BE Seminars & Events

This talk will describe the use of microfluidic technology to control and manipulate drops whose volume is about one picoliter. These can serve as reaction vessels for biological assays. These drops can be manipulated with very high precision using an inert carrier oil to control the fluidics, ensuring the samples never contact the walls of the fluidic channels. Small quantities of other reagents can be injected with a high degree of control. The drops can also encapsulate cells, enabling cell-based assays to be carried out. Examples of the application of these devices to the study of fundamental biology will be described. In addition, I will describe the impact this class of microfluidics is having on biotechnology.

One of the fundamental mysteries of biology lies in the ability of cells to convert from one phenotype to another in response to external control inputs. We have been studying the Epithelial-to-Mesenchymal Transition (EMT), which allows organized groups of epithelial cells to scatter into lone mesenchymal cells. EMT is critical for normal development and wound healing, and may be important for cancer metastasis. First, I'll brief you on our efforts to use statistical methods to summarize about 12,500 publications on EMT. This analysis revealed interesting statistical anomalies. For example, the number of discrete factors that authors invoked to explain EMT and its regulation was bounded above by the capacity limit of the human brain to follow statistical interactions among variables. In the second part of my talk, I'll show you our recent data on disorganizing mammary epithelial structures. We have used CRISPR to insert fluorescent tags directly into eight EMT-related genes (such as E-cadherin and Vimentin), which allows us to monitor the transition in real time, subject only to delays imposed by fluorophore folding/maturation times.

Many of us are privileged and knowledgable to access advanced medicine when we unfortunately need it. A number of factors limit this access to the general population. I will demonstrate with two examples how we can brake that boundary.

First, we will show how to help deep brain stimulation (DBS), in particular for motor disorders, with advanced algorithms that permit to detect with high precision the surgical target. This opens the door to orders of magnitude expansion of DBS. From there we move to the use of technology, image processing, and machine learning to design screening tools for child mental health. We will illustrate this with Autism screening. Both examples illustrate results already in use in the OR and clinic, and exemplify both the need for the tools we develop and the value of having an incredible interdisciplinary team, all of which will be mentioned and introduced during the talk.

Imaging neurons deeply buried inside a live mouse using a microscope shares many similarities with gazing at distant stars with a telescope. In both cases, imaging capacity is limited by optical aberration and scattering. Wavefront shaping using adaptive optics has revolutionized astronomy by allowing us to obtain sharp images of celestial objects through the turbulent atmosphere. Similar concepts may be applied to microscopy for optically transparent samples but not the scattering mammalian brains. In this talk, I will describe recent developments in adaptive optical microscopy, which allowed us to image both the input and output of mouse cerebral cortex with diffraction-limited resolution. By making it possible to functionally image axons and neurons deep inside the mouse brain, these techniques enabled novel discoveries on the origin of orientation selectivity in mouse primary visual cortex.

Liver regeneration is a clinically important tissue repair process, which involves the interplay of carefully orchestrated signals from different cell types integrated with systemic factors to recover functional tissue mass. At present, there is limited theoretical understanding of how the regulatory mechanisms operating at multiple scales integrate towards an overall liver response when mounting an effective regenerative program. We pursue a systems biology strategy that combines multiscale modeling with single cell scale data sets to fill this major gap in our knowledge. In this presentation, I will describe a novel computational model we developed to account for various cellular and molecular aspects of liver regeneration following partial hepatectomy. Our modeling studies led to novel predictions on how dynamic regulation of hepatic stellate cell phenotypes can control the integrated liver tissue response in health and disease, across multiple organisms. We validated the model predictions using pathway-scale single cell gene expression data sets. Our results provide new insights into how the dynamic state transitions between multiple cell phenotypes are integrated towards a coordinated control of the liver regeneration process. We are presently translating the network model to the human condition for improving liver surgery and transplant outcomes for a broader cohort of patients.

Cardiovascular disease is the leading cause of death in the US and rapidly becoming the leading cause of death worldwide. While a number of therapies have sought to arrest the progression to heart failure following myocardial infarction (e.g. cell therapy and tissue engineering), these have fallen short in promoting the restoration of normal cardiac function following injury. Similarly, congenital heart defects (CHDs) are the leading cause of mortality in live-born infants and young children. Children with severe CHDs such as Hypoplastic Left Heart Syndrome and Tetralogy of Fallot require several major reconstructive surgeries starting within the first few days after birth. However, these surgeries do not replicate normal heart anatomy and function, and many patients suffer from serious secondary complications throughout life. In each of these situations there are significant changes to the mechanical environment, both in terms of the mechanical stresses presented to the cells via the normal function of the organ and in the composition and mechanical properties of the extracellular matrix (ECM). Given the growing body of evidence on the role of ECM properties in signaling cell fate and function, understanding the role of the alterations in the complex mechanical signaling environment in health and disease could be critical to the development of a new class of therapeutics aimed at altering mechanotransductive signaling in disease. In this talk I will highlight some of our work aimed at understanding the role of alterations in the properties of the complex ECM during normal and pathological development in promoting specific cell fates and/or functions. I will also discuss how these findings may be utilized in the future to develop new therapeutic strategies for treating the injured or malformed heart.

Glycans are the most abundant and diverse of nature's biopolymers. In the past decade, the study of glycans has entered a Renaissance fueled by the development of new analytical tools designed to probe glycan structure and biochemistry, as well as a widespread realization of glycoscience's potential to innovate in areas of human health, bio-sustainable energy, and materials science. In addition to their recognized biochemical activities, glycans also contribute directly to the bulk physical properties of proteins, cells, and tissues. In living systems, glycans are concentrated on the cell surface in a dense, complex structure that is referred to as the glycocalyx. From a physical perspective, the glycocalyx has long been considered a simple "slime" that protects cells from mechanical disruption or against pathogen interactions, but the dramatic complexity of the structure argues for the evolution of more advanced functionality. Combining new optical imaging methodologies with approaches from computational biology and cell biology, we have now begun to dissect how changing patterns of glycosylation and glycoprotein expression alter cell surface receptor function at nanometer length scales. I will discuss these findings and describe how biophysical changes in the glycocalyx can play a role in aggressive, lethal cancers. This discussion will include our more recent findings related to the role of cancer-associated glycoproteins in vesicle biogenesis. Together, these findings emphasize the need for biophysical questioning, research and understanding in the emerging field of glycoscience.

The self-assembly of a protein shell around a cargo is a common mechanism of encapsulation in biology, and is inspiring development of drug delivery vehicles that form by self-assembly. However, the physics underlying such multicomponent assembly processes is incompletely understood. In this talk I will describe how minimal computational models can elucidate two biological examples in which icosahedral protein shells assemble around cargos. In each case we find that the material properties of the cargo play a key role in directing its encapsulation.

The first example concerns viruses with single-stranded RNA (ssRNA) genomes. For many ssRNA viruses, formation of an infectious virus requires the spontaneous assembly of an icosahedral protein shell (called a capsid) around the genome. I will describe simulations that investigate how this co-assembly process depends on the physical properties of RNA: its length, electrostatic charge, and 3D structure. When applied to specific virus capsids, the calculated optimal RNA lengths closely correspond to the natural viral genome lengths. This suggests that evolution of viral RNA is driven not only by the fitness of the proteins that it encodes for, but also by how its material properties favor encapsulation. We then show that assembly can proceed through two qualitatively different classes of pathways, which can be tuned by solution conditions or changing the capsid protein properties.

The second example concerns carboxysomes, which are large, roughly icosahedral protein shells that facilitate carbon fixation in cyanobacteria. Carboxysomes assemble around a cargo which is topologically different from ssRNA, a noncovalently linked, amorphous complex of the enzyme RuBisCO. Motivated by this problem, we study assembly of icosahedral shells around a fluid cargo. We find different assembly pathways and different critical control parameters as compared to assembly around RNA, and that the predominant assembly pathway depends strongly on the cargo fluidity. We discuss relationships between simulated assembly pathways and recent experiments observing assembly of individual carboxysomes in bacteria.

A complex movement is optimally efficient if it is executed as one continuous optimal trajectory. However, the computational cost of optimizing movement efficiency grows exponentially with the planning horizon. Thus, for a fixed computational cost, there is a limit to how efficient a movement can be. Here we suggest that this tradeoff can explain why complex movements are executed as a string of discrete shorter movements; a phenomenon known as “chunking”. We show that monkeys learning a reaching sequence initially improve movement efficiency by locally optimizing trajectories within chunks, and then achieve further efficiency gains by expending greater costs. This two-stage strategy results in significant cost advantages over the course of learning, relative to a strategy of learning the entire movement without chunks. Thus chunks are integral for motor learning.

Living cells are capable of processing a variety of mechanical signals encoded within their microenvironment, which can in turn act through the cellular structural machinery to regulate many fundamental behaviors. In this sense, cells may be regarded as "smart materials” that dynamically and locally modulate their physical properties in response to environmental stimuli. I will discuss our recent efforts to understand and control these living materials, and to create new, bio-inspired materials that mimic sequence/structure/function relationships of cytoskeletal networks. Key areas of emphasis will include: (1) Understanding and targeting biomechanical regulation of tumor infiltration in the brain; (2) Applying materials and genetic strategies to probe the timing of mechanosensitive stem cell fate decisions; and (3) Engineering stimulus-sensitive intrinsically disordered protein brushes based on neuronal cytoskeletal networks.

Viable tumor-derived circulating tumor cells (CTCs) have been identified in peripheral blood from cancer patients and are not only the origin of intractable metastatic disease but also marker for early cancer. However, the ability to isolate CTCs has proven to be difficult due to the exceedingly low frequency of CTCs in circulation. As a result their clinical use until recently has been limited to prognosis with limited clinical utility. More recently, we introduced several microfluidic methods to improve the sensitivity of rare event CTC isolation, a strategy that is particularly attractive because it can lead to efficient purification of viable CTCs from unprocessed whole blood. The micropost CTC-Chip (μpCTC-Chip) relies on laminar flow of blood cells through anti-EpCAM antibody-coated microposts, whereas the herringbone CTC-Chip (HbCTC-Chip) uses micro-vortices generated by herringbone-shaped grooves to efficiently direct cells toward antibody-coated surfaces. These antigen-dependent CTC isolation approaches, also called “positive selection”, led to the development of a third technology, which is tumor marker free (or antigen-independent) sorting of CTCs. We call this integrated microfluidic system the CTC-iChip, based on the inertial focusing strategy, which allows positioning of cells in a near-single file line, such that they can be precisely deflected using minimal magnetic force. The major advantage of the approach stems from the fact that it is based on “negative depletion” of blood cells and hence it is applicable to all solid tumors and does not require tagging or labeling the tumor cells. As a result the CTCs are isolated in pristine conditions and are amenable to analysis using imaging, molecular, and other approaches. We applied these three microfluidic platforms to blood samples obtained from lung, prostate, breast, colon, melanoma, and pancreatic cancer patients. We isolated CTCs from patients with metastatic non-small-cell-lung cancer and identified the EGFR activating mutation in CTCs. We also detected the T790M mutation, which confers drug resistance. We also applied microchip to isolate CTCs from blood specimens of patients with either metastatic or localized prostate cancer, and showed the presence of CTCs in early disease. Remarkably, the low shear design of the HBCTC-chip revealed micro-clusters of CTCs in a subset of patient samples. Microscopic CTC aggregates may contribute to the hematogenous dissemination of cancer. More recently, we used microfluidic capture of CTCs to measure androgen receptor (AR) signaling readouts before and after therapeutic interventions using single-cell immunofluorescence analysis of CTCs. The results support the relevance of CTCs as dynamic tumor-derived biomarkers, reflecting “real time” effects of cancer drugs on their therapeutic targets, and the potential of CTC signaling analysis to identify the early emergence of resistance to therapy. We also characterized epithelial-to-mesenchymal transition (EMT) in CTCs from breast cancer patients. While a few primary tumor cells simultaneously expressed mesenchymal and epithelial markers, mesenchymal cells were highly enriched in CTCs, and most importantly, serial CTC monitoring suggested an association of mesenchymal CTCs with disease progression suggesting a role for EMT in the blood-borne dissemination of human breast cancer. We have also identified the presence of CTC clusters, which led to the development of a microchip that is designed to sort clusters of cells from whole blood without any labeling. The propensity of CTC clusters to lead to metastasis is significantly higher than single CTCs, and underlies the importance these cells play in the metastatic cascade. This presentation will share our integrated strategy to simultaneously advance the engineering and microfluidics of CTC-Chip development, the biology of these rare cells, and the potential clinical applications of circulating tumor cells.

The native extracellular matrix is a space in which signals can be displayed dynamically and reversibly, positioned with nanoscale precision, and combined synergistically to control cell function. Artificial forms of this matrix for tissue regeneration need to recapitulate these three characteristics in a single molecular platform. Most efforts in this area have effectively addressed only one of these three key phenomena, and focused mainly on static cell adhesion or irreversible switching of bioactivity. This talk will describe a molecular system based on peptide-DNA conjugates that can be programmed to control the dynamics, spatial positioning, and combinatorial synergies of signals in extracellular matrices. This peptide-DNA platform controls the way different signals are presented to cells and their relative spacing and confers superior reversibility by employing a set of bio-friendly stimuli. Multiple orthogonal DNA handles can be designed to allow for the selective presentation of different signals, with the ability to independently up- or down-regulate each over time. This talk will also demonstrate the formation of one-dimensional assemblies of peptide-DNA hybrids with filamentous architecture and three-dimensional hydrogel networks based on DNA- peptide amphiphiles that mimic the structure and function of the natural extracellular environment. These novel constructs will enable to elucidate how external cues direct cell behavior and orchestrate cellular processes, which may have great importance for mimicking in vivo tissue remodeling and dynamics.

Seizures are often compared to electric storms in the brain and to some extent this analogy is correct. Seizures consist of abnormal neural firing in specific parts of the brain and can often travel throughout the brain to alter the firing patterns of neurons away from the seizure. Electrical stimulation can also modulate neural firing of these cells and if applied carefully control their abnormal patterns. In this lecture I will show how electric pulses applied to the brain can control the excitability of single cells and prevent seizures in patients with temporal lobe epilepsy Short CV: Dominique M. Durand is E.L. Linsedth Professor of Biomedical Engineering and Neurosciences and Director of the Neural Engineering Center at Case Western Reserve University in Cleveland, Ohio. He received an engineering degree from Ecole Nationale Superieure d'Electronique, Hydrolique, Informatique et Automatique de Toulouse, France in 1973. In 1974, he received a M.S. degree in Biomedical Engineering from CWRU in Cleveland OH., worked several years and in 1982 received a Ph.D. in Electrical Engineering from the University of Toronto in the Institute of Biomedical Engineering. He received an NSF Young Investigator Presidential Award as well as the Diekhoff and Wittke awards for graduate and undergraduate teaching and the Mortar board top-prof awards at CWRU. He is an IEEE Fellow and also Fellow of the American Institute for Medical and Biomedical Engineering and Fellow of the Institute of Physics. He serves on many editorial boards of peer-reviewed scientific journals and he is the editor-in-chief and founding editor of the Journal of Neural Engineering. His research interests are in neural engineering and include computational neuroscience, neurophysiology and control of epilepsy, non-linear dynamics of neural systems, neural prostheses and applied magnetic and electrical field interactions with neural tissue.

Optical molecular imaging holds a pivotal role in biology and medicine due to its ability to provide invaluable insight into disease mechanisms at molecular and cellular levels. The rich source of molecular information available to optical methods originates from the multitude of light-matter interactions that reveal detailed biochemical and biophysical properties. However, the most widely applied strategies for optical imaging only take advantage of a small fraction of the available interactions. This has particularly limited the use of endogenous biochemical species for molecular/functional imaging.

In this talk I will discuss emerging optical spectroscopic methods (linear and nonlinear) that are able to more fully utilize the available sources of endogenous molecular and functional contrast. The application of these novel strategies to biology and medicine, particularly for melanoma detection and staging, will be discussed.

Many questions at the forefront of biology depend on the individual properties and interactions of millions of single cells. My lab develops methods for analyzing, sorting, and engineering single cells using droplet-based microfluidics. I will describe methods in which we are using this to detect rare cells in a population and evolve new cells with enhanced properties. I will also describe how we are extending this approach to synthetic systems to generate artificial antibody-like affinity reagents.

A longstanding barrier to progress, both in clinical settings and research trials, has been the difficulty of accurately measuring the human phenotype, including but not limited to behavioral patterns, social interactions, physical mobility, gross motor activity, and speech production. Smartphones are now ubiquitous and can be harnessed to offer medicine a wealth of data on the human phenotype, and subjects can be instrumented with scientific apps that generate continuous streams of data. We have coined the term "digital phenotyping" to refer to the moment-by-moment quantification of the individual-level human phenotype, in situ, using data from personal digital devices. I’ll outline this approach, describe the Beiwe platform that we have developed for use in biomedical research, discuss methodological developments, and share some of our early results.

It has long been proposed that turgor pressure plays an essential role during bacterial growth by driving mechanical expansion of the cell wall. This hypothesis is based on analogy to plant cells, for which this mechanism has been established, and on experiments in which the growth rate of bacterial cultures was observed to decrease as the osmolarity of the growth medium was increased. To distinguish the effect of turgor pressure from pressure-independent effects that osmolarity might have on cell growth, we monitored the elongation of single Escherichia coli cells while rapidly changing the osmolarity of their media. By plasmolyzing cells, we found that cell-wall elastic strain did not scale with growth rate, suggesting that pressure does not drive cell-wall expansion. Furthermore, in response to hyper- and hypoosmotic shock, E. coli cells resumed their pre-shock growth rate and relaxed to their steady-state rate after several minutes, demonstrating that osmolarity modulates growth rate slowly, independently of pressure. Oscillatory hyperosmotic shock revealed that while plasmolysis slowed cell elongation, the cells nevertheless “stored” growth such that once turgor was re-established the cells elongated to the length that they would have attained had they never been plasmolyzed. In contrast, Bacillus subtilis cells exhibit highly regular growth oscillations in response to hypoosmotic shock that are dependent on peptidoglycan synthesis. The period of these oscillations scales linearly with the magnitude of the shock. By applying a simple mathematical theory to these data, we show that growth oscillations are initiated by mechanical-strain-induced growth arrest. This demonstrates that B. subtilis has developed an elegant system by which turgor pressure both up- and down-regulates the final steps of cell growth.

As technology continues to evolve at a rapid pace, scientists are able to observe and record more and more of the underlying dynamical behavior contributing to biological diseases. With these advances in technology comes a growing interest in applying dynamical systems and control theoretic tools to provide new insight into treatment options for medically intractable diseases. My particular focus has been on the creation and utilization of mathematical tools which can reduce the dimensionality and complexity of the differential equations describing nonlinear biological systems, making them amenable for further study. Attention is given to the problem of understanding the role deep brain stimulation (DBS) as a treatment for patients with Parkinson’s disease. Model reduction strategies provide starting point for merging two competing hypotheses for the therapeutic mechanism of DBS as a treatment for Parkinson’s disease and can also be used to suggest better stimulation strategies than those currently available. In addition to neuroscience applications, model reduction techniques facilitate the development of low energy electrical stimulation methods for the elimination of cardiac arrhythmias such as alternans, tachycardia, and fibrillation; all of which are associated with the emergence of cardiac arrest, a leading cause of death in the industrialized world.
 

Altered cellular metabolism is commonly observed in many disease states.  Arising from early work by Britton Chance, high-resolution spectroscopic imaging approaches utilizing the natural fluorescence of metabolic cofactors (NADH and FAD) have been developed and used effectively in a number of cancer research applications.  However, the sensitivity of these imaging techniques to specific metabolic pathways and different cell functions is not well defined.  In this talk I will describe how we have obtained a more nuanced understanding of the sensitivity of NADH and FAD autofluorescence to changes in metabolism during stem cell differentiation and precancerous transformation through correlative metabolic assays. I will also discuss new applications in cutaneous wound healing for metabolic and microstructural imaging using label-free multiphoton microscopy. Through quantitative image analysis of this non-invasive depth-resolved imaging technique, we are developing a suite of optical biomarkers to evaluate wound healing therapies in vivo with the end goal of establishing real-time diagnostic readouts to evaluate wounds in the clinic.

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As technology continues to evolve at a rapid pace, scientists are able to observe and record more and more of the underlying dynamical behavior contributing to biological diseases. With these advances in technology comes a growing interest in applying dynamical systems and control theoretic tools to provide new insight into treatment options for medically intractable diseases. My particular focus has been on the creation and utilization of mathematical tools which can reduce the dimensionality and complexity of the differential equations describing nonlinear biological systems, making them amenable for further study. Attention is given to the problem of understanding the role deep brain stimulation (DBS) as a treatment for patients with Parkinson’s disease. Model reduction strategies provide starting point for merging two competing hypotheses for the therapeutic mechanism of DBS as a treatment for Parkinson’s disease and can also be used to suggest better stimulation strategies than those currently available. In addition to neuroscience applications, model reduction techniques facilitate the development of low energy electrical stimulation methods for the elimination of cardiac arrhythmias such as alternans, tachycardia, and fibrillation; all of which are associated with the emergence of cardiac arrest, a leading cause of death in the industrialized world.

With the extensive development and investigation of magnetic nanoparticles for biomedical applications, it is important to recognize the challenges and opportunities for translating this class of nanomaterials, as well as others, to clinical uses. This presentation will highlight the importance of understanding the interface/interaction of engineered nanomaterials and biological systems, which led to our rational design and preparation of sub-5 nm ultrafine magnetic iron oxide nanoparticles with T1-T2 switchable magnetic resonance imaging contrast to probe and enhance tumor-specific delivery and improve the biocompatibility and clearance profile. Furthermore, through the different surface functionalization strategies, such as using anti-biofouling amphiphilic polymers and protein coating, we are able to achieve improved biomarker targeting of magnetic nanoparticles by reducing off-target background and obtain novel MRI capable drug delivery systems for therapy.

When creating new biomedical technologies, the entire design and production process must be considered. In this talk, the steps taken to translate the needs of a multidisciplinary team of engineers, clinicians and immunologists into therapeutic nucleic acid-based technologies will be highlighted. The first half of this talk will focus on the design and pre-clinical translation of nanomaterials for RNA delivery to vascular endothelial cells in nonhuman primates. The second half will examine the ways in which nanotechnology can be designed to deliver new self-amplifying nucleic acid payloads for the rapid-response vaccination of evolving pathogens such as Ebola virus, influenza and parasitic microorganisms.

Reconstruction or regeneration of living tissues is a daunting project for biomedical engineers and surgeons alike. Our overall aim is to bring tissue engineering closer to the patient. To reach this goal, we hypothesized that successful translational regenerative medicine requires a coherent combination of mechanically sound “niche” scaffolds, cells with the potential to regenerate and revitalize the scaffolds and adequate biological and biomechanical stimuli. Cardiac valves are the most mechanically challenged tissues in the body, and yet knowledge on cell biology, biochemistry, matrix homeostasis, genetics, mechanics, pathology, replacement and regeneration is still incomplete. Our approach combines the outstanding mechanical and biological properties of xenogeneic valves with the plasticity of autologous adult stem cells. We started by completely decellularizing porcine aortic and pulmonary roots using devices and procedures invented in our labs. Quality control tests ensured lack of porcine cells and antigens and preservation of major matrix components and mechanical characteristics. Next, adipose-derived stem cells were collected from sheep from selected anatomical sites, tested for plasticity in vitro and multiplied several passages before being seeded within the acellular valve scaffolds. Autologous stem cell-seeded valve roots were then implanted as right ventricle to pulmonary artery shunts in sheep and followed by echography for up to 10 months.

Our results showed that: 1) preservation of valve mechanical and biological properties was possible by controlled decellularization in specialized devices and bioreactors, 2) adult stem cells differentiated in vitro into valvular interstitial cells when exposed to appropriate biochemical and mechanical signals in purpose-built bioreactors, 3) successful valve implantation with minimally invasive surgery approaches was possible and yielded excellent animal recovery. To date most valves functioned properly and explant analysis is ongoing. Large animal pre-clinical testing in sheep revealed the feasibility of this approach and these promising results increase enthusiasm for the future of cardiac valve tissue regeneration.

This multidisciplinary project was made possible by contributions from several multinational research teams specialized in bioengineering, stem cell biology, biochemistry, cardiac surgery, cardiology, echography, veterinary medicine and animal care, pathology, histology and immunohistochemistry and project management.

This project was funded in part by NHLBI of the National Institutes of Health under award number RO1HL093399, by NIGMSof the National Institutes of Health under award number5P20GM103444-07, by the Harriet and Jerry Dempsey Associate Professorship in Bioengineering Award (to DS) and by a grant from the Romanian National Authority for Scientific Research, CNCS-UEFISCDI, project number PNII-ID-PCCE-2011-2-0036.

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Articular cartilage is the bearing material of diarthrodial joints. It supports contact stresses of up to 12 MPa while exhibiting a friction coefficient as low as 0.002. Cartilage degeneration is a hallmark of osteoarthritis, a debilitating degenerative joint disease that afflicts 30 million Americans. As there is no cure for osteoarthritis, significant focus has been placed on repair strategies such as tissue engineering. Though much progress has been made from empirical approaches in the field of cartilage tissue engineering, we believe that culture conditions that help reproduce functional properties in cartilage constructs may be optimized using suitable theories of growth mechanics. There are two competing theoretical frameworks in growth mechanics today, one which is based on the evolution of mass content and the other on the evolution of shape. In this presentation, I will discuss how these two growth frameworks differ with regard to the concept of observable versus hidden variables, and how this difference is manifested in other continuum theories relevant to biological tissue mechanics, including damage mechanics and viscoelasticity.

Mesenchymal stem cell (MSC) is a cell type that holds promise for cell therapy and regenerative medicine applications. However, one of the challenges associated with the use of MSCs for regenerative medicine is that MSCs isolated from adult tissues are often composed of heterogeneous cell populations. Another challenge is that MSCs become aged and senescent after several passages of cell expansion. To overcome these limits, we investigated MSCs derived from bone marrow (BM) and H1- and H9-embryonice stem cell (ESC) lines in terms of morphology, surface marker and growth factor receptor expression, proliferative capability, modulation of immune cell growth and multipotency, in order to evaluate ESC-MSCs as a cell source for potential regenerative applications. Our findings suggest that ESC-MSCs and BM-MSCs show differences in their surface marker profile and the capacities of proliferation, immunomodulation, and most importantly multi-lineage differentiation. Using modified chondrogenic medium with BMP7 and TGFβ1, H1-MSCs can be effectively induced as BM-MSCs for chondrogenesis.

In addition, our group has demonstrated that MSC differentiation is indeed greatly dependent on the environment of pre-differentiation culture. We found that more cells retained MSC surface markers in hypoxic culture than those in normoxic culture, and hypoxia was able to enhance multilineage differentiation of MSCs and delay cellular senescence through increased production of macrophage migration inhibitory factor and activation of AKT signaling compared to normoxia. Recently, we demonstrated that endothelin-1 (ET1) secreted by endothelial cells (ECs) can direct bone marrow-derived MSCs for osteo- and chondro-lineage differentiation through activation of the AKT signaling pathway, suggesting that ET1 plays a crucial role in regulation of MSC activity. Taken together, our results suggest that the environment of MSC predifferentiation culture plays a critical role in regulating the differentiation capability of undifferentiated MSCs prior to committing to a tissue-specific lineage.

Strategies for promoting tissue growth provide enabling technologies for either enhancing regeneration for diseased or injured tissues, or to investigate abnormal tissue formation such as cancer. Given the complexity inherent in tissues, my laboratory is working towards the concept of "Systems Tissue Engineering", which indicates the dual need i) to develop systems capable of presenting combinations of factors that drive tissue growth, as well as ii) to incorporate systems biology approaches that can identify the appropriate combination of factors.Biomaterial scaffolds represent a central component of many approaches and provide the enabling tools for creating an environmentand/or deliver factors that candirect cellular processes toward tissue formation. We have developed scaffolds that are employed for cell transplantation, and the success of cell based therapies is impacted by the ability to modulate the innate and adaptive immune responses. Localized presentation or delivery of immunomodulatory factors has been able to delay or prevent cell rejection, whereas nanoparticles have been developed that present antigens with subsequent development of immune tolerance. Finally, scaffolds were adapted to simulate the pre-metastatic niche for the early detection of metastatic disease. The immune response has become a central focus, and will discuss the contributions of the immune cells to metastatic progression. The ability to modulate immune responses locally and/or systemically can enable the development of novel therapies for wide-ranging applications.

Neuroscience is slowly transitioning from a discipline that is primarily limited by the lack of available data to a field where interpretation is a central bottleneck. Concentrating on Bayesian approaches, Dr. Kording's lab is constructing models and developing data analysis methods. They have recently focused on the problem of being able to measure neural activities and movements, but not being able to directly observe when movement is planned. They have tackled this data analysis problem using a latent variable approach that estimates, trial-by-trial, the timing of planning relative to the timing of movement. This approach considerably improves spike train predictions. However, current data sets are still too small to ask many relevant questions about neural computation. Dr. Kording is thus collaborating with multiple teams on neurotechnology approaches, including DNA recording, large-scale electrical recording, and large-scale X-ray tomography, to produce the large data sets needed to test complex models.

Controlled materials design and synthesis play a significant role in addressing various drug delivery challenges in vivo.  In this seminar, I will present our work on the development of helical charged polypeptides for cell penetration, gene and siRNA delivery.  By controlling polypeptide side-chains, we developed ionic helical polypeptides capable of mediating efficient membrane penetration, addressing cellular trafficking challenges.  I will also describe our work on silica nanomedicine and size controlled nanomedicine in tumor penetration and identification of optimal size of nanomedicine in cancer therapy. Finally, I will present sugar molecular mediated in vivo cancer targeting.  We successfully developed azido-sugar derivatives that can label triple negative breast cancer and enable successful in vivo targeting.

A longstanding barrier to progress, both in clinical settings and research trials, has been the difficulty of accurately measuring the human phenotype, including but not limited to behavioral patterns, social interactions, physical mobility, gross motor activity, and speech production. Smartphones are now ubiquitous and can be harnessed to offer medicine a wealth of data on the human phenotype, and subjects can be instrumented with scientific apps that generate continuous streams of data. We have coined the term "digital phenotyping" to refer to the moment-by-moment quantification of the individual-level human phenotype, in situ, using data from personal digital devices. I’ll outline this approach, describe the Beiwe platform that we have developed for use in biomedical research, discuss methodological developments, and share some of our early results.