritis and Cartilage Damage

Discussion Lead: Karen Hasty PhD (Director of Basic Orthopaedic Research, UTHSC/ Campbell Clinic)

Treatments for the most prevalent form of arthritis, osteoarthritis (OA), currently are primarily palliative until joints become totally dysfunctional and prosthetic replacement is needed. There are numerous obstacles for developing effective OA therapy. One is the lack of good diagnostic tools for efficiently identifying early stages of the disease and monitoring its progression in small animal models typically used for therapeutic testing. Histopathological evaluation is the traditional assessment for OA, but this requires sacrifice of the animal, uses tedious subjective criteria, may contain sampling error and cannot be used for serial measurements in a single animal. Our overall goal is to establish an innovative method to identify early cartilage damage in OA and to quantitatively assess its progression in vivo. Identification of early OA would permit interventional therapy at the earliest stages of disease when the pathology may be more amenable to intervention. We propose to use monoclonal antibodies (Mab) to native type II collagen (CII) that bind damaged cartilage to identify early subclinical lesions and quantitate disease progression in OA. If successful, this will provide an inexpensive and reproducible method that can be used for diagnosis and to monitor the effects of therapy on OA progression over relatively short to intermediate time periods. We have established the validity of our approach, using animal models of OA; a well characterized mouse model of surgical transection for destabilization of the medial meniscus (DMM) in mice, and two models of spontaneous osteoarthritis with Dunkin-Hartley guinea pigs and Str/Ort mice that share many features of human OA. In addition, we have examined an overload mechanical knee injury in mice. We have used and compared two methods of localization of targeted fluorescent probes to damaged cartilage; MabCII labeled with near infrared emitting fluorescent (NIF) dyes and MabCII-targeted nanosomes encapsulating NIF intravenously injected into these animals. The degree of damage was quantified using IVIS® imaging technology and correlated with traditional histopathological indices for the joints identified by fluorescently labeling and in collaborative studies for high resolution MRI. Our hypothesis, supported by preliminary data, is that the fluorescently labeled antibodies (NIF-MabCII) selectively localized to joints in which the surface of articular cartilage is eroded and CII is exposed. The technique is extremely sensitive and identifies minimal cartilage damage and that larger and more advanced lesions will bind larger quantities of NIF-MabCII. We propose to encapsulate drugs for delivery to early stages of OA that will modulate chondrocyte metabolism to delay or prevent disease progression. In addition, this approach could be used for fluorescent arthroscopy to diagnosis of cartilage damage or to target a site for engineered tissue replacement or engraftment or for local application of treatment.

Discussion Participants: Madhu Dhar PhD (Core Faculty, iBME), Dustin Osborne PhD (Core Faculty, iBME), Mohamed Mahfouz PhD (Core Faculty, iBME), Emam Abdel Fatah PhD (Core Faculty, iBME), Michael Best PhD (Core Faculty, iBME)

 

Surveillance of Medical Devices Utilizing a Large-Linked Automated Database

Discussion Lead: Robert Davis MD MPH (Governor’s Chair, UTHSC-ORNL Center in Biomedical Informatics)

The widespread availability of electronic medical record data for research has revolutionized public health surveillance efforts. Since 1990, the CDC has used electronic administrative and EMR data from HMOs to carry out vaccine safety surveillance and vaccine safety research on 4-6% of all children in the United States. More recently, the FDA created the Sentinel Initiative, which uses insurance company and managed care organization EMR data to carry out medication safety surveillance activities on approximately 130 million people in the United States.  This session will discuss the possibility of using this type of data for large scale evaluations of the effectiveness, comparative effectiveness, and safety of orthopedic devices and/or orthopedic procedures. The talk will discuss the necessary data elements for such activities, and will also show how subject matter expertise would play a crucial role in the development and success of such databases.

Discussion Participants: Xiaopeng Zhao PhD (Core Faculty, iBME), Mohamed Mahfouz PhD (Core Faculty, iBME), Emam Abdel Fatah PhD (Core Faculty, iBME), Randy Sessler MBA (VP of Strategic Planning & Business Development, Zimmer Orthopedics)

 

Importance of Animal Models in Cell-based Therapies

Madhu Dhar PhD (Core Faculty, iBME)

Stem cell research has the potential to substantially improve medical care.  The prospective clinical use of adult mesenchymal stem cells holds enormous promise for improved treatment of a large number of diseases in humans and companion animals. Although the use of bone-marrow-derived mesenchymal stem cells appears to be a popular therapy; the therapy suffers from the donor-to-donor variation in the quality and quantity of harvested cells.  This observation has been reported in humans, mice, dogs, and horses.  One critical biological factor that researchers and clinicians must take into account is this variability and how it may affect the clinical outcome in regenerative therapy.  The focus of research in the Laboratory of Regenerative Medicine at the College of Veterinary Medicine is to understand this variation in large animals.  We have optimized in vitro molecular and cellular assays to isolate, characterize, and differentiate horse and goat adult mesenchymal stem cells; we can generate an ex vivo model of a specific disease, and finally we can design a controlled animal (in vivo) study to test their biological function in regeneration. The goal of this three-step process is to improve clinical outcomes as well as increase our basic knowledge of stem cell function.  Currently, we are carrying out experiments to test the efficiency of adult mesenchymal stem cells in wound healing, treatment of corneal ulcers and bone tissue engineering.  Additionally, we are the only research laboratory that has generated and use off-the-shelf equine allogeneic mesenchymal stem cell stocks for immediate administration into clinical cases.

 

Readout Circuitry for Monitoring Temperature Variations in Biological Substances

Farhan Quaiyum (Electrical Engineering and Computer Science)

The lab-on-a-chip concept has made significant impact in the biomedical field, because of its superiority in terms of performance, power, and size. Fast and accurate temperature monitoring is essential in medical diagnosis and a polymer pyroelectric transducer provides superior performance in terms of dimensions, sensitivity, and large scale of integration. The ferroelectric polymer polyvinylidene fluoride (PVDF) has been used for monitoring of temperature variations of biological substances in a microchannel system. The transducer produces a charge according to the temperature variation of the substance. In this presentation, we propose a new scheme of a charge sensitive pre-amplifier that can convert the temperature-dependent charge generated by the transducer to a proportional voltage.

 

Genetic Risk Factors for Concussion in College Athletes

Tom Terrell MD (Associate Professor, Family Medicine, Graduate School of Medicine)

To investigate associations between genotypes previously found to be associated with traumatic brain injury or other neurological disorders (APOE promoter G-219T, Tau exon 6 Ser53Pro, Tau exon 6 Hist47Tyr, Interleukin [IL]-6, IL-6R 572) and prospectively occurring and self-reported prior (SRP) sports-related concussions.

 

Keynote Presentation: Navigating and Understanding FDA: How to Get Your Medical Device To Market In The US

Elisa D. Harvey DVM PhD (Senior Regulatory Consultant, CardioMed Device Consultants, LLC)

This presentation will provide an overview of the FDA and the framework for medical device regulation in the US, including the definition of a medical device, description of the most common pathways to market, nonclinical and clinical testing requirements for medical devices, content of a marketing application, and how to interact with FDA to maximize your chances of success.

 

Intelligent Patient Monitoring and Control

Xiaopeng Zhao PhD (Core Faculty, iBME)

Modern physiological monitoring faces various challenges including data heterogeneity, noise, gaps, and nonlinear and nonstationary transitions. We will explore methods for intelligent patient monitoring that integrate state-of-the-art technologies, advanced computer algorithms, and expertise of clinicians to improve the quality of healthcare and to minimize costs and environmental impact. Examples will be drawn from intensive care, bioelectricity diagnosis, as well as smart and connected health.

 

A Rapid and Facile Sensor Platform for Biomolecular Interactions

Jayne Wu PhD (Affiliate Faculty, iBME)

Our research group has developed a capacitive biosensor (a type of impedance sensor) for detection of disease-specific antibodies and pathogens.  Innovation of our biosensor system resides in using a unique protocol, which incorporates an AC electrokinetic (ACEK) effect into the capacitive sensing step, allowing us to direct the flow/biomolecules within the fluid chamber to the electrode array. This enriches the immediate environment with target analyte molecules, and greatly reduces assay time to less than two minutes. Our preliminary data showed that binding of target analyte molecules (i.e. antibodies and biomarker) can be quantitatively detected under 1 minute.  Our system was also shown to work with complex fluids such as serum samples.  So sample pretreatment can be kept at a minimum for our system, –only dilution of samples with buffer is needed. Experimental data suggest that signal from non-specific binding is reduced by our protocol.  Together with its electrical interrogation, diagnosis can be automated as a “single button” operation to achieve “from sample to result” in real time, minimizing human interference for better repeatability.  Our diagnostic device demonstrated high sensitivity; the limit of detection of the system was well below 10 ng/mL for proteins and around 2 ng/mL for virus.  Further development of our diagnostic system will not only yield a rapid, reliable, easy, and inexpensive tool to detect toxins/virus, but also provide a foundation technology for microfluidic binding assay, and will have vast applications in immunoassay systems in general.

 

Incorporating the Social and Behavioral Sciences into iBME

Kenneth J. Levine PhD (Affiliate Faculty, iBME)

Many of the goals of UT’s iBME are based in the hard sciences and address the important needs to improve medical care.  However, other goals include improving interactions between and among patients, caregivers, physicians, nurses, pharmacists, therapists and technicians.   To understand the human element in health case, it is imperative that the social and behavioral sciences be a component of iBME’s research.  Human behavior is complex and often inconsistent and confusing.  In the social sciences, the correlations between variables are lower than would be acceptable in the hard sciences, but these relationships no less vital in helping to understand how to improve and optimize efficiency in the healthcare setting.

 

Development of Non-Invasive Sensing Technologies

Justin Baba PhD (Affiliate Faculty, iBME)

Noninvasive sensing technology development is at a crossroad. Whereas there has been a recent emphasis in the past two decades on micro- and nano-technology based platforms, primarily, advances have been regulated to lower detection limits, smaller sample volume sizes and greater sample processing throughput. Thus, great headway has been made in increasing diagnostic efficiency and reducing the invasiveness but not necessarily in non-invasiveness. Is this a practical consideration or are we out of fundamental approaches for non-invasive perturbations that can still yield much needed diagnostic information?

 

Control of Physiological State in Human Cell Lines by Electrochemical Interface

James Fleming PhD (Research Assistant Professor, Center for Environmental Biotechnology)

The monitoring and manipulation of external oxidoreduction potential (ORP) has been used for decades to optimize and control cellular processes in both bacteria and mammalian cells. Here we demonstrate in vivo electrochemical ORP control of: 1) light in a human redox reporter cell line 2) cell proliferation and apoptotic activities in human colon cancer cells.  Our experimental system uses microfabricated interdigitated platinum electrodes on silica chips in a three electrode configuration interfaced with an electrochemical potentiostat.  Cells are grown on the chips in media contained within silicon gasket frames.

The light output of human embryonic kidney cells (HEK293) transfected with plasmids harboring bacterial luciferase was repeatedly modulated above and below constitutive levels using cyclic voltammetry and chronopotentiometry.   Exposure of cells to a 90 µA current for 20 min resulted in an 11.5 fold increase in light in no significant adverse effect on cell viability.  The molecular mechanism for this effect is presumed to be the alternate direct oxidation and reduction of flavin mononuclease (FMN), one of the integral components of the bacterial luciferase pathway.

Based on the results of our HEK cell experiments, we hypothesized that ORP manipulation might be a useful approach to treat cancer cells.  Human SW480 and HCT116 colon cancer cells were grown on electrode chips and exposed for 300 s (six controls, six test) to a DC field strength of 1.6-2.3 V/cm with current densities ranging from 0.05 -5 µA/cm2.  After 24 h the cells were tested for: 1) cell viability (2 x 104cells/chip) using a tetrazolium/formazan assay and 2) apoptosis (2 x 104cells/chip) using a caspase 3/7 assay.  We found that caspase activities increased directly in proportion to electric current exposure and significant increases occurred at currents below those that adversely affect cell viability.  Interestingly, compared to SW480 cells, HCT116 tolerated higher currents before exhibiting caspase induction or loss of cell viability.  Because of the correlation between ORP and cellular processes such as proliferation, apoptosis and gene expression, control of ORP by direct electrochemical interface may be a useful therapeutic intervention for other mammalian cell disease states.

 

A Low Power Implantable Glucose Monitoring System Implemented in 130 nm CMOS Process

Ifana Mahbub (Electrical Engineering and Computer Science)

A low power implantable glucose concentration monitoring system has been implemented which consists of a potentiostat, a signal processing unit (SPU) and a low dropout regulator (LDO). The potentiostat is designed to maintain a constant voltage potential of 0.7 V between the working and the reference electrodes (WE-RE) to facilitate the chemical reaction for the sensing operation. The counter electrode (CE) of the potentiostat outputs a current that is proportional to the glucose concentration produced in the chemical reaction. The SPU converts this current to a frequency-modulated signal where the frequency is proportional to the sensor current. The LDO regulator is designed to provide a stable power supply to the circuits. It regulates an irregular supply voltage of 1.5 V- 2 V from the solar/photo cells and provides a constant 1.3 V at the output. Test results show a high linearity (R2=0.9974) of the SPU with a frequency modulated output signal of 500 Hz to 8 KHz over the physiological glucose concentration range (2 mM/Liter to 22 mM/Liter which produces 100 nA to 10 µA sensor current). The entire system has been realized using 130 nm CMOS technology that consumes about 35 µA of current and occupies an area of 0.018 mm2.

 

Smart Silicon: Ultra-low-power Circuits for Intelligent Wireless Sensors

Jeremy Holleman PhD (Core Faculty, iBME)

Advancements in semiconductor technology have brought smart micro-scale wireless sensors within reach for many applications. However, power continues to be a critical obstacle; battery technology has not kept pace with semiconductors and harvested energy sources tend to be weak and sporadic.  Innovative ultra-low-power analog, mixed-signal, and RF circuit design is necessary to realize the promise of micro-scale ubiquitous wireless sensors. This talk will describe low-power circuits that address challenges at each stage in the signal chain of a wireless sensor: signal acquisition, processing, and communication.  These will include efficient low-noise amplifiers for neural recording, sensing of sub-picoampere currents, a deep machine learning system implemented in analog circuits, and a low-power wireless transmitter.

 

Synthetic Lipid Analogs for the Characterization of Lipid Biological Activities and Development of Delivery Strategies

Michael Best PhD (Core Faculty, iBME)

Lipids represent important biomolecules since these compounds control many critical disease-related biological processes, and also because they are useful for applications such as drug delivery. For these reasons, lipid analogs generated through synthetic organic chemistry are beneficial for studies aimed at elucidating the roles of lipids in disease onset as well as the development of novel strategies for drug delivery. This presentation will provide an overview of our interests in the development of synthetic lipid analogs for chemical biology and drug delivery applications. Biological studies involving lipid analogs are represented by the application of lipid activity probes that are effective for the selective labeling and discovery of proteins that are regulated through the binding of particular lipid structures. Drug delivery applications will be exemplified by the development of derivatized lipids for the selective targeting and triggered release of liposomes as biocompatible molecular cargo containers.

 

How Tech Can Make the Head of the Operating Room Bed Smarter

Matt Bell MSN CRNA (College of Nursing)

The practice of anesthesia is a data rich, multi-faceted, highly stressful, and rapidly changing environment.  The number of baby boomers entering their retirement years brings the ‘silver tsunami’ of increasing anesthetic cases coupled with complex comorbidities.  We’ve no choice but to work smarter, not harder.  We can further optimize anesthetic practice by leveraging existing technologies bent for perioperative use.

 

Keynote Presentation: Fundraising Strategies for Medical Device Companies – Public & Private Capital

Jim Stefansic PhD MBA (Director of Commercialization, LaunchTN)

Fundraising for medical device companies faces new challenges that did not exist even a few years ago.  New medical technologies & devices should now not only be developed to improve the standard of care but also to reduce the cost to deliver care. Success now depends greatly on reimbursement; device entrepreneurs and investors have an evolved sense of what is innovative, relying less on technological advancement than on improved health outcomes that can ultimately cut costs in the healthcare system.  With this focus, both private and public (SBIR/STTR) fundraising strategies will be discussed, along with resources available to companies in Tennessee.

 

Fundraising Strategies for Medical Device Companies

Discussion Lead: Jim Stefansic PhD MBA (Director of Commercialization, LaunchTN)

Fundraising for medical device companies faces new challenges that did not exist even a few years ago.  New medical technologies & devices should now not only be developed to improve the standard of care but also to reduce the cost to deliver care. Success now depends greatly on reimbursement; device entrepreneurs and investors have an evolved sense of what is innovative, relying less on technological advancement than on improved health outcomes that can ultimately cut costs in the healthcare system.  With this focus, both private and public (SBIR/STTR) fundraising strategies will be discussed, along with resources available to companies in Tennessee.

Discussion Participants: Chuck Witkowski (CEO, Hubble Telemedical), David Page PhD (Partner, Third Dimension Technologies), Grady Vanderhoofven (Co-founder & Co-fund Manager, Meritus Ventures)