Biomaterials 26 (2005) 2165–2172
Multi-channel 3-D cell culture device integrated on a silicon chip for
anticancer drug sensitivity test
, Hitoshi Shiku
*, Tomoyuki Yasukawa
, Matsuhiko Nishizawa
Graduate School of Environmental Studies, Tohoku University, Aramaki Aoba 07, Sendai 980-8579, Miyagi, Japan
Department of Bioengineering and Robotics, Graduate School of Engineering, Tohoku University, Sendai 980-8579, Japan
Received 12 March 2004; accepted 12 May 2004
Available online 19 July 2004
A novel three-dimensional cell culture system was constructed with an array ofcell panels (4 Â 5) in a silicon chip, together with
multi-channel drug containers. Human breast cancer (MCF-7) cells were embedded in a collagen–gel matrix and entrapped in a
pyramidal-shaped silicon hole. Each cell panel can be isolated by a channel composed ofa microﬂuid part and a reservoir. A cell
panel was exposed to 200 mm KCN for 2 days to demonstrate that each cell panel could be independently evaluated under various
stimulation conditions. Based on the cellular respiration activity, the proliferation behavior was continuously monitored on the
silicon-based cell array for 5 days using scanning electrochemical microscopy (SECM). The cells entrapped in the device (3-D
culture) proliferated normally, and the proliferation rate was lower than that of cells grown in a monolayer cell culture (2-D culture).
The effects of three anticancer drugs measured simultaneously on the cell chip were in good agreement with those obtained by a
conventional colorimetric assay. Our results suggest that the silicon-based device for 3D culture is appropriate for a chemosensitivity
assay involving multi-chemical stimulation.
r 2004 Elsevier Ltd. All rights reserved.
Keywords: Biosensor; Collagen; Cytotoxicity; Electrochemistry; Polydimethylsiloxane
The cell-based assay has been widely used for the
functional characterization and detection of drugs,
toxicants, and other chemicals. This assay has now
contributed to developing a high-throughput system [1–
6], along with recent advancements in techniques for
micropatterning and the integration ofliving cells on a
solid support [5–12]. Further, various microsensors have
been developed and applied for monitoring cellular
activity, e.g., the change in cell morphology [13–16], the
rates ofextracellular acidiﬁcation [13,14,17–20], and
respiratory activity [13,14,21–26]. These biosensors are
advantageous in realizing continuous monitoring and
short evaluation time with very small amount of
Cell-based biosensors have been applied to evaluate
the individualized chemosensitivity oftumor cells [27–
30]. The sensitivities ofanticancer drugs to tumor cells
vary in certain situations. This makes it necessary to
obtain information on the chemosensitivity of individual
patients for effective cancer chemotherapy. Therefore,
various in vitro chemosensitivity tests have been
developed and applied to primary specimens [31–36].
Among the tests, the collagen gel droplet embedded-
culture drug sensitivity test (CD-DST) has been
recognized as the most suitable assay at present to
accurately predict chemosensitivity [36–38]. The col-
lagen gel-embedded culture has been found to show a
high success rate in the primary culture oftumor cells
Recently, the 3-D culture technique, in which cells are
cultivated within an extracellular matrix (ECM) such as
collagen gel or matrigel, has received a great deal of
attention in the ﬁeld ofcancer research [42–44]. The
ECM is known to support cellular proliferation and
induce cellular differentiation. Therefore, the 3-D
ARTICLE IN PRESS
*Corresponding author. Tel./fax: +81-22-217-7209.
E-mail addresses: email@example.com (H. Shiku),
firstname.lastname@example.org (T. Matsue).
Also for correspondence.
0142-9612/$ - see front matter r 2004 Elsevier Ltd. All rights reserved.