- Email: [email protected]
A wearable oxygen sensor for transcutaneous blood gas monitoring at the conjunctiva
Sensors and Actuators B 108 (2005) 733–737
A wearable oxygen sensor for transcutaneous blood gas monitoring at the conjunctiva Shigehito Iguchia , Kohji Mitsubayashib,∗ , Takayuki Ueharac , Mitsuhiro Ogawab a
Graduate School of Engineering, Tokai University, 1117 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan b Department of Biomedical Devices and Instrumentation, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan c Department of Electrical Engineering, Tokai University, Hiratsuka, Kanagawa 259-1292, Japan Received 14 July 2004; received in revised form 29 November 2004; accepted 11 December 2004 Available online 6 February 2005
Abstract A thinner and flexible oxygen sensor as one of the Soft-MEMS devices was developed in order to monitor transcutaneous oxygen tension from conjunctiva. The wearable oxygen sensor with membrane structure was constructed by pouching KCl electrolyte solution by nonpermeable membrane and gas-permeable membrane with Pt- and Ag/AgCl electrode patterned by using photolithography and sputtering methods. The wearable oxygen sensor (width: 3 mm, thickness: 84 m) was applied to the electrochemical measurement with a fixed potential of −550 mV versus Ag/AgCl, thus obtaining the calibration range to dissolved oxygen from 0.01 to 8.0 mg/l. The sensor was also evaluated in gas phase by purging with 10% oxygen gas and the response time to reach 90% of the steady current after purging was approximately 45 s, sensor outputs and responses were stable during repeated measurements at 3.66% of the coefficient of variance. As the physiological application, the wearable sensor was placed onto a conjunctiva of a Japanese white rabbit without any thermoregulation. As an experiment, the rabbit inhaled standard air and high concentration oxygen (60 and 90%). As the result, sensor output increased and decreased synchronously with high concentration oxygen and standard air inhaling, respectively. This suggests that the sensor can be a new transcutaneous oxygen sensor. © 2005 Elsevier B.V. All rights reserved. Keywords: Transcutaneous oxygen monitoring; Oxygen sensor; Wearable sensor; Conjunctiva; Rabbit conjunctiva
1. Intruduction In recent decades, the partial pressure of oxygen in arterial blood (PaO2 ) has been used for noninvasive medical monitoring. One of the commonly used methods entails transcutaneous oxygen monitoring (tc pO2 monitoring) [1,2]. This technique is widely used to monitor arterial oxygen pressure in infants, in the prevention of oxygen poisoning caused by retinopathy of prematurity, and in the prevention of hypoxia in neonatal intensive care units. Although transcutaneous oxygen electrodes are commercially available and are widely used, problems still exist. Consequently, there have ∗
Corresponding author. Tel.: +81 3 5280 8091; fax: +81 3 5280 8094. E-mail address: [email protected] (K. Mitsubayashi).
0925-4005/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.snb.2004.12.099
been many attempts to improve sensors and measurement systems; one of the current main topics of the improvements has been on miniaturization and the integration of the sensor with the electrodes [3–6]. We have focused on developing less invasive means of monitoring tc pO2 . Because existing units are rigid and must be fixed to the skin with adhesive plaster, they may cause skin rashes. Additionally, heating of the skin to about 45 ◦ C is required for transcutaneous measurement to improve the penetration of gas from arterial vessels through the skin surface. As this may cause skin burns, frequent changes to the position of the sensor are required [7]. Using photolithography and sputtering techniques, we have developed a wearable oxygen sensor that is easy to attach at any site [8,9]. We have now applied these thinner and more
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flexible sensors to human transcutaneous oxygen monitoring. This application has resulted in a novel medical monitoring device that is easy to handle and does not cause skin rashes. However, since it is still necessary to heat the skin to achieve accurate transcutaneous measurements, it does not obviate the risk of skin burn. Therefore, we examined an alternative measurement site, the conjunctiva. Because the conjunctiva has high gas penetration and supplies the cornea with oxygen [10,11], conjunctival oxygen monitoring [12–18] was considered as a possible application for the new oxygen sensor, which would obviate the need for heating. Isenberg et al. evaluated a conjunctival oxygen monitor using 10 newborn subjects and published a pilot report in 2002 [18]. The correlation coefficient between conjunctival oxygen tension and pulse oximetry was significant (p < 0.001). Although the sensor unit they used was placed on the eye, the size of the sensor was too large for general application. In the present study, we evaluated a novel small, thin, flexible oxygen sensor that is of a suitable size for application to the conjunctiva, using rabbits.
2. Experimental 2.1. Sensor fabrication A novel wearable oxygen sensor based on the Clarktype electrode was developed using a flexible gas-permeable membrane. The sensor has three layers, a flexible gaspermeable membrane (FEP, film thickness: 25 m), a membrane filter with dimensions of 1 mm × 1.5 mm (Isopore TKTP04700, Millipore Corp., USA) containing electrolytic solution (0.1 mol/L KCl 198-03545, Wako Pure Chemical Industries, Ltd., Japan) and a nonpermeable membrane (Ionomer, film thickness: 50 m). Au and Ag/AgCl electrodes were fabricated on gas-permeable membranes using photolithography and sputtering methods. The electrodes were of a simple strip-shaped design; the width of the Au electrode was 1 mm and that of the Ag/AgCl electrode was 0.5 mm. The fabrication of the sensor was achieved by stacking and heat deposition of a gas-permeable membrane containing the electrodes, a membrane filter, and a nonpermeable membrane. The assembled sensor is 3 mm wide, 50 mm long (length of the terminal area is 20 mm) and 84 m thick. Fig. 1 illustrates the structure of the wearable oxygen sensor. Its electrochemical reactions are followings. cathode (Pt) :
O2 + 2H2 O + 4e− → 4OH−
anode (Ag/AgCl) :
4Ag + 4Cl− → 4AgCl + 4e−
2.2. Evaluation of the sensor In the first stage of evaluating the sensor, a cyclic voltammogram was recorded at a sampling interval of 1 s for sweep rates of 5 mV s−1 using distilled water saturated with dis-
Fig. 1. Structure of the wearable oxygen sensor with gas-permeable membrane coated electrodes, membrane with KCl solution and nonpermeable membrane.
solved oxygen at room temperature. The medium was prepared by bubbling oxygen gas through the water for 30 min. A two-electrode electrochemical configuration was used between the working (Au) and reference electrode (Ag/AgCl). The sensor was subjected to currents that ranged from 0 to −1100 mV. A function generator (Potential Sweep Unit, Model 1114, BAS Inc., Tokyo, Japan) was used to control the current. The sensor was evaluated using the liquid phase prior to application of the gas phase. The sensor was calibrated at room temperature using a 50 mL measuring cell filled with water containing dissolved oxygen. The dissolved oxygen content of the solution was adjusted using a sodium sulfite (Na2 SO3 198-03412, Wako Pure Chemical Industries, Ltd., Japan) solution and measured with a Clark-type dissolved oxygen electrode (TYPE BO-P, Able Co., Ltd., Japan). The sensor was evaluated by measurement of dissolved oxygen contents, which ranged from 0.01 to 8.2 mg/L. After the liquid phase evaluation, the sensor was evaluated in air, gas containing 90% nitrogen (90% N2 and 10% O2 ), or 30% oxygen (70% N2 and 30% O2 ). To evaluate the sensor response time, a chamber filled with air was purged with 90% nitrogen gas. To evaluate repeatability of sensor output, the chamber was purged with 30% oxygen gas. During purging, the gasses were introduced as quickly as possible into an acrylic cuboid chamber (50 mm × 140 mm × 15 mm) filled with standard air. The 30% oxygen gas mixture was supplied by an oxygen gas generator (Air Charger, Panasonic, Japan) and the 90% nitrogen mixture was supplied from a steel cylinder. A Japanese white rabbit (16 months of age, female) was used in the initial evaluation of transcutaneous oxygen measurement from the conjunctiva. The body of the rabbit was immobilized using a fixing apparatus before attaching the sensor. The electrode part of the sensor was applied directly to the left side of the conjunctiva. The sensor was held in place
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Fig. 3. Cyclic voltammogram of the wearable oxygen sensor with Ptworking and Ag/AgCl-counter/reference electrodes.
Fig. 2. Illustrations of attachment of the sensor for rabbit conjunctival oxygen monitoring. Illustration of affixing the wearable oxygen sensor onto the conjunctiva (upper figure) and cross section of attached sensor (lower figure).
by the natural pressure that exists between the eyeball and the conjunctiva. A special lightweight grip-type connecting jig was used to connect the sensor to electric wires at the terminal end. The jig was attached to the fixing apparatus used to immobilize the rabbit. No sedative medicine or anesthetic was used. After applying the sensor and allowing the rabbit to quieten, it was given standard air, 60% oxygen (40% N2 and 60% O2 ) or 90% oxygen (10% N2 and 90% O2 ) to inhale. The 30% oxygen mixture or the 60% oxygen mixture was supplied from steel cylinders. Room air was considered to be a standard air mixture. When inhaling oxygen gas, the rabbit’s mouth was covered by an acrylic bowl that was connected to the oxygen generator or the steel cylinder. The sensor that was attached to the rabbit was exposed to 60% oxygen gas to verify its functioning before and after the experiment. Fig. 2 shows how the sensor was attached to the rabbit’s conjunctiva. A computer-controlled potentiostat (Potentiostat, Model 1112, BAS Inc., Tokyo, Japan) was used for cyclic voltammetry and chronoamperometry, and the voltage-converted sensor output current was monitored by an A/D converter (ADC-16, Pico Technology Co. Ltd., UK) and a notebooktype PC with 16-bit precision. Data were observed on a computer graphic display and recorded on a hard disk for later analysis.
sensor were compared with the dissolved oxygen contents measured by the oxygen sensor, after which the sensor was calibrated over a range of 0.01–8.00 mg/L. A regression coefficient of 0.999 was estimated by least squares regression analysis from the following equation: output current (A) = 0.04 + 0.02 dissolved oxygen (mg/L) Fig. 4 shows the relationship between output current and dissolved oxygen concentration. Sensor output was significantly decreased by purging the air-filled chamber with 90% nitrogen gas (Fig. 5). The response time to reach 90% of the steady current after purging with nitrogen gas was approximately 45 s. This is considered acceptable for transcutaneous oxygen monitoring in humans. As shown in Fig. 5, the sensor output was stable in the presence of nitrogen gas after purging and a stable output was confirmed during the 50-min experiment in the gas phase. In order to evaluate the repeatability of sensor outputs in the gas phase, purging of a chamber that had been filled with standard air and with 30% oxygen gas was repeated five times. As shown in Fig. 6, sensor outputs and responses were stable even with repeated measurements; the average output current change was 0.85 ± 0.03 A, and the coefficient of variance
3. Results and discussion The cyclic voltammogram is shown in Fig. 3. After the measurements and experiments had been completed, a potential of −550 mV versus Ag/AgCl was applied to prolong the durability of the sensor. The steady current outputs of the
Fig. 4. Calibration curve of the wearable oxygen sensor for dissolved oxygen concentration measurements.
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Fig. 5. Typical sensor response of the wearable oxygen sensor in gas phase for purging with 10% oxygen gas.
was 3.66%. It is suggested that the sensor is stable enough to measure PaO2 . In the rabbit experiment, the sensor was found to be sufficiently flexible and thin and small enough to attach to the rabbit conjunctiva. The sensor was light enough to be held in place on the conjunctiva by the natural pressure between the eye and the conjunctiva of the rabbit. The sensor output increased with inhalation of gases high in oxygen and decreased with inhalation of air. Fig. 7(b) shows a typical response of transcutaneous oxygen monitoring at the rabbit conjunctiva by the wearable sensor for standard air and high oxygen concentration gas inhalation. Sensor output during inhalation of 90% oxygen was greater than during inhalation of 60% oxygen. This suggests that this sensor can detect changes in oxygen tension level in living tissue and that the output current changes correspond to PaO2 levels. As shown in Fig. 7(a) and (c), the characteristics of the sensor were
Fig. 6. Repeatability evaluation with purging of 30% oxygen gas. Thirty percentage of oxygen gas was applied five times for the wearable oxygen sensor.
not changed by application to the conjunctiva. This suggests that the sensor can be used as a transcutaneous oxygen sensor without the need for warming. Future research should include a comparison of sensor outputs with PaO2 levels. Because the sensor makes direct contact with the conjunctiva, which is a mucosal membrane, and the eyeball, the ingredients used to manufacture the sensor must be carefully selected. Chemicals that are absorbed through the mucosa are unacceptable. This sensor is fabricated with a gas-permeable membrane (FEP) on the conjunctiva side and a nonpermeable membrane (Ionomer) on the eyeball side. These membranes can be sealed using heat, avoiding the use of poisonous chemicals. Therefore, the sensor is appropriate for biological, physiological, and medical monitoring. Our goal of measuring transcutaneous oxygen from the conjunctiva without the application of heat was achieved.
Fig. 7. Typical response of transcutaneous oxygen monitoring at the rabbit conjunctiva by the wearable sensor. (a) Sensor characteristics before applying to the conjunctiva. (b) Sensor response of rabbit conjunctival transcutaneous oxygen monitoring in inhalation of high concentration of oxygen. (c) Sensor characteristics after the experiment.
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However, the sensor can also be used for transcutaneous measurement from the skin. The small dimensions of the sensor results in decreased inertial mass, and it is lighter than current commercially available electrodes. The 84 m thickness also reduces its moment of inertia. Therefore, rigid attachment of the sensor is not necessary for human skin. The tack strength required of the adhesive plaster or tape is less, and the area of adhesion is narrower. These attributes can help to prevent skin rashes. In transcutaneous skin measurements, thermoregulation may be necessary. Although thermoregulation at about 45 ◦ C would be required to improve gas penetration, the sensor is smaller than current electrodes. Therefore, the heated area would be smaller and the heat current from the sensor to the human body would be reduced. Hence, the risk of skin burn would decrease. A small, thinner heating unit would be necessary for the sensor. Lam et al. have already developed a small heating unit that is 0.635 mm thick using the screen-printing method for their transcutaneous oxygen sensor [6]. It proved to be very useful in their experiments. There have been many attempts at conjunctival oxygen monitoring [13–18] over the past three decades but it has not found widespread acceptance. We think that one of the reasons for this is the difficulty of handling sensor devices. Because the sensor that was developed is easy to use and functions with high reliability, it should find acceptance for conjunctival oxygen monitoring.
4. Conclusions A novel transcutaneous oxygen sensor was developed for monitoring arterial oxygen pressure in the conjunctiva. This wearable, thin, and flexible oxygen sensor was developed using functional polymers. The sensor was fabricated using photolithography and sputtering methods. The sensor is 3 mm wide and 84 m thick. It was applied to a rabbit conjunctiva without any thermoregulation. When the rabbit inhaled standard air, 60% oxygen, or 90% oxygen, the sensor provided output that changed accordingly. Additionally, sensor output during the inhalation of 60% oxygen was greater than with 30% oxygen. This suggests that it can be successfully used as a transcutaneous oxygen sensor without the need for heating.
References [1] J.P. Baumberger, R.B. Goldfriend, Determination of arterial oxygen tension in man by equilibration through intact skin, Fed. Proc. 10 (1951) 10–21. [2] S.V. Rithalia, Developments in transcutaneous blood gas monitoring: a review, J. Med. Eng. Technol. 15 (1991) 143–153. [3] H. Suzuki, T. Hirakawa, I. Watanabe, Y. Kikuchi, Determination of blood pO2 using a micromachined Clark-type oxygen electrode, Anal. Chim. Acta 431 (2001) 249–259.
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[4] H. Suzuki, T. Hirakawa, S. Sasaki, I. Karube, An integrated module for sensing pO2 , pCO2 , and pH, Anal. Chim. Acta 405 (2000) 57–65. [5] C. Dumschat, A. Corbach, T. Jaeckel, M. Borchardt, F. Zuther, K. Cammann, Disposable blood gas sensors, Chem. Biol. Sens. Anal. Electrochem. Meth. (1997) 969–973. [6] Y.Z. Lam, J.K. Atkinson, Screen-printed transcutaneous oxygen sensor employing polymer electrolytes, Med. Biol. Eng. Comput. 41 (2003) 456–463. [7] J.F. Lucey, Clinical uses of transcutaneous blood gas measurements, Adv. Pediatr. 28 (1981) 27–56. [8] K. Mitsubayashi, Y. Wakabayashi, D. Murotomi, T. Yamada, T. Kawase, S. Iwagaki, I. Karube, Wearable and flexible oxygen sensor for transcutaneous oxygen monitoring, Sens. Actuat. B Chem. 95 (2003) 373–377. [9] K. Mitsubayashi, Wearable chemical sensors for non-invasive monitoring and bio-sniffer devices for a smell informatics, Chem. Sens. 18 (2002) 106–117. [10] W.C. Shoemaker, P.M. Lawner, Method for continuous conjunctival oxygen monitoring during carotid artery surgery, Crit. Care Med. 11 (1983) 946–947. [11] B.A. Weissman, I. Fatt, J. Rasson, Diffusion of oxygen in human corneas in vivo, Invest. Ophthalmol. Vis. Sci. 20 (1981) 123–125. [12] S. Podolsky, J. Wertheimer, S. Harding, The relationship of conjunctival and arterial blood gas oxygen measurements, Resuscitation 18 (1989) 31–36. [13] H. Haljamae, I. Frid, J. Holm, S. Holm, Continuous conjunctival oxygen tension (Pcj O2 ) monitoring for assessment of cerebral oxygenation and metabolism during carotid artery surgery, Acta Anaesthesiol. Scand. 33 (1989) 610–616. [14] M. Brown, J.S. Vender, Noninvasive oxygen monitoring, Crit. Care Clin. 4 (1988) 493–509. [15] A.I. Webb, R.T. Daniel, H.S. Miller, P.C. Kosch, Preliminary studies on the measurement of conjunctival oxygen tension in the foal, Am. J. Vet. Res. 46 (1985) 2566–2569. [16] S.J. Isenberg, W.C. Shoemaker, The transconjunctival oxygen monitor, Am. J. Ophthalmol. 95 (1983) 803–806. [17] M. Kwan, I. Fatt, A noninvasive method of continuous arterial oxygen tension estimation from measured palpebral conjunctival oxygen tension, Anaesthesiology 35 (1971) 309–314. [18] S.J. Isenberg, D. Neumann, S. Fink, R. Rich, Continuous oxygen monitoring of the conjunctiva in neonates, J. Perinat. 22 (2002) 46–49.
Biographies Shigehito Iguchi has been a graduate student at Tokai University. He has investigated wearable chemical sensors. Kohji Mitsubayashi is a professor of Tokyo Medical and Dental University (Department of Biomedical Devices and Instrumentation). His research interests include wearable chemical sensors for human monitoring, a newly olfactometric system using biological materials, biomolecular and medical devices, microsystem technology, etc. Takayuki Uehara had been an undergraduate student at Tokai University. He had investigated wearable oxygen sensors. Mitsuhiro Ogawa is a research assistant of Tokyo Medical and Dental University (Department of Biomedical Devices and Instrumentation). His research interests include wearable electrical and chemical devices for health care monitoring.
A wearable oxygen sensor for transcutaneous blood gas monitoring at the conjunctiva Shigehito Iguchia , Kohji Mitsubayashib,∗ , Takayuki Ueharac , Mitsuhiro Ogawab a
Graduate School of Engineering, Tokai University, 1117 Kitakaname, Hiratsuka, Kanagawa 259-1292, Japan b Department of Biomedical Devices and Instrumentation, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan c Department of Electrical Engineering, Tokai University, Hiratsuka, Kanagawa 259-1292, Japan Received 14 July 2004; received in revised form 29 November 2004; accepted 11 December 2004 Available online 6 February 2005
Abstract A thinner and flexible oxygen sensor as one of the Soft-MEMS devices was developed in order to monitor transcutaneous oxygen tension from conjunctiva. The wearable oxygen sensor with membrane structure was constructed by pouching KCl electrolyte solution by nonpermeable membrane and gas-permeable membrane with Pt- and Ag/AgCl electrode patterned by using photolithography and sputtering methods. The wearable oxygen sensor (width: 3 mm, thickness: 84 m) was applied to the electrochemical measurement with a fixed potential of −550 mV versus Ag/AgCl, thus obtaining the calibration range to dissolved oxygen from 0.01 to 8.0 mg/l. The sensor was also evaluated in gas phase by purging with 10% oxygen gas and the response time to reach 90% of the steady current after purging was approximately 45 s, sensor outputs and responses were stable during repeated measurements at 3.66% of the coefficient of variance. As the physiological application, the wearable sensor was placed onto a conjunctiva of a Japanese white rabbit without any thermoregulation. As an experiment, the rabbit inhaled standard air and high concentration oxygen (60 and 90%). As the result, sensor output increased and decreased synchronously with high concentration oxygen and standard air inhaling, respectively. This suggests that the sensor can be a new transcutaneous oxygen sensor. © 2005 Elsevier B.V. All rights reserved. Keywords: Transcutaneous oxygen monitoring; Oxygen sensor; Wearable sensor; Conjunctiva; Rabbit conjunctiva
1. Intruduction In recent decades, the partial pressure of oxygen in arterial blood (PaO2 ) has been used for noninvasive medical monitoring. One of the commonly used methods entails transcutaneous oxygen monitoring (tc pO2 monitoring) [1,2]. This technique is widely used to monitor arterial oxygen pressure in infants, in the prevention of oxygen poisoning caused by retinopathy of prematurity, and in the prevention of hypoxia in neonatal intensive care units. Although transcutaneous oxygen electrodes are commercially available and are widely used, problems still exist. Consequently, there have ∗
Corresponding author. Tel.: +81 3 5280 8091; fax: +81 3 5280 8094. E-mail address: [email protected] (K. Mitsubayashi).
0925-4005/$ – see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.snb.2004.12.099
been many attempts to improve sensors and measurement systems; one of the current main topics of the improvements has been on miniaturization and the integration of the sensor with the electrodes [3–6]. We have focused on developing less invasive means of monitoring tc pO2 . Because existing units are rigid and must be fixed to the skin with adhesive plaster, they may cause skin rashes. Additionally, heating of the skin to about 45 ◦ C is required for transcutaneous measurement to improve the penetration of gas from arterial vessels through the skin surface. As this may cause skin burns, frequent changes to the position of the sensor are required [7]. Using photolithography and sputtering techniques, we have developed a wearable oxygen sensor that is easy to attach at any site [8,9]. We have now applied these thinner and more
734
S. Iguchi et al. / Sensors and Actuators B 108 (2005) 733–737
flexible sensors to human transcutaneous oxygen monitoring. This application has resulted in a novel medical monitoring device that is easy to handle and does not cause skin rashes. However, since it is still necessary to heat the skin to achieve accurate transcutaneous measurements, it does not obviate the risk of skin burn. Therefore, we examined an alternative measurement site, the conjunctiva. Because the conjunctiva has high gas penetration and supplies the cornea with oxygen [10,11], conjunctival oxygen monitoring [12–18] was considered as a possible application for the new oxygen sensor, which would obviate the need for heating. Isenberg et al. evaluated a conjunctival oxygen monitor using 10 newborn subjects and published a pilot report in 2002 [18]. The correlation coefficient between conjunctival oxygen tension and pulse oximetry was significant (p < 0.001). Although the sensor unit they used was placed on the eye, the size of the sensor was too large for general application. In the present study, we evaluated a novel small, thin, flexible oxygen sensor that is of a suitable size for application to the conjunctiva, using rabbits.
2. Experimental 2.1. Sensor fabrication A novel wearable oxygen sensor based on the Clarktype electrode was developed using a flexible gas-permeable membrane. The sensor has three layers, a flexible gaspermeable membrane (FEP, film thickness: 25 m), a membrane filter with dimensions of 1 mm × 1.5 mm (Isopore TKTP04700, Millipore Corp., USA) containing electrolytic solution (0.1 mol/L KCl 198-03545, Wako Pure Chemical Industries, Ltd., Japan) and a nonpermeable membrane (Ionomer, film thickness: 50 m). Au and Ag/AgCl electrodes were fabricated on gas-permeable membranes using photolithography and sputtering methods. The electrodes were of a simple strip-shaped design; the width of the Au electrode was 1 mm and that of the Ag/AgCl electrode was 0.5 mm. The fabrication of the sensor was achieved by stacking and heat deposition of a gas-permeable membrane containing the electrodes, a membrane filter, and a nonpermeable membrane. The assembled sensor is 3 mm wide, 50 mm long (length of the terminal area is 20 mm) and 84 m thick. Fig. 1 illustrates the structure of the wearable oxygen sensor. Its electrochemical reactions are followings. cathode (Pt) :
O2 + 2H2 O + 4e− → 4OH−
anode (Ag/AgCl) :
4Ag + 4Cl− → 4AgCl + 4e−
2.2. Evaluation of the sensor In the first stage of evaluating the sensor, a cyclic voltammogram was recorded at a sampling interval of 1 s for sweep rates of 5 mV s−1 using distilled water saturated with dis-
Fig. 1. Structure of the wearable oxygen sensor with gas-permeable membrane coated electrodes, membrane with KCl solution and nonpermeable membrane.
solved oxygen at room temperature. The medium was prepared by bubbling oxygen gas through the water for 30 min. A two-electrode electrochemical configuration was used between the working (Au) and reference electrode (Ag/AgCl). The sensor was subjected to currents that ranged from 0 to −1100 mV. A function generator (Potential Sweep Unit, Model 1114, BAS Inc., Tokyo, Japan) was used to control the current. The sensor was evaluated using the liquid phase prior to application of the gas phase. The sensor was calibrated at room temperature using a 50 mL measuring cell filled with water containing dissolved oxygen. The dissolved oxygen content of the solution was adjusted using a sodium sulfite (Na2 SO3 198-03412, Wako Pure Chemical Industries, Ltd., Japan) solution and measured with a Clark-type dissolved oxygen electrode (TYPE BO-P, Able Co., Ltd., Japan). The sensor was evaluated by measurement of dissolved oxygen contents, which ranged from 0.01 to 8.2 mg/L. After the liquid phase evaluation, the sensor was evaluated in air, gas containing 90% nitrogen (90% N2 and 10% O2 ), or 30% oxygen (70% N2 and 30% O2 ). To evaluate the sensor response time, a chamber filled with air was purged with 90% nitrogen gas. To evaluate repeatability of sensor output, the chamber was purged with 30% oxygen gas. During purging, the gasses were introduced as quickly as possible into an acrylic cuboid chamber (50 mm × 140 mm × 15 mm) filled with standard air. The 30% oxygen gas mixture was supplied by an oxygen gas generator (Air Charger, Panasonic, Japan) and the 90% nitrogen mixture was supplied from a steel cylinder. A Japanese white rabbit (16 months of age, female) was used in the initial evaluation of transcutaneous oxygen measurement from the conjunctiva. The body of the rabbit was immobilized using a fixing apparatus before attaching the sensor. The electrode part of the sensor was applied directly to the left side of the conjunctiva. The sensor was held in place
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Fig. 3. Cyclic voltammogram of the wearable oxygen sensor with Ptworking and Ag/AgCl-counter/reference electrodes.
Fig. 2. Illustrations of attachment of the sensor for rabbit conjunctival oxygen monitoring. Illustration of affixing the wearable oxygen sensor onto the conjunctiva (upper figure) and cross section of attached sensor (lower figure).
by the natural pressure that exists between the eyeball and the conjunctiva. A special lightweight grip-type connecting jig was used to connect the sensor to electric wires at the terminal end. The jig was attached to the fixing apparatus used to immobilize the rabbit. No sedative medicine or anesthetic was used. After applying the sensor and allowing the rabbit to quieten, it was given standard air, 60% oxygen (40% N2 and 60% O2 ) or 90% oxygen (10% N2 and 90% O2 ) to inhale. The 30% oxygen mixture or the 60% oxygen mixture was supplied from steel cylinders. Room air was considered to be a standard air mixture. When inhaling oxygen gas, the rabbit’s mouth was covered by an acrylic bowl that was connected to the oxygen generator or the steel cylinder. The sensor that was attached to the rabbit was exposed to 60% oxygen gas to verify its functioning before and after the experiment. Fig. 2 shows how the sensor was attached to the rabbit’s conjunctiva. A computer-controlled potentiostat (Potentiostat, Model 1112, BAS Inc., Tokyo, Japan) was used for cyclic voltammetry and chronoamperometry, and the voltage-converted sensor output current was monitored by an A/D converter (ADC-16, Pico Technology Co. Ltd., UK) and a notebooktype PC with 16-bit precision. Data were observed on a computer graphic display and recorded on a hard disk for later analysis.
sensor were compared with the dissolved oxygen contents measured by the oxygen sensor, after which the sensor was calibrated over a range of 0.01–8.00 mg/L. A regression coefficient of 0.999 was estimated by least squares regression analysis from the following equation: output current (A) = 0.04 + 0.02 dissolved oxygen (mg/L) Fig. 4 shows the relationship between output current and dissolved oxygen concentration. Sensor output was significantly decreased by purging the air-filled chamber with 90% nitrogen gas (Fig. 5). The response time to reach 90% of the steady current after purging with nitrogen gas was approximately 45 s. This is considered acceptable for transcutaneous oxygen monitoring in humans. As shown in Fig. 5, the sensor output was stable in the presence of nitrogen gas after purging and a stable output was confirmed during the 50-min experiment in the gas phase. In order to evaluate the repeatability of sensor outputs in the gas phase, purging of a chamber that had been filled with standard air and with 30% oxygen gas was repeated five times. As shown in Fig. 6, sensor outputs and responses were stable even with repeated measurements; the average output current change was 0.85 ± 0.03 A, and the coefficient of variance
3. Results and discussion The cyclic voltammogram is shown in Fig. 3. After the measurements and experiments had been completed, a potential of −550 mV versus Ag/AgCl was applied to prolong the durability of the sensor. The steady current outputs of the
Fig. 4. Calibration curve of the wearable oxygen sensor for dissolved oxygen concentration measurements.
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Fig. 5. Typical sensor response of the wearable oxygen sensor in gas phase for purging with 10% oxygen gas.
was 3.66%. It is suggested that the sensor is stable enough to measure PaO2 . In the rabbit experiment, the sensor was found to be sufficiently flexible and thin and small enough to attach to the rabbit conjunctiva. The sensor was light enough to be held in place on the conjunctiva by the natural pressure between the eye and the conjunctiva of the rabbit. The sensor output increased with inhalation of gases high in oxygen and decreased with inhalation of air. Fig. 7(b) shows a typical response of transcutaneous oxygen monitoring at the rabbit conjunctiva by the wearable sensor for standard air and high oxygen concentration gas inhalation. Sensor output during inhalation of 90% oxygen was greater than during inhalation of 60% oxygen. This suggests that this sensor can detect changes in oxygen tension level in living tissue and that the output current changes correspond to PaO2 levels. As shown in Fig. 7(a) and (c), the characteristics of the sensor were
Fig. 6. Repeatability evaluation with purging of 30% oxygen gas. Thirty percentage of oxygen gas was applied five times for the wearable oxygen sensor.
not changed by application to the conjunctiva. This suggests that the sensor can be used as a transcutaneous oxygen sensor without the need for warming. Future research should include a comparison of sensor outputs with PaO2 levels. Because the sensor makes direct contact with the conjunctiva, which is a mucosal membrane, and the eyeball, the ingredients used to manufacture the sensor must be carefully selected. Chemicals that are absorbed through the mucosa are unacceptable. This sensor is fabricated with a gas-permeable membrane (FEP) on the conjunctiva side and a nonpermeable membrane (Ionomer) on the eyeball side. These membranes can be sealed using heat, avoiding the use of poisonous chemicals. Therefore, the sensor is appropriate for biological, physiological, and medical monitoring. Our goal of measuring transcutaneous oxygen from the conjunctiva without the application of heat was achieved.
Fig. 7. Typical response of transcutaneous oxygen monitoring at the rabbit conjunctiva by the wearable sensor. (a) Sensor characteristics before applying to the conjunctiva. (b) Sensor response of rabbit conjunctival transcutaneous oxygen monitoring in inhalation of high concentration of oxygen. (c) Sensor characteristics after the experiment.
S. Iguchi et al. / Sensors and Actuators B 108 (2005) 733–737
However, the sensor can also be used for transcutaneous measurement from the skin. The small dimensions of the sensor results in decreased inertial mass, and it is lighter than current commercially available electrodes. The 84 m thickness also reduces its moment of inertia. Therefore, rigid attachment of the sensor is not necessary for human skin. The tack strength required of the adhesive plaster or tape is less, and the area of adhesion is narrower. These attributes can help to prevent skin rashes. In transcutaneous skin measurements, thermoregulation may be necessary. Although thermoregulation at about 45 ◦ C would be required to improve gas penetration, the sensor is smaller than current electrodes. Therefore, the heated area would be smaller and the heat current from the sensor to the human body would be reduced. Hence, the risk of skin burn would decrease. A small, thinner heating unit would be necessary for the sensor. Lam et al. have already developed a small heating unit that is 0.635 mm thick using the screen-printing method for their transcutaneous oxygen sensor [6]. It proved to be very useful in their experiments. There have been many attempts at conjunctival oxygen monitoring [13–18] over the past three decades but it has not found widespread acceptance. We think that one of the reasons for this is the difficulty of handling sensor devices. Because the sensor that was developed is easy to use and functions with high reliability, it should find acceptance for conjunctival oxygen monitoring.
4. Conclusions A novel transcutaneous oxygen sensor was developed for monitoring arterial oxygen pressure in the conjunctiva. This wearable, thin, and flexible oxygen sensor was developed using functional polymers. The sensor was fabricated using photolithography and sputtering methods. The sensor is 3 mm wide and 84 m thick. It was applied to a rabbit conjunctiva without any thermoregulation. When the rabbit inhaled standard air, 60% oxygen, or 90% oxygen, the sensor provided output that changed accordingly. Additionally, sensor output during the inhalation of 60% oxygen was greater than with 30% oxygen. This suggests that it can be successfully used as a transcutaneous oxygen sensor without the need for heating.
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Biographies Shigehito Iguchi has been a graduate student at Tokai University. He has investigated wearable chemical sensors. Kohji Mitsubayashi is a professor of Tokyo Medical and Dental University (Department of Biomedical Devices and Instrumentation). His research interests include wearable chemical sensors for human monitoring, a newly olfactometric system using biological materials, biomolecular and medical devices, microsystem technology, etc. Takayuki Uehara had been an undergraduate student at Tokai University. He had investigated wearable oxygen sensors. Mitsuhiro Ogawa is a research assistant of Tokyo Medical and Dental University (Department of Biomedical Devices and Instrumentation). His research interests include wearable electrical and chemical devices for health care monitoring.