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Biomedelical micodevices, 3-2, (2001), 97-108. [3] J. C. Jones, “The feeding behavior of mosquitoes”, Scientific American, 238, (1978), 112-120. [4] K. Tsuchiya ...

Development of Wearable Medical Device for Bio-MEMS Naoyuki NAKANISHI1, Hidetake YAMAMOTO2, Kazuyoshi TSUCHIYA3, Yasutomo UETSUJI4 and Eiji NAKAMACHI4 1

Graduate School, Osaka Institute of Technology, 5-16-1 Omiya, Asahi-ku, Osaka 535-8585, Japan. ASTM Research Institute of Kyoto, 134 Chudojiminamicho, Shimogyo-ku, Kyoto 600-8813, Japan. 3 Dept. of Precision Eng., Tokai University, 1117 Kitakaname, Hiratsuka, Kanagawa, 259-1292, Japan. 4 Faculty of Mech. Eng., Osaka Institute of Technology, 5-16-1 Omiya, Asahi-ku, Osaka 535-8585, Japan. 2

ABSTRACT Biomedical Micro Electro Mechanical Systems (Bio-MEMS) have been applied to the development of a variety of health care related products including health Monitoring Systems (HMS) and Drug Delivery Systems (DDS). We focus on research to develop the new type compact medical device used for blood sugar control. The new type compact medical device comprises (1) a micropump system to extract blood using a pressure change occurred by electrolysis, (2) a platinum (Pt) electrode as a blood sugar sensor immobilized Glucose Oxidase (GOx) and attached to the gate electrode of Metal-Oxide-Semiconductor Field Effect Transistor (MOSFET) to detect the amount of glucose in extracted blood, and (3) a micropump system to inject insulin using a pressure change occurred by electrolysis. GOx was immobilized on a self assemble spacer combined with a Pt electrode by the cross-link method using BSA as an additional bonding material. The device can extract blood in a few microliter through a painless microneedle with the micropump, which used the pressure change occurred by electrolysis. The liquid extraction ability of the micropump system through a microneedle, which is 3.8 mm in length and 100 μm in internal diameter, was measured. The wearable medical device with using the micropump controlled by electrolysis could extract human blood at the speed of 0.15 μl/sec. If the wearable medical device extracts human blood for 6 seconds, it is enough human blood volume to measure a glucose level, compared to the amount of commercial based glucose level monitor. The electrode embedded in the blood extraction device chamber could detect electrons generated by the hydrolysis of hydrogen peroxide produced by the reaction between GOx and glucose in extracted blood of a few microliter, using the constant electric current measurement system of the MOSFET type hybrid glucose sensor. The output voltage for the glucose diluted in the chamber was increased lineally with increase of the glucose concentration. The compact medical device with the air bubble that occurred by electrolysis could inject insulin at the speed of 6.15μl/sec. Key words: Bio-MEMS, Wearable medical device, Blood sugar level control, Micropump controlled by electrolysis, Microneedle, Glucose sensor, Inslin

1.

INTRODUCTION

The development of safe and compact electric machines for the human body based on Biomedical Micro Electro Mechanical Systems (Bio-MEMS) technology is one of the most important research themes in the field of medical engineering. Bio-MEMS has been applied to the development of a variety of health care related products including Health Monitoring Systems (HMS) [1] and Drug Delivery Systems (DDS) [2]. An important objective in HMS is to be able to continuously monitor human health by checking blood conditions because human blood contains manifold health index markers. For instance, in diabetes mellitus, the determination of blood glucose level in extracted blood is extremely important for its diagnosis and effective management. If diabetes patients have to check the blood sugar level 4 to 7 times a day by the Self Monitoring of Blood Glucose (SMBG) and inject insulin to control the value. However, a frequent study of these processes has some trouble to patients.

In this study, we have developed a wearable medical device for bio-MEMS such as the SMBG. The SMBG device can extract a few microliters of blood through a painless microneedle by a negative pressure produced by the deflection of an actuator in a blood tank. This approach is similar to a method used by the female mosquito when it flexes and relaxes its muscles in order to extract human blood. Figure 1 shows the wristwatch type medical device where the components are contained in the back case of the watch. The wristwatch type medical device comprises five elements: (1) a painless biocompatible microneedle; (2) an indentation unit to force the microneedle through the skin; (3) a micropump system to extract human blood; (4) a glucose sensor to detect and evaluate the amount of glucose in the extracted blood; and (5) a micropump system to inject insulin. In this paper, we will report the production of three of these elements. (1) a development of wristwatch type medical device, (2) a micropump system to extract blood using an air bubble that occurred by electrolysis, and (3) a micropump system to inject insulin using a pressure change occurred by electrolysis. The extracted blood is analyzed by using a glucose sensor fixed in the chamber of the device. We aim to use a micropump device to extract less than 1 μl of human blood, and measure a liquid extraction speed and injecting speed for insulin solutions.

Transmit data by radio Medical device

SMA indentation actuator

SMA indentation actuator

Blood extraction micropump Glucose sensor

Home PC (data base)

Blood extraction device

Drug injection micropump

Drug microneedle injection Microneedle device Figure 1: Schematic diagram of wristwatch type medical system.

2.

DESIGN OF WRISTWATCH TYPE MEDICAL DEVICE

A schematic diagram of wristwatch type medical device as a proto type is shown in Fig.2. The device consists of the main body, the circuit board, a Shape Memory Alloy (SMA) indentation actuator and two types of the micropump system, which has a painless microneedle. These micropumps are a blood extraction and a drug injection micropump, respectively. A SMA actuator is employed to generate the skin penetration force in combination with a microneedle and a bias spring. The SMA actuator is heated by an electric current and moves a micropump three millimeters to generate a skin penetration force. It is held steady for few seconds, for a micropump. During that time, a micropump extracts blood or injects insulin by applied AC voltage. The electric current is then shut off and the bias spring returns the microneedle and micropump to the initial position. And also, this device can transmit a blood sugar level to the PC data storage by radio frequency after a blood sugar level was measured by using a glucose sensor. An extracted blood is sensed by a glucose sensor immobilized on a platinum plate embedded in a lower tank of the micropump, a plate type studying electrode is connected with a gate electrode of Metal-Oxide-Semiconductor Field Effect Transistor (MOSFET).

52

52

Drug injection micropump Wrist belt

Circuit board 35

SMA indentation actuator

Pin probe electrode Blood extraction micropump

Figure 2: Mechanism of blood extraction and drug injection micropumps in wearable medical device.

Circuit board

Data base

Main body Signal reception base

Drug Injection micropump

Medical device

Blood extraction micropump Figure 3: Proto type of Wristwatch type medical system.

3.

PERFORMANCE OF BLOOD EXTRACTION MICROPUMP SYSTEM CONTROLLED BY ELECTROLYSIS FOR HMS

When a female mosquito sucks blood, the labium is penetrated to a skin at the speed of 6 to 7 Hz by its head moving like a hammer [3]. After a labium was penetrated to a skin, the penetrated labium is used to extract a human blood. For the extraction method, first of all, a muscle valve is relaxed and a muscle of the mouth pump is tensed. Therefore, human blood is extracted through the labium into a mouth pump. Secondly, the muscle is relaxed and the extracted blood is sent into a pharyngeal pump. Finally, a posterior pharynx valve is loosened. The extracted blood is sent into an esophagus. Consequently, the mosquito’s blood pumping system is driven by negative pressure. For a blood extraction device to generate negative pressure, a piezoelectric micropump is one of the candidates. In our previous study, a piezoelectric micropump has been developed by using a bimorph PZT piezoelectric actuator to extract the blood. However, a blood extracting speed by the micropump using a bimorph PZT piezoelectric actuator is so slow, which speed is 0.033 μl/sec [4]. This micropump is not suitable for blood extraction. Therefore, from another viewpoint, we will propose a new micropump to extract blood using a pressure change occurred by electrolysis. Figure 4,

figure 5 and figure 6 show the principle of blood extraction using a pressure change occurred by electrolysis, the proto design of a blood extraction micropump and the proto type of a blood extraction micropump. This blood extraction micropump consists of a microneedle with an inner diameter of 100 μm, an upper chamber, a lower chamber and a chamber separator between an upper and a lower chamber. The chamber separator is made of a silicon rubber sheet. The upper chamber and the lower one are called electrolytic cell and sensor cell, respectively. The blood extraction micropump has two electrode plates in the electrolytic cell. The silicon rubber separates the electrolytic cell off the sensor cell. The upper chamber, the lower chamber and the inside of a microneedle are full filled by a solution such as physiological saline. The size of platinum electrode is 3 mm in length, 2 mm in width and 0.2 mm in thickness. The reason is that platinum shows very small ionization tendency and is a very stable material of all. The blood extraction mechanism is as follows. First, when AC voltage is applied to two electrode plates, air bubbles are generated on the electrode surface. Secondly, when the cubical expansion in the electrolytic cell is occurred by the generated bubble, the silicon rubber push a physiological saline in the sensor cell and a physiological saline is drained from the edge of microneedle to outer the sensor cell. Thirdly, when the electric current is shut off, silicon rubber is restored to initial shape by elastic recover of the silicon rubber. At the same time, electrolytic solution will be drained from an upper outlet to outside. Finally, the blood extraction micropump extracts human blood through microneedle. The extracted blood dilutes with physiological saline in the sensor cell. This allows us to extract human blood. It is possible to inject insulin by adding positive pressure to an insulin tank with a microneedle. Therefore, a micropump to inject insulin has the same mechanism as blood extraction micropump.

Electrolytic solution

Electrode plate

Physiological saline

Outlet

Microneedle

Silicon rubber

Bubble (a) Initial position

Deflection (c) Stop voltage (Blood extraction)

(b) Impression voltage (Drainage)

Figure 4: Principle of blood extraction controlled by electrolysis.

Upper chamber

Outlet Connection clip

Lower chamber

Glucose sensor

Microneedle Figure 5: Proto design of blood extraction micropump.

Electrolytic cell

Medicine cell

Electrode plates

Silicon rubber

Upper chamber

Lower chamber (a) Upper chamber

(b) Lower chamber

Figure 6: Proto type of blood extraction micropump.

Figure 7 shows verification result of volumetric expansion occurred by the electrolysis reaction in the upper chamber. The air bubbles were appeared on the surface of two electrode plates when AC voltage was applied. Therefore, when the volume of the tank is increased by generation of air bubbles, a physiological saline will be able to be drained due to the pressure increase in the chamber.

Electrode plates, Pt Acrylic chamber Electrolytic solution (a) Initial condition Generation of bubble

(b) Start of electrolysis (t=0s) Volumetric expansion of solution

(c) Volumetric expansion in upper chamber (t=5s) Figure 7: Verification of volumetric expansion by electrolysis in upper chamber of drug injection micropump.

The liquid extracting ability by using the micropump was measured. The liquid sampling ability of the pumping unit varies with a draining time and an extracting time. Therefore, a draining time and a extracting time are determined 5 and 10 seconds, and 3, 5, 7 and 10 seconds, respectively.

Figure 8 shows an extraction speeds for distilled water, where the applied voltage and AC frequency is 20V and 16Hz, respectively. In this study, blood extraction micropump has no outlet. When silicon rubber is flexed down below, physiological saline is sensor cell is drained from microneedle to outer sensor cell. The micropump could extract distilled water at the speed of 4 μl, when draining time was 5 seconds and extracting time was 3 seconds. Furthermore, the micropump when the draining time was 10 seconds and the extracting time was 3 or 10 seconds could extract distilled water at the speed of 5μl and 14μl, respectively. The extraction volume increased linearly with the extracting time. Moreover the extraction volume of t=10 was larger than that of t=5. 16 Drai nage time t=5sec

Extracted volume (μl)

14

Drai nage time t=10sec

12 10 8 6 4 2 0 0

2

4

6 Extracting time (sec)

8

10

12

Figure 8: Relationship between extracting time and extracted volume using water.

Figure 9 shows the extracted volume of distilled water and a human whole blood, where the applied voltage and AC frequency were 20V and 16Hz, respectively. The micropump could extract distilled water and human blood at the volume of 2.54 and 0.4 μl, when the draining time is 5 seconds and the extracting time is 3 seconds. Further the micropump could extract distilled water and human blood at the speed of 14 and 3.05 μl, when the draining time 5 seconds and the extracting time were 20 seconds. So, as for the extracted volume of human blood, the amount of 1 μl approximately is needed in order to analyze blood sugar level, when the draining time is 5 seconds and the extracting time is 7 seconds.

Extracted volume (μl)

15 Bl ood W ate r

12 9 6 3 0 0

5

10 15 Extracting ti m e (se c)

20

25

Figure 9: Relationship between extracting time and extracted volume using blood and water.

Figure 10 shows the comparison of the liquid extracting ability of the micropumps by the electrolysis method and the piezoelectric method. The blood extracting ability of the micropump by the electrolysis method was 4.6 times larger than the blood extracting ability of the micropump by a bimorph PZT piezoelectric actuator. Therefore, it is clear that the micropump by electrolysis method is superior to the one by piezoelectric method in the extracting speed.

Flow volume (μl/sec)

1 0.8

Wate r Blood

0.6 0.4 0.2 0 pie z oe le ctric

Ele ctrolysis

Figure 10: Comparison of Flow volume of blood extraction between the piezoelectric and the electrolysis micropumps.

4.

PERFORMANCE OF INSULIN INJECTION MICROPUMP SYSTEM CONTROLLED BY ELECTROLYSIS FOR DDS

Amount of insulin to control the blood sugar level is 20 several units on a day. Amount of insulin for the injection one time is determined 60 μl approximately. In order to control the blood sugar level, the accuracy of the drug injection micropump to inject insulin in a few ten’s of microliters is need. In this chapter, the injection speed and the accuracy of the micropump developed in this study were discussed. In this measurement, the microneedle which was 3.8 mm in length and 100 μm in internal diameter was used. The same mechanism as blood extraction micropump was used for the micropump to inject insulin. The drug injection micropump has no outlet and no glucose sensor. And physiological saline is insulin. The drug injection micropump was mounted in SMA indentation actuator and was used to inject insulin. Figure 11 shows verification result of injecting insulin by the drug injection micropump. Firstly, a micropump with microneedle was going down by a SMA actuator. Secondly, the micropump drained insulin from a microneedle. Drug injection micropump

SMA indentation actuator

(a) Initial condition Indentation stroke of SMA Drainage of insulin

(b) SMA action

(b) Drain of drug

Figure 11: Verification of SMA action and drug drain.

The liquid draining ability of the micropump through a microneedle was measured as the applied voltage was 20V and AC frequency was changed from 16Hz and larger. Here, distilled water was used as a simulation medicine to the measurement. Figure 12 shows the relationship between flow volume and AC frequency varying with silicon rubber sheet thickness as a chamber separator when insulin is drained by using the drug injection micropump. According to the result, the flow volume decreased linearly with increasing AC frequency and partition thickness. The micropump could drain distilled water at the speed of 6.5 μl/sec with a maximum, where the applied frequency was 16Hz and the partition thickness was 0.1 mm. The flow volume of micropump using 0.1mm thickness of the silicon rubber sheet was 36 % larger than that using 0.5mm of it. The draining time took 9.2, 9.3, and 14 seconds in order to drain 60 μl when partition thicknesses were 0.1, 0.3 and 0.5 mm.

7 Partition thickness 0.1mm Partition thickness 0.3mm

Flow volume (μl/sec)

6 5

Partition thickness 0.5mm

4 3 2 1 0 0

50

100 150 AC frequency (Hz)

200

250

Figure 12: Relationship between flow volume and AC frequency.

5.

CONCLUSIONS

In this study, a new type micropump driven by electrolysis, which was able to be used as both mechanisms of blood extraction and drug injection for a wearable medical device to control blood sugar level, has been developed and injection capability was evaluated. The following knowledge were obtained: ・A proto type of wristwatch type medical device was developed, which consisted of a main body, a circuit board, a SMA indentation actuator and blood extraction and drug injection micropumps, which had a painless microneedle. ・A extracting speed for whole blood extracted by a pressure change occurred by electrolysis for a drug injection micropump was 0.15 μl/sec. ・A draining speed for insulin drained by a pressure change occurred by electrolysis for a drug injection micropump was 6.15 μl/sec.

ACHNOWLEDGEMENTS This study is a result on development of wristwatch type medical device supported by Japan Science and Technology Agency and Kyoto City Collaboration of Regional Entities for the Advancement of Technological Excellence.

REFERENCES [1] Oki A., Takai M., Ogawa H., Takamura Y., Fukasawa T., Kikuchi J., Ito Y., Ichiki T. and Horiike Y., Jpn. J. Appl. Phys., 42, (2003) 3722-3727 (in Japanese). [2] F. J. Martin and C. Grove, “Microfablicated drug delivery systems, Concepts to improve clinical benefit”, Biomedelical micodevices, 3-2, (2001), 97-108. [3] J. C. Jones, “The feeding behavior of mosquitoes”, Scientific American, 238, (1978), 112-120. [4] K. Tsuchiya, N. Nakanishi, T. Komeda, Y. Uetsuji, K. Mori, E. Nakamachi, Trans. of Jpn. Soc. Mech. Eng. Series C, 71-702, (2005), 603-609 (in Japanese). [5] S. Caras, and J.Janata, “Field effect transistor sensitive to penicillin”, Anal. Chem., 52, (1980), 1935-1937. [6] S. Caras, D. Petelenz, and J.Janata, “pH-based enzyme potentiometric sensors. Part 2. Glucose-sensitive field effect transistor”, Anal. Chem., 57, (1985), 1920-1923. [7] A. A. Shul’ga, A. C. Sandrovsky, V. I. Strikha, A. P. Soldatkin, N. F. Starodub, and A. V. EI’skaya, “Overall characterization of ISFET-based glucose biosensor”, Sensors and Actuators, B10, (1992), 41-46. [8] I. Willner, and E. Katz, “Integration of layered redox protein and conductive supports for bioelectric applications”, Angew. Chem. Int. Ed., 39, (2000), 1180-1218.

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