Traction force optical coherence microscopy: a new method to study the dynamic mechanical behavior of cells and multicellular collectives within scattering media
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Mechanobiology is a prominent research field which seeks to elucidate the role of physical forces and mechanical interactions throughout various biological processes, including morphogenesis, wound healing, and cancer metastasis, among others. Traction force microscopy (TFM) is an important family of experimental techniques used by mechanobiologists to study and quantify the forces that cells exert upon their surroundings. Recent years have seen a growing demand for TFM methods capable of studying the dynamic, 3D, and collective behaviors of cells embedded within optically scattering media. However, traditional imaging modalities for TFM (e.g., confocal microscopy) do not currently allow researchers to satisfy these demands. In this dissertation, I present traction force optical coherence microscopy (TF-OCM), a TFM platform based on optical coherence tomography (OCT), to address the as yet unmet imaging needs of mechanobiology researchers and study the dynamic mechanical behavior of cells and multicellular collectives within scattering media. In the first half of this dissertation, I summarize current methods and emerging needs of the TFM field and provide detailed derivations and discussions regarding signal processing methods for OCT imaging. In the latter half, I present the key experimental findings of my research. A pilot study was first performed to demonstrate the ability of OCT imaging to capture substrate deformations induced by cellular traction forces (CTFs). This was followed by a proof-of-concept study which enabled the quantitative reconstruction of time-varying CTFs exerted by isolated cells, resulting in the realization of TF-OCM as a full-fledged experimental technique. The critical image reconstruction procedures developed along the way have since proven useful in the context of other OCT imaging applications as well. Finally, a collaborative application-focused study was performed, which demonstrated the ability of TF-OCM to study the dynamics of large multicellular collectives embedded within scattering collagen substrates. Although much work remains to be done in order to enable quantitative TF-OCM in such complex settings, these findings show that TF-OCM offers a promising avenue to pursue new and valuable research endeavors in mechanobiology.
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Pollock, Clifford