Tissue Dynamics Spectroscopy for Three-Dimensional Tissue-Based Drug Screening

Abstract

Tissue dynamics spectroscopy combines dynamic light scattering with short-coherence digital holography to capture intracellular motion inside multicellular tumor spheroid tissue models. The cellular mechanical activity becomes an endogenous imaging contrast agent for motility contrast imaging. Fluctuation spectroscopy is performed on dynamic speckle from the proliferating shell and hypoxic core to generate drug–response spectrograms that are frequency versus time representations of the changes in spectral content induced by an applied compound or an environmental perturbation. A combination of 28 reference compounds and conditions applied to rat osteogenic UMR-106 spheroids generated spectrograms that were crosscorrelated in a similarity matrix used for unsupervised hierarchical clustering of similar compound responses. This work establishes the feasibility of tissue dynamics spectroscopy for three-dimensional tissue-based phenotypic profiling of drug response as a fully endogenous probe of the response of tissue to reference compounds.

Quantitative Phase Imaging for Label-Free Analysis of Cancer Cells—Focus on Digital Holographic Microscopy

“…Consequently, a successful analysis of individual cells will require some degree of automation. Cellular and tissue dynamics were measured nearly ten years ago by studying speckle fluctuations caused by cellular and sub-cellular motions [94,95], and several studies have since investigated the characterization and separation of blood cells [96,97]. Abnormalities of erythrocytes are important markers for disease.…”

Tissue dynamics spectroscopy for phenotypic profiling of drug effects in three-dimensional culture

“…The motility contrast is sensitive to applied drugs and can be used to construct dose-responses. Motility contrast imaging recently has been extended to tissue dynamics spectroscopy (TDS) [44] that is a coherence-gated form of diffusing wave spectroscopy [45,46]. Depth-sectioned dynamic speckle is captured at a high frame rate and analyzed across broad frequencies that correspond to a subcellular velocity range between 2 nm/sec and 2 μm/sec.…”

“…Depth-sectioned dynamic speckle is captured at a high frame rate and analyzed across broad frequencies that correspond to a subcellular velocity range between 2 nm/sec and 2 μm/sec. Spectrograms were cross-correlated previously to highlight similarities and differences among tissue responding to applied drugs [44]. In this paper, we demonstrate the use of tissue dynamics spectroscopy as a new phenotypic screening technology, based on spectrogram feature extraction and dimensionality reduction, and we study the phenotypic drug response of normoxic tissue relative to hypoxic tissue inside multi-cellular tumor spheroids.…”

Phenotypic Profiling of Raf Inhibitors and Mitochondrial Toxicity in 3D Tissue Using Biodynamic Imaging

“…18,19 These techniques have been applied to phenotypic profiling of a range of reference compounds through clustering and multidimensional analysis. 20,21 …”