Transcript 投影片 1

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Sensing and Actuation in
Miniaturized Systems
FABRICATION PROCESS OF INTEGRATED
MULTI-ANALYTE BIOCHIP SYSTEM FOR
IMPLANTABLE APPLICATION
Author: NY. -C. Tsai, N.-F. Chiu, P.-C. Liu, Y.-C Ou, H.-H. Liao, Y.-J. Yang, L.-J.
Yang, U. Lei, F.-S. Chao, S.-S. Lu, C.-W. Lin, P.-Z. Chang, and W. -P. Shih
Professor: Dr. Cheng-Hsien Liu (劉承賢教授)
Student: Han-Yi Chen (陳翰儀)
Date: 2009.12.29
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Outline
 Introduction
•
•
•
Implantable multi-analyte biochip system
Review
Biocompatible package
Design
 Fabrication
•
•
•
Electrode/glass chip
PDMS microchannel
Biochip integration
PDMS micro-channel
Control and wireless chip
Battery and RF power
Blood inlet and outlet
 Test result and discussion
•
•
DEP micropump test
Cyclic voltammetric measurement
• Current Response Measurement
 Conclusions
 References
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Introduction
Implantable Multi-analyte Biochip System
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 Purpose:
Monitor the physiological parameters (such as glucose concentration)
continuously and simultaneously.
stable and accurate implantable biosensor systems
Thermal metabolic
sensor integrated with
microfluidics
Silicon nanochannel
biological field effect
transistors
Flexible biocompatible
polymer glucose
sensors
Micromachining techniques
used for biosensors
Amperometric biochip
Not been miniaturized
Flexible polymer tube
lab-chip integrated with
microsensors
Smart microcatheter
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Implantable Multi-analyte Biochip System
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 Issues:
 The incompatibility between the biomaterials and the MEMS
processes
 System miniaturization
Schematic of the wireless implantable biochip system
 Coated by parylene-C:
Biocompatible package biocompatibility.
 Circular shape: avoid the tissue
injury during
implantation.
Connected
to blood
vessels for inPDMS micro-channel situ biological detections: increase
the 
performance
of the measurement
Control module:
(1) drive the DEP micropump
Control and wireless chip (2) supply the working voltage to
the electrochemical electrodes
 Wireless
Battery and RF power Supplies
a 3.7 sub-module:
V voltage
microcontroller unit (MCU),
amplifier, and RF transmission
Blood inlet and outlet
section for signal transmission
and process
The programmatic target is to fabricate the microchannel which contains the
micropump and the biosensors to apply implantable multi-analyte biochip system.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Implantable Multi-analyte Biochip System
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 The DEP micropump and electrochemical electrodes are
embedded in the microchannel
Schematic of the PDMS microchannel which contains
dielectrophoresis electrodes and chemical electrodes
Dielectrophoresis
electrodes for separation
of erythrocyte and plasma
Outlet
The motion of the electrolytes can urge
the blood flow in the microchannel
Electrochemistry
detection electrodes
Inlet
 GOD enzyme is coated on the gold working electrode
 Pt & Ag improve the sensor lifetime and accuracy.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Fabrication
Electrode/Glass Chip
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 The electrodes are deposited by e-beam evaporation and patterned by using lift-off
process.
 Dielectrophoresis electrodes:
Number: 36 gold electrodes
Thickness: 180 nm
Area: 500 μm*15 μm
Gap between adjacent DEP electrodes: 15 μm
Dielectrophoresis
electrodes for separation
of erythrocyte and plasma
Outlet
Electrochemistry
detection electrodes
Inlet
Electrochemistry electrodes:
Area: 500 μm*500 μm
Gap: 500 μm
Thickness: Au180 nm, Pt 200 nm, Ag 250 nm
Adhesion layer: 10 nm chromium
Han-Yi Chen, NEMS, NTHU, 12/29/2009
PDMS Microchannel
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500 µm
Dielectrophoresis
electrodes for separation
of erythrocyte and plasma
Outlet
12 mm
40 µm
Electrochemistry
detection electrodes
Inlet
 SU-8 mold on a silicon substrate is patterned by photolithography.
 Then PDMS is applied and cured on the SU-8 mold. The cured PDMS is peeled off
the SU-8 mold and then bonded on electrode/glass substrate.
 The length, width, and height of the PDMS microchannel are 12mm, 500μm, and
40μm, respectively.
 The inlet/outlet section in the microchannel has a large circular area in which the
interconnection can be easily implemented.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Biochip Integration
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Chip assembly process:
(a) Fixing the electrode/glass chip on the
PCB by AB glue.
(d) Bonding the PDMS microchannel by
oxygen plasma.
(b) Wire-bonding and applying AB glue on
the wires for protection.
(e) Connecting the tubes to the microchannel
and then welding ICs on the PCB.
(c) Placing the PDMS lump on the working
and reference electrodes, respectively.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
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Pictures
 Pictures of the electrochemistry detection system and the DEP control module.
(a) Front side: micro-channel and DEP control ICs. (b) Back side: circuit for electrochemical detection.
 The integration of the microchannel electrodes and the control ICs enables
the multi-analyte detection on a single chip and has made the implantable
system practicable.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Test Result and Discussion
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DEP Micropump Test
Optical images of the blood flow driven by the four-phase DEP micropump
 Human blood is used to test the transport capability of the DEP micropump.
Dielectrophoresis
electrodes for
separation of
erythrocyte and plasma
Outl
et
Electrochemistry
detection
electrodes
Inlet
 The driving signal of the DEP micropump is a 25 MHz, 5 V four-phase sine wave.
 The measured blood flow velocity is 14 μm/s.
 This driving condition requires low electric voltage so that the low power
consumption of the DEP micropump can be achieved and be suitable for the
implantable biochip system.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Cyclic Voltammetric Measurement
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Cyclic voltammetric measurement result of different glucose concentrations
 The phosphate buffer solution (PBS) and different glucose concentration solution are
injected into microchannel individually for measurement.
0.25 V
 The measured peak potential for different glucose concentration is about 0.25 V.
 The current response increases with the increasing glucose concentration at 0.25 V.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Current Response Measurement
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Measurement result of the current response after
injecting 50mM potassium ferrocyanide
Constant voltage 0.25 V
50nA
 An current response about 50 nA is obtained after the glucose and 50 mM potassium
ferrocyanide mediator (as a means of shuttling electrons between the immobilized glucose
oxidase enzyme and the electrode surface) is injected into the microchannel.
 The current response decreases with time due to the decreasing concentration.
 Then the phosphate buffer solution is injected to the microchannel, the current level
returns to its initial value.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Conclusions
Conclusions (1)
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 The integration of an implantable multi-analyte system for
continuously in-vivo monitoring important physiological signals
has been proposed and demonstrated.
 By protecting the biomaterials during the oxygen plasma
bonding, multiple biosensors can be easily integrated in the
microchannel.
 The proposed process sequences of the implantable biosensor
system can overcome the difficulty in the system
miniaturization.
 The glucose detection is achieved by using electrochemical
method, and the function of the DEP micropump is verified.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
Conclusions (2)
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 The electrochemistry and DEP control circuits are integrated
with the inductive power coupling and wireless communication
modules.
 A fully packaged miniature system with the total volume of 13
c.c. is achieved. In addition, the GOD enzyme can be replaced
by other enzymes or other bio-marker for different implantable
applications.
Picture of the wireless implanted biochip system
Han-Yi Chen, NEMS, NTHU, 12/29/2009
References (1)
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[1] H. Kudo, T. Sawada, E. Kazawa, H. Yoshida, Y. Iwasaki, K. Mitsubayashi,
“A flexible and wearable glucose sensor based on functional polymers
with Soft-MEMS techniques”, Biosensors and Bioelectronics, vol. 22,
pp. 558-562, 2006.
[2] K. Mitsubayashi, S. Iguchi, T. Endo, S. Tanimoto, D. Murotomi, “Flexible
glucose sensors with a film-type oxygen electrode by microfabrication
techniques”, in Digest Tech. Papers Transducers‘03 Conference,
Boston, June 8-12, 2003, pp. 1201-1204.
[3] L. Wang, D. M. Sipe, Y. Xu, Q. Lin, “A MEMS thermal biosensor for
metabolic monitoring applications“, Journal of Microelectromechanical
Systems, vol. 17, no. 2, pp. 318-327, 2008.
[4] X. Wang, Y. Chen, K. A. Gibney, S. Erramilli, P. Mohanty, “Silicon-based
nanochannel glucose sensor”, Applied Physics Letters, vol. 92, 013903,
2008.
[5] J. Wu, J. Suls, W. Sansen, “The glucose sensor integratable in the
microchannel”, Sensors and Actuators B, vol. 78, pp. 221-227, 2001.
[6] A. Guiseppi-Elie, S. Brahim, G. Slaughter, K. R. Ward, “Design of a
subcutaneous implantable biochip for monitoring of glucose and
lactate”, IEEE Sensors Journal, vol. 5,no. 3, pp. 345-355, 2005.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
References (2)
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[7] M. Pepper, N. S. Palsandram, P. Zhang, M. Lee, H. J. Cho,
“Interconnecting fluidic packages and interfaces for micromachined
sensors”, Sensors and Actuators A, vol. 134, pp. 278-285, 2007.
[8] C. Li, P.-M. Wu, J. Han, C. H. Ahn, “A flexible polymer tube lab-chip
integrated with microsensors for smart microcatheter“, Biomed
Microdevices, vol. 10, pp. 671-679, 2008.
[9] C. Y. Yang, U. Lei, “Dielectrophoretic force and torque on an ellipsoid in
an arbitrary time varying electric field”, Applied Physics Letters, vol. 90,
153901, 2007.
[10] P. A. Fiorito, S. I. Cordoba de Torresi, “Glucose amperometric biosensor
based on the Co-immobilization of glucose oxidase (GOx) and Ferrocene
in poly(pyrrole) generated from ethanol/water mixtures”, J. Braz. Chem.
Soc., vol. 12, no. 6, pp. 729-733, 2001. 207
Han-Yi Chen, NEMS, NTHU, 12/29/2009
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Thank you for
your attention!!
Han-Yi Chen, NEMS, NTHU, 12/29/2009
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Back-up Foil
Biochip Integration
The process for fabricating the implantable biosensor system should be carefully
designed to resolve the incompatibility of the biomaterials and to achieve the
system miniaturization. The electrode/glass chip is fixed on the printed circuit
board (PCB) by AB glue (Figure 3(a)). The electrodes on the glass substrate are
connected to the corresponding pads on the PCB by applying wire-bonding.
The wires are then covered by the AB glue which serves as the protection layer in
the following process steps (Figure3(b)). The wire-bonding process should be
carried out prior to bonding the PDMS microchannel on the glass substrate.
Otherwise, the PDMS microchannel would hinder the view for aligning the
electrodes with the bonding pads in the wire-bonding process. The AB glue must
not cover the electrodes on the electrode/glass chip for the success of bonding the
PDMS microchannel. Before bonding the PDMS microchannel, the Ag/AgCl
reference electrode is chloridized. The enzyme polymerization on the Au working
electrode should also be carried out prior to bonding the PDMS microchannel
because it is difficult to proceed in the microchannel. The electroplating method is
used to chloridize the Ag/AgCl reference electrode. A 0.1M NaCl solution is applied
on the electrode/glass chip. Meanwhile, the platinum and silver electrodes are
protected. In the electroplating process, the current density is 40μA/cm2. The
processing time is 10 minutes. The polypyrrole (from Merck) and GOD mixture is
electrochemically polymerized on the working electrode by controlling the voltage
from 0V to 1.2V in a cyclic voltammetry. After the GOD polymerization, the working
electrode becomes dark brown.
Han-Yi Chen, NEMS, NTHU, 12/29/2009
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Back-up Foil
To bond the PDMS microchannel onto the glass substrate, the bonding surfaces
should be modified by using oxygen plasma. It should be noted that the working
electrode and the Ag/AgCl reference electrode should be covered for avoiding direct
contact with the oxygen plasma (Figure 3(c)). Otherwise, the enzyme on the working
electrode will be damaged, and the Ag/AgCl reference electrode will be oxidized. The
microchannel which is bonded on the glass substrate is illustrated in Figure 3(d).
Finally, the tubes are connected with PDMS microchannel. The interconnection is
sealed by AB glue (Figure 3(e)). The polyethylene tube has 0.86mm inner diameter
and 1.27mm outer diameter. In order to make the compact interconnection, the “L”
shape passage of 1.25mm diameter is used. The diameter of the passage is slightly
smaller than the outer diameter of the tube. The elastic PDMS passage can tightly
clamp the tube and avert the AB glue from permeating into the microchannel by
capillary force.
Han-Yi Chen, NEMS, NTHU, 12/29/2009