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Abstract
In this paper, we propose a laboratory-on-chip (LOC) integration technique based on a novel electro-fluidic implementation and packaging
procedures for blood-based diagnostics. LOC-based diagnostic tool is a complex, hybrid system consisting of various electrical, fluidic, and
biochemical components, connected electrically and through fluidic channels on a single platform. The microfluidic fabrication technique is based
on a direct-write fabrication process (DWFP) while the conventional wire bonding makes needed electrical connections. The microelectronic
parts of proposed LOC put forward a high precision capacitive sensor carried out in TSMC’s 0.18 m CMOS process. Experimental results allow
demonstrating the capability of the proposed DWFP to fabricate polymer-based microfluidics on top of CMOS chips for LOCs. In addition, the
preliminary results of the proposed capacitive sensor show a sensitivity of 250 mV/fF with a noise level equivalent to less than 10 aF where the
existing parasitic capacitances can be more than 150 fF.
© 2006 Elsevier B.V. All rights reserved.
0924-4247/$ – see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.sna.2006.05.022
28 E. Ghafar-Zadeh et al. / Sensors and Actuators A 134 (2007) 27–36
ation, have also attracted the attention of many researchers in ical electrodes, in addition to above mentioned task, can offer a
microelectronics [4]. Gascoyne and Vykoucal proposed a pro- non-invasive technique for monitoring metabolic activity in sin-
grammable diagnostic instrument based on dielectrophoretic gle cells by detecting the extracellular metabolic gradient [13].
sample handling. They successfully demonstrated many of the Since capacitive sensors represent important building blocks
standard procedures in cellular biology such as cell sorting, of LOC diagnostic tool for the detection of bioparticles, we
focusing, detection, manipulation and cell lysis. focus in Section 2 on novel highly sensitive circuit topology and
A key role of microelectronics in these procedures, in addi- sensing electrode design, which are both realized onto CMOS
tion to offering a precise bioparticle sensor, would be to create process. Also, in this section, the design and simulation results
a non-uniform, time-variant, reliable, precise and controllable of proposed capacitive sensor are demonstrated and discussed
electrical field in order to such dielectrophoresis manipulation. as the microelectronic part of LOC system. The novel polymer-
Among the techniques proposed by various researchers, Medoro based DWFP technique is presented in Section 3, which also
et al. have, for the first time, demonstrated the dielectrophoretic deals with the implementation procedure, fabrication results, and
manipulation on CMOS [5]. In addition, they developed a capac- advantages of this technique to construct novel LOC systems.
itive and optical sensor realized on CMOS circuitry. CMOS In this section, we first introduce our experimental procedure
standard technology can offer active circuit, programmability and some of our microfluidic fabrication results, and then some
and processing. Localization of cells is necessary to determine experimental considerations of DWFP for integration and pack-
the points to create dielectrophoretic force. This localization can aging in a LOC system are discussed. In Section 4, this paper is
be carried out by integrated capacitive sensors. Moreover, cell concluded with brief discussion about the integration and pack-
suspensions need microfluidic channels along with virtual chan- aging of all required electrodes and chips for a full-automated
nel created by dielectrophoretic forces, for continuous flow. LOC system fabricated in different technologies.
So far, an extensive variety of techniques has been employed
to realize the fabrication of microfluidics for cellular and molec- 2. High sensitivity capacitive sensor
ular applications [6]. And also, a number of techniques have
been published about the CMOS-compatible microfluidic fab- The proposed capacitive sensor consists of sensing electrodes
rication [7], but only a few papers reported the results of a followed by interface circuit as shown in Fig. 1a. The perfor-
biological application using CMOS-based microfluidic hybrid mance (P) of a capacitive sensor is defined in Eq. (1)
systems. Mastrangelo and co-workers demonstrated a polymer
surface micromachining to fabricate the microfluidic channels δC
P= (1)
on a previously processed CMOS integrated circuit, which con- Ceq
tained the control, detection, drive, and communication elec-
where δC is the variation of input sensing capacitance (C) result-
tronic modules [8]. In another attempt, for the fabrication of
ing from existing bioparticles exposed to sensing electrode, and
capillary electrophoresis (CE) and polymerase chain reaction
Ceq is the equivalent sensing capacitance. For a single and dif-
(PCR) devices, they developed a low cost epoxy microcasting
ferential output capacitive sensor:
technique [9]. Chartier et al. reported the design of a polymer-
based microfluidic structure fabricated through hot embossing, Ceq-single = δC + C (2a)
using an adhesive bonding [10]. This design was then inte-
grated in a microelectronic chip, as described by Medoro et Ceq-differential = δC + σC (2b)
al. [5]. It should be noted that most of the recent microflu-
In Eq. (2b), Ceq-differential includes σC, which is an error, resulting
idic techniques are based on polymers because they offer many
from the difference between initial values of sensing capacitance
advantages including low cost, fabrication flexibility and bio-
and reference ones. Therefore, for single and differential capac-
compatible with several biomedical applications. The increasing
itive sensors, P results on Eqs. (3a) and (3b).
need for 3D microfluidic devices has been widely recognized for
LOC systems. To date, several efficient, but expensive and com- δC δC
Psingle = ≈ (3a)
plex techniques such as LIGA have been developed to fabricate δC + C C
such fluidic structures [11]. Direct-write assembly is a high effi-
δC
ciency, low complexity and can be used for the fabrication of Pdifferential = (3b)
3D microfluidics or the integration of fluidic or electronic chips δC + σC
from different technologies [12]. Psingle is very small due to small variation of sensing capacitance
In addition to biological cells in blood, molecules such as δC, but Pdifferential can be high if σC is cancelled, using a cali-
glucose, cholesterol, triglycerides, disease-causing antigens and bration technique. The sensitivity (Sν ) of the capacitive interface
hormones can provide valuable information in medical diagnos- circuit is defined as follows:
tics. This would require a biosensor that includes a bioelectrode
δVout
with a chemically functionalized surface (such as an enzyme) to Sν = (4)
selectively recognize and bind to the biomolecule in the blood δC
and a conducting interface, such as polypyrrole or carbon nan- where Vout is the output signal of this circuit and δVout shows its
otubes, to immobilize the sensing molecule and transduce this differential variation. The value of Sν depends on the character-
biochemical interaction to an electric signal. Such electrochem- istics of both the sensing electrode and its interface circuit.
E. Ghafar-Zadeh et al. / Sensors and Actuators A 134 (2007) 27–36 29
Fig. 1. Schematic representation of sensing electrodes: (a) interdigital electrode and (b) configuration presented in [5].
Fig. 2. Passivation layers: (a) onto CMOSP18 (TSMSC) and (b) after using removal “pad” mask.
2.1. Capacitive sensing electrodes where C is a differential capacitance including all parasitic
capacitors standing on nodes A and B. The simplified block
Few designs of sensing electrodes for bioparticle detec- diagram of proposed capacitive sensor circuit and complete
tion on CMOS process have been reported in the literature. interface circuit topology are depicted in Figs. 3 and 4, respec-
Fig. 1b shows a sensing capacitance created between an elec- tively. Because, the symmetrical and differential topology of
trode designed in the uppermost metal layer of CMOS chip, proposed circuit, the output voltage is almost independent of
covered with passivation layers, and a conductive lid [5]. A initial value of C. In this circuit, two current mirrors (M5–M6
non-standard process using fiber optic as spacer between two and M7–M8) amplify (AI ) the charging currents I1 and I2 and
electrodes was carried out to realize this sensing electrode. a third current mirror (M9–M10) is being used to transfer the
A schematic representation of our proposed interdigital resulting I to node C. Then, I is converted to voltage by
capacitive sensor is shown in Fig. 1a. As an advantage of this the integrating capacitance Cint , and the following output stage
technique, there is no need to extra post-processing to create an (M11–M12) is buffered (AV ).
extra electrode onto fabricated chip in standard technology. The
design and implementation of the sensing electrode has been
2.3. Sensitivity optimization and circuit simulation results
carried out in Virtuoso layout editor using a thick metal 6 and
“Pad” mask layer. As shown in Fig. 2a, in standard CMOSP18
The output voltage of the proposed capacitive sensor is given
technology, the passivation layers stacked in the last step of fab-
by Eq. (6) where V is a dc offset voltage resulting largely from
rication can be removed using this mask layer which decreases C
parasitic capacitors:
due to less insulating passivation layers between the conductors
of the electrodes (Fig. 2b). The mask removal also increases C C
as a result of more space for the presence of bioparticles between Vout = AI Vdd + V (6)
Cint
electrodes.
However, the combination of Eqs. (4) and (6) states that AI and sensor with the ability to detect less than 1 fF is a challeng-
Cint are two effective parameters on the sensitivity, the opti- ing issue. As a solution, the smaller dimensions of devices, the
mization process using Mont Carlo technique (Spectre S and weaker their parasitic capacitances. Post-layout simulation in the
Cadence) allow to determine that the channel length (L) of tran- section of simulation and experimental results ensure us about
sistors M9–M10 along with AI are major parameters in this issue. the right functionality of the interface circuit in exist of large
This is because the channel length in a transistor is proportional environmental parasitic capacitances.
to its output impedance. Also, the small values of Cint (less than Along with the already discussed capacitive sensor, a large
100 fF) do not increase the sensitivity due to the comparable interdigital electrode using metal layer 6 is also embedded in
parasitic capacitors (Fig. 5). Therefore, the critical parameters the chip area. This electrode is considered to investigate dielec-
are identified as the gain of current mirrors AI and L for a given trophoresis (DEP) handling in the microchannel fabricated in
range of C and C. DWFP technique onto CMOS chip. The CMOS layout design
rules allow the fabrication of a metal 6 conductor as small as
2.4. Layout implementation of interface circuit and 140 nm width with 150 nm space between them. Generating such
electrodes precise electrical fields along with a grounded electrode on top
of microchannel (e.g., conductive epoxy or indium thin oxide
The implemented layout of our proposed circuit includes layer [10]) can strengthen DEP forces with precision for LOC
two similar sensing electrodes and other devices schematically applications.
shown in Fig. 4. Microelectronic circuits are often plagued with
parasitic capacitor; hence the need to design a high sensitivity 2.5. Capacitive sensor calibration
Fig. 6. Schematic representation of DWFP technique: (a) ink deposition, (b) encapsulation in epoxy and (c) ink extraction.
calibration of this highly capacitive sensor is necessary, because melt the ink and air pressure (100 kPa) was applied at the inlet
extraneous σC may positively or negatively increase dc offset of microfluidic channel for the ink removal. Robot speed and
included in I resulting in the electronic characteristics being dispensing pressure, obtained experimentally (microscope slide
altered to an unstable state. as substrate, 100 m nozzle and petroleum jelly included 25%
A multidisciplinary real-time set-up is provided to adjust microcrystalline wax) are 1 mm/s and 10 kPa, respectively.
these potentiometers, and to characterize microelectronic circuit The set-up system and materials, which are required for
parameters. In this set-up, the injection of bioparticles into the DWFP are not expensive. This can be a good choice for
channel using a syringe pump, observation of bioparticles using researchers studying chemical, biological through microfluidics
an ultraviolet (UV) microscope and electrical measurements are because using this technique, there is no need to deal with labo-
performed simultaneously. rious and complex infrastructure relevant to microfabrication
clean rooms.
2.6. Direct-write fabrication and assembly process
2.8. CMOS integrated circuit compatibility
Direct-write assembly is a robotic deposition technique used
to produce layer-by-layer microscale structures composed of DWFP is compatible with standard CMOS technology
filaments with either cylindrical, hexagonal or square cross- because it is a low temperature technique with no destructive
sections [16–18]. The filaments are formed during the extrusion chemical solution to damage underlying microelectronic cir-
of a paste-like material through a micronozzle and deposited on cuitries. In addition, DWFP enables the direct fabrication and
a substrate in order to build planar or three-dimensional (3D) integration of microfluidic components on top of CMOS chips.
structures. The DWFP was used to fabricate complex polymer- With other techniques [8,9], microfluidic components are first
based 3D microfluidic structures [19]. The deposition of a fugi- fabricated and subsequently bonded to the chip, requiring care-
tive organic ink scaffold was followed by the infiltration of an ful alignment. DWFP avoids misalignment errors resulting from
uncured epoxy resin. After polymerization, the ink was extracted the adhesive bonding procedure.
at moderate temperature in order to obtain the desired microflu-
idic network (Fig. 6). The compatibility between DWFP and 3. Simulation and experimental results
standard CMOS technology was previously demonstrated [10].
In this section, simulation and experimental results of sens-
2.7. Experimental procedure ing capacitance, interface circuit, microchannel fabrication and
microreservoir fabrication are presented and discussed.
A robotic apparatus (Model I and J 2200, I and J FISNAR
Inc.) controlled by a computer (JR Points, I and J FISNAR Inc.) 3.1. Post-layout interface circuit simulation
was used to perform the deposition pattern. The air-operated
dispensing system (Model 2400, EFD Inc.) was used to extrude The transient output voltage of the interface circuit (Fig. 4)
the fugitive binary organic ink [20] through different micronoz- simulated by CAD tools (Spectre S and Cadence) for different
zles (10, 100 and 200 m inner diameters). The ink was either values of input sensing capacitances (Cs1) are shown in Fig. 7
deposited onto a microscope slide or CMOS chip. During the and the linear relation between output voltage and input sens-
deposition, the speed of the substrate motion was 1 mm/s and the ing capacitances is highlighted in Fig. 8 where the reference
extrusion pressure was experimentally determined. An optically capacitance Cs2 is 5 fF. As shown in these figures, this design
clear epoxy resin (Epoxide 835, Epoxitech Inc.) was poured results in 250 mV/fF sensitivity. Also, in the frequencies lower
to encapsulate the deposited ink filaments and cured at room than 25 MHz, the simulated noise is less than 40 V, which is
temperature. Then, the part was heated to ∼75 ◦ C in order to equivalent to 10 aF.
32 E. Ghafar-Zadeh et al. / Sensors and Actuators A 134 (2007) 27–36
Fig. 11. Conic microreservoir: (a) fluorescent dye filled microchannel and (b) illustration of first layer deposition pattern schematic.
Fig. 12. Microfluidic fabrication on electrical packaged chip: (a) over view and (b) close-up view up die.
of a conic micro-reservoir which will be used to create a required 4 m when using the stereomicroscope (SZX7, Olympus Inc.)
chamber on top of sensor or to attach microscale fluidic fittings. for the manual alignment. In addition, the microrobot step size
The fabrication of this 3D structure was achieved by depositing D is 10 m (Model I and J 2200). Thus, the alignment accuracy
eight layers, each composed of 340 data arc points. The deposi- is (D + E)/2 or ∼7 m.
tion pattern of the first layer is illustrated in Fig. 11b. Optical microscope image of the microelectronic CMOS chip
shown in Fig. 12 indicates the compatibility between electrical
3.4. On-chip microchannel fabrication and fluidic packaging. The microchannel-crossing die is zoomed
in Fig. 12b. The simultaneous fabrication and integration of
A microfluidic fabrication and fluidic connection processes microchannel on top of a CMOS chip was performed in two
are performed on an electrically packaged CMOS chip. The steps: epoxy deposition to fill the spaces around die covering
alignment of the ink deposition process over the desired features the bonding wires and simultaneous fabrication and integration
of the CMOS chip is performed manually. First, the CMOS chip of microchannel by DWFP. Fig. 14d shows the microchip after
is fixed onto the microrobot platform. Then, a small tip needle performing the first step. As shown in this figure, the microchip
(10 m, World Precision Inc.) is moved by the microrobot, set in die is still uncovered by epoxy resin.
manual mode, at specific locations over the substrate (e.g., sens-
ing electrodes) while the alignment is visually performed using a
stereomicroscope. The x, y and z coordinates of the points of the 4. Discussion
deposition trajectory are determined and recorded into the trajec-
tory file. For the fabrication of the straight microchannel shown Microfluidics fabrication, integration and fitting connection
in Fig. 12, the deposition started at one edge of the CMOS chip, can be simultaneously performed onto microelectronic loose die
crossed over the sensing electrodes and ended at the other edge or chip. We demonstrated the flexibility of DWFP for CMOS
of the chip. The minimum feature size of this sensing electrode is based LOC as shown in Fig. 13. The microchannel is fabricated
approximately the same size as the micronozzle tip used during by DWFP right on top of the microelectronic chip and electrodes
this alignment technique. The observation error E is estimated at for a bioparticle sensor.
34 E. Ghafar-Zadeh et al. / Sensors and Actuators A 134 (2007) 27–36
Fig. 14. Optical microscope images of (a) the fugitive ink and fitting, (b) deposited ink from fitting, (c) ink deposition between two substrates in different heights
and (d) epoxy resin surrounding the die.
E. Ghafar-Zadeh et al. / Sensors and Actuators A 134 (2007) 27–36 35
5. Conclusion
(CBCM) technique and three-dimensional simulation, J. Solid-State Cir- tronics. Dr. Sawan’s scientific interests focus on the design and testing of
cuits IEEE 33 (3) (1998). mixed-signal (analog, digital and RF) circuits and systems; digital and ana-
[16] D. Therriault, Directed Assembly of Three-Dimensional Microvascular log signal processing; and the modelling, design, integration, assembly and
Networks, Ph.D. Thesis, University of Illinois at Urbana-Champaign, 2003. validation of advanced wirelessly powered and controlled monitoring and mea-
[17] J.A. Lewis, Direct-write assembly of ceramics from colloidal inks, Curr. surement techniques. These topics are oriented toward biomedical implantable
Opin. Solid State Mater. Sci. 6 (3) (2002) 245–250. devices and telecommunications applications. Dr. Sawan is holder of the Canada
[18] R. Rao, A. Morales, K. Kracik, J.A. Lewis, Micro-fabricated deposition Research Chair in Smart Medical Devices. He heads the Microsystems Strategic
nozzles for direct write assembly of 3D periodic structures, Adv. Mater. 17 Alliance of Québec – ReSMiQ and is founder of the Eastern Canada Chap-
(3) (2005). ter of the IEEE-Solid State Circuits Society. He also founded the International
[19] D. Therriault, S.R. White, J.A. Lewis, Chaotic mixing in three-dimensional IEEE-NEWCAS conference, co-founded the International Functional Electrical
microvascular networks, Nat. Mater. 2 (4) (2003). Stimulation Society, and founded the Polystim Neurotechnologies Laboratory
[20] D. Therriault, R.F. Shepherd, S.R. White, J.A. Lewis, Fugitive inks for at Ecole Polytechnique. He is the editor of Springer mixed-signal letters, Dis-
direct-write assembly of three-dimensional microvascular networks, Adv. tinguished Lecturer for the IEEE Circuits and Systems (CAS) Society, Chair of
Mater. 17 (4) (2005). the IEEE Biomedical CAS (BioCAS) Technical Committee, and member of the
[21] T.T. Kanagasabapathi, C.J. Backhouse, K.V.I.S. Kaler, Dielectrophoresis Biotechnology Council representing the IEEE-CAS Society. He has published
(DEP) of cells and microparticle in PDMS microfluidic channels, in: Pro- more than 350 papers in peer-reviewed journals and conference proceedings, and
ceedings of the NSTI Nanotechnology Conference, 2004. has been awarded seven patents. He received the Barbara Turnbull Award for
[22] L. Shifeng, C. Shaochen, Polydimethylsioxane fluidic interconnects for spinal cord research, the Medal of Merit from the Lebanese President (2005), and
microfluidic systems, Trans. Adv. Pack. IEEE 26 (3) (2003). the J.-A. Bombardier Award from the Association Francophone pour le savoir
[23] A.M. Christensen, D.A. Chang-Yen, B.K. Gale, Characterization of inter- (ACFAS). Dr. Sawan is a Fellow of both the Canadian Academy of Engineering
connects used in PDMS microfluidic systems, J. Micromech. Microeng. 15 and the IEEE.
(5) (2005).
Daniel Therriault received his BEng in Mechanical Engineering and MEng
in Aerospace Engineering from École Polytechnique (1998 and 1999, respec-
Biographies tively). He obtained his PhD in December 2003 from the Department of
Aerospace Engineering at the University of Illinois at Urbana-Champaign
Ebrahim Ghafar-Zadeh received the BSc and MSc degrees in Electrical Engi- (UIUC), where he worked as member of the Autonomic Materials research group
neering from KNT and Tehran Universities, Tehran, Iran, in 1992 and 1994, under the guidance of his advisor, Prof. Scott White. In 2004, he became a faculty
respectively. He is currently pursuing the PhD degree in Ecole Polytechnique de member in the Department of Mechanical Engineering at École Polytechnique.
Montreal, Canada, in circuit and system design, implementation and packaging His current fields of interest are in microfabrication, microfluidics, nanocom-
technologies for lab-on-chip applications. posites, thermal analysis and advanced materials. His patented microfabrication
method based on the direct-write assembly of 3D microvascular networks was
Mohamad Sawan received his BSc in Electrical Engineering from Université published in Nature Materials (2003) and Advanced Materials (2005). Also,
Laval (1984), and MSc (1986) and PhD (1990) both in Electrical Engineer- Daniel worked on several research and development projects including thermal
ing from Université de Sherbrooke. He then completed post-doctoral training analyses of aerospace structures at EMS Technologies (Montreal, Que.) and CU
at Montréal’s McGill University in 1991, and in that same year, joined École Aerospace (Urbana, IL), and structural analyses at the Canadian Space Agency
Polytechnique de Montréal, where he is currently a Professor of Microelec- (St-Hubert, Que.).