CTW: Tissue Engineering and Regenerative Medicine

(April 30,2012 - May 4,2012 )

Organizers


Keith Gooch
Biomedical Engineering, The Ohio State University
Douglas Kniss
OB&GYN, The Ohio State University
Anita Layton
Mathematics, Duke University
Chandan Sen
College of Medicine, The Ohio State University
Qi Wang
Mathematics, University of South Carolina

Over the past 40 years, tissue engineering / regenerative medicine (TERM) has grown from concepts to established medical treatments used in over one million patients. As of 2007, there were approximately 50 firms offering TERM products with annual sales in excess of $1.3 billion, which represent more than a ten-fold increase from 5 years before. Despite the impressive economic growth of the field and its growing impact on human health, often TERM is understood largely at a phenomenological level. If one considers a historical perspective, developing fields often begin at such a phenomenological stage. For example, chemical engineering initially considered each type of chemical plant as unique. Later in the field's development, it was recognized that regardless of what chemical is being made, a number of 'unit operations' were involved (e.g., distillation, mixing, pumping). A major development in the practice of chemical engineering was made when it was recognized that these different unit operations could be understood in the terms of just a few fundamental processes such as transport phenomena, reaction kinetics, and thermodynamics. Importantly these fundamental processes can be rigorously understood with mathematics, thereby enabling one to understand and rationally design complex systems from a bottom-up approach. TERM has already advanced from considering each application (e.g., tissue engineering of a blood vessel) as unique to considering the underlying and unifying fundamental processes such as cell proliferation, differentiation, and migration. A critical challenge in the TERM field is to develop a rigorous mathematical understanding of these fundamental processes and to develop appropriate mathematical or computational approaches to enable one to use this rigorous understanding to rationally design complex biological systems relevant to TERM. The workshop will contribute to this critical challenge by bringing together a mix of participants with clinical, basic biology, engineering and mathematical backgrounds.

Accepted Speakers

Peter Anderson
Materials Science and Engineering, The Ohio State University
Praveen Arany
Harvard School of Engineering and Applied Sciences, Harvard University
Victor Barocas
Biomedical Engineering, University of Minnesota
Lauren Black
Department of Biomedical Engineering, Tufts University
Torsten Blunk
Department of Trauma, Hand, Plastic and Reconstructive Surgery,
Nenad Bursac
Biomedical Engineering, Duke University
John Dallon
Department of Mathematics, Brigham Young University
Robert Diegelman
Biochemistry & Molecular Biology, Medical College of Virginia
Elliot Elson
Biochemistry and Molecular Biophysics, Washington University School of Medicine
Samir Ghadiali
Biomedical Engineering, The Ohio State University
Keith Gooch
Biomedical Engineering, The Ohio State University
Chinlin Guo
Bioengineering, California Institute of Technology
Rich Hart
Biomedical Engineering, The Ohio State University
Jeffrey Holmes
Biomedical Engineering, University of Virginia
Jay Humphrey
Biomedical Engineering, Yale University
Sharon Lubkin
Mathematics, North Carolina State University
Roger Markwald
Regenerative Medicine, Medical University of South Carolina
Laura Miller
Mathematics , University of North Carolina, Chapel Hill
Nicanor Moldovan
Internal Medicine, The Ohio State University
Sarah Olson
Department of Mathematical Sciences, Worcester Polytechnic Institute
Heather Powell
Biomedical Engineering/Materials Science Engineering, The Ohio State University
Michael Sacks
Biomedical Engineering/ICES, University of Texas
Leonard Sander
Physics, University of Michigan
Edward Sander
Biomedical Engineering, University of Iowa
Alisha Sarang-Sieminski
Bioengineering,
Yoram Vodovotz
Department of Surgery, University of Pittsburgh
Qi Wang
Mathematics, University of South Carolina
Valerie Weaver
Surgery, University of San Francisco
Chuan Xue
Department of Mathematics, The Ohio State University
Monday, April 30, 2012
Time Session
09:30 AM
10:15 AM
- Engineered Skin: New Strategies for Biomechanical Mimicry
Engineered tissues must reproduce the biological and mechanical function of their native counterparts if they are to provide health benefits to society. However, the current generation of engineered skin (ES) fails to match the mechanical properties of native skin, limiting its use in vivo. This is due, in part, to the static, non-physiological conditions used during synthesis. Using mechanical stimuli during tissue culture is known to improve function and strength in engineered tissues. However, this advance has not been fully realized in skin or other complex, hierarchical tissues with multiple cell lineages and extracellular environments. This presentation will focus on the use of novel mechanical-bioreactor technology in conjunction with materials processing techniques, computational modeling and biological tools to understand the role of scaffold mechanics, stress gradients and cell communication during mechanical stimulation of engineered skin.
10:15 AM
10:45 AM
Peter Anderson - Simulating the mechanical response of fibrous scaffolds for tissue engineering
The use of scaffolds for tissue engineering involves aspects of mechanotransduction that are controlled by scaffold properties and structure at the local, cellular scale. For fibrous, electrospun scaffolds, such features include the local fiber stress-strain behavior, fiber density, and undulations in fiber orientation. These serve to provide variations in local stiffness and anisotropy that cannot be quantified through macroscopic testing alone. A combined computational-experimental approach is adopted whereby finite element simulations of electrospun scaffolds are used to link the macroscopic stress-strain response to underlying fiber geometry and fiber stress-strain response. These simulations capture the discrete fiber-straightening, reorientation, and fiber-fiber contact that occurs during scaffold deformation. They can also provide scaffold "Green's functions" to quantify local response to concentrated forces exerted by cells, enabling extraction of "cellular force footprints" in principle. The present simulations are informed by actual fiber geometries from high-resolution confocal microscopy images and macroscopic stress-strain data. An output is the local fiber stress-strain response, which is notoriously difficult to obtain by direct experimental measurement. The calibrated simulations underscore the highly non-uniform (non-affine) and anisotropic nature of the deformation. They also reveal the scale-dependent nature of mechanical response. The talk concludes with challenges to simulation "scale-up" and other pertinent issues. This work is supported by a Multidisciplinary Team Grant, Institute for Materials Research, The Ohio State University.
11:00 AM
12:00 PM
Robert Diegelman - Overview of Wound Healing
The normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors and cytokines such as platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-Ÿ). Following hemostasis, the neutrophils then enter the wound site and begin the critical task of phagocytosis to remove foreign materials, bacteria and damaged tissue. As part of this inflammatory phase, the macrophages appear and continue the process of phagocytosis as well as releasing more PDGF and TGFŸ. Once the wound site is cleaned out, fibroblasts migrate in to begin the proliferative phase and deposit new extracellular matrix. The new collagen matrix then becomes cross-linked and organized during the final remodeling phase. In order for this efficient and highly controlled repair process to take place, there are numerous cell-signaling events that are required. In pathologic conditions such as non-healing pressure ulcers, this efficient and orderly process is lost and the ulcers are locked into a state of chronic inflammation characterized by abundant neutrophil infiltration with associated reactive oxygen species and destructive enzymes. Healing proceeds only after the inflammation is controlled. On the opposite end of the spectrum, fibrosis is characterized by excessive matrix deposition, contraction and reduced remodeling. New technologies utilizing PTFE tube implantation have been developed to analyze inflammation and tissue repair in humans. On days 3, 5, 7 and 14 the tubes are removed and the newly deposited cells and matrix components are characterized using histologic, immuno-staining and proteomic analysis. These ongoing studies will be discussed.
01:30 PM
02:30 PM
Melissa Knothe Tate - Multiscale Computational and Experimental Approaches to Harness the Regenerative Power of the Periosteum
The periosteum is a composite tissue that provides a niche for stem cells and exhibits a remarkable regenerative capacity to generate bone de novo within critical sized defects, even in the absence of the medullary cavity (e.g. when it is filled by an intramedullary nail for mechanical stabilization after tumor resection). Clinical reports and recent experiments indicate that the regenerative capacity of the periosteum is enhanced by mechanical loading. Furthermore, implementation of directional delivery implants designed as periosteum substitutes show that periosteum-derived cells as well as other biologic factors intrinsic to periosteum play a key role for infilling of critical sized defects. In this talk we will review the mechanobiological factors shown to promote emergence of anisotropic structure and function by stem cells, to facilitate de novo tissue building by periosteum derived cells, as well as surgical and engineering approaches to unleash the power of the periosteum for tissue engineering as well as trauma and reconstruction surgery.
02:30 PM
03:30 PM
Praveen Arany - Directed Differentiation of Stem Cells using Lasers
With the renewed excitement in the inducible stem cell field, regenerative medicine is poised at our ability to efficiently direct differentiation of stem cells into functional tissues and organ systems. Besides the vast amount of work currently addressing the mechanistic underpinnings of the directed differentiation process, practical tools to harness this into a clinical utility are lacking. In this talk, I present our work with low power lasers as an innovative tool for clinical regenerative applications. Our current work has uncovered the physical, chemical and molecular events mediating the molecular mechanism mediating these effects using a wide range of in vitro analytical techniques. These observations were validated in vivo assessing directed differentiation of adult dental stem cells in animal models. In summary, low power laser can directs differentiation of resident stem cells via activation of endogenous morphogen.
04:00 PM
05:00 PM
Yoram Vodovotz - Measurement, Modeling, and Rational Modulation of Inflammation and Wound Healing
Properly-regulated inflammation is central to homeostasis, but in adequate or overly-robust inflammation can lead to disease. Like many biological processes, inflammation and its various manifestations in disease are multi-dimensional. The advent of multiplexed platforms for gathering biological data, while providing an unprecedented level of detailed information about the dynamics of complex biological systems such as the inflammatory response, has paradoxically also flooded investigators with data they are often unable to use. Systems approaches, including data-driven and mechanistic computational modeling, have been used to decipher aspects of the inflammatory responses that characterize trauma/hemorrhage and sepsis. Through combined data-driven and mechanistic modeling based on LuminexTM datasets, computational models of acute inflammation in mice, rats, swine, and humans were generated. These studies suggest that acute inflammation goes awry when the positive feedback loop of inflammation -> tissue damage/dysfunction -> inflammation, driven by damage-associated molecular pattern molecules, fails to resolve under the influence of anti-inflammatory/pro-healing mediators. This positive feedback loop also underlies agent-based computational models of inflammation and tissue injury in skin and liver, leading to tissue-realistic simulations and tissue-specific outcomes including chronic non-healing wounds and liver fibrosis, cirrhosis, and hepatocellular carcinoma, respectively. These systems-based insights have led to novel, rationally-designed therapies based on a biohybrid framework.
Tuesday, May 1, 2012
Time Session
09:00 AM
10:00 AM
Valerie Weaver - Matrix stiffness and cell behavior
Not Available.
10:00 AM
10:45 AM
Chinlin Guo - Long-range mechanical force enables scaffold-free self-assembly of epithelial tubules
In nature, self-assembly is a common process for living systems to build large-scale architectures without pre-existing positional cues from scaffolds or templates. At molecular scales, scaffold-free self-assembly has also been used to create bio-mimetic supra-molecular architectures and sub-cellular components. However, the principles of cell-microenvironment self-assembly have not been widely used to construct large-scale functional cellular devices. For example, current engineering of un-branched epithelial tubules of lengths above hundred micrometers is achieved on premade scaffolds only. Here, we show that adult epithelial cells and type I collagen molecules can self-assemble into centimeter-long, hundred micrometer-wide and un-branched tubules under scaffold-free conditions. These tubules develop apicobasal polarity and lumens similar to those found in situ. The observed tubule self-assembly requires cell-collagen interactions in the liquid phase to form the initial linear templates. In contrast with conventional thoughts, such template formation is primarily mediated by long-range (~ 600 micrometers) mechanical interactions rather than gradients of soluble factors between cells. The stability of linear templates increases with their lengths. Moreover, the ability of the cells to form tubules depends on the initial and boundary conditions of the culturing systems, and could be prevented by cell-substrate interactions. Only large culture systems containing a sufficient density of cells cultured on low-adhesive substrates enables the formation of centimeter-long, un-branched tubules. Our findings illustrate the feasibility of building long tubules under scaffold-free conditions and provide insights into the principles of cell-microenvironment self-assembly that could be used for the engineering of functional organs.
01:45 PM
02:30 PM
Chuan Xue - Continuum approximations of cell-based models for bacterial chemotaxis
Chemotaxis is the active movement of cells or organisms in response to external chemical signals. The chemotactic movement of bacteria populations can lead to intricate spatial and temporal patterns. Traditionally, these patterns have been modeled using continuum approaches, which describe the evolution of the cell density by partial differential equations (PDEs). However, these models are phenomenological and their connection with mechanistic cellular processes such as signal transduction and cell movement is not well understood. In the first part of this talk, I will present cell-based models of bacterial chemotaxis, which integrate great details of fundamental cellular mechanisms, and address several bacterial patterns. For problems that involve large numbers of cells, cell-based models are computationally intensive and time-consuming. In the second part of this talk, I will show connections between the continuum/phenomenological models and cell-based/mechanistic models derived by asymptotic methods.
Wednesday, May 2, 2012
Time Session
12:00 AM
11:00 AM
Sarah Olson - Computational modeling of cartilage regeneration
Articular cartilage is a connective tissue lining bony surfaces in diarthrodial joints (knees, hips, and shoulders). When degradation exceeds the synthesis of extracellular matrix constituents, cartilage will start eroding and fragmenting, eventually leading to defects. Since cartilage has a limited capacity for growth and repair, defects due to osteoarthritis and injury may rapidly progress to complete tissue degradation, necessitating a joint replacement. Prior to complete tissue degradation, defects could be filled with cell-seeded biocompatible porous scaffolds, with the hopes of repairing and regenerating new tissue. In order to achieve biological and mechanical functionality of these constructs, many factors need to be considered. This talk will highlight key aspects such as nutrient transport, cell proliferation and migration, matrix synthesis, and mechanical interactions in the context of cartilage regeneration. Previous computational work will be described that ranges from the use of neural networks, reaction diffusion models, level set methods, and continuum modeling frameworks to investigate and understand aspects of cartilage tissue engineering.
09:00 AM
09:45 AM
Victor Barocas - Multiscale Models of Collagenous Materials
Multiscale Models of Collagenous Materials.
09:45 AM
10:00 AM
Edward Sander - Multiscale Computational Simulations of Fiber Remodeling and Cell Compaction in Collagen Gels
Multiscale mechanical interactions are scale spanning physical interactions between the tissue and the extracellular matrix (ECM). They are involved in a variety of biological phenomena, including tissue growth, remodeling, disease, and damage. These interactions are important to characterize because they control both the mechanical behavior of the tissue and the manner in which mechanical signals are propagated to the cellular level. In this talk I will discuss recent work where we incorporate (1) fiber-level rules that govern enzymatic degradation and growth and (2) contractile elements that simulate cell compaction and a redistribution of forces within the surrounding fiber networks into our multiscale modeling framework. Understanding the role of these processes is crucial to comprehending and controlling the integrated response of the mechanical environment in a number of biological contexts.
10:00 AM
10:50 AM
Torsten Blunk - Adipose TE - The Matrix Matters
In reconstructive surgery, there is a tremendous clinical need for adequate implants to repair soft tissue defects resulting from tumor resection (e.g., breast reconstruction after mastectomy), traumatic injury, or congenital anomalies. Adipose tissue engineering holds the promise to provide answers to this still increasing demand. While many different biomaterials have been explored, a recent review of the field shows that cell carriers which are more adipose-specific are desirable. Current developments will be presented that focus on biomaterials based on structures that are derived from the extracellular matrix of adipose tissue. This includes decellularized native ECM, but also synthetic materials exhibiting characteristics of the adipose ECM, such as adhesion peptides and peptides that are substrates for matrix-degrading enzymes. Besides aiming at the generation of tissue constructs for clinical use, 3D engineered adipose tissue constructs can also be utilized as models for basic research investigating the influence of tissue-inherent factors on adipogenesis. A new model based on 3D spheroids made from human adipose-derived stem cells (ASC) will be presented that provides, without any exogenous material, cell-cell and cell-ECM interactions in a more in vivo-like context, as compared to conventional 2D cell culture. Different aspects with regard to the ECM that are investigated utilizing the ASC spheroids will be discussed.

Work done in collaboration with Jürgen Groll.
01:40 PM
02:20 PM
Alisha Sarang-Sieminski - Interplay between active and passive mechanical forces in microvascular network formation
Understanding how matrix properties influence cell behavior has implications for our understanding of many processes and applications, including fundamentals of cell and developmental biology, wound healing, tumor formation, and design of biomaterials for tissue engineering. While it is widely appreciated that the mechanical properties of the matrix, as well as cell force generation, are important aspects of the differentiated functions of numerous cell types, the interplay between these passive and active mechanical forces is less well understood. We have used an in vitro model of microvascular network (MVN) formation to investigate the dynamic and reciprocal relationship between cells and biomaterial supports. Macroscopic matrix remodeling due to endothelial cell force generation, as indicated by biomaterial gel compaction, is a key feature of MVN formation. To understand this phenomenon at the cellular length scale, we have employed confocal microscopy to image endothelial cells and their surrounding collagen matrix during various stages of MVN formation. Gathering of matrix around cells precedes cell elongation and MVN formation and decreases as a function of increasing cell-cell distance and collagen stiffness. Additionally, the patterns of matrix gathering are consistent with the hypothesis that nearby cells form lines of matrix tension or alignment that they elongate along in order to form multi-cellular structures. This work fits into the larger picture of increasing our understanding of the role of cell-derived forces and matrix remodeling in differentiated cell functions with implications for mechanobiology and design of new tissue engineering scaffolds.
02:20 PM
02:50 PM
Rich Hart - Extracellular Matrix Fibers and Stress Transmission Between Cells
In addition to chemical signals, cells are able to communicate via mechanical signaling. We are investigating the hypothesis that the fibers in the extracellular matrix (ECM) are the key factor for transmitting mechanical signals between fibroblast cells as an alternative to the hypothesis in the literature that the strain-hardening behavior of the ECM is responsible for long-range cell-cell mechanical signals. To compare the two hypotheses, confocal reflectance microscopy was used to develop image-based 2-D finite-element models of stress transmission within fibroblast-seeded collagen gels. Models that include the gel's fibers were compared with homogenous linear-elastic and strain-hardening models to investigate the mechanisms of stress propagation. Experimentally, cells were observed to contract collagen fibers centripetally and align collagen fibers between neighboring cells within 24 hours. Finite-element analysis revealed that stresses generated by a centripetally contracting cell are concentrated in the relatively stiff ECM fibers and are propagated farther in a fibrous matrix as compared to linear elastic or strain-hardening homogenous materials. These results support the hypothesis that ECM fibers play the key role in long-range stress transmission, and that strain-hardening effects are secondary.

Joint work with Xiaoyue Ma, Maureen Weber, Mark D. Stevenson, Alisha L. Sarang-Sieminski, Keith J. Gooch, and Samir N. Ghadiali. This work was supported by NSF CMMI-0928739.
03:20 PM
04:00 PM
Keith Gooch - Mathematical and computational modeling of cell-matrix interactions
This talk will discuss mathematical and computational modeling of cell-matrix interactions at different length scales. Agent-based models were developed where cells and ECM fibers are each considered as systems of multiple interacting agents. In these models, the physical properties of cell and fibers are based on a set of conceptually reasonable mechanical processes and the dynamics of cell-matrix binding and unbinding are considered as simple position- and strain-dependent processes. From these relatively simple sets of rules, complex behaviors arise that are consistent with experimental data including cell-mediated compaction of ECM fiber networks, the alignment of ECM fibers between cells, and the directed migration of pairs of cells towards one another. In addition, there is evidence consistent with durotaxis and haptotaxis arising as emergent behaviors from these simple sets of rules. The implications of the peri-cellular distribution of ECM predicted in these agent-based models and observed experimentally are explored in a mathematical model of cell-mediated compaction of ECM.

Joint work with James Reinhardt, Mark Stevenson, Victor Barocas, and Alisha L. Sarang-Sieminski. This work was supported by NSF CMMI-0928739
04:00 PM
04:30 PM
Samir Ghadiali - Mathematical Analysis of Traction Force Microscopy: Influence of Cell Mechanics, Adhesion and Morphology
Several biological processes depend on interactions between cells as their extracellular matrix (ECM). Cells typically attach to the ECM via specific focal adhesions and exert traction stresses on the ECM by generating internal contractile or tensile forces. The generation of these contractile forces is essential to numerous biological and pathological processes including development, growth, wound healing and cancer cell migration/invasion. A common technique used to assess the contractile properties of cells is Traction Force Microscopy (TFM). In TFM, the displacements of fluorescently labeled beads embedded into the ECM or substrate are measured and converted into a traction stress field using inverse analytical or finite element methods. Recently, standard 2D TFM methods have been extended into 3D and the traction stress field generally used as a measure of cell contractility. However, we hypothesize that changes in several biomechanical and morphological properties (i.e. cell stiffness, cell-substrate adhesion and aspect ratio) may alter the traction stress field measured by TFM. The fact that multiple parameters other than contractility can influence TFM measurements may lead to inappropriate interpretation of experimental results. Therefore, we have developed an idealized finite element model of 2D and 3D TFM and have used this model to evaluate how cell mechanical and morphological properties influence TFM measurements. Results indicate that even for equivalent contractile stress, changes in cell stiffness (Young's Modulus) and adhesion energy can lead to dramatic changes in the contractility as determine by TFM. These results therefore indicate that in addition to TFM, several other biomechanical measurements of stiffness and adhesion are required to appropriate interpret TFM measurements and assess changes in cell contractility.

This work was supported by NSF CAREER 0852417 and NSF 1134201.
Thursday, May 3, 2012
Time Session
09:00 AM
10:00 AM
Michael Sacks - Cell-Matrix interactions in TE heart valve
Cell-Matrix interactions in TE heart valve
10:00 AM
11:00 AM
Laura Miller - Towards a complete neuromechanical model of pumping in tubular hearts
Recent advancements in computational fluid dynamics have enabled researchers to efficiently explore problems that involve moving elastic boundaries immersed in fluids for problems such as cardiac fluid dynamics, fish swimming, and the movement of bacteria. These advances have also made modeling the interaction between a fluid and a neuromechanical model of an elastic organ feasible. The tubular hearts of some ascidians and vertebrate embryos offers a relatively simple model organ for such a study. Blood is driven through the heart by either peristaltic contractions or valveless suction pumping through localized periodic contractions. Models considering only the fluid-structure interaction aspects of these hearts are insufficient to resolve the actual pumping mechanism. The electromechanical model presented here will integrate feedback between the conduction of action potentials, the contraction of muscles, the movement of tissues, and the resulting fluid motion.
11:30 AM
12:30 PM
Nenad Bursac - Coaxing Myogenic Stem Cells into Highly Functional Engineered Tissues
Cardiac and skeletal muscle development and regeneration involve complex interactions among different cell types, biochemical and biophysical stimuli, and extracellular matrix molecules. Studies of how each of these components influences the tissue morphogenesis, function, and disease are often precluded by the complex structure of the native tissue and the inability to directly control or monitor cellular processes and fates in vivo. The use of tissue engineering technologies, on the other hand, allows for the generation and manipulation of 3-dimensional cell culture systems to both improve our understanding of the myogenic processes in vitro and enable the development of new therapies for heart and muscle disease. Recently, our efforts have been focused on the use of stem cells and natural hydrogels to construct cardio- and myo-mimetic tissue culture systems with enhanced functional output. We find that specific combinations of hydrogel composition, dynamic biochemical culture environment, boundary conditions imposed on cells, and supporting non-myogenic cell types can uniquely advance structural and electromechanical properties of engineered muscle to resemble those found in age-matched tissues in vivo. These studies provide insights into the principles of functional myogenesis that could lead to the development of efficient tissue engineering therapies for human disease.
02:15 PM
03:00 PM
Lauren Black - Alterations in Extracellular Matrix Properties Effect Cardiac Differentiation and Cardiomyocyte Proliferation
While the impact of single extracellular matrix (ECM) proteins and mechanical stiffness on cell function have been thoroughly probed individually, little work has been put into to understanding their interactions in the context of cell function. This is particularly important as the ECM is a complex mixture of proteins that change throughout normal development both in composition and stiffness. Recent work by others has demonstrated that cells respond differently to both static substrate stiffness and mechanical stretch when plated on substrates of different compositions. In addition, the effects of growth factor treatment can also be modulated by substrate composition and stiffness. In this talk I will cover our own recent work investigating the effects of alterations in stiffness and composition of the substrate on cardiac differentiation of stem cells and cardiomyocyte proliferation. The system we use is a polyacrylamide gel system with binding sites generated from solubilized decellularized cardiac ECM. This setup effectively allows us to decouple stiffness and composition to investigate their individual roles and any synergistic/ antagonistic effects. Preliminary data indicate that ECM composition and stiffness interact in a complex manner to effect cardiac differentiation of mesenchymal stem cells. Moreover, fetal cardiac ECM composition enhances neonatal cardiomyocyte proliferation over adult cardiac ECM or normal tissue culture plastic.
03:00 PM
03:30 PM
Nicanor Moldovan - Quantification of "Actin Grips", a New Cytoskeletal Mechanism of Cell-Fiber Interaction
Tissue engineering constructs comprising cells and extracellular matrix-like scaffolds in fiber form are increasingly used for regenerative medicine applications. While cell types, fibers and modes of attachment vary, a simple classification can be made regarding the relative cell size versus fiber diameter. We became interested in the situation when the two dimensions are comparable, during a project aiming at the colonization with endothelial progenitor cells (EPC) of scaffolds made of polymeric fibers obtained by electrospinning. The goal is to use these cell-seeded scaffolds as carriers for various purposes, such as manipulating neovascularization at the site of implantation. In the process, we found that EPC engage with the fibers by a novel filamentous (F) actin-rich, highly dynamic cytoskeletal structure, that we named 'actin grip'. These F-actin bundles are finely regulated by the intracellular levels of reactive oxygen species. Therefore, they could be instrumental for controlled attachment to and detachment of the cells from the fibers, independent of their adhesiveness. To quantify the number and geometry of these 'grips', their co-localization with signaling molecules, and their impact on cell density and shape within the scaffolds, we are developing an automatic analysis program of three dimensional confocal microcopy images. I will discuss the methods and the main results obtained in this project so far.
Friday, May 4, 2012
Time Session
09:00 AM
10:00 AM
Jeffrey Holmes - Computational Modeling of Myocardial Infarct Healing
The mechanics of healing myocardial infarcts are a critical determinant of left ventricular function. We recently showed that infarcts healing in different mechanical environments develop different collagen fiber structures and mechanical properties. We developed an agent-based model to evaluate the mechanisms by which mechanical environment directs collagen deposition and remodeling by cardiac fibroblasts and to better understand the effects of therapeutic interventions on the evolving scar structure. Parameters for this model were derived from a combination of published literature and new experiments in engineered tissue-equivalents, focusing particularly on features of cell-matrix interaction such as contact guidance and collagen remodeling. Our results suggest that different environmental cues regulate scar formation in different tissues. In contrast to previous models of skin wound healing showing that chemokine gradients are a dominant regulator of scar formation, we find that mechanical environment is the dominant regulator of evolving scar structure following myocardial infarction. Our results suggest that a number of regenerative and device therapies that alter infarct mechanics, including stem cell injection, polymer injection, surgical reinforcement, and peri-infarct pacing, will also alter scar structure. Our computational model of infarct healing should enable in silico screening of novel therapies for potential adverse effects on scar formation.
09:45 AM
10:45 AM
Elliot Elson - Myofibroblasts in the Electromechanical Function of TE Heart
Myofibroblasts in the Electromechanical Function of TE Heart
11:00 AM
11:45 AM
Qi Wang - Modeling fusion of multicellular aggregates and endotheliation with applications to biofabrication
Modeling fusion of multicellular aggregates and endotheliation with applications to biofabrication.
Name Email Affiliation
Anderson, Peter anderson.1@osu.edu Materials Science and Engineering, The Ohio State University
Arany, Praveen parany@seas.harvard.edu Harvard School of Engineering and Applied Sciences, Harvard University
Barocas, Victor baroc001@umn.edu Biomedical Engineering, University of Minnesota
Black, Lauren Lauren.Black@tufts.edu Department of Biomedical Engineering, Tufts University
Blunk, Torsten Blunk_T@chirurgie.uni-wuerzburg.de Department of Trauma, Hand, Plastic and Reconstructive Surgery,
Bursac, Nenad nenad.bursac@duke.edu Biomedical Engineering, Duke University
Cooper, Racheal cooperrl2@vcu.edu Statistics and Operations Research and Mathematics Departments, Virginia Commonwealth University
Dallon, John dallon@math.byu.edu Department of Mathematics, Brigham Young University
Diegelman, Robert rdiegelm@vcu.edu Biochemistry & Molecular Biology, Medical College of Virginia
Elson, Elliot elson@biochem.wustl.edu Biochemistry and Molecular Biophysics, Washington University School of Medicine
Ghadiali, Samir ghadiali.1@osu.edu Biomedical Engineering, The Ohio State University
Gooch, Keith gooch.20@osu.edu Biomedical Engineering, The Ohio State University
Guo, Chinlin guochin@its.caltech.edu Bioengineering, California Institute of Technology
Hart, Richard hart.322@osu.edu Biomedical Engineering, The Ohio State University
Holmes, Jeffrey holmes@virginia.edu Biomedical Engineering, University of Virginia
Humphrey, Jay jay.humphrey@yale.edu Biomedical Engineering, Yale University
Kniss, Douglas kniss.1@osu.edu OB&GYN, The Ohio State University
Knothe Tate, Melissa knothetate@case.edu Biomedical Engineering, Case Western Reserve University
Liu, Xinfeng xfliu@math.sc.edu Mathematics, University of South Carolina
Lubkin, Sharon lubkin@math.ncsu.edu Mathematics, North Carolina State University
Markwald, Roger markwald@musc.edu Regenerative Medicine, Medical University of South Carolina
Miller, Laura lam9@email.unc.edu Mathematics , University of North Carolina, Chapel Hill
Moldovan, Nicanor nicanor.moldovan@osumc.edu Internal Medicine, The Ohio State University
Olson, Sarah sdolson@wpi.edu Department of Mathematical Sciences, Worcester Polytechnic Institute
Powell, Heather powell@matsceng.ohio-state.edu Biomedical Engineering/Materials Science Engineering, The Ohio State University
Reynolds, Angela areynolds2@vcu.edu Mathematics and Applied Mathematics, Virginia Commonwealth University
Roy, Sashwati roy.63@osu.edu Department of Surgery, The Ohio State University
Sacks, Michael msacks@ices.utexas.edu Biomedical Engineering/ICES, University of Texas
Sander, Leonard lsander@umich.edu Physics, University of Michigan
Sander, Edward edward-sander@uiowa.edu Biomedical Engineering, University of Iowa
Sarang-Sieminski, Alisha alisha.sieminski@olin.edu Bioengineering,
Segal, Rebecca rasegal@vcu.edu Mathematics, Virginia Commonwealth University
Sen, Chandan Chandan.Sen@osumc.edu College of Medicine, The Ohio State University
Simon, David dave.d.simon@gmail.com Biomedical Engineering, Yale University
Spardy, Lucy weijus@umn.edu
Sun, Yi yisun@math.sc.edu Mathematics, University of South Carolina
Threlkeld, Elizabeth elizabeth.threlkeld@students.olin.edu College of Engineering, Olin College of Engineering
Vodovotz, Yoram vodovotzy@upmc.edu Department of Surgery, University of Pittsburgh
Wang, Qi qwang@math.sc.edu Mathematics, University of South Carolina
Weaver, Valerie weaverv@surgery.ucsf.edu Surgery, University of San Francisco
Wen, Qi qwen@wpi.edu Physics, Worcester Polytechnic Institute
Xue, Chuan cxue@math.ohio-state.edu Department of Mathematics, The Ohio State University
Simulating the mechanical response of fibrous scaffolds for tissue engineering
The use of scaffolds for tissue engineering involves aspects of mechanotransduction that are controlled by scaffold properties and structure at the local, cellular scale. For fibrous, electrospun scaffolds, such features include the local fiber stress-strain behavior, fiber density, and undulations in fiber orientation. These serve to provide variations in local stiffness and anisotropy that cannot be quantified through macroscopic testing alone. A combined computational-experimental approach is adopted whereby finite element simulations of electrospun scaffolds are used to link the macroscopic stress-strain response to underlying fiber geometry and fiber stress-strain response. These simulations capture the discrete fiber-straightening, reorientation, and fiber-fiber contact that occurs during scaffold deformation. They can also provide scaffold "Green's functions" to quantify local response to concentrated forces exerted by cells, enabling extraction of "cellular force footprints" in principle. The present simulations are informed by actual fiber geometries from high-resolution confocal microscopy images and macroscopic stress-strain data. An output is the local fiber stress-strain response, which is notoriously difficult to obtain by direct experimental measurement. The calibrated simulations underscore the highly non-uniform (non-affine) and anisotropic nature of the deformation. They also reveal the scale-dependent nature of mechanical response. The talk concludes with challenges to simulation "scale-up" and other pertinent issues. This work is supported by a Multidisciplinary Team Grant, Institute for Materials Research, The Ohio State University.
Directed Differentiation of Stem Cells using Lasers
With the renewed excitement in the inducible stem cell field, regenerative medicine is poised at our ability to efficiently direct differentiation of stem cells into functional tissues and organ systems. Besides the vast amount of work currently addressing the mechanistic underpinnings of the directed differentiation process, practical tools to harness this into a clinical utility are lacking. In this talk, I present our work with low power lasers as an innovative tool for clinical regenerative applications. Our current work has uncovered the physical, chemical and molecular events mediating the molecular mechanism mediating these effects using a wide range of in vitro analytical techniques. These observations were validated in vivo assessing directed differentiation of adult dental stem cells in animal models. In summary, low power laser can directs differentiation of resident stem cells via activation of endogenous morphogen.
Multiscale Models of Collagenous Materials
Multiscale Models of Collagenous Materials.
Alterations in Extracellular Matrix Properties Effect Cardiac Differentiation and Cardiomyocyte Proliferation
While the impact of single extracellular matrix (ECM) proteins and mechanical stiffness on cell function have been thoroughly probed individually, little work has been put into to understanding their interactions in the context of cell function. This is particularly important as the ECM is a complex mixture of proteins that change throughout normal development both in composition and stiffness. Recent work by others has demonstrated that cells respond differently to both static substrate stiffness and mechanical stretch when plated on substrates of different compositions. In addition, the effects of growth factor treatment can also be modulated by substrate composition and stiffness. In this talk I will cover our own recent work investigating the effects of alterations in stiffness and composition of the substrate on cardiac differentiation of stem cells and cardiomyocyte proliferation. The system we use is a polyacrylamide gel system with binding sites generated from solubilized decellularized cardiac ECM. This setup effectively allows us to decouple stiffness and composition to investigate their individual roles and any synergistic/ antagonistic effects. Preliminary data indicate that ECM composition and stiffness interact in a complex manner to effect cardiac differentiation of mesenchymal stem cells. Moreover, fetal cardiac ECM composition enhances neonatal cardiomyocyte proliferation over adult cardiac ECM or normal tissue culture plastic.
Adipose TE - The Matrix Matters
In reconstructive surgery, there is a tremendous clinical need for adequate implants to repair soft tissue defects resulting from tumor resection (e.g., breast reconstruction after mastectomy), traumatic injury, or congenital anomalies. Adipose tissue engineering holds the promise to provide answers to this still increasing demand. While many different biomaterials have been explored, a recent review of the field shows that cell carriers which are more adipose-specific are desirable. Current developments will be presented that focus on biomaterials based on structures that are derived from the extracellular matrix of adipose tissue. This includes decellularized native ECM, but also synthetic materials exhibiting characteristics of the adipose ECM, such as adhesion peptides and peptides that are substrates for matrix-degrading enzymes. Besides aiming at the generation of tissue constructs for clinical use, 3D engineered adipose tissue constructs can also be utilized as models for basic research investigating the influence of tissue-inherent factors on adipogenesis. A new model based on 3D spheroids made from human adipose-derived stem cells (ASC) will be presented that provides, without any exogenous material, cell-cell and cell-ECM interactions in a more in vivo-like context, as compared to conventional 2D cell culture. Different aspects with regard to the ECM that are investigated utilizing the ASC spheroids will be discussed.

Work done in collaboration with Jürgen Groll.
Coaxing Myogenic Stem Cells into Highly Functional Engineered Tissues
Cardiac and skeletal muscle development and regeneration involve complex interactions among different cell types, biochemical and biophysical stimuli, and extracellular matrix molecules. Studies of how each of these components influences the tissue morphogenesis, function, and disease are often precluded by the complex structure of the native tissue and the inability to directly control or monitor cellular processes and fates in vivo. The use of tissue engineering technologies, on the other hand, allows for the generation and manipulation of 3-dimensional cell culture systems to both improve our understanding of the myogenic processes in vitro and enable the development of new therapies for heart and muscle disease. Recently, our efforts have been focused on the use of stem cells and natural hydrogels to construct cardio- and myo-mimetic tissue culture systems with enhanced functional output. We find that specific combinations of hydrogel composition, dynamic biochemical culture environment, boundary conditions imposed on cells, and supporting non-myogenic cell types can uniquely advance structural and electromechanical properties of engineered muscle to resemble those found in age-matched tissues in vivo. These studies provide insights into the principles of functional myogenesis that could lead to the development of efficient tissue engineering therapies for human disease.
Overview of Wound Healing
The normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers the platelets to release clotting factors as well as essential growth factors and cytokines such as platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-ß). Following hemostasis, the neutrophils then enter the wound site and begin the critical task of phagocytosis to remove foreign materials, bacteria and damaged tissue. As part of this inflammatory phase, the macrophages appear and continue the process of phagocytosis as well as releasing more PDGF and TGFß. Once the wound site is cleaned out, fibroblasts migrate in to begin the proliferative phase and deposit new extracellular matrix. The new collagen matrix then becomes cross-linked and organized during the final remodeling phase. In order for this efficient and highly controlled repair process to take place, there are numerous cell-signaling events that are required. In pathologic conditions such as non-healing pressure ulcers, this efficient and orderly process is lost and the ulcers are locked into a state of chronic inflammation characterized by abundant neutrophil infiltration with associated reactive oxygen species and destructive enzymes. Healing proceeds only after the inflammation is controlled. On the opposite end of the spectrum, fibrosis is characterized by excessive matrix deposition, contraction and reduced remodeling. New technologies utilizing PTFE tube implantation have been developed to analyze inflammation and tissue repair in humans. On days 3, 5, 7 and 14 the tubes are removed and the newly deposited cells and matrix components are characterized using histologic, immuno-staining and proteomic analysis. These ongoing studies will be discussed.
Myofibroblasts in the Electromechanical Function of TE Heart
Myofibroblasts in the Electromechanical Function of TE Heart
Mathematical Analysis of Traction Force Microscopy: Influence of Cell Mechanics, Adhesion and Morphology
Several biological processes depend on interactions between cells as their extracellular matrix (ECM). Cells typically attach to the ECM via specific focal adhesions and exert traction stresses on the ECM by generating internal contractile or tensile forces. The generation of these contractile forces is essential to numerous biological and pathological processes including development, growth, wound healing and cancer cell migration/invasion. A common technique used to assess the contractile properties of cells is Traction Force Microscopy (TFM). In TFM, the displacements of fluorescently labeled beads embedded into the ECM or substrate are measured and converted into a traction stress field using inverse analytical or finite element methods. Recently, standard 2D TFM methods have been extended into 3D and the traction stress field generally used as a measure of cell contractility. However, we hypothesize that changes in several biomechanical and morphological properties (i.e. cell stiffness, cell-substrate adhesion and aspect ratio) may alter the traction stress field measured by TFM. The fact that multiple parameters other than contractility can influence TFM measurements may lead to inappropriate interpretation of experimental results. Therefore, we have developed an idealized finite element model of 2D and 3D TFM and have used this model to evaluate how cell mechanical and morphological properties influence TFM measurements. Results indicate that even for equivalent contractile stress, changes in cell stiffness (Young's Modulus) and adhesion energy can lead to dramatic changes in the contractility as determine by TFM. These results therefore indicate that in addition to TFM, several other biomechanical measurements of stiffness and adhesion are required to appropriate interpret TFM measurements and assess changes in cell contractility.

This work was supported by NSF CAREER 0852417 and NSF 1134201.
Mathematical and computational modeling of cell-matrix interactions
This talk will discuss mathematical and computational modeling of cell-matrix interactions at different length scales. Agent-based models were developed where cells and ECM fibers are each considered as systems of multiple interacting agents. In these models, the physical properties of cell and fibers are based on a set of conceptually reasonable mechanical processes and the dynamics of cell-matrix binding and unbinding are considered as simple position- and strain-dependent processes. From these relatively simple sets of rules, complex behaviors arise that are consistent with experimental data including cell-mediated compaction of ECM fiber networks, the alignment of ECM fibers between cells, and the directed migration of pairs of cells towards one another. In addition, there is evidence consistent with durotaxis and haptotaxis arising as emergent behaviors from these simple sets of rules. The implications of the peri-cellular distribution of ECM predicted in these agent-based models and observed experimentally are explored in a mathematical model of cell-mediated compaction of ECM.

Joint work with James Reinhardt, Mark Stevenson, Victor Barocas, and Alisha L. Sarang-Sieminski. This work was supported by NSF CMMI-0928739
Long-range mechanical force enables scaffold-free self-assembly of epithelial tubules
In nature, self-assembly is a common process for living systems to build large-scale architectures without pre-existing positional cues from scaffolds or templates. At molecular scales, scaffold-free self-assembly has also been used to create bio-mimetic supra-molecular architectures and sub-cellular components. However, the principles of cell-microenvironment self-assembly have not been widely used to construct large-scale functional cellular devices. For example, current engineering of un-branched epithelial tubules of lengths above hundred micrometers is achieved on premade scaffolds only. Here, we show that adult epithelial cells and type I collagen molecules can self-assemble into centimeter-long, hundred micrometer-wide and un-branched tubules under scaffold-free conditions. These tubules develop apicobasal polarity and lumens similar to those found in situ. The observed tubule self-assembly requires cell-collagen interactions in the liquid phase to form the initial linear templates. In contrast with conventional thoughts, such template formation is primarily mediated by long-range (~ 600 micrometers) mechanical interactions rather than gradients of soluble factors between cells. The stability of linear templates increases with their lengths. Moreover, the ability of the cells to form tubules depends on the initial and boundary conditions of the culturing systems, and could be prevented by cell-substrate interactions. Only large culture systems containing a sufficient density of cells cultured on low-adhesive substrates enables the formation of centimeter-long, un-branched tubules. Our findings illustrate the feasibility of building long tubules under scaffold-free conditions and provide insights into the principles of cell-microenvironment self-assembly that could be used for the engineering of functional organs.
Extracellular Matrix Fibers and Stress Transmission Between Cells
In addition to chemical signals, cells are able to communicate via mechanical signaling. We are investigating the hypothesis that the fibers in the extracellular matrix (ECM) are the key factor for transmitting mechanical signals between fibroblast cells as an alternative to the hypothesis in the literature that the strain-hardening behavior of the ECM is responsible for long-range cell-cell mechanical signals. To compare the two hypotheses, confocal reflectance microscopy was used to develop image-based 2-D finite-element models of stress transmission within fibroblast-seeded collagen gels. Models that include the gel's fibers were compared with homogenous linear-elastic and strain-hardening models to investigate the mechanisms of stress propagation. Experimentally, cells were observed to contract collagen fibers centripetally and align collagen fibers between neighboring cells within 24 hours. Finite-element analysis revealed that stresses generated by a centripetally contracting cell are concentrated in the relatively stiff ECM fibers and are propagated farther in a fibrous matrix as compared to linear elastic or strain-hardening homogenous materials. These results support the hypothesis that ECM fibers play the key role in long-range stress transmission, and that strain-hardening effects are secondary.

Joint work with Xiaoyue Ma, Maureen Weber, Mark D. Stevenson, Alisha L. Sarang-Sieminski, Keith J. Gooch, and Samir N. Ghadiali. This work was supported by NSF CMMI-0928739.
Computational Modeling of Myocardial Infarct Healing
The mechanics of healing myocardial infarcts are a critical determinant of left ventricular function. We recently showed that infarcts healing in different mechanical environments develop different collagen fiber structures and mechanical properties. We developed an agent-based model to evaluate the mechanisms by which mechanical environment directs collagen deposition and remodeling by cardiac fibroblasts and to better understand the effects of therapeutic interventions on the evolving scar structure. Parameters for this model were derived from a combination of published literature and new experiments in engineered tissue-equivalents, focusing particularly on features of cell-matrix interaction such as contact guidance and collagen remodeling. Our results suggest that different environmental cues regulate scar formation in different tissues. In contrast to previous models of skin wound healing showing that chemokine gradients are a dominant regulator of scar formation, we find that mechanical environment is the dominant regulator of evolving scar structure following myocardial infarction. Our results suggest that a number of regenerative and device therapies that alter infarct mechanics, including stem cell injection, polymer injection, surgical reinforcement, and peri-infarct pacing, will also alter scar structure. Our computational model of infarct healing should enable in silico screening of novel therapies for potential adverse effects on scar formation.
Multiscale Computational and Experimental Approaches to Harness the Regenerative Power of the Periosteum
The periosteum is a composite tissue that provides a niche for stem cells and exhibits a remarkable regenerative capacity to generate bone de novo within critical sized defects, even in the absence of the medullary cavity (e.g. when it is filled by an intramedullary nail for mechanical stabilization after tumor resection). Clinical reports and recent experiments indicate that the regenerative capacity of the periosteum is enhanced by mechanical loading. Furthermore, implementation of directional delivery implants designed as periosteum substitutes show that periosteum-derived cells as well as other biologic factors intrinsic to periosteum play a key role for infilling of critical sized defects. In this talk we will review the mechanobiological factors shown to promote emergence of anisotropic structure and function by stem cells, to facilitate de novo tissue building by periosteum derived cells, as well as surgical and engineering approaches to unleash the power of the periosteum for tissue engineering as well as trauma and reconstruction surgery.
Towards a complete neuromechanical model of pumping in tubular hearts
Recent advancements in computational fluid dynamics have enabled researchers to efficiently explore problems that involve moving elastic boundaries immersed in fluids for problems such as cardiac fluid dynamics, fish swimming, and the movement of bacteria. These advances have also made modeling the interaction between a fluid and a neuromechanical model of an elastic organ feasible. The tubular hearts of some ascidians and vertebrate embryos offers a relatively simple model organ for such a study. Blood is driven through the heart by either peristaltic contractions or valveless suction pumping through localized periodic contractions. Models considering only the fluid-structure interaction aspects of these hearts are insufficient to resolve the actual pumping mechanism. The electromechanical model presented here will integrate feedback between the conduction of action potentials, the contraction of muscles, the movement of tissues, and the resulting fluid motion.
Quantification of "Actin Grips", a New Cytoskeletal Mechanism of Cell-Fiber Interaction
Tissue engineering constructs comprising cells and extracellular matrix-like scaffolds in fiber form are increasingly used for regenerative medicine applications. While cell types, fibers and modes of attachment vary, a simple classification can be made regarding the relative cell size versus fiber diameter. We became interested in the situation when the two dimensions are comparable, during a project aiming at the colonization with endothelial progenitor cells (EPC) of scaffolds made of polymeric fibers obtained by electrospinning. The goal is to use these cell-seeded scaffolds as carriers for various purposes, such as manipulating neovascularization at the site of implantation. In the process, we found that EPC engage with the fibers by a novel filamentous (F) actin-rich, highly dynamic cytoskeletal structure, that we named 'actin grip'. These F-actin bundles are finely regulated by the intracellular levels of reactive oxygen species. Therefore, they could be instrumental for controlled attachment to and detachment of the cells from the fibers, independent of their adhesiveness. To quantify the number and geometry of these 'grips', their co-localization with signaling molecules, and their impact on cell density and shape within the scaffolds, we are developing an automatic analysis program of three dimensional confocal microcopy images. I will discuss the methods and the main results obtained in this project so far.
Computational modeling of cartilage regeneration
Articular cartilage is a connective tissue lining bony surfaces in diarthrodial joints (knees, hips, and shoulders). When degradation exceeds the synthesis of extracellular matrix constituents, cartilage will start eroding and fragmenting, eventually leading to defects. Since cartilage has a limited capacity for growth and repair, defects due to osteoarthritis and injury may rapidly progress to complete tissue degradation, necessitating a joint replacement. Prior to complete tissue degradation, defects could be filled with cell-seeded biocompatible porous scaffolds, with the hopes of repairing and regenerating new tissue. In order to achieve biological and mechanical functionality of these constructs, many factors need to be considered. This talk will highlight key aspects such as nutrient transport, cell proliferation and migration, matrix synthesis, and mechanical interactions in the context of cartilage regeneration. Previous computational work will be described that ranges from the use of neural networks, reaction diffusion models, level set methods, and continuum modeling frameworks to investigate and understand aspects of cartilage tissue engineering.
Cell-Matrix interactions in TE heart valve
Cell-Matrix interactions in TE heart valve
Multiscale Computational Simulations of Fiber Remodeling and Cell Compaction in Collagen Gels
Multiscale mechanical interactions are scale spanning physical interactions between the tissue and the extracellular matrix (ECM). They are involved in a variety of biological phenomena, including tissue growth, remodeling, disease, and damage. These interactions are important to characterize because they control both the mechanical behavior of the tissue and the manner in which mechanical signals are propagated to the cellular level. In this talk I will discuss recent work where we incorporate (1) fiber-level rules that govern enzymatic degradation and growth and (2) contractile elements that simulate cell compaction and a redistribution of forces within the surrounding fiber networks into our multiscale modeling framework. Understanding the role of these processes is crucial to comprehending and controlling the integrated response of the mechanical environment in a number of biological contexts.
Interplay between active and passive mechanical forces in microvascular network formation
Understanding how matrix properties influence cell behavior has implications for our understanding of many processes and applications, including fundamentals of cell and developmental biology, wound healing, tumor formation, and design of biomaterials for tissue engineering. While it is widely appreciated that the mechanical properties of the matrix, as well as cell force generation, are important aspects of the differentiated functions of numerous cell types, the interplay between these passive and active mechanical forces is less well understood. We have used an in vitro model of microvascular network (MVN) formation to investigate the dynamic and reciprocal relationship between cells and biomaterial supports. Macroscopic matrix remodeling due to endothelial cell force generation, as indicated by biomaterial gel compaction, is a key feature of MVN formation. To understand this phenomenon at the cellular length scale, we have employed confocal microscopy to image endothelial cells and their surrounding collagen matrix during various stages of MVN formation. Gathering of matrix around cells precedes cell elongation and MVN formation and decreases as a function of increasing cell-cell distance and collagen stiffness. Additionally, the patterns of matrix gathering are consistent with the hypothesis that nearby cells form lines of matrix tension or alignment that they elongate along in order to form multi-cellular structures. This work fits into the larger picture of increasing our understanding of the role of cell-derived forces and matrix remodeling in differentiated cell functions with implications for mechanobiology and design of new tissue engineering scaffolds.
Measurement, Modeling, and Rational Modulation of Inflammation and Wound Healing
Properly-regulated inflammation is central to homeostasis, but in adequate or overly-robust inflammation can lead to disease. Like many biological processes, inflammation and its various manifestations in disease are multi-dimensional. The advent of multiplexed platforms for gathering biological data, while providing an unprecedented level of detailed information about the dynamics of complex biological systems such as the inflammatory response, has paradoxically also flooded investigators with data they are often unable to use. Systems approaches, including data-driven and mechanistic computational modeling, have been used to decipher aspects of the inflammatory responses that characterize trauma/hemorrhage and sepsis. Through combined data-driven and mechanistic modeling based on LuminexTM datasets, computational models of acute inflammation in mice, rats, swine, and humans were generated. These studies suggest that acute inflammation goes awry when the positive feedback loop of inflammation -> tissue damage/dysfunction -> inflammation, driven by damage-associated molecular pattern molecules, fails to resolve under the influence of anti-inflammatory/pro-healing mediators. This positive feedback loop also underlies agent-based computational models of inflammation and tissue injury in skin and liver, leading to tissue-realistic simulations and tissue-specific outcomes including chronic non-healing wounds and liver fibrosis, cirrhosis, and hepatocellular carcinoma, respectively. These systems-based insights have led to novel, rationally-designed therapies based on a biohybrid framework.
Modeling fusion of multicellular aggregates and endotheliation with applications to biofabrication
Modeling fusion of multicellular aggregates and endotheliation with applications to biofabrication.
Matrix stiffness and cell behavior
Not Available.
Continuum approximations of cell-based models for bacterial chemotaxis
Chemotaxis is the active movement of cells or organisms in response to external chemical signals. The chemotactic movement of bacteria populations can lead to intricate spatial and temporal patterns. Traditionally, these patterns have been modeled using continuum approaches, which describe the evolution of the cell density by partial differential equations (PDEs). However, these models are phenomenological and their connection with mechanistic cellular processes such as signal transduction and cell movement is not well understood. In the first part of this talk, I will present cell-based models of bacterial chemotaxis, which integrate great details of fundamental cellular mechanisms, and address several bacterial patterns. For problems that involve large numbers of cells, cell-based models are computationally intensive and time-consuming. In the second part of this talk, I will show connections between the continuum/phenomenological models and cell-based/mechanistic models derived by asymptotic methods.
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Directed Differentiation of Stem Cells using Lasers
Praveen Arany With the renewed excitement in the inducible stem cell field, regenerative medicine is poised at our ability to efficiently direct differentiation of stem cells into functional tissues and organ systems. Besides the vast amount of work currently addr

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Alterations in Extracellular Matrix Properties Effect Cardiac Differentiation and Cardiomyocyte Proliferation
Lauren Black While the impact of single extracellular matrix (ECM) proteins and mechanical stiffness on cell function have been thoroughly probed individually, little work has been put into to understanding their interactions in the context of cell function. This

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Simulating the mechanical response of fibrous scaffolds for tissue engineering
Peter Anderson The use of scaffolds for tissue engineering involves aspects of mechanotransduction that are controlled by scaffold properties and structure at the local, cellular scale. For fibrous, electrospun scaffolds, such features include the local fiber stres

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Multiscale Computational Simulations of Fiber Remodeling and Cell Compaction in Collagen Gels
Edward Sander Multiscale mechanical interactions are scale spanning physical interactions between the tissue and the extracellular matrix (ECM). They are involved in a variety of biological phenomena, including tissue growth, remodeling, disease, and damage. These

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Multiscale Models of Collagenous Materials
Victor Barocas Multiscale Models of Collagenous Materials.

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Overview of Wound Healing
Robert Diegelman The normal healing response begins the moment the tissue is injured. As the blood components spill into the site of injury, the platelets come into contact with exposed collagen and other elements of the extracellular matrix. This contact triggers th