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Abstracts and Talk Materials
Medical Device-Biological Interactions at the Material-Tissue Interface
September 13 - 15, 2010

Mark S. Alber (University of Notre Dame)

Modeling of bacterial swarming on different surfaces
September 13, 2010

Most infections are the result of a surface-attached community of bacteria that displays many unique characteristics. Our understanding is still limited, however, with respect to how pathogens are colonizing surfaces to begin infection. It is known that the arrival of bacteria to host tissues is often aided by self-generated motility of the organism. Pathogens such as Salmonella enterica, Vibrio cholerae, Proteus mirabilis, and Pseudomonas aeruginosa are able to spread rapidly over surfaces by the process of swarming. Many bacteria generate flat, spreading colonies, called swarms because they resemble swarms of insects. In the beginning of the talk, swarms of the myxobacterium, Myxococcus xanthus will be described in detail. Individual M. xanthus cells are elongated; they always move in the direction of their long axis; and they are in constant motion, repeatedly touching each other. Remarkably, they regularly reverse their gliding directions. We have constructed a detailed cell- and behavior-based computational model of M. xanthus swarming that allows the organization of cells to be simulated [1]. By using the model, it will be shown that reversals of gliding direction are essential for swarming and that specific reversal frequencies result in optimal swarming rate of the whole population [2]. This suggests that the circuit regulating reversals evolved to its current sensitivity under selection for growth achieved by swarming. Also, an orientation correlation function will be used to show that microscopic social interactions help to form the ordered collective motion observed in swarms. In the second part of the talk we will discuss a model of the swarming of the Pseudomonas aeruginosa.

1. Wu, Y., Jiang, Y., Kaiser, D., and M. Alber [2007], Social Interactions in Myxobacterial Swarming, PLoS Computational Biology 3 12, e253.

2. Wu, Y., Jiang, Y., Kaiser, D., and M. Alber [2009], Periodic reversal of direction allows Myxobacteria to swarm, Proc. Natl. Acad. Sci. USA 106 4 1222-1227 (featured in the Nature News, January 20th, 2009, doi:10.1038/news.2009.43).

Bruce P. Ayati (The University of Iowa)

Dormancy in planktonic and biofilm cultures
December 31, 1969

Microbial populations, particularly those in biofilms, contain cells in varying phenotypic states. Here we consider one such phenotype, dormancy (possibly related to the phenomenon of persister cells) where, in response to an environ- mental stress, cells differentiate into a protected, slow- or non-growing state. We present modeling and computational tools designed to study dormancy within batch, chemostat, and biofilm population dynamics, in particular with respect to competitiveness.

John Christopher Bischof (University of Minnesota, Twin Cities)

Biomedical applications of heat transfer: Rare cell preservation to diseased cell destruction
September 14, 2010

Heat transfer plays a crucial role in many biomedical applications in cryobiology (biopreservation and cryosurgery) and hyperthermic biology (thermal therapies). In these applications, thermal excursions are used to selectively preserve or destroy cells and tissues. Biopreservation is an enabling technology to many biomedical fields including cell and tissue banking, cell therapeutics, tissue engineering, organ transplantation and assisted reproductive technologies. Thermal therapies including cryosurgery are increasingly important in all surgical sub-specialties for minimally invasive thermal destruction of tissues for cancer and cardiovascular disease treatment. In this talk work predominantly from our lab will be reviewed focusing on cellular and molecular phenomena that are important in defining outcomes of both cryobiological and hyperthermic biomedical applications. During these applications microscale cellular phenomena linked to viability are mechanistically shown to depend on the heat transfer process in vitro. These events include: cellular dehydration, intracellular ice formation, and membrane hyperpermeability and blebbing. In addition, new approaches to assess molecular targets of heating and cooling using calorimetric and spectroscopic methods (i.e. lipid hydration, protein denaturation and solute segregation) will be discussed. In vivo, new approaches will be reviewed to define gene regulated events (inflammation and apoptosis) and control them with targeted adjuvants such as TNF-a for cancer treatments. Finally, recent work will be reviewed with nanoparticles showing their dramatic potential to both enhance and control thermal therapy outcomes through adjuvant (drug) delivery, and laser and inductive (RF) heating within the body.

Bio: John Bischof is a Professor in the Department of Mechanical Engineering with joint appointments in Biomedical Engineering and Urologic Surgery at the University of Minnesota. Dr. Bischof received his B.S. in Bioengineering from U.C. Berkeley (UCB) an M.S. from UCB and U.C. San Francisco in 1989, and a Ph.D. in Mechanical Engineering from UCB in 1992. After a Post-doctoral Fellowship at Harvard in what is now the Center for Engineering in Medicine, he joined the University of Minnesota in 1993. Professor Bischof is an author on numerous peer-reviewed publications; he has several patents filed or issued and numerous best paper, young investigator and society Fellow awards for his work in bioheat and mass transfer. He currently holds a Distinguished McKnight University Professorship at the University of Minnesota.

Jiande Chen (University of Texas Medical Branch)

Gastrointestinal electrical stimulation: potential applications
September 14, 2010

Similar to the heart, there is electrical activity in the gastrointestinal tract that is the basis of gastrointestinal contractions. Gastrointestinal electrical stimulation (GIES) is able to modify electrical activity of the gut and therefore altering the functions of smooth muscles of the gut. Depending on stimulation parameters and configurations, GIES may enhance or inhibit gastrointestinal contractions or tone and therefore may have therapeutic potentials for the treatment of gastrointestinal motility disorders and eating disorders, such as obesity.

First, different methods of GIES will be introduced, including short pulse, long pulses and pulse trains. In addition, stimulation electrodes can be placed at different locations, such as on the serosa and mucosa of the gut lumen as well as the abdominal skin. Secondly, the effects of GIES with different parameters on pressure and contractions of the gut will be discussed. With appropriate settings, GIES may enhance or inhibit tone and contractions of the gut, thereby altering the transit of ingested food through the stomach. In patients with functional gastrointestinal diseases, the transit of food through the gut is usually delayed due to lack or impairment in luminal contractions. By enhancing or inducing contractions, GIES may be able to improve gastrointestinal transit and therefore treat patients with gastrointestinal motility disorders. On the other hand, by electrical inhibiting contractions of the stomach, GIES is able to delay emptying of the stomach and therefore enhance postprandial satiety and inter-meal fullness, leading to a reduced food intake. That is, GIES also have an attractive therapeutic potential for obesity. In addition to its mechanical effects on the gut lumen, GIES also activates peripheral and central nerves and alter certain hormones related to food intake and satiety. An overview of electrical therapies for these applications will be given in this talk.

Dennis E. Discher (University of Pennsylvania)

Stem cell differentiation and the influence of microenvironment
September 13, 2010

Cells make a number of key decisions by actively adhering to a substrate and applying forces. Naive mesenchymal stem cells (MSCs) from human bone marrow will be shown to specify lineage and commit to phenotypes on collagen-coated hydrogels with tissue-level elasticity. Soft matrices that mimic brain appear neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. Inhibition of myosin blocks all elasticity directed lineage specification – without strongly perturbing many other aspects of cell function and shape. Physical studies of nuclei suggest an unusual degree of plasticity for stem cell nuclei, and a "Cysteine Shotgun" Mass Spectrometry method for in situ labeling of the 'foldome' reveals distinct structural differences attributable to unfolding and/or dissociation of cellular proteins. The results have significant implications for understanding physical effects of the in vivo microenvironment and also – as will be shown – for therapeutic uses of stem cells such as in muscle repair.

A. Engler, S. Sen, H.L. Sweeney, and D.E. Discher. Matrix elasticity directs stem cell lineage specification. Cell 126: 677-689 (2006).

J.D. Pajerowski, K.N. Dahl, F.L. Zhong, P.J. Sammak, and D.E. Discher. Physical plasticity of the nucleus in stem cell differentiation. PNAS (Proceedings of the National Academy of Science – USA) 104: 15619-15624 (2007).

C.P. Johnson, H-Y. Tang, C. Carag, D.W. Speicher, and D.E. Discher. Forced unfolding of proteins within cells. Science 317: 663-666 (2007).

A. Engler, C. Carag, C. Johnson, M. Raab, H-Y. Tang, D. Speicher, J. Sanger, J. Sanger, and D.E. Discher. Embryonic cardiomyocytes beat best on a matrix with heart-like elasticity: scar-like rigidity inhibits beating. Journal of Cell Science 121: 3794-3802 (2008).

D.E. Discher, D.M. Mooney, P. Zandstra. Growth factors, matrices, and forces combine and control stem cells. Science 324: 1673-1677 (2009).

Lisa J. Fauci (Tulane University)

Understanding the fluid dynamics of microorganisms: successes and challenges
September 14, 2010

Microorganisms such as bacteria and spermatozoa move in a world where viscous forces completely dominate inertial forces, and the time evolution of their motion may be thought of as a sequence of steady state snapshots. In this world, what motility strategies give rise to efficient locomotion? The study of the fluid dynamics of microorganism motility began with the classic work of G.I. Taylor in 1951, and has been an active area of research in the last decades. Current modeling challenges include the collective dynamics of microorganisms and their interactions with surrounding physical and chemical environments, coupling of their internal force-generating mechanisms with external fluid dynamics, as well as their motion through viscoelastic fluids. We will present recent work that sheds light on these complex systems.

Aaron Fogelson (University of Utah)

An introduction to the mathematical modeling of blood clotting
September 14, 2010

The intertwined processes of platelet deposition and coagulation can lead to the development of blood clots inside a blood vessel or on an implanted medical device. Their disregulation is responsible for immense morbidity and mortality, particularly in the western world.

The development of a blood clot involves complex interactions of diverse type (e.g., biochemistry, cell signaling and adhesion, fluid dynamics) on diverse spatial and temporal scales. Exploring how these interactions function together as a system is a task for which mathematical/computational modeling is well suited.

In this tutorial talk, I will give a brief introduction to the biology, chemistry, and physics of blood clotting, and I will describe two of our recent efforts to model different aspects of clotting. Both models include the formation of platelet masses (thrombi) adherent to the vascular wall. In one model the developing mass is treated as a porous material whose porosity evolves with the addition of platelets to the thrombus. This model includes a comprehensive treatement of the coagulation system and its interaction with platelet deposition. The other model emphasizes the evolution of the thrombus' mechanical properties as it forms (and sometimes breaks up) in situations in which fluid-mediated stresses vary substantially.

Kerwyn Casey Huang (Stanford University)

Understanding and manipulating bacterial growth through cell-wall modeling
September 14, 2010

Bacterial cells come in a wide variety of shapes and sizes, with the peptidoglycan cell wall as the primary stress-bearing structure that dictates cell shape. In recent years, cell shape has been shown to play a critical role in regulating many important biological functions including attachment, dispersal, motility, polar differentiation, predation, and cellular differentiation. How much control does a cell have over its shape, and can we tap into control mechanisms to synthetically engineer new morphologies? Though many molecular details of the composition and assembly of the cell wall components are known, how the peptidoglycan network organizes to give the cell shape during normal growth, and how it reorganizes in response to damage or environmental forces have been relatively unexplored. We have introduced a quantitative mechanical model of the bacterial cell wall that predicts the response of cell shape to peptidoglycan damage in the rod-shaped Gram-negative bacterium Escherichia coli. To test these predictions, we use time-lapse imaging experiments to show that damage often manifests as a bulge on the sidewall, coupled to large-scale bending of the cylindrical cell wall around the bulge. Our simulations based on our physical model also suggest a surprising robustness of cell shape to damage, allowing cells to grow and maintain their shape even under conditions that limit crosslinking. Our current research focuses on identifying the molecular factors responsible for cell shape determination and characterizing their phylogenetic diversity. Our work has shown that many common bacterial cell shapes can be realized within both our model and in experiments via simple spatial patterning of the cytoplasm and cell wall, suggesting that subtle patterning changes could underlie the great diversity of shapes observed in the bacterial kingdom.

Chiu-Yen Kao (The Ohio State University)

Mathematical tools in biomedical image processing
September 14, 2010

The basic medical science research and clinical diagnosis and treatment have strongly benefited from the development of various noninvasive biomedical imaging techniques, e.g. magnetic resonance imaging (MRI) and computed tomography (CT). The mathematical tools provide many different ways to analyze these valuable images. In this talk, we will give examples of morphology and connectome study of human brains, the shape analysis of ciliary muscle of human eyes, and the estimate of oxygen transport in tissue transfer.

Isaac Klapper (Montana State University)

Continuum models of biofilms
September 13, 2010

Biofilms are often key players in human, animal, and plant infections, fouling of industrial equipment, contamination of water systems, as well as in waste remediation, not even to mention their central roles in all geochemical cycles. Viewed as materials, biofilms are quite interesting: they are living, growing viscoelastic fluids with surprising ability to respond to and defend against environmental challenges. However, they are also complex systems in which biological, chemical, and physical factors are, in general, strongly coupled. For all of these reasons, biofilms are attractive modeling targets. Thus this talk will present a quick survey of efforts to characterize and model biofilms on a continuum macroscale, emphasizing issues especially relevant to medical contexts.

WanZhan Liu (Medtronic)

Challenges in making MRI safe implantable devices
September 14, 2010

I will go over the basic interactions between the MRI system and the implantable medical devices focusing on the RF heating.

MRI has three kinds of fields: static field B0, gradient fields, and radiofrequency (RF) fields. Individual field or combined fields can interact with the implanted devices and might cause tissue damage from heating, unwanted nerve stimulation, and image distortion.

The RF energy from MRI can cause tissue heating around the implantable devices, especially around long metallic structures such as pacemaker leads or deep brain stimulator leads. It might also be rectified by the device and cause unwanted stimulation of the tissue surrounding the electrodes.

The gradient fields produce eddy currents on the surface of the devices and might cause devices and tissue heating. The gradient fields can also cause unwanted stimulation at the electrode-tissue interface since their frequency range is comparable to the therapeutic frequency. Combined with the static field, they can also generate mechanic vibration of the device that might cause tissue damage or patient’s discomfort.

The greatest challenge of making MRI safe devices is to accurately characterize all the interactions between MRI fields, the human bodies, and the medical devices. Computer modeling has been an indispensable tool to tackle this issue. Challenges in RF and thermal modeling will be discussed.

Xinfeng Liu (University of South Carolina)

Computational analysis of biofabrication in tissue engineering
December 31, 1969

Bioprinting or organ printing can be operationally defined as computer-aided, layer-by-layer deposition of biologically relevant material with the purpose of engineering functional 3D tissues and organs. Printing or fabricating an organ requires computer-aided design of the organ, self-assembling cell aggregates or single cells, a bioprinter or dispenser of the bioink, scaffolds or processible biomimetric hydrogels. In this poster, we shall present computational tools using two computational technologies: phase-field model and front-tracking approach, to numerically study morphogenesis of cell aggregates during maturation and corase-grain internal mesoscale structures. The numerical results exhibit a great promise of our approach.

Cameron C. McIntyre (Case Western Reserve University)

Deep brain stimulation models of the electrode-tissue interface
September 14, 2010

Deep brain stimulation (DBS) represents a powerful clinical technology, but we are only beginning to understand the details of the interaction between the electrode(s) and the brain. This presentation will provide an overview of the latest advances in experimental and theoretical characterization of the electrode-tissue interface (ETI) for in vivo DBS electrodes. We use electrode impedance spectroscopy to guide development of equivalent circuit models of the ETI. We then perform microelectrode recordings of the in vivo voltage distribution generated by DBS to guide development of finite element models of the stimulation. These models are then used to predict the effects of stimulation on a patient-specific basis using magnetic resonance imaging data from the patient. Patient-specific models have progressed to the point of enabling the prospective prediction of stimulation parameter settings that rival the therapeutic benefit of settings selected by clinicians. In turn, scientific characterization of the ETI is clinically relevant and can assist in the optimization of clinical outcomes from DBS devices.

Hans G. Othmer (University of Minnesota, Twin Cities)

Cell-based, hybrid and continuum models of tissue dynamics: when to use which where — ?
September 13, 2010

New techniques in cell and molecular biology have produced huge advances in our understanding of signal transduction and cellular response in many systems, and this has led to better cell-level models for problems ranging from biofilm formation to embryonic development. However, many problems involve very large numbers of cells, and detailed cell-based descriptions are computationally prohibitive at present. Thus rational techniques for incorporating cell-level knowledge into macroscopic equations are needed for these problems. In this talk we discuss several examples that arise in the context of cell motility and pattern formation. We will discuss systems in which the micro-to-macro transition can be made more or less completely, and also describe other systems that will require new insights and techniques.

Edgardo Luis Sanabria-Valentín (Harvard Medical School)

PROR - A novel transcriptional reporter system to study gene repression
December 31, 1969

Transcriptional reporters (genetic constructs in which the promoter of a gene of interest drives the expression of a reporter gene whose expression can be easily observed and/or measured) are valuable tools in molecular biology, and can aid in the search for small molecules affecting the expression of individual genes. Cells exposed to a condition that induces the expression of your gene of interest will have an output of reporter signal, which can be detected. This poses a problem when the gene of interest is constitutively turned on and are looking for treatments that selectively repress expression of your gene. Treatments that inhibit reporter output can be affecting a myriad of processes that are not specific to your gene (cell toxicity, generalized transcriptional repression, direct interference with your reporter output, etc.). We have designed a new transcriptional reporter system to study gene repression. That is, reporter output (in our case, fluorescence) is produced when your gene of interest is not being expressed or is being directly repressed. We have designated this system as PROR for Promoter-Repressor-Operator-Reporter. The system is composed of two modules; the first one contains the promoter of interest driving the expression of the λ phage transcriptional repressor cI (1), and the second contains a modified constitutive promoter with the operator sequences of λcI placed in front of the reporter gene yfp. Under conditions in which the gene of interest is being transcribed λcI is also transcribed, inhibiting expression of YFP. Under conditions in which the gene of interest is being repressed, λcI will not be transcribed and YFP is expressed. We have tested our system using expression of the genes coding for the protein component of the B. subtilis biofilm matrix (the yqxM operon), in growth conditions that promote or inhibit development of biofilms, and also with addition of the small molecule zaragozic acid, a potent inhibitor of matrix production in B. subtilis (2). We are currently using this tool to search for novel small molecules and natural products that selectively inhibit matrix production in B. subtilis.

Edgardo Luis Sanabria-Valentín (Harvard Medical School)

The biology of biofilms
September 13, 2010

Biofilms form when microbes grow attached to a surface and become encased in a self-produced extracellular matrix. The fact that biofilm growth has been observed in most bacteria studied to date suggests that this form of growth is important in the ecology and physiology of most, if not all, bacteria. Biofilms have profound impact on human health, since they can form on the surfaces of indwelling medical devices and are inherently more resistant to most antimicrobial agents, making them extremely difficult to eradicate. In this talk, I will present the biological aspects of biofilm formation using Bacillus subtilis as a model system. Furthermore, I will discuss how this understanding is helping in the search for compounds that inhibit biofilm development.

Darrel F. Untereker (Medtronic)

Implantable medical devices – we have come a long way, but where next?
September 13, 2010

While we tend to think of implantable medical devices as new, high tech products, they have actually been around for quite some time now. Two of the most well known types of these devices, heart valves and pacemakers, have been on the market for around 50 years. During that time, these, and similar, products have come a long ways as measured by complexity, sophistication and reliability. There are two basic classes of implantable devices, passive and active. Active devices are powered, like pacemakers and defibrillators, while passive devices are not powered, such as heart valves and spinal appliances. Implantable medical devices have come to be very important elements of modern health care. What was once thought of as a small market opportunity has now become a large market, well over $50B in annual revenue and perhaps a dozen or more major categories of products.

While the technology and engineering of the devices themselves has become very sophisticated, one aspect of these devices has not changed very much over their history. That aspect is our detailed understanding of how the device and the body interact. Biocompatibility is the catch-all phrase used in connection with the device-body interface. It refers to the body being able to tolerate the device, and in turn, the device’s ability to being able to reliably function in the body. We have come to understand that the main criteria for biocompatibility is a well behaved, inert material. That means a stable material that will not interact with the body at a rate that would be detrimental to either the body or the device. However, this is an empirical criteria and there is little understanding of what actually happens at either a molecular, or a cellular level. Such a knowledge gap puts limitations on our ability to improve existing devices or create new ones as we have little idea how to best engineer the interfaces for optimum performance; in fact we really do not know if there is any meaningful engineering we can do to control how the device and body interact. The goal of this talk is to suggest some frames for thinking about how the body and devices interact at fundamental levels.

Howard Winet (University of California, Los Angeles)

Biocompatibility from the host's point of view
September 13, 2010

An implant enters a host during trauma, the wounding process of surgery. Trauma initiates a healing course that naturally progresses through inflammatory and repair phases before host tissue settles down to scar or in some tissues progresses to regeneration. The presence of an implant alters healing if only by occupying space once filled with host tissue. In the most desirable scenario host tissue returns to normal function at a level above the condition that initiated implantation, and soon enough to ensure the overall health of the patient. The ability of an implant to achieve this goal is a measure of its biocompatibility as defined by Jonathan Black.

There is ample evidence to warn any implant developer that host tissue is aware of the foreign object it surrounds, from nanoparticles to lung transplants. Response to the construct may range from coating it with a thin layer of fibroblasts to development of life-threatening anaphylactic shock. A successful biomaterials developer understands host wound healing physiology in the presence of an implant well enough to anticipate and reduce undesirable host responses. Where surgical trauma was preceded by an injury that opened skin, there is the complication of infection to anticipate.

Host reaction begins with a molecular race to initiate a biofilm on the implant surface. The critical molecules are proteins like albumin and complement. Within seconds platelets and then cells adhere to the molecular film. These cells are also in the race for the surface. Those that remain adhered to the film are often determined by the molecular composition of the film. If some of these cells are bacteria the future of the implant is in danger.

The most influential adherent cell at this stage is the macrophage. Macrophages direct the healing process and decide if implant material is a threat. If the biomaterial is deemed a threat a foreign body reaction will be initiated. This response is part of what is called the innate immune response that is initiated by attached complement. The function of an FBR is to destroy the threat. Failing this, macrophages will direct walling it off from healthy host tissue with scar tissue.

Innate immunity gets its name from the fact that it is programmed and prepared to operate before triggered by any implant. Natural selection in the form of rapid bacterial evolution has pushed higher animals to develop responses to materials not covered by innate immunity. These come from the adaptive immune system and involve lymphocytes.

The interaction of macrophages, lymphocytes and a close relative of macrophages, dendritic cells creates a rather complex scheme of host reaction to implants that challenge the design of biomaterials meant reside for long terms in human hosts. Recent discovery of previously unknown ways by which these cells communicate with each other (e.g. Toll-like receptors) intensify the challenge.

As the implant ages and appears to have achieved compatibility, a new challenge may emerge. Wear. Corrosive body fluids and abrasion may create effectively new materials. Wear particles and metal ions not released by the original implant may challenge the host. Bacteria that succeeded in forming a biofilm at implantation may grow colonies large enough to break the film membrane and spread infection into surrounding tissue. Consideration of these possibilities may induce an implant designer to consider inclusion of removal facilitation in the original design. Recently a number of laboratories have designed anti-bacterial films to block establishment of biofilms.

These challenges will be described in more detail.

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