Measurement Science in the Circulatory System

Jones, Claude R.; Baker‐Groberg, Sandra M.; Cianchetti, Flor A.; Glynn, Jeremy J.; Healy, Laura D.; Lam, Wai Yan; Nelson, Jonathan W.; Parrish, Diana C.; Phillips, Kevin G.; Scott-Drechsel, Devon E.; Tagge, Ian J.; Zelaya, Jaime E.; Hinds, Monica T.; McCarty, Owen J. T.

doi:10.1007/s12195-013-0317-4

Cited by 24 publications

(27 citation statements)

References 103 publications

(102 reference statements)

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“…Cellular specimens appear semitransparent when imaged under standard bright-field microscopy (14,27). This low endogenous contrast is a result of the amplitude of the waves travelling through the cell remaining relatively unchanged owing to weak scattering and absorption over the visible wavelength range.…”

Section: Noninterferometric Quantitative Phase Microscopy (Niqpm): Trmentioning

confidence: 99%

“…Interestingly, the thickness and spatially variable density of the cell give rise to appreciable phase lag of the transmitted waves through the specimen. This fact has inspired the utilization of phase as a contrast mechanism in cellular imaging in modalities such as phase-contrast microscopy and differential interference contrast (DIC) microscopy (14).…”

Section: Noninterferometric Quantitative Phase Microscopy (Niqpm): Trmentioning

confidence: 99%

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A physical sciences network characterization of circulating tumor cell aggregate transport

King

Phillips

Mitrugno

et al. 2015

American Journal of Physiology-Cell Physiology

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Circulating tumor cells (CTC) have been implicated in the hematogenous spread of cancer. To investigate the fluid phase of cancer from a physical sciences perspective, the multi-institutional Physical Sciences-Oncology Center (PS-OC) Network performed multidisciplinary biophysical studies of single CTC and CTC aggregates from a patient with breast cancer. CTCs, ranging from single cells to aggregates comprised of 2-5 cells, were isolated using the high-definition CTC assay and biophysically profiled using quantitative phase microscopy. Single CTCs and aggregates were then modeled in an in vitro system comprised of multiple breast cancer cell lines and microfluidic devices used to model E-selectin mediated rolling in the vasculature. Using a numerical model coupling elastic collisions between red blood cells and CTCs, the dependence of CTC vascular margination on single CTCs and CTC aggregate morphology and stiffness was interrogated. These results provide a multifaceted characterization of single CTC and CTC aggregate dynamics in the vasculature and illustrate a framework to integrate clinical, biophysical, and mathematical approaches to enhance our understanding of the fluid phase of cancer.circulating tumor cell; metastasis; breast cancer; cell lines; fluid dynamics; physics of cancer; hemodynamics; quantitative phase microscopy; microfluidics; immersed finite element method WHILE THE PRESENCE of circulating tumor cells (CTCs) in the vasculature has been implicated in the metastatic cascade of epithelial carcinomas, new evidence has revealed a putative role of CTC aggregates as a potential form of stromal-assisted metastasis across a variety of epithelial tumor types (6). In concert, the presence of homotypic interactions among CTCs leading to aggregation occurring at sites of endothelial attachment suggest the involvement of CTC aggregates in the hematogenous dissemination of cancer. Despite compelling evidence suggesting a role for CTC aggregates in metastatic progression (28), the physics underlying CTC vascular transport including the influence of blood flow, coagulation, intercellular adhesion, and collisions with cells of the vasculature, such as red blood cells (RBCs) and endothelial cells (ECs), remains poorly understood. Better physical understanding of CTC transport and mechanobiology could enable, for example, new strategies to monitor patient response to chemotherapy (22).Here, we demonstrate a multidisciplinary approach (29) that utilizes clinical measurements on single CTCs and CTC aggregates from a patient with breast cancer as a quantitative guide in the rational design of in vitro and in silico models to investigate the dynamics of CTC transport in the vasculature. Using the high-definition (HD) CTC assay to identify circulating tumor cells in the blood, coupled with quantitative phase microscopy (QPM) to quantify the subcellular density organization of CTCs, we profiled the biophysical properties of CTCs in a patient with breast cancer. These metrics, including geometric and density features,...

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Section: Noninterferometric Quantitative Phase Microscopy (Niqpm): Trmentioning

confidence: 99%

Section: Noninterferometric Quantitative Phase Microscopy (Niqpm): Trmentioning

confidence: 99%

A physical sciences network characterization of circulating tumor cell aggregate transport

King

Phillips

Mitrugno

et al. 2015

American Journal of Physiology-Cell Physiology

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“…A multiscale particle-based model is proposed to combine the DPD-CGMD methods for modeling the dynamics of platelets flowing in response to extracellular flow-induced stresses [18]. The model adapts the dissipative particle dynamics (DPD) method for describing macroscopic transport of blood plasma in vessels and the coarse-grained molecular dynamics (CGMD) method for handling individual platelets.…”

Section: Introductionmentioning

confidence: 99%

“…Extensive numerical experiments were conducted using performance metrics, to measure the relative performances of standard single-scaled time-stepping (STS) algorithm vs. ours. This study is an integral part to a full multiscale particle-based model that studies flow-induced platelet-mediated thrombosis composed of: (i) the spatial interface of the top-scale and bottom-scale methods: DPD and CGMD, whereby the microscale model of platelets allows to continuously undergo microstructural changes in response to extracellular flow-induced stresses [18, 36] and (ii) the temporal interface of the top-scale and bottom-scale integrators in which the step sizes are appropriately specified as multiple scales in order to enhance the computational efficiency while keeping the solutions within predefined error boundaries.…”

Section: Introductionmentioning

confidence: 99%

A multiple time stepping algorithm for efficient multiscale modeling of platelets flowing in blood plasma

Zhang

Deng

et al. 2015

Journal of Computational Physics

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We developed a multiple time-stepping (MTS) algorithm for multiscale modeling of the dynamics of platelets flowing in viscous blood plasma. This MTS algorithm improves considerably the computational efficiency without significant loss of accuracy. This study of the dynamic properties of flowing platelets employs a combination of the dissipative particle dynamics (DPD) and the coarse-grained molecular dynamics (CGMD) methods to describe the dynamic microstructures of deformable platelets in response to extracellular flow-induced stresses. The disparate spatial scales between the two methods are handled by a hybrid force field interface. However, the disparity in temporal scales between the DPD and CGMD that requires time stepping at microseconds and nanoseconds respectively, represents a computational challenge that may become prohibitive. Classical MTS algorithms manage to improve computing efficiency by multi-stepping within DPD or CGMD for up to one order of magnitude of scale differential. In order to handle 3–4 orders of magnitude disparity in the temporal scales between DPD and CGMD, we introduce a new MTS scheme hybridizing DPD and CGMD by utilizing four different time stepping sizes. We advance the fluid system at the largest time step, the fluid-platelet interface at a middle timestep size, and the nonbonded and bonded potentials of the platelet structural system at two smallest timestep sizes. Additionally, we introduce parameters to study the relationship of accuracy versus computational complexities. The numerical experiments demonstrated 3000x reduction in computing time over standard MTS methods for solving the multiscale model. This MTS algorithm establishes a computationally feasible approach for solving a particle-based system at multiple scales for performing efficient multiscale simulations.

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“…This study aimed to investigate the physical and biochemical effects of X-ray IR on the HNSCC cell line, UM-SCC-22A, through the use of label-free, quantitative phase microscopy in conjunction with fluorescence microscopy. 17 We have previously utilized the non-interferometric quantitative phase microscopy (NIQPM) technique to measure dry mass and density of formed platelet aggregates and thrombi, circulating tumor cells isolated from ovarian cancer patients, and isogenic primary and metastasized colon adenocarcinoma cell cytoplasm and nuclei. 2,9,27,28 Here we performed NIQPM and high numerical aperture (NA) 2D and 3D image segmentation in conjunction with DAPI and fluorescent γ-H2AX antibody staining to elucidate HNSCC cell body, cytoplasm, nuclei, and γ-H2AX foci volume, height, area, and mass density after exposure to 8 Gy of IR.…”

Section: Introductionmentioning

confidence: 99%

Effect of Ionizing Radiation on the Physical Biology of Head and Neck Squamous Cell Carcinoma Cells

et al. 2015

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Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide. Although there are numerous treatment options for HNSCC, such as surgery, cytotoxic chemotherapy, molecularly targeted systemic therapeutics, and radiotherapy, overall survival has not significantly improved in the last 50 years. This suggests a need for a better understanding of how these cancer cells respond to current treatments in order to improve treatment paradigms. Ionizing radiation (IR) promotes cancer cell death through the creation of cytotoxic DNA lesions, including single strand breaks, base damage, crosslinks, and double strand breaks (DSBs). As unrepaired DSBs are the most cytotoxic DNA lesion, defining the downstream cellular responses to DSBs are critical for understanding the mechanisms of tumor cell responses to IR. The effects of experimental IR on HNSCC cells beyond DNA damage in vitro are ill-defined. Here we combined label-free, quantitative phase and fluorescent microscopy to define the effects of IR on the dry mass and volume of the HNSCC cell line, UM-SCC-22A. We quantified nuclear and cytoplasmic subcellular density alterations resulting from 8 Gy X-ray IR and correlated these signatures with DNA and γ-H2AX expression patterns. This study utilizes a synergistic imaging approach to study both biophysical and biochemical alterations in cells following radiation damage and will aid in future understanding of cellular responses to radiation therapy.

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Measurement Science in the Circulatory System

Cited by 24 publications

References 103 publications

A physical sciences network characterization of circulating tumor cell aggregate transport

A physical sciences network characterization of circulating tumor cell aggregate transport

A multiple time stepping algorithm for efficient multiscale modeling of platelets flowing in blood plasma

Effect of Ionizing Radiation on the Physical Biology of Head and Neck Squamous Cell Carcinoma Cells

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