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Understanding cell mechanotransduction is important for discerning matrix structure-cell function relationships underlying health and disease. Despite the crucial role of mechanochemical signaling in phenomena such as cell migration, proliferation, and differentiation, measuring the cell-generated forces at the interface with the extracellular matrix during these biological processes remains challenging. An ideal method would provide continuous, non-destructive images of the force field applied by cells, over broad spatial and temporal scales, while simultaneously revealing the cell biological process under investigation. Toward this goal, we present the integration of a new real-time traction stress imaging modality, Hilbert phase dynamometry (HPD), with the technique of spatial light interference microscopy (SLIM) for label free monitoring of cell growth. HPD relies on extracting the displacement field in a deformable substrate, which is chemically patterned with a fluorescent grid. The displacements introduced by the cell are captured by thephaseof the periodic signal associated with the grid, borrowing concepts from holography. The displacement field is uniquely converted into forces by solving an elasticity inverse problem. Because the measurement of displacement only uses the epi-fluorescence channel of an inverted microscope, we can simultaneously achieve measurements in transmission. We performed SLIM and extracted cell mass on the same field of view in addition to the measured displacement field. We used this technique to study mesenchymal stem cells and found that cells undergoing osteogenesis and adipogenesis exerted larger and more dynamic stresses than their precursor. Our results indicate that the MSCs develop the smallest forces and growth rates. We anticipate that simultaneous cell growth and traction measurements will improve our understanding of mechanotransduction, particularly during dynamic processes where the matrix properties provide context to guide cells towards a physiological or pathological outcome, e.g., tissue morphogenesis, or cancer metastasis.

Optical microscopy is an indispensable diagnostic tool in modern healthcare. As a prime example, pathologists rely exclusively on light microscopy to investigate tissue morphology in order to make a diagnosis. While advances in light microscopy and contrast markers allow pathologists to visualize cells and tissues in unprecedented detail, the interpretation of these images remains largely subjective, leading to inter- and intra-observer discrepancy. Furthermore, conventional microscopy images capture qualitative information which makes it difficult to automate the process, reducing the throughput achievable in the diagnostic workflow. Quantitative Phase Imaging (QPI) techniques have been advanced in recent years to address these two challenges. By quantifying physical parameters of cells and tissues, these systems remove subjectivity from the disease diagnosis process and allow for easier automation to increase throughput. In addition to providing quantitative information, QPI systems are also label-free and can be easily assimilated into the current diagnostic workflow in the clinic. In this paper we review the advances made in disease diagnosis by QPI techniques. We focus on the areas of hematological diagnosis and cancer pathology, which are the areas where most significant advances have been made to date. [Image adapted from Y. Park, M. Diez-Silva, G. Popescu, G. Lykotrafitis, W. Choi, M. S. Feld, and S. Suresh, Proc. Natl. Acad. Sci. 105, 13730-13735 (2008).].