Next Seminar

Kristen Billiar, Worcester Polytechnic Institute
Heart Valve Mechanobiology: Implications for Disease and Treatment

Heart valve interstitial cells live in a highly dynamic, heterogeneous environment. Yet to date, much of what has been learned about mammalian cell function has been gleaned from in vitro studies of cells cultured on stiff glass or plastic substrates. Based upon the relatively recent realization that cells are acutely sensitive to mechanical cues, many researchers have adopted model systems with tunable, dynamic mechanical environments, and the field of mechanobiology has rapidly emerged. This seminar will focus on studies in our laboratory which highlight novel experimental approaches for investigating how mechanical cues regulate heart valve cell behavior, with implications for calcific heart valve disease and tissue engineering of heart valve substitutes.

All are welcome, (attendance required for graduate students). Lunch is provided.

Contact: Prof. Qi Wang.

Day/Time/Location: Fridays 11-12 noon, 633 Mudd Building (unless otherwise noted)

Spring 2016 Departmental Seminar Schedule

    Ge Wang, Rensselaer Polytechnic Institute
    Modern X-ray Imaging Methods and Beyond

    Due to its penetrating power, fine resolution, unique contrast, high-speed, and cost-effectiveness, x-ray imaging is one of the earliest and most popular imaging modalities in biomedical and other applications. Traditional x-ray radiographs and CT images are black and white, since they only reflect overall energy attenuation. Recent advances in x-ray detection and image reconstruction technologies have changed our perception and expectation of x-ray imaging capabilities, and generated an increasing interest in imaging biological soft tissues in terms of energy-sensitive material decomposition, x-ray induced fluorescence and luminescence, phasecontrast, and small angle scattering properties. These kinds of new information can be effectively utilized with compressed sensing, interior tomography and multimodality fusion. In addition to a general storyline, recent results from our Biomedical Imaging Center will be reported, along with our new ideas, including machine-learning-aided image-reconstruction and x-ray-modulated opto-genetics (x-optogenetics).

    Raul San Jose Estepar, Harvard University
    Quantitative Imaging Enables Clinical and Genetic Investigations of Chronic Obstructive Pulmonary Disease

    Chronic Obstructive Pulmonary Disease (COPD) is a chronic, inflammatory lung disease that arises from exposure to cigarette smoke and other inhaled toxins. It is the 3rd leading cause of death worldwide affecting about 10% of the general population but its prevalence among heavy smokers can reach 50%. The main clinical feature of COPD is a limitation of airflow that is not fully reversible. Despite the simplicity of the clinical definition, the heterogeneity of this disease makes the clinical assessment and treatment complex. In-vivo Quantitative Chest Computed Tomography provides high-resolution structural information of the lung that enables a better characterization of patients suffering from COPD. I will give an overview of the image-based biomarkers that are being developed to phenotype the different pathophysiological components of COPD: airway disease, emphysema and pulmonary vascular disease. I will introduce a scale-space particle approach that enables a rich parameterization of vascular and airway structures as a basis to resolve the main structural components. I will also present our work in the identification of parenchyma subtypes and how those techniques are used in COPD Gene, a 10,000 subject multicenter study, to identify novel clinical and genetic associations.

    Jennifer M. Munson, Dept. of Biomedical Engineering, University of Virginia
    Interstitial Fluid Flow and the Cellular Tumor Microenvironment: Effects on Invasion and Therapy

    Invasion of cancer cells is a primary mode of treatment resistance, and is an initiating step of metastatic spread. Though many cancers invade, glioblastoma, the deadliest form of brain cancer, is defined by the invasive nature of its cells. Invasion in the brain follows distinctive routes that correlate with interstitial and bulk flow pathways. In brain cancer, increased interstitial fluid flow develops due to the increase in interstitial pressure in the tumor bulk interfacing with the relatively normal pressure of the surrounding brain tissue. This differential leads to fluid transport specifically across the invasive edge of the tumor where cells are prone to both interact with the surrounding brain tissue and to evade localized, transport-limited therapies. To examine how interstitial fluid flow affects the invasion of brain cancer cells, we have developed a number of in vitro and in vivo methods to examine fluid flow responses. In vitro, we have found that interstitial flow can enhance invasion of brain cancer cells using both cell lines and patient-derived glioma stem cells in tissue-engineered models of the brain-tumor interface. These effects are mediated simultaneously by both chemotactic and mechanobiological mechanisms. In vivo, we have seen interstitial flow both correlate and increase invasion of implanted cancer cells through the brain. By conducting in vivo measurements of interstitial flow, using MRI techniques, we have seen correlations between interstitial fluid flow and patterns of glial activation, extracellular matrix deposition, and receptor activation in tumor-associated brain along these invasive pathways. By examining molecular markers and cellular components distinctive in these flow regions, we can inhibit flow-stimulated invasion in patient-designed 3D tissue-engineered models. Further, the role of interstitial fluid flow in the response to therapies (radiation and chemotherapy) is multilevel, affecting both the transport of drugs and cellular resistance. These findings further implicate interstitial fluid flow as a driver of tissue morphology and indicate multiple mechanisms through which fluid flow can mediate cellular invasion and therapeutic outcomes.

    Marjan Rafat, Dept. of Radiation Oncology Stanford University
    Deconstructing the Tumor and Tissue Microenvironment

    Despite aggressive surgical, radiological, and chemotherapeutic intervention, triple- negative breast cancer patients experience high rates of recurrence. The role of the microenvironment in recurrence is not well understood. To test the hypothesis that the irradiated microenvironment guides tumor and immune cell behavior, I characterized the effects of normal tissue irradiation on tumor and immune cell migration. I found that radiation promotes tumor cell recruitment in immunocompromised mice and that CD8+ T cells inhibit tumor cell migration to normal tissues. Tumor cell recruitment was shown to be coupled with macrophage infiltration. My work suggests that the tumor stroma may facilitate tumor cell invasion and regrowth following radiotherapy in immunocompromised patients. Future studies will use these results to engineer improved in vitro tumor microenvironment models to probe the complex physical, chemical, and biological cues that influence cancer recurrence and metastasis. To address this, I developed methods for manipulating cell adhesion and cell infiltration in vitro by using biomaterials to model microenvironmental factors that influence cancer metastasis and recurrence. Cell-cell interactions between tumor cells and the endothelium are known to facilitate metastasis. I designed photopolymerizable polyvinyl alcohol hydrogels with varying surface properties. Rather than using the common cell adhesion peptide arginine- glycine-aspartic acid (RGD), I established that conjugating antibodies to cell adhesion molecules that mimic cell surface expression synergistically induced endothelial cell attachment. In addition, because decreased pH in the tumor microenvironment has been shown to promote local cell invasion, I fabricated environmentally-responsive scaffolds that promoted cell infiltration and survival by encouraging enhanced oxygen and nutrient diffusion in acidic environments. Taken together, these techniques can be used in the design of microenvironment models.

    João Silva Soares, Ph.D., Center for Cardiovascular Simulation, Department of Biomedical Engineering, University of Texas at Austin
    Modeling, experimentation, and simulation: design-aid tools for cardiovascular tissue engineering

    Tissue engineering is a high impact area that contains a rich variety of problems ranging from the bulk-scale mechanics at the organ- and tissue-levels, down to the cell- and molecular-scales of systems biology. Many opportunities for integrative modeling approaches currently exist in tissue engineering systems, and most importantly, a large amount of translational advances and clinical successes is currently due and will spur the field even further. My current research interest is on dense connective tissue formation in mechanically-conditioned cardiovascular tissue engineering, specifically targeted for small diameter vascular grafts for CABG surgery and epicardial restraint patches. The current state-of-the-art to grow and develop engineered tissue constructs is a large array of concurrent methodologies, all obtained after extensive trial-and-error effort. While studies have yielded some insight into engineered tissue development and function, there remains significant bioengineering challenges in understanding the underpinnings of the maturational process either in vitro inside the bioreactor or in vivo after implantation. To complement TE technology development, alleviate the over-reliance on inefficient empiricism, and relieve critical barriers to its progress, my research program aims to: (i) improve mechanistic understanding and help hypothesis formulation, (ii) complement empirical trial-and-error approaches; and (iii) provide cost-effective and predictive methods for in silico optimization of processes and product design.

    Sethuraman Sankaran, Heartflow Inc., Redwood City, CA
    Personalized blood flow simulations and virtual treatment planning: A stochastic multi-scale framework

    Computational modeling of biological systems enables clinical decision making and treatment planning without the risk of invasive measurements. In this talk, I will describe the development of a multiscale computational framework for patient-specific modeling of blood flow in coronary arteries using non-invasive data such as coronary computed tomography angiography. The framework couples a computational fluid dynamics model of blood flow in the larger coronary arteries with a lumped parameter model of flow in smaller vessels such as arterioles, capillaries and veins, and a model of the heart (the different chambers and the valves). I will demonstrate that this framework is able to capture global circulatory dynamics, blood flow waveforms in coronary arteries, and has a good diagnostic accuracy compared to invasive measurements. I will then describe an adaptive stochastic collocation technique to quantify uncertainties. The stochastic multiscale framework is combined with a derivative-free optimization algorithm to perform robust design of coronary artery bypass graft (CABG) surgery. I will demonstrate that (a) regions of low wall shear stress are correlated with locations at risk of re-stenosis, (b) higher attachment angle improves CABG outcomes and (c) enforcing robustness influences optimal surgical configuration. I will then outline future directions on performing simulations accounting for predictive modeling of the slow dynamics of tissue growth and remodeling.

    Mona Eskandari, Stanford University
    Medically Driven Engineering Framework for Pulmonary Mechanics

    Lung disease is the third leading cause of death in the United States and has an even higher fatality rate in countries with excessive pollution. Strikingly, pulmonary mechanics and airway obstruction remain drastically understudied. The airway is a living system, and its disease-driven adaption induces remodeling of its geometry and material properties, resulting in airway occlusion. Using computational simulations and experimental characterization of airway mechanical properties, I confront clinically relevant questions pertaining to airway collapse in diseases such as asthma and bronchitis. My computational results—based on the theory of finite growth, solid mechanics, and nonlinear finite element analysis—rationalize my medical collaborators’ observations and elucidate the complex phenomenon of airway obstruction. My complementary porcine tissue experiments address the pressing need for airway-specific material characterization to inform the biophysical response of the small bronchi, the predominant site of obstruction. This talk will highlight the tightly connected, iterative computational-experimental nature of my research, which will enable translational discoveries in the clinic through predictive modeling, advanced medical diagnostics, and optimized interventions in pulmonary healthcare.

    Alison Marsden, Stanford University
    Computational Methods for Personalized Medicine in Cardiovascular Disease

    Computational simulation has become a powerful tool for non-invasive assessment of cardiovascular hemodynamics, enabling quantitative patient risk assessment, and systematic design of devices and surgical methods. Patient-specific image based modeling increasingly allows simulations to be used in personalized medicine and individualized treatment planning. With the first FDA approval of simulations for routine clinical use in coronary artery disease at the end of 2014, the door is now open for a wide range of simulation technologies to significantly impact clinical care in both children and adults. In this talk we will discuss recent advances in cardiovascular simulation methodology, including patient specific multiscale modeling, fluid structure interaction, uncertainty quantification and optimization. We will provide an overview of our open source SimVascular project that makes these tools available to the scientific community. We will then discuss the clinical application of these methods to patients with congenital and acquired cardiovascular disease, including surgical planning for single ventricle physiology, and mechanobiology in coronary bypass graft surgery. We will discuss recent successes and challenges of translating simulation technology to animal studies and ultimately to the clinical setting.

    Jeff Weiss, University of Utah
    Probing Probing Probing Molecular Damage and Failure of of Collagen in Connective Tissues

    Collagen is the major structural component of all connective tissues, and many painful and physically debilitating conditions involve subfailure tissue damage, or mechanical damage to seemingly intact connective tissues. Examples include rotator cuff disease, tendinosis, whiplash, and low back pain, which result from over-use, repeated subfailure injury, or trauma. However, the exact nature and evolution of damage to collagen across its hierarchy of structure is poorly understood, and the role and mechanisms of collagen molecular damage have not been established. We utilized collagen hybridizing peptide (CHP), which binds unfolded collagen by triple helix formation, to detect molecular level subfailure damage to collagen in mechanically stretched tendon fascicles. Our results directly reveal that collagen triple helix unfolding occurs during tensile loading of collagenous tissues and thus is an important damage mechanism. Steered molecular dynamics simulations suggest that a likely mechanism for triple helix unfolding is intermolecular shearing of collagen α-chains. Our results elucidate a probable molecular failure mechanism of collagen associated with subfailure injuries, and demonstrate the potential of CHP targeting for diagnosis, treatment, and monitoring of tissue disease and injury.

    Michael Mitchell, MIT
    Engineering Blood and Marrow for Cancer Therapy

    It has become apparent that the surrounding tumor microenvironment can promote the growth, drug resistance, and metastasis of malignant cells. In this talk, I will discuss how cells within the vascular and bone marrow microenvironments can be engineered and exploited for cancer therapy. I will first discuss an approach to engineer the surface of innate immune cells in the bloodstream with cancer therapeutics in vivo. Mimicking the cytotoxic activity of natural killer cells, the approach exploits the extensive surface area of circulating immune cells to display both the cancer-specific TNF related apoptosis-inducing ligand (TRAIL) and E-selectin adhesion receptor to metastatic cells in the vascular microenvironment. The resulting “unnatural killer cells” neutralized tumor cells within the circulation in vivo, and prevented metastatic tumor formation in spontaneous metastasis mouse models of prostate cancer. I will then present our most recent work on the development of gene delivery materials that target the bone marrow microenvironment in vivo, as a means to treat cancers that colonize in marrow. Through the synthesis of a diverse library of polymer-lipid hybrids in combination with high throughput in vivo screening methods, we have identified novel biomaterials that efficiently deliver nucleic acid therapeutics to target cells in the bone marrow microenvironment at low dosages. By targeting physical interactions between tumor cells and the surrounding microenvironment, these materials disrupted multiple myeloma progression in clinically relevant, humanized mouse models of the disease.

    Daniel Cohen, Stanford
    Title and abstract TBA

    Title and abstract TBA

    Kristen Billiar, Worcester Polytechnic Institute
    Heart Valve Mechanobiology: Implications for Disease and Treatment

    Heart valve interstitial cells live in a highly dynamic, heterogeneous environment. Yet to date, much of what has been learned about mammalian cell function has been gleaned from in vitro studies of cells cultured on stiff glass or plastic substrates. Based upon the relatively recent realization that cells are acutely sensitive to mechanical cues, many researchers have adopted model systems with tunable, dynamic mechanical environments, and the field of mechanobiology has rapidly emerged. This seminar will focus on studies in our laboratory which highlight novel experimental approaches for investigating how mechanical cues regulate heart valve cell behavior, with implications for calcific heart valve disease and tissue engineering of heart valve substitutes.

    Hala Zreiqat, Radcliffe
    Title and abstract TBA

    Title and abstract TBA


Fall 2016 Departmental Seminar Schedule

    Tal Danino, Columbia University
    Synthetic Biology: From Microbial Gene Circuits to New Therapies

    Rapid advances in the field of synthetic biology have enabled the design and construction of genetic circuits capable of generating programmed behavior in microbes. Concurrently, the last decade of microbiome research has revealed an astounding prevalence of microbes in diverse tissues previously thought to be sterile, such as solid tumors. These emergent fields have prompted the exploration of microbes as a natural platform for the development of engineered therapies and diagnostics. In this research talk, I will describe our progress towards a new design framework for engineering microbial gene circuits that bridges computational modeling and in vitro characterization, to diagnostic and therapeutic applications for cancer in vivo. This talk will begin with a description of bacterial gene circuits that generate synchronized oscillations, and will then describe development of programmed bacteria as both diagnostic and therapeutic agents for cancer.

    Mariah Hahn, Rensselaer Polytechnic Institute
    The influence of cell membrane depolarization on macrophage activation

    Macrophages are plastic cells that reside in every tissue and that take on various activation states in response to external cues. The three basic functions of macrophages are host defense (classically activated), wound healing and tissue repair, and the general maintenance of tissues (regulatory). Dysregulation of these phenotypes is implicated in a wide range of diseases (osteo- and rheumatoid arthritis, cancer, and diabetes), and contributes to preventing regeneration after injury. Bioelectric signals such as cell resting transmembrane potential (V mem ) have been shown to be involved not only in the regulation of tissue patterning at the scale of the organ, but also in the control of behavior at the scale of the cell. Specifically, at the level of the cell, V mem can control cell proliferation, migration, and differentiation (Fig A). A depolarized membrane potential is generally associated with proliferative cells such as stem cells, whereas a hyperpolarized membrane potential is associated with differentiated/specialized cells such as neurons. This work aims to establish a relationship between macrophage phenotype and V mem (Fig B). In our hands, classically activated macrophages appear to transition from a pro-inflammatory to a regulatory/wound healing phenotype (anti-inflammatory) following membrane depolarization. These shifts in macrophage phenotype following depolarization occurred despite continued macrophage stimulation with pro-inflammatory stimulant LPS. Immediate future work will investigate the duration of the beneficial effects of membrane depolarization. In addition, the ability of membrane hyperpolarization to modulate macrophage phenotype will be probed. Longer term future work will focus on incorporating V mem control mechanisms into biomaterials to promote regeneration.

    Jay Humphrey, Yale University (held in 501 Northwest Corner Building)
    Mechanics & Mechanobiology of Large Artery Stiffness and Effects on Cardiovascular Function

    Advances in basic science and clinical research over the past 15 years have revealed that an increased stiffness of large (elastic) arteries is an important initiator of diverse disease conditions of the heart, kidneys, and brain. There is, therefore, a pressing need to understand better the associated mechanics. Large arteries exhibit complex nonlinear, anisotropic material behaviors over finite strains, which results in significant challenges for constitutive formulations. Large arteries are also characterized by complex geometries, which results in significant challenges for computational solid and fluid mechanics. The goal of this work is to present new interpretations of arterial stiffness that capture better the loss of mechanical function that arises with aging and hypertension, which are significant risk factors for diverse arterial diseases including aneurysms. We also present a new formulation for performing stress analyses that highlights the importance of different constituents within the different layers of the arterial wall, which in turn affect the mechanobiological responses by the cells. In conclusion, we must seek not just to apply mechanics to problems of biology and medicine. Rather, we must seek to develop and extend our mechanics in order to address biologically important problems that underlie many human diseases, particularly the cardiovascular diseases that continue to be responsible for significant disability and death. The promise and potential of biomechanics thus remains very high.

    Cato Laurencin, University of Connecticut (held in 501 Northwest Corner Building)
    Bone Regenerative Engineering

    The treatment of injuries to bone that necessitate bone regeneration continues to be a major challenge for the orthopaedic surgeon. This burden is compounded by the constraints of supply and morbidity associated with autograft tissues, the gold standard of repair. The use of allografts, xenografts, or metal and ceramic implants overcomes many of the limitations associated with autografts, but fails to provide a viable solution. We have worked in the area of engineering of bone with a focus on biomaterial selection, scaffold development, cell selection, cell/material interaction, growth factor delivery, and more recently developing inducible materials.
    This entire body of work over more than twenty-five years has made matrix-based musculoskeletal tissue engineering a viable clinical alternative, and has motivated the establishment of a new field: regenerative engineering.
    Regenerative Engineering involves new technologies harnessed over the past decade: advanced materials science including nanotechnology, advanced stem cell science, morphogenesis and developmental biology cues, the knowledge and appreciation of physical forces, and clinical translation. Our work has encompassed many aspects of these new technologies and heralds a bright future for the regeneration of bone and other complex tissues.

    Johnny Huard, University of Texas at Houston
    Strategies in Stem Cell Based Regenerative Medicine for the Musculoskeletal System

    We have isolated various populations of myogenic cells from the postnatal skeletal muscle, on the basis of the cells’ adhesion characteristics, proliferation behavior, and myogenic and stem cell marker expression profiles. Although most of these cell populations display characteristics similar to those of satellite cells, we also have identified a unique population of muscle-derived stem cells (MDSCs). MDSCs exhibit long-term proliferation and high self-renewal rates and can differentiate toward various lineages, both in vitro and in vivo. Although the origin of these MDSCs is still unclear, their origin is potentially associated with the blood vessel walls namely endothelial and perivascular cells. Therefore, modalities to increase angiogenesis is being investigated to improve tissue repair -- such as exercise and neuromuscular stimulation.
    The transplantation of MDSCs, in contrast to that of other myogenic cells, can improve tissue regeneration through their ability to survive the microenvironment, and to secrete paracrine factors in response to local environmental cues. This survivability appears to be due to increased resistance to oxidative and inflammatory stress. I will discuss the use of MDSCs in gene therapy and tissue engineering applications designed to improve skeletal muscle, peripheral nerve, bone and articular cartilage healing. Further, I will discuss the genetic modification of MDSCs to express osteogenic proteins (BMP2 and -4), angiogenic factor VEGF and anti-angiogenic factors, and how these types of modifications can enhance the cells’ ability to regenerate these various tissues. I will also outline new results obtained with adult stem cell technology to delay aging in an animal model of accelerated aging (progeria). Finally, I will present new results on human muscle derived stem cells, which we believe will open new avenues for the use of adult stem cell-based gene therapy and tissue engineering to improve tissue regeneration after injury, disease and aging.

    John Foxe, University of Rochester
    Mapping Multisensory Networks of the Brain: Emerging Principles and Clinical Perspectives

    Our research group has employed multiple methodologies in both human and non-human primate models to develop understanding of the neural circuits implicated in the integration of multisensory inputs and to detail the mechanisms and principles by which these multisensory integration processes proceed. This talk will discuss a number of findings from this work: 1) Multiple lines of electrophysiological, neuroimaging, and anatomical tracing evidence make it clear that multisensory integration processes are achieved extremely early during processing. Evidence now shows that these processes are initiated as early as the initial sensory afferent volley within hierarchically early sensory cortices, and that these are sometimes subserved by convergent feedforward mechanisms. 2) That spatial alignment of sensory inputs is, perhaps surprisingly, quite unnecessary for cortical multisensory integrative processing to occur. 3) That the integration of multisensory speech inputs is crucial for speech recognition under noisy environmental conditions and that there are severe deficits in this ability in a number of clinical populations, primarily children with an Autism Spectrum Disorder (ASD). 4) That functional connectivity patterns across a left-hemisphere dominant audio-visual network predict out-of-scanner performance on a multisensory speech-in-noise challenge task, separating super-integrators from those with impoverished multisensory speech abilities. 5) That neural oscillations, particularly phase-reset mechanisms, play a key modulatory role in coordinating sensory inputs across widely separated cortical sensory regions.

    Spyretta Golemati, University of Athens
    Ultrasound Image Analysis of the Carotid Artery: A Powerful Tool towards Improving Stroke Prediction

    Management of carotid artery disease, towards preventing strokes, currently relies on a simple algorithm, which has proved insufficient for many asymptomatic subjects, posing a significant clinical challenge. Ultrasound imaging combined with advanced image analysis holds promise for addressing this challenge, through the in vivo estimation of various features of the carotid artery, the artery that brings blood to the brain. Morphological (texture) features can describe different patterns of tissue allocation, presumably as a consequence of exerted stresses. Mechanical features characterise tissue elasticity and are more sensitive to early tissue changes due to ageing or disease. Anatomical features, including arterial diameters, wall thickness and lesion size, can be automatically extracted using segmentation tools. These methodologies, along with biochemical and clinical indices, are integrated in a web-based platform, which allows for intelligent archival and retrieval of data, thus facilitating and enhancing the diagnostic procedure, towards improved risk stratification and cost-efficiency.

    Taiji Adachi, Kyoto University
    Mechanical force feedback in multicellular morphogenesis: In silico and in vitro studies

    Mechanical forces play important roles in living tissues and organs to determine their functional shape and structure. In this presentation, by illustrating examples of multicellular morphogenesis, we will discuss how locally generated mechanical forces and their feedback result in the macroscopic regulation of tissue/organ morphology, and how such multiscale approach based on modeling and simulation allows us to explore the roles of mechanical force feedback in determining the tissue/organ-level functional shapes.
    In multicellular morphogenesis, tissue folding is controlled by local internal mechanical forces such as tensile (contractile) forces generated in actin-myosin networks and compressive (pushing) forces due to tissue volumetric increase by cell division and proliferation. Mechanical forces at the adherens junctions are sensed at the microscopic molecular level by mechanosensory protein alpha-catenin, and integrated to determine the macroscopic tissue morphology through multiscale interactions. To better understand such complex multiscale phenomena, mathematical modeling and computer simulation based on mechanics will give us a powerful framework for conducting in silico experiments by combining with in vitro experiments.

    Stavros Thomopoulos, Professor of Biomechanics in Orthopedic Surgery and Biomedical Engineering Columbia University
    Enhanced tendon healing through growth factor and cell therapies

    Musculoskeletal injuries in the United States result in significant disability and high costs. Almost half of these injuries are to tendons and ligaments, including lacerations of the flexor tendons of the hand, tears of the Achilles tendon of the ankle, and tears of the rotator cuff of the shoulder. Despite significant advances in suture techniques and rehabilitation methods, outcomes after tendon repair remain unsatisfactory, with high rates of rupture and lost joint range of motion. Therefore, our long-term goal is to develop cell- and growth factor-based strategies to enhance tendon repair. Tendon healing progresses through well-defined stages of inflammation, proliferation, extracellular matrix (ECM) formation, and ECM remodeling. There is a dramatic upregulation of inflammatory factors in the earliest stage of tendon healing and insufficient cell migration and ECM synthesis in the later stages of tendon healing, leading to poor healing outcomes. Recent stem cell and growth factor studies have demonstrated the potential for biologically augmenting tendon repair. We are using novel approaches to deliver growth factors and adipose derived stromal cells (ASCs) to enhance tendon repair. Our central hypothesis is that ASCs can be used to modulate the early inflammatory response and growth factors can be used to modulate the later remodeling responses, ultimately improving tendon healing. Based on ongoing in vitro culture and in vivo animal model experiments, these approaches hold great promise for enhanced tendon repair.

    Karl Grosh, U of Michigan
    The Signal in the Noise: Cochlear Mechanics

    The cochlea is the sound-processing organ of the auditory periphery. It performs a real-time, time-frequency analysis of the acoustic signal and transmits this information to the brain for processing. Normal hearing relies on the carefully orchestrated, tripartite response of the mechanical, electrical, and acoustical (fluidic) domains of the cochlea. Using a physiologically based model, we show that a feedback control scheme hard-coded into the mechanics of the cochlear structures can provide for the fine frequency discrimination and nonlinearity seen in vivo. The electromechanical design of the cochlea takes advantage of high frequency biologically piezoelectric cells activated by similarly rapid mechano-electric transduction channels. However, and somewhat incongruously, the free-standing hair bundles of the cochlear inner hair cells responsible for transducing this signal are immersed in a 2-5 mm thick viscous boundary layer in a fluid channel. While the viscous coupling may enhance sensitivity to motion, this sensitivity comes at a cost, namely noise. We develop an analytical model to predict the thermoviscous and stochastic noise at the hair bundle of the inner hair cell. We determine the variation of the noise from base to apex, derive the relation between noise and sensitivity, and speculate on how the cochlea may have evolved to solve these design challenges.

    Marjolein van der Meulen , Cornell University
    Mechanobiology of Musculoskeletal Tissues

    Mechanical loading is important to the growth, development and repair of musculoskeletal tissues, particularly bone. While this role for mechanical stimuli is recognized, the mechanisms of musculoskeletal adaptation to mechanical stimuli are not well understood. We have developed in vivo models of controlled mechanical loading as tools to examine mechanotransduction in bone and other musculoskeletal tissues that allow us to characterize the mechanics and examine signaling. I will summarize our recent work examining in vivo musculoskeletal adaptation, focusing on increasing bone mass and the concomitant development of osteoarthritis in the joint.

    Princess Imoukhuede, University of Ilinois Urbana-Champaign
    Predicting Angiogenic Cell Response by Merging Quantitative-Experimental & Computational Biology

    Directed control of angiogenesis can improve the treatment of over 70 diseases. We hypothesize that such control can be reached by computationally integrating two types of parameters: protein concentrations and protein-protein interaction (PPI) kinetics. In support of this hypothesis, we report three key advancements: (1) engineering of new quantitative fluorescent nanosensors (qFluors) to measure plasma membrane VEGFR and PDGFR concentrations; (2) discovery and measurement of new cross-family interactions between PDGFs and VEGFR2 and (3) development of computational models that accurately predict VEGFR-mediated protein phosphorylation, cell proliferation, and cell migration.
    Our approaches are advancing towards the much needed goal of directed angiogenic control. Firstly, our qFluors are establishing a new method for quantifying biomarkers, which can be translated to clinical pathology. More immediately, this approach is providing the receptor concentration data necessary for accurate computational model development. Additionally, our discovery and measurement of cross-family binding represents a paradigm shift,where PPI interaction kinetics, not family, define our view of protein function. More immediately, these kinetic measurements provide the necessary data for predicting cell responses. Finally, our computational models are integrating each of the aforementioned parameters and providing validated predictions of angiogenic cell response.


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