Tissue Fracture in Development and Disease

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Sustaining and generating mechanical forces is a normal part of physiology for mammalian tissue: Intestinal epithelia are stretched during peristaltic movements in the gut, lung alveoli deform during breathing and skin epidermal layers provide a mechanical barrier to the external environment. Mechanical integrity and force transmission in even the simplest tissues is critical to their proper function. This is particularly apparent in diseased states where point mutations to cytoskeletal or intercellular adhesion proteins result in mechanical failures such as blistering, cracking and hemorrhaging. Despite the fundamental significance, we do not have a fundamental understanding of the modes through which simple tissues mechanically fail, or a molecular understanding of how different components combine to create durable tissues. This is primarily due to the lack of appropriate experimental tools and the inherent complexity of in vivo tissues. This research program will combine experimental tools from mechanical engineering and molecular biology to understand how simple epithelial tissues fracture under high mechanical loads and the key molecular determinants of tissue durability. I have developed a novel system to characterize the mechanical properties of simple epithelial tissues. This system will be further developed for the simultaneous measurement of tissue-level mechanical forces and imaging of monolayer fracture. Fractures can occur on the sub-millisecond timescale, which is too rapid for conventional microscopy. A high-speed camera will be used to capture the mode of failure at a rate of hundreds of frames per second and a rapid DAQ system to record the changes in tissue forces. This will allow for the characterization of the crack front as it propagates through the tissue under controlled mechanical forces. A novel mechanical description of tissue fracture will be developed that will be compared across different molecular conditions. The contribution of different cytoskeletal networks to monolayer durability will be investigated by taking a `top down' approach. The propagation of cracks (speed, force, shape) will be measured in tissues where different cytoskeletal components have been perturbed using a combination of genetic and pharmacological inhibition. This data will provide new insights into how these cytoskeletal networks synergistically generate durable tissues capable of sustaining mechanical loads. Working across disciplines will allow for a fundamental understanding of how tissues mechanically fail and fracture from both a mechanical and molecular perspective. Given the general significance of tissue mechanical integrity for normal physiology in both adult tissue and development and the interesting fundamental material properties of epithelial tissue, the outcomes will be of interest to engineers, clinicians and developmental biologists alike.