Isolation of tumor cells using size and deformation

Mohamed, Hisham; Murray, M. H.; Turner, James N.; Casini, Michèle

doi:10.1016/j.chroma.2009.05.036

Cited by 190 publications

(149 citation statements)

References 27 publications

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“…Microfabrication-assisted technology, using microscale arrays of round or rectangular posts, channels, or other simple patterns, has the potential to solve this problem (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Here, we focused on the mechanical properties of cancer cells in designing a unique cell purification system for the purpose of generating subpopulations enriched in highly deformable cells.…”

mentioning

confidence: 99%

Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Zhang

Kai

Choi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

192

172

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Here we report a microfluidics method to enrich physically deformable cells by mechanical manipulation through artificial microbarriers. Driven by hydrodynamic forces, flexible cells or cells with high metastatic propensity change shape to pass through the microbarriers and exit the separation device, whereas stiff cells remain trapped. We demonstrate the separation of (i) a mixture of two breast cancer cell types (MDA-MB-436 and MCF-7) with distinct deformabilities and metastatic potentials, and (ii) a heterogeneous breast cancer cell line (SUM149), into enriched flexible and stiff subpopulations. We show that the flexible phenotype is associated with overexpression of multiple genes involved in cancer cell motility and metastasis, and greater mammosphere formation efficiency. Our observations support the relationship between tumor-initiating capacity and cell deformability, and demonstrate that tumor-initiating cells are less differentiated in terms of cell biomechanics.cell mechanics | cytoskeleton | genomic profiling C ell deformability is commonly measured using magnetic twisting cytometry, particle tracking rheometry, optical tweezers, micropipette aspiration, atomic force microscope, and other derivative cell stretching or poking methods (1-4). Applications of these methods to stem cells have revealed the greater deformability of the cytoskeleton and nucleoskeleton in less differentiated cells, whereby deformability generally decreases during differentiation to mature cells (5-8). Research on cancer cell deformability has also consistently revealed that increased deformability is correlated with increased metastatic potential (9-15).Despite the success achieved using cell deformability measurements, isolation of cells with differential deformabilities remains a great challenge (10, 16). Microfabrication-assisted technology, using microscale arrays of round or rectangular posts, channels, or other simple patterns, has the potential to solve this problem (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Here, we focused on the mechanical properties of cancer cells in designing a unique cell purification system for the purpose of generating subpopulations enriched in highly deformable cells. We used microfabrication technology and obtained a subpopulation of SUM149 breast cancer cells with stem-cell-like deformability and mammosphere formation capability.The separation device, a mechanical separation chip (MS-chip), employs artificial microbarriers in combination with hydrodynamic force to separate deformable from stiff cells (Fig. 1A). Both the microbarrier structures and the fluidic parameters are essential to the cell-enrichment process. The most notable feature of the device is the precise placement of the microbarriers to impede the passage of stiff cells. Published in vivo observations suggest that the minimum crossable barrier for cancer cells is ∼8 μm or less (28,29). Here, we took those barrier dimensions into account in designing the MSchip to separate cells based on perfusion through constrictions. As...

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mentioning

confidence: 99%

Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Zhang

Kai

Choi

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

192

172

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“…The critical dimension in these devices is the size of the pore/structure which is designed to allow maximum CTCs trapping with little contamination. Using gap sizes between 5 to 10 µm, these microfluidic devices are able to demonstrate isolation of cancer cells with high efficiency (>80%), but the isolation purity varies greatly due to trapping of the bigger leukocytes [87][88][89]. The trapped CTCs usually deforms at the pores under constant shear during sample processing, making their retrieval difficult and thus requiring post-sorting analysis to be done on chip.…”

Section: Circulating Tumor Cellsmentioning

confidence: 99%

“…Due to the large size differences between CTCs and other blood cellular components (CTCs ~16-20 µm; RBC ~8 µm; leukocytes ~10-15 µm) [85,86], size-based CTCs separation in microfluidic devices is often achieved using microstructures of different geometries to physically trap the larger CTCs [87][88][89][90]. The critical dimension in these devices is the size of the pore/structure which is designed to allow maximum CTCs trapping with little contamination.…”

Section: Circulating Tumor Cellsmentioning

confidence: 99%

Microfluidic Devices for Blood Fractionation

et al. 2011

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Blood, a complex biological fluid, comprises 45% cellular components suspended in protein rich plasma. These different hematologic components perform distinct functions in vivo and thus the ability to efficiently fractionate blood into its individual components has innumerable applications in both clinical diagnosis and biological research. Yet, processing blood is not trivial. In the past decade, a flurry of new microfluidic based technologies has emerged to address this compelling problem. Microfluidics is an attractive solution for this application leveraging its numerous advantages to process clinical blood samples. This paper reviews the various microfluidic approaches realized to successfully fractionate one or more blood components. Techniques to separate plasma from hematologic cellular components as well as isolating blood cells of interest including certain rare cells are discussed. Comparisons based on common separation metrics including efficiency (sensitivity), purity (selectivity), and OPEN ACCESSMicromachines 2011, 2 320 throughput will be presented. Finally, we will provide insights into the challenges associated with blood-based separation systems towards realizing true point-of-care (POC) devices and provide future perspectives.

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“…Nonetheless, we expect to easily apply our microfluidic chip to other forms of cancer, since spectroscopy studies have noted characteristic backscattering from other types cancer cells (23)(24)(25). As the number of studies increasingly supports the clinical value of enumerating circulating tumor cells in blood, researchers are developing microfluidic-based platforms to capture circulating epithelial cancer cells (42,43). One example is a microfluidic chip developed to capture epithelial tumor cells, without blood pre-processing, using antibody coated microposts (42).…”

Section: Original Articlementioning

confidence: 99%

Confocal backscattering‐based detection of leukemic cells in flowing blood samples

et al. 2011

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The prognostic value of assessing minimal residual disease (MRD) in leukemia has been established with advancements in flow cytometry and PCR. Nonetheless, these techniques are limited by high equipment costs, complex, and costly cell processing and the need for highly trained personnel. Here, we demonstrate the potential of exploiting differences in the relative intensities of backscattered light at three wavelengths to detect the presence of leukemic cells in samples containing varying mixtures of white blood cells (WBCs) and leukemic cells flowing through microfluidic channels. Using 405, 488, and 633 nm illumination, we identify distinct light scattering intensity distributions for Nalm-6 leukemic cells, normal mononuclear (PBMC) and polymorphonuclear (PMN) white blood cells and red blood cells. We exploit these differences to develop cell classification algorithms, whose performance is evaluated based on simultaneous acquisition of light scattering and fluorescence flow cytometry data. When this algorithm is used prospectively for the analysis of samples consisting of mixtures of PBMCs and leukemic cells, we achieve an average specificity and sensitivity of leukemic cell detection of 99.6 and 45.2%, respectively. When we consider samples that include leukemic cells along with PMNs and PBMCs, which can be acquired using a simple red blood cell lysis step following venipuncture, the specificity and sensitivity of the approach decreases to 91.6 and 39.5%, respectively. On the basis of the performance of these algorithms, we estimate that 42 or 71 lL of blood would be adequate to confirm the presence of leukemia at an 80% power level in samples containing 0.01% leukemia to either PBMCs or PBMCs and PMNs, respectively. Therefore, light scattering-based flow cytometry in a microfluidic platform could provide a low cost, highly portable, minimally invasive approach for detection and monitoring of leukemic patients. This could offer significant improvements especially for pediatric patients and for patients in developing countries. ' 2011 International Society for Advancement of Cytometry

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Isolation of tumor cells using size and deformation

Cited by 190 publications

References 27 publications

Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Microfluidics separation reveals the stem-cell–like deformability of tumor-initiating cells

Microfluidic Devices for Blood Fractionation

Confocal backscattering‐based detection of leukemic cells in flowing blood samples

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