Sensors and Actuators B 78 (2001) 279±284

New technology for multi-sensor silicon needles for biomedical applications A. Errachid*, A. Ivorra, J. AguiloÂ, R. Villa, N. Zine, J. Bausells Centro Nacional de MicroelectroÂnica (IMB-CSIC), Campus UAB, E-08193 Bellaterra, Barcelona, Spain

Abstract A multi-sensor silicon needle including two ion-sensitive ®eld effect transistor (ISFET) sensors, a platinum pseudo-reference electrode (Pt) and a temperature sensor has been fabricated by using a CMOS-compatible technology and silicon micromachining. This paper presents a summary of the fabrication process and results of the device characterisation. The feasibility of the fabrication technology has been demonstrated and all devices have operated satisfactorily, with a response showing good sensitivity and linearity. The multi-sensor has been developed for the detection of myocardial ischemia during cardiac surgery. # 2001 Elsevier Science B.V. All rights reserved. Keywords: Silicon needle; ISFET sensor; Multi-sensor; Ischemia; Temperature sensor

1. Introduction Cardiovascular diseases are one of the most prevalent causes of mortality in developed countries. Recent advances in cardiac surgery have decreased cardiac mortality, but a high number of postoperative deaths can be attributed to inappropriate myocardial protective techniques applied during the operative phase of extracorporeal circulation. During this surgical period, the heart is arti®cially arrested and therefore, the electrocardiogram is not reliable to detect myocardial injury (ischemia). Studies carried out in animal models have demonstrated that myocardial ischemia induced fast alterations in the myocardial tissue impedance and in extracellular pH and pK concentrations [1,2]. These variables can be accurately recorded in arrested hearts if adequate electrodes and sensors are used [3,4]. Silicon technologies allow the integration of different sensors in a small size device, and therefore, can be suitable for the development of a multi-sensor device to be used for myocardial ischemia monitoring and other biomedical applications. In particular, micromachined silicon probes for electrical measurements have been used for some time [5]. In the framework of an effort to explore the capabilities of silicon technology in health care monitoring and implantable devices, we have developed a multi-sensor silicon needle * Corresponding author. Tel.: ‡34-93-594-7700; fax: ‡34-93-580-1496. E-mail address: [email protected] (A. Errachid).

for the simultaneous measurement of ions like K‡, H‡ and temperature on the myocardial tissue. Ion measurements are based on ion-sensitive ®eld effect transistors (ISFETs). This paper reports the fabrication technology that has been used for the needle, and the ®rst sensor characterisation results. The system presented is complementary to a similar silicon needle with platinum electrodes that is used for impedance measurements, that has been reported elsewhere [6]. The multi-sensor silicon needle includes two ISFET sensors, one platinum pseudo-reference electrode and a temperature sensor based on a platinum resistor. Fig. 1 shows a schematic view of the device structure. The next section of the paper discusses the needle fabrication technology. In Section 3 the experimental procedures used to characterise the sensors in the needle are discussed. The results obtained from the ®rst measurements on the sensors are presented in Section 4. In order to make useful measurements with the ISFETs, a differential measurement approach should be used, which is also discussed in Section 4. 2. Technology The devices have been fabricated on h1 0 0i-oriented, ptype silicon wafers with nominal resistivity of 4±40 O cm, which corresponds to a doping level of 1  1015 cm 3. The fabrication process uses an approach in which the ISFET devices are fabricated ®rst, and a ®nal silicon micromachining step is used to de®ne the silicon needles. The ISFETs are fabricated by a simple (six photolithography

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Fig. 1. Schematic view of the silicon needle structure.

levels) non-self-aligned NMOS process with a gate dielecÊ of silicon dioxide plus 1000 A Ê of tric consisting of 800 A LPCVD silicon nitride. The metal used for the interconnects Ê of platinum. Fig. 2(a) is a thin titanium layer plus 1500 A shows a simpli®ed cross-section of the device after the ISFET fabrication. To release the needle structures from the silicon wafer, an aluminium layer is used as a mask (Fig. 2(b)) for the micromachining process. A deep reactive ion etching (RIE) process is then used to etch the silicon through the complete wafer thickness, thus, de®ning the shape of the needle (Fig. 2(c)). The dry RIE process has the advantage over more common wet silicon micromachining processes that the etching does not depend on the crystalline planes of silicon, which allows an easy de®nition of complex structures, such as the needle. Fig. 3 shows a photograph of the complete fabricated device. The total length of the device shown is 13 mm, including the connecting pad area. The length of the straight

Fig. 2. Schematic cross-sections of the fabrication process. The cross section is taken transverse to the needle axis, and through an ISFET device: (a) after the ISFET fabrication; (b) after deposition and patterning of the aluminium mask used for the micromachining process; (c) final structure.

part of the needle is 7 mm and its width is about 0.8 mm. After micromachining, the needles remain ®xed to the silicon wafer by a support on the rectangular end of the structure, which can be easily broken to release the

Fig. 3. Photograph of the fabricated silicon needle.

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individual needles. The broken support is clearly visible in the ®gure. Membrane-ISFET (MEMFET) devices sensitive to potassium were obtained by depositing a plasticised potassiumsensitive membrane on the ISFET devices. Most of the chemical products used were supplied by FLUKA: valinomycin (Val, #94675); bis(2-ethyl-hexyl)sebacate (dos, #84818); potassium tetrakis(4-chlorophenyl)borate (KTpClPB, #60591) and carboxylated poly-vinyl chloride (PVC-COOH, #81395). The membranes were prepared by dissolving the ionophore material valinomycin (1%), KTpClPB (0.5%), DOS (49.5%) and PVC-COOH (49%) in tetrahydrofuran (THF, Merck). The MEMFETs were made by solvent-casting of the liquid membrane mixture on the gate region of the ISFETs on the needles. The solvent THF was allowed to evaporate overnight. 3. Experimental For the characterisation of the sensors, the needles were bonded near the tip of a long rectangular printed circuit board (PCB), and wire-bonded in the usual manner. The bonding area of the devices, the bonding wires and the copper tracks of the PCB were then encapsulated using an epoxy resin (Epo-Tek H77, from Epoxy Technology) to protect them from the liquid environment. All chemical response experiments were performed at room temperature, using double distilled water and chemicals of analytical reagent grade. The pH response of the standard silicon nitride gate ISFETs in the needle has been characterised in vitro. The response to pH has been obtained by the addition of small volumes of 1 and 0.1 M HCl solutions to a buffer solution of tris(hydroxymethyl)-aminomethane with pH ˆ 9, containing the multi-sensor needle and an Ag/AgCl reference electrode. After each addition, the pH of the solution was monitored continuously with a digital pH-meter and a glass electrode calibrated with standard buffer solutions. The electrical response of the ISFET devices as ®eld-effect transistors has been measured by using an HP4145B semiconductor parameter analyser. Given the electrical response curves for different pH values, the corresponding chemical response of the ISFET is obtained from the voltage shift of these curves as a function of the solution pH. The response of the MEMFET devices to pK has been measured with a source/drain follower [7] ISFET-meter with a constant drain current (I D ˆ 100 mA) and a constant drainto-source potential (V DS ˆ 500 mV). Calibration curves have been obtained in the concentration range 10 6 to 10 1 M in pure KCl solutions by adding a known amount of prepared stock under stirring. The activities of the ions were calculated using the Debye±HuÈckel approximation. Before the measurements were recorded, the K-sensitive membranes on the ISFETs were conditioned in a 10 2 M aqueous KCl solution for one night.

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For sensing the needle temperature, a platinum serpentine acting as a thermal dependent resistor is used. The resistance is measured by using the four-probe (Kelvin) method applying a low dc current to avoid self-heating. As seen in Fig. 3, the two leads with wider lines are connected to the resistor, and carry the current. The two pads that are out of the main pad line and closer to the broken support are also connected to the resistor through narrow lines, which are connected as shown schematically in Fig. 1. They are used to measure the voltage. A module able to measure up to 16 temperature sensors simultaneously has been developed. It measures the applied current and the resulting voltage for each sensor. A LabView based program collects all these data through and ADC board (ComputerBoard CIO-DAS802/16) and correlates it with the temperature given by a digital thermometer (Crison GLP22 Temperature Probe). This system allows us to calibrate automatically several temperature sensors in warm water that decreases its temperature with time due to a lower room temperature. 4. Results and discussion The electrical characteristics of the ISFET devices in the needles are very good and comparable with those obtained for other standard ISFETs fabricated in our laboratory [8]. The drain current versus gate voltage characteristics IDS± VGS are shifted in voltage when the pH value of the liquid solution changes, corresponding to a shift in the threshold voltage Vth of the ®eld-effect transistor. Fig. 4 shows the corresponding sensitivity plot, in which the threshold voltage shift E is plotted versus the solution pH. A value of about 53 mV/pH has been obtained, which is a usual result for LPCVD Si3N4-gate ISFETs, with a good linearity between pH 2 and 9.

Fig. 4. Chemical response of the pH-sensitive ISFETs. The shift of the threshold voltage, with an arbitrary zero, is plotted as a function of the solution pH.

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Fig. 5. Potassium ion response of a MEMFET based on the ionophore valinomycin.

A typical response curve for the potassium sensitive MEMFETs is shown in Fig. 5. Linear responses have been obtained between 8  10 5 and 8  10 2 M, with an almost Nerstian sensitivity (50  2 mV per decade) and a detection limit of 2  10 5 M. The response time is less than 1 s. To make useful measurements with the needles in their ®nal application, the use of conventional reference electrodes, which are big and fragile, should be avoided. This can be done if a differential setup is used with two ISFETs that show different sensitivities to the measuring ion. In that case only a metallic quasi-reference electrode is required [9]. The electrical potential at the electrode-electrolyte interface is unstable, but it is measured by the differential ISFET pair as a common mode voltage and is eliminated. The needle has two ISFETs and one platinum electrode, and therefore, a differential measurement can be performed if one of the ISFETs is made insensitive to the measuring ion (reference-ISFET, or REFET [9]). We have made

Fig. 6. (a) Potassium ion responses of a K‡-sensitive MEMFET and a REFET on a needle, both measured with respect to an external reference electrode; (b) differential response of the MEMFET±REFET pair, using a Pt pseudo-reference electrode.

Fig. 7. Response curves (resistance vs. temperature) for six different temperature sensors.

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differential measurements of potassium by de®ning one ISFET as a potassium MEMFET and de®ning the other as a REFET by using a polymeric PVC membrane [10]. Fig. 6 shows the results of preliminary differential measurements on one needle. Fig. 6(a) shows a particular pair of MEMFET and REFET responses, as measured with respect to an external reference electrode. In Fig. 6(b), the corresponding differential output, using the Pt pseudo-reference electrode, is presented. Note that this particular pair of devices does not show optimised responses, which results in a low overall sensitivity. In the practical application of the sensor needles to cardiac surgery, there will be both changes of pH and pK. Therefore, meaningful results will only be obtained if the two parameters can be measured independently. This can be done by using three ISFETs in one needle: one for pH, one for pK and a REFET, plus the Pt pseudo-reference electrode. The ®nal version of the silicon needle in our development will, therefore, be designed with three integrated ISFET devices. In Fig. 7 the response of the temperature sensor for different needles is presented. It can be seen that every needle has shown a different nominal resistance value due to fabrication tolerances. However, their response with the temperature is highly linear and repetitive with a temperature coef®cient of the resistance of 2687 ppm/C. 5. Conclusions In summary, this work demonstrates the feasibility of fabricating a silicon needle with ion sensors, platinum electrodes and temperature sensors. All sensors have shown good operating characteristics, which means that the micromachining process that de®nes the needles has not affected their performance. The feasibility of using only one needle and a differential set-up for the ion measurements has also been tested, although further work will be required to optimise the sensor response. Work will continue by using these devices in in vivo experiments to test their applicability for ischemia monitoring during cardiac surgery. Acknowledgements This work has been supported by the European Commission through projects 23485 and 33485 (MICRO-CARD) of the ESPRIT-4 Programme. References [1] R. Coronel, J.W.T. Fiolet, F.J.G. Wilms-Schopman, A.F.M. Schaapherder, T.A. Johnson, L.S. Gettes, M.J. Janse, Distribution of extracellular potassium and its relation to electrophysiologic changes during acute myocardial ischemia in the isolated perfused porcine heart, Circulation 77 (1988) 1125±1138.

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[2] J. Cinca, M. Warren, A. CarrenÄo, M. TresaÂnchez, Ll. Armadans, P. GoÂmez, J. Soler-Soler, Changes in myocardial impedance induced by coronary artery occlusion in pigs with and without preconditioning. Correlation with local ST segment potential and ventricular arrhytmias, Circulation 96 (1997) 3079±3086. [3] V.V. Cosofret, E. Lindner, T.A. Johnson, M.R. Neuman, Planar micro sensors for in vivo myocardial pH measurements, Talanta 41 (1994) 931±938. [4] V.V. Cosofret, M. ErdoÈsy, E. Lindner, T.A. Johnson, R.P. Buck, W.J. Kao, M.R. Neuman, J.M. Anderson, Ion-selective microchemical sensors with reduced preconditioning time. Membrane biostability studies and applications in blood analysis, Anal. Lett. 27 (1994) 3039±3063. [5] K. Najafi, T. Mochizuki, K.D. Wise, A high-yield IC-compatible multichannel recording array, IEEE Trans. Electron. Devices 32 (1985) 1206±1211. [6] A. Benvenuto, L. Beccai, F. Valvo, A. Menciassi, P. Dario, M.C. Carrozza, J. AguiloÂ, A. Ivorra, R. Villa, J. MillaÂn, P. Godignon, J. Bausells, A. Errachid, Impedance microprobes for myocardial ischemia monitoring, in: Proceedings of the IEEE-EMBS Conference on Microtechnologies in Medicine and Biology, Lyon, France, 10±14 October 2000. [7] P. Bergveld, The operation of an ISFET as an electronic device, Sens. Actuators 1 (1981) 17±29. [8] C. CaneÂ, I. GraÁcia, A. Merlos, M. Lozano, E. Lora-Tamayo, J. Esteve, Compatibility of ISFET and CMOS technologies for smart sensors, in: Proceedings of the International Conference on Solid-State Sensors and Actuators (Transducers'91), San Francisco, CA, USA, 1991, pp. 225±228. [9] P. Bergveld, A. van den Berg, P.D. van der Wal, M. SkowronskaPtasinska, E.J.R. SudhoÈlter, D.N. Reinhoudt, How electrical and chemical requirements for REFETs may coincide, Sens. Actuators 18 (1989) 309±327. [10] A. Errachid, J. Bausells, N. Jaffrezic-Renault, A simple REFET for pH detection in differential mode, Sens. Actuators B 60 (1999) 43±48.

Biographies Abdelhamid Errachid was born in Khenifra, Morocco, in 1966. He graduated in Physics from the University M. Ismail, Meknes, in 1992, and received a PhD degree in Electronics Engineering from Universitat AutoÁnoma de Barcelona, Spain, in 1998. His research interests are the development of ISFET devices for the measurement of different ions, and integrated instrumentation for ISFETs. Antoni Ivorra was born in Barcelona, Spain, in 1974. He received his degree in Electronics Engineering from the Universitat PoliteÁcnica de Catalunya in 1998. Currently he is working in the Biomedical Applications Group at the CNM. His research focuses the development of biomedical instrumentation and portable chemical analysis systems. Jordi Aguilo was born in 1950. He joined the Department of Electronics and Electromagnetism at the Autonoma University of Barcelona in 1972 as Assistant Professor, and obtained the PhD degree in Physical Sciences in 1976. He joined the Computer Science Department in 1976 where he now holds the position of Full Professor in the area of Computers Architecture and Technology. In 1985, he became researcher at the Design Department of CNM that he led until 1997. Now he holds the position of ViceDirectorate of CNM. His Research interest fields are, in general, the design of analog and digital systems and the ASIC development. In particular, he is interested in biomedical applications, like advanced micro-multisensors, microelectrodes, neural interfaces, telemetry systems and auditory coding. Rosa Villa received a Medicine Doctor degree from Universitat de Barcelona in 1981, and a PhD from Universitat Autonoma de Barcelona in

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1993. She specialised in nuclear medicine, and won the Spanish National award on Nuclear Medicine in 1985. She joined the Design Department of CNM in 1986 where she became researcher in 1992. Now, she belongs to the Biomedical Applications Group at CNM. Her current research interest fields are in the microsystem biomedical applications mainly in the neural stimulation area and in the use of neural networks and fuzzy logic for the definition of clinical prediction areas where she has actively participated in many research projects. Nadia Zine was born in Meknes, Morocco, in 1969. She graduated in chemistry from the University M. Ismail, Meknes in 1994. She is currently working at CNM towards her PhD degree. Her research interest is the

chemical characterization of silicon chemical sensors, and specially, of ISFET devices. Joan Bausells was born in Barcelona, Spain, in 1957. He graduated in Physics in 1980, and received MS (1982) and PhD (1986) degrees in SolidState Physics, all from the University of Barcelona. From 1981 to 1986, he worked as a process and R&D engineer in the semiconductor industry. In 1986, he joined CNM, where he is a permanent researcher since 1988. At CNM he has worked in ion implantation processing and has been manager of the Sensor and Actuator Group, in which he started working in 1990. His current research interests are silicon sensor and actuator devices and their applications to silicon microsystems.