Multiscale modeling of epithelial tissue dynamics and engineering

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The prospect of growing artificial tissues and organs in the lab is generating much excitement, with the recent reports of human retina and brain tissues grown from embryonic stem cells. However, great scientific and technical barriers remain to be surmounted before widespread clinical use becomes reality. The potential benefits for health care, where artificial tissues can be implanted to restore, repair, and improve the function of failing natural organs, are as enormous as the challenges are daunting. **Progress will hinge on new research in two areas: developmental biology and biomaterials engineering. The research proposed here seeks a nonconventional approach that integrates molecular-genetic information from developmental biology with engineering knowledge of the mechanics of epithelial tissues. This integration is motivated by the fact that biological tissues grow not only according to a genetic blueprint, but also subject to the mechanical forces and deformation in their physical environment. Mechanically, soft tissues often behave in ways that resemble complex fluids and soft solids. The central idea of this proposal is to translate computational methods developed for complex fluids and soft matter to a novel class of problems in the dynamics and growth of epithelial issues. **Epithelium refers to the skin that encloses organs and embryos. It is also the key structure that folds during early development of embryos to form internal organs. Toward a quantitative understanding of such processes, we develop a mathematical model that bridges the cellular scale and the much larger tissue scale. A crucial feature of the model is to properly capture the information exchange between the two scales. For example, sustained stress on a skin tissue tends to trigger structural changes in polymers that form the skeleton of each cell, and to dissolve the adhesive connection among neighboring cells. Thus the whole tissue can deform or "flow". In return, small-scale biochemistry inside a cell produces signaling proteins that control cell division and death, and these events ultimately feed back to the overall behavior of the tissue on the large scale. We further carry out computer simulations of various scenarios of tissue growth, adapting an extensive numerical toolkit that we have developed for the dynamics of complex fluids, interfaces and soft membranes. **In scientific terms, we expect two major outcomes from this research. The first is to lay the foundation for a quantitative understanding of epithelium dynamics. In particular, we wish to clarify how mechanical forcing and deformation change the properties of a tissue and affect its ability to grow under laboratory conditions. The second is to develop the ability to solve "inverse problems" in tissue engineering. That is the ability to prescribe optimal experimental conditions and protocols that will produce the desired morphology for a tissue or organ. Such outcomes will be major advances toward the goal of custom-designed artificial organs, with far-reaching health-care benefits for Canada and beyond. **A less tangible but equally important benefit of the research will be the specialized training of young scientists in this emerging field. They will be exposed to cutting edge, interdisciplinary research that uses physics and engineering tools to study biology and to inform medicine. This will prepare them for the expanding frontiers of Research and Development in the decades to come.