CN116636853B - Implanted micro-needle electrode array device, production method and nerve interface system - Google Patents
Implanted micro-needle electrode array device, production method and nerve interface system Download PDFInfo
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Abstract
The application provides an implanted micro-needle electrode array device, a production method and a nerve interface system, wherein the implanted micro-needle electrode array device constructs an insulating substrate and a plurality of insulating micro-needle matrixes into an integrated communication structure by adopting the same insulating material, has enough mechanical strength and fracture toughness far higher than that of the existing silicon-based implanted micro-needle electrode array, is enough to easily invade cerebral cortex, has low fracture risk and greatly improves biological safety; on the basis, a channel for signal transmission, which is formed by the first conductive layer, the first conductive disc, the through hole conductive film and the second conductive disc, of the microneedle electrode tip for signal acquisition is also constructed, and the signal acquisition and transmission functions of the microneedle electrode array are realized.
Description
Technical Field
The application relates to the technical field of invasive nerve interfaces, in particular to an intracutaneous implanted micro-needle electrode array device, a production method of the micro-needle electrode array device and an implanted nerve interface system with the micro-needle electrode array device.
Background
The implantable brain cortex internal invasive nerve electrode can collect action potential emitted by single neurons and local field potential from brain neuron clusters, has highest signal space-time resolution, can realize the complex fine decoding capability of far-beyond non-invasive (such as scalp electroencephalogram) electrodes and semi-invasive (such as cortex electroencephalogram) electrodes, and has an irreplaceable position in the fields of neuroelectrophysiology research and high-performance brain-computer interfaces.
The Utah electrode with the silicon microneedle array as a core structure is the only brain-computer interface which passes the U.S. FDA authentication and is successfully implanted in the human brain, has mature technology, small size, high signal resolution and low damage to tissues, and has shown a plurality of attractive achievements in implantation verification of non-human primates and human beings. Since 2004, multiple research institutions at home and abroad realize complex brain-computer interface functions of human subjects through a neural interface system of Utah electrodes, including controlling a computer cursor by a paralyzed patient through 'ideas', manipulating a mechanical arm/prosthesis and obtaining tactile feedback by stimulating a tactile cortex, enabling a completely blocked gradually frozen patient to resume communication with the outside in spelling, writing, speech synthesis and the like, and enabling the blind to resume light perception and the like by stimulating a visual cortex.
However, for the aspect of truly long-term clinical application, the invasive nerve interface represented by the Utah electrode has limitations on the electrode and the signal transmission mode, cannot meet the requirements of clinical performance and long-term implantation, stays in the clinical experimental stage all the time, and mainly has the following problems that are difficult to overcome: (1) Silicon is a brittle material, the silicon microneedle structure with high depth-to-width ratio is extremely fragile, and is easy to break in implantation and application, and long-term biocompatibility is to be verified; (2) The manufacturing of the microneedle electrode array is based on a silicon batch processing technology, the structure and the geometric parameters of the microneedle electrode array are relatively fixed, and the microneedle electrode array cannot be customized for different patients, brain areas and applications, so that the optimization of the performance is limited; (3) Most invasive neural interface systems employ wired connections, with the interconnection lines being noisier. More importantly, all percutaneous wires and interfaces can not overcome the infection problem, and thus, the practical application is greatly restricted; (4) A few wireless systems implanted in the brain are limited by narrow intracranial space, and the requirements of most brain-computer interface system performances cannot be met due to insufficient information transmission quantity, transmission distance and duration, and the requirements of high-flux brain information long-time transmission cannot be met due to narrow application range.
Disclosure of Invention
Therefore, the technical problem to be solved by the application is to overcome the defect that the silicon-based implanted micro-needle electrode array is easy to break in implantation and application in the prior art, so as to provide the intra-cortical implanted micro-needle electrode array device which is not easy to break in implantation and application.
The application solves the other technical problem that the manufacturing of the micro-needle electrode array based on the silicon batch processing technology in the prior art has relatively fixed structure and geometric parameters, can not be customized for different patients, brain areas and applications, and limits the defect of performance optimization, thereby providing the device with the structure and geometric parameters capable of being customized individually according to different application requirements.
The application aims to solve the technical problems that the implanted nerve interface system in the prior art adopts wired connection, the noise of interconnection lines is large, and all percutaneous connection lines and interfaces can not overcome the infection problem, and the defect of great restriction on practical application is formed, so that the implanted nerve interface system which is completely implanted under the skin is provided.
To this end, a first aspect of the present application provides an intracutaneous implanted microneedle electrode array device comprising
An insulating substrate board having a plurality of through holes formed therein to penetrate the first and second surfaces thereof;
the insulation microneedle matrix array comprises a plurality of slender insulation microneedle matrixes, is arranged on the first surface of the insulation substrate base plate, and is of an integral communication structure made of the same insulation material with the insulation substrate base plate;
the first conductive layer is coated on the outer side of the insulating microneedle matrix array, and a first conductive disc is formed at the joint of the root of each insulating microneedle matrix and the first surface of the insulating substrate;
a second conductive layer including a plurality of second conductive pads provided on the second face of the insulating substrate base in the same number as the first conductive pads, at least one of the second conductive layer and the first conductive layer extending toward the through hole to form a conductive film for electrically connecting the first conductive pad and the second conductive pad on an inner wall of the through hole;
and the insulating layer is coated on the outer side of the first conductive layer and extends to cover the whole first surface of the insulating substrate base plate, and the first conductive layer at the needle point of the insulating microneedle base body is exposed from the insulating layer.
Optionally, the plurality of insulating microneedle matrixes and the insulating substrate are integrally formed by adopting a high-precision 3D printing technology.
Optionally, the conductive area of the conductive layer at the tip of the insulating microneedle matrix is similar to the dimension of a single neuron implanted in the brain of the object, so as to realize the nerve signal acquisition resolution of the single cell.
Optionally, the through hole is a cylinder with a vertical inner wall, a round table with an inclined inner wall or a cylinder with a hyperboloid inner wall.
Optionally, the surface modification layer is arranged on the outer side of the conductive layer at the tip of the insulating microneedle matrix and used for enhancing the contact between the conductive layer and the biological interface so as to reduce the contact resistance.
Optionally, the surface modification layer comprises a drug release material that is degradable within the brain skin layer and releases the drug.
Optionally, the insulating substrate is formed into a solid structure including a plurality of the through holes; the through holes and the root of the insulating microneedle matrix are arranged in a staggered manner in the horizontal direction.
Optionally, the first conductive pad and/or the second conductive pad is circular, oval, rectangular or intersecting circular.
Optionally, the insulating material is an insulating polymer material.
Alternatively, the microneedle electrode has a high aspect ratio, the root diameter of the microneedle electrode is 30-300 μm, the tip diameter is less than 50 μm, and the height is 100 μm-10mm; and/or, the center-to-center distance between adjacent microneedle electrodes is 200 μm-1mm.
The second aspect of the present application provides a method for producing an intracutaneous implanted microneedle electrode array device, comprising the steps of:
s1, insulating microneedle array additive manufacturing: an integrated communication structure of an insulating substrate and an insulating micro-needle matrix array is manufactured by using an additive manufacturing process, wherein the insulating substrate and the insulating micro-needle matrix array are made of the same insulating material, and a plurality of through holes penetrating through a first surface and a second surface of the insulating substrate are formed in the insulating substrate;
s2, coating a first conductive layer: conducting layer coating is conducted on the insulating micro-needle matrix in the step S1, and the insulating micro-needle matrix extends to the joint of the root of the insulating micro-needle matrix and the first surface of the insulating substrate board to form a first conducting disc;
s3, coating a second conductive layer: conducting layer coating is conducted on the second surface of the insulating microneedle substrate obtained in the step S2, so that second conducting discs with the same number as the first conducting discs are formed on the second surface; in step S3 and/or step S2, when the first conductive layer and/or the second conductive layer is coated, the first conductive layer and/or the second conductive layer extends to the inner wall of the through hole to form a conductive film on the inner wall of the through hole for electrically connecting the first conductive pad and the second conductive pad;
S4, depositing an insulating layer: performing insulation layer deposition on the microneedle array obtained in the step S2 or the step S3, so that the insulation layer covers the outer layers of all the microneedles and extends to cover the whole first surface of the microneedle array;
s5, etching the insulating layer: an etching process is used to remove the insulating layer at the tip of the insulating microneedle substrate to expose the first conductive layer from the insulating layer.
Optionally, in step S1, the additive manufacturing process is a high precision 3D printing technique.
Optionally, step S2 includes:
s21, embedding a prepared first mask plate on an insulating microneedle matrix array, covering a first surface of the insulating substrate base plate, arranging the first mask plate to have a hollowed-out hole array structure, exposing the root parts and the through holes of the insulating microneedle matrix, and depositing a first conductive layer on the surface of the composite body by adopting a vacuum coating process;
s22, removing the first mask plate, coating a first conductive layer on the surface of the insulating micro-needle matrix, and manufacturing a first conductive disc at the joint of the root of the insulating micro-needle matrix and the insulating substrate base plate, wherein the through hole is positioned in the first conductive disc.
Optionally, step S3 includes:
s31, covering a second mask plate on the second surface of the insulating substrate, wherein the second mask plate is provided with a hollowed-out hole array structure, so that the through holes on the insulating substrate are exposed, and a second conductive layer is deposited on the surface of the assembly by adopting a vacuum coating process;
S32, removing the second mask plate, and manufacturing a second conductive disc on the second surface of the insulating substrate, wherein the through hole is positioned in the second conductive disc;
in step S21 and/or step S31, the conductive layer is extended to the inside of the through hole exposed to the outside when the conductive layer is deposited on the surface of the respective combination body so that the inner wall of the through hole is covered with the conductive film for connecting the first conductive pad and the second conductive pad.
Optionally, the step S4 includes:
s41, covering a third mask plate on the second surface of the insulating substrate, wherein the third mask plate has no hollowed-out structure, and depositing an insulating layer on the surface of the composite body by adopting a vacuum vapor deposition process or a lifting coating process;
s42, removing the third mask plate, wherein all the other surfaces except the second surface of the insulating substrate are coated with insulating materials.
Optionally, the step S5 includes:
s51, a fourth mask plate is nested on the micro-needle array, the fourth mask plate is provided with a hollowed hole array structure, the fourth mask plate is fixed on the tip of the micro-needle array, only the tip of the micro-needle array is exposed, other structures below the micro-needle array are shielded, and a reactive ion etching process is adopted to remove the tip insulating layer exposed above the fourth mask plate;
S52, removing the fourth mask plate to form a microneedle electrode structure with conductive tips and insulated other needle bodies.
Optionally, in step S1, the formed through holes are offset from the root of the insulating microneedle substrate.
A third aspect of the application provides an implantable neural interface system comprising
The device is suitable for being implanted into the cerebral cortex to collect nerve signals;
the multichannel nerve signal processing chip is integrated with the in-cortex implanted micro-needle electrode array device into an interconnection packaging structure and is used for carrying out in-situ amplification, filtering, noise elimination and analog-to-digital conversion treatment on the nerve signals acquired by the in-cortex implanted micro-needle electrode array device;
the post-processing module is suitable for being implanted into a subclavian clearance area, receives and processes the digital signals processed by the multichannel neural signal processing chip, and is also used for wirelessly transmitting data to an external instrument, wirelessly receiving external instructions, transmitting an electric stimulation signal to the micro-needle electrode array device implanted in the cortex and wirelessly charging.
Optionally, the device further comprises an intracutaneous connection wire, wherein the intracutaneous connection wire is suitable for being buried in a subcutaneous tunnel, one end of the intracutaneous connection wire is connected with the interconnection packaging structure, the other end of the intracutaneous connection wire is connected with the post-processing module, and the intracutaneous connection wire is used for transmitting the digital signals processed by the multichannel nerve signal processing chip to the post-processing module.
Optionally, the microneedle electrodes are connected with the multichannel neural signal processing chip through a flip-chip bonding technology, the microneedle electrodes are in one-to-one correspondence with the input ends of the bare chips of the multichannel neural signal processing chip, and are electrically communicated through solder balls, and gaps are completely filled by insulating glue; the insulating substrate base plate and the multichannel neural signal processing chip are integrally packaged in a shell, a peripheral circuit board and an output interface which are required by the operation of the multichannel neural signal processing chip are contained in the shell, and the output interface is connected with the Pi Nalian wiring.
The technical scheme provided by the application has the following advantages:
1. compared with the silicon-based implanted microneedle electrode array in the prior art, the device provided by the application is a brand-new implanted microneedle electrode array device, firstly, the integrated communication structure made of the same insulating material is adopted by the insulating substrate and the insulating microneedle matrix array, and compared with the silicon-based microneedle array in the prior art, the mechanical strength and toughness are greatly improved, so that the device can easily invade cerebral cortex, has low fracture risk and greatly improves the biosafety; in addition, the device for embedding the microneedle electrode array into the cortex, provided by the application, also constructs a channel for signal transmission, which is formed by the first conductive layer, the first conductive disc, the through hole conductive film and the second conductive disc of the microneedle electrode, of signals collected by the tip of the microneedle electrode, and realizes the signal collection and transmission functions of the microneedle electrode array.
2. According to the device for embedding the microneedle electrode array in the cortex, disclosed by the application, the insulating substrate and the plurality of insulating microneedle matrixes are integrally formed by adopting a high-precision 3D printing technology, complex micro-nano processing process steps such as physical isolation, static/dynamic silicon wet etching and ultra-high step photoetching which are necessary for a silicon-based microneedle electrode array are not involved, the flexibility of process parameters is strong, the structures and geometric parameters such as the length, the number, the layout and the shape of the electrodes can be adjusted according to application requirements, and personalized customization can be performed for different patients and different brain areas.
3. The application provides a cortical-embedded microneedle electrode array device, wherein the inner wall of a through hole is a truncated cone with an inclined plane or a hyperboloid column. When the second conductive layer of the inner wall of the through-hole is manufactured by using a vacuum plating process, the design has the outstanding advantage of being beneficial to the step coverage characteristic of the plating layer and enhancing the reliability of the first conductive pad and the second conductive pad capable of being electrically conducted through the through-hole.
4. The micro-needle electrode further comprises a surface modification layer of the tip electrode point, and the surface modification layer can be made of conductive polymers or platinum black and the like with nano rough structures, so that the contact of an electrode-biological interface can be remarkably enhanced, and the contact impedance is greatly reduced.
5. According to the implanted nerve interface system provided by the application, the microneedle electrode array and the multichannel nerve signal processing chip are integrated and interconnected at the near end, so that intracranial in-situ low-noise signal processing is realized, the subcutaneous connecting wire transmits digital signals which are not easy to interfere, the transmission distance is short, and the problem that high noise is introduced by a long interconnecting wire is avoided.
6. The implanted nerve interface system provided by the application has the advantages that the whole system is implanted into the body, no percutaneous connection or interface is needed, the battery is not needed to be replaced by operation, and the risks of infection and secondary injury can be obviously avoided. Meanwhile, the subclavian space is provided with a far-beyond intracranial space, so that the size and power consumption limitation imposed by the post-processing module are reduced, high-performance data processing and wireless communication can be realized, and long-time endurance and wireless charging of a large battery are supported.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present application, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic diagram of a device with two micro-needle electrode arrays implanted in the cortex under different angles of view;
FIG. 2 is a side view and a partial enlarged view of the microneedle array device of FIG. 1;
FIG. 3 is a detail view and a vertical cross-section of a microneedle electrode;
FIG. 4 is a top and bottom view of the microneedle array device of FIG. 1;
FIG. 5 is a schematic diagram of the structure of three different first conductive pads;
FIG. 6 is a schematic view of two different via shapes;
FIG. 7 is a detail view and a vertical section view of a tip of a microneedle electrode comprising a surface modification layer;
FIG. 8 is a schematic diagram of an electrode-biological interface equivalent circuit model;
FIG. 9 is a block diagram of a microneedle array apparatus of varying microneedle numbers;
FIG. 10 is a block diagram of a microneedle array device of different microneedle electrode array shapes;
FIG. 11 is a schematic structural view of an implantable neural interface system based on a microneedle electrode array;
FIG. 12 is a vertical cross-sectional view of an integrated interconnect structure of a microneedle electrode array device and a multichannel neural signal processing chip;
fig. 13 is a process flow diagram of a method of manufacturing an intra-cortical implanted microneedle electrode array device.
Reference numerals illustrate:
1-microneedle electrode array, 11-insulating substrate, 12-microneedle electrode, 121-insulating microneedle matrix, 122-first conductive layer, 123-insulating layer, 124-surface modification layer, 13-first conductive disk, 15-second conductive disk, 14-through hole, 141-conductive film; 161-a first mask plate; 162-a second mask; 163-a third mask; 164-a fourth mask plate;
2-multichannel nerve signal processing chip, 21-bare chip, 22-solder ball, 23-insulating adhesive and 24-shell;
3-Pi Nalian wiring;
4-post-processing module.
Detailed Description
The following description of the embodiments of the present application will be made apparent and fully in view of the accompanying drawings, in which some, but not all embodiments of the application are shown. All other embodiments, which can be made by those skilled in the art based on the embodiments of the application without making any inventive effort, are intended to be within the scope of the application.
In the description of the present application, it should be noted that the directions or positional relationships indicated by the terms "center", "upper", "lower", "left", "right", "vertical", "horizontal", "inner", "outer", etc. are based on the directions or positional relationships shown in the drawings, are merely for convenience of describing the present application and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a specific orientation, be configured and operated in a specific orientation, and thus should not be construed as limiting the present application. Furthermore, the terms "first," "second," and "third" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance.
In the description of the present application, it should be noted that, unless explicitly specified and limited otherwise, the terms "mounted," "connected," and "connected" are to be construed broadly, and may be either fixedly connected, detachably connected, or integrally connected, for example; can be mechanically or electrically connected; can be directly connected or indirectly connected through an intermediate medium, and can be communication between two elements. The specific meaning of the above terms in the present application will be understood in specific cases by those of ordinary skill in the art.
In addition, the technical features of the different embodiments of the present application described below may be combined with each other as long as they do not collide with each other.
FIG. 1 is a schematic diagram of a device with two micro-needle electrode arrays implanted in the cortex under different angles of view; as shown in fig. 1, the intracutaneous implanted microneedle electrode array device mainly comprises: an insulating substrate base 11, an insulating microneedle matrix array, a first conductive layer 122, a second conductive layer, and an insulating layer 123. Wherein,
the insulating base substrate 11 has a plurality of through holes 14 formed therein to penetrate the first surface and the second surface. In some embodiments, the first face is an upper surface of the insulating substrate 11, and correspondingly, the second face is a lower surface of the insulating circular substrate 11. Of course, in other embodiments, the reverse may be provided. The number of through holes 14 is identical to that of the insulating microneedle base 121, and the through holes are independent and not communicated with each other on the insulating substrate.
The insulating microneedle array comprises a plurality of slender insulating microneedle matrixes 121, the number of the insulating microneedle matrixes is consistent with that of the through holes, the insulating microneedle matrixes are arranged on the first surface of the insulating substrate, and the insulating microneedle array and the insulating substrate 11 are of an integral communication structure made of the same insulating material.
The first conductive layer 122 is coated on the outer side of each insulating microneedle matrix of the insulating microneedle matrix array, and forms a first conductive disc 13 at the connection position of the root of each insulating microneedle matrix and the first surface (upper surface) of the insulating substrate base plate, that is, the number of the first conductive discs is consistent with that of the insulating microneedle matrixes.
The second conductive layer includes a plurality of second conductive pads 15 provided on the second face (lower surface) of the insulating base plate in the same number as the first conductive pads, and at least one of the second conductive layer and the first conductive layer extends toward the through hole to form a conductive film 141 for electrically connecting the first conductive pads and the second conductive pads on an inner wall of the through hole. In some embodiments, the conductive film 141 is formed such that the first conductive layer extends toward the inside of the via hole to be formed on the inner wall of the via hole; in other embodiments, the conductive film 141 is formed such that the second conductive layer extends toward the inside of the via hole to be formed on the inner wall of the via hole; in still other embodiments, the conductive film 141 is formed by extending the first conductive layer and the second conductive layer from the upper and lower directions toward the inside of the via hole, respectively. How the conductive layer extends into the interior of the via will be described in detail below.
The insulating layer is coated on the outer side of the first conductive layer and extends to cover the whole first surface of the insulating substrate base plate, and the first conductive layer at the needle point of the insulating microneedle base body is exposed from the insulating layer.
When the micro-needle electrode is used, signals collected by the tip ends of the micro-needle electrodes can be conducted through a signal conduction path formed by the first conductive layer of the outer layer of the insulating micro-needle matrix, the first conductive disc positioned on the first surface of the insulating micro-needle matrix, the conductive film on the inner wall of the through hole and the second conductive disc positioned on the second surface of the insulating micro-needle matrix.
In the present application, the first conductive plate and the second conductive plate are preferably disk-shaped, but may be other than disk-shaped in other embodiments, for example, may be customized to be columnar, spherical, or other regular or irregular solid shapes.
Compared with the silicon-based implanted microneedle electrode array in the prior art, the device provided by the application is a brand-new implanted microneedle electrode array device, firstly, the integrated communication structure made of the same insulating material is adopted by the insulating substrate and the insulating microneedle matrix array, and compared with the silicon-based microneedle array in the prior art, the mechanical strength and toughness are greatly improved, so that the device can easily invade cerebral cortex, has low fracture risk and greatly improves the biosafety; in addition, the device for embedding the microneedle electrode array into the cortex, provided by the application, also constructs a channel for signal transmission, which is formed by the first conductive layer, the first conductive disc, the through hole conductive film and the second conductive disc of the microneedle electrode, of signals collected by the tip of the microneedle electrode, and realizes the signal collection and transmission functions of the microneedle electrode array.
As a preferred embodiment, the microneedle electrodes 12 have a high aspect ratio with a root diameter of 30-300 μm, a tip diameter of less than 50 μm, a length of 100 μm-10 mm, and a distance between adjacent microneedle centers of 200 μm-1 mm.
Preferably, in some embodiments, the insulating substrate base is integrally formed with the plurality of insulating microneedle matrices using high precision 3D printing techniques. The insulating substrate base plate and the insulating microneedle matrix array are integrally formed through the high-precision 3D printing technology, complex micro-nano processing process steps such as physical isolation, static/dynamic silicon wet etching and ultra-high step photoetching which are necessary for the silicon-based microneedle electrode array are not involved, the flexibility of process parameters is high, the length, the number, the layout, the shape and other structural and geometric parameters of the electrodes can be adjusted according to application requirements, and personalized customization can be carried out for different patients and different brain areas.
In some embodiments, as shown in fig. 2, the insulating microneedle substrate and the through hole are arranged in a staggered manner in the transverse direction, so that the bottom of the insulating microneedle substrate is of a solid structure, the mechanical strength of the insulating microneedle substrate is further improved, the through hole is formed on one side close to the bottom of the insulating microneedle substrate, and the volume of the micro-needle electrode array device implanted in the cortex is reduced as much as possible while the electrical path is ensured. It should be noted that, in the preferred embodiment of the present application, the through holes and the root portions of the insulating microneedle substrates are completely staggered, so that the strength of the insulating microneedle substrates can be ensured to be maximized, but in some other embodiments, the through holes and the root portions of the insulating microneedle substrates may be arranged to be semi-staggered, and the specific arrangement mode is adjusted according to actual requirements.
Fig. 3 shows a detailed structure and a cross-sectional view of the microneedle electrode 12, including an insulating microneedle substrate 121, a first conductive layer 122, and an insulating layer 123. The insulating microneedle substrate 121 is made of a polymer material, and is processed by a high-precision 3D printing technology together with the insulating substrate 11, and its structure and geometric parameters can be customized individually according to different application requirements. The insulating material is further preferably an insulating polymer material, and further preferably an insulating polymer material including a photosensitive resin. The first conductive layer 122 is a conductive material with high biocompatibility, such as titanium, gold, platinum iridium alloy, iridium oxide, etc., and is in electrical communication with the first conductive pad 13. The insulating layer 123 is a highly biocompatible insulating material such as parylene, polyimide, polyurethane, polytetrafluoroethylene, etc. The insulating layer 123 entirely covers the portions except the tips (several micrometers to several tens micrometers) of the microneedle electrodes 12 and extends to the upper surface of the insulating substrate base plate 11 so that the needle bodies of the microneedle electrodes 12, the first conductive pads 13, and the inner wall conductive layers 141 of the through holes 14 are covered with the insulating layer. When the microneedle electrode array is implanted into the brain skin, only the tip of the microneedle electrode 12 is made of exposed conductive material, and the conductive area is similar to the size of a single neuron, so that single-cell-level nerve signal acquisition resolution is realized.
It should be noted that the present application is not limited to the insulating material being a polymer material, and in other embodiments, the insulating material may be a non-polymer insulating material.
Fig. 4 shows a top view and a bottom view of a microneedle electrode array. It should be noted that the relative positions of the microneedle electrode 12, the first conductive pad 13, the via hole 14, and the second conductive pad 15 are not limited to those shown in the drawings, and the outline of the first conductive pad 13 does not necessarily completely surround the microneedle electrode 12 and the via hole 14, and the outline of the second conductive pad 15 does not necessarily completely surround the via hole 14, as long as the interconnection of the conductive structures is satisfied.
In other embodiments of the microneedle electrode array, as shown in fig. 5, the shape of the first conductive disk 13 is not limited to a circle, and may be elliptical, rectangular, intersecting circular (gourd-shaped), or other shapes, depending on the geometric design of the electrode array and the matching requirements of the manufacturing process. Similarly, the shape of the second conductive plate 14 is not limited to the circular shape shown in fig. 2.
In other embodiments of microneedle electrode arrays, as shown in fig. 6, the through-holes 14 are not limited to cylinders with vertical sidewalls, which may be beveled or hyperboloid. When the hole inner wall conductive layer 141 is manufactured using a vacuum plating process, a prominent advantage of this design is to facilitate the step coverage characteristic of the plating layer, enhancing the reliability with which the first conductive pad 13 and the second conductive pad 14 can be electrically conducted through the through hole 14.
In other embodiments of the microneedle electrode array, as shown in fig. 7, the microneedle electrode 12 further comprises a surface modification layer 124 of a tip electrode point, which may be a conductive polymer with a nano-roughened structure or platinum black, etc., so as to significantly enhance the contact of the electrode-biological interface and greatly reduce the contact resistance. As shown in fig. 8, the equivalent circuit model of the electrode-biological interface, vsignal is the original potential signal from the neuron, zcontact is the contact impedance of the electrode-biological interface, vinput is the actual potential signal picked up by the electrode and input to the signal processing system, and Zinput is the input impedance of the signal processing system. Zcontact and Zinput are in series connection, according to the voltage division principle shown in the following formula 1, when the input impedance Zinput of the signal processing system is fixed, the smaller the contact impedance Zcontact of the electrode-biological interface is, the less potential reduction is caused by the contact interface, and the more nerve signals can be picked up by the electrode and input into the signal processing system, so that the signal quality and the signal to noise ratio are improved.
Equation 1:，
in addition, the surface modification layer 124 can also be a drug release material, can be degraded in the cerebral cortex and release drugs, can inhibit local inflammatory reaction and immune reaction caused by electrode implantation, reduce the influence of inflammatory reaction and immune reaction on signal quality, and promote the long-term usability of the electrode.
As shown in fig. 9, in other embodiments of the microneedle electrode array, the number of microneedle electrodes 12 is not limited to 100 as shown in fig. 1, and may be arbitrarily customized to other numbers, such as 96, 36, 32, etc. The array is not limited to square arrays, and can be arbitrarily customized to other shapes, such as circular arrays, etc.
In other embodiments of the microneedle electrode array, as shown in fig. 10, the geometric parameters of the different microneedle electrodes 12 may be different, and fig. 10 illustrates several cases of different-length microneedle electrodes, and may be arbitrarily customized to various forms with different lengths, different diameters, different pitches, or different shapes according to the application requirements.
Fig. 11 shows an implantable neural interface system based on a microneedle electrode array, which comprises a microneedle electrode array 1, a multichannel neural signal processing chip 2, an intradermal connection 3 and a post-processing module 4. The whole system is implanted in the body, and no percutaneous connecting wire or interface is led out to external equipment. After the nerve signals are collected by the microneedle electrode array 1, in-situ amplification, filtering, noise elimination, analog-to-digital conversion and other treatments are realized in the multichannel nerve signal processing chip 2 which is integrated and interconnected with the electrode array, and the processed digital signals are transmitted to the post-processing module 4 implanted in the subclavian clearance area through the intradermal connection 3 buried in the subcutaneous tunnel. The post-processing module 4 contains a signal post-processing circuit (including but not limited to a data compression algorithm, a nerve signal classification and identification algorithm, a data packaging algorithm and the like), a microcontroller, a wireless signal transceiver, a power supply unit and the like, and can realize the functions of complex processing of nerve signals, wireless data transmission to an external instrument, wireless receiving of external instructions, sending of electrical stimulation signals to electrodes, wireless charging and the like.
Specifically, as shown in fig. 12, the section of the integrated interconnection structure of the microneedle electrode array 1 and the multichannel neural signal processing chip 2 is interconnected between the electrodes and the chip by a flip-chip bonding technology, the microneedle electrodes 12 are in one-to-one correspondence with the input ends of the chip die 21, and are electrically connected through solder balls 22, and the gaps are completely filled with insulating glue 23. The electrode insulating substrate 11 and the chip are integrally packaged in a shell 24, and a peripheral circuit board and an output interface required by the operation of the chip are contained in the shell, and are connected to a Pi Nalian wiring 3.
The implanted nerve interface system provided by the embodiment has the advantages that the whole system is implanted in the body, no percutaneous connecting wire or interface exists, the battery is not required to be replaced by an operation, and the risks of infection and secondary injury can be obviously avoided. Meanwhile, the subclavian space is provided with a far-beyond intracranial space, so that the size and power consumption limitation imposed by the post-processing module are reduced, high-performance data processing and wireless communication can be realized, and long-time endurance and wireless charging of a large battery are supported.
Fig. 13 shows a process flow of a method for producing an intracutaneous implanted microneedle electrode array device. The specific production method comprises the following steps:
s1, insulating microneedle array additive manufacturing: an additive manufacturing process is used, and an integrated communication structure of an insulating substrate base plate and an insulating microneedle matrix array is manufactured by adopting the same insulating material; forming a plurality of through holes penetrating through a first surface (upper surface) and a second surface (lower surface) of the insulating substrate on the insulating substrate in the formed integral communication structure; the insulating base substrate 11 and the plurality of insulating microneedle bodies 121 are integrally connected to each other by using an additive manufacturing process from bottom to top.
In step S1, an additive manufacturing process is adopted, so that the flexibility of technological parameters of the insulated microneedle array is high, the structures and geometric parameters such as the length, the number, the layout, the shape and the like of the electrodes can be adjusted according to application requirements, and personalized customization can be performed for different patients and different brain areas.
In some embodiments, the additive manufacturing process in step S1 uses high precision 3D printing techniques to make an insulated microneedle array with higher precision.
Additionally, in some embodiments, the shaped through holes are offset from the root of the insulating microneedle substrate. It should be noted that, in the preferred embodiment of the present application, the through holes and the root portions of the insulating microneedle substrates are completely staggered, so that the strength of the insulating microneedle substrates can be ensured to be maximized, but in some other embodiments, the through holes and the root portions of the insulating microneedle substrates may be arranged to be semi-staggered, and the specific arrangement mode is adjusted according to actual requirements.
S2, coating a first conductive layer: and (2) conducting layer coating is conducted on the insulating microneedle substrate in the step (S1) and extends to the connection position of the root of the insulating microneedle substrate and the first surface of the insulating substrate to form a first conducting disc.
The first conductive layer is formed on the surface of the insulating microneedle substrate by coating the surface of the insulating microneedle substrate with a conductive layer, and the first conductive layer is allowed to extend toward the junction of the root of the insulating microneedle substrate and the first face (upper surface) of the insulating substrate to form a first conductive pad connected to the first conductive layer at the root of the insulating microneedle substrate. It should be noted that the first conductive plate need not be disk-shaped, and in some embodiments, the first conductive plate may be cylindrical or have another shape.
In some embodiments, step S2 comprises:
s21, a prepared first mask plate 161 is nested on the insulating microneedle array substrate to cover the first surface of the insulating substrate base plate, the first mask plate is provided with a hollowed hole array structure, the root parts and the through holes of the insulating microneedle array substrate are exposed, and a first conductive layer is deposited on the surface of the assembly body by adopting a vacuum coating process.
The coverage area of the holes of the first mask plate is required to cover the root parts and the through holes of the insulating microneedle matrix, when the first mask plate is nested, the holes on the first mask plate are required to be nested at the root parts of the insulating microneedle matrix one by one and the through holes are exposed out of the holes, and then a first conductive layer is deposited on the surface of the combination body formed by the first mask plate and the insulating microneedle array by adopting a vacuum coating process;
s22, removing the first mask plate, and forming a first conductive disc by the first conductive layer deposited inside the holes of the first mask plate. Thus, the first conductive pad contains the insulating microneedle matrix and covers the via.
S3, coating a second conductive layer: conducting layer coating is conducted on the second surface of the insulating microneedle substrate obtained in the step S2, so that second conducting discs with the same number as the first conducting discs are formed on the second surface;
In some embodiments, step S3 comprises:
s31, covering a second mask plate 162 on the second surface of the insulating substrate, wherein the second mask plate is provided with a hollowed-out hole array structure, so that the through holes on the insulating substrate are exposed, and a second conductive layer is deposited on the surface of the assembly by adopting a vacuum coating process;
s32, removing the second mask plate, and manufacturing a second conductive disc on the second surface of the insulating substrate, wherein the through hole is positioned in the second conductive disc;
in step S21 and/or step S31, the conductive layer is extended to the inside of the through hole exposed to the outside when the conductive layer is deposited on the surface of the respective combination body so that the inner wall of the through hole is covered with the conductive film for connecting the first conductive pad and the second conductive pad.
Specifically, when the inner wall of the through hole is hyperboloid, in step S21, when the first conductive layer is deposited on the surface of the assembly by adopting the vacuum plating process, the first conductive layer is deposited on the upper part of the inner wall of the through hole to form the conductive layer; in step S31, when a second conductive layer is deposited on the surface of the assembly by using a vacuum plating process, the second conductive layer is deposited on the lower portion of the inner wall of the through hole to form a conductive layer, and the upper conductive layer and the lower conductive layer together form a conductive film. When the inner wall of the through hole is a circular table with an inclined surface, for example, the opening at the upper end of the through hole is large, the opening at the lower end is large, in step S21, when the first conductive layer is deposited on the surface of the assembly by using the vacuum plating process, only a small amount of conductive material is deposited on the upper portion of the inner wall of the through hole, and in step S31, when the second conductive layer is deposited on the surface of the assembly by using the vacuum plating process, the conductive material can be spread over the inner wall of the through hole along the inclined surface to form a conductive film due to the large opening at the lower end of the through hole.
S4, depositing an insulating layer: performing insulation layer deposition on the microneedle array obtained in the step S2 or the step S3, so that the insulation layer covers the outer layers of all the microneedles and extends to cover the whole first surface of the microneedle array;
in some embodiments, the step S4 includes:
s41, covering a third mask plate 163 on the second surface of the insulating substrate, wherein the third mask plate has no hollow structure, and an insulating layer is deposited on the surface of the combination body by adopting a vacuum vapor deposition process or a lifting film coating process;
s42, removing the third mask plate, wherein all the other surfaces except the second surface of the insulating substrate are coated with insulating materials.
S5, etching the insulating layer: an etching process is used to remove the insulating layer at the tip of the insulating microneedle substrate to expose the first conductive layer from the insulating layer.
In some embodiments, the step S5 includes:
s51, a fourth mask plate 164 is nested on the microneedle array, the fourth mask plate is provided with a hollowed hole array structure, the fourth mask plate is fixed at the tip of the microneedle array, only the range from a few micrometers to tens micrometers of the tip is exposed, other structures below the tip are shielded, and a reactive ion etching process is adopted to remove the tip insulating layer exposed above the fourth mask plate 164;
S52, removing the fourth mask plate to form a microneedle electrode structure with conductive tips and insulated other needle bodies.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. And obvious variations or modifications thereof are contemplated as falling within the scope of the present application.
Claims (16)
1. The production method of the intradermal-implantation type microneedle electrode array device is characterized by comprising the following steps of:
s1, insulating microneedle array additive manufacturing: an integrated communication structure of an insulating substrate and an insulating micro-needle matrix array is manufactured by using an additive manufacturing process, wherein the insulating substrate and the insulating micro-needle matrix array are made of the same insulating material, and a plurality of through holes penetrating through a first surface and a second surface of the insulating substrate are formed in the insulating substrate;
s2, coating a first conductive layer: conducting layer coating is conducted on the insulating micro-needle matrix in the step S1, and the insulating micro-needle matrix extends to the joint of the root of the insulating micro-needle matrix and the first surface of the insulating substrate board to form a first conducting disc;
S3, coating a second conductive layer: conducting layer coating is conducted on the second surface of the insulating microneedle substrate obtained in the step S2, so that second conducting discs with the same number as the first conducting discs are formed on the second surface; in step S3 and/or step S2, when the first conductive layer and/or the second conductive layer is coated, the first conductive layer and/or the second conductive layer extends to the inner wall of the through hole to form a conductive film on the inner wall of the through hole for electrically connecting the first conductive pad and the second conductive pad;
s4, depositing an insulating layer: performing insulation layer deposition on the microneedle array obtained in the step S2 or the step S3, so that the insulation layer covers the outer layers of all the microneedles and extends to cover the whole first surface of the microneedle array;
s5, etching the insulating layer: removing the insulating layer at the tip of the insulating microneedle substrate by adopting an etching process to expose the first conductive layer from the insulating layer;
the step S2 comprises the following steps:
s21, embedding a prepared first mask plate on an insulating microneedle matrix array, covering the first surface of the insulating substrate base plate, arranging the first mask plate to be provided with a hollowed-out hole array structure, exposing the root parts and the through holes of the insulating microneedle matrix, and depositing a first conductive layer on the surface of a combination body formed by the insulating microneedle matrix array and the first mask plate by adopting a vacuum coating process;
S22, removing the first mask plate, coating a first conductive layer on the surface of the insulating microneedle matrix, and manufacturing a first conductive disc at the joint of the root of the insulating microneedle matrix and the insulating substrate base plate, wherein the through hole is positioned in the first conductive disc;
the step S3 comprises the following steps:
s31, covering a second mask plate on the second surface of the insulating substrate, wherein the second mask plate is provided with a hollowed-out hole array structure, so that the through holes on the insulating substrate are exposed, and depositing a second conductive layer on the surface of a combination formed by the insulating substrate and the second mask plate by adopting a vacuum coating process;
s32, removing the second mask plate, and manufacturing a second conductive disc on the second surface of the insulating substrate, wherein the through hole is positioned in the second conductive disc;
in step S21 and/or step S31, the conductive layer is extended to the inside of the through hole exposed to the outside when the conductive layer is deposited on the surface of the respective combination thereof so that the inner wall of the through hole is covered with a conductive film for connecting the first conductive pad and the second conductive pad;
the step S4 includes:
s41, covering a third mask plate on the second surface of the insulating substrate, wherein the third mask plate has no hollow structure, and an insulating layer is deposited on the surface of an assembly formed by the insulating substrate and the third mask plate by adopting a vacuum vapor deposition process or a lifting film coating process;
S42, removing the third mask plate, wherein all the surfaces except the second surface of the insulating substrate are coated with insulating materials;
the step S5 comprises the following steps:
s51, a fourth mask plate is nested on the micro-needle array, the fourth mask plate is provided with a hollowed hole array structure, the fourth mask plate is fixed on the tip of the micro-needle array, only the tip of the micro-needle array is exposed, other structures below the micro-needle array are shielded, and a reactive ion etching process is adopted to remove the tip insulating layer exposed above the fourth mask plate;
s52, removing the fourth mask plate to form a microneedle electrode structure with conductive tips and insulated other needle bodies.
2. The method of claim 1, wherein in step S1, the additive manufacturing process is a high precision 3D printing technique.
3. The method of claim 1, wherein in step S1, the molded through holes are offset from the root portions of the insulating microneedle substrates.
4. An intra-cortical implant microneedle electrode array apparatus obtained by the method for producing an intra-cortical implant microneedle electrode array apparatus according to any one of claims 1 to 3, comprising
An insulating substrate board having a plurality of through holes formed therein to penetrate the first and second surfaces thereof;
the insulation microneedle matrix array comprises a plurality of slender insulation microneedle matrixes, is arranged on the first surface of the insulation substrate base plate, and is of an integral communication structure made of the same insulation material with the insulation substrate base plate;
the first conductive layer is coated on the outer side of the insulating microneedle matrix array, and a first conductive disc is formed at the joint of the root of each insulating microneedle matrix and the first surface of the insulating substrate;
a second conductive layer including a plurality of second conductive pads provided on the second face of the insulating substrate base in the same number as the first conductive pads, at least one of the second conductive layer and the first conductive layer extending toward the through hole to form a conductive film for electrically connecting the first conductive pad and the second conductive pad on an inner wall of the through hole;
and the insulating layer is coated on the outer side of the first conductive layer and extends to cover the whole first surface of the insulating substrate base plate, and the first conductive layer at the needle point of the insulating microneedle base body is exposed from the insulating layer.
5. The intracutaneous-implanted microneedle electrode array device of claim 4, wherein a plurality of said insulating microneedle matrices are integrally formed with said insulating substrate base using high precision 3D printing techniques.
6. The intracutaneous implanted microneedle electrode array device of claim 4, wherein the conductive area of the conductive layer at the tip of the insulating microneedle matrix is similar to the dimensions of individual neurons in the brain of the implanted subject for achieving single cell neural signal acquisition resolution.
7. The device of claim 4, wherein the through hole is a cylinder with a vertical inner wall or a truncated cone with an inclined inner wall or a cylinder with a hyperboloid inner wall.
8. The array device of any one of claims 4-7, further comprising a surface modification layer disposed outside the insulating microneedle matrix tip conductive layer for enhancing contact of the conductive layer with a biological interface to reduce contact resistance.
9. The intracutaneous implanted microneedle electrode array device of claim 8 wherein the surface modification layer comprises a drug release material that is degradable within the brain cortex and releases a drug.
10. The intracutaneous-implanted microneedle electrode array device of claim 4, wherein said insulating substrate base plate is molded into a solid structure comprising a plurality of said through holes; the through holes and the root of the insulating microneedle matrix are arranged in a staggered manner in the horizontal direction.
11. The intracutaneous implanted microneedle electrode array device of any one of claims 4-7, wherein the first conductive pad and/or the second conductive pad is circular, oval, rectangular or intersecting circular.
12. The intracutaneous implanted microneedle electrode array device of any one of claims 4-7, wherein said insulating material is an insulating polymer material.
13. The array of intracutaneous implanted microneedle electrodes of any one of claims 4-7, wherein the microneedle electrodes have a high aspect ratio, the root diameter of the microneedle electrodes is 30-300 μm, the tip diameter is less than 50 μm, and the height is 100 μm-10mm; and/or, the center-to-center distance between adjacent microneedle electrodes is 200 μm-1mm.
14. An implantable neural interface system, comprising
The intracutaneous implanted microneedle electrode array device of any one of claims 4-13 adapted for implantation into the cerebral cortex for acquiring neural signals;
the multichannel nerve signal processing chip is integrated with the in-cortex implanted micro-needle electrode array device into an interconnection packaging structure and is used for carrying out in-situ amplification, filtering, noise elimination and analog-to-digital conversion treatment on the nerve signals acquired by the in-cortex implanted micro-needle electrode array device;
The post-processing module is suitable for being implanted into a subclavian clearance area, receives and processes the digital signals processed by the multichannel neural signal processing chip, and is also used for wirelessly transmitting data to an external instrument, wirelessly receiving external instructions, transmitting an electric stimulation signal to the micro-needle electrode array device implanted in the cortex and wirelessly charging.
15. The implantable neural interface system of claim 14, further comprising an intradermal connection adapted to be buried in a subcutaneous tunnel, one end connected to the interconnect packaging structure and the other end connected to the post-processing module for transmitting the digital signal processed by the multichannel neural signal processing chip to the post-processing module.
16. The implantable neural interface system according to claim 14, wherein the microneedle electrodes are interconnected with the multichannel neural signal processing chip by a flip-chip bonding technique, the microneedle electrodes are in one-to-one correspondence with input ends of a die of the multichannel neural signal processing chip, and are electrically connected with each other by solder balls, and gaps are completely filled with insulating glue; the insulating substrate base plate and the multichannel neural signal processing chip are integrally packaged in a shell, the shell contains a peripheral circuit board and an output interface which are required by the operation of the multichannel neural signal processing chip, and the output interface is connected with an intradermal connection wire.
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| CN114469113A (en) * | 2021-12-31 | 2022-05-13 | 北京大学 | Multi-channel flexible microneedle electrode and preparation method |
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| CN113777145A (en) * | 2021-09-14 | 2021-12-10 | 北京大学 | Method for manufacturing micro-needle biosensor |
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