SE@RS ACtl~AfoRs

ELSEVIER Sensors and Actuator5 A 64 (1998) 57-63 A

PHYSICAL

Partly disposable three-way rnicrovalve for a medical micro total analysis system (pTAS)

Takahiro Ohori *, Shuichi Shoji, Keisuke Miura, Akira Yotsumoto Departfllent of Electronics, Information and Communication Engineering, Waseda Uni\vrsir): 3-4-1, Old&o, Shinjh-klr, TO/~YJ 169, Japn

Abstract

In order to realize a practical medical micro total analysis system ( pTAS), a partly disposable three-way microvalve has been developed. The separate channel structure and pneumatic actuation are employed considering the problems of whole-blood handling. The microvalve has

advantages of easy assembly, large on/off flow ratio (about IO’), no bubble problem, low cost due to the partly disposable structure and perfect process matching to microchemical sensors (amperometric sensors or ISFETs). 0 1998 Elsevier Science S.A.

Keyw~ords: Microvalves; Pneumatic actuators; ,uTAS: Three-way valves; Disposable valves

1. Introduction

Many micro flow-control devices consisting of microval- ves, micropumps and micro flow sensors have been devel- oped in the past 10 years [ 11. These devices open new possibilities for the miniaturization of conventional chemical and biochemical analysis systems. The micro total analysis system ( PTAS), including microfabricated detectors (sili- con-based chemical sensors, optical sensors, etc.), micro flow-control devices and control/detection circUits is a practical microelectromechanical system (MEMS). Two approaches of monolithic and hybrid integration of these devices have been studied in PTAS. Both the monolithic type and the hybrid type of flow-injection analysis (FIA) systems have been demonstrated [ 2,3]. In fact, a combination of the partly integrated components and discrete components will be useful in many cases [4]. To fabricate such systems, bonding and assembling methods play very important roles [51.

In medical and biomedicalapplications, a yTAS has to be designed considering the properties of the sample fluid. espe- cially in a whole-blood analysis (for example, coagulation, adhesion of proteins and biological cells, viscosity, etc.). Prototypes of whole-blood-gas analysis systems using microvalves driven by shape memory alloy (SMA) actuators [ 61 and piezobimorph actuators [7] have been developed. Problems of blood coagulation and protein adhesion have to be solved in such systems. To avoid blood coagulation, a

* Corresponding author.

0924-4247/98/$19.00 0 1998 Elsevier Science S.A. All rights reserved PIISO924-4247(97)01654-3

simple and smooth channel structure which has no dead vol- ume is required. Another problem is that whole blood has a high viscosity, making the microchannel resistance high. Handling whole blood is very challenging work; however, it is very important to realize a medical ,uTAS. In this paper. general considerations for a medical ,uTAS are described first. Then the design, fabrication and characteristics of a novel three-way microvalve suitable for whole-blood handling are presented.

2. General consideration of medical pTAS

A disposable ,uTAS will be ideal for medical use. How- ever, the high fabrication cost of a sophisticated ,LLTAS including micropumps and microvalves is a problem. One basic setup of a medical ,uTAS considering this problem is illustrated in Fig. 1. A detector cell consisting of microsensors and a three-way microvalve is placed at the sample inlet. The sample flow and cleaning solution flow are controlled by a suction pump and an injection pump connected to the detector cell. The calibration solution flow is also controlled by another injection pump. The calibration flow and the cleaning solution flow are switched by a three-way valve. The sample solution after measurement, the calibration solution and the cleaning solution are wasted through the three-way micro- valve on the cell. In this system, sample flow comes up only to the detector cell. Since the upper parts of the system are free from contamination and corr&, the system can be reused by disposing only of the detector cell. To realize this

58 T. Ohori et al. /Sensors andiictuntors A 64 (1998) 57-62

3-way V&T

Bloixi Sample Ink

Fig. 1. Schematic of a blood total analysis system

system, a three-way microvalve which can handle whole blood is indispensable.

Blood viscosity in the 40 to 150 p,rn wide, 20 and 40 pm deep microchannels was studied [ 81. The viscosity depends on blood cell content, plasma protein concentration, temper- ature, etc. Flow characteristics of the shallow microchannels, 20 and 12 pm deep, 11 mm long, 400 pm wide fabricated between silicon and glass were measured for deionized (DI) water, albumin content water (1 and 10 wt.‘%) and whole blood. The results are shown in Fig. 2. The 12 pm deep channel shows quite high flow resistance, compared to the 20 pm deep one. in blood flow. The depth of the flow channels should thus be larger than 20 pm.

3. Design and fabrication

3.1. Design

A separable channel-type microvalve whose channel part is disposable while the actuator part is reusable is useful for the three-way microvalve. Mechanically fixed stack struc- tures, including disposable parts, will be practical in a medical ,uTAS. The structure of the three-way microvalve is shown in Fig. 3. It consists of two mechanically fixed parts: a dis- posable channel part and an actuator part. This structure ena- bles easy assembly, which is most important in practical use.

40 Glass 400~.

35 - -Waler -c 1wtZ Albumin + lOwt% Albumin

0 llmnl long

0.0 b.5 1.0 1.5 2.0

la) Applied Pressure [m’l&O]

o]-’

llmm long

Channel Structure

0.0

(b) 1.0 2.0 3.0 Applied Pressure [mH;O]

4.0

Fig. 2. Applied pressure vs. flow rate of the microchannel for water, albumin content water and whole blood: (a) 20 pm deep, 400 p,rn wide, 11 mm long; (b) 12 pm deep, 400 pm wide, 1 I mm long.

i< 8.5 ---- m m ’

(a) Bottom View of the Channel Part

(b) Cross-Sectional Vielv i-1

Pneumatic C%amber

I J (c) Top View of the Actuator Part

Fig. 3. Structure of the three-way microvalve.

A pneumatic actuator was chos,en because of its large dis- placement and relatively high available pressure. Slow response of the actuator (about 1 s) is not a big problem because the typical flow rate in the microvalve ranged from one to tens of microliters per minute. The flow channel and

T. Ohori er al. /Sensors rXActuarors A 6+‘-11998) 57-62 59

Closed

(1) Mode 1

Of

. Clc ,sed

(2) Mode 2

pen

(3) Mode 3 Fig. 4. Operation modes of the three-way microvalve

the pneumatic chambers are made between the polymer membrane and the silicon substrate using positive photoresist as a sacrificial layer [ 91.

A microvalve using spin-coated silicone rubber has been reported [ lo]. The flow channel is divided into three zones having one inlet/outlet port, each of which is driven by the pneumatic actuator. The channel part has an oval cavity and three through-holes. The actuator part has right and left C- shaped chambers, and a center oval chamber. Three different modes of operation are possible, as shown in Fig. 4. Since each zone of the flow channel is covered entirely with the flexible membrane, dead volume is minimized and a perfect seal is obtained even if small particles exist. Silicone rubber about 40 p,rn thick is used as the polymer membrane.

3.2. Fabsication

The fabrication process of the channel part is as follows (Fig. 5): 1. The oval cavity 30 brn in depth was fabricated by TMAH

anisotropic etching (a). 2. After oxidation, three through-holes were engraved by

hydrazine-water anisotropic etching from the backside, leaving a thin SiO, layer 3000 A thick on the top side (b)

3. Thick positive photoresist (30 p.,m thick, Tokyo Ohka, OFPR-800) was spin-coated and was patterned to fill up the oval cavity (c) .

4. A silicone rubber membrane about 40 p,rn in thickness (Shinetsu Silicone, KE47 ) was formed by spin-coating using diluted silicone with xylene (d) .

- -

Si

(4

(b)

Si anisotropic etching

-- :. 1 Si anisotropic etching

Positive Photoresist

3, ., :’ ’ ., - ‘- .- I

Positive photoresist patterning

(4

’ 7 f-7 I” +$ kCOMector (e) Oxide etching and photoresist removing

Fig. 5. Fabrication process of the channel part.

5. Inlet/outlet connectors were glued to the wafer with an epoxy resin (Varian Vacuum Products, Torrl Seal) (e) .

6. The SiO, membrane was etched from the backside. The positive photoresist was subsequently removed thxugh the hole using acetone. The wafer was immersed in iso- propyl alcohol and then dried (e) During the drying proc- ess, compressed air flow was applied to the channel to prevent the membrane from sticking to the substrate. The fabrication process of the actuator part is as follows

(Fig. 6): 1. After oxidation, a through-hole was engraved by hydra-

zinc-water anisotropic etching, leaving a thin SiOz layer on the top side (a).

2. Thick positive photoresist (5 p,rn in thickness) was spin- coated and patterned (b) .

3. A silicone rubber membrane about 40 p,m thick was formed by spin-coating (c)

4. Connectors were bonded with epoxy resin (d) , 5. The SiO, was etched from the backside. The positive

photoresist was subsequently removed through the hole using acetone. The wafer was immersed in isopropyl alco- hol and dried (e)

4. Characteristics

Flow characteristics of the microvalve were measured with the setup illustrated in Fig. 7. The three operation modes shown in Fig. 4 were tested. First, port 2 of the channel part was used as the inlet. Port 1 and port 3 were used as outlet 1 and outlet 2, respectively (mode 1). DI water was used as a sample liquid (at 25°C). Fig. 8(a) and (b) shows the flow

60 T. Ohori et al. /Sensors and Amotors A 64 (1998) 57-62

._ SiO7

@) Positive photoresist patterning

(c) Silicone rubber spin-coating

: t ! 1 i _ .j ‘+ ‘) { ‘k !

Connector (d) Oxide etching and photoresist removing

Fig. 6. Fabrication process of the actuator part

Sample Liquid

Micro Pipet (Outlet 1)

Standard Pressure Generator

3-way Valves Leak Leak

Fig. 7. Measurement setup of the three-way microvaive.

rate of DI water from outlet 1 and outlet 2 versus the air pressure applied to the right-hand pneumatic chamber. A shut-off flow rate smaller than lo- ’ ~1 min.- ’ is obtained at the inlet pressure of 1 mH,O. The on/offflow ratio was about 104. Next, port 1 of the channel part was used as the inlet, and port 2 and port 3 were used as outlet 1 and outlet 2 (mode 2). Fig. 9(a) and (b) shows changes of the flow rate of DI water from outlet 1 and outlet 2 versus the airpressure applied to the center pneumatic chamber. A shut-off flow rate smaller than 10-l $ min-’ is also obtained at the inlet pressure of 1 mH,O. The on/off flow ratio was about 10’. Hysteresis due to the stiction between membrane and substrate was some- times observed.

0 1 2 3 Applied Pressure [m&O]

(a) Outlet 1 100

K

Inlet Pressure +-0.1

wwl - 0.3 -0.5

\r, -H-l

0 1 2 3 4 5 Applied Pressure [mHzO]

@) Outlet 2 Fig. 8. Characteristics of the microvalve (mode 1).

6

1000 g 100

Inlet Pressure hO.1 - 0.3

: s 10 2 Ffi!ii I~201 -0.5

-1

i-2 1

E 0.1

0.01 !ssz 0 1 Appliei PresZre 4 5 6

[m&O]

(a) Oiltlet 1

Inlet Pressure [m&O] -0.1 -0.3

0 1 2 3 4 Applied Pressure [mH,O]

(b) Outlet 2 Fig. 9. Characteristics of the microvalve (mode 2).

T. Ohori er al. /Sensors and Aciuators A M(1998) 57-62 61

+-0.1 -0.3

0.1 '

0 0.2 0.4 0.6

Applied Pressure [mHzO] Fig. 10. Characteristics of the microvalve without the membrane of the channel part (mode 2, outlet 1).

5. Discussion

A simple three-way microvalve has also been fabricated removing the silicone membrane of the channel part. The flow characteristics of the microvalve were measured (mode 2). Fig. 10 shows the change of the flow rate of DI water from the outlet 1 on increasing the air pressure applied to the center pneumatic chamber. A shut-off flow rate less than 1 O- ’ p+l min- ’ is obtained for small applied pressure. The on/off flow ratio was larger than 104, which is better than that of the three-way valve described above. This structure can be useful in some applications.

Sticking of the silicone membrane to the substrate is a problem to be solved for actual use. To avoid this during the fabrication, the drying process after the removal of the sac- rificial layer was devised as described above. Sticking is sometimes observed during the valve operation. This problem can be improved by roughening the surface of the silicon substrate using plasma dry etching [ 1 l] or by making shallow channels on the substrate.

6. Conclusions

A partly disposable three-way microvalve driven by a pneumatic actuator was developed. It has advantages of easy assembly, large on/off flow ratio (about 104), no bubble problem, low cost due to the partly disposable structure and perfect process matching to microchemical sensors, The valve structure will be applicable for many medical flow systems.

Acknowledgements

The authors are grateful to IS. Yanagisawa and E. Shino- hara of Olympus Co. for their support. We also thank T. Sekiguchi of Nikon Kohden Co. and J. Mizuno of Zexel Co. for their assistance in the fabrication of the device. This work is partly supported by the Japanese Ministry of Education Science and Culture under a Grant-in-Aid for Scientific Research (C) No. 076505 13.

References

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[ 21 S. Shoji, S. Nakagawa and M. Esashi, Micropump and sample-injector for integrated chemical analyzing systems, Sensors and Actuators, A21-A23 (1990) 189-192.

[3] B.H. van der Schoot, E.M.J. Verpoorte, S. Jeanneret, A. Manz and N.F. de Rooij, Microsystems for analysis in flowing solutions, in A. van den Berg and P. Bergveld (eds.), Micro Total Analysis Systems, KIuwer, Dordrecht, The Netherlands, 1993, pp. 181-190.

[4] T.S.J. Lammerink, V.L. Spiering, M. Elwenspoek. J.H.J. Fluitmanand A. van den Berg, Modular concept for fluid handling systems - a demonstrator micro analysis system, Proc. IEEE Micro Electra Mechanical Systems Workshop, San Diego, CA, USA, Feb. 1996, pp. 389-394.

[5] S. Shoji and M. Esashi, Bonding and assembling methods forrealizing a PTA.% in A. van den Berg and P. Bergveld (eds.), Micro Total Analysis Systems, Kluwer, Dordrecht. The Netherlands, 1994, pp~ 165-179.

[ 61 S. Shoji, M. Esashi and T. Matsuo, Prototype miniature blood gas analyzer fabricated on a silicon wafer, Sensors and Actuators, 14 (1988) 101-107.

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Biographies

Tahahiro Ohori received his B.Eng. and MSc. degrees in electronics and communication engineering from Waseda University, Tokyo, in 1995 and 1997. He is currently working at Toshiba Co. His research interests are micro fluidic devices and systems.

Shuichi ,Shoji received his B.Eng. and Ph.D degrees in electronics engineering from Tohoku University, Sendai, Japan, in 1979 and 1984. From 1979 to 1992 and from 1992 to 1994, he was a research associate and an associate professor of Tohoku University. He moved to the Department of Elec- tronics and Communication Engineering, Waseda Univer- sity, Tokyo, as an associate professor in 1994. Since 1997, he has been a professor of the Department of Electronic$ Information, and Communication Engineering, Waseda Uni- versity. He is working on silicon-based microsensors and microsystems mainly for medical use.

62 7. Ohori et nl. /Sensors and Actuators A 64 (1998) 57-62

Keiwke Micra received his B.Eng. degree in 1997 from Waseda University and is currently a graduate student in the Department of Electronics, Information and Communication Engineering. His research work is oriented towards the devel- opment of microsensing systems for blood analysis.

Akira Yutsz~~~o received his B.Eng. degree from Waseda University in 1997 and is currentIy a graduate student in the Department of Electronics, Information and Communication Engineering. His interests lie in micro chemical total analysis systems, biochemical analysis and reaction systems.