Single-cell mechanobiology: microengineered tools to study cell-matrix remodelling

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Cells play an active role in restructuring their surrounding environment, and these remodeling processes are critical factors in wound healing and disease progression. Abnormal remodeling activity of the biomolecular matrix is associated with 45% of all mortalities, but little is known about the interaction between individual cells in driving a tissue-wide remodeling process. For example, cells within a collagen matrix will rapidly contract the surrounding tissue, stiffening the material. Cells actively respond to mechanical signals such as applied forces and matrix stiffness to initiate remodeling activity. However, collagen is a mechanically complex material, displaying strain-stiffening behaviour, and mediating cellular response to applied forces. Understanding and characterizing how multiple cells interact in this feedback loop will provide new insight into remodeling-related diseases. More immediately, this knowledge may be used to develop new classes of stimuli-responsive cell-based materials, for advanced tissue engineering applications. To study the interaction between mechanics, cells, and the surrounding matrix in three-dimensional environments at the level of individual cells, this research proposes to develop novel microengineered strategies for single-cell studies of mechanobiology. A team of 2 doctoral and 2 masters candidates, assisted by 5 undergraduate summer students will develop these approaches, to (i) fabricate three-dimensional tissues with single-cell positioning resolution; and (ii) enable the measurement of local forces and local matrix stiffness within the deforming matrices. Though broadly applicable to several problems, we will then leverage these technologies to develop single-cell resolution models of contracting tissues, which can be used to engineer smart materials capable of undergoing programmed shape changes as a result of contractile activity. These `transformer tissues' provide a platform to simultaneously assess our understanding of contractile mechanics, while developing strategies for tissue engineering and manufacturing challenges. This research program develops tools for studies of single-cell mechanobiology, and is hence of critical importance to the study of mechanically-oriented diseases, such as those associated with aging, in which a single cell can have long-range repercussions. These engineering technologies may ultimately enable novel therapeutic strategies for these conditions, and is hence of considerable importance to Canada, given current healthcare costs and our aging population. More immediately, this research provides an exciting program for trainees to gain broad interdisciplinary expertise in various techniques that are relevant in both research and industrial areas, enabling contributions to Canadian society through biotechnology or bioengineering career paths.