ISSCC 2004 / SESSION 12 / BIOMICROSYSTEMS / 12.
12.4 Capacitive Sensor Array for Localization of
Bioparticles in CMOS Lab-on-a-Chip
Aldo Romani1, Nicolò Manaresi2, Luca Marzocchi1, Gianni Medoro2,
Andrea Leonardi1, Luigi Altomare1, Marco Tartagni1, Roberto Guerrieri1
University of Bologna, Bologna, Italy
1 electric field in the liquid. DEP forces must be restored before
Silicon Biosystems, Bologna, Italy
2 particles significantly change their positions or stick to the sur-
The design of integrated CMOS sensors/actuators for applica-
tions in molecular and cell biology is a challenging issue on the
road towards automating of biological analyses. Recent papers
about CMOS labs-on-a-chip [1][2] have presented different kinds
of strategies for implementing sensors and reducing the need of
bulky and expensive external equipment such as microscopes
and cameras. Moreover, contributions in the area of CMOS sen-
sors for accurate localization of cells or particles are emerging. In
[3] a CMOS lab-on-a-chip (LOAC) makes use of embedded opti-
cal sensors to detect particle positions. However, external equip-
ment (i.e. special lamps, optical fiber, etc.) is still necessary and
labelling of cells with fluorescent markers may also be needed to
boost detection sensitivity. Other works [4][5] describe imped-
ance sensing as a suitable approach for characterization of indi-
vidual biological cells. However, sensitivity is strongly limited by
the possibility of shrinking the devices implemented in those
technologies.
This paper describes a CMOS capacitive sensor array which is
able to detect overlying particles. Moreover, the circuit imple-
ments the moving DEP-cages approach described in [3] for par-
ticle manipulation. Capacitive sensing overcomes the limits of
optical detection and does not rely on any external equipment.
The device consists of a CMOS chip covered by a conductive glass
lid and separated by 100µm. A pierced piece of double adhesive
tape acts as a gasket. In the resulting closed micro-chamber, par-
ticles and cells in their suspending medium can be injected
through holes in the glass.
A highly parallel array of sensors and actuators is the core of the
device described herein. A closer view of each microsite is shown
in Fig. 12.4.1. The aim is to detect variations in dielectric permit-
tivity caused by the presence of particles in the region above
superficial electrodes, which affects the coupling capacitance
with the lid.
The circuit operates as a sensor or as a DEP actuator. During the
actuation phase ROWS and COLS are inactive. The circuit gen-
erates the electric fields necessary to deploy DEP forces by con-
necting the superficial metal electrode through CMOS transfer
gates to an in-phase (Vphip) or to a counter-phase sinusoidal
voltage (Vphim), while the lid is connected to Vphim. Once a
microsite (i,j) is addressed, the selection is controlled by a mem-
ory element driven by ROWW, COLW and BROW.
During the sensing phase the sinusoidal voltages are halted and
the electrode of the addressed cell is disconnected from Vphip
and Vphim. Figure 12.4.2 shows a schematic view of the featured
sensing scheme. The input capacitance Ci can be thought of as
the coupling capacitance between the lid and the microsite elec-
trode. The cascode inverter implements a charge amplifier. The
output of the sensor array Voarr is generated by a source follow-
er driving an active load through the addressed row multiplexer.
By activating RESCOL the output of the charge amplifier is
brought to the reference value Vbn, corresponding to the thresh-
old voltage of the cascode inverter. Then, RESCOL is deactivat-
ed and after charge injection the readout stage samples the reset
• 2004 IEEE International Solid-State Circuits Conference
voltage (t1). A voltage step on the lid will induce in Vocell a volt-
age variation which is proportional to the input and feedback
capacitance ratio Ci/Cr and to the step amplitude. In t3 the out-
put voltage is sampled again by the readout stage which ampli-
fies and outputs the sensed variation. An equal duration opposite
voltage pulse is applied to the lid to prevent the build-up of a DC
face.
An auxiliary capacitance Caux is included to subtract a program-
mable offset (t2) to avoid saturating the charge amplifier when
higher voltage pulses are applied on the lid to maximize the out-
put voltage swing.
This elementary unit is replicated to form a 320x320 array. The
pitch of each site is 20µm. A block diagram of the chip is shown
in Fig. 12.4.3. Each microsite is addressed by specific control sig-
nals generated by the row and column decoders through the row
and column circuits. The readout stage mainly consists of a fully
differential charge integrator based on a folded cascode SC oper-
ational amplifier with common mode feedback. The gain is pro-
grammable and an offset (Voff) can be subtracted during readout
in order to boost sensitivity while preventing saturation.
Figures 12.4.4 and 12.4.5 show comparisons of sensors and opti-
cal microscope images. In Fig. 12.4.4, 50µm polystyrene beads
are individually detected. Detection of 10µm beads, Yarrowia
lipolytica yeasts and human erythro-leukaemia K562 cells is
shown in Fig. 12.4.5. The worst case measured output voltage
variation associated to particle presence was 145mV, correspon-
ding to a SNR of 39dB and to a 0.42fF input capacitance varia-
tion.
The circuit noise measured on the output voltage (Voutdiff) is, in
90% of the pixels, below the 1.6mV resolution of the external 12b
ADC, which is equivalent to 15 electrons on the input of the
charge amplifier.
The chip has been fabricated in a 0.35µm 2P 3M standard CMOS
technology with a supply voltage of 3.3V. The chip micrograph is
shown in Fig. 12.4.6. Superficial electrodes have been realized
with the top metal layer of the CMOS process. The feedback (Cr)
and auxiliary capacitance (Caux) are poly capacitors. Vlid is
external and can range between +/- 9V. No further processing nor
micromachining have been used.
Acknowledgements:
This work has been supported by the European Community 5th FP (IST-
2001-32437), and by Italian MIUR-PRIN 2000. The authors acknowledge
A. Fuchs of CEA, P. Marche of INSERM for their suggestions on biological
aspects and S. Ronconi of University of Bologna for his valuable contribu-
tion to the test board design.
References:
[1] M.Xue et al., “A High Density Conduction Based Micro-DNA-
Identification Array Fabricated in a CMOS Compatible Process,” ISSCC
Dig. Tech. Papers, pp.198-199, Feb., 2003.
[2] B. Eversmann, et al., “A 128 x 128 CMOS Bio-Sensor Array for
Extracellular Recording of Neural Activity,” ISSCC Dig. Tech. Papers, pp.
222-223, Feb., 2003.
[3] N. Manaresi et al., “A CMOS Chip for Individual Cell Manipulation
and Detection,” ISSCC Dig. Tech. Papers, pp.192-193, Feb., 2003.
[4] S. Gawad et al., “Micromachined Impedance Spectroscopy Flow
Cytometer for Cell Analysis and Particle Sizing,” Lab on a Chip, vol. 1, pp.
76-82, 2001.
[5] G. Medoro et al., “A Lab-on-a-Chip for Cell Detection and
Manipulation,” IEEE Sensors J., vol. 3, pp.317-325, June 2003.
0-7803-8267-6/04 ©2004 IEEE
 ISSCC 2004 / February 17, 2004 / Salon 1-6 / 3:15 PM

Figure 12.4.1: Schematic view of the micro-site circuit. Figure 12.4.2: Capacitive sensing scheme and principle.

Figure 12.4.4: Sensor images of 50µm polystyrene beads in a 280mM

Figure 12.4.3: Block diagram of the chip. mannitol solution are compared with optical microscope images.

Figure 12.4.5: Sensor and microscope images of 10µm polystyrene beads,

Yarrowia lipolytica yeasts and human erythro-leukaemia K562 cells in a
280mM mannitol solution. Particles brighter than the background have εparticle
> εmedium, while darker ones have εparticle < εmedium. Figure 12.4.6: Micrograph of the sensor array.

• 2004 IEEE International Solid-State Circuits Conference 0-7803-8267-6/04 ©2004 IEEE

Figure 12.4.1: Schematic view of the micro-site circuit.

• 2004 IEEE International Solid-State Circuits Conference 0-7803-8267-6/04 ©2004 IEEE

Figure 12.4.2: Capacitive sensing scheme and principle.

• 2004 IEEE International Solid-State Circuits Conference 0-7803-8267-6/04 ©2004 IEEE

Figure 12.4.3: Block diagram of the chip.

• 2004 IEEE International Solid-State Circuits Conference 0-7803-8267-6/04 ©2004 IEEE

Figure 12.4.4: Sensor images of 50µm polystyrene beads in a 280mM mannitol solution are compared with optical microscope images.

• 2004 IEEE International Solid-State Circuits Conference 0-7803-8267-6/04 ©2004 IEEE

Figure 12.4.5: Sensor and microscope images of 10µm polystyrene beads, Yarrowia lipolytica yeasts
and human erythro-leukaemia K562 cells in a 280mM mannitol solution. Particles brighter than the
background have εparticle > εmedium, while darker ones have εparticle < εmedium.

• 2004 IEEE International Solid-State Circuits Conference 0-7803-8267-6/04 ©2004 IEEE

Figure 12.4.6: Micrograph of the sensor array.

• 2004 IEEE International Solid-State Circuits Conference 0-7803-8267-6/04 ©2004 IEEE