Revealing cell mechanics with light-sheet microscopy

University of St Andrews
Physics and Astronomy

The importance of mechanics in biology has been known since the first observations of cells through the microscope. Highly dynamic processes, like cell migration, ciliary movement, and blood flow, are
ever-present, and can be as important as chemical and genetic factors in determining health and disease development. For example, mechanics can solely direct cells to become cancerous, and mechanics must be precisely controlled to enable lab-grown tissues. Despite this, it is only in the past 20 years that this critical role of mechanics has emerged, owing to recent advances in imaging and measurement technologies. These methods have observed single cells, often intrusively. Little to no capacity exists to quantify cell mechanics in living tissues in their three-dimensional microenvironment.

A dominant imaging technique in this area, optical coherence tomography, has demonstrated exceptional capacity to measure mechanics of tissue in 3D to understand and diagnose cancers, eye disease and cardiovascular disease. However, it is unable to breach the resolution needed to see individual cells. Very little has been done towards imaging 3D cell mechanics using light microscopy, arguably the most historically important tool at the disposal of cell biologists. This project proposes to develop a novel instrument that can quantify cell mechanics using light-sheet microscopy, a variant of microscopy that provides exceptional resolution over large volumes with little damage to the tissue. It will do so by observing the deformation of tissues in response to controlled manipulation by compressive or acoustic forces. This knowledge will be used to compute solutions to the inverse problem of mechanics using numerical and deep-learning means, enabling powerful quantification of elasticity and forces in cells and their local microenvironments.

Such unprecedented capacity will open a new window into the biological processes integral to healthy
development and regeneration, and will help elucidate mechanical pathways for many diseases. Specifically, this project will focus on demonstrating new capacity for understanding embryological disorders and neurodegenerative diseases. The proposed embodiment of the instrument has, further, the potential to be low-cost and accessible to biomedicine. Such a new grasp on cells’ mechanical processes promises improved targeted therapies, lab-grown tissues, and early disease detection.