Online citations, reference lists, and bibliographies.
Please confirm you are human
(Sign Up for free to never see this)
← Back to Search

Pinched Flow Coupled Shear-modulated Inertial Microfluidics For High-throughput Rare Blood Cell Separation.

A. Bhagat, H. Hou, L. Li, C. T. Lim, J. Han
Published 2011 · Chemistry, Medicine

Save to my Library
Download PDF
Analyze on Scholarcy
Share
Blood is a highly complex bio-fluid with cellular components making up >40% of the total volume, thus making its analysis challenging and time-consuming. In this work, we introduce a high-throughput size-based separation method for processing diluted blood using inertial microfluidics. The technique takes advantage of the preferential cell focusing in high aspect-ratio microchannels coupled with pinched flow dynamics for isolating low abundance cells from blood. As an application of the developed technique, we demonstrate the isolation of cancer cells (circulating tumor cells (CTCs)) spiked in blood by exploiting the difference in size between CTCs and hematologic cells. The microchannel dimensions and processing parameters were optimized to enable high throughput and high resolution separation, comparable to existing CTC isolation technologies. Results from experiments conducted with MCF-7 cells spiked into whole blood indicate >80% cell recovery with an impressive 3.25 × 10(5) fold enrichment over red blood cells (RBCs) and 1.2 × 10(4) fold enrichment over peripheral blood leukocytes (PBL). In spite of a 20× sample dilution, the fast operating flow rate allows the processing of ∼10(8) cells min(-1) through a single microfluidic device. The device design can be easily customized for isolating other rare cells from blood including peripheral blood leukocytes and fetal nucleated red blood cells by simply varying the 'pinching' width. The advantage of simple label-free separation, combined with the ability to retrieve viable cells post enrichment and minimal sample pre-processing presents numerous applications for use in clinical diagnosis and conducting fundamental studies.
This paper references
10.1002/BIT.260270713
Shear stress effects on human embryonic kidney cells in Vitro
N. Stathopoulos (1985)
10.1158/0008-5472.CAN-05-0616
Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition?
E. Thompson (2005)
10.1016/J.CHROMA.2007.05.064
Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells.
Siyang Zheng (2007)
10.1017/S0022112005004738
Wall-induced forces on a rigid sphere at finite Reynolds number
Lanying Zeng (2005)
10.1016/J.CHROMA.2007.06.025
Biochip for separating fetal cells from maternal circulation.
H. Mohamed (2007)
10.1002/BIT.260400903
Estimation of disruption of animal cells by laminar shear stress
C. Born (1992)
10.1016/0022-1759(94)00303-E
Altered expression of CD11b/CD18 and CD62L on human monocytes after cell preparation procedures.
J. Lundahl (1995)
10.1021/AC049863R
Pinched flow fractionation: continuous size separation of particles utilizing a laminar flow profile in a pinched microchannel.
Masumi Yamada (2004)
10.1182/BLOOD.V56.5.866.BLOODJOURNAL565866
Morphometry of human leukocytes.
G. W. Schmid-Schönbein (1980)
10.1002/ADMA.19970090914
Stability of molded polydimethylsiloxane microstructures
E. Delamarche (1997)
10.1016/j.chroma.2009.05.036
Isolation of tumor cells using size and deformation.
H. Mohamed (2009)
10.1007/s10544-009-9305-9
Microdevice for the isolation and enumeration of cancer cells from blood
S. J. Tan (2009)
10.1039/b917959c
Capture of circulating tumor cells from whole blood of prostate cancer patients using geometrically enhanced differential immunocapture (GEDI) and a prostate-specific antibody.
J. Gleghorn (2010)
10.1016/J.HUMPATH.2006.08.027
Case study of the morphologic variation of circulating tumor cells.
D. Marrinucci (2007)
10.1016/J.EXPHEM.2004.07.007
Enrichment of rare cancer cells through depletion of normal cells using density and flow-through, immunomagnetic cell separation.
Oscar R. Lara (2004)
10.1007/s11517-010-0611-4
Microfluidics for cell separation
A. Bhagat (2010)
10.1038/sj.bjc.6602871
The measurement and therapeutic implications of circulating tumour cells in breast cancer
J. Smerage (2006)
10.1093/bmb/ldq011
New technologies for the detection of circulating tumour cells.
N. Gerges (2010)
10.1039/B601554A
Direct measurement of the impact of impaired erythrocyte deformability on microvascular network perfusion in a microfluidic device.
S. Shevkoplyas (2006)
10.1021/AC061659B
Perfusion in microfluidic cross-flow: separation of white blood cells from whole blood and exchange of medium in a continuous flow.
V. Vandelinder (2007)
10.1021/ja8015022
Highly efficient circulating tumor cell isolation from whole blood and label-free enumeration using polymer-based microfluidics with an integrated conductivity sensor.
André A. Adams (2008)
10.1146/ANNUREV.BIOENG.7.011205.135108
Blood-on-a-chip.
M. Toner (2005)
10.1039/B512049G
Microfluidic diffusive filter for apheresis (leukapheresis).
P. Sethu (2006)
10.1152/JAPPL.1990.69.5.1767
Retention of leukocytes in capillaries: role of cell size and deformability.
G. Downey (1990)
10.1189/jlb.72.1.133
Centrifugation attenuates the fluid shear response of circulating leukocytes
Shunichi Fukuda (2002)
10.1021/ac101222x
Size-selective microcavity array for rapid and efficient detection of circulating tumor cells.
M. Hosokawa (2010)
10.1073/pnas.0813188106
Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device
Amirali H. Talasaz (2009)
10.1021/AC049037I
Biomimetic autoseparation of leukocytes from whole blood in a microfluidic device.
S. Shevkoplyas (2005)
10.1002/cyto.a.10071
Cell filtration‐laser scanning cytometry for the characterisation of circulating breast cancer cells
L. Zabaglo (2003)
10.2516/OGST:2004006
Lateral Forces on a Sphere
Jean-Philippe Matas (2004)
10.1073/pnas.0704958104
Continuous inertial focusing, ordering, and separation of particles in microchannels
D. Di Carlo (2007)
10.1016/S0002-9440(10)64348-9
Enrichment, immunomorphological, and genetic characterization of fetal cells circulating in maternal blood.
G. Vona (2002)
10.1038/jid.2010.141
Application of a filtration- and isolation-by-size technique for the detection of circulating tumor cells in cutaneous melanoma.
V. De Giorgi (2010)
10.1063/1.2998844
Enhanced particle filtration in straight microchannels using shear-modulated inertial migration
A. Bhagat (2008)
10.1111/J.1365-3083.1976.TB03851.X
Isolation of lymphocytes, granulocytes and macrophages.
A. Bøyum (1976)
10.1021/ac9005765
Multiorifice flow fractionation: continuous size-based separation of microspheres using a series of contraction/expansion microchannels.
Jaesung Park (2009)
10.1159/000086626
Cancer Invasion and Metastasis
C. Wittekind (2005)
10.1039/b813952k
Continuous focusing of microparticles using inertial lift force and vorticity via multi-orifice microfluidic channels.
J. Park (2009)
10.1056/NEJMOA040766
Circulating tumor cells, disease progression, and survival in metastatic breast cancer.
M. Cristofanilli (2004)
10.1122/1.550863
Migration of particles undergoing pressure-driven flow in a circular conduit
R. Hampton (1997)
10.1039/c003873c
Deformability based cell margination--a simple microfluidic design for malaria-infected erythrocyte separation.
H. Hou (2010)
10.1007/s10544-008-9262-8
Deformability study of breast cancer cells using microfluidics
H. Hou (2009)
10.1023/B:BREA.0000036787.59816.01
High Ep-CAM Expression is Associated with Poor Prognosis in Node-positive Breast Cancer
G. Spizzo (2004)
10.1017/S002211206200110X
Behaviour of macroscopic rigid spheres in Poiseuille flow Part 1. Determination of local concentration by statistical analysis of particle passages through crossed light beams
G. Segré (1962)
10.1039/B513524A
Flow-induced deformation of shallow microfluidic channels.
T. Gervais (2006)
10.1002/cyto.a.20050
Deformability‐based flow cytometry
Bryan Lincoln (2004)
10.1007/S10404-008-0377-2
Inertial microfluidics for continuous particle filtration and extraction
A. Bhagat (2009)
10.1039/B502930A
Isolation of plasma from whole blood using planar microfilters for lab-on-a-chip applications.
T. A. Crowley (2005)
10.1021/AC060042R
Separation of plasma from whole human blood in a continuous cross-flow in a molded microfluidic device.
V. Vandelinder (2006)
10.1039/B612966H
A microfluidic device for practical label-free CD4(+) T cell counting of HIV-infected subjects.
X. Cheng (2007)
10.1038/nature06385
Isolation of rare circulating tumour cells in cancer patients by microchip technology
S. Nagrath (2007)
10.1016/J.CANLET.2006.12.014
Circulating tumor cells (CTC) detection: clinical impact and future directions.
P. Paterlini-Bréchot (2007)
10.1038/189209A0
Radial Particle Displacements in Poiseuille Flow of Suspensions
G. Segré (1961)
10.1017/S0022112098003474
The inertial lift on a spherical particle in a plane Poiseuille flow at large channel Reynolds number
E. S. Asmolov (1999)
10.1039/b807107a
Continuous particle separation in spiral microchannels using Dean flows and differential migration.
A. Bhagat (2008)
10.1017/S0022112004000254
Inertial migration of rigid spherical particles in Poiseuille flow
Jean-Philippe Matas (2004)
10.1146/annurev.anchem.111808.073610
Microsystems for the capture of low-abundance cells.
Udara Dharmasiri (2010)
10.1073/pnas.0605967103
Deterministic hydrodynamics: Taking blood apart
J. A. Davis (2006)
10.1158/1078-0432.CCR-05-2821
Circulating Tumor Cells at Each Follow-up Time Point during Therapy of Metastatic Breast Cancer Patients Predict Progression-Free and Overall Survival
D. Hayes (2006)
10.1016/S0002-9440(10)64706-2
Isolation by size of epithelial tumor cells : a new method for the immunomorphological and molecular characterization of circulatingtumor cells.
G. Vona (2000)
10.1083/jcb.200601018
The epithelial–mesenchymal transition: new insights in signaling, development, and disease
J. Lee (2006)
10.1063/1.2176587
Inertial migration of neutrally buoyant particles in a square duct: An investigation of multiple equilibrium positions
B. Chun (2006)
10.1039/B705203K
Continuous blood cell separation by hydrophoretic filtration.
Sungyoung Choi (2007)
10.1038/nrc2375
Detection, clinical relevance and specific biological properties of disseminating tumour cells
K. Pantel (2008)
10.1158/1078-0432.CCR-05-1769
Circulating Tumor Cells versus Imaging—Predicting Overall Survival in Metastatic Breast Cancer
G. Budd (2006)



This paper is referenced by
10.1021/CM501596S
Fabrication of Low-Cost Paper-Based Microfluidic Devices by Embossing or Cut-and-Stack Methods
M. Thuo (2014)
10.1049/iet-nbt.2015.0060
Emerging microfluidic devices for cancer cells/biomarkers manipulation and detection.
V. H. Perez-Gonzalez (2016)
Microfluidic Nanoparticles Focusing and Separation
Chao Zhao (2015)
10.1002/cyto.a.23592
VTX‐1 Liquid Biopsy System for Fully‐Automated and Label‐Free Isolation of Circulating Tumor Cells with Automated Enumeration by BioView Platform
Elodie Sollier-Christen (2018)
10.1109/ISVLSI.2018.00126
Accelerating Simulation of Particle Trajectories in Microfluidic Devices by Constructing a Cloud Database
Junchao Wang (2018)
10.1007/s00542-020-05012-3
A 3D printed three-dimensional centrifugal fluidic system for blood separation
Qin Xian-ming (2020)
10.1038/s41598-017-08826-w
Separation of extracellular nanovesicles and apoptotic bodies from cancer cell culture broth using tunable microfluidic systems
Soojeong Shin (2017)
10.7150/thno.5195
Detecting Circulating Tumor Cells: Current Challenges and New Trends
Bin Hong (2013)
10.1016/j.bpj.2016.02.043
Biophysical Tools for Cellular and Subcellular Mechanical Actuation of Cell Signaling.
A. Liu (2016)
10.1039/c8an01061g
A review of sorting, separation and isolation of cells and microbeads for biomedical applications: microfluidic approaches.
A. Dalili (2018)
10.1038/s41598-018-27779-2
Isolation of cells from whole blood using shear-induced diffusion
J. Zhou (2018)
10.1039/C7RA09212A
Enhancement of isolation sensitivity for the viable heterogeneous circulating tumor cells swelled by hypo-osmotic pressure
J. Bu (2017)
10.1039/C6AY01077F
Rapid separation of human breast cancer cells from blood using a simple spiral channel device
D. Huang (2016)
10.1039/d0lc00853b
Tunnel dielectrophoresis for ultra-high precision size-based cell separation.
Y. Kung (2020)
10.14288/1.0166023
Microfluidic device for continuous deformability based separation of circulating tumor cells
Chao Jin (2014)
10.1002/smll.201201770
High throughput-per-footprint inertial focusing.
A. T. Çiftlik (2013)
10.1039/C5RA10634F
Staged Inertial Microfluidic Focusing for Complex Fluid Enrichment.
Amy E. Reece (2015)
10.1016/j.cis.2014.03.002
Hydrodynamic lift of vesicles and red blood cells in flow--from Fåhræus & Lindqvist to microfluidic cell sorting.
T. M. Geislinger (2014)
10.1039/c7lc00970d
Multi-size spheroid formation using microfluidic funnels.
M. Marimuthu (2018)
10.1002/chem.201800305
Microfluidic Devices in the Fast-Growing Domain of Single-Cell Analysis.
Mashooq Khan (2018)
10.1039/c8lc01335g
Rapid liquid biopsy for Mohs surgery: rare target cell separation from surgical margin lavage fluid with a high recovery rate and selectivity.
W. Zhou (2019)
10.1002/elps.201600386
Hybrid microfluidics combined with active and passive approaches for continuous cell separation
S. Yan (2017)
10.1016/j.biotechadv.2013.08.016
Detection and isolation of circulating tumor cells: principles and methods.
H. Esmaeilsabzali (2013)
10.1021/ac401472y
Enabling systems biology approaches through microfabricated systems.
Mei Zhan (2013)
10.1007/s00216-015-8966-x
Paper membrane-based SERS platform for the determination of glucose in blood samples
H. Torul (2015)
10.1039/c3lc00052d
Advances of lab-on-a-chip in isolation, detection and post-processing of circulating tumour cells.
L. Yu (2013)
MICROFLUIDIC DEVICE FOR CONTINUOUS DEFORMABILITY BASED SEPARATION OF CIRCULATING TUMOR CELLS by
S. M. McFaul (2014)
10.1063/1.5052171
Shape-based separation of micro-/nanoparticles in liquid phases.
B. Behdani (2018)
10.1002/9783527690237.CH1
High‐Speed Microfluidic Manipulation of Cells
A. Chung (2015)
10.1007/s10544-015-9956-7
A transfer function approach for predicting rare cell capture microdevice performance
J. Smith (2015)
Microluidic Sorting of Blood Cells by Negative Selection
Hua Gao (2016)
10.1002/smll.201200996
Microfluidics for manipulating cells.
Xuan Mu (2013)
See more
Semantic Scholar Logo Some data provided by SemanticScholar