We propose to continue our multiscale mechanical analysis of bioengineered tissues. In the previous grant period, we used a two-scale model, with the microscopic scale representing collagen fibers via a discrete network and the macroscopic scale representing tissue as a whole via continuous finite elements;the two scales are fully coupled, and we have applied the model to a variety of systems. Major advances include (1) An image-based model generation scheme, (2) Biphasic analysis, including both network-fluid and network-solid systems, (3) Dynamic modification of individual fibers to represent enzymatic degradation or damage, and (4) Experimental studies of pure gels (collagen) and co-gels (collagen-agarose and collagen-fibrin). The current model has been extremely successful, but there is still more work to be done before a proper materials science of engineered tissues can be said to exist. In this renewal, we propose three major advances that will create the next generation theoretical description of a bioengineered tissue: (1) We will add cell mechanics to the model via a third scale. The three scales will represent the tissue, the cell-matrix composite with discrete cells, and the fiber matrix. This model will be a significant advance over existing models of cell-gel composites in that it will provide a mechanism to capture the internal mechanics of the matrix and to explore a wide range of cytomechanical models. (2) We will extend our initial model of fiber failure into a model that can capture progressive damage to the fibers and damage to the interfibrillar material, the latter potentially important because of the high strength of collagen relative to many other ECM components. (3) We will supplement our existing model with viscoelastic terms due to the fiber network, the interfibrillar material, and he cells, as well as add an extra water phase to the model to account for the effect of interstitial flow through the interfibrillar materials (extending our earlier biphasic models). The first advanc will address tissue complexity but remains prefailure and quasistatic. The second will allow the study of failing or damaged systems, and the third will capture dynamic tissue behavior. All three proposed theoretical advances will be combined with experiments to specify and test the models. Tissue engineering, the creation of replacements for damaged or diseased tissues, is an important area, especially for mechanical tissues such as artery, heart valve, and skin. A major impediment to advances in tissue engineering, especially to the creation and use of wholly bioengineered tissues, is our inability to design tissues as we design other engineered products. This project relates directly to public health because it will provide tools to help creae the next generation of replacement tissues.

Public Health Relevance

We continue to develop models that allow us to predict the mechanical behavior of bioengineered replacement tissues based on their structure and composition. The work will enable design of the next generation of engineered tissues by helping to determine what components, in what arrangement, are needed to achieve tissue properties similar to the native tissue. This project relates directly to public health, particulary to cardiovascular health, because of the need for mechanically functioning replacements for arteries and heart valves.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Peng, Grace
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University of Minnesota Twin Cities
Biomedical Engineering
Schools of Engineering
United States
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Dhume, Rohit Y; Shih, Elizabeth D; Barocas, Victor H (2018) Multiscale model of fatigue of collagen gels. Biomech Model Mechanobiol :
Korenczuk, Christopher E; Votava, Lauren E; Dhume, Rohit Y et al. (2017) Isotropic Failure Criteria Are Not Appropriate for Anisotropic Fibrous Biological Tissues. J Biomech Eng 139:
Witzenburg, Colleen M; Dhume, Rohit Y; Shah, Sachin B et al. (2017) Failure of the Porcine Ascending Aorta: Multidirectional Experiments and a Unifying Microstructural Model. J Biomech Eng 139:
Lai, Victor K; Nedrelow, David S; Lake, Spencer P et al. (2016) Swelling of Collagen-Hyaluronic Acid Co-Gels: An In Vitro Residual Stress Model. Ann Biomed Eng 44:2984-2993
Ban, Ehsan; Barocas, Victor H; Shephard, Mark S et al. (2016) Softening in Random Networks of Non-Identical Beams. J Mech Phys Solids 87:38-50
Witzenburg, Colleen M; Barocas, Victor H (2016) A nonlinear anisotropic inverse method for computational dissection of inhomogeneous planar tissues. Comput Methods Biomech Biomed Engin 19:1630-46
Witzenburg, Colleen M; Dhume, Rohit Y; Lake, Spencer P et al. (2016) Automatic Segmentation of Mechanically Inhomogeneous Tissues Based on Deformation Gradient Jump. IEEE Trans Med Imaging 35:29-41
Ban, Ehsan; Barocas, Victor H; Shephard, Mark S et al. (2016) Effect of Fiber Crimp on the Elasticity of Random Fiber Networks With and Without Embedding Matrices. J Appl Mech 83:0410081-410087
Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A et al. (2016) Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention. Ann Biomed Eng 44:2642-60
Gyoneva, Lazarina; Hovell, Carley B; Pewowaruk, Ryan J et al. (2016) Cell-matrix interaction during strain-dependent remodelling of simulated collagen networks. Interface Focus 6:20150069

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