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ONGOING PROJECTS

• RECODE: Organoid model of growth plate development​
  • Source of funding: National Science Foundation
  • Project in Collaboration with Profs. Stephanie Bryant, Karin Payne, Robert McLeod & Mike Zuscik, ¶¶ÒõÂÃÐÐÉä-Boulder and ¶¶ÒõÂÃÐÐÉä Anschutz
  •  Abstract: The growth plate is a cartilage tissue located at the end of children’s long bones that is responsible for bone growth. It begins as a cluster of stem cells that become specialized and organize themselves into columns to form a functioning growth plate. This process is driven by both chemical cues and mechanical forces, although it is unclear how they work together to form the structure and function of the growth plate. This Reproducible Cells and Organoids via Directed-Differentiation Encoding (RECODE) project will develop a reproducible growth plate organoid that will allow one to study how stem cells form a mature growth plate, which can lead to novel approaches for bone and cartilage regeneration particularly in children. This project will train a diverse group of graduate, undergraduate, and high school students in mathematical modeling, biomaterial development, and stem cell and developmental biology and will provide opportunities to the broader community through outreach activities and events open to the public. The overarching goal for this RECODE project is to gain fundamental insight into the link between biophysical cues, cellular differentiation, and cellular organization that leads to the development of a functioning growth plate. This project combines experimental and computational approaches to gain insight into the local cues that govern directional cell division (Task 1), chondrogenic differentiation followed by columnar organization (Task 2), and hypertrophic differentiation, the characteristic phenotype of the growth plate (Task 3). This project will uncover how biophysical cues combined with spatially localized biochemical cues dovetail to drive the self-assembly of stem cells into a growth plate organ with the appropriate structure and function. By utilizing novel tools in biology, advanced biomaterials in 3D printing, and physics-based mathematical modeling, this project will create the first growth plate organoid to date. This organoid will provide a model system for deeper study of stem cell and chondrocyte differentiation, in normal and abnormal bone growth. Understanding the mechanisms that direct the differentiation of MSCs into a mature growth plate organoid will help guide the design of novel biomaterials for regenerative medicine approaches to treat growth plate injury, an area that currently lacks a viable and clinically accepted treatments.

• Theoretical study of cavitation and fracture in polymer networks
  • Source of funding: 3M Corporation
  • Abstract: Not disclosed.

• The Role of Percolation in the Hydrogel-to-Tissue Transition for Cartilage Growth.
  • Source of funding: National Science Foundation, CBET Engineering of Biomedical Systems program.
  • Project in Collaboration with Prof. Stephanie Bryant, Chemical and Biological Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Abstract: The encapsulation of living cells in a three-dimensional hydrogel offers tremendous potential for tissue engineering by providing instructive cues to cells and a structural support for new tissue formation. A critical barrier to success is the need to couple the degrading/breaking down of the hydrogel to the synthesis of new tissue in order to maintain mechanical integrity during the transition from hydrogel to tissue. This project combines computational modeling and experimental studies to identify the underlying fundamental principles that govern tissue growth in a hydrogel. The outcomes from the project will enable hydrogel designs for a wide range of cell populations including those that have poor tissue synthesis capabilities (e.g., older adults), thus enabling a more personalized approach to tissue engineering. Planned activities include active learning modules for K-12 and undergraduate students, the involvement of these students in research, and unique training opportunities to graduate students at the interface of materials, tissue engineering, and mathematical modeling. The research goal of this project is to gain fundamental insight into the mechanisms that govern tissue growth in hydrogels. A functional requirement in the process of tissue growth is a seamless transition from hydrogel to tissue that retains mechanical integrity of the three-dimensional (3D) construct. One way to maintain connectivity during the transition is through the co-existence of an interpenetrating network made of hydrogel and tissue, a concept described by the theory of mechanical percolation. To this end, this project introduces mechanical percolation into a physically-driven multiscale mathematical model to capture the mechanisms responsible for hydrogel degradation and neotissue growth. Applying an integrated experimental and computational approach, the overall research objectives for this project are to (a) demonstrate rational control over the gel-to-tissue transition at the cellular level, (b) build mesoscale heterogeneities to control the mechanical transition from gel-to-tissue, and (c) apply a model-assisted approach to designing hydrogels that achieve a seamless gel-to-tissue transition across different types of donors whose tissue synthesis capabilities vary. The knowledge gained from this research will fill a critical gap in our current understanding of tissue growth in hydrogels and will aid in the successful translation of hydrogels for use in tissue engineering.

• Mechanics of Active Slide-Ring Networks: from Molecular Motors to Molecular Machine
  • Source of funding: National Science Foundation, Mechanics of Materials program.
  • Project in Collaboration with Prof. Carson Bruns, Mechanical Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Abstract: This project focuses on understanding how the molecular structure of novel polymers affects their ability to contract - similar to how natural muscles contract and lengthen to generate motion and force. Most soft biological materials rely on the efficient transfer of mechanical work from nanoscopic molecular motors to the macroscale. This is ensured by a sophisticated and architected internal network. That network consists of molecular machines that cooperatively pull on polymer ropes. This action is a microscopic tug-of-war that drives contraction. This project will focus on the replication of such mechanisms by combining artificial molecular machines (rotaxanes). For this, the project will develop a multiscale model, complemented by experiments, that can bridge active molecular mechanisms and the macroscopic response. Outcomes of this research will enable the creation of active materials/machines with a myriad of biomechanical applications. It will also promote collaborations and inspire a new generation of researchers at the edge of mechanics and materials science. Planned activities include active learning modules for high-school and undergraduate students, the involvement of these students in research, and the dissemination of research findings in social media. The specific goal of the research is to understand the relationship between molecular mechanisms in slide-ring gels, the energy input in molecular motors, and the emergent contraction of the macroscopic gel. For this, the research project will integrate theoretical/computational mechanics, chemical synthesis, and mechanical characterization in a feed-back loop, where model and experiments will learn from one-another. The model, based on statistical mechanics, will provide a clear connection between molecular processes (ring sliding, ring collapse) and the macroscopic rheology, elasticity, and contraction. In turn, experiments will be guided by the model so that a rational design can be achieved. The objectives of the project are specifically to (a) develop a model for isotropic topological gels to connect molecular architecture and mechanical response, (b) use this model to explore the mechanics of anisotropic slide-ring/cellulose networks, and (c) investigate and identify conditions that amplify the force transfer across scales during contraction. Through these aims, the project will advance the inner workings of slide ring networks to be used as molecular machines and enable the rational development of a biomimetic material capable of contracting as does natural muscle.

• Biophysical Cues Governing Growth Plate Organization: A Computational and Experimental Approach
  • Source of funding: ​¶¶ÒõÂÃÐÐÉä-Boulder AB-Nexus grant
  • Project in Collaboration with Stephanie Bryant, Karin Payne, Robert McLeod & Mike Zuscik
  • Abstract: This project will develop the first growth plate organoid with the ability to recapitulate the columnar organization of cells, a key structural determinant that is required for normal growth in children. This organoid will allow for deeper study of bone growth and genetic diseases affecting growth plate development, and will have regenerative medicine relevance in children with growth plate injuries and growth disorders.

• Center for Micromorphic Multiphysics Porous and Particulate Materials Simulations with Exascale Computing Workflows
  • ​Source of funding: ​Department of Energy and National Nuclear Security Administration
  •  Collaborative project involving multiple universities (lead: ¶¶ÒõÂÃÐÐÉä-Boulder, Stanford UNiversity, Columbia University) and 16 research teams.
  • Abstract: The overall objective of the Center is to simulate with quantified uncertainty, from pore-particle-to-continuum-scales, a class of problems involving granular flows, large deformations, and fracture/fragmentation of unbonded and bonded particulate materials. The overarching problem is the processing and thermo-mechanical behavior of compressed virgin and recycled mock High Explosive (HE) material subjected to quasi-static and high-strain-rate confined and unconfined compression, in-situ quasi-static X-ray computed tomography (CT), and dynamic (impact) experiments with ultrafast and high-speed X-ray imaging at the Advanced Photon Source (APS), Argonne National Laboratory (ANL). To accomplish the objective, a micromorphic multiphysics multiscale computational framework will be developed, verified, and validated with quantified uncertainty, and executed on Exascale computing platforms seamlessly through a scientific software workflow to reduce FTE effort on handling data from beginning to end of simulation. Machine Learning (ML) algorithms will be applied to fill the gaps in multiscale constitutive modeling via coordinated pore-particle-scale experiments and Direct Numerical Simulations (DNS). An extensive, integrated, experimental program at quasi-static, dynamic, and high-strain rates (some within the ultrafast high-speed X-ray imaging facility at the APS and also pRad at Los Alamos National Laboratory, LANL), ranging from pore-particle-to-specimen-scales, will be conducted to validate heterogeneous pore-particle-to-continuum-scale computational models, calibrate model parameters, and validate the overall computational framework. Exascale computing is needed to simulate these more sophisticated micromorphic multiphysics bridged-DNS simulations, with offline ML training of micromorphic constitutive relations to DNS. Furthermore, for Validation and Uncertainty Quantification (UQ) requiring multiple instances of these simulations over statistical distributions of inputs (such as particle size distribution), with high and low fidelity, Exascale computing is a necessity.

• Transient Network Theory: Bridging Molecular Mechanisms to the Viscoelasticity of Soft Polymers
  • ​​Source of funding: National Science Foundation, Mechanics of Materials program
  • Abstract: The ability to organize large populations of molecules into materials can open the door to making dynamic materials or soft machines, thus advancing the national health, prosperity, and welfare; and even securing the national defense by facilitating the emerging area of soft robotics. Such materials are often found in nature in the form of transient polymeric networks which are at the source of muscle contraction as well as self-healing and adaptation in biological tissues. Although similar molecular networks can be synthesized in the laboratory, their performance still lags far behind their biological counterparts; raising the need for a better theoretical understanding and experimental control. This project will provide a route to fundamentally understand how the organization and dynamics of such polymer networks can lead to a well-targeted emerging response. It will promote the progress of soft matter science by bridging the gap between our understanding of the behavior of a single molecule and that of an entire network, not only enabling a fundamental understanding of bio-polymers, but also in improving our ability to control synthetic materials. The project will also develop an educational program around the concept of "materials of the future and bio-inspiration" in high-schools, the enhancement of undergraduate curriculum, and dissemination of scientific knowledge through social media. From a fundamental viewpoint, this project will support the development of a transient network theory that will describe, in a statistical sense, the time evolution of a transient polymer network based on molecular processes such as chain detachment, reputation, or diffusion. Going beyond phenomenological viscoelastic models, key concepts in statistical mechanics will be used to obtain a clearer connection between transient molecular interactions between many polymer chains and the time-dependent response of the network. The project brings three key contributions: (a) a new fundamental understanding of the relation between molecular processes and rheology, elasticity and energy dissipation; (b) the ability to generate new hypotheses regarding dynamic polymers and explore their macroscopic outcome in terms of growth, fracture resistance, and self-healing, and (c) a new continuum framework to describe the extreme deformation of soft materials whose behavior lies between that of solids and fluids. A computational methodology based on finite elements will be introduced to solve the research theory and used to study and characterize the viscoelastic response of synthetic and biopolymers in terms of their inner structure.

• Tenocyte Mechanobiology in a Fiber Composite Mimetic
  • ​​Source of funding: National Science Foundation, Biomechanics and Mechanobiology program
  • Project in Collaboration with Stephanie Bryant, Chemical and Biological Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Abstract: Tendons are an important tissue for musculoskeletal function -- they connect muscles to bones. They are also a very slow healing tissue, due in part to the limited blood supply and small concentration of cells within the highly fibrous structure. If tendon cells, tenocytes, are going to be stimulated to enhance tendon growth and regeneration, it is vitally important that the understanding of how these cells respond to their mechanical environment is substantially increased. This project will use a combination of computer modeling and experimental studies to investigate how tenocytes respond to complex loading normally seen in a tendon. The work will focus on the micro-level -- in order to understand how variations in the mechanical environment just around the cell relate to the cellular response. In addition to advancing knowledge that will support future work in tissue engineering of tendons and other fibrous connective tissue, this project includes several educational and outreach activities. First, the research team will integrate students from high school through graduate school in order to help them understand the importance of research in this area and of integrating experimental and computational techniques. Next, there will be an opportunity for graduate students to travel to an international collaborator's laboratory to enhance their scientific preparation. Finally, hands-on workshops will be developed to provide participants with a broader understanding of connective tissue biomechanics. The overall objectives for this project are to: (1) determine the micromechanics and the type and magnitude of the local cellular strains as a function of fiber composite properties under physiologically relevant tensile strains; (2) determine tenocyte anabolic and catabolic metabolism as a function of the type and magnitude of the local cellular strains and the typed of integrin-ligand interaction; and (3) elucidate intracellular signaling pathways based on MAP kinase signaling that are involved in integratin-mediated mechanotransduction within tenocytes. This will be done through the development of a computational model of tenocytes within a fiber-reinforced structure and the validation of this model with experimental studies using a novel hydrogel-fiber composite mimetic that captures aspects of the tendon's fiber composite mechanics.

COMPLETED PROJECTS

• Membrane pore connectivity, tortuosity, and soft particle
  • ​​Source of funding: Membrane Science, Engineering and Technology center,
  • Collaboration: Dr. John Pellegrino, Mechanical Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Project dates: 01/01/2020 — 12/31/2020

• Eulerian Approach to Model Extreme Deformations in Visco-elastic Adhesives
  • ​​Source of funding: 3M Corporation
  • Collaboration: N/A
  • Project dates: 03/01/18 — 02/28/20

• Ultrathin Deformable Materials and Protective Coatings Bio-inspired by Scaled Skins
  • ​​Source of funding: National Science Foundation, Div. Materials Research, Biomaterials Program
  • Collaboration: Dr. Mark Stoykovitch, Chemical and Biological Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Project dates: 07/15/14 — 07/14/17

• CAREER, In-Silico Tissue Engineering: An Active- Learning Computational Methodology to Guide the Design of Tissue Scaffolds
  • ​​Source of funding: National Science Foundation
  • Collaboration: N/A
  • Project dates: 02/01/14 — 12/31/19

• Personalizing Matrix Assisted Autologous Chondrocyte Implantation
  • ​​Source of funding: National Institute of Health, R01 AR065441-01
  • Collaboration: Prof. Stephanie Bryant, Chemical and Biological Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Project dates: 09/12/13 – 08/31/18

• Interaction between soft particles and membranes
  • ​​Source of funding: Membrane Science, Engineering and Technology center
  • Collaboration: Dr. John Pellegino, Mechanical Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Project dates: 01/01/14 — 05/31/18

• Engineering Bimodal Degrading Hydrogels
  • ​​Source of funding: National Institute of Health
  • Collaboration: Prof. Stephanie Bryant, Chemical and Biological Engineering, ¶¶ÒõÂÃÐÐÉä-Boulder
  • Project dates: 04/01/11 – 03/31/13

• An innovative look at fibroblast evolution through multi-physics modeling
  • ​​Source of funding: CRCW Seed Grant, University of Colorado
  • Collaboration: N/A
  • Project dates: 09/01/10 – 08/31/12