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It is generally accepted that most cancer-related mortalities
result from metastatic disease.1 While the process of metastasis
is not well understood, a number of chemical, physical, and
molecular events occur that ultimately result in the dissemination
and deposition of tumor cells into targeted organs using the
circulatory system and/or bone marrow as the carrier(s). This
“seed and soil” process was proposed as early as 1889 by Paget
and was later modified with the caveat that shed tumor cells
consist of a heterogeneous population with subpopulations
possessing different metastatic potentials. The fundamental
entities primarily responsible for spawning metastatic disease
are circulating tumor cells (CTCs), which can be produced
during early stages of tumorigenesis.4 Elucidating the quantity
of CTCs in peripheral blood or bone marrow can serve as an
indicator for the clinical management of several cancer-related
diseases by providing information on the success/failure of
therapeutic intervention and disease stage forecasting.5, The
isolation and enumeration of exfoliated CTCs in peripheral blood
or bone marrow for a variety of cancer-related diseases has
already been reported for a variety of cancer-related diseases,
such as breast,79 colorectal,10 prostate,11 renal,12 bladder,13 and
nonsmall cell lung14 cancers. As an example of the clinical utility
of CTC information, Cristofanilli et al. recently reported a study
of 177 breast cancer patients using the amount of CTCs in
peripheral blood as an indicator of survival.7 Patients with g5
CTCs per 7.5 mL of whole blood possessed a median progression-
free survival of 2.7 months versus 7.0 months for those
patients containing <5 CTCs in 7.5 mL of their peripheral blood.
The major issue with securing viable clinical information via
quantification of CTC levels is the extremely low abundance
or rare-event nature of these cells among a high number of
† Department of Chemistry, Louisiana State University.
‡ Department of Mechanical Engineering, Louisiana State University.
§ Center for BioModular Multi-scale Systems, Louisiana State University.
| Center for Advanced Microstructures and Devices, Louisiana State
University.
⊥ Department of Bioengineering, Louisiana Tech University.
(1) Leaf, C. Fortune 2004, 76–94.
(2) Paget, S. Lancet 1889, 1, 571.
(3) Fidler, I. J.; Yano, S.; Zhang, R. D.; Fujimaki, T.; Bucana, C. D. Lancet
Oncol. 2002, 3, 53–57.
(4) Loberg, R. D.; Fridman, Y.; Pienta, B. A.; Keller, E. T.; McCauley,
L. K.; Taichman, R. S.; Pienta, K. J. Neoplasia 2004, 6, 302–309.
(5) Braun, S.; Marth, C. New Engl. J. Med. 2004, 351, 824–6.
(6) Singletary, S. E.; Connolly, J. L. Ca-Cancer J. Clin. 2006, 56, 37–
47.
Published on Web 06/17/2008
10.1021/ja8015022 CCC: $40.75  2008 American Chemical Society J. AM. CHEM. SOC. 2008, 130, 8633–8641 9 8633
spectator cells in peripheral blood.6,15–18 For example, it is
clinically useful to quantitatively enumerate 0-10 CTCs in
whole blood composed of >109 erythrocytes and >106 leukocytes
per mL.7
For sampling rare events in a large population, three important
metrics must be assessed: (1) throughput, the number of cell
identification or sorting steps per unit time; (2) recovery, an
indicator of the fraction of target cells collected from the input
sample; and (3) purity, which depends on the number of
“interfering” cells excluded from the analysis.19 In addition to
these three metrics, highly efficient quantification of the number
of enriched cells must be provided as well.
The approaches used to date to enrich CTCs from clinical
samples have provided lower-than-desired recoveries with high
purity, relatively poor purity but with high recoveries, or, in
other cases, highly specialized sample processing and handling
whose success is laboratory dependent.20–25 For example,
immunomagnetic approaches for CTC enrichment using ferromagnetic
micrometer-sized particles coated with molecular
recognition elements specific for antigenic-bearing target cells
can interrogate diluted blood samples typically yield modest
recoveries (∼70%) but extremely favorable purity.22 In the case
of size-based separations employing nuclear tracked membranes,
polycarbonate membranes with varying pore sizes (8-14 μm)
can filter large volumes (9.0-18 mL) of blood and recover
nearly 85% of the CTCs, but significant numbers of leukocytes
are also retained (i.e., low purity) potentially complicating the
enumeration process.26 Investigations utilizing reverse-transcription
PCR, in which mRNAs are used as surrogates to report
CTC levels, have the ability to detect one CTC in an excess of
106 mononucleated cells.27 However, these assays are prone to
high interlaboratory variability and require extensive sample
handling and manipulation.
Most of the CTC isolation/sorting tools currently in use
possess some common procedural characteristics that make them
prohibitively difficult to implement, such as the ability to sort
only the mononucleated fraction of whole blood requiring
density gradient centrifugation prior to enrichment and the use
of either flow cytometry or fluorescence microscopy following
cell staining to enumerate the enriched CTCs. These additional
steps require sample handling and transfer, which can induce
cell loss or contamination that can dramatically affect the assay
result, especially when dealing with low numbers of targets.
Microfluidics provides a venue for producing integrated
systems that can process clinical samples in closed architectures
to minimize sample contamination and loss. However, high
throughput sampling of relatively large volumes (>1 mL) has
not been a mainstay for microfluidics due to the macro-to-micro
dilemma resulting from the small dimensional features associated
with these devices. For example, exhaustively sampling a
1.0 mL volume input using a microchannel of 30 μm × 30 μm
at a linear velocity of 1.0 mm s-1 would require 309 h (12.9
days). This sampling bottleneck was recently addressed by
studies with a glass-based microfluidic device fabricated using
deep reactive ion etching.28 The high-surface area immunological
capture bed consisted of microposts (100 μm diameter × 100 μm tall) arranged in an equilateral triangular format; the
device was capable of capturing ∼60% of CTCs from untreated
whole blood with enumeration achieved by cell staining and
microscopic visualization.
Herein we report our efforts aimed toward the development
of a self-contained system capable of meticulously separating
intact CTCs from peripheral blood and directly quantifying the
CTC level upon isolation and enrichment. As a result of careful
fluidic design rules and system integration methods, we have
successfully employed a microfluidic system capable of exhaustively
and rapidly interrogating >1.0 mL of unprocessed
whole blood possibly harboring low-abundant CTCs. At the
heart of the system were carefully engineered, exceedingly
efficient high-aspect ratio capture beds decorated with mABs
specific for antigenic integral membrane proteins expressed in
CTCs of epithelial origin and a label-free, highly specific singlecell
conductivity sensor. The device operational characteristics
were achieved by tailoring the dominant CTC capture dynamics,
specific device architecture, and suspension linear velocity in a
high throughput microsampling unit (HTMSU) containing highaspect
ratio microstructures replicated in a polymeric substrate.
Direct single-cell counting of the captured cells was made
possible by their release as a result of enzymatic digestion of
cell-antigen/antibody-surface complexes. Quantitative assessment
of CTC numbers was accomplished using an integrated
conductivity sensor capable of specifically detecting CTCs via
their electrical signatures without requiring cell staining or
microscopic visualization.

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