TWI512286B - Microfluidic bio-sensing system - Google Patents

Description

Microfluid biomedical sensing system

The present invention relates to a sensing system, and more particularly to a biomedical sensing system constructed in a microfluidic device.

The medical electronics industry is a must-have industry that assists in the prevention, diagnosis, mitigation and treatment of human diseases. With the advent of old age, many demands for medical care and health care are expected to drive rapid market growth.

Microelectromechanical technology is an emerging technology in the fields of mechanics, electronics, medical, biochemical, control and optoelectronics. The goal is to develop tiny precision products or to miniaturize existing products to improve their performance, quality, reliability, precision and add-on. Value, while reducing costs through standard processes, is currently widely used in biomedical test wafers. Micro-electromechanical technology can be used to introduce liquids as small as a few microliters or even nanoliters into a microchannel with an inner diameter of several hundred micrometers (μm) for mixing, separation, reaction, detection, etc. mechanism.

At present, the domestic patent documents on microfluidic analysis and detection can refer to the certificates of the Republic of China Patent Nos. I305019, I314162, I247626, I310786 and I294965.

In view of the above, the present invention provides a microfluidic biomedical sensing system for detecting dynamic characteristics of a solution to be tested, including at least one front end system and a back end system, wherein the front end system includes: a micro flow channel formed with a Detecting a region, and the solution to be tested flows through the detection region; a sensor corresponding to the detection region and interconnecting with the microchannel, wherein the sensor detects the solution to be tested under dynamic conditions and generates at least one sensing And a back-end system comprising: a readout circuit device coupled to the sensor to receive the sense signal; a data capture and processing device coupled to the readout circuit device to convert the analog signal to Digital signal; a signal receiving device for analyzing the digital signal and performing functions such as storing, analyzing, and displaying.

In one embodiment, the front end system further includes a plurality of sensors arranged in an array, wherein each sensor comprises: a substrate; a sensing film formed on the substrate; and a wire layer formed on the substrate And electrically connecting the sensing film and the foregoing readout circuit device; and an insulating layer formed on the sensing film and the wire layer, wherein the insulating layer has an opening corresponding to the position of the sensing film to expose the sensing film.

101‧‧‧Microfluid biomedical sensing system

103‧‧‧ Front End System

105‧‧‧ Backend system

201‧‧‧Microchannel

205‧‧‧Test solution injection port

207‧‧‧Measure solution outlet

209‧‧‧Detection area

301‧‧‧ sensor

303‧‧‧Substrate

305‧‧‧Sensing film

307‧‧‧ wire layer

309‧‧‧Insulation

401‧‧‧Microfluid biomedical sensing device

403‧‧‧ first joint

405‧‧‧Fixed substrate

407‧‧‧Second junction

503‧‧‧Test solution

505‧‧Injection pump

507‧‧‧Connecting tube

509‧‧‧Waste reservoir

603-1~603-N‧‧‧Sensor

605-1~605-N‧‧‧Amplifier

607‧‧‧Readout circuit device

609‧‧‧Information acquisition and processing device

611‧‧‧Signal receiving device

61~64‧‧‧Steps

GND‧‧‧reference potential node

S1‧‧‧Sensor signal

S1-1~S1-N‧‧‧Sensor signal

D1‧‧‧ digital signal

D1-1~D1-N‧‧‧Digital Signal

Fig. 1 is a schematic view showing a microfluid biomedical sensing system according to an embodiment of the present invention.

Figure 2 is a schematic diagram showing the front end system of the microfluidic biomedical sensing system of Figure 1.

Figure 3 shows an exploded view of the microfluidic biosensor sensing device at the front end of Figure 2.

Fig. 4A is a plan view showing the micro flow path of Fig. 3.

Fig. 4B is a cross-sectional view taken along line X1-X2 of Fig. 4A.

Fig. 5 is a view showing the explosion of the sensor of Fig. 3.

Figure 6A is a diagram showing the signal transmission of the microfluidic biomedical sensing system according to an embodiment of the present invention.

Figure 6B is a flow chart showing the operational steps of the microfluidic biomedical sensing system in accordance with an embodiment of the present invention.

Fig. 7 is a view showing the impedance analysis of the cerium oxide sensing film of Fig. 5.

Fig. 8A is a graph showing the flow rate of the microfluid biomedical sensing system of the embodiment of the present invention at a flow rate of 5 μl per second.

Fig. 8B is a graph showing the flow rate of the microfluidic biosensor system of the embodiment of the present invention at a flow rate of 10 μl per second.

Fig. 8C is a graph showing the measurement of a microfluid biomedical sensing system (flow rate of 15 μl per second) according to an embodiment of the present invention.

Fig. 8D is a graph showing the measurement of a microfluid biomedical sensing system (flow rate of 20 μl per second) according to an embodiment of the present invention.

Fig. 8E is a graph showing the measurement of the microfluid biomedical sensing system (flow rate of 15 μl per second) according to an embodiment of the present invention.

Fig. 8F is a graph showing the microfluidic biomedical sensing system (flow rate of 30 μl per second) according to an embodiment of the present invention.

1 is a schematic diagram of a microfluid biomedical sensing system according to an embodiment of the present invention, wherein the microfluid biomedical sensing system 101 mainly includes at least one front end system 103 and a back end system 105. The front end system 103 injects the solution to be tested 503 into a microfluid biomedical sensing device 401 by using an injection pump 505, wherein the microfluid biomedical sensing device 401 is responsible for detecting the solution to be tested and obtaining at least one sensing signal S1; The end system 105 includes a readout circuit device 607 coupled to one of the microfluidic biosensor sensing devices 401 (shown in FIG. 3) to receive the sensing signal S1, wherein the data is captured. The processing device 609 is coupled to the readout circuit device 607 and can convert the analog signal of the measurement into the digital signal D1, and finally through the signal receiving device 611 to perform functions such as storage, analysis, display and the like. The front end system 103 and the back end system 105 will be described in detail below.

Please refer to FIG. 2, which shows a front end system diagram of the microfluid biomedical sensing system of FIG. 1 , wherein the front end system 103 includes a microfluid biomedical sensing device 401, an injection pump 505, and a plurality of connecting tubes. 507 and a waste liquid storage 509. The solution 503 to be tested can be injected into the microfluid biomedical sensing device 401 through the injection pump 505 and the connecting tube 507, and the microfluid biomedical sensing device 401 is provided with a sensor (not shown), which can be self-solved. The sense signal S1 is measured and passed to the backend system 105. Further, the measured solution is again returned to the waste liquid reservoir 509 via the connection pipe 507 for collection.

Figure 3 is a view showing the exploded view of the microfluidic biomedical sensing device of Figure 2, as shown in the figure, the microfluidic biomedical sensing device 401 is composed of a plurality of first knots. The joint portion 403, the plurality of second joint portions 407, and the two fixed substrates 405 are formed by fixing the micro flow passage 201 and the sensor 301 to the middle of the fixed substrates 405. The fixed substrate 405 is preferably made of poly-methyl methacrylate (PMMA), the first joint portion 403 is preferably a stainless steel nut, and the second joint portion 407 is preferably made of stainless steel screws.

In addition, the microchannel 201 of the microfluid biomedical sensing device 401 generally includes at least one solution injection port 205 to be tested, at least one solution solution outlet port 207, and a detection region 209, such as FIG. 4A (top view) and 4B. Figure (cross-sectional view) shows.

The material of the micro flow channel 201 is preferably poly-dimethyl siloxane (PDMS), or may include poly-methyl methacrylate (PMMA) or other plastic materials. By mixing PDMS and curing agent in a volume ratio of 10:1, and standing on a master substrate of microchannel 201, curing at a temperature of 120 ° C and 90 minutes, finally removing the film to obtain a microfluid Road 201. The master substrate of the micro flow channel 201 can be fabricated using a ruthenium wafer, glass and other plastic substrates and through the yellow lithography technology used by standard MEMS. The size of the microchannel 201 in one embodiment of the present invention is as follows: height is 100 μm, width is 100 μm, depth is 100 μm; and the detection region cavity has a height of 100 μm, a width of 200 μm, and a depth of 100 μm.

Figure 5 is a view showing the explosion of the sensor 301 of the microfluidic biosensor sensing device 401, wherein the sensor 301 includes a substrate 303; The sensing film 305 is formed on the substrate 303; a wire layer 307 is formed on the substrate 303 and is in electrical contact with the sensing film 305; and an insulating layer 309 is over the sensing film 305 and the wire layer 307, wherein The insulating layer 309 has a plurality of openings to expose the sensing film 305.

In addition, the substrate 303 is preferably a flexible plastic substrate, and can be deposited by a radio frequency sputtering method to deposit a patterned ruthenium dioxide (RuO ₂ ) film, wherein the sensing film 305 can form a plurality of circles having a diameter of 0.8 mm. . Next, silver paste is formed on the substrate 303 by screen printing, and baked at a temperature of 100 ° C to 140 ° C for 20 to 40 minutes to harden the silver paste to form a wiring layer 307. The wire layer 307 includes a plurality of wires, and one end of each wire is in electrical contact with the sensing film 305, and the other end is coupled to the readout circuit device 607 (shown in FIG. 1). It should be understood that the material of the wire layer 307 may also include other conductive colloids. Finally, an epoxy resin (or other insulating glue) is formed on the sensing film 305 and the wire layer 307 by screen printing, and baked at a temperature of 120 ° C to 140 ° C to fix the epoxy resin. Insulation layer 309. The insulating layer 309 in this embodiment is formed with a plurality of circular openings having a diameter of 1 mm and corresponding to the sensing film 305. It should be noted that the sensor 301 corresponds to the detection area 209 of the micro flow channel 201 and is combined with the micro flow channel 201.

Next, please refer to the signal transmission architecture diagram of the microfluid biomedical sensing system according to an embodiment of the present invention shown in FIG. 6A. As shown in the figure, a plurality of sensors 603-1 to 603 as shown in FIG. -N series are arranged in an array, wherein The sensors 603-1 to 603-N may share one substrate 303, or may use a plurality of substrates 303 and are combined with the micro flow channels 201 (not shown), thereby simultaneously measuring a plurality of solutions to be tested and A plurality of sensing signals S1 (including S1-1 to S1-N) are obtained.

In addition, the readout circuit device 607 may include a plurality of amplifiers 605-1 to 605-N, wherein the inputs of the amplifiers 605-1 to 605-N are respectively electrically connected to the corresponding sensors 603-1 to 603-N. Connected, and the other input is electrically connected to a reference potential node GND. The aforementioned amplifiers 605-1 to 605-N are more instrumentation amplifiers, which have the advantage of high input impedance, and can completely load a plurality of sensing signals S1-1 to S1- from the sensors 603-1 to 603-N. N, and through its low output impedance characteristics, fully load the amplified sensing signals S1-1 to S1-N to the transmitting node (connected to the data acquisition and processing device 609). In one embodiment, the voltage amplification of the amplifiers 605-1 to 605-N can also be set to 1 as a voltage follower. The data acquisition and processing device 609 can include a single converter or multiple converters for signal processing and multiplex sampling, and converts the analog signals into digital signals D1 (including D1-1 through D1-N). The signal receiving device 611 can include a personal computer, a notebook computer, a gate array chip of a field openable program, or a digital signal processor.

The flowchart of the operation steps of the microfluidic biomedical sensing system in the above embodiment is as shown in FIG. 6B, wherein the microfluid biomedical sensing device 401 can generate a plurality of sensing signals S1 after detecting the solution 503 to be tested ( Step 61); And receiving, by the readout circuit device 607, the sensing signals S1 (step 62); and then capturing, by the data acquisition and processing device 609, the analog signals, and converting the analog signals into digital signals D1 ( Step 63); finally, the signal receiving device 611 receives the digital signal D1 and performs functions of storing, analyzing, displaying, etc. (step 64).

In summary, the microfluidic biomedical sensing system 101 provided by the present invention can measure the characteristic values of the plurality of solutions 503 to be tested under dynamic conditions, wherein the characteristic value can be an electron transfer amount or a pH value, etc. And the solution to be tested 503 may include various enzyme solutions as well as ionic solutions.

It should be noted that, in an embodiment of the invention, the sensing film 305 passes the method of Electrochemical Impedance Spectroscopy (EIS) to measure the characteristic value of the solution 503 to be tested. Please refer to Fig. 7. If red blood salt (0.06M~1M) is added to the solution to be tested, and the electron transport impedance of the cerium oxide sensing film 305 is observed, the higher the amount of red blood salt added, The lower the electron transmission impedance, the lower the curve radius.

Figures 8A-8F show a microfluidic biosensing system according to another embodiment of the present invention for measuring the pH of the phosphate buffer solution from pH 1 to pH 13, wherein the flow rate of the injection pump is 5 μl per second, 10 μl, 15 μl, 20 μl, 25 μl, 30 μl. It can be seen from the results that the optimal flow rate of the microfluidic biosensing system is 15 μl, and the sensing signal of the ceria sensing film is 55.33 mV/pH from the sensing windows S1 to S6, respectively. 56.81mV/pH, 56.90 mV/pH, 56.01 mV/pH, 55.75 mV/pH, 55.12 mV/pH; linearity was 0.987, 0.986, 0.984, 0.985, 0.983, 0.986, respectively.

Although the present invention has been disclosed above in the foregoing embodiments, it is not intended to limit the invention. Those skilled in the art having the ordinary skill in the art can make some modifications and refinements without departing from the spirit and scope of the invention. Therefore, the scope of the invention is defined by the scope of the appended claims.

101‧‧‧Microfluid biomedical sensing system

103‧‧‧ Front End System

105‧‧‧ Backend system

401‧‧‧Microfluid biomedical sensing device

503‧‧‧Test solution

505‧‧Injection pump

509‧‧‧Waste reservoir

607‧‧‧Readout circuit device

609‧‧‧Information acquisition and processing device

611‧‧‧Signal receiving device

S1‧‧‧Sensor signal

D1‧‧‧ digital signal

Claims (14)

A microfluidic biomedical sensing system for detecting dynamic characteristics of a solution to be tested, comprising at least one front end system and a back end system, wherein the front end system comprises: a micro flow channel, forming a detection area, wherein the Measuring a solution flow through the detection area; a sensor corresponding to the detection area and being combined with the micro flow path, wherein the sensor detects the solution to be tested under dynamic conditions and generates at least one sensing signal, wherein The sensor includes: a substrate; a sensing film formed on the substrate; a wire layer formed on the substrate and electrically connected to the sensing film and a readout circuit device; an insulating layer formed on The sensing film and the wire layer, wherein the insulating layer has an opening corresponding to the position of the sensing film to expose the sensing film; and the back end system includes: the readout circuit device coupled to the sensing The device is configured to receive the sensing signal; a data acquisition and processing device coupled to the readout circuit device to convert the analog signal of the measurement into a digital signal; and a signal receiving device for analyzing the digital signal And performs storage, analysis or display. The microfluidic biomedical sensing system of claim 1, wherein the characteristic of the solution to be tested comprises a pH value or an electron transporting amount, and the solution to be tested is an enzyme solution or an ionic solution. The microfluidic biomedical sensing system of claim 1, wherein the front end system further comprises a plurality of sensors arranged in an array. The microfluid biomedical sensing system of claim 1, wherein the substrate is a flexible substrate. The microfluid biomedical sensing system of claim 1, wherein the material of the sensing film comprises cerium oxide. The microfluidic biomedical sensing system of claim 1, wherein the material of the wire layer comprises silver paste, and the material of the insulating layer comprises an epoxy resin. The microfluidic biomedical sensing system of claim 1, wherein the sensing membrane uses electrochemical impedance analysis to analyze the amount of electron transport of the solution to be tested. The microfluidic biomedical sensing system of claim 1, wherein the material of the microchannel comprises dimethyl siloxane, polymethyl methacrylate or a plastic material. The microfluid biomedical sensing system of claim 1, wherein the master substrate of the microchannel comprises a tantalum wafer, a glass or a plastic substrate. The microfluidic biomedical sensing system of claim 1, wherein the front end system further comprises a plurality of first bonding portions, a plurality of second bonding portions, and a plurality of fixed substrates, wherein the micro flow channels and the The sensor is disposed in the middle of the fixed substrates, and the first bonding portions and the second bonding portions are respectively connected to fix the micro flow channel, the sensor and the fixed substrates. The microfluidic biomedical sensing system of claim 10, wherein the material of the fixed substrate comprises polymethyl methacrylate or stainless steel, and the first bonding portion and the second bonding portions are respectively For stainless steel screws and nuts. The microfluidic biomedical sensing system of claim 1, wherein the readout circuit device comprises an amplifier. The microfluidic biomedical sensing system of claim 1, wherein the data acquisition and processing device comprises a single converter or a multiple converter for signal processing and multiplex sampling, and converting the analog signal to Digital signal. The microfluidic biomedical sensing system of claim 1, wherein the signal receiving device comprises a personal computer, a notebook computer, a field openable gate array chip or a digital signal processor.