TWI695174B - Miniaturized sensing probe and manufacturing method thereof - Google Patents

Abstract

A miniaturized sensing probe and a manufacturing method thereof are provided. The miniaturized sensing probe includes: a probe substrate including a probe part and a circuit connection part; a sensor disposed on the probe part and electrically connected to the circuit connection part; and a needle unit for accommodating the probe part of the probe substrate. Wherein, the sensor performs sensing while being imbedded into an object to be detected via the needle unit, and transmits a sensing signal by the circuit connection part. The miniaturized sensing probe can be easily placed into the object to be detected with no need of extra instraments or surgical operations such that it could help the clinician to diagnose the peripheral vascular disease, or to real-time monitor the biological value of the muscle during surgery.

Description

Miniaturized sensing probe and manufacturing method thereof

The invention relates to a sensing probe and a manufacturing method thereof, in particular, a miniaturized sensing probe for monitoring biological values such as temperature, pH value, and ions in the food and medical fields.

In the medical field, in order to avoid the sudden deterioration of the patient's condition during surgery, treatment or examination, it is usually necessary to monitor various physiological values in real time, especially during cardiac surgery, because the routine procedures of cardiac surgery need to be stopped by Heart, lower the temperature and perfuse the myocardial vasculature with cardioplegia, which often causes various sequelae after surgery, such as systemic non-specific inflammatory reactions, organ function deterioration, endocrine system changes, metabolism and electrolyte abnormalities Wait. However, the medical staff can only monitor the postoperative status of patients after surgery by monitoring methods such as electrocardiogram, arterial pressure catheter, or conventional blood drawing, etc. Blood method.

In addition, with the rise of the average age of Chinese people, changes in living habits and diets, the population with chronic diseases such as diabetes, hypertension, and dyslipidemia has also gradually increased, so the prevention of peripheral vascular diseases is more important. Symptoms of peripheral vascular disease include muscle soreness, weakness, or intermittent claudication caused by ischemia of the lower limbs. When the condition is more serious, there may be rest pain or even skin ulcers. Ulcers and other symptoms. In general, the conventional diagnosis method of peripheral vascular diseases today is to roughly judge the location of vascular obstruction by palpation. If further and more accurate diagnosis is required, angiography is required to effectively determine the location of vascular obstruction. However, this test method can only find the location of the occlusion of blood vessels. If you need to further determine the necrosis of the extremities, you need to use the accumulated experience of the doctor for many years to accurately judge.

In addition, in terms of food safety, in order to reduce or avoid consumers’ doubts about food safety, items that may cause consumer health hazards are often evaluated in a scientific manner. However, there are thousands of food types on the market and there are There are many projects, and even sampling inspection still requires very large human resources and inspection costs. Therefore, in order to detect the freshness of the food or whether the food has potential safety concerns without affecting the food, a simple and fast detection method is urgently needed.

Although various sensors have been developed for biomedical applications, the conventional sensor size usually has an area of a few square millimeters, and implantation into tissues for sensing has not yet been achieved. Therefore, an object of the present invention is to provide a miniaturized sensing probe. The miniaturized sensor is provided on a probe substrate and combined with a medical needle, so that it can be easily placed in tissues and foods for sensing.

According to one aspect of the present invention, a miniaturized sensing probe is provided, which includes: a probe substrate including a probe portion and a circuit connection portion; the probe portion is disposed on the probe portion and electrically connected to the sensing of the circuit connection portion ; And a needle unit for accommodating the probe part of the probe substrate, wherein the sensor senses when the needle unit is placed in an object to be measured, and transmits a sense through the circuit connection part Test signal.

Preferably, the probe substrate in this case may be a silicon substrate or a flexible substrate.

Preferably, when a silicon substrate is used as the probe substrate in this case, the sensor provided on the probe portion may include at least one of a temperature sensor, a pH sensor, and an ion sensor.

Preferably, when a flexible substrate is used as the probe substrate in this case, the sensor provided on the probe portion may include at least one of a temperature sensor, a pH sensor, an ion sensor, and a protein sensor One kind.

Preferably, the protein sensed by the protein sensor in this case may be lactic acid or troponin.

Preferably, the flexible substrate in this case may be a biocompatible substrate or a biodegradable substrate.

Preferably, the caliber of the needle unit in this case may have a caliber equal to or smaller than that of a 23 gauge needle.

Preferably, the sensor in this case may further include a reference electrode, and a polyvinyl chloride (PVC) layer containing chlorine may be disposed on the reference electrode.

Preferably, the sensor in this case may further include a working electrode, and a polyvinyl chloride layer containing ions may be provided on the working electrode.

According to another aspect of the present invention, there is provided a method for manufacturing a miniaturized sensing probe, which includes the following steps: (a) forming a reference electrode on a part of a probe substrate by electroplating or an inkjet process; (b ) The working electrode is formed on the other part of the probe substrate by the chemical vapor deposition method or the inkjet process; (c) The polyvinyl chloride layer is formed on at least one of the reference electrode and the working electrode by the inkjet process Upper; and (d) disposing the probe substrate in the needle unit.

The miniaturized sensing probe according to the present invention can have the following advantages:

(1) The miniaturized sensing probe of the present invention can be protected by medical needles, so that the probe substrate can be easily placed into tissues without any other instruments or surgery, which helps clinicians apply to peripheral blood vessels Disease patients can be diagnosed early, or they can be used to monitor various biological values of muscles without interfering with cardiac surgery, so that they can immediately know the state of myocardial ischemia, and can prevent or reduce various sequelae caused by postoperative.

(2) The miniaturized sensing probe of the present invention can integrate various sensors such as temperature sensor, pH sensor, ion sensor or protein sensor on the probe substrate based on needs. To help medical staff monitor the patient's immediate condition.

(3) The miniaturized sensing probe of the present invention can also use a flexible probe substrate. In this case, since the probe substrate can be rolled into a cylindrical shape, the installation area of the sensor can be increased, and the cylindrical The probe substrate can be placed in the flat manner of the inner wall of the needle unit, and an opening is provided in the tube wall of the needle unit corresponding to the sensor, which can achieve multiple measurement positions and multiple sensors. The effect of increasing sensing sensitivity and stability.

10: Probe substrate

100: silicon substrate

110: Probe section

111, 112, 113, 131: wire

120: Circuit connection part

121: connection point

20: Circuit board

210: oxide layer

220: nitride layer

230: Seed layer

240: protective layer

250: PVC layer

30: Needle unit

40: waterproof element

INS: ion sensor

KE: potassium ion electrode

NAE: sodium ion electrode

OP1: the first opening

OP2: second opening

OP3: third opening

PHM: pH sensor

PRS: protein sensor

RTD: temperature sensor

RE: Reference electrode

WE: working electrode

W1, W2, W3: width

L1, L2, L3: length

FIG. 1 is a schematic diagram of the first embodiment of the miniaturized sensing probe of the present invention.

FIG. 2 is a plan view of the probe substrate of the miniaturized sensing probe of FIG. 1. FIG.

Figure 3 is an enlarged view of part D1 of Figure 2.

4A to 4F are cross-sectional views of the manufacturing process of the miniaturized sensing probe of the present invention.

Figure 5 is an image diagram of a miniaturized sensing probe made according to the first process of the present invention, where (a) is an image of the probe substrate of the first embodiment of the present invention; (b) is Probe Electron microscopic observation diagram of the probe part of the substrate; (c) is an electron microscopic observation diagram of the pH sensor formed on the probe part; (d) is a temperature sensing formed on the probe part Electron microscopic observation diagram of the device; (e) is the image of the combination of the probe substrate and the circuit substrate; (f) is the image of the miniaturized sensing probe of the present invention.

Figure 6 is the measurement result of measuring the temperature and pH value using the probe substrate of the first embodiment of the present invention, where (a) is the result of the temperature sensor sensing the temperature; (b) is the pH sensor The result of the sensor sensing the pH value; (c) is the restorative result of the pH sensor.

Figure 7 shows a graph of the effect of the pH sensor in the needle unit and the addition of 0.1M KCl on the pH value.

Figure 8 is a graph of the application of the miniaturized sensing probe of the present invention to monitor rabbit lower limb muscles, where (a) is the result of monitoring the pH value and blood LDH concentration of rabbit lower limb muscles; and (b) is The result of monitoring the temperature of the rabbit's lower limb muscles.

FIG. 9 is a schematic diagram of a second embodiment of the miniaturized sensing probe of the present invention.

FIG. 10 is a plan view of the probe substrate of the miniaturized sensing probe of FIG. 9. FIG.

FIG. 11 is an image diagram of a miniaturized sensing probe made according to the second process of the present invention, where (a) is an image of the probe portion of the probe substrate of the second embodiment of the present invention; And (b) is an electron microscopic cross-sectional view of each electrode on the probe part.

FIGS. 12A to 12F show the comparison results of measuring the Na+ and K+ ion concentrations in the buffer solutions of different ion concentrations using the probe substrate and the commercial electrode of the second embodiment of the present invention.

Figure 13 shows the comparison results of a reference electrode covered with or without a PVC layer containing chlorine measured in a buffer solution at pH 7 relative to a commercial reference electrode, where (a) is without a PVC layer Of the reference electrode relative to the commercial reference; and (b) the result of the reference electrode with the PVC layer relative to the commercial reference.

FIG. 14 shows an electron microscopic observation diagram of the flexible probe substrate and needle unit of the present invention.

FIG. 15 is a schematic diagram of a third embodiment of the miniaturized sensing probe of the present invention.

The advantages, features, and technical methods of the present invention will be described in more detail with reference to the exemplary embodiments and the accompanying drawings to make it easier to understand, and the present invention can be implemented in different forms, so it should not be understood that it is limited to the The described embodiments, on the contrary, for those of ordinary skill in the art, the provided embodiments will make the disclosure more thorough, comprehensive, and complete to convey the scope of the present invention.

The various exemplary embodiments described herein with reference to the drawings are schematic illustrations of idealized exemplary embodiments and/or intermediate structures. For example, due to manufacturing techniques and/or tolerances, changes in the shape of the drawings are expected, so the exemplary embodiments of the present disclosure should not be interpreted as being limited to the specific shape of the region, but should include, for example, shape deviations caused by manufacturing . In addition, in the drawings, the size of elements may be exaggerated for convenience of explanation. Throughout the specification and drawings, the same element symbol may refer to the same element.

Please refer to FIGS. 1 to 3, FIG. 1 is a schematic diagram of a first embodiment of the miniaturized sensing probe of the present invention, and FIG. 2 is a probe of the miniaturized sensing probe of FIG. 1 The plan view of the substrate and FIG. 3 are enlarged views of the sensor portion provided in FIG. 1. According to the first implementation For example, the present invention provides a miniaturized sensing probe, which includes: a probe substrate 10 having a probe portion 110 with a narrow width and a circuit connection portion 120 with a wider width and having a connection point 121; The needle 110 is electrically connected to the temperature sensor RTD and the pH sensor PHM of the circuit connection 120. However, the type of sensor setting is only exemplary, that is, the user can set, for example, sodium ions as needed Sensors, potassium ion sensors, calcium ion sensors, and other various types of sensors; electrically connected to the circuit connection portion 120 of the probe substrate 10 to transmit signals sensed by the sensors The circuit board 20 to be analyzed to the outside; and the needle unit 30 accommodating the probe part 110 of the probe board 10. In this embodiment, the probe substrate 10 may be a <100> silicon substrate with a thickness of about 200 μm to 400 μm, preferably 250 μm or 300 μm, wherein the width W1 of the circuit connection portion 120 may be 2 mm to 6 mm, preferably The width W1 is approximately 4.3 mm, and the length L1 may be approximately 2 mm to 6 mm, the preferred length L1 is approximately 4.75 mm, the width W2 of the probe portion 110 may be approximately 300 μm to 700 μm, and the preferred width W2 is approximately 400 μm. The length L2 may be about 13 mm to 25 mm, and the preferred length L2 is about 15 mm. In addition, the edge of the probe portion 110 may have a characteristic angle of 54 degrees, however, the present invention is not limited thereto, that is, the user may set the edge of the probe portion 110 to be easily inserted into the needle unit 30 based on needs. edge. Therefore, since the miniaturized sensing probe of the present invention has the above-mentioned specific size and angle, the probe portion 110 can be flatly arranged in the needle unit 30, and then the signal is transmitted to the outside through the circuit connection portion 120 and the circuit board 20 . It is worth mentioning that the needle unit 30 used in this case is a medical steel needle, and its inner diameter may have an inner diameter equal to or smaller than that of a 23-gauge needle, preferably a 18-gauge to 22-gauge needle, more preferably a 20-gauge needle The inner diameter of the ~21 gauge needle can be, for example, about 0.838, 0.686, 0.603, 0.514, 0.413 or 0.337mm, but the present invention is not limited to this, that is, according to the purpose and needs of use, an appropriate inner diameter can be used Needles of a large or small size, that is, for example, for food inspection, a 17 gauge needle can also be used.

Further referring to FIGS. 2 and 3, the pH sensor PHM is disposed on the end of the probe part 110 away from the circuit connection part 120, and the pH sensor PHM may include a reference electrode RE and a working electrode WE, the reference electrode The signals sensed by the RE and the working electrode WE can be transmitted to the connection point 121 on the circuit connection part 120 through the wires 111 and 112 respectively, and then transmitted to the circuit board 20 through the connection point 121. Among them, the material of the reference electrode RE may be silver (Ag) and/or silver chloride (AgCl), and the material of the working electrode WE may be iridium oxide (IrO _x ), which has good biocompatibility, high sensitivity and High stability, but the invention is not limited to this, that is, the reference electrode RE and the working electrode WE can be formed by selecting other suitable metal materials. In addition, a polyvinyl chloride (PVC) layer containing chloride ions may be additionally formed on the reference electrode RE. The width W3 of the reference electrode RE or the working electrode WE may be 100-200 μm, the preferred width W3 is 120-150 μm, and the length L3 may be 200-850 μm, and the preferred length L3 is 240-750 μm. In this embodiment The dimensions of the reference electrode RE and the working electrode WE are 150×750 μm ² . The pH sensor PHM in this case can be based on the Nernst equation, as shown in the following formula (1):

Among them, F represents Faraday constant, its value is 96500C/mole, R represents gas constant, its value is 8.314J/mole K, E ⁰ is the standard potential of silver chloride 577mV. According to the above formula (1), at room temperature of 25° C., the theoretical value of the acid-base sensing is about -59 mV/pH.

In this embodiment, the temperature sensor RTD on the probe part 110 may be a resistance temperature sensor, and may be disposed adjacent to the pH sensor PHM, but the present invention is not limited thereto, that is, The temperature sensor RTD or the pH sensor PHM can be respectively disposed at a desired position along the length direction of the probe part 110 according to the actual depth position to be sensed. The basic principle of the temperature sensor RTD according to the present invention is that the metal resistance changes linearly with temperature. Therefore, according to the following formula (2), the method of measuring the resistance by a four-point probe, the conductor 131 at both ends of the periphery conducts current ( Current 5X10 ^-4 A), the resistance value is converted by measuring the voltage at both ends of the middle, and then the temperature is converted.

為在不同溫度下的電阻變化，

為溫度變化量。 Among them, TCR is the temperature coefficient of resistance, R is the resistance at the reference temperature,

For the resistance change at different temperatures,

It is the temperature change.

The resistance wire used in this case is a copper metal wire of about 25Ω, because copper has a good temperature coefficient (TCR~4.27x10 ^-3 /℃), low cost, wide sensing range, high accuracy, fast response time, stability The advantages of high, easy electroplating and suitable for silicon process, so choose copper as a conductive material and cover the gold layer after nickel-gold replacement for oxidation protection. Based on the width dimension of the probe part 110, the line width of the copper wire is about 8-12 μm, preferably 10 μm, and the total length of the resistance wire of the meander winding is about 7000 μm.

Next, referring to FIGS. 4A to 4F, which are cross-sectional views of the manufacturing process of the miniaturized sensing probe of the present invention. The process steps of the miniaturized sensing probe of the present invention include: depositing an oxide layer 210 (thickness 500nm) and a nitride layer 220 (thickness 800nm) by a low pressure chemical vapor deposition (LPCVD) to a thickness of about 250μm< After 100>Si on the silicon substrate 100, use RIE to open the front mask layer for defining the pattern of the probe substrate 10 (refer to FIG. 4A); then, the thickness of 30nm~120nm containing titanium (Ti) and/or A seed layer 230 of copper (Cu) and a coating (not shown) defining the area of the wire and the external electrical connection point are deposited on the nitride layer 220, followed by electroplating of a copper layer (Cu) of 1 μm and electroless plating of 0.1 μm ~0.4μm of nickel (Ni) and/or gold (Au) as the protective layer 240 to form a temperature sensor RTD (see Figure 4B); electroplating materials containing silver and/or silver chloride on the protective layer 240 To form a reference electrode RE (refer to Figure 4C) with a thickness of about 1.5 μm; use KOH for etching Engrave to form a probe substrate pattern (refer to Figure 4D); deposit and pattern a material containing iridium oxide (Ir) to form a working electrode WE (refer to Figure 4E); PVC layer 250 by inkjet printing Formed on the reference electrode RE and immersed in 0.01M KCl for 3 days to form a pH sensor PHM (refer to FIG. 4F); and the probe substrate 10 and the circuit substrate 20 on which the sensor is formed Electrically connect, the probe portion 110 of the probe substrate 10 is disposed in the needle unit 30 and the circuit connecting portion 120 and the circuit substrate 20 are fixed with, for example, glue, to produce a miniaturized sensing probe.

Please refer to FIGS. 5 to 6, FIG. 5 is an image diagram of a miniaturized sensing probe made according to the process of the present invention, and FIG. 6 is a probe substrate using the first embodiment of the present invention Measurement results of temperature and pH value. According to the first embodiment of the present invention, the temperature and pH value of the probe substrate obtained by the above process are actually measured to confirm its sensitivity and stability. The resistance change of the temperature sensor of the present invention is measured with Keysight B2902A as a four-point probe, a 5x10 ^-4 Å current measurement voltage value is applied to convert the resistance value, and the temperature measurement correction is to place the temperature sensor in Heat the water on the hot plate and measure every 2°C from 20°C to 40°C. According to the result of Fig. 6 (a), the temperature sensor of the present invention can achieve a linear sensitivity of about 0.105Ω/°C and a correlation coefficient of 99.825%.

Then, the probe substrate of the present invention is further used to detect the Open Circuit Potential (OCP) corresponding to the pH value. The pH value detection is Jiehan-5600 Electrochemical Workstation to measure the OCP sensed by the probe substrate of the present invention. Human blood and tissue fluids have a pH range of about 7.4, so OCP was measured in phosphate buffers at pH 6, pH 6.5, pH 7, pH 7.5, and pH 8, respectively. According to the result of Fig. 6(b), the pH sensor of the present invention can achieve a linear sensitivity of -57.4mV/pH and a correlation coefficient of 98.118% at room temperature. Furthermore, according to the result of FIG. 6(c), the pH sensor of the present invention is used at pH 6, pH 6.5, pH 7, pH 7.5 and Three cycles were measured at pH 8, and the results showed that each pH value could be accurately detected under all three cycles, indicating that the pH sensor of the present invention has good resilience.

)的線性靈敏度僅可到達-44.6mV/pH，顯示將緩衝液加入0.1M KCl後，溶液中的Cl離子可參考電極RE稍為的回復穩定，而在含有氯的PVC層250覆蓋在參考電極RE上則可更接近理論值，其表示參考電極覆蓋RE含有Cl離子的PVC層250的重要性。 Please refer to Figure 7, which shows a graph of the effect of the pH sensor on the pH value after the medical needle is inserted and 0.1M KCl is added. Since the probe substrate 10 of the present invention is installed in the needle unit 30, the pH sensor PHM will not be seriously affected, resulting in a short circuit of the probe. According to the results in Figure 7, it is shown that the linear sensitivity of the probe added with KCl (˙ in Figure 7) and the probe with the reference electrode RE of the PVC layer 250 and incorporated in the needle unit 30 (▲ in Figure 7) are close The theoretical value is -59mV/pH. The reason for speculation is that the reference electrode on the market generally needs to be stored in a 3M KCl solution. However, the reference electrode is placed in the air for a period of time and the probe with no PVC layer on it is exposed. (Figure 7

) The linear sensitivity can only reach -44.6mV/pH, which shows that after adding the buffer to 0.1M KCl, the Cl ions in the solution can be slightly restored by the reference electrode RE, while the PVC layer 250 containing chlorine covers the reference electrode RE The above can be closer to the theoretical value, which indicates the importance of the reference electrode covering the RE-containing PVC layer 250 containing Cl ions.

)所量測到的pH值在6小時至2天的時間點皆顯著小於對照組的右肢動脈(第8圖(b)中的˙)所量測的pH，顯示本發明的pH感測器PHM確實對於感測不同部位的pH值具有良好的靈敏度，且左肢動脈的pH值變化與血液中LDH值(第8圖(b)中的△)的變化具有相關性。此外，根據第8圖(c)的結果顯示，左肢動脈(第8圖(c)中的

)所量測到的肌肉溫度更接近環境溫度並且明顯低於右肢動脈(第8圖(c)中的˙)的溫度，顯示由於兔子左腳的血液循環不良將造成左腳部分的體溫下降。 With further reference to FIG. 8, the mechanism and performance of muscle necrosis caused by occlusion of peripheral arteries is similar to that of myocardium. Therefore, the miniaturized sensing probe of the present invention is further applied to the monitoring of lower limb muscles of living animals. As shown in Figure 8 (a), the experimental method is to tie the blood vessels of the left foot of the rabbit to necrosis, and use the blood vessels of the right foot as a control and monitor the pH value and temperature changes with miniature sensing probes, respectively. Then, the measured pH value is compared with the lactic dehydrogenase (LDH) value of the blood vessel to find the correlation when the organism has muscle necrosis. Since lactate dehydrogenase is usually stored in the heart, liver, muscles and other organs, when muscle necrosis occurs in the body, it will cause a large amount of LDH present in muscle cells to be released into the blood, and the concentration of LDH in the blood will increase with muscle necrosis The degree of increase. Similarly, after muscle ischemic necrosis, a large amount of acidic substances such as phosphate and sulfate are also released into the blood, causing the pH in the blood to decrease with the degree of muscle necrosis. According to the results in Figure 8(b), the left limb arteries are tied (the ones in Figure 8(b)

) The measured pH value is significantly smaller than the measured pH value of the right limb artery (˙ in Figure 8(b)) at the time point of 6 hours to 2 days, showing the pH sensing of the present invention The PHM device does have a good sensitivity for sensing the pH of different parts, and the change in the pH of the left extremity artery is related to the change in the blood LDH value (△ in Figure 8(b)). In addition, according to the results of Figure 8(c), the left limb artery (Figure 8(c)

) The measured muscle temperature is closer to the ambient temperature and is significantly lower than the temperature of the right limb artery (˙ in Figure 8(c)), indicating that due to poor blood circulation in the left foot of the rabbit will cause the body temperature of the left foot to drop .

If the probe substrate 10 is used only to penetrate the muscle, the probe portion 110 is likely to be broken and the muscle cannot be penetrated. Therefore, the present invention uses the probe substrate 10 having a pH sensor PHM and a temperature sensor RTD Combined with the needle unit 30, and according to animal experiments, through real-time monitoring of the pH value and temperature of the rabbit's lower limbs caused by muscle necrosis by tying blood vessels, it is shown that the pH value and temperature changes in muscle tissue fluid are similar to lactate dehydrogenase (LDH) Therefore, the miniaturized sensing probe of the present invention can be effectively used to monitor muscle ischemia, thereby reducing the risk of muscle necrosis.

Referring to FIGS. 9 and 10, FIG. 9 is a schematic diagram of a second embodiment of the miniaturized sensing probe of the present invention, and FIG. 10 is a probe substrate of the miniaturized sensing probe of FIG. Plan view. The main difference between the second embodiment and the above embodiment is that the probe substrate 10 is a flexible substrate. According to the second embodiment, the present invention provides a miniaturized sensing probe, which includes: a probe substrate 10 having a probe part 110 and a circuit connection part 120; disposed on the probe part 110 and electrically connected to a circuit The ion sensor INS of the connection part 120; and the needle unit 30 accommodating the probe part 110 of the probe substrate 10, wherein the circuit connection part 120 can be connected to an external circuit to transmit the sensing signal for analysis. In this embodiment, since the probe substrate 10 is a flexible substrate that is biodegradable, and the probe substrate 10 and the needle unit 30 are separable, the micro After the typed sensing probe is inserted into the body by the needle unit 30, the needle unit 30 can be drawn out to leave the probe substrate 10 in the tissue. Therefore, after the detection is completed, the probe substrate 10 can be directly Degraded in vivo. In addition, the ion sensor INS of this embodiment may be disposed at the end of the probe part 110 away from the circuit connection part 120, and it includes a sodium ion electrode NAE, a potassium ion electrode KE, and a sodium ion electrode NAE and a potassium ion electrode The reference electrode RE between the KE, and the reference electrode RE, the potassium ion electrode KE, and the sodium ion electrode NAE can transmit the sensed signal to the sense points via the wires 111, 112, and 113 extending to the connection point 121 of the circuit connection part 120, respectively Analyze externally.

The miniaturized sensing probe of this embodiment can be manufactured using the CPLoP (Combined Process of Lift-off and Printing) process. The steps are as follows: (a) Pattern the negative type on the probe substrate 10 Photoresist SU-8, used to define the shape of the wires 111, 112 and 113; (b) inkjet process using materials containing, for example, silver (Ag) to form the wires 111, 112 and 113; (c) remove the negative type Photoresist SU-8; pattern another negative photoresist SU-8 to define the working electrode and reference electrode RE; (d) Print and chlorinate with a material containing Ag to form an Ag/AgCl layer , And print the chlorine-containing solution shown in Table 1 on the Ag/AgCl layer to form a chlorine-containing polyvinyl chloride (PVC) layer, and complete the manufacture of the reference electrode RE; (e) using poly (3, 4 -Vinyl dioxythiophene): polystyrene sulfonate (poly(3,4-ethylenedioxythiophene) polystyrene sulfonate, PEDOT: PSS) inkjet printing to form a working electrode having a size of, for example, 120x240 μm ² ; and (f) The solutions containing potassium and sodium shown in Table 1 were printed on the working electrode to form a sodium ion electrode NAE and a potassium ion electrode KE.

As shown in FIG. 11, it is an image view of a miniaturized sensing probe made according to the above process of the present invention, which shows that the reference electrode RE formed of a material containing Ag/AgCl is disposed at the end of the probe part 110 The middle position, and the sodium ion electrode NAE and the potassium ion electrode KE adjacent to the reference electrode RE, respectively, show that the above process of the present invention can form a small and scalable electrode without additional patterning of the mask On the probe substrate 10.

Please refer to FIGS. 12A to 12F, which show the comparison results of the Na ⁺ and K ⁺ ion concentrations measured in the buffer solutions of different ion concentrations using the probe substrate and the commercial electrode of the second embodiment of the present invention, of which the 12A Figures and Figure 12B are the measurement results of sodium ion and potassium ion of sodium ion and potassium ion electrodes compared to the commercial electrode of Van London 5771423 at different ion concentrations; sodium ion and potassium ion of OCP are measured at different ion concentrations; Figures 12C and 12D are sodium The ion electrode and the potassium ion electrode are compared with the reference electrode of the Ag/AgCl and Pt counter electrode to measure the measurement results of sodium ion and potassium ion of OCP at different ion concentrations; and Figures 12E and 12F are completely printed sodium Sensitivity measurement of ion electrode and potassium ion electrode, of which the linear sensitivity of sodium ion electrode is 74mV/decimal, and the sensing range is 0.6~200mM, and the linear sensitivity of potassium ion electrode is 67mV/decimal, and the sensing range is 0.4~30mM. Compared with Figures 12C and 12D, Figures 12A and 12B show that the printed sodium ion electrode and potassium ion electrode have good stability and low noise performance relative to the commercial reference electrode. The linear sensitivities are 61 and 50mV/decimal, respectively. In addition, the ion sensor requires an additional Pt counter electrode in the buffer solution for measurement to stabilize the electrode current. This is mainly due to the instability of the printed reference electrode, which is affected by changes in the ambient chlorine (Cl)-concentration on the miniaturized reference electrode.

Next, referring to FIG. 13, it shows the comparison results of the reference electrode covered with or without a PVC layer containing chlorine measured in a buffer solution at pH 7 relative to a commercial reference electrode, where (a) is the reference electrode without a PVC layer Results with respect to commercial references; and (b) are results of reference electrodes with PVC layers relative to commercial references. Compared with the commercial reference electrode, the reference electrode with a PVC layer containing chlorine doping exhibited better stability than without the PVC layer. The PVC layer doped with chlorine provides a stable redox reaction to maintain a stable potential. The above results show that the probe substrate of the present invention can accurately and accurately measure the concentration of sodium ions and potassium ions, and its sensing range is also suitable for human body detection.

Please refer to FIG. 14, which shows an electron microscopic observation diagram of the integration of the flexible probe substrate 10 and the needle unit 30 of the present invention. As shown in the figure, the probe substrate 10 is provided with a reference electrode RE and an ion sensing electrode, by which it can be applied to the sodium and potassium ion monitoring of deep muscles, but the present invention is not limited to this, that is, the user may also Monitor the concentration of other ion species as needed, such as calcium ions, magnesium ions, etc. According to the above embodiments, the miniaturized sensing probe of the present invention can print the temperature sensor, pH sensor or ion sensor on the probe substrate 10 by inkjet printing without the need for The mask is patterned and other processes, so even in the environment of a hospital, for example, it can be designed according to the needs of each patient, and a customized probe can be quickly completed.

Please refer to FIG. 15, which is a schematic diagram of a third embodiment of the miniaturized sensing probe of the present invention. The main difference between the third embodiment and the second embodiment is that the probe substrate 10 provided in the needle unit 30 may be cylindrical, and the surface of the needle unit 30 may further include a plurality of openings. When the probe substrate 10 is provided In the case of the needle unit 30, the sensors located on the probe part 110 may be arranged to correspond to the positions of the openings, respectively, and the waterproof element 40 is provided at appropriate positions between the openings OP. As shown in FIG. 15, the probe substrate 10 made of a material with biocompatibility and flexibility has a cylindrical shape, and a reference electrode RE, a pH sensor PHM, and an ion sensor are provided on the surface Sensor INS and protein sensor PRS. In this embodiment, the protein sensor PRS and the reference electrode RE may be disposed on the probe substrate 10 near the opening of the needle unit 30 and correspond to the position of the first opening OP1 at the same time, the pH sensor PHM and the reference electrode RE may The probe substrate 10 disposed close to the position of the circuit connection portion 120 and corresponding to the position of the second opening OP2, and the ion sensor INS and the reference electrode RE may be disposed between the pH sensor PHM and the protein sensor PRS And at the same time correspond to the position of the third opening OP3. Furthermore, between the positions of the first opening OP1 and the third opening OP3, waterproof elements 40 are respectively provided. The waterproof elements 40 can tightly close the space between the probe substrate 10 and the needle unit 30 to isolate the fluid from each sensing Sensors that circulate between the sensors to achieve different positions can simultaneously sense the values at different depths. In this embodiment, the protein sensed by the protein sensor PRS may be lactic acid or troponin. In an alternative embodiment, an ion sensor INS may be provided corresponding to the positions of the first opening OP1 to the third opening OP3 to detect the ion concentration at different depth positions.

According to the third embodiment of the present invention, since the probe substrate 10 has the characteristics of biocompatibility, even if the probe of the present case is placed in the body tissue for a long time, it will not cause allergic reactions, etc. Long-term data monitoring of the body. In addition, since the probe substrate 10 The shape is cylindrical, so that sensors and wiring can be installed on the 360-degree surface, so the number of sensors can be increased, and at the same time, the problem of ineffective signal transmission caused by the dense lines is avoided. In the miniaturized sensing probe of this embodiment, a plurality of openings can be provided on the tube wall of the needle unit 30, and the sensors on the probe substrate 10 can be arranged at positions corresponding to the openings, respectively, to increase the The contact area of the sensor with the tissue or blood, thereby achieving better sensing sensitivity. In addition, a waterproof element 40 may be additionally provided between the openings to prevent fluid from flowing between the sensors, thereby achieving the effect of detecting tissues at different depths.

Although the present invention has been shown and described with reference to its exemplary embodiments, those of ordinary skill in the art will understand that without departing from the spirit and scope of the present invention as defined by the following patent application scope, Make various changes in form and detail.

10: Probe substrate

110: Probe section

120: Circuit connection part

121: connection point

20: Circuit board

30: Needle unit

PHM: pH sensor

PTD: temperature sensor

Claims (8)

A miniaturized sensing probe includes: a probe substrate including a probe portion and a circuit connection portion, the probe substrate is a silicon substrate or a flexible substrate; at least one sensor is provided on the A probe part, which is electrically connected to the circuit connection part; and a needle unit, which is a medical steel needle, having at least one opening for accommodating the probe part of the probe substrate, wherein the sensing The sensor is sensed when it is placed in an object to be measured through the needle unit, and transmits a sensing signal through the circuit connection portion; wherein the sensor further includes a reference electrode and a polyvinyl chloride containing chlorine The layer system is disposed on the reference electrode. The miniaturized sensing probe as described in item 1 of the patent application scope, where the probe substrate is a silicon substrate, the sensor includes a temperature sensor, a pH sensor and an ion sensor At least one. The miniaturized sensing probe as described in item 1 of the patent application scope, where the probe substrate is a flexible substrate, the sensor includes a temperature sensor, a pH sensor, and an ion sensor And at least one of protein sensors. The miniaturized sensing probe as described in item 3 of the patent application range, wherein the protein sensed by the protein sensor is lactic acid or troponin. The miniaturized sensing probe as described in item 1 of the patent application scope, wherein the flexible substrate is a biocompatible substrate or a biodegradable substrate. The miniaturized sensing probe as described in item 1 of the patent application scope, wherein the needle The caliber of the unit has a caliber equal to or smaller than the 23 gauge needle. The miniaturized sensing probe as described in item 1 of the patent application scope, wherein the sensor further includes a working electrode, and a polyvinyl chloride layer containing ions is disposed on the working electrode. A method for manufacturing miniaturized sensing probes for monitoring biological values, which includes the following steps: (a) forming a reference electrode on a part of a probe substrate by an electroplating or ink-jet process; (b) Forming a working electrode on the other part of the probe substrate by a chemical vapor deposition method or an inkjet process; (c) forming a polyvinyl chloride layer on the reference electrode and the working electrode by an inkjet process At least one of; and (d) disposing the probe substrate in a needle unit using a medical steel needle with at least one opening.

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