A diagnosis and treatment integrated microneedle array device and a preparation method thereof

Abstract

This invention relates to the field of biomedical engineering technology, specifically providing a diagnostic and therapeutic microneedle array device and its preparation method. The device includes a press-fitted cap, a microfluidic channel layer, an encapsulation layer, a microchannel adhesive layer, and a microneedle array layer. After bonding, a unidirectional drug delivery pathway is formed within the microfluidic channel layer, encapsulation layer, microchannel adhesive layer, and microneedle array layer, with hollow microneedles at the ends. The hollow microneedles have biorecognition materials on their surfaces, and multiple hollow microneedles are divided into working electrodes, counter electrodes, and reference electrodes. The working electrodes, reference electrodes, and counter electrodes are respectively connected to an external detection circuit for detecting the analyte. This invention's microneedle array device combines diagnostic and therapeutic functions, is small in size, highly portable, and provides low pain during drug injection.

Description

Technical Field

[0001] This invention relates to the field of biomedical engineering technology, specifically providing a microneedle array device integrating diagnosis and treatment and its preparation method. Background Technology

[0002] Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia. Its global incidence continues to rise, and it is showing a trend towards a longer disease course, more complications, and younger onset. Diabetic patients often suffer from multiple complications such as cardiovascular and cerebrovascular diseases, retinopathy, kidney damage, and peripheral neuropathy. Therefore, long-term, continuous blood glucose monitoring and medication management are crucial for these patients.

[0003] Traditional medical diagnosis primarily relies on blood analysis, which requires complex laboratory equipment, is cumbersome to operate, has a long testing cycle, and the blood collection process can cause pain and discomfort for patients, making it unsuitable for high-frequency sampling and real-time monitoring. To alleviate the inconvenience of high-frequency blood collection, researchers have turned their attention to the detection of non-invasive biological fluids such as sweat, saliva, and tears. However, the correlation between biomarkers in these bodily fluids and blood indicators is still unclear, and they contain a large number of impurities that can easily interfere with test results. Interstitial fluid, as a substitute for plasma, is distributed in the dermis of the skin, and its glucose concentration is highly correlated with blood glucose, making it considered an ideal medium for diabetes monitoring.

[0004] Diabetic patients need to frequently monitor their blood glucose levels and take insulin as needed to maintain stable blood glucose levels. However, traditional drug administration methods (such as oral or injectable) can cause gastrointestinal irritation and skin damage, leading to poor patient compliance. With the development of microfabrication technology, microneedle technology has emerged. Miniaturizing traditional needles into microneedle arrays allows for the collection of fresh interstitial fluid samples, avoiding pain nerve endings in the skin, thus enabling minimally invasive testing. Simultaneously, microneedles can deliver drugs directly to skin tissue, bypassing the first-pass metabolism in the gastrointestinal tract and liver, achieving controlled and continuous drug release, thereby improving bioavailability and reducing side effects.

[0005] In recent years, wearable microneedle arrays have made rapid progress in biosensing and drug delivery. However, existing microneedle systems still have many shortcomings: traditional rigid microneedle electrodes are difficult to adapt to the dynamic deformation of the skin, which can easily cause skin tears and inflammation; drug delivery often relies on syringes or external pumping systems, resulting in bulky and complex devices; in addition, disease detection and drug delivery functions are usually achieved independently by different components, with monitoring and treatment processes separated, making operation cumbersome and lagging. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a microneedle array device integrating diagnosis and treatment, and its preparation method. The microneedle array device includes a one-way flow channel for the drug solution, a propulsion device for propelling the drug solution, and hollow microneedles for promoting the drug solution to achieve treatment. At the same time, the hollow microneedles are equipped with a three-electrode system and a sensitive membrane layer, which can perform electrochemical detection of target biomarkers such as glucose. The structure is simple and supports the treatment and diagnosis of various diseases.

[0007] The diagnostic and therapeutic microneedle array device provided by this invention includes: The structure consists of a functional capping layer, a microfluidic channel layer, an encapsulation layer, a microchannel adhesive layer, and a microneedle array layer, which are bonded together from top to bottom. The functional capping layer includes a pressing chamber cap, the encapsulation layer has liquid communication holes, the microchannel adhesive layer has flow channels, and the microneedle array layer has multiple hollow microneedles. The microfluidic channel layer is provided with a liquid inlet, a liquid storage chamber, a buffer channel, a press pump liquid inlet chamber, a press pump liquid outlet chamber, and a liquid transfer channel connected in sequence; the other end of the liquid transfer channel is connected to a liquid connecting hole, a flow channel, and a hollow microneedle to form a drug liquid channel. The pressing chamber cover covers the liquid inlet chamber and liquid outlet chamber of the pressing pump. A microfluidic valve membrane assembly is installed under the pressing chamber cover. The microfluidic valve membrane assembly is used to control the unidirectional flow of the drug solution. Repeated pressing of the pressing chamber cover promotes the unidirectional flow of the drug solution in the drug solution channel. The hollow microneedles are modified with biometric materials. Multiple hollow microneedles are divided into working electrode area, reference electrode area and counter electrode area. The working electrode area, reference electrode area and counter electrode area are respectively connected to an external detection circuit for detecting the analyte.

[0008] Preferably, the functional cover layer also includes a liquid storage chamber cover, which covers the liquid storage chamber to form a sealed liquid storage chamber.

[0009] Preferably, the microfluidic channel layer further includes an air inlet and multiple exhaust ports. The air inlet is connected to the liquid storage chamber, and the multiple exhaust ports are respectively connected to multiple liquid transport channels, and the multiple exhaust ports penetrate through the microfluidic channel layer. The air inlet and exhaust ports are used to balance the internal air pressure of the microneedle array device for diagnosis and treatment.

[0010] Preferably, it also includes a plurality of vent membranes, which are disposed on the upper surface of the microfluidic channel layer to cover the plurality of vents.

[0011] Preferably, the microfluidic valve membrane assembly includes a first valve membrane and a second valve membrane with identical structures. The first valve membrane includes an inlet movable plate and an outlet through-hole, and the second valve membrane includes an inlet through-hole and an outlet movable plate. The first valve membrane and the second valve membrane are arranged in a 180° mirror symmetrical fit, with the inlet through-hole aligned with the inlet movable plate and the outlet movable plate aligned with the outlet through-hole.

[0012] Preferably, the functional capping layer, the microfluidic valve membrane assembly, the microfluidic channel layer, and the encapsulation layer are all made of the same material, namely polydimethylsiloxane.

[0013] Preferably, the working electrode region, the reference electrode region, and the counter electrode region are all connected to an external detection circuit.

[0014] A preparation method for fabricating a microneedle array device integrating diagnosis and treatment, the preparation method comprising: Fabrication of functional capping layer, microfluidic channel layer and encapsulation layer: Male molds are prepared according to the shapes of functional capping layer, microfluidic channel layer and encapsulation layer respectively, and the functional capping layer, microfluidic channel layer and encapsulation layer are prepared using the male molds respectively; Preparation of microchannel adhesive layer: Select medical pressure-sensitive adhesive film or silicone film, and prepare microchannel adhesive layer using laser etching method; Fabrication of microneedle array layer: Prepare a master mold for hollow microneedle array, use the master mold to prepare a PDMS negative mold, use the PDMS negative mold to prepare a solid hollow microneedle array, and then drill through the pinholes of the hollow microneedle array with laser. An adhesion layer and a conductive layer are sequentially deposited on the surface of hollow microneedles using magnetron sputtering. In the working electrode region, Prussian blue electrodeposition, enzyme layer modification, and Nafion anti-interference layer modification are performed sequentially. In the reference electrode region, Ag / AgCl slurry is coated to form a conductive coating. In the counter electrode region, a conductive layer is formed using electrochemical deposition.

[0015] Preferably, a functional membrane layer is disposed on the microfluidic channel layer, the functional membrane layer including an inlet membrane, an outlet membrane, a microfluidic valve membrane assembly, and an outlet membrane; the preparation method of the functional membrane layer is as follows: Inlet and outlet membranes are obtained by cutting PTFE films; micro-patterns are prepared on metal sheets to form metal molds, and microfluidic valve membrane assemblies are prepared using the metal molds; silicone pressure-sensitive adhesive is die-cut to obtain inlet sealing membranes.

[0016] Compared with the prior art, the present invention can achieve the following beneficial effects: This invention proposes a diagnostic and therapeutic microneedle array device and its fabrication method, integrating a flexible hollow microneedle array, mass-produced using microfabrication technology, with a microfluidic structure onto a single wearable platform. The microneedles feature a three-electrode system and a sensitive membrane layer, enabling electrochemical detection of target biomarkers such as glucose. The hollow channels also serve as drug delivery pathways, integrating detection and drug delivery functions into a single needle. This effectively reduces the number of needles and punctures, lowering the pain and infection risks associated with blood collection, and significantly reducing the overall size, portability, and system integration. The microfluidic chip incorporates a reservoir, buffer channel, and a pump. The pump, consisting of a valve membrane and a pump chamber cap, enables unidirectional flow and quantitative output upon pressure release, automatically replenishing fluid upon depressurization. This eliminates the need for an external power supply and electromechanical pump, allowing for on-demand drug delivery and significantly reducing system complexity and ease of use. The entire device utilizes biocompatible flexible materials, conforming to skin deformation while maintaining a sealed connection, exhibiting excellent skin compatibility. Furthermore, this device is not limited to glucose detection and insulin administration. By changing the sensitive layer and drug solution, it can be extended to the detection of various biomarkers such as lactic acid and uric acid, as well as the quantitative delivery of various drugs, demonstrating scalability and personalized application value. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the microneedle array device structure provided in an embodiment of the present invention; Figure 2 This is a schematic diagram of the internal drug channel of the microneedle array device according to an embodiment of the present invention; Figure 3 This is a schematic diagram of the shape of the liquid storage chamber at point AA according to an embodiment of the present invention; Figure 4 This is a schematic diagram of the shape of the pump chamber at BB according to an embodiment of the present invention; Figure 5 This is a schematic diagram of a microfluidic valve membrane assembly structure provided in an embodiment of the present invention; Figure 6 This is a schematic diagram of the surface structure of the microfluidic channel layer provided in an embodiment of the present invention; Figure 7 This is a schematic diagram of another surface structure of the microfluidic channel layer provided in an embodiment of the present invention; Figure 8 This is a schematic diagram of the encapsulation layer structure provided in an embodiment of the present invention; Figure 9 This is a schematic diagram of the microchannel adhesive layer structure provided in an embodiment of the present invention; Figure 10 This is a schematic diagram of the microneedle array layer structure provided in an embodiment of the present invention; Figure 11 This is a schematic diagram of the electrode region of the microneedle array layer according to an embodiment of the present invention.

[0018] The reference numerals in the figures include: 11. Liquid reservoir cover, 12. Pressing chamber cover, 21. Air inlet membrane, 22. Liquid inlet sealing membrane, 23. Microfluidic valve membrane assembly, 231. First valve membrane, 2311. Liquid inlet movable piece, 2312. Liquid outlet through hole, 2322. Second valve membrane, 2321. Liquid inlet through hole, 2322. Exhaust membrane, 24. Microfluidic channel layer, 301. Air inlet, 302. Liquid inlet, 303. Liquid reservoir, 304. Buffer channel, 305. Pressing pump liquid inlet chamber, 306. Pressing pump liquid outlet chamber, 307. Liquid transfer channel, 308. Exhaust hole, 4. Encapsulation layer, 401. Liquid communication hole, 402. Microchannel adhesive layer, 5. Flow channel, 51. Microneedle array layer, 6. Hollow microneedles, 61. Reference electrode area A, working electrode area B, counter electrode area C. Detailed Implementation

[0019] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be understood that the specific embodiments described herein are only for explaining the invention and do not constitute a limitation thereof. Similar elements in different embodiments are referred to by associated similar element reference numerals. In the following embodiments, many details are described to facilitate a better understanding of the invention. However, those skilled in the art will readily recognize that some features may be omitted in different situations, or may be replaced by other elements, materials, or methods. In some cases, some operations related to the invention are not shown or described in the specification. This is to avoid obscuring the core parts of the invention with excessive description. For those skilled in the art, detailed description of these related operations is not necessary; they can fully understand the related operations based on the description in the specification and general technical knowledge in the art.

[0020] It should be noted that, unless otherwise specified, the embodiments and features described in this invention can be combined to form various implementations. Furthermore, the order of the steps or actions in the method description can be changed or adjusted in a manner readily apparent to those skilled in the art. Therefore, the various orders in the specification and drawings are merely for the clear description of a particular embodiment and do not imply a mandatory order, unless otherwise stated that a particular order must be followed.

[0021] In the description of this invention, it should be understood that the terms "center," "longitudinal," "lateral," "length," "width," "thickness," "upper," "lower," "front," "rear," "left," "right," "vertical," "horizontal," "top," "bottom," "inner," "outer," "clockwise," and "counterclockwise," etc., indicating orientations or positional relationships based on the orientations or positional relationships shown in the accompanying drawings, are only for the convenience of describing this invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation on this invention. Furthermore, the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of indicated technical features. Thus, features defined with "first," "second," etc., may explicitly or implicitly include one or more of that feature. In the description of this invention, unless otherwise stated, "a plurality of" means two or more.

[0022] In the description of this invention, it should be noted that, unless otherwise explicitly specified and limited, the terms "installation," "connection," and "linking" should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; and they can refer to the internal connection of two components. Those skilled in the art will understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0023] The invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0024] like Figure 1 and Figure 2 As shown, this embodiment of the invention provides a microneedle array device integrating diagnosis and treatment, including a functional capping layer, a functional membrane layer, a microfluidic channel layer 3, an encapsulation layer 4, a microchannel adhesive layer 5, and a microneedle array layer 6. The encapsulation layer 4 is disposed on the lower surface of the microfluidic channel layer 3, the microchannel adhesive layer 5 is disposed on the lower surface of the encapsulation layer 4, the microneedle array layer 6 is disposed on the lower surface of the microchannel adhesive layer 5, and both the functional capping layer and the functional membrane layer are disposed on the microfluidic channel layer 3. The microfluidic channel layer 3 is made of polydimethylsiloxane (PDMS) material, but transparent polymer materials such as COC or PC can also be selected according to structural requirements.

[0025] like Figure 2 , Figure 6 and Figure 7As shown, the microfluidic channel layer 3 includes an air inlet 301, a liquid inlet 302, a liquid storage chamber 303, a buffer channel 304, a pump inlet chamber 305, a pump outlet chamber 306, a liquid transfer channel 307, and an exhaust port 308. The air inlet 301, liquid inlet 302, liquid storage chamber 303, pump inlet chamber 305, pump outlet chamber 306, and exhaust port 308 connect the upper and lower surfaces of the microfluidic channel layer 3. The buffer channel 304 and liquid transfer channel 307 are located on the lower surface of the microfluidic channel layer 3 and are exposed thereon. The air inlet 301 and liquid inlet 302 are connected to one end of the liquid storage chamber 303 through the same channel, and the other end of the liquid storage chamber 303 is connected to one end of the buffer channel 304. The buffer channel 304 is approximately serpentine with multiple bends, used to buffer the pressure from the pump inlet chamber 305, reducing its disturbance to the liquid in the reservoir 303. The other end of the buffer channel 304 connects to the pump inlet chamber 305. The pump inlet chamber 305 penetrates both the upper and lower surfaces of the microfluidic channel layer 3, with its end connected to the buffer channel 304 located on the lower surface of the microfluidic channel layer 3. The pump outlet chamber 306 is adjacent to the pump inlet chamber 305 and also penetrates the microfluidic channel layer 3. The end of the pump outlet chamber 306 located in the microfluidic channel layer 3 connects to the liquid transfer channel 307. There are multiple liquid transfer channels 307; in this embodiment, there are five. One end of each of the multiple liquid transfer channels 307 is connected to the pump outlet chamber 306. The number of vent holes 308 is the same as the number of liquid transfer channels 307. Multiple vent holes 308 penetrate the microfluidic channel layer 3, and each of the multiple vent holes 308 corresponds to a multiple liquid transport channel 307. The corresponding vent holes 308 and liquid transport channels 307 are aligned in the length direction of the microfluidic channel layer 3.

[0026] like Figure 1 and Figure 2 As shown, a functional capping layer and a functional membrane layer are disposed on the upper surface of the microfluidic channel layer 3. The functional capping layer includes a liquid storage chamber cap 11 and a pressing chamber cap 12. The functional capping layer as a whole has good elastic recovery performance and sealing stability, and can maintain stable operation during multiple pressing cycles. The functional membrane layer includes an air inlet membrane 21, a liquid inlet sealing membrane 22, a microfluidic valve membrane assembly 23, and an exhaust membrane 24. The air inlet membrane 21 covers the surface of the air inlet 301, allowing only gas to pass through. In this embodiment of the invention, the air inlet membrane 21 is a microporous membrane made of polytetrafluoroethylene (PTFE). The liquid inlet sealing membrane 22 covers the surface of the liquid inlet 302 and is used to seal the liquid in the liquid storage chamber 303 to prevent leakage. In this embodiment of the invention, the liquid inlet sealing membrane 22 is made of polyester (PET) or a medical pressure-sensitive adhesive film. Figure 3As shown, the liquid storage chamber cover 11 is concave and approximately elliptical, covering the liquid storage chamber 303 of the microfluidic channel layer 3. The liquid storage chamber cover 11 and the liquid storage chamber 303 together form a sealed liquid storage chamber for storing the drug solution. Figure 4 As shown, the pressing chamber cover 12 is a concave circle, covering the microfluidic valve membrane 23 and the pressing pump inlet chamber 305 and outlet chamber 306, forming a pump chamber. The pressing chamber cover 12 is made of PDMS, has a concave circular shape, a thickness of approximately 2 mm, and a concave depth of 1 mm. The pressing chamber cover 12 is elastic and can deform when pressed. The microfluidic valve membrane assembly 23 is disposed between the pressing chamber cover 12 and the upper surface of the microfluidic channel layer 3, and covers the inside of the pressing chamber cover 12. The outer diameter of the pressing chamber cover 12 is the same as the outer diameter of the microfluidic valve membrane assembly 23, and the pressing chamber cover 12 presses against the outer edge of the upper surface of the microfluidic valve membrane assembly 23. Figure 5 As shown, the microfluidic valve membrane assembly 23 consists of two flexible PDMS valve membranes. The elasticity of the flexible valve membranes forms a check valve. The surface of the flexible valve membranes has micro-patterns, namely, micro-patterns corresponding to the inlet movable plate 2311 and the outlet through-hole 2312, and the outlet movable plate 2322 and the inlet through-hole 2321. The two flexible valve membranes are the first valve membrane 231 and the second valve membrane 232. The first valve membrane 231 has the inlet movable plate 2311 and the outlet through-hole 2312, and the second valve membrane 232 has the inlet through-hole 2321 and the outlet movable plate 2322. The first valve membrane 231 and the second valve membrane 232 have identical structures, and their planes are parallel to each other. The first valve diaphragm 231 and the second valve diaphragm 232 are bonded together as a single structure. The liquid inlet movable piece 2311, liquid outlet through hole 2312, liquid inlet through hole 2321, and liquid outlet movable piece 2322 on the first valve diaphragm 231 and the second valve diaphragm 232 are staggered and mirror-symmetrically arranged at 180°. That is, the liquid inlet movable piece 2311 is aligned vertically with the liquid inlet through hole 2321, and the liquid outlet movable piece 2322 is aligned vertically with the liquid outlet through hole 2312. Because the first valve diaphragm 231 and the second valve diaphragm 232 are bonded together, and the first valve diaphragm 231 is located on the upper surface of the second valve diaphragm 232, the liquid inlet movable piece 2311 can only open upwards, and the liquid outlet movable piece 2322 can only open downwards, forming a one-way passage. When the pressing chamber cover 12 is pressed, it deforms, increasing the pump chamber pressure between it and the microfluidic valve membrane assembly 23. At this time, the liquid outlet movable piece 2322 opens downwards, connecting to the liquid outlet through-hole 2312 to form a downward-only passage, expelling the liquid from the pump chamber into the pressing pump's liquid outlet chamber 306. When the pressing chamber cover 12 is released, its deformation returns to normal, creating a negative pressure in the pump chamber. The liquid inlet movable piece 2311 opens upwards, connecting to the liquid inlet through-hole 2321 to form an upward-only passage, drawing in liquid from the pressing pump's liquid inlet chamber 305. Therefore, repeatedly pressing the pressing chamber cover 12 creates a passage from the liquid inlet through-hole 2321 to the liquid inlet movable piece 2311, entering the pump chamber, and then from the pump chamber through the liquid outlet through-hole 2312 back to the liquid outlet movable piece 2322.

[0027] like Figure 2 , Figure 7 , Figure 8 and Figure 9 As shown, the encapsulation layer 4 has multiple liquid communication holes 401 and multiple vent communication holes 402, with the same number of liquid communication holes 401 and vent communication holes 402, and they correspond one-to-one. The encapsulation layer 4 is made of a transparent rigid polymer material, such as PMMA or COC, with a thickness of approximately 500 μm. The microchannel adhesive layer 5 has multiple flow channels 51, with each end of the microchannel adhesive layer 5 corresponding to a liquid communication hole 401 and a vent communication hole 402, respectively. The microchannel adhesive layer 5 is made of medical pressure-sensitive adhesive film or silicone film, with a thickness of 25–150 μm. Multiple flow channels 51 are engraved on the surface of the microchannel adhesive layer 5, with a width of approximately 400 μm, slightly larger than the inner diameter of the hollow microneedle 61. The pump outlet chamber 306 is connected to multiple liquid transfer channels 307, which are respectively connected to multiple liquid connecting holes 401. These liquid connecting holes 401 are respectively connected to multiple flow channels 51. The other ends of the multiple flow channels 51 are connected to multiple venting holes 308 through multiple venting connecting holes 402, thereby connecting to the upper surface of the microfluidic channel layer 3 to form an excess gas emission path. The diameter of the through-hole in the excess gas emission path is 500 μm, which can be formed by laser drilling or micro-milling to ensure stable connection and reliable sealing. Figure 1 As shown, multiple vent membranes 24 sequentially cover multiple vent holes 308. The vent membranes 24 are made of semi-permeable nylon or PTFE membranes, allowing gas to escape while preventing liquid leakage. Vent connection holes 402 connect to the vent holes 308 and further connect to the upper surface of the microfluidic channel layer 3 to form a venting channel for venting excess gas from the microneedle array device. The microchannel adhesive layer 5 is formed by laser etching or die-cutting, and then bonded and fixed after plasma activation to ensure sealing and channel integrity.

[0028] like Figure 1 , Figure 2 and Figure 10 As shown, multiple hollow microneedles 61 arranged in a two-dimensional pattern are disposed on the microneedle array layer 6. The hollow microneedles 61 are arranged along multiple flow channels 51 and are all connected to the flow channels 51. The hollow microneedles 61 are made of polymer materials such as COC, PLA, and PI. The height of the hollow microneedles 61 is 300-1000 μm, the inner diameter is 20-80 μm, and the tip radius of the hollow microneedles 61 is less than 20 μm. The hollow channels inside the hollow microneedles 61 allow for drug delivery.

[0029] In this embodiment of the invention, the number of liquid transmission channels 307, vent holes 308, liquid communication holes 401, vent communication holes 402, and flow channels 51 are all the same. When the microneedle array device is used as a treatment device, the medication is supplied through the hollow microneedles 61. Medication is added to the storage chamber 303 through the inlet 302. Repeatedly pressing the pressing chamber cover 12 causes the medication in the storage chamber 303 to pass through the buffer channel 304 to reduce pressure fluctuations, and then sequentially enters the pressing pump inlet chamber 305, pressing pump outlet chamber 306, liquid transmission channel 307, liquid communication hole 401, and flow channel 51 into multiple hollow microneedles 61, achieving uniform distribution of the medication, which ultimately enters the body through the hollow microneedles 61. By designing the geometry and pressing stroke of the pressing chamber cover 12, the microneedle array device can achieve a basically constant propulsion volume under each pressing action. The air inlet 301 allows external gas to enter the medication channel of the microneedle array device to balance the pressure inside and outside the channel. The vent 308 is used to expel excess gas and maintain the overall gas pressure balance of the microneedle array device. The vent membrane 24 provides gas permeability and liquid blocking, ensuring a stable venting process without liquid leakage. In this embodiment of the invention, the drug channels on the microfluidic channel layer are all formed by photolithography casting or laser etching, wherein the height of the drug channels is 200~300μm, the width is 300~500μm, and the thickness of the microfluidic channel layer 3 is between 1mm and 1.2mm. The layers are assembled layer by layer by plasma activation, hot pressing lamination, or pressure-sensitive adhesive bonding to ensure accurate alignment of the through holes and channels and connectivity of the venting pathway, ultimately forming a compact, interconnected microneedle array device with both liquid transport and gas emission functions.

[0030] When replenishing the medication, inject the medication into the storage chamber 303 through the inlet 302 and slowly push the liquid to fill the buffer channel 304 and the pump inlet chamber 305 in sequence. Exhaust should be discharged through the microchannel adhesive layer 5, the exhaust communication hole 402, and the exhaust hole 308 (covered with exhaust hole membrane 24). After filling, seal the inlet 302 with the inlet sealing membrane 22 to prevent leakage.

[0031] like Figure 11 As shown, when implementing the detection function using this application, the hollow microneedle array 61 is divided into different regions, from left to right: reference electrode region A, working electrode region B, and counter electrode region C. Each region can be connected to an external detection circuit. The hollow microneedle array 61 in this embodiment of the invention has four... The array consists of 5 layers. The reference electrode region A contains one row of hollow microneedles 61, the working electrode region B contains two rows of hollow microneedles 61, and the counter electrode region C contains two rows of hollow microneedles 61. The hollow microneedles 61 in the reference electrode region A, working electrode region B, and counter electrode region C are the corresponding reference electrode, working electrode, and counter electrode. The reference electrode region A, working electrode region B, and counter electrode region C are connected to an external detection circuit (external detection circuit is existing technology) via a plug-in connection. The external detection circuit, in conjunction with the hollow microneedles 61 in the reference electrode region A, working electrode region B, and counter electrode region C, achieves the detection function. In use, the outer surface of the hollow microneedles 61 is modified with glucose oxidase, an electrochemical sensitive membrane, or other biorecognition materials. When the hollow microneedles 61 pierce the skin, the biorecognition material on their outer surface reacts chemically with the corresponding body fluids. The microneedle array layer 6 is then inserted into the external detection circuit (similar to inserting a blood glucose test strip into a blood glucose meter) for detection, further obtaining the concentration of the analyte.

[0032] In addition to the aforementioned integrated diagnostic and therapeutic microneedle array device, this invention also provides a method for preparing the microneedle array device, as detailed below: The functional capping layer, microfluidic channel layer 3, and encapsulation layer 4 can be fabricated using molds, each with its own independent male mold. The male molds for the functional capping layer, microfluidic channel layer 3, and encapsulation layer 4 are designed according to the shape of the microneedle array device. The microstructure shape of the male mold is opposite to that of the microneedle array device, and a barrier is set around the outer edge of the male mold. The male mold can be obtained through photolithography, laser cutting, or 3D printing. The male mold is cleaned sequentially with ethanol and deionized water and then dried for later use. In this embodiment of the invention, the drying temperature is 80°C.

[0033] In this embodiment of the invention, the functional capping layer, microfluidic channel layer 3, and encapsulation layer 4 are all made of polydimethylsiloxane (PDMS). After preparing the positive mold, the PDMS prepolymer and curing agent are mixed and stirred evenly at a mass ratio of 10:1 to form a mixture. The mixture is then placed in a vacuum environment to degas until no visible bubbles are visible. In this embodiment of the invention, the degassing time is approximately 5 to 10 minutes. A portion of the degassed mixture is poured into the corresponding positive mold and cured at 70°C for approximately 2 hours. After curing, the mold is demolded to obtain the main structures of the functional capping layer, microfluidic channel layer 3, and encapsulation layer 4. The microfluidic channel layer 3 is divided using a scalpel and a punch, and through holes are machined on the microfluidic channel layer to make the air inlet 301, liquid inlet 302, liquid storage chamber 303, press pump liquid inlet chamber 305, press pump liquid outlet chamber 306, and exhaust port 308 connected. The edges are then trimmed according to the design dimensions. Use a punch to machine liquid communication hole 401 and vent communication hole 402 on the encapsulation layer 4, and trim the edges.

[0034] In addition, the method for preparing the functional membrane layer is as follows: the inlet membrane 21 and the outlet membrane 24 are made of hydrophobic and breathable PTFE film, and are obtained by cutting. The inlet sealing membrane 22 is made of medical-grade silicone pressure-sensitive adhesive. The substrate film forming the adhesive layer is die-cut to obtain the inlet sealing membrane 22. In use, the inlet sealing membrane 22 is attached to the surface of the microfluidic channel layer 3 to achieve sealing. The microfluidic valve membrane assembly 23 is prepared using a mold. First, the mold for the microfluidic valve membrane assembly 23 is prepared: a micro-pattern with through holes and serpentine movable pieces is formed on a metal sheet by laser micromachining to form a metal mold. The microfluidic valve membrane thin layer is prepared using the metal mold. The PET substrate is cleaned and dried sequentially with ethanol and deionized water. The PDMS mixture is spin-coated onto the surface of the PET membrane. The spin-coating parameters are adjusted so that the cured film thickness is approximately 50-100 μm. The film is cured at 60°C for about 3 hours to obtain a uniform PDMS film. The obtained PDMS film is placed under a metal mold for imprinting to form a first valve membrane 231 and a second valve membrane 232, which include through holes (i.e., liquid inlet through holes 2321 and liquid outlet through holes 2312) and serpentine movable plates (i.e., liquid inlet movable plates 2311 and liquid outlet movable plates 2322).

[0035] The preparation method of the microchannel adhesive layer 5 is as follows: select a medical pressure-sensitive adhesive film or silicone film with a thickness of 25-150μm, and process the pattern corresponding to the pre-designed flow channel 51 by laser etching, so that it has both adhesive and microfluidic conduction functions.

[0036] The microneedle array layer 6 needs to be fabricated separately. The fabrication method is as follows: a master mold is created according to the designed parameters of the hollow microneedle array 61. The microstructure shape of the master mold is opposite to that of the hollow microneedle array 61, and a barrier is set on the outer edge of the master mold. The master mold can be obtained by photolithography, laser etching, or micromilling. The material can be silicon wafer, PMMA, or a metal substrate. The master mold is cleaned sequentially with ethanol and deionized water and then dried for later use. In this embodiment of the invention, the drying temperature is 80°C.

[0037] The aforementioned degassed mixture was poured onto the surface of the master mold, covering the area corresponding to the hollow microneedle 61 array, and then heated and cured at 60℃~80℃ for 1~2 hours. After curing, it was slowly peeled off to obtain a PDMS negative mold with the opposite morphology to the hollow microneedle 61.

[0038] A polymer material is selected as the molding material for the hollow microneedles 61. The polymer can be polystyrene (PS), polymethyl methacrylate (PMMA), polylactic acid (PLA), or polyurethane (PU). Depending on the properties of the selected polymer material, the polymer solution or molten material is poured into a PDMS negative mold cavity, and after solidification, solid hollow microneedles 61 are formed. After solidification, the material is cooled to room temperature and demolded to obtain a complete array of solid hollow microneedles 61. The array of solid hollow microneedles 61 is fixed on a laser processing platform with the needle tips facing upwards. A femtosecond or picosecond laser is used to laser drill holes in each hollow microneedle 61 along its axial direction from the needle tip to the needle base. The laser drilling parameters are adjusted according to the material type and needle size of the hollow microneedles 61 to obtain through channels with a diameter of 50μm to 120μm. Gas purging can be used during processing to reduce the heat-affected zone and keep the needle hole walls smooth. After drilling, the hollow microneedle 61 array is cleaned and post-processed. First, ultrasonic cleaning with anhydrous ethanol or isopropanol is used to remove molten residue, followed by oxygen plasma treatment to remove the carbonized layer and activate the surface. The final result is a microneedle array with hollow channels.

[0039] After preparing the above structure, each layer is assembled step by step through alignment and bonding. The assembly method is as follows: the bonding surfaces of the functional capping layer, microfluidic valve membrane assembly 23, microfluidic channel layer 3, and encapsulation layer 4 are sequentially cleaned with anhydrous ethanol and deionized water, and then dried for later use. A mask or peelable shielding film is used to cover the active areas of the movable sheets (liquid inlet movable sheet 2311 and liquid outlet movable sheet 2322) on the surface of the microfluidic valve membrane assembly 23, exposing only the bonding areas. The bonding areas are then activated by oxygen plasma for 30-60 seconds at a power of 50-100W. After removing the mask (or shielding film), the sheets are immediately aligned and bonded to the corresponding positions in the microfluidic channel layer 3 at room temperature. After bonding, the sheets are thermo-cured at 70°C for approximately 30 minutes to form an elastically deformable movable sheet structure (liquid inlet movable sheet 2311 and liquid outlet movable sheet 2322).

[0040] The air inlet membrane 21 and the exhaust membrane 24 are sequentially attached to cover the air inlet 301 and the exhaust port 308 respectively, ensuring that the air inlet membrane 21 and the exhaust membrane 24 are flat and attached to the corresponding surfaces.

[0041] The bonding interface between the functional capping layer and the microfluidic channel layer 3 was treated with oxygen plasma for 30–60 seconds, followed by immediate alignment and bonding at room temperature. After bonding, it was cured at 70°C for approximately 30 minutes.

[0042] The bonding interface between the encapsulation layer 4 and the microfluidic channel layer 3 is treated with oxygen plasma, and then bonded at room temperature. During bonding, the liquid connecting hole 401 is aligned with the end of the liquid transport channel 307, and the vent connecting hole 402 is aligned with the vent hole 308. After bonding, it is cured at 70°C for 30 minutes.

[0043] The microchannel adhesive layer 5 and the microneedle array layer 6 are aligned on the fixture so that the flow channel 51 of the microchannel adhesive layer 5 is consistent with the pinhole of the hollow microneedle 61 of the microneedle array layer 6.

[0044] The bottom surface of the encapsulation layer 4 and the upper surface of the microchannel adhesive layer 5 are activated with oxygen plasma and immediately aligned and bonded at room temperature. During bonding, it is ensured that the liquid communication hole 401, the exhaust communication hole 402, the liquid flow channel within the microchannel adhesive layer 5, and the pinhole of the hollow microneedle 61 are continuously connected, while ensuring that the exhaust communication hole 402, the exhaust hole 308, and the flow channel 51 maintain their corresponding relationship. After bonding, it is cured at 70°C for approximately 30 minutes. After natural cooling, the outer edge is trimmed, and all channels and flow paths are checked for continuity and that the valve cavity maintains normal deformation. This completes the assembly of the microneedle array device, with the inlet sealing film 22 sealing the inlet 302 after liquid injection. The assembled microneedle array device is then obtained.

[0045] The diagnostic and therapeutic microneedle array device of this invention also possesses detection (i.e., diagnostic) functions. This process fabricates an electrochemical microneedle sensor array based on a hollow microneedle 61 array, which can construct a three-electrode integrated structure including a working electrode (WE), a reference electrode (RE), and a counter electrode (CE). By sequentially performing steps such as array cleaning, conductive layer construction, insulating layer formation, and electrode functionalization modification, a stable electrochemical reaction interface can be obtained on the microneedle surface. Specifically: The hollow microneedle 61 array was sequentially ultrasonically cleaned in ethanol and deionized water for 5 minutes each to remove surface impurities, and then dried at 90°C to obtain a clean surface and improve the adhesion of the subsequent conductive layer. A chromium (Cr) or titanium (Ti) adhesion layer and a gold (Au) conductive layer were sequentially deposited on the surface of the hollow microneedle 61 array using magnetron sputtering. The adhesion layer thickness was approximately 5 nm–10 nm, and the conductive layer thickness was approximately 200 nm, forming the conductive leads and electrode substrate structure, providing a stable electrical connection layer for the subsequent three-electrode system. An insulating layer was deposited on the bottom, pinholes, and non-reactive areas of the hollow microneedle 61 array using a polyimide (PI) and polymethyl methacrylate (PMMA) solution, leaving only the pin tip or sidewall as an exposure window. After curing in an oven at 80°C–100°C, a uniform insulating film layer was formed to prevent signal interference caused by short circuits between electrodes or uneven film edges.

[0046] Ag / AgCl slurry was uniformly coated onto the exposed area of ​​the designated reference electrode microneedles and dried at 90°C to form an Ag / AgCl conductive coating. Subsequently, a PVB / NaCl solution was prepared. In this embodiment, the mass ratio of PVB to NaCl in the PVB / NaCl solution was approximately 1.6:1, and the PVB was dissolved in methanol and then ultrasonically dispersed. 1 μL of the solution was drop-coated onto the surface of the reference electrode, and this coating was repeated three times at 15-20 minute intervals, followed by overnight drying at room temperature to form a stable reference electrode structure. A platinum (Pt) conductive layer was formed on the exposed area of ​​the designated counter electrode microneedles using electrochemical deposition to improve the electrochemical stability of the counter electrode. The electrochemical deposition process was carried out at a constant potential in a solution containing chloroplatinic acid (H₂PtCl₆), with a constant potential of approximately [missing value]. 0.2V vs Ag / AgCl. After deposition, cyclic voltammetry activation was performed in phosphate-buffered saline (PBS) at a potential range of 0V–1.0V and a scan rate of 20mV / s–50mV / s for 10–20 cycles to stabilize the electrode interface. Prussian blue electrodeposition, enzyme layer modification, and Nafion anti-interference layer modification were sequentially performed on the exposed areas of the designated working electrode microneedles. Prussian blue was electrochemically deposited on the working electrode surface; the enzyme layer, formed by cross-linking glucose oxidase (GOx) with glutaraldehyde, was applied at a rate of 0.5–1 μL / needle and allowed to air dry; Nafion solution was applied at a rate of 0.5–1 μL / needle and dried overnight at room temperature to form a continuous and dense multilayer film structure, thereby achieving high selectivity and stable electrochemical response to glucose.

[0047] Before using the integrated diagnostic and therapeutic microneedle array device, clean the target skin area with deionized water or 75% alcohol and allow it to air dry. Insert the hollow microneedle array 61 vertically into the skin and leave it in place for approximately 1 hour. Use the auxiliary tape or adhesive backing provided on the microneedle array device for proper attachment. Press the pressure chamber cap 12 to administer a measured dose of medication. The hollow microneedle array 61 continuously samples and outputs signals, allowing for real-time analysis and threshold indication. When the detected value exceeds the set threshold, press the pressure chamber cap 12 again to administer medication in multiple doses, thus forming a closed-loop or semi-closed-loop control. After completing the detection or medication administration, slowly remove the device; if reuse is required, clean and replenish the medication according to the following cleaning and maintenance method.

[0048] The diagnostic and therapeutic microneedle array device of this invention requires regular cleaning and maintenance in practical applications. Therefore, the following cleaning and maintenance methods are also provided: Device Cleaning: After use, inject deionized water or saline solution through the inlet 302 to clean the internal drug channels. Use a low-pressure push method to allow the cleaning solution to flow sequentially through the buffer channel 304, the press pump inlet chamber 305, the press pump outlet chamber 306, the press pump cover 12, the liquid transfer channel 307, the liquid connecting hole 401, the flow channel 51, and the hollow microneedles 61 to remove residual body fluids or drugs. If necessary, repeat the operation 1-2 times until the discharged solution is clear.

[0049] Drying and disinfection: After cleaning, the inside of the microneedle array device is dried by natural air drying or low-temperature vacuum drying. The outer surface of the device is disinfected by wiping with anhydrous ethanol or irradiating with ultraviolet light. High-temperature methods are prohibited to prevent deformation of the PDMS or film structure.

[0050] Storage and Maintenance: Store the dried microneedle array device in inert packaging to prevent dust and moisture ingress. Before use, check the sealing structure and electrode connections. If wear, delamination, or performance degradation is found in the hollow microneedle array, replace the affected components. Dispose of single-use parts according to medical waste management regulations.

[0051] By following the above cleaning, drying and maintenance steps, the internal channels of the microneedle array device can be kept clean and the seal can be kept intact, ensuring the stable performance of the microneedle array device after reuse or long-term storage, and ensuring safe use.

[0052] Although embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions, and variations to the above embodiments within the scope of the present invention.

[0053] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A microneedle array device integrating diagnosis and treatment, characterized in that, include: The structure consists of a functional capping layer, a microfluidic channel layer, an encapsulation layer, a microchannel adhesive layer, and a microneedle array layer, which are attached together from top to bottom. The functional capping layer includes the pressing cavity cap, the encapsulation layer has a liquid communication hole, the microchannel adhesive layer has a flow channel, and the microneedle array layer has multiple hollow microneedles. The microfluidic channel layer is provided with a liquid inlet, a liquid storage chamber, a buffer channel, a press pump liquid inlet chamber, a press pump liquid outlet chamber, and a liquid transport channel connected in sequence; the other end of the liquid transport channel is connected in sequence to the liquid communication hole, the flow channel, and the hollow microneedle to form a drug liquid channel; The pressing chamber cover covers the liquid inlet chamber and the liquid outlet chamber of the pressing pump, and a microfluidic valve membrane assembly is provided under the pressing chamber cover; the microfluidic valve membrane assembly is used to control the unidirectional flow of the liquid, and repeatedly pressing the pressing chamber cover promotes the unidirectional flow of the liquid in the liquid channel; The hollow microneedles are modified with biometric materials; the hollow microneedles are divided into a working electrode region, a reference electrode region, and a counter electrode region, and the working electrode region, the reference electrode region, and the counter electrode region are respectively connected to an external detection circuit for detecting the analyte.

2. The diagnostic and therapeutic microneedle array device according to claim 1, characterized in that, The functional cover layer also includes a liquid storage chamber cover, which covers the liquid storage chamber to form a sealed liquid storage chamber.

3. The diagnostic and therapeutic microneedle array device according to claim 1, characterized in that, The microfluidic channel layer also includes an air inlet and multiple exhaust ports. The air inlet is connected to the liquid storage chamber, and the multiple exhaust ports are respectively connected to multiple liquid transport channels, and the multiple exhaust ports penetrate the microfluidic channel layer. The air inlet and the exhaust ports are used to balance the internal air pressure of the diagnostic and therapeutic microneedle array device.

4. The diagnostic and therapeutic microneedle array device according to claim 3, characterized in that, It also includes a plurality of vent membranes, which are disposed on the upper surface of the microfluidic channel layer to cover the plurality of vents.

5. The integrated diagnostic and therapeutic microneedle array device according to claim 1, characterized in that, The microfluidic valve membrane assembly includes a first valve membrane and a second valve membrane with identical structures. The first valve membrane includes an inlet movable plate and an outlet through-hole, and the second valve membrane includes an inlet through-hole and an outlet movable plate. The first valve membrane and the second valve membrane are arranged in a 180° mirror symmetrical fit, with the inlet through-hole aligned with the inlet movable plate and the outlet movable plate aligned with the outlet through-hole.

6. The integrated diagnostic and therapeutic microneedle array device according to claim 1, characterized in that, The functional capping layer, the microfluidic valve membrane assembly, the microfluidic channel layer, and the encapsulation layer are all made of the same material: polydimethylsiloxane.

7. The diagnostic and therapeutic microneedle array device according to claim 1, characterized in that, The working electrode area, reference electrode area, and counter electrode area are all connected to an external detection circuit.

8. A preparation method for preparing the diagnostic and therapeutic microneedle array device according to any one of claims 1 to 7, characterized in that, Preparation methods include: Fabrication of functional capping layer, microfluidic channel layer and encapsulation layer: Male molds are prepared according to the shapes of the functional capping layer, microfluidic channel layer and encapsulation layer respectively, and the functional capping layer, microfluidic channel layer and encapsulation layer are prepared using the male molds respectively; Preparation of microchannel adhesive layer: Select medical pressure-sensitive adhesive film or silicone film, and prepare microchannel adhesive layer using laser etching method; Fabrication of microneedle array layer: Prepare a master mold for hollow microneedle array, use the master mold to prepare a PDMS negative mold, use the PDMS negative mold to prepare a solid hollow microneedle array, and then drill through the pinholes of the hollow microneedle array with laser. An adhesion layer and a conductive layer are sequentially deposited on the surface of the hollow microneedles using magnetron sputtering. In the working electrode region, Prussian blue electrodeposition, enzyme layer modification, and Nafion anti-interference layer modification are sequentially performed. An Ag / AgCl slurry is coated in the reference electrode region to form a conductive coating. An electrochemical deposition method is used to form a conductive layer in the counter electrode region.

9. The preparation method according to claim 8, characterized in that, A functional membrane layer is disposed on the microfluidic channel layer, the functional membrane layer including an inlet membrane, an outlet membrane, a microfluidic valve membrane assembly, and an outlet membrane; the preparation method of the functional membrane layer is as follows: The air inlet membrane and air outlet membrane are obtained by cutting a PTFE film; micro-patterns are prepared on a metal sheet to form a metal mold, and the microfluidic valve membrane assembly is prepared using the metal mold; the silicone pressure-sensitive adhesive is die-cut to obtain the liquid inlet sealing film.

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