Flexible hollow electrical stimulation electrode array device and preparation method thereof

Abstract

The invention provides a flexible hollow electrical stimulation electrode array device and a preparation method thereof, and belongs to the technical field of medical instruments, and the flexible hollow electrical stimulation electrode array device specifically comprises a flexible substrate and a microneedle array; the microneedle array comprises a plurality of microneedles, and at least parts of the microneedles are different in height; the lead wire end of the microneedle is used for being electrically connected with detection equipment and electric pulse generation equipment. When macromolecular medicine needs to enter intracellular fluid by means of electroporation, the flexible hollow electrical stimulation electrode array device is implanted into human tissue, the microneedles with different heights penetrate into different depths in the tissue, the lead ends of the microneedles are firstly connected with detection equipment, neural electrophysiological signals of a target brain area are detected through the detection equipment, and the detection equipment is used for detecting the intracellular fluid in the target brain area. According to the method, the position and the type of a disease are judged, then electric pulse generation equipment is connected to provide pulse current for the microneedle, so that macromolecular drugs can open nanometer through holes of cell membranes through electroporation to enter intracellular fluid to treat the focus position, and after treatment is conducted for a period of time, detection equipment is connected to judge the treatment effect.

Description

Technical Field

[0001] The present application relates to the technical field of medical devices, and more particularly, to a flexible hollow electrical stimulation electrode array device and a preparation method thereof. Background Art

[0002] For some macromolecular drugs such as nucleic acids or plasmids, the drugs need to enter the intracellular fluid to play their roles. Limited by the selective permeability of the cell membrane, these drugs are difficult to directly enter the intracellular fluid through the cell membrane and need to rely on external methods to assist the drugs to efficiently enter the intracellular fluid. Electroporation technology is a commonly used method to assist drugs to enter cells. Its principle is to use an electric pulse to instantaneously open the cell membrane, and then generate instantaneous nano-pores. These nano-pores allow macromolecular drugs such as nucleic acids to diffuse into the intracellular fluid by virtue of the concentration difference inside and outside the cell membrane to play their roles. After removing the external electric pulse (electric field), the nano-pores on the cell membrane surface can be restored.

[0003] For some neurological diseases, before electroporation, it is necessary to first implant a detection electrode to detect the lesion, and then implant an electroporation electrode to perform electroporation on the lesion site. This method requires two insertions into the lesion site, which is likely to cause insertion damage to the patient's lesion site. Summary of the Invention

[0004] An object of the present application is to provide a flexible hollow electrical stimulation electrode array device and a preparation method thereof, aiming to solve the problem in the related art that it is necessary to first implant a detection electrode and then an electroporation electrode, which requires two insertions into the lesion site and is likely to cause insertion damage to the patient's lesion site.

[0005] Additional aspects and advantages of the present application will be partly described in the following description, and partly will become apparent from the description, or can be learned through the practice of the present application.

[0006] According to a first aspect of the present application, there is provided a flexible hollow electrical stimulation electrode array device, including a flexible substrate and a microneedle array. A drug delivery channel is provided inside the flexible substrate. The microneedle array is disposed on the flexible substrate. The microneedle array includes a plurality of microneedles, and at least some of the plurality of microneedles have different heights so that the microneedles can penetrate into tissues at different depths. The lead ends of the microneedles are used for electrically connecting to a detection device and an electric pulse generating device. The microneedles have hollow channels, one end of the hollow channel is open at the tip of the microneedle, and the other end is connected to the drug delivery channel.

[0007] In an exemplary embodiment of the present application, a plurality of independent conductive leads are disposed on the flexible substrate, and the plurality of conductive leads are respectively electrically connected to the lead ends of the plurality of microneedles. The other ends of the conductive leads extend out of the flexible substrate for electrically connecting to a detection device and an electrical pulse generating device.

[0008] In an exemplary embodiment of the present application, in the microneedle array, at least some of the plurality of microneedles in the first direction have different heights, and in the second direction, at least some of the plurality of microneedles have different heights; or In the second direction, the heights of the plurality of microneedles gradually change.

[0009] In an exemplary embodiment of the present application, the lead ports of several of the conductive leads converge into three buses, and the three buses are respectively connected to three electrodes of the electrical pulse generating device for controlling the change of the corresponding microneedle electrodes between the anode and the cathode.

[0010] In an exemplary embodiment of the present application, the lead ports of the conductive leads of the microneedles in the same row converge on the same bus, and the conductive leads of the microneedles in adjacent two rows converge on different buses.

[0011] In an exemplary embodiment of the present application, the bus where the conductive lead connected to any one of the plurality of microneedles is located is different from the buses where the conductive leads connected to the surrounding microneedles are located.

[0012] In an exemplary embodiment of the present application, barbs for restricting the position of the flexible hollow electrical stimulation electrode array device in human tissue are provided on the needle body of the microneedle structure.

[0013] According to a second aspect of the present application, a method for manufacturing a flexible hollow electrical stimulation electrode array device is provided, including the following steps: Processing the surface layer of the substrate matrix, processing a plurality of through holes on the flexible substrate base, and processing a plurality of conductive leads on the surface of the substrate base, and the plurality of conductive leads respectively correspond to the plurality of through holes; Additive manufacturing of the microneedle array, constructing a plurality of microneedle electrode matrices with different heights from bottom to top on the upper surface of the surface layer of the substrate matrix by aligning with the through holes through 3D printing technology; Coating the microneedle array, covering a first mask plate on the upper surface of the surface layer of the substrate matrix, the unblocked part of the first mask plate is the area where the microneedle electrode matrix is located, and depositing a conductive thin layer on the unblocked part of the first mask plate by using a vacuum coating process, and removing the first mask plate after completion; Depositing an insulating layer, using a vacuum vapor deposition process or a dip coating process to cover the whole with an insulating layer; For reactive ion etching, a second mask plate is nested on the upper surface of the substrate matrix surface layer. The second mask plate only exposes the tip part of the microneedle electrode matrix, shields all other surfaces, and liquid polyethylene glycol is filled between the second mask plate and the microneedle electrode matrix. After filling, the polyethylene glycol is cured. Using the reactive ion etching process, the insulating layer of the exposed tip part of the microneedle electrode matrix is removed. After the etching is completed, the second mask plate is removed, and at the same time, the polyethylene glycol is liquefied to remove the polyethylene glycol.

[0014] In an exemplary embodiment of the present application, before depositing the insulating layer, the following steps are further included: For electroplating, the hollow electropermeable microneedle array electrode with surface metallization completed is placed in the electroplating solution, and all electrode lead wires are connected to the cathode of the power supply device. The anode of the power supply device is connected to the plating metal electrode or the inert electrode, and a 2-10 μm conductive layer is electroplated on the conductive thin layer deposited by the coating process.

[0015] In an exemplary embodiment of the present application, the following steps are further included: Processing the flexible substrate, 3D printing the master mold, obtaining the negative mold through the mold turning process, and then obtaining the flexible substrate with the liquid storage pool through the mold turning process. The lower surface of the substrate matrix surface layer after reactive ion etching is attached to the flexible substrate to complete the preparation of the electrostimulation electrode array device.

[0016] The exemplary embodiments of the present application may have the following partial or all beneficial effects: In the flexible hollow electrostimulation electrode array device provided by the exemplary embodiment of the present application, it includes a flexible substrate and a microneedle array. The flexible substrate is provided with a drug delivery channel. The microneedle array is arranged on the flexible substrate. The microneedle array includes multiple microneedles. At least some of the multiple microneedles have different heights so that the microneedles can penetrate into tissues at different depths. The lead end of the microneedle is used for electrical connection with the detection device and the electrical pulse generating device. The microneedle has a hollow channel. One end opening of the hollow channel is located at the tip of the microneedle, and the other end opening is connected to the drug delivery channel. When it is necessary to use electropermeation to enable macromolecular drugs to enter the intracellular fluid, the flexible hollow electrostimulation electrode array device is implanted into the human tissue. Microneedles with different heights penetrate into different depths of the tissue. The lead end of the microneedle is first connected to the detection device, and the neuroelectrophysiological signals of the target brain region are detected by the detection device to judge the location and type of the disease. After the detection is completed, the lead end of the microneedle is connected to the electrical pulse generating device. The electrical pulse generating device provides pulsed current for the microneedles at the corresponding depth to perform electropermeation on the tissue between the microneedles, so that the macromolecular drugs can enter the intracellular fluid through the nano-pores opened in the cell membrane by electropermeation to treat the lesion location. And after a period of treatment, the lead end of the microneedle is connected to the detection device again to detect the treatment effect.

[0017] In addition, a plurality of independent conductive leads are provided on the flexible substrate, and the plurality of conductive leads are respectively electrically connected to the lead ends of the plurality of microneedles. Each of the plurality of microneedles is separately connected to an independent conductive lead. When connected to an electrical pulse generating device through the lead end, the polarity of each microneedle can be controlled, and the polarities of adjacent microneedles can be made as different as possible, further slowing down the intensification of water electrolysis and the accumulation of hydroxide ions, and avoiding cell death caused by too high pH value around the cathode.

[0018] It should be understood that the above general description and the following detailed description are only exemplary and explanatory, and do not limit the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] The accompanying drawings herein are incorporated into the specification and constitute a part of this specification, showing embodiments consistent with the present application, and are used together with the specification to explain the principles of the present application. Obviously, the drawings in the following description are only some embodiments of the present application, and those of ordinary skill in the art can obtain other drawings based on these drawings without creative efforts.

[0020] Figure 1 FIG. shows a schematic structural diagram of a flexible hollow electrical stimulation electrode array device in Embodiment 1 of the present application; Figure 2 FIG. shows a side view of the flexible hollow electrical stimulation electrode array device in Embodiment 1 of the present application; Figure 3 FIG. shows a schematic layout diagram of the conductive leads of the flexible substrate in Embodiment 1 of the present application; Figure 4 FIG. shows a schematic back structure diagram of the flexible substrate in Embodiment 1 of the present application; Figure 5 FIG. shows a schematic tip structure diagram of the microneedle in Embodiment 1 of the present application; Figure 6 FIG. shows a schematic structure diagram of the flexible substrate connected to an infusion tube in Embodiment 1 of the present application; Figure 7 FIG. shows a schematic convergence structure diagram of the conductive leads in Embodiment 1 of the present application; Figure 8 FIG. shows a schematic top surface diagram of the surface layer of the substrate matrix processed in Embodiment 2 of the present application; Figure 9 FIG. shows a schematic bottom surface diagram of the surface layer of the substrate matrix processed in Embodiment 2 of the present application; Figure 10 FIG. shows a schematic structure diagram of the microneedle matrix fabricated by additive manufacturing in Embodiment 2 of the present application; Figure 11 FIG. shows a schematic structure diagram of covering the first mask plate in Embodiment 2 of the present application; Figure 12Shows a schematic structural diagram of the deposited insulating layer in Embodiment 2 of the present application; Figure 13 Shows a schematic structural diagram of the reactive ion etching in Embodiment 2 of the present application; Figure 14 Shows a side view of the reactive ion etching in Embodiment 2 of the present application; Figure 15 Shows a schematic structural diagram of the flexible substrate matrix processed by the mold turning process in the first angle in Embodiment 2 of the present application; Figure 16 Shows a schematic structural diagram of the flexible substrate matrix processed by the mold turning process in the second angle in Embodiment 2 of the present application.

[0021] Description of the reference numerals: 001, the first mask plate; 002, the second mask plate; 11, the flexible substrate; 111, the through hole; 112, the conductive lead; 113, the lead port; 12, the micro-needle array; 121, the electrode matrix; 122, the electrode conductive layer; 123, the electrode insulating layer; 13, the hollow channel; 14, the liquid storage pool; 15, the drug delivery port; 21, the conductive silver paste; 22, the signal line; 31, the infusion tube. Detailed implementation manners

[0022] Now, the exemplary embodiments will be described more fully with reference to the accompanying drawings. However, the exemplary embodiments can be implemented in various forms and should not be construed as limited to the embodiments set forth herein; on the contrary, these embodiments are provided so that this application will be thorough and complete, and the concept of the exemplary embodiments will be fully conveyed to those skilled in the art. The same reference numerals in the figures denote the same or similar structures, and thus their detailed descriptions will be omitted. In addition, the drawings are only schematic illustrations of the present application and are not necessarily drawn to scale.

[0023] Although relative terms such as "upper" and "lower" are used in this specification to describe the relative relationship of one component of the icon to another component, these terms are used in this specification only for convenience, for example, according to the direction of the example in the accompanying drawings. It can be understood that if the device of the icon is turned upside down, the component described as "upper" will become the component "lower". When a structure is "on" another structure, it may mean that a structure is integrally formed on another structure, or that a structure is "directly" disposed on another structure, or that a structure is "indirectly" disposed on another structure through another structure.

[0024] The terms "a", "an", "the" and "at least one" are used to denote the presence of one or more elements / components / etc.; the terms "comprising" and "having" are used to mean an open inclusion and refer to the possibility of the existence of additional elements / components / etc. in addition to the listed elements / components / etc.; the terms "first", "second" are used only as labels and are not limitations on the quantity of their objects. Example 1

[0025] This example provides a specific implementation of the flexible hollow electrostimulation electrode array device, as Figure 1 and Figure 2 shown, including a flexible substrate 11 and a microneedle array 12. The microneedle array 12 is disposed on the flexible substrate 11. The microneedle array 12 includes multiple microneedles. Among them, at least some of the multiple microneedles have different heights, so that the microneedles can penetrate into tissues at different depths. The lead ends of the microneedles are used for electrical connection with a detection device and an electrical pulse generating device; a drug delivery channel is provided in the flexible substrate 11. The microneedles have a hollow channel 13. One end opening of the hollow channel 13 is located at the tip of the microneedle, and the other end opening is connected to the drug delivery channel. When it is necessary to use electropermeabilization to assist in opening the cell membrane to generate transient nanopores 111, the flexible hollow electrostimulation electrode array device is implanted into human tissue. The microneedles in the microneedle array 12 penetrate into tissues at different depths. The lead ends of the microneedles are first connected to the detection device, and the electrophysiological signals of nerves at different depths are detected by the detection device to detect the location and type of target brain region diseases. After the detection is completed, the lead ends of the microneedles are then connected to the electrical pulse generating device. The electrical pulse generating device provides pulsed current for the microneedles, which can instantaneously open the cell membrane, and then generate transient nanopores 111. At this time, macromolecular drugs can enter the intracellular fluid through the nanopores 111; during the electropermeabilization process, the hollow channels 13 of the microneedles are in communication with external drugs through the drug delivery channel. The drugs enter the hollow channels 13 through the drug delivery channel and reach the tip position of the microneedles in the hollow channels 13, waiting for the electropermeabilization to generate transient nanopores 111, and then the drugs enter the intracellular fluid; moreover, after a period of treatment, the lead ends of the microneedles can be connected to the detection device again to detect the treatment effect.

[0026] In the related art, the cerebral cortex is not a flat two-dimensional surface, but is composed of complex sulci and gyri (for example, the depth of the sulci in the human brain is 1-2 cm, and the width of the gyri is 2-3 cm). This complex anatomical structure means that existing microelectrode arrays may not be able to cover the target cortical area, resulting in limitations in the coverage and accuracy of neural signal capture. When performing electroporation, for some neurological diseases, it is usually necessary to detect first and then perform electroporation. During the detection process, due to the unique structure of the cerebral cortex, the length of the detection needle may be insufficient or too long, and it may be necessary to replace the detection needle multiple times to detect the location of the lesion. It is even possible that due to the length of the detection needle being too long or too short, the detection by the detection needle may deviate. The technical solution of the present application provides a micro-needle array device for electroporation with micro-needles of different heights. The height of the micro-needles is flexibly adjusted according to the depth of the target area. After the micro-needles of different heights penetrate into the human tissue, their needle tips can penetrate into different depths of the tissue. During the detection process, the conditions at different depths within the tissue can be detected, thereby weakening the possible negative impacts caused by the length problem of the detection needle. At the same time, the lead ends of the micro-needles are respectively connected to the detection device and the electric pulse generating device, and the detection device is detected first and then the electric pulse generating device is connected. In this way, during the electroporation process, without replacing the implanted micro-needles, the operations of detection and electroporation can be completed simultaneously, saving operation steps and reducing the harm to human tissue.

[0027] In this embodiment, as Figure 3 and Figure 4 shown, a plurality of independent conductive leads 112 are arranged on the flexible substrate 11. The plurality of conductive leads 112 are respectively electrically connected to the lead ends of the plurality of micro-needles. The other ends of the conductive leads 112 extend out of the flexible substrate 11 for electrically connecting to the detection device and the electric pulse generating device. Through the conductive leads 112, the micro-needles can be electrically connected to the external detection device and the electric pulse generating device.

[0028] In this embodiment, as Figure 6 shown, in the micro-needle array 12, the heights of the plurality of micro-needles in the first direction are the same. In the second direction, the heights of at least some of the plurality of micro-needles are different. Specifically, the heights of two adjacent micro-needles can be different, or the heights of the spaced micro-needles can be different. In some other embodiments, the heights of the micro-needles can be arranged in a staggered manner, as long as there are micro-needles of different heights for detecting the corresponding tissue depths.

[0029] In some other embodiments, the heights of the micro-needles in the second direction can be gradually changed. Of course, whether it is the first direction or the second direction, the micro-needle array 12 as a whole can be uneven. Among them, the first direction and the second direction can be the horizontal and vertical directions, or two directions at a certain angle, and no specific limitation is made here.

[0030] In the related art, the electroporation electrodes are all single-phase or biphasic electric pulses, which will lead to intensified water electrolysis and accumulation of hydroxide ions. The high pH value around the cathode will cause cell death. To solve this problem, in this embodiment, the lead ports 113 of several conductive leads 112 are converged into three buses, and the three buses are respectively connected to the three electrodes of the electric pulse generating device, and are used to control the electrodes of the corresponding microneedles to change between the anode and the cathode, so that the tip of the electrode performs electroporation on the surrounding tissue, and three-phase electric pulses are adopted; when applying electrical stimulation, the lead ports 113 of several leads are converged into three buses, and the time interval is set according to requirements, and one of the buses is alternately set as the anode, and the other two buses are set as the cathodes, and the three buses are correspondingly connected to the positive and negative electrodes of the electric pulse generating device to apply a stimulating pulse voltage; on the other hand, when detecting nerve signals, each wire of the lead port 113 is connected to the detecting device as a channel.

[0031] Furthermore, the lead ports of the conductive leads 112 of the microneedles in the same row are converged on the same bus, and the conductive leads 112 of the microneedles in two adjacent rows are converged on different buses. Such a design can make the microneedles in two adjacent rows be the anode and the cathode respectively. For example, the three adjacent rows are the first row, the second row, and the third row. The first row and the third row are the cathodes, and the second row is the anode, which enhances the electroporation effect and can slow down the water electrolysis and the accumulation of hydroxide ions.

[0032] Specifically, the bus where the conductive lead 112 connected to any one of the multiple microneedles is located is different from the buses where the conductive leads 112 connected to the surrounding adjacent microneedles are located. This makes not only the polarities of the microneedles in different rows different, but also the polarities of two adjacent microneedles in the same row different, further slowing down the intensification of water electrolysis and the accumulation of hydroxide ions, and avoiding cell death caused by too high pH value around the cathode. Specifically, as Figure 4 shown, the positions corresponding to the through holes 111 are used to construct microneedles. For a clearer display, taking Figure 4 as an example, Ⅰ, Ⅱ, and Ⅲ respectively correspond to three buses, and each bus is respectively electrically connected to the three electrodes of the electric pulse generating device. The electric pulse generating device can independently control each bus to change between the anode and the cathode, and by continuously changing the polarity of the microneedles, the phenomenon of intensified water electrolysis and the accumulation of hydroxide ions are further slowed down.

[0033] In this embodiment, the use of the flexible substrate 11 can better fit the organizational structure of the brain. Since the cerebral cortex has a certain curvature, the flexible substrate 11 can be adjusted according to the curvature of the cerebral cortex and can better fit on the cerebral cortex.

[0034] In this embodiment, barbs for restricting the position of the flexible hollow electrical stimulation electrode array device in human tissue are provided on the needle body of the microneedle structure.

[0035] Specifically, the needle body of the microneedle includes an upper cone and a lower frustum. The diameter of the bottom of the upper cone is greater than the diameter of the top surface of the lower frustum. The part of the bottom surface of the upper cone that is larger than the top surface of the lower frustum forms a barb structure. After piercing into human tissue, the part of the bottom surface of the upper cone that exceeds the top surface of the lower frustum will block the outward movement of the microneedle, thereby restricting the position of the microneedle array 12 device.

[0036] In some other embodiments, the barb structure can also be a claw or other structure protruding from the side of the needle body of the microneedle as long as it can prevent the microneedle from moving outward.

[0037] In this embodiment, as Figure 5 shown, the tip of the microneedle includes an electrode substrate 121, an electrode conductive layer 122, and an electrode insulating layer 123. The electrode conductive layer 122 completely covers the surface of the electrode substrate 121, and the electrode conductive layer 122 is connected to the conductive lead 112 on the surface of the flexible substrate 11. In order to accurately achieve the function of local nerve signal acquisition, while reducing unnecessary damage to tissues such as the skin caused by the stimulating voltage conducted through the conductive interface, and improving the biosafety of the hollow electroperforation microneedle array electrode and the accuracy of the stimulation area, a conformal coverage insulating layer design is adopted on the electrode surface. The electrode insulating layer 123 exposes an area of several micrometers to dozens of micrometers at the tip of the microneedle. The size of the exposed area at the tip of the microneedle is adjusted according to the actual acquisition and stimulation range and the acquisition and stimulation effect. Specifically, the electrode conductive layer of the microneedle is made of a conductive material with high electrical conductivity, high biocompatibility, and stable electrochemical properties, including but not limited to gold and platinum. The electrode insulating layer 123 is made of a biocompatible insulating material, including but not limited to parylene, polyimide, polyurethane, and polytetrafluoroethylene.

[0038] In this embodiment, as Figure 7 shown, the lead port 113 of the microneedle array electrode is connected to the signal line 22 through the conductive silver paste 21. When realizing the function of collecting nerve electrical signals, the other end of the signal line 22 is connected to an external interface or device; when realizing the electrical stimulation function, the signal lines 22 converge into three buses, and the other end is connected to a three-phase power supply that applies an electroperforation stimulation voltage. The bottom surface drug delivery port 15 of the hollow electroperforation microneedle array electrode is connected to the infusion tube 31. In other embodiments, the conductive silver paste 21 can be replaced with a conductive binder such as solder or conductive paste; the signal line 22 can be a conductive lead such as a Dupont wire or a metal wire; the infusion tube 31 can be replaced with other pipes that can be used for drug injection.

[0039] In this embodiment, the thickness of the flexible substrate 11 is preferably 5 μm - 25 μm, and it is characterized by being able to conform to the tissue structure of the experimental brain. Its length and width are determined by the number of microneedles and the layout of the electrode interconnection structure, and are preferably 3 mm - 10 mm. The preferred size of the microneedle array 12 is: height 100 μm - 2 mm, bottom diameter 30 - 300 μm, tip diameter less than 10 μm, and the center distance between adjacent microneedles is preferably 200 - 2000 μm. The size of the hollow channel 13 is limited by the size of the microneedle array 12, and the side wall thickness between the hollow channel and the microneedle is preferably 20 - 400 μm. The size of the liquid reservoir 14 is set according to the overall size of the substrate matrix 11 and the microneedle array 12, and it is characterized by being smaller than the overall size of the substrate matrix 11 and larger than the overall size of the microneedle array 12; the size of the drug delivery port 15 depends on the size of the liquid injection hose used subsequently.

[0040] Example 2 This embodiment provides a specific implementation method of the flexible hollow electrostimulation electrode array device. To fabricate the flexible hollow electrostimulation electrode array device in Example 1, the following steps are included: Processing the surface layer of the substrate matrix, processing a plurality of through holes 111 on the flexible substrate matrix, and processing a plurality of conductive leads 112 on the surface of the substrate matrix. The plurality of conductive leads 112 respectively correspond to the plurality of through holes 111; Furthermore, as Figure 8 and Figure 9 shown, in the process of processing the conductive leads 112, processes such as photolithography, development, and coating can be adopted for processing, and the through holes 111 can be processed by processes such as mechanical drilling, laser drilling, and etching; specifically, the materials of the surface layer of the substrate matrix include but are not limited to flexible materials such as polyimide and polyethylene terephthalate.

[0041] Additive manufacturing of the microneedle array 12, as Figure 10 shown, several microneedle electrode substrates 121 with different heights are constructed from bottom to top through 3D printing technology in alignment with the through holes 111 on the upper surface of the surface layer of the substrate matrix; Coating of the microneedle array 12, as Figure 11 shown, covering the upper surface of the surface layer of the substrate matrix with the first mask plate. The unobstructed part of the first mask plate is the area where the microneedle electrode substrates 121 are located. A conductive thin layer is deposited on the unobstructed part of the first mask plate by vacuum coating process, and the first mask plate is removed after completion; Depositing an insulating layer, as Figure 12 shown, the overall is covered with an insulating layer by vacuum vapor deposition process or dip coating process; Reactive ion etching, as Figure 13 and Figure 14As shown, the second mask 002 is nested on the upper surface of the substrate matrix surface layer. The second mask 002 only exposes the tip part of the microneedle electrode matrix 121, shields all other surfaces, and fills the liquid polyethylene glycol between the second mask 002 and the microneedle electrode matrix 121. After filling, the polyethylene glycol is cured. The reaction ion etching process is used to remove the insulating layer of the exposed tip part of the microneedle electrode matrix 121. After the etching is completed, the second mask 002 is removed, and at the same time, the polyethylene glycol is liquefied to remove the polyethylene glycol.

[0042] Further, the second mask 002 is a sleeve, and the sleeve is sleeved outside the microneedle electrode matrix 121. The height of the sleeve is slightly lower than the height of the microneedle electrode matrix 121. For example, the height of the microneedle electrode matrix 121 is 50-100 μm higher than the sleeve. After filling the liquid polyethylene glycol in the sleeve, the liquid polyethylene glycol is cured, so that only the tip of the microneedle electrode matrix 121 is exposed, which is convenient for etching. At the same time, it can avoid etching other parts of the microneedle electrode matrix 121 during the etching process. Specifically, since the microneedle electrode matrix 121 in the microneedle array 12 provided in this application has different heights, and during the window opening (that is, etching the tip of the microneedle electrode matrix to expose the internal conductive part), the microneedle tips with the same height need to be exposed. The traditional mask is usually a plate covering the tip of the microneedle electrode matrix, covering the tip of the microneedle electrode matrix 121 before depositing the insulating layer, and the depth of penetration of the tip is the exposed height. Through the shielding of the mask, the tip part is not deposited with the insulating layer and the conductive layer is exposed. However, this mask is obviously not suitable for the microneedle electrode matrix 121 with different heights in this application. Therefore, this application adopts a unique sleeve structure, and uses 3D printing to print sleeves with a preset height on the outer circumference of each microneedle electrode matrix 121, so that sleeves with different heights can be printed according to the heights of different microneedle electrode matrix 121. This method greatly reduces the design difficulty of the mask, can adapt to the etching of microneedle electrode matrix 121 with different heights, ensures the shielding of the parts of the microneedle electrode matrix 121 that do not need to be etched, ensures the uniform consistency of window opening, can improve the equality during signal array analysis, and avoids signal aliasing or large spatial positioning errors caused by the size differences of the microneedle electrode matrix 121.

[0043] In this embodiment, before depositing the insulating layer, there is also a plating step. The plating process is to put the hollow electroporation microneedle array 12 electrodes that have completed surface metallization into the plating solution, connect all the electrode leads to the cathode of the power supply device, and connect the anode of the power supply device to the plating metal electrode or the inert electrode, and plate a 2-10 μm conductive layer on the surface of the conductive thin layer deposited by the coating process.

[0044] In this embodiment, there is also a step of processing the flexible substrate 11, such asFigure 15 and Figure 16 As shown in Figure 16 , the main mold is 3D printed, and then the negative mold is obtained through the mold turning process. Then, the flexible substrate 11 with the liquid storage pool 14 is obtained through the mold turning process. The lower surface of the substrate matrix surface after reactive ion etching is bonded to the flexible substrate 11 to complete the preparation of the entire electrostimulation electrode array device.

[0045] After considering the specification and practicing the embodiments of the present application, those skilled in the art will readily conceive of other embodiments of the present application. The present application is intended to cover any variations, uses, or adaptations of the present application, which follow the general principles of the present application and include known common knowledge or conventional technical means in the technical field not claimed in the present application. The specification and embodiments are only regarded as exemplary, and the true scope and spirit of the present application are pointed out by the appended claims.

Claims

1. A flexible hollow electrical stimulation electrode array device, comprising a flexible substrate and a microneedle array, characterized in that: A drug delivery channel is provided in the flexible substrate; The microneedle array is disposed on the flexible substrate, and the microneedle array includes a plurality of microneedles, and at least some of the microneedles have different heights, so that the microneedles can penetrate into the tissue at different depths; The lead end of the microneedle is used to be electrically connected to a detection device and an electric pulse generating device; The microneedle has a hollow channel, one end of the hollow channel is opened at the tip of the microneedle, and the other end is opened to connect to the drug delivery channel; A plurality of independent conductive leads are arranged on the flexible substrate, and the plurality of conductive leads are electrically connected to the lead ends of the plurality of microneedles respectively. The other ends of the conductive leads extend out of the flexible substrate for being electrically connected to the detection device and the electric pulse generating device.

2. The flexible hollow electrical stimulation electrode array device according to claim 1, wherein In the microneedle array, at least some of the microneedles in the first direction have different heights, and at least some of the microneedles in the second direction have different heights; or In the second direction, the heights of the plurality of microneedles gradually change.

3. The flexible hollow electrostimulation electrode array device according to claim 1, wherein The lead ports of the conductive leads are combined into three buses, which are respectively connected to three electrodes of the electric pulse generating device to control the corresponding microneedle electrodes to change between the anode and the cathode.

4. The flexible hollow electrostimulation electrode array device according to claim 3, wherein The lead wire ports of the conductive leads of the microneedles in the same row are gathered on the same bus, and the conductive leads of the microneedles in two adjacent rows are gathered on different busses.

5. The flexible hollow electrical stimulation electrode array device according to claim 3, wherein The bus line where the conductive leads connected to any one of the plurality of microneedles are located is different from the bus line where the conductive leads connected to the surrounding adjacent microneedles are located.

6. The flexible hollow electrical stimulation electrode array device according to claim 1, wherein The needle body of the microneedle structure is provided with a barb structure for limiting the position of the flexible hollow electrical stimulation electrode array device in human tissue.

7. A preparation method of a flexible hollow electrical stimulation electrode array device, characterized in that, The following steps are involved: Processing the surface layer of the substrate base, processing a plurality of through holes on the flexible substrate base, and processing a plurality of conductive leads on the surface of the substrate base, wherein the plurality of conductive leads correspond to the plurality of through holes respectively; Additive manufacturing of microneedle arrays, using 3D printing technology to build a number of microneedle electrode matrices of different heights from bottom to top on the upper surface of the substrate matrix layer aligned with the through holes; Microneedle array coating, covering the upper surface of the substrate base surface layer with a first mask plate, the portion not covered by the first mask plate is the area where the microneedle electrode base is located, and using a vacuum coating process to deposit a conductive thin layer on the portion not covered by the first mask plate, and removing the first mask plate after completion; Depositing an insulating layer, using a vacuum vapor deposition process or a pulling coating process to cover the entire structure with an insulating layer; Reactive ion etching, embedding the second mask plate on the upper surface of the substrate base surface layer, the second mask plate only exposes the tip of the microneedle electrode base and shields all other surfaces, and filling liquid polyethylene glycol between the second mask plate and the microneedle electrode base. After filling, the polyethylene glycol is solidified, and the insulating layer of the exposed tip of the microneedle electrode base is removed by reactive ion etching process. After etching is completed, the second mask plate is removed, and the polyethylene glycol is liquefied and removed.

8. The preparation method according to claim 7, characterized in that, Before depositing the insulating layer, the method further comprises the following steps: Electroplating: The hollow electroperforated microneedle array electrodes with surface metallization completed are placed in the electroplating solution. All electrode leads are connected to the cathode of the power supply device, and the anode of the power supply device is connected to the coating metal electrode or the inert electrode. A 2 - 10 μm conductive layer is electroplated on the surface of the conductive thin layer deposited by the coating process.

9. The preparation method according to claim 8, characterized in that, It also includes the following steps: Processing the flexible substrate, 3D printing the master mold, obtaining the negative mold through the mold - turning process, then obtaining the flexible substrate with a liquid reservoir through the mold - turning process, and attaching the lower surface of the substrate matrix surface after reactive ion etching to the flexible substrate to complete the preparation of the electro - stimulation electrode array device.

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