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Design and fabrication of MEMS based intracranial pressure sensor for neurons study
Vacuum 163 (2019) 204–209
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Vacuum journal homepage: www.elsevier.com/locate/vacuum
Design and fabrication of MEMS based intracranial pressure sensor for neurons study
T
Nagarajan Manikandana,∗, Shanmugam Murugananda, Muthukumar Divagarb, Chinnuswamy Viswanathanb a b
Department of Electronics and Instrumentation, Bharathiar University, Coimbatore, India Department of Nano Science and Technology, Bharathiar University, Coimbatore, India
A R T I C LE I N FO
A B S T R A C T
Keywords: MEMS Pressure sensor Micro electrode array (MEA) Temperature sensor and neural sensing
Neural sensing has been the backbone of neuroscience research, brain-machine interfaces and clinical neuromodulation therapies for decades. To date, most of the neural stimulation systems have relied on sharp thin film electrodes with poor electrical properties that cause extensive damage to the tissue and significantly degrade the long-term stability of implantable systems. So, here in view of a safer course of action and better results, a flexible microelectrode array is proposed, which is capable of sensing neural stimulation from the neuron surface, without penetrating the tissue. A multi electrode array (MEA) is a micro-fabricated cell culture dish with embedded microelectrodes at the bottom of the dish. The size of the sensor is decided by the size of the sensor chip and package. The sensor chip is based on silicon wafer ,which is piezo resistive effect and the size is 100 × 200 μm2. It is much smaller than the reported polymer intracranial pressure sensors such as liquid crystal polymer sensors. Recently MEAs with different cell-adhesive patterns are actively used to analyse the behaviours under study in vitro neural systems. The MEAs also integrate with pressure sensor and temperature sensor. So the MEAs confirm the synaptic connection of the in vitro neuron stimulation, and a passive piezo resistive resonant sensor that accurately monitors intracranial pressures based on the Wheatstone bridge. Also it shows the present temperature condition of culture dish. As the device is fabricated using MEMS technology with biocompatible material, it has been shown to be non-irritating to cells even if it works for long term measurement. The sensitivity of the sensor is 0.84 × 10−2 mV/kPa and the minimum level of pressure is acquired in the range of 112 Pa in average. From the MEA, temperature and pressure data, the neurological disorder is identified.
1. Introduction As neuroscience research progresses, questions are raised about the highly complex functions of the neurons. So the need for more advanced experimental method and analysis on their activity emerges. The electrophysiological characteristics of neural networks have long been studied to unravel the function of the brain. So the cultured neuronal network has been used for the in vitro study in the field of neuroscience, which includes synaptogenesis, axon guidance and neuron simulation. In bioelectric signal recording the stimulation have played critically important roles in studying basic neural processes underlying human behaviour and causes of neurological disorders [1]. Current clinical practices for recording and stimulation mostly rely on penetrating deep brain areas with millimeter-scale electrodes [2]. While brain computer interfaces (BCIs) generally utilize silicon-based sharp microelectrode arrays implanted in the cortex part of the brain.
∗
The implantation process is makes damage, tissue inflammatory response, and corrosion of the electrodes remain as the major issues regarding long-term stability of these penetrations. So it requires a special methodology such as onsite electrode chambers, micro-island cultures [3]. The electrode patterning over neuron culture and organotypic cell culture which have been developed for the investigation of the mechanism of neural information processing in neural networks. In vitro Micro Electrode Array (MEA) technology has been developed to describe in finer details of the cultured neural networks. Neurons are cultured on a planar type microelectrode array that is capable of sensing electrical signals from neurons or neural circuits. MEAs are created using micro fabrication processes originally developed in the semiconductor industry and it is embedded into the bottom of the culture dish [4]. For a neural culture, MEA provides electronic interfaces for recording electrical signals and applying electrical stimulations to the cultures growing on the dish. Recently MEAs with different cell-
Corresponding author. E-mail address: [email protected] (N. Manikandan).
https://doi.org/10.1016/j.vacuum.2019.02.018 Received 26 November 2018; Received in revised form 6 February 2019; Accepted 11 February 2019 Available online 12 February 2019 0042-207X/ © 2019 Elsevier Ltd. All rights reserved.
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work. Ag and Pt are the sputtering target 2”, Su8 is negative photo resistant, Si (100) is the wafer, and the last item, poly amide. All the above mentioned source materials were procured from the sigma Aldrich. The microelectrode arrays are the precious parts for the health care system for acquiring the bio potential signal from the body. Here the main objective of the system's design is to record and measure the signal simultaneously from the striation. The dimension of the designed microelectrode is 100μm x 500μm x 200μm (l x w x h) [6,7]. The over all space as calsified into five parts . First part is allocate for micro electrode, it placed with four round shaped Ag/Pt microelectrode employed in an even distance distribution, Remining three sites would be allocate for sensor such as, simulation sites, electro physiological recording side, pressure sensor side and multi electrode array (MEA) [8]. Remaining positions can be used for the other experimental purpose in future development. It could be experimentally used for detection of a protein matrix layer which contains glutamate oxide for glutamate sensors. The electrode is placed at a mutual distant space from a central one. Each sensor electrode line is connected with individual connecting pad which is in the side of 500μm x 500μm Only with the use of the connecting pad, the signal could be acquired and transferred. Electrodes contain two parts, one is the counterpart and the other, the reference part. They play vital roles in recording side [9]. Once the signal is acquiried from the reference and the counter electrode, the voltage differences of these two electrodes using detecting circuit could be measured and also the manner in which it confirms the signal variations could be comprehended.
adhesive patterns have been used to analyse these behaviours in vitro neural systems with various morphological structures. And also the properties of the in vitro neural networks which would provide the more information regarding the same activity of real brain are studied. By interfacing microelectrodes with individual neurons and measuring extracellular action i.e., potentials (spikes), MEAs assure spatiotemporal information of the network activity that can be utilized for the quantitative study of cultured neuronal networks. The quality of the neural recordings is one of the most important factors that determine the success of each experiment as well as that of overall MEA technology. Success follows when the networks of neurons are biologically active and the sensors are effective in measuring the bioelectric signals. The neurons on an MEA constitute an extremely complex network. While the MEA cultivation technology has advanced rapidly, it is hard to confirm experimentally how neurons are synoptically connected in the network. Typical methods for analysis are based on a black-box analysis when electrical stimulation acquired from the neurons externally, a few numbers of electrodes were subsequent effects on electrodes are analysed. Compared with direct implant, MEA on the electrode (in vivo) method has proved to be more effective. Also the MEA, as fabricated by MEMS technology with the use of biomaterial, easily adopt with culture neuron networks without damage. Hence the MEA has provided electrical activity of neuron, from which electrical simulation, a neural prostheses and neurological disorder treatments are developed. The analysis for patterned MEAs should take into consideration the whole process including neuron seeding, axon growth, synaptic connection establishment, and the spike transfer among neurons as it not only measures the electrical simulation by the MEA device but also temperature and pressure. MEA also consists of pressure and the temperature sensors. So the culture neurons have acted as same as a real human brain. The device has been placed at the bottom of the dish so it could measure the pressure and the temperature variations of the neurons. The pressure and temperature are directly connected to the behaviour activity of neurons. The whole experimental activity is focused on the behaviour of cultured neurons with synaptic potential and the functional pressure of neurons by MEMS piezo electric transducer, and the temperature from the model is measured. MEA provides a noninvasive cell-electrode interface that allows long-term recording stimulation process for fifteen days. The cultured neural network on MEA can maintain electrical activities by controlling the temperature and pH level of culture environment. From the raw data of neurons pressure, temperature and electrical potential, prevention of the neurological disease and identity of neurology disorder can be done. This paper describes the fabrication of MEMS based on multisensory electrode to record electrophysiological signal [5]. However, the body surface has its own electrical potential and, it implies of many voltage range with frequency so it make some noise.So even a with a small noise it becomes a critical issue within the frequency. Moreover a designed sensor is matched with impedance of human body and so acquires signal from the body. When compared with previous sensor it has excellent impedance matched with the body to acquire bio potential signal. Even though it is a single module, it consists of temperature, pressure and has bio potential ability to acquire signal from the body, and helps in correlation and sequencing with previous data base in identifying the disease.
3. Fabrication Fig. 1 shows silicon based multisensory array, the base substrate which is in the diameter of 4” double-side polished and N. dopped (100) crystalline silicon wafer with 210μm thickness. In the first design, the portfolios of developed 3D structures are incorporated into different electrodes, spacing over all 1 mm center dot center pitches. Hence, for a minute at 4000 rpm spun at 420° c and, for a hour in vacuum atmosphere, cured polyimide foil substrate was enclosed. Being associated with circular sharp electrode with line trace at 400 nm thickness, it sputtered. Ag/Pt electrodes are presented with resistive based pressure [10,11] and temperature sensors. Designed 3D structure was fabricated in a very high vacuum as it implies over the substrate in a standard mask, and subsequently the sputtering over the unmasked place and
2. Material and methods Suitable materials form the source code for the electrode fabrication. Compared with the previous thin films electrode, MEMS electrode has special characteristics for acquiring the signals, and so the selection of material for the electrode is a very crucial factor. This is because the material should have less resistance and high conductance, high impedance and good biocompatible properties needed for the study. The required materials purchased for the work deserve a special mention. Ag, Pt, su8, Si and Poly amide were the core materials used for this
Fig. 1. Fabrication process for neural probe with integrated temperature sensor. (a) 15 μm thick PI was coated on Si substrate. (b) 50 μm Au/pt was evaporated and patterned for electrodes and temperature sensor. (c) Second PI layer was coated on surface. (d) Contact openings were defined for electrodes. (e) PI was etched to expose electrodes by reactive ion etching (RIE). (f) Neural probe was peeled off from silicon substrate. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) 205
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the bottom, which does not exceed the maximum thickness of LCP when it is applied to the highest pressure. One the top of diaphragm, the gold strain gauges with 180Ω resistance value are sputtered on the four sides of diaphragm. Two of them are on the edges of diaphragm and the others, placed close to the other sides that are operated as half bridge configuration. At the edges of diaphragm, the maximum strain happens at the center of each edge due to the deflection of diaphragm, the maximum strain, ɛmax, of the diaphragm is [14,15].
also encapsulate with pyrelene on the designed 3D structure. The above Fig. 1 describes the flow of MEA fabrication [12]. In the first section, Fig. 1a describes the polyamide coated spun on the silicon substrate at 4000 rpm in a minute and how it could be dried at 4500c.Fig. 1b scribes the photo mask for lithography on the substrate after the unexposed areas were removed by using piranha solution. Next, sputtering of 50μm Ag/pt is coated over the polyamide 3D structure. The negative photo resist was coated over the metal by spin coating method. After the photolithography process the unexposed area was removed by piranha solution. Next it was covered by production layer except MEA as it is the only part that is connected with bio body [8]. The temperature sensor could be measured and the temperature variation in the tissues at a particular position [13] is also recorded. The Ag/Pt resistive based pressure sensor integrated in surface of tissue and recording physical parameter of the tissue activity, Here Ag/Pt resistive based temperature sensor were also integrated with electrode array as well as pressure sensor [14,15]. The Ag as coated over the silicon substrate by RF sputtering, silver was coated over the substrate at high vacuum 1x10−6 mbar, substrate temperature is 350 °C and thickness of the materials is 200 nm. The coupling of sensor side is very tiny compared with marker sensor for the utilization of Ag metal electrode and resistance sensor. Thus the results showed that the Pt integrated pressure sensor could be recorded and monitored as the pressure varies according to tissue condition. The space area of sensor was placed uniformly as to maintain 100 μm distance. Each cavity with the 100 nm layer is coated and 3D module structure follows the traditional Wheatstone bridge. Its work depends on the load applied and the temperature acquired. When the load is increased, the voltage responds to input load. According to piezoresistance design, the sensor is working in the non-linear manner. The resistance value has been derived with relevance to minimum and maximum levels of pressure using a mathematical tool.
εmax = 0.308(1 − V 2)
Pb2 Eh2
According to the relative change in the resistance of a resistor segment, it gets deformed from the top of the plate is
ΔR 1 2v − 1 ≈ εl + εw R 1−v 1−v where ɛl and ɛw are the strains along resistor's length and width. ɛl = ɛw can be defined from the stress at the center of an edge in four fixed edges plate [12], and substituted with ν = 0.3, b = 2000 μm, h = 50 μm and E = 2.1 GPa (LCP). The relative change in resistance in term of applied pressure P is
ΔR = (1.831X 10−7Pa−1) P R Accordingly Vout is described by using
Vout =
(R2 + ΔR2)(R 4 + ΔR 4 ) − (R1 + ΔR1)(R3 + ΔR3) (R1 + ΔR1 + R2 + ΔR2) X (R3 + ΔR3 +R 4 + ΔR 4 )
Where R1, R2, R3, R4 are of equal resistance and as R is of original piezo resistance, it is denoted as L &W ie. length and width of the resistance. The ideal conditions of R1 = R2 = R3 = R4 = R0 at zero pressure means the output voltage is equal to zero. In a constant stress, the internally scattering of carrier in the grains is caused by the changes of tunnelling the barrier by its stress in the piezo resister. So the change of resistance is directly proportional to the relative variety ΔR , where
3.1. Design of structure and sensitivity
R0
The built in design of Wheatstone bridge circuit over the sensing diaphragm makes the resistor of the bridge respond to diaphragm's change under the uniform pressure. The deflection of diaphragm's design is taken for consideration in defining the size under the maximum expecting load. As the resistors were fixed in the square edge of diaphragm, the maximum stress appeared at the place of piezoresistor surface. This is Xmax which is calculated by
L R 0 = R∇ W is the position of the piezo resistor location and its direct phase of silicon. 4. Result and discussion
Xmax = c (1-v2)
The fabrication of micro electrode array by MEMS technology. Fig. 2 describes the use of sensor with fabrication module. Sensor has a vital role in all fields especially in biomedical one, in biomedical each and every signal is important even a minor variation in body may cause
As the design of built-in Wheatstone bridge circuit on the top of sensing diaphragm is changed under uniform pressure applied on strain of each resistor, the deflection of diaphragm is considered to make the proper size of diaphragm under maximum loading condition. With respect to all the edges of fixed square plate, the maximum deflection w max appears at the center of the plate and can be approximated by Ref. [13],
Wmax = c (1 − V 2)
Pb2 Eh3
Where
c=
0.032 1 + α4
α is the ratio of width and length of diaphragm. From above equation, p is the uniform applied pressure, E is the Young's modulus and ν is the Poisson ratio. Moreover, b is the length and h is the thickness of diaphragm. This equation utilizes the design of diaphragm which concerns about the deflection to be smaller than the thickness of diaphragm under maximum pressure. According to the design of 0–50 mm Hg pressure range, the maximum thickness of LCP membrane is defined to be 50 μm thick with the cavity size of 2000 μm x 2000 μm x 50 μm at
Fig. 2. Calibration of pressure sensor using external set up. 206
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Perhaps a polyamide may play a major role on this sensor fabrication since sensors were mostly fabricated on a silicon substrate but here sensors were fabricated on polyamide substrate. They were fabricated by mask-based conductive paths along almost vertical sites with base side walls of about 60° in 50 μm diameter from the base substrate and potentially optimized achievable low SNR signals [17]. Choice of polymer is very important for flexible substrate, because it is vital to choose a material that satisfies USP class VI and ISO standards of biomaterials and bio compatibility so that it could be safely used without the risk of causing chronic damage and inflammation at the site of injury. However, the rigorous tests are required to achieve the standards of the material. The biocompatibility of material can be chosen by the user as per the need in hand [18]. Before selection of material for micro fabrication, material's physical characteristic, temperature, pressure level are to be checked. Polyamide has found wide use in electronics as an insulation layer due to its low moisture penetration and high thermal and chemical stability and so is increasingly becoming a more common material for biological applications. So MEA and Pt were fabricated on polyamide film as well as Si substrate and each sensor has a high standard of taper etched multilayer PI foil Ag/Pt, and except the sensing area, the remaining part of sensor is encapsulated with electrode for omission of environmental noise.
Fig. 3. Micro electrode on the polyamide.
5. Electrode Fig. 4. Pressure sensor in the Si wafer.
Fig. 3 describes the electrode fabrication and its design. Each electrode is placed at the right distance and each part of electrode serves as a counter and a reference electrode. The potential variation of signal from the bio body is acquired from the MEMS electrode. The sensor is flexible as well as bio compatible. So it does not irritate or damage the human skin [19]. And so it is placed outside the body where the signal is analysed. There is no need of any special gel or paste because it could be moulded in a single patch that has a sticky nature. The sensor has acquired signal from the culture medium. Also the pressure of the neurons gets measured. The fabricated sensor is optimized for various temperature and pressure levels that is 10–100 mbar [20]. Fig. 4 describes the structure of the pressure sensor with four resistors such as Ps1, Ps2, Ps3 and Ps4. In which Ps3 and Ps4 are calibrated for the measurement of pressure variation. As prepared sensor was placed in the cultured medium to measure the pressure variation. Further, the output signal of the sensor was amplified with differential amplifier and feeded to display unit as shown in Fig. 5. As per Fig. 6 the sensor can acquire signal, condition and switch to processing unit which eliminate all noise and unwanted signal. Fig. 7 describes the signal got from the MEA, though micro electrode is directly connected with the subject. The measurement of bio potential's signal is done continuously, to detect even a minor variation. The system eliminates the power noise, electromyogram signal and environmental noise. Fig. 8 shows the temperature and pressure sensors in the polyamide film and silicon wafer, which are integrated in a single module. and it shows the SEM image of fabricated sensor. All sensors form the essential part of integrated systems. In a single module temperature and pressure are measured. Each and every sensor was calibrated for individuals.
Fig. 5. Neurons study in the culture medium.
some deficiency or syndrome [16]. So each and every part of body signal is very important for analysis. That role is fulfilled by the sensor. Even though the sensor is used extensively, there is lagging still and only a partial fulfillment in sensor placement is gained in medical field so far. As each individual is unique, potential signal also varies from person to person. As per the recorded analysis, signal is to be considered as the physical parameter of humans so that the sensor which keeps acquiring signal from the body is important for patients. Here is the coupling of sensor in a single module for measurement of physical parameter [14]. In fabrication a flexible sensor as well as MEA are given a predominant challenging task. The fabrication of micro electrode and temperature sensor were introduced into the body at micro levels.
Fig. 6. Sensor processing and flow. 207
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Fig. 7. Electrode signal from the bio body.
Fig. 8. Pressure sensor designed structure.
Fig. 10. Piezoresistive sensor in Wheatstone Bridge.
Fig. 11. Shows the changes of the pressure with temperature of the neurons when the sensitivity and reputability were tested for 15 days.
sensor can be classified according to the targeted type of pressure measurement, for example absolute pressure measurement, differential pressure measurement and gauge pressure measurement [21]. The piezoresistive pressure sensor detects the change of external pressure by changing its resistance. The piezeoresistive pressure sensor consists of a semiconductor material such as silicon mounted on the elastic diaphragm as shown in Fig. 10. The devices have been designed and fabricated by means of Wheatstone bridge and each side of the resistor is
Fig. 9. Temperature response in the cell medium.
Fig. 9 describes the temperature measurement of sensor in the culture medium, and also sensor calibrated in the range of 0–50 °C.The temperature was sensed from the neurons with different run time to measure the sensitivity and linearity. Next the second part of sensor is calibrated individually with respect to pressure change. The pressure 208
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designed by flexible method. When the load or resistance varies the corresponding signal is measured by its output. Also it is calibrated for 0–50 °C for the measurement of neurons culture medium. When the load is applied into the resistor, the piezo resistive material's length and width vary due to
author wishes to record his heartfelt gratitude to UGC for providing research fellowship. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.vacuum.2019.02.018.
R = ρL/(Wt ) The variation in W, L and t the value is calculated and result is shown in the graph, with pressure level against resistance changes. The sensor‘s heat is increased, due to that, the resistance of material varies and temperature sensor is calibrated with standard resistance. As the sensor is very tiny the minor changes are also acted by TS and measured. The best aspect of sensor MEMS is, that it is more accurate even though it combines all sensors together. All data is duly presented. Compared to individual sensor and thin film sensor it gives better result as shown in graphs. From Fig. 11 it is clear that the sensor has responded with respect to various temperature levels for Ps3 and Ps4 resistor. As the resistor is temperature dependant, it is calibrated at cool and hot temperature levels and also it is tested around 50 thousand times. Fig. 2 shows the calibration setup and its uses for repeatability and sensitivity of the sensor. But neurons are never live in below freezing temperature for the sensor calibration it could be tested in −20 °C to 20 °C. Fig. 10 shows that: −20 °C gave better response compared to other temperature range but in long duration of checking, 20°C is more efficient in the level of 0–90 mbar pressure variation. From the measured data, it is understood that the variations of pressure and temperature in the in-vivo studies help in knowing and describing the neurological diseases and their stages.
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6. Conclusion The objective and subsequently the core study of this work are to fabricate MEA with high conductive electrode. Here a single sensor is coupled with pressure and temperature sensor to measure long term, continuous pressure from the subject to measure health activity, with respect to variations of pressure and temperature. Chronological diseases can be identified and detected while maintaining low power consumption, and biocompatible and hermetic package are among the top design challenges. Here, fabricated sensor works in the range of −20° to 20 °C and, as it give a better performance in the initial stage −20°, it is tested for long durability test 20 °C and also gives an efficient output. Also the sensor has high sensitivity and linearity when compared with traditional sensor that is 0.84 × 10−2 mV/kPa and the minimum level of pressure is acquired in the range of 112 Pa in average amount with the accuracy of 89%. Though ICP plays a major role in body in detecting any abnormal changes, it has not led to the finding of any chronological disease so far, but this kind of multisensory can easily identify early detection of neurological disease. In future the single module sensor will be extended for the bio implantation with wireless data transmission in long term recording as it has proved in the successful implementation in the diagnosis of anti-parallelism. Acknowledgement We express our sincere thanks to Sivarasan G, Research Associate of Kowsiyang Medical University,Taiwan. N. Manikandan one of the
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Vacuum journal homepage: www.elsevier.com/locate/vacuum
Design and fabrication of MEMS based intracranial pressure sensor for neurons study
T
Nagarajan Manikandana,∗, Shanmugam Murugananda, Muthukumar Divagarb, Chinnuswamy Viswanathanb a b
Department of Electronics and Instrumentation, Bharathiar University, Coimbatore, India Department of Nano Science and Technology, Bharathiar University, Coimbatore, India
A R T I C LE I N FO
A B S T R A C T
Keywords: MEMS Pressure sensor Micro electrode array (MEA) Temperature sensor and neural sensing
Neural sensing has been the backbone of neuroscience research, brain-machine interfaces and clinical neuromodulation therapies for decades. To date, most of the neural stimulation systems have relied on sharp thin film electrodes with poor electrical properties that cause extensive damage to the tissue and significantly degrade the long-term stability of implantable systems. So, here in view of a safer course of action and better results, a flexible microelectrode array is proposed, which is capable of sensing neural stimulation from the neuron surface, without penetrating the tissue. A multi electrode array (MEA) is a micro-fabricated cell culture dish with embedded microelectrodes at the bottom of the dish. The size of the sensor is decided by the size of the sensor chip and package. The sensor chip is based on silicon wafer ,which is piezo resistive effect and the size is 100 × 200 μm2. It is much smaller than the reported polymer intracranial pressure sensors such as liquid crystal polymer sensors. Recently MEAs with different cell-adhesive patterns are actively used to analyse the behaviours under study in vitro neural systems. The MEAs also integrate with pressure sensor and temperature sensor. So the MEAs confirm the synaptic connection of the in vitro neuron stimulation, and a passive piezo resistive resonant sensor that accurately monitors intracranial pressures based on the Wheatstone bridge. Also it shows the present temperature condition of culture dish. As the device is fabricated using MEMS technology with biocompatible material, it has been shown to be non-irritating to cells even if it works for long term measurement. The sensitivity of the sensor is 0.84 × 10−2 mV/kPa and the minimum level of pressure is acquired in the range of 112 Pa in average. From the MEA, temperature and pressure data, the neurological disorder is identified.
1. Introduction As neuroscience research progresses, questions are raised about the highly complex functions of the neurons. So the need for more advanced experimental method and analysis on their activity emerges. The electrophysiological characteristics of neural networks have long been studied to unravel the function of the brain. So the cultured neuronal network has been used for the in vitro study in the field of neuroscience, which includes synaptogenesis, axon guidance and neuron simulation. In bioelectric signal recording the stimulation have played critically important roles in studying basic neural processes underlying human behaviour and causes of neurological disorders [1]. Current clinical practices for recording and stimulation mostly rely on penetrating deep brain areas with millimeter-scale electrodes [2]. While brain computer interfaces (BCIs) generally utilize silicon-based sharp microelectrode arrays implanted in the cortex part of the brain.
∗
The implantation process is makes damage, tissue inflammatory response, and corrosion of the electrodes remain as the major issues regarding long-term stability of these penetrations. So it requires a special methodology such as onsite electrode chambers, micro-island cultures [3]. The electrode patterning over neuron culture and organotypic cell culture which have been developed for the investigation of the mechanism of neural information processing in neural networks. In vitro Micro Electrode Array (MEA) technology has been developed to describe in finer details of the cultured neural networks. Neurons are cultured on a planar type microelectrode array that is capable of sensing electrical signals from neurons or neural circuits. MEAs are created using micro fabrication processes originally developed in the semiconductor industry and it is embedded into the bottom of the culture dish [4]. For a neural culture, MEA provides electronic interfaces for recording electrical signals and applying electrical stimulations to the cultures growing on the dish. Recently MEAs with different cell-
Corresponding author. E-mail address: [email protected] (N. Manikandan).
https://doi.org/10.1016/j.vacuum.2019.02.018 Received 26 November 2018; Received in revised form 6 February 2019; Accepted 11 February 2019 Available online 12 February 2019 0042-207X/ © 2019 Elsevier Ltd. All rights reserved.
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work. Ag and Pt are the sputtering target 2”, Su8 is negative photo resistant, Si (100) is the wafer, and the last item, poly amide. All the above mentioned source materials were procured from the sigma Aldrich. The microelectrode arrays are the precious parts for the health care system for acquiring the bio potential signal from the body. Here the main objective of the system's design is to record and measure the signal simultaneously from the striation. The dimension of the designed microelectrode is 100μm x 500μm x 200μm (l x w x h) [6,7]. The over all space as calsified into five parts . First part is allocate for micro electrode, it placed with four round shaped Ag/Pt microelectrode employed in an even distance distribution, Remining three sites would be allocate for sensor such as, simulation sites, electro physiological recording side, pressure sensor side and multi electrode array (MEA) [8]. Remaining positions can be used for the other experimental purpose in future development. It could be experimentally used for detection of a protein matrix layer which contains glutamate oxide for glutamate sensors. The electrode is placed at a mutual distant space from a central one. Each sensor electrode line is connected with individual connecting pad which is in the side of 500μm x 500μm Only with the use of the connecting pad, the signal could be acquired and transferred. Electrodes contain two parts, one is the counterpart and the other, the reference part. They play vital roles in recording side [9]. Once the signal is acquiried from the reference and the counter electrode, the voltage differences of these two electrodes using detecting circuit could be measured and also the manner in which it confirms the signal variations could be comprehended.
adhesive patterns have been used to analyse these behaviours in vitro neural systems with various morphological structures. And also the properties of the in vitro neural networks which would provide the more information regarding the same activity of real brain are studied. By interfacing microelectrodes with individual neurons and measuring extracellular action i.e., potentials (spikes), MEAs assure spatiotemporal information of the network activity that can be utilized for the quantitative study of cultured neuronal networks. The quality of the neural recordings is one of the most important factors that determine the success of each experiment as well as that of overall MEA technology. Success follows when the networks of neurons are biologically active and the sensors are effective in measuring the bioelectric signals. The neurons on an MEA constitute an extremely complex network. While the MEA cultivation technology has advanced rapidly, it is hard to confirm experimentally how neurons are synoptically connected in the network. Typical methods for analysis are based on a black-box analysis when electrical stimulation acquired from the neurons externally, a few numbers of electrodes were subsequent effects on electrodes are analysed. Compared with direct implant, MEA on the electrode (in vivo) method has proved to be more effective. Also the MEA, as fabricated by MEMS technology with the use of biomaterial, easily adopt with culture neuron networks without damage. Hence the MEA has provided electrical activity of neuron, from which electrical simulation, a neural prostheses and neurological disorder treatments are developed. The analysis for patterned MEAs should take into consideration the whole process including neuron seeding, axon growth, synaptic connection establishment, and the spike transfer among neurons as it not only measures the electrical simulation by the MEA device but also temperature and pressure. MEA also consists of pressure and the temperature sensors. So the culture neurons have acted as same as a real human brain. The device has been placed at the bottom of the dish so it could measure the pressure and the temperature variations of the neurons. The pressure and temperature are directly connected to the behaviour activity of neurons. The whole experimental activity is focused on the behaviour of cultured neurons with synaptic potential and the functional pressure of neurons by MEMS piezo electric transducer, and the temperature from the model is measured. MEA provides a noninvasive cell-electrode interface that allows long-term recording stimulation process for fifteen days. The cultured neural network on MEA can maintain electrical activities by controlling the temperature and pH level of culture environment. From the raw data of neurons pressure, temperature and electrical potential, prevention of the neurological disease and identity of neurology disorder can be done. This paper describes the fabrication of MEMS based on multisensory electrode to record electrophysiological signal [5]. However, the body surface has its own electrical potential and, it implies of many voltage range with frequency so it make some noise.So even a with a small noise it becomes a critical issue within the frequency. Moreover a designed sensor is matched with impedance of human body and so acquires signal from the body. When compared with previous sensor it has excellent impedance matched with the body to acquire bio potential signal. Even though it is a single module, it consists of temperature, pressure and has bio potential ability to acquire signal from the body, and helps in correlation and sequencing with previous data base in identifying the disease.
3. Fabrication Fig. 1 shows silicon based multisensory array, the base substrate which is in the diameter of 4” double-side polished and N. dopped (100) crystalline silicon wafer with 210μm thickness. In the first design, the portfolios of developed 3D structures are incorporated into different electrodes, spacing over all 1 mm center dot center pitches. Hence, for a minute at 4000 rpm spun at 420° c and, for a hour in vacuum atmosphere, cured polyimide foil substrate was enclosed. Being associated with circular sharp electrode with line trace at 400 nm thickness, it sputtered. Ag/Pt electrodes are presented with resistive based pressure [10,11] and temperature sensors. Designed 3D structure was fabricated in a very high vacuum as it implies over the substrate in a standard mask, and subsequently the sputtering over the unmasked place and
2. Material and methods Suitable materials form the source code for the electrode fabrication. Compared with the previous thin films electrode, MEMS electrode has special characteristics for acquiring the signals, and so the selection of material for the electrode is a very crucial factor. This is because the material should have less resistance and high conductance, high impedance and good biocompatible properties needed for the study. The required materials purchased for the work deserve a special mention. Ag, Pt, su8, Si and Poly amide were the core materials used for this
Fig. 1. Fabrication process for neural probe with integrated temperature sensor. (a) 15 μm thick PI was coated on Si substrate. (b) 50 μm Au/pt was evaporated and patterned for electrodes and temperature sensor. (c) Second PI layer was coated on surface. (d) Contact openings were defined for electrodes. (e) PI was etched to expose electrodes by reactive ion etching (RIE). (f) Neural probe was peeled off from silicon substrate. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.) 205
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the bottom, which does not exceed the maximum thickness of LCP when it is applied to the highest pressure. One the top of diaphragm, the gold strain gauges with 180Ω resistance value are sputtered on the four sides of diaphragm. Two of them are on the edges of diaphragm and the others, placed close to the other sides that are operated as half bridge configuration. At the edges of diaphragm, the maximum strain happens at the center of each edge due to the deflection of diaphragm, the maximum strain, ɛmax, of the diaphragm is [14,15].
also encapsulate with pyrelene on the designed 3D structure. The above Fig. 1 describes the flow of MEA fabrication [12]. In the first section, Fig. 1a describes the polyamide coated spun on the silicon substrate at 4000 rpm in a minute and how it could be dried at 4500c.Fig. 1b scribes the photo mask for lithography on the substrate after the unexposed areas were removed by using piranha solution. Next, sputtering of 50μm Ag/pt is coated over the polyamide 3D structure. The negative photo resist was coated over the metal by spin coating method. After the photolithography process the unexposed area was removed by piranha solution. Next it was covered by production layer except MEA as it is the only part that is connected with bio body [8]. The temperature sensor could be measured and the temperature variation in the tissues at a particular position [13] is also recorded. The Ag/Pt resistive based pressure sensor integrated in surface of tissue and recording physical parameter of the tissue activity, Here Ag/Pt resistive based temperature sensor were also integrated with electrode array as well as pressure sensor [14,15]. The Ag as coated over the silicon substrate by RF sputtering, silver was coated over the substrate at high vacuum 1x10−6 mbar, substrate temperature is 350 °C and thickness of the materials is 200 nm. The coupling of sensor side is very tiny compared with marker sensor for the utilization of Ag metal electrode and resistance sensor. Thus the results showed that the Pt integrated pressure sensor could be recorded and monitored as the pressure varies according to tissue condition. The space area of sensor was placed uniformly as to maintain 100 μm distance. Each cavity with the 100 nm layer is coated and 3D module structure follows the traditional Wheatstone bridge. Its work depends on the load applied and the temperature acquired. When the load is increased, the voltage responds to input load. According to piezoresistance design, the sensor is working in the non-linear manner. The resistance value has been derived with relevance to minimum and maximum levels of pressure using a mathematical tool.
εmax = 0.308(1 − V 2)
Pb2 Eh2
According to the relative change in the resistance of a resistor segment, it gets deformed from the top of the plate is
ΔR 1 2v − 1 ≈ εl + εw R 1−v 1−v where ɛl and ɛw are the strains along resistor's length and width. ɛl = ɛw can be defined from the stress at the center of an edge in four fixed edges plate [12], and substituted with ν = 0.3, b = 2000 μm, h = 50 μm and E = 2.1 GPa (LCP). The relative change in resistance in term of applied pressure P is
ΔR = (1.831X 10−7Pa−1) P R Accordingly Vout is described by using
Vout =
(R2 + ΔR2)(R 4 + ΔR 4 ) − (R1 + ΔR1)(R3 + ΔR3) (R1 + ΔR1 + R2 + ΔR2) X (R3 + ΔR3 +R 4 + ΔR 4 )
Where R1, R2, R3, R4 are of equal resistance and as R is of original piezo resistance, it is denoted as L &W ie. length and width of the resistance. The ideal conditions of R1 = R2 = R3 = R4 = R0 at zero pressure means the output voltage is equal to zero. In a constant stress, the internally scattering of carrier in the grains is caused by the changes of tunnelling the barrier by its stress in the piezo resister. So the change of resistance is directly proportional to the relative variety ΔR , where
3.1. Design of structure and sensitivity
R0
The built in design of Wheatstone bridge circuit over the sensing diaphragm makes the resistor of the bridge respond to diaphragm's change under the uniform pressure. The deflection of diaphragm's design is taken for consideration in defining the size under the maximum expecting load. As the resistors were fixed in the square edge of diaphragm, the maximum stress appeared at the place of piezoresistor surface. This is Xmax which is calculated by
L R 0 = R∇ W is the position of the piezo resistor location and its direct phase of silicon. 4. Result and discussion
Xmax = c (1-v2)
The fabrication of micro electrode array by MEMS technology. Fig. 2 describes the use of sensor with fabrication module. Sensor has a vital role in all fields especially in biomedical one, in biomedical each and every signal is important even a minor variation in body may cause
As the design of built-in Wheatstone bridge circuit on the top of sensing diaphragm is changed under uniform pressure applied on strain of each resistor, the deflection of diaphragm is considered to make the proper size of diaphragm under maximum loading condition. With respect to all the edges of fixed square plate, the maximum deflection w max appears at the center of the plate and can be approximated by Ref. [13],
Wmax = c (1 − V 2)
Pb2 Eh3
Where
c=
0.032 1 + α4
α is the ratio of width and length of diaphragm. From above equation, p is the uniform applied pressure, E is the Young's modulus and ν is the Poisson ratio. Moreover, b is the length and h is the thickness of diaphragm. This equation utilizes the design of diaphragm which concerns about the deflection to be smaller than the thickness of diaphragm under maximum pressure. According to the design of 0–50 mm Hg pressure range, the maximum thickness of LCP membrane is defined to be 50 μm thick with the cavity size of 2000 μm x 2000 μm x 50 μm at
Fig. 2. Calibration of pressure sensor using external set up. 206
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Perhaps a polyamide may play a major role on this sensor fabrication since sensors were mostly fabricated on a silicon substrate but here sensors were fabricated on polyamide substrate. They were fabricated by mask-based conductive paths along almost vertical sites with base side walls of about 60° in 50 μm diameter from the base substrate and potentially optimized achievable low SNR signals [17]. Choice of polymer is very important for flexible substrate, because it is vital to choose a material that satisfies USP class VI and ISO standards of biomaterials and bio compatibility so that it could be safely used without the risk of causing chronic damage and inflammation at the site of injury. However, the rigorous tests are required to achieve the standards of the material. The biocompatibility of material can be chosen by the user as per the need in hand [18]. Before selection of material for micro fabrication, material's physical characteristic, temperature, pressure level are to be checked. Polyamide has found wide use in electronics as an insulation layer due to its low moisture penetration and high thermal and chemical stability and so is increasingly becoming a more common material for biological applications. So MEA and Pt were fabricated on polyamide film as well as Si substrate and each sensor has a high standard of taper etched multilayer PI foil Ag/Pt, and except the sensing area, the remaining part of sensor is encapsulated with electrode for omission of environmental noise.
Fig. 3. Micro electrode on the polyamide.
5. Electrode Fig. 4. Pressure sensor in the Si wafer.
Fig. 3 describes the electrode fabrication and its design. Each electrode is placed at the right distance and each part of electrode serves as a counter and a reference electrode. The potential variation of signal from the bio body is acquired from the MEMS electrode. The sensor is flexible as well as bio compatible. So it does not irritate or damage the human skin [19]. And so it is placed outside the body where the signal is analysed. There is no need of any special gel or paste because it could be moulded in a single patch that has a sticky nature. The sensor has acquired signal from the culture medium. Also the pressure of the neurons gets measured. The fabricated sensor is optimized for various temperature and pressure levels that is 10–100 mbar [20]. Fig. 4 describes the structure of the pressure sensor with four resistors such as Ps1, Ps2, Ps3 and Ps4. In which Ps3 and Ps4 are calibrated for the measurement of pressure variation. As prepared sensor was placed in the cultured medium to measure the pressure variation. Further, the output signal of the sensor was amplified with differential amplifier and feeded to display unit as shown in Fig. 5. As per Fig. 6 the sensor can acquire signal, condition and switch to processing unit which eliminate all noise and unwanted signal. Fig. 7 describes the signal got from the MEA, though micro electrode is directly connected with the subject. The measurement of bio potential's signal is done continuously, to detect even a minor variation. The system eliminates the power noise, electromyogram signal and environmental noise. Fig. 8 shows the temperature and pressure sensors in the polyamide film and silicon wafer, which are integrated in a single module. and it shows the SEM image of fabricated sensor. All sensors form the essential part of integrated systems. In a single module temperature and pressure are measured. Each and every sensor was calibrated for individuals.
Fig. 5. Neurons study in the culture medium.
some deficiency or syndrome [16]. So each and every part of body signal is very important for analysis. That role is fulfilled by the sensor. Even though the sensor is used extensively, there is lagging still and only a partial fulfillment in sensor placement is gained in medical field so far. As each individual is unique, potential signal also varies from person to person. As per the recorded analysis, signal is to be considered as the physical parameter of humans so that the sensor which keeps acquiring signal from the body is important for patients. Here is the coupling of sensor in a single module for measurement of physical parameter [14]. In fabrication a flexible sensor as well as MEA are given a predominant challenging task. The fabrication of micro electrode and temperature sensor were introduced into the body at micro levels.
Fig. 6. Sensor processing and flow. 207
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Fig. 7. Electrode signal from the bio body.
Fig. 8. Pressure sensor designed structure.
Fig. 10. Piezoresistive sensor in Wheatstone Bridge.
Fig. 11. Shows the changes of the pressure with temperature of the neurons when the sensitivity and reputability were tested for 15 days.
sensor can be classified according to the targeted type of pressure measurement, for example absolute pressure measurement, differential pressure measurement and gauge pressure measurement [21]. The piezoresistive pressure sensor detects the change of external pressure by changing its resistance. The piezeoresistive pressure sensor consists of a semiconductor material such as silicon mounted on the elastic diaphragm as shown in Fig. 10. The devices have been designed and fabricated by means of Wheatstone bridge and each side of the resistor is
Fig. 9. Temperature response in the cell medium.
Fig. 9 describes the temperature measurement of sensor in the culture medium, and also sensor calibrated in the range of 0–50 °C.The temperature was sensed from the neurons with different run time to measure the sensitivity and linearity. Next the second part of sensor is calibrated individually with respect to pressure change. The pressure 208
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designed by flexible method. When the load or resistance varies the corresponding signal is measured by its output. Also it is calibrated for 0–50 °C for the measurement of neurons culture medium. When the load is applied into the resistor, the piezo resistive material's length and width vary due to
author wishes to record his heartfelt gratitude to UGC for providing research fellowship. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.vacuum.2019.02.018.
R = ρL/(Wt ) The variation in W, L and t the value is calculated and result is shown in the graph, with pressure level against resistance changes. The sensor‘s heat is increased, due to that, the resistance of material varies and temperature sensor is calibrated with standard resistance. As the sensor is very tiny the minor changes are also acted by TS and measured. The best aspect of sensor MEMS is, that it is more accurate even though it combines all sensors together. All data is duly presented. Compared to individual sensor and thin film sensor it gives better result as shown in graphs. From Fig. 11 it is clear that the sensor has responded with respect to various temperature levels for Ps3 and Ps4 resistor. As the resistor is temperature dependant, it is calibrated at cool and hot temperature levels and also it is tested around 50 thousand times. Fig. 2 shows the calibration setup and its uses for repeatability and sensitivity of the sensor. But neurons are never live in below freezing temperature for the sensor calibration it could be tested in −20 °C to 20 °C. Fig. 10 shows that: −20 °C gave better response compared to other temperature range but in long duration of checking, 20°C is more efficient in the level of 0–90 mbar pressure variation. From the measured data, it is understood that the variations of pressure and temperature in the in-vivo studies help in knowing and describing the neurological diseases and their stages.
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6. Conclusion The objective and subsequently the core study of this work are to fabricate MEA with high conductive electrode. Here a single sensor is coupled with pressure and temperature sensor to measure long term, continuous pressure from the subject to measure health activity, with respect to variations of pressure and temperature. Chronological diseases can be identified and detected while maintaining low power consumption, and biocompatible and hermetic package are among the top design challenges. Here, fabricated sensor works in the range of −20° to 20 °C and, as it give a better performance in the initial stage −20°, it is tested for long durability test 20 °C and also gives an efficient output. Also the sensor has high sensitivity and linearity when compared with traditional sensor that is 0.84 × 10−2 mV/kPa and the minimum level of pressure is acquired in the range of 112 Pa in average amount with the accuracy of 89%. Though ICP plays a major role in body in detecting any abnormal changes, it has not led to the finding of any chronological disease so far, but this kind of multisensory can easily identify early detection of neurological disease. In future the single module sensor will be extended for the bio implantation with wireless data transmission in long term recording as it has proved in the successful implementation in the diagnosis of anti-parallelism. Acknowledgement We express our sincere thanks to Sivarasan G, Research Associate of Kowsiyang Medical University,Taiwan. N. Manikandan one of the
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