TWI839006B - Method of manufacturing biosensor, and biosensor chip - Google Patents

Abstract

A biosensor chip and a method for manufacturing a biosensor are provided. A method for manufacturing the biosensor, comprising the following steps: providing a wafer; setting a basic nano-layer with a nano-structure on the surface of the wafer; placing the wafer with the basic nano-layer on a wafer carrier; by the print head sprays the nanoparticle solution with a preset droplet size onto the surface of the basic nanolayer according to a preset pattern; the patterned nanoparticle solution is solidified by the curing control module, so that the nanoparticle solution is on the surface of the basic nanoparticle layer to form the nano-sensing film layer; an electrode layer is set on the back of the wafer, and the electrode layer is a bottom layer of the biosensor; and a sensing window is set around the nano-sensing film layer to form a biosensor module.

Description

Biosensing module manufacturing method and biosensing chip

The present invention relates to a sensing module manufacturing method and a sensing chip, and in particular to a biological sensing module manufacturing method and a biological sensing chip.

In recent years, due to the development of electrochemical technology, electrochemical biosensors have combined the advantages of enzymes' specificity for specific substances, fast response time, and simple operation, and the diversification of nanomaterials has improved the performance of many electrochemical biosensors.

For example, metal oxide nanostructures have the unique ability to promote faster electron transfer between the electrodes of electrochemical biosensors and the active sites of the required enzymes. Among them, the biomedical chip with an electrolyte-insulator-semiconductor (EIS) structure is used to measure the potential-capacitance change between the lower electrode (BT) and the reference electrode of the test liquid. It has the characteristics of fast initial response, stable solid structure, miniaturization potential, compatibility with CMOS process technology and low cost. Many inorganic nanomaterials, such as iron oxide, gold spheres, vanadium dioxide, and zirconium dioxide, have long been considered chemically inert under conditions close to physiological conditions. However, in recent years, it has been gradually discovered that a variety of inorganic nanomaterials (such as ZnO and ZrO ₂ ) have activities similar to those of natural enzymes and can catalyze a series of chemical reactions under physiological conditions.

At present, the surface nanoparticle manufacturing process of many materials has been studied and revealed. It is known that they are scattered freely on the surface of the chip and cannot form a specific pattern in a specific area.

In view of the above problems of the prior art, the purpose of the present invention is to provide a method for manufacturing a biosensing module and a biosensing chip, wherein a base nanolayer having a nanostructure is arranged on the surface of a wafer, and a liquid containing nanoparticles is placed in a high-resolution inkjet printing nozzle, and each ejected droplet is about several picoliters (pl). The liquid containing nanoparticles is ejected on the surface of the base nanolayer according to a preset pattern using program control to form any two-dimensional or three-dimensional pattern that can increase the reaction contact area, thereby increasing more areas that can contact the biological fluid to be tested, and greatly improving the sensing sensitivity.

According to the purpose of the present invention, a method for manufacturing a biosensing module is proposed, comprising the following steps: providing a wafer; setting a base nanolayer having a nanostructure on the surface of the wafer; placing the wafer having the base nanolayer on a chip carrier of a micro-droplet printing system; using a print head of the micro-droplet printing system to spray a nanoparticle solution in droplets of a preset droplet size onto the surface of the base nanolayer according to a preset pattern; using a curing control module of the micro-droplet printing system to cure the patterned nanoparticle solution so that the nanoparticle solution is cured on the base nanolayer to form a nanosensing film layer; setting an electrode layer on the back of the wafer, the electrode layer being the bottom layer of the biosensing module; and setting a sensing window around the nanosensing film layer to form a biosensing module.

The default droplet size may be a few picoliters (pl).

The nano-sensing film layer is a plurality of three-dimensional structures.

In one embodiment, the curing control module is a UV light source, and the UV light source is spaced apart from the print head by a distance, and the nanoparticle solution is a photocurable adhesive.

In another embodiment, the curing control module is a heater and is disposed in the chip carrier, and the nanoparticle solution is a thermal curing glue.

The micro-droplet printing system further includes a driver and a computer. The driver is connected to the print head, and the driver controls the movement of the print head. The computer is connected to the chip carrier, the print head and the driver, and the step of the micro-droplet printing system spraying droplets of nanoparticle solution onto the base nanolayer according to a preset pattern further includes: the computer generates a control program according to the preset pattern; and the computer executes the control program to operate the driver to drive the print head, and control the print head to output droplets of nanoparticle solution, so that the print head sprays droplets of nanoparticle solution onto the base nanolayer during the process of moving relative to the chip carrier according to the preset pattern.

According to the purpose of the present invention, a biosensor chip is further provided, comprising a substrate, a biosensor module and a covering layer. A metal layer is provided on the surface of the substrate. The biosensor module manufactured by the aforementioned manufacturing method is adhered to the substrate and electrically connected to the metal layer. The covering layer is provided on the substrate and covers the surrounding area outside the biosensor module and the metal layer.

The following examples illustrate the preferred implementation of this application, and are illustrated with accompanying drawings.

The embodiments of the present invention will be further explained below in conjunction with the relevant drawings. As much as possible, the same reference numerals in the drawings and the specification represent the same or similar components. In the drawings, the shapes and thicknesses may be exaggerated for the sake of simplicity and convenience. It is understood that the components not specifically shown in the drawings or described in the specification are of a form known to those skilled in the art. Those skilled in the art can make various changes and modifications based on the content of the present invention.

Please refer to Figures 1, 2 and 3 together. Figure 1 is a flow chart of the biosensor module manufacturing method of the present invention, Figure 2 is a schematic diagram of the biosensor chip of the present invention, and Figure 3 is a schematic diagram of an embodiment of the micro-droplet printing system of the present invention. The biosensor module manufacturing method proposed by the present invention is used to manufacture a biosensor module, and the manufacturing method includes the following steps:

Step S10: Provide a wafer 23. The wafer 23 is preferably a silicon chip.

Step S20: Disposing a base nanolayer 24 having a nanostructure on the surface of the wafer 23.

It can be formed on the surface of the wafer 23 by a thin film deposition method (such as radio frequency sputtering) or a sol-gel coating method.

The base nanolayer 24 may be formed by a first material and a second material by radio frequency sputtering. The first material may be yttrium oxide (Y ₂ O ₃ ) or titanium dioxide (TiO ₂ ), and the second material may be titanium (Ti) or yttrium (Y). The formed base nanolayer 24 has a preset thickness, which may be less than 30 nm (nanometer).

The rapid annealing system can make the base nanolayer 24 more nanostructured, and appropriate heat treatment can make the base nanolayer 24 more dense, so nitrogen or oxygen can be introduced for rapid annealing.

Step S30: placing the wafer with the base nanolayer 24 on the wafer carrier 11 of the micro-droplet printing system.

Step S40: The print head 12 of the micro-droplet printing system sprays the nanoparticle solution 121 onto the surface of the base nanolayer 24 in droplets of a preset droplet size according to a preset pattern.

In order to stably print high-resolution droplets, the viscosity, surface tension, nanoparticle size, dispersion uniformity of the nanoparticles in the solution, pH value, etc. of the nanoparticle solution 121 must be optimized to match the microchannel design in the inkjet printing chip. At the same time, the microchannel material of the inkjet chip must also be optimized accordingly so that the solution containing nanoparticles can be stably sprayed into microdroplets.

In this embodiment, the preset droplet size of the droplets is several pl (picoliters), and a further preferred preset droplet size is less than or equal to 0.01 pl (picoliter).

The nanoparticle solution 121 preferably contains zinc oxide (ZnO) or zirconium dioxide (ZrO ₂ ). The nanoparticle solution 121 may also contain at least one kind of suspended particles as appropriate. The composition of the suspended particles is the nanoparticles to be formed on the surface of the chip. In this embodiment, the nanoparticle powder is first prepared into a nanoparticle solution 121 suitable for the high-resolution printing nozzle 12, and the nanoparticles are uniformly dispersed in the solution to form suspended particles. Then, the droplets containing the nanoparticles are sprayed on the surface of the chip by a printing method. After heating or UV treatment, most of the solution will evaporate, and the nanoparticles will eventually remain on the surface of the chip. Preferably, the suspended particles include yttrium oxide (Y ₂ O ₃ ) or titanium dioxide (TiO ₂ ), wherein the viscosity of the nanoparticle solution 121 is preferably 1-8 m Pas (milliPascal seconds), and the surface tension is preferably 25-75 m N/m (milliNewton/meter).

Step S50: Use the curing control module of the micro-droplet printing system to cure the patterned nanoparticle solution, so that the nanoparticle solution is cured on the base nanolayer 24 to form a nanosensing thin film layer 25a. The nanosensing thin film layer 25a is located on the surface of the base nanolayer 24 away from the wafer 23.

The preset patterns can be programmed to form nanodots, nanorods, nanowires, nanogrids, or any two-dimensional or three-dimensional pattern that can increase the reactive contact area.

Step S60: An electrode layer 22 is provided on the back of the wafer 23. In this step, a metal film (e.g., aluminum) is plated on the back of the wafer to form the electrode layer 22, which is the bottom layer of the biosensor module. The thickness of the electrode layer 22 is preferably 300 nm (nanometer).

Step S70: A sensing window 31 is provided around the nano-sensing film layer 25a to form a biosensing module. The sensing window 31 is preferably SU8 epoxy negative photoresist.

As shown in FIG2 , the biosensor chip includes a substrate 21, a biosensor module and a cover layer 32. A metal layer 211 is disposed on the surface of the substrate 21. The substrate 21 may be a PCB printed circuit board, and the metal layer 211 may be a copper foil.

The biosensing module is manufactured by the aforementioned biosensing module manufacturing method, and the biosensing module includes an electrode layer 22, a wafer 23, a base nanolayer 24, and a nanosensing film layer 25a. The electrode layer 22 is defined as the bottom layer of the biosensing module, and the electrode layer 22 is disposed on the substrate 21. The wafer 23 is disposed on the electrode layer 22. The base nanolayer 24 is disposed on the wafer 23. The nano-sensing film layer 25a is disposed on the base nano-layer 24. The nano-sensing film layer 25a includes a specific pattern. The nano-particle solution is sprayed onto the surface of the base nano-layer 24 in droplet sizes by a micro-droplet printing system. The base nano-layer 24 with the nano-particle solution is heated to form a nano-sensing film layer 25a with a specific pattern. The shape of the nano-sensing film layer 25a in FIG. 2 is only used as an example and is not limited thereto. The biosensing module is attached to the substrate 21 and electrically connected to the metal layer 211. The biosensing module can be attached to the substrate 21 using silver glue. The metal layer 211 is extended to the bottom of the biosensing module, and the metal layer 211 and the electrode layer 22 are in contact with each other.

The covering layer 32 is disposed on the substrate and covers the surrounding area outside the biosensor module and the metal layer 211. The epoxy adhesive can be used to seal the area outside the biosensor module and the metal layer 211 to ensure that the sample and the copper wire are sealed and not affected by the measurement solution. The epoxy resin AB glue is formed by cross-linking and curing epoxy resin (component A) and multifunctional curing agent (component B).

Furthermore, the biosensor chip produced by the biosensor module manufacturing method of the present invention can be applied to the field of biomedical sensing technology to sense the pH value of biological fluids, Na ⁺ K ⁺ ion concentration, blood sugar, urea, etc., or some early blood chemistry test indicators of cancer, such as serum AST, serum ALT and their ratio (AST/ALT) of renal cell carcinoma (RCC), so as to achieve the purpose of early detection and prevention of diseases.

FIG. 4 is a schematic diagram of another embodiment of the curing control module of the present invention. Please refer to FIG. 3 and FIG. 4 for further details.

The micro-droplet printing system includes a chip carrier 11, a print head 12, a curing control module, a driver 13 and a computer 14.

The chip carrier 11 is used to place the object 10 to be manufactured. In this embodiment, the chip carrier 11 is used to place the base nanolayer and the wafer that have completed the rapid annealing process.

The print head 12 contains a nanoparticle solution 121 , and the ejection hole of the print head 12 ejects droplets of the nanoparticle solution 121 with a preset droplet size onto one surface of the object 10 .

The temperature control unit controls the surface temperature of the chip carrier 11 and heats the object 10 having the nanoparticle solution 121 on the surface thereof, thereby forming a specific pattern on the surface of the object 10 .

The curing control module can be disposed on the chip carrier 11 or installed separately. In FIG. 3 , the curing control module is a heater and is installed in the chip carrier 11 (so the curing control module is not numbered in the figure), but the present invention is not limited thereto. In the present embodiment, the nanoparticle solution 121 is a heat curing glue. When the nanoparticle solution 121 is sprayed onto the surface of the object 10 (base nanolayer), the curing control module controls the temperature in real time and heats the chip carrier 11, so that the temperature of the base nanolayer with the nanoparticle solution 121 on the surface is increased, and a nanosensing film layer corresponding to a preset pattern is formed on the surface of the base nanolayer.

The driver 13 is connected to the print head 12 and controls the print head 12 to move.

The computer 14 is connected to the chip carrier 11, the print head 12 and the driver 13 to form a specific pattern through the program control of the computer 14. The step of the micro-droplet printing system spraying the droplets of the nanoparticle solution 121 onto the base nanolayer according to the preset pattern further includes: the computer 14 generates a control program according to the preset pattern; and the computer 14 executes the control program to operate the driver 13 to drive the print head 12, and control the print head 12 to output the droplets of the nanoparticle solution 121, so that the print head 12 sprays the droplets of the nanoparticle solution 121 onto the base nanolayer during the process of moving relative to the chip carrier 11 according to the preset pattern.

The computer 14 can also control subsequent stacking printing to form more three-dimensional space, so that the nanostructure has more area that can be contacted by the biological fluid to be tested, so as to improve the sensing sensitivity.

In this way, the nanoparticle solution 121 can be printed on the surface of the base nanolayer in the form of microdroplets according to the programmed two-dimensional or three-dimensional pattern, and the surface containing the nanoparticle microdroplets can be heat-treated using a temperature-controllable chip carrier 11, or UV light can be used to irradiate the surface to form a nanosensing film layer with a specific pattern.

As shown in FIG4 , the curing control module may be an ultraviolet light source 15, and the ultraviolet light source 15 is spaced apart from the print head, and the nanoparticle solution 121 is a light-curing glue. When the nanoparticle solution 121 is sprayed onto the surface of the object 10 (base nanolayer), the ultraviolet light source 15 is moved in real time and irradiated onto the base nanolayer having the nanoparticle solution 121, and a nanosensing film layer corresponding to a preset pattern is formed on the surface of the base nanolayer.

Please refer to FIG. 5 to FIG. 8 , which are first, second, third and fourth schematic diagrams of the nano-sensing thin film layer of the present invention. In the above embodiments, the nano-sensing thin film layer can be a plurality of three-dimensional structures.

In FIG. 5 , the nanosensing film layer 25 b is a nanodots structure.

In FIG. 6 , the nanosensing film layer 25 c is a nanowire structure.

In FIG. 7 , the nanosensing film layer 25 d is a nanorod structure.

In FIG. 8 , the nanosensing film layer 25 e is a nanogrids structure.

The above is only an example to illustrate the preferred implementation of the present invention, and is not intended to limit the scope of implementation. All simple substitutions and equivalent changes made according to the scope of the patent application of the present invention and the content of the patent specification are within the scope of the patent application of the present invention.

S10~S70: Steps 10: Object to be manufactured 11: Chip carrier 12: Print head 121: Nanoparticle solution 13: Driver 14: Computer 15: UV light source 21: Substrate 211: Metal layer 22: Electrode layer 23: Wafer 24: Base nanolayer 25a, 25b, 25c, 25d, 25e: Nanosensing film layer 31: Sensing window 32: Covering layer

Figure 1 is a flow chart of the biosensing module manufacturing method of the present invention; Figure 2 is a schematic diagram of the biosensing chip of the present invention; Figure 3 is a schematic diagram of an embodiment of the micro-droplet printing system of the present invention; Figure 4 is a schematic diagram of another embodiment of the curing control module of the present invention; Figure 5 is a first schematic diagram of the nanosensing film layer of the present invention; Figure 6 is a second schematic diagram of the nanosensing film layer of the present invention; Figure 7 is a third schematic diagram of the nanosensing film layer of the present invention; Figure 8 is a fourth schematic diagram of the nanosensing film layer of the present invention.

S10~S70: Steps

Claims (8)

A method for manufacturing a biosensor module comprises the following steps: providing a wafer; arranging a base nanolayer having a nanostructure on the surface of the wafer; placing the wafer having the base nanolayer on a chip carrier of a micro-droplet printing system; and spraying a nanoparticle solution in the form of droplets of a preset droplet size onto the base nanolayer by a print head of the micro-droplet printing system according to a preset pattern. The nanoparticle solution is solidified on the surface of the substrate layer; a solidification control module of the micro-droplet printing system is used to solidify the patterned nanoparticle solution so that the nanoparticle solution is solidified on the substrate nanolayer into a nanosensing film layer, wherein the nanosensing film layer is a plurality of three-dimensional structures; an electrode layer is disposed on the back of the wafer; and a sensing window is disposed around the nanosensing film layer to form a biosensing module. A manufacturing method as described in claim 1, wherein the preset droplet size is less than or equal to 0.01 pl (picoliter). The manufacturing method as described in claim 1, wherein the nanoparticle solution is doped with at least one type of suspended particles. The manufacturing method as described in claim 1, wherein the curing control module is an ultraviolet light source, and the ultraviolet light source is separated from the print head by a distance, and the nanoparticle solution is a photocurable glue. The manufacturing method as described in claim 1, wherein the curing control module is a heater and is disposed in the chip carrier, and the nanoparticle solution is a thermal curing glue. The manufacturing method as described in claim 1, wherein the micro-droplet printing system comprises a driver and a computer, the driver is connected to the print head, the computer is connected to the chip carrier, the print head and the driver, and the step of the micro-droplet printing system spraying the droplets of the nanoparticle solution onto the base nanolayer according to the preset pattern further comprises: the computer generates a control program according to the preset pattern; and the computer executes the control program to operate the driver to drive the print head, and control the print head to output the droplets of the nanoparticle solution, so that the print head sprays the droplets of the nanoparticle solution onto the base nanolayer during the process of moving relative to the chip carrier according to the preset pattern. A biosensor chip comprises: a substrate, a metal layer is provided on the surface of the substrate; a biosensor module manufactured by the manufacturing method described in any one of claims 1 to 6 is adhered to the substrate and electrically connected to the metal layer. The biosensor chip as described in claim 7 further comprises: a covering layer disposed on the substrate and covering the surrounding area outside the biosensor module and the metal layer.

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