CN108853717B - Flexible nerve electrode and implantation method thereof - Google Patents
Flexible nerve electrode and implantation method thereof Download PDFInfo
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- CN108853717B CN108853717B CN201810630076.0A CN201810630076A CN108853717B CN 108853717 B CN108853717 B CN 108853717B CN 201810630076 A CN201810630076 A CN 201810630076A CN 108853717 B CN108853717 B CN 108853717B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
- A61N1/0526—Head electrodes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
- A61N1/0526—Head electrodes
- A61N1/0529—Electrodes for brain stimulation
- A61N1/0531—Brain cortex electrodes
Abstract
The invention discloses a flexible nerve electrode and an implantation method of the flexible nerve electrode. The flexible nerve electrode comprises a flexible substrate, a flexible insulating layer, and a conducting layer and a magnetic material layer which are positioned between the flexible substrate and the flexible insulating layer; the conductive layer comprises at least one conductive wire, and the conductive wire comprises an interconnection wire, and recording sites and welding spots which are respectively positioned at two ends of the interconnection wire; the magnetic material layer comprises a plurality of magnetic material parts, and the magnetic material parts correspond to the first part interconnection wires one to one; at least one through hole is formed in the flexible insulating layer, the through holes correspond to the recording sites one to one, and the through holes penetrate through the flexible insulating layer and expose the corresponding recording sites. According to the technical scheme provided by the embodiment of the invention, the flexible nerve electrode has magnetism, and can be implanted into the cerebral cortex under the traction action of magnetic field force, so that the implantation of the flexible nerve electrode cannot cause great acute injury to brain tissues.
Description
Technical Field
The embodiment of the invention relates to the field of nerve electrodes, in particular to a flexible nerve electrode and an implantation method of the flexible nerve electrode.
Background
The nerve electrode is a hot problem in neuroscience research, is a bridge for connecting a neuron with external electronic equipment, and can measure electrophysiological signals of the cerebral cortex, including local field potential and action potential, through the nerve electrode, so that the nerve electrode has great significance for development of the neuroscience and diagnosis of brain diseases, such as epilepsy, Parkinson's disease, Alzheimer's disease and the like. The excellent performance of the neural electrode needs to have the following two conditions: firstly, the implantation damage is small, and the rejection reaction of brain tissues to the electrodes is reduced; and secondly, the neural signal measurement device can have higher space-time resolution.
At present, the silicon-based rigid nerve electrode is widely applied, has higher space-time resolution and can record action potential of a single neuron, but the mechanical property of the silicon-based nerve electrode is greatly different from that of a cerebral cortex, so that micromotion is easily generated in brain tissues to cause larger immunoreaction, and a large number of glial cells are generated around the electrode to cause electrode failure.
In order to solve the problems, flexible nerve electrodes are developed, the mechanical property of the flexible nerve electrodes is more matched with that of the cerebral cortex, and the tissue immune response is greatly reduced.
Disclosure of Invention
The invention provides a flexible nerve electrode and an implantation method of the flexible nerve electrode, which are used for avoiding great acute injury to brain tissue caused by implantation of the flexible nerve electrode.
In a first aspect, an embodiment of the present invention provides a flexible neural electrode, including:
the flexible circuit board comprises a flexible substrate, a flexible insulating layer, and a conductive layer and a magnetic material layer which are positioned between the flexible substrate and the flexible insulating layer;
wherein the conductive layer comprises at least one conductive line comprising an interconnection wire and recording sites and pads at both ends of the interconnection wire, respectively;
the flexible nerve electrode comprises a probe area, an auxiliary area and a connecting area, the recording sites and a first part of interconnection leads connected with the recording sites are located in the probe area, a second part of interconnection leads except the first part of interconnection leads are located in the auxiliary area, and welding spots are located in the connecting area;
the magnetic material layer comprises a plurality of magnetic material parts, the magnetic material parts correspond to the first part interconnection lead one by one, and the magnetic material parts are arranged in a laminating mode corresponding to the first part interconnection lead in the laminating direction of the flexible substrate and the flexible insulating layer;
the flexible insulating layer at least covers the conducting layer and the magnetic material layer, at least one through hole is formed in the flexible insulating layer, the through holes correspond to the recording sites one to one, and the through holes penetrate through the flexible insulating layer and are exposed out of the flexible insulating layer and correspond to the recording sites;
the flexible substrate in the probe region comprises a plurality of strip-shaped structures which correspond to the conductive wires one to one.
In a second aspect, an embodiment of the present invention further provides an implantation method of a flexible neural electrode, which is applied to the flexible neural electrode in the first aspect, and the implantation method of the flexible neural electrode includes:
fixing the head of the anesthetized animal to be implanted;
drilling a skull to expose the cerebral cortex of the head;
determining a location on the cerebral cortex to be implanted;
moving the flexible nerve electrode to enable the position to be implanted to be located on the extended long line of the conducting wire in the flexible nerve electrode;
placing a magnetic field generating component on a side of a mandible of the head away from the flexible nerve electrode;
moving the flexible neural electrode closer to the head;
and implanting the probe area of the flexible nerve electrode into the cerebral cortex of the animal to be implanted under the traction action of the magnetic force generated by the magnetic field generating component.
According to the technical scheme provided by the embodiment of the invention, the magnetic material layer is arranged in the probe area of the flexible nerve electrode, so that the flexible nerve electrode in the probe area has magnetism, can move and be implanted into cerebral cortex under the action of an external magnetic field, and the acute injury of the flexible nerve electrode implanted into the cerebral tissue is greatly reduced because the auxiliary or curing treatment of a rigid part is not needed any more, and the long-term stable measurement of nerve signals can be carried out.
Drawings
In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, a brief description is given below of the drawings used in describing the embodiments. It should be clear that the described figures are only views of some of the embodiments of the invention to be described, not all, and that for a person skilled in the art, other figures can be derived from these figures without inventive effort.
Fig. 1 is a schematic top view of a flexible neural electrode according to an embodiment of the present invention;
FIG. 2 is a schematic cross-sectional view taken along the dashed line AB of FIG. 1;
FIG. 3 is a schematic diagram of the structure of the conductive layer of FIG. 1;
FIG. 4 is a schematic diagram of the structure of the magnetic material layer of FIG. 1;
FIG. 5 is a schematic structural diagram of another magnetic material layer according to an embodiment of the present invention;
fig. 6 is a flow chart of a method for implanting a flexible neural electrode according to an embodiment of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the accompanying drawings and examples. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention. It should be further noted that, for the convenience of description, only some but not all of the relevant aspects of the present invention are shown in the drawings. Before discussing exemplary embodiments in more detail, it should be noted that some exemplary embodiments are described as processes or methods depicted as flowcharts. Although a flowchart may describe the operations (or steps) as a sequential process, many of the operations can be performed in parallel, concurrently or simultaneously. In addition, the order of the operations may be re-arranged. The process may be terminated when its operations are completed, but may have additional steps not included in the figure. The processes may correspond to methods, functions, procedures, subroutines, and the like.
Fig. 1 is a schematic top view of a flexible neural electrode according to an embodiment of the present invention. Fig. 2 is a schematic sectional view along a broken line AB in fig. 1. As shown in fig. 2, the flexible neural electrode includes a flexible substrate 100, a flexible insulating layer 400, and a conductive layer 200 and a magnetic material layer 300 between the flexible substrate 100 and the flexible insulating layer 400. Fig. 3 is a schematic view of the structure of the conductive layer in fig. 1. As shown in fig. 3, the conductive layer 200 includes at least one conductive line 210, and the conductive line 210 includes an interconnection line 211 and recording sites 212 and pads 213 respectively located at both ends of the interconnection line 211. With continued reference to fig. 1 and 3, the flexible neural electrode includes a probe region 10, an auxiliary region 20, and a connection region 30, the recording site 212 and a first portion of interconnection lead 211/1 connected to the recording site 212 are located in the probe region 10, a second portion of interconnection lead 211/2 other than the first portion of interconnection lead 211/1 is located in the auxiliary region 20, and the solder joint 213 is located in the connection region 30. Fig. 4 is a schematic structural diagram of the magnetic material layer in fig. 1. As shown in fig. 4, the magnetic material layer 300 includes a plurality of magnetic material portions 310. With continued reference to fig. 2 and 4, the magnetic material portions 310 are in one-to-one correspondence with the first-part interconnection leads 211/1, and the magnetic material portions 310 are arranged in a lamination with the corresponding first-part interconnection leads 211/1 in the lamination direction Y of the flexible substrate 100 and the flexible insulating layer 400. It should be noted that, in order to avoid the confusion of the structure, fig. 1 does not show the flexible substrate 100, the conductive layer 200, the magnetic material layer 300 and the flexible insulating layer 400, but the same structure in fig. 1 as that in fig. 2 to 4 is marked by the same hatching, and thus the position and shape of each structure can be determined in fig. 1. As can be seen from fig. 2 to 4, in fig. 1, the flexible insulating layer at least covers the conductive layer and the magnetic material layer, at least one through hole 410 is formed on the flexible insulating layer, the through hole 410 corresponds to the recording site one to one, the through hole 410 penetrates through the flexible insulating layer and is exposed to correspond to the recording site, and the flexible substrate 100 in the probe region 10 includes a plurality of strip structures corresponding to the conductive lines 210 one to one.
It should be noted that, for example, as shown in fig. 1, the shape of the flexible substrate 100 in the auxiliary area 20 may be a block shape, the shape of the flexible substrate 100 in the connection area 30 may be the same as the shape of the plurality of solder joints, and the size and shape of the flexible insulating layer in the auxiliary area 20 may be the same as the flexible substrate. It will be appreciated that since only the structure in the probe area 10 will be implanted in the cerebral cortex of the animal, the shape of the flexible substrate and the shape of the flexible insulating layer in the auxiliary area 20 and the connection area 30 may be other than the one shown in fig. 1, but it should be noted that in order to ensure high reliability of the flexible nerve electrode, i.e., the properties of the magnetic material layer and the conductive layer are not changed, the flexible insulating layer should cover at least the conductive layer and the magnetic material layer, and on the other hand, in order to ensure that the flexible nerve electrode is a unitary structure, at least one of the flexible substrate and the flexible insulating layer is a continuous structure in the auxiliary area 20 and/or the connection area 30.
In addition, in order to increase the recording sites of the flexible neural electrode, at least one additional conductive layer may be further disposed on the side of the flexible insulating layer 400 away from the flexible substrate 100, and one additional flexible insulating layer is disposed on the side of each additional conductive layer away from the flexible substrate 100, the shape of each additional conductive layer is the same as that of the conductive layer, and the lengths of the additional conductive layers in the probe region 10 are sequentially decreased along the direction in which the flexible substrate 100 points to the flexible insulating layer 400, and additional through holes are disposed on all the additional flexible insulating layers on the side of each additional conductive layer away from the flexible substrate 100, corresponding to the recording sites 212 in the additional conductive layer.
According to the technical scheme provided by the embodiment, the magnetic material layer 300 is arranged in the probe area 10 of the flexible nerve electrode, so that the flexible nerve electrode in the probe area 10 has magnetism and can move and be implanted into a cerebral cortex under the action of an external magnetic field, and the acute injury of the flexible nerve electrode to the cerebral tissue is greatly reduced due to no need of assistance or curing treatment of rigid parts, and long-term stable measurement can be performed on nerve signals.
Optionally, as shown in fig. 3, when the number of the at least one conductive line 210 is greater than 1, the conductive lines 210 are arranged in parallel. Due to the arrangement, each conducting wire 210 can be perpendicular to the area to be implanted on the cerebral cortex, so that each corresponding probe 101 can be subjected to larger magnetic field force, and the occurrence probability of the bending phenomenon caused by insufficient stress of part of probes 101 in the implantation process is reduced.
Preferably, as shown in fig. 2, the magnetic material layer 300 may be located on a side of the conductive layer 200 away from the flexible substrate 100. Such an arrangement enables the conductive layer 200 to be located on the flat flexible substrate 100 surface, and prevents the recording sites 212 in the same conductive line 210 from being connected to the interconnection leads 211 weakly due to the presence of the film step.
Illustratively, the material of the flexible substrate 100 may be any one of polyimide, parylene, and SU8 photoresist or a combination of at least two of any two of the above.
Optionally, the thickness of the flexible substrate 100 may range from 0.5 um to 4 um. It should be noted that, too small thickness of the flexible substrate 100 may result in insufficient mechanical properties and insulation properties, which may further affect formation of each film layer on the flexible neural electrode and measurement of brain signals, and too large thickness may increase the overall thickness of the flexible neural electrode, which is not favorable for micro-formation of the flexible neural electrode, and may also result in decreased flexibility of the flexible neural electrode. Specifically, the thickness of the flexible substrate 100 is preferably 1-3 um, and more preferably 2 um.
Illustratively, the material of the conductive layer 200 may be any one or a combination of at least two of gold, platinum, and iridium. The material is convenient for preparing fine film patterns on one hand, and has better electrical characteristics on the other hand, thereby being beneficial to the miniaturization of the flexible nerve electrode and the improvement of the sensitivity.
Optionally, the thickness of the conductive layer 200 may range from 20 nm to 500 nm. The conductive layer 200 can achieve relatively better electrical sensitivity within the above value range. Specifically, the thickness of the conductive layer 200 is preferably 50 to 300nm, and more preferably 100 nm.
Optionally, the width of the interconnection wire 211 may range from 2um to 100 um. It should be noted that, under the condition that the thickness of the interconnection wire 211 is determined, the width of the interconnection wire 211 is related to the current intensity flowing through the interconnection wire 211, so that the flexible neural electrode has a better signal transmission characteristic, the width of the interconnection wire 211 is preferably set to range from 2um to 100um in the present embodiment. Specifically, the width of the interconnection wire 211 preferably ranges from 10um to 30um, and more preferably ranges from 12 um.
In this embodiment, the length of the strip structure may range from 1 mm to 15 mm. It is understood that the conductive layer 200, the magnetic material layer 300 and the flexible insulating layer 400 formed on the flexible substrate 100 have no dimension greater than that of the flexible substrate 100 in the corresponding region, and therefore, the length of the strip structure is the length of each probe 101 of the flexible neural electrode in the probe region 10. The probe is implanted into the head of an animal to be implanted, if the probe is too short, the recording site 212 connected with the probe cannot penetrate into an effective area, if the probe is too long, the implantation difficulty is increased due to the flexibility characteristic, and in consideration of the two reasons, the length of the probe is preferably set to be 1-15 mm. Specifically, the length range of the strip-shaped structure is preferably 2-5 mm, and more preferably 3 mm.
Optionally, the width value range of the strip-shaped structure can be 5-100 um. It is understood that the width of the strip-shaped structure is the width of each probe 101 of the flexible neural electrode in the probe region 10. Too large or too small a width of the probe 101 increases the implantation difficulty, and thus, a preferable setting value range is 5 to 100 um. Specifically, the width value range of the strip-shaped structure is preferably 10-30 um, and further preferably 20 um.
In this embodiment, the number of the conductive lines 210 may range from 1 to 500. In a certain quantity range, the greater the number of the conductive wires 210, the greater the recording sites 212 of the flexible neural electrode, the greater the brain area for signal recording, and on the other hand, considering that the increase in the number increases the implantation difficulty, the preferred value range of the number of the conductive wires 210 is 1-500. Specifically, the number of the conductive wires 210 preferably ranges from 1 to 16, and more preferably ranges from 4.
Optionally, when the number of the conductive lines 210 is greater than 1, the range of the distance between the adjacent strip structures may be 20 to 1000 um. It should be noted that, the distance between adjacent strip-shaped structures is the distance between adjacent probes 101, and when the distance is too small, the signal portions detected by the adjacent probes 101 may be repeated, resulting in resource waste, and when the distance is too large, the implantation process using the magnetic force is not facilitated, and the above two reasons are considered comprehensively, the preferable range of the distance is set to be 20-1000 um in this embodiment. Specifically, the range of the distance between adjacent strip-shaped structures is preferably 200-600 um, and more preferably 500 um.
For example, an adhesion layer may be disposed between the flexible substrate 100 and the conductive layer 200. The adhesion layer can increase the adhesion of the conductive layer 200 on the substrate, avoiding the conductive layer 200 from peeling off during the use of the flexible neural electrode.
Optionally, the material of the adhesion layer may be chromium or titanium.
Optionally, the thickness of the adhesion layer may range from 5nm to 60 nm. The adhesion layer is too thin and can not reach the effect of increasing adhesion, and too thick can increase the whole thickness of flexible nerve electrode, and the thickness value range that sets up the adhesion layer of here preferred is 5 ~ 60 nm. Specifically, the thickness of the adhesion layer is preferably 5-15 nm, and more preferably 5 nm.
Alternatively, the recording site 212 may be circular in shape. Such an arrangement enables the recording site 212 to be larger in size relative to the interconnect wires, increasing the contact area of the recording site 212 with the brain nerves. It is understood that, in other embodiments of the present embodiment, the recording site 212 may also have other shapes, which is not specifically limited in the present embodiment.
Preferably, the diameter of the recording site 212 may range from 5um to 30 um. The small size of the recording site 212 can cause the contact area between the recording site and the brain nerve to be small, so that the electrochemical impedance of the recording site is large and is not beneficial to brain signal measurement, the spatial resolution of the flexible nerve electrode for signal measurement is reduced if the electrochemical impedance is too large, the implantation difficulty of the probe 101 is increased, and in consideration of the above problems, the diameter value range of the recording micro-point is preferably set to be 5-30 um. Specifically, the diameter of the recording site 212 is preferably in a range of 5 to 20um, and more preferably 10 um.
Alternatively, the material of the magnetic material layer 300 may be any one of FeNi, FePt and CoPt or a combination of at least two of them. So that the probe 101 with the flexible nerve electrode in the probe region 10 has better magnetism, and the flexible nerve electrode can be conveniently implanted.
Optionally, the thickness of the magnetic material layer 300 may range from 0.5 um to 4 um. The magnetic material layer 300 is too thin, which causes the magnetic material layer 300 to have low magnetism, and too thick increases the overall thickness of the flexible neural electrode, thereby reducing the flexibility of the flexible neural electrode, and therefore, the thickness value range of the magnetic material layer 300 is set to be 0.5-4 um. Specifically, the thickness of the magnetic material layer 300 preferably ranges from 1.5um to 3um, and more preferably ranges from 2.5 um.
Alternatively, the magnetic material layer 300 may be formed by an electroplating process. Specifically, the temperature adopted in the electroplating process can be 20-70 ℃, preferably 30-50 ℃, and further preferably 45 ℃; the value range of the electroplating time can be 1-15 min, preferably 3-7 min, and further preferably 5 min; the current density can be in the range of 50-600A/m 2, preferably 150-500A/m 2, and more preferably 350A/m 2.
It is understood that, in other embodiments of the present embodiment, the magnetic material layer 300 may also be formed by other processes, which is not specifically limited in the present embodiment.
For example, the width of the magnetic material portion 310 may range from 2um to 90 um. In order to ensure that the magnetic material layer 300 has better magnetism and the overall size of the probe 101 is not increased, the width value range of the magnetic material portion 310 of the present embodiment is preferably 2-90 um. Specifically, the width of the magnetic material portion 310 preferably ranges from 5um to 20um, and more preferably ranges from 10 um.
Alternatively, the magnetic material portion 310 may be a stripe or include at least two discrete sub-portions 311 arranged along the extending direction of the conductive line 210. The magnetic material portion 310 is used to make the probe 101 of the flexible neural electrode located in the probe region 10 have magnetism, and therefore, the magnetic material portion 310 may be a strip shape or may include at least two discrete sub-portions 311 arranged along the extending direction of the conductive wire 210, specifically, the magnetic material portion 310 in fig. 4 is a strip shape. Fig. 5 is a schematic structural diagram of another magnetic material layer according to an embodiment of the invention. As shown in fig. 5, the magnetic material portion 310 includes a plurality of discrete sub-portions 311 arranged along the extending direction of the conductive line 210. It should be noted that, since the magnetic material portion 310 is disposed corresponding to the first interconnection line, and the width is relatively small, the process difficulty of disposing it to include a plurality of discrete sub-portions 311 arranged along the extending direction of the conductive line 210 is lower than that of other dividing methods.
Illustratively, the material of the flexible insulating layer 400 may be any one of polyimide, parylene, and SU8 photoresist, or a combination of at least two of any two of the foregoing.
Optionally, the thickness of the flexible insulating layer 400 may range from 0.5 um to 4 um. Thickness undersize can lead to its mechanical properties and insulating properties not enough, and then influences implantation process and brain signal measurement, and thickness too big will increase flexible neural electrode's whole thickness, is unfavorable for flexible neural electrode's miniaturization, and still can lead to flexible neural electrode flexibility to descend, considers above-mentioned problem, and the thickness value range that sets up flexible insulating layer 400 of this embodiment preferred is 0.5 ~ 4 um. Specifically, the thickness value range of the flexible insulating layer 400 is preferably 1-3 um, and more preferably 2 um.
Alternatively, the materials of the flexible substrate 100 and the flexible insulating layer 400 may be the same. Due to the arrangement, the same flexible material is only needed to be used in the preparation process of the flexible nerve electrode, and the main process parameters only need to be designed once, so that the beneficial effect of simplifying the preparation process of the flexible nerve electrode is achieved.
The following are three specific design schemes of each structural parameter in the flexible neural electrode provided by the embodiment of the invention:
the number of conductive lines is 4; the conducting layer is made of gold and has the thickness of 100 um; the length of the conductive wire in the probe area is 3um, and the width of the interconnection wire is 12 um; the material of the adhesion layer is chromium, and the thickness is 5 nm;
the recording sites were circular in shape and 10um in diameter;
the welding spots are rectangular, the length of the welding spots is 1000um, the width of the welding spots is 200um, and the distance between every two adjacent welding pads is 500 um;
the flexible insulating layer is made of polyimide and is 2um thick; the length of the flexible insulating layer covering one conductive wire in the probe area is 3um, the width of the flexible insulating layer is 20um, and through holes are formed in the flexible insulating layer corresponding to each recording site; the flexible insulating layer does not cover the solder joints.
Scheme 2, the flexible substrate is made of polyimide and has a thickness of 2 um; the length of the flexible substrate of the strip-shaped structure in the probe area is 2mm, and the width of the flexible substrate is 20 um; the distance between the flexible substrates of the adjacent strip-shaped structures in the probe area is 200 um;
the number of conductive lines is 8; the conducting layer is made of gold and has the thickness of 100 um; the length of the conductive wire in the probe area is 2um, and the width of the interconnection wire is 12 um; the material of the adhesion layer is chromium, and the thickness is 5 nm;
the recording sites were circular in shape and 10um in diameter;
the welding spot is rectangular, the length of the welding spot is 1000um, the width of the welding spot is 200um, and the distance between adjacent welding pads is 200 um;
the flexible insulating layer is made of polyimide and is 2um thick; the length of the flexible insulating layer covering one conductive wire in the probe area is 2um, the width of the flexible insulating layer is 20um, and through holes are formed in the flexible insulating layer corresponding to each recording site; the flexible insulating layer does not cover the solder joints.
Scheme 3, the flexible substrate is made of polyimide and is 2um thick; the length of the flexible substrate of the strip-shaped structure in the probe area is 1.5mm, and the width of the flexible substrate is 20 um; the distance between the flexible substrates of the adjacent strip-shaped structures in the probe area is 150 um;
the number of conductive lines is 16; the conducting layer is made of gold and has the thickness of 100 um; the length of the conductive wire in the probe area is 1.5um, and the width of the interconnection wire is 12 um; the material of the adhesion layer is chromium, and the thickness is 5 nm;
the recording sites were circular in shape and 10um in diameter;
the welding spots are rectangular, the length of the welding spots is 1000um, the width of the welding spots is 200um, and the distance between every two adjacent welding pads is 150 um;
the flexible insulating layer is made of polyimide and is 2um thick; the length of the flexible insulating layer covering one conductive wire in the probe area is 1.5um, the width of the flexible insulating layer is 20um, and through holes are formed in the flexible insulating layer corresponding to each recording site; the flexible insulating layer does not cover the solder joints.
The following is a preparation process of the flexible neural electrode provided by the embodiment of the invention:
step 11, preparation of sacrificial layer (the material of the sacrificial layer is Al)
1) Cleaning a silicon wafer: placing a silicon wafer with the diameter of four inches in a clean culture dish, sequentially carrying out ultrasonic cleaning for 10min (power of 30W) by using acetone, isopropanol and water, drying by using nitrogen, placing the silicon wafer on a hot plate with the temperature of 105 ℃ for heating for 3min, removing water vapor, cooling to room temperature, and then cleaning for 3min by using oxygen plasma (power of 100W).
2) Glue homogenizing: the clean silicon wafer is placed in the center of a sucker of a spin coater to be fixed, parameters of the spin coater (500rpm, 5S plus, 2000rpm, 60S) are set, 4mL of S1813 photoresist is dripped in the center of the silicon wafer by a dropper, and then the photoresist is spun.
3) Pre-baking: and (3) placing the silicon wafer after the glue homogenizing treatment on a hot plate at the temperature of 115 ℃, drying for 3min, and then taking down and cooling to room temperature.
4) Exposure: a double-sided alignment contact type ultraviolet lithography machine (model: MA6) is used, a chromium mask corresponding to an Al layer is installed, a silicon wafer is placed on a workbench of the lithography machine, exposure parameters (exposure time 65s, mode Vac and gap of 40um) are set, and exposure is started.
5) And (3) developing: pouring a proper amount of S1813 developing solution into a clean culture dish, then putting the silicon wafer into the clean culture dish, moderately shaking the silicon wafer for 1min, cleaning the silicon wafer with water after the development is finished, and drying the silicon wafer with nitrogen.
6) Removing residual glue: the wafer was cleaned with oxygen plasma for 1min (power 50W).
7) Al deposition: an Al layer was deposited to a thickness of 100nm using a magnetron sputtering coating system (model: Lab-18).
8) And (3) Al stripping: pouring a proper amount of acetone into a clean culture dish, then placing a silicon wafer into the clean culture dish, heating the silicon wafer on a hot plate at the temperature of 80 ℃ for 1 hour, and blowing off all the stripped Al by using a dropper; then respectively cleaning with acetone, isopropanol and water, blowing with nitrogen, drying on a hot plate at 105 deg.C for 3min, and removing water vapor.
Step 12, preparing a flexible substrate (the material of the flexible substrate is polyimide)
1) Surface cleaning: and cleaning the silicon wafer by using oxygen plasma for 3min (with the power of 100W).
2) Glue homogenizing: the silicon chip is placed in the center of a chuck of a spin coater to be fixed, parameters of the spin coater (500rpm, 5s plus 2000rpm, 60s) are set, 4mL of 15% polyimide is dripped into the center of the silicon chip by a dropper, and then spin coating is started.
3) Drying: and (3) drying the silicon wafer after the glue homogenizing is finished on a hot plate at 120 ℃ for 10min, then putting the silicon wafer into a vacuum drying oven at 200 ℃ for 2 h, and cooling along with the oven.
Step 13, preparing a conductive layer (the conductive layer is made of Au):
1) surface cleaning: cleaning the silicon wafer with acetone, isopropanol and water respectively, blowing to dry with nitrogen, drying on a hot plate at 105 deg.C for 3min to remove water vapor, cooling to room temperature, and cleaning with oxygen plasma for 1min (power 50W).
2) Glue homogenizing: the silicon chip is placed in the center of a chuck of a spin coater to be fixed, parameters of the spin coater (500rpm, 5S plus 2000rpm, 60S) are set, 4mL of S1813 photoresist is dripped in the center of the silicon chip by a dropper, and the photoresist is spun.
3) Pre-baking: and (3) placing the silicon wafer after the glue homogenizing treatment on a hot plate at the temperature of 115 ℃, drying for 3min, and then taking down and cooling to room temperature.
4) Exposure: a double-sided alignment contact type ultraviolet lithography machine (model: MA6) is used, a chromium mask corresponding to an Au layer is installed, a silicon wafer is placed on a workbench of the lithography machine, exposure parameters (exposure time 65s, mode Vac and gap of 40um) are set, and exposure is started.
5) And (3) developing: pouring a proper amount of S1813 developing solution into a clean culture dish, then putting the silicon wafer into the clean culture dish, moderately shaking the silicon wafer for 1min, cleaning the silicon wafer with water after the development is finished, and drying the silicon wafer with nitrogen.
6) Removing residual glue: the wafer was cleaned with oxygen plasma for 1min (power 50W).
7) And Au deposition: an electron beam evaporation coating system (model: OHMIKER-50B) was used to deposit an adhesion layer of 5nm in thickness of chromium followed by a 100nm thickness of Au.
8) Au stripping: pouring a proper amount of acetone into a clean culture dish, then placing a silicon wafer into the clean culture dish, heating the silicon wafer on a hot plate at the temperature of 80 ℃ for 1 hour, and blowing off all the stripped Au by using a dropper; then respectively cleaning with acetone, isopropanol and water, blowing with nitrogen, drying on a hot plate at 105 deg.C for 3min, and removing water vapor.
Step 14, magnetic coating (the material of the magnetic coating is FeNi):
1) surface cleaning: the wafer was cleaned with oxygen plasma for 1min (power 50W).
2) Glue homogenizing: the silicon chip is placed in the center of a chuck of a spin coater to be fixed, parameters of the spin coater (500rpm, 5S plus 2000rpm, 60S) are set, 4mL of S1813 photoresist is dripped in the center of the silicon chip by a dropper, and the photoresist is spun.
3) Pre-baking: and (3) placing the silicon wafer after the glue homogenizing treatment on a hot plate at the temperature of 115 ℃, drying for 3min, and then taking down and cooling to room temperature.
4) Exposure: a double-sided alignment contact type ultraviolet lithography machine (model: MA6) is used, a chromium mask corresponding to the FeNi layer is installed, the silicon wafer is placed on a workbench of the lithography machine, exposure parameters (exposure time 65s, mode Vac, gap of 40um) are set, and exposure is started.
5) And (3) developing: pouring a proper amount of S1813 developing solution into a clean culture dish, then putting the silicon wafer into the clean culture dish, moderately shaking the silicon wafer for 1min, cleaning the silicon wafer with water after the development is finished, and drying the silicon wafer with nitrogen.
6) Removing residual glue: the wafer was cleaned with oxygen plasma for 1min (power 50W).
7) Electroplating FeNi: electroplating with an electrochemical workstation (model: Gamry Reference 3000), controlling the electroplating temperature at 45 deg.C, electroplating time at 5min, and current density at 350A/m 2. After the electroplating is finished, the plating solution on the surface of the silicon wafer is cleaned by deionized water and dried by nitrogen
8) Removing the S1813 template: pouring an appropriate amount of acetone into a clean culture dish, then putting the silicon wafer into the clean culture dish, soaking for 5min, taking out, respectively cleaning with isopropanol and water, blow-drying with nitrogen, and drying on a hot plate at 105 ℃ for 3min to remove water vapor.
Step 15, a flexible insulating layer (the material of the flexible insulating layer is polyimide)
1) Glue homogenizing: the silicon chip is placed in the center of a chuck of a spin coater to be fixed, parameters of the spin coater (500rpm, 5s plus 2000rpm, 60s) are set, 4mL of 15% polyimide is dripped into the center of the silicon chip by a dropper, and then spin coating is started.
2) Drying: and (3) drying the silicon wafer after the glue homogenizing is finished on a hot plate at 120 ℃ for 10min, then putting the silicon wafer into a vacuum drying oven at 200 ℃ for 2 h, and cooling along with the oven.
Step 16, patterning of the flexible neural electrode
1) Surface cleaning: a reaction plasma etcher (model: ETCHLAB-200) is used for putting a silicon wafer into a cavity of the etcher, vacuumizing and etching for 10s (power of 200W).
2) Glue homogenizing: the silicon chip is placed in the center of a sucker of a spin coater to be fixed, parameters of the spin coater (500rpm, 5s plus, 2000rpm, 60s) are set, 4mL of AZ4620 photoresist is dripped in the center of the silicon chip by a dropper, and then the photoresist is spun.
3) Pre-baking: and (3) placing the silicon wafer after the glue homogenizing treatment on a hot plate at 120 ℃, drying for 5min, and then taking down and cooling to room temperature.
4) Exposure: a double-sided alignment contact type ultraviolet lithography machine (model: MA6) is used, a Cr mask corresponding to the patterning is installed, a silicon wafer is placed on a workbench of the lithography machine, exposure parameters (exposure time 180s, mode Vac and gap of 40um) are set, and exposure is started.
5) And (3) developing: pouring a proper amount of AZ4620 developing solution into a clean culture dish, then putting the silicon wafer into the clean culture dish, moderately shaking the silicon wafer for 10min, and cleaning the silicon wafer with water and drying the silicon wafer with nitrogen after the development is finished.
6) Reactive ion etching: a reaction plasma etcher (model: ETCHLAB-200) is used for placing the silicon wafer into a cavity of the etcher, vacuumizing and etching for 7.5min (power of 200W).
7) Removing AZ4620 residual glue: pouring an appropriate amount of acetone into a clean culture dish, then putting the silicon wafer into the clean culture dish, soaking for 5min, taking out, respectively cleaning with isopropanol and water, blow-drying with nitrogen, and drying on a hot plate at 105 ℃ for 3min to remove water vapor.
Step 17, solder joint connection
1) Scribing: and scribing the whole silicon wafer into discrete electrodes by using a silicon knife along the crystal direction of the silicon wafer.
2) Pressing a flexible flat cable: the spacing between the flexible flat cables is 0.5mm, ACF adhesive with proper size is adhered to the welding point, the flexible flat cables are aligned with the welding point, and hot pressing is carried out for 1min at 120 ℃.
3) Packaging: and packaging the joint of the welding point and the flexible flat cable by using AB glue, and drying for 2 hours in vacuum at 60 ℃.
4) Releasing the Al sacrificial layer: and immersing the packaged electrode into 0.5mol/L FeCl3 solution, and etching the Al sacrificial layer to separate the probe region of the flexible nerve electrode from the silicon chip substrate.
5) And (4) scratching off redundant silicon wafers: and (3) scratching the redundant silicon wafer below the probe in the probe area by using a silicon knife, transferring the silicon wafer to a glass slide fully covered with isopropanol from water, and finishing the preparation of the flexible nerve electrode after the isopropanol is naturally dried.
Fig. 6 is a flow chart of a method for implanting a flexible neural electrode according to an embodiment of the present invention. The implantation method of the flexible nerve electrode is applied to the flexible nerve electrode according to any embodiment of the invention. As shown in fig. 6, the implantation method of the flexible neural electrode specifically includes the following steps:
And 2, drilling a skull to expose the cerebral cortex of the head.
And 3, determining the position to be implanted on the cerebral cortex.
And 4, moving the flexible nerve electrode to enable the position to be implanted to be located on the extended long line of the conductive wire in the flexible nerve electrode.
And 5, placing a magnetic field generating component on one side of the lower jaw of the head, which is far away from the flexible nerve electrode.
Illustratively, the magnetic field generating member may be a permanent magnet. It is understood that the magnetic field generating component may also be other components capable of generating a magnetic field, and this embodiment is not particularly limited thereto.
And 6, moving the flexible nerve electrode to be close to the head.
And 7, implanting the probe area of the flexible nerve electrode into the cerebral cortex of the animal to be implanted under the traction action of the magnetic force generated by the magnetic field generating component.
The following is a specific implementation process of the implantation method of the flexible neural electrode provided by the embodiment of the invention:
step 21, preoperative preparation
Preparing a C57 mouse, a brain stereotaxic apparatus, an operating microscope, a cold light source, a weight scale, isoflurane, sodium pentobarbital, a 1mL injector, normal saline, aureomycin eye ointment, iodophors, elbow scissors, straight-head scissors, pointed-end tweezers, clean cloth, clean paper, gauze, a permanent magnet, a flexible nerve electrode connected with the rear end, a cranial drill, a cotton swab and the like in advance.
Step 22, anaesthetizing
A mouse with good health condition is taken and weighed, the injection amount of the sodium pentobarbital is calculated according to the standard of 0.01mL/g, and the mouse is anesthetized by the sodium pentobarbital.
Step 23, surgical procedure
1) After the mice are deeply anesthetized, the mice are fixed on a brain stereotaxic apparatus, a cotton swab is dipped in iodophor to wipe and disinfect the heads of the mice, and head hair is cut off.
2) The scalp of the mouse is cut along the middle seam by scissors to expose the skull, the skull is drilled to expose the cerebral cortex and the dura mater is picked up, and the brain stereotaxic apparatus is adjusted to ensure that the brain area to be implanted is positioned under the flexible nerve electrode.
6) The permanent magnet is placed below the lower jaw of a mouse, the flexible nerve electrode connected with the rear end is fixed on an electrode rod of the brain stereotaxic apparatus and slowly approaches to the cerebral cortex of the mouse, when the flexible nerve electrode is close enough to the cerebral cortex of the mouse, the form of the flexible nerve electrode is controlled by slowly moving the permanent magnet to keep the flexible nerve electrode in a vertical relation with the surface of the cerebral cortex, and the flexible nerve electrode is slowly implanted into the cerebral cortex under the auxiliary implantation force provided by the magnetic field.
7) The back end of the flexible nerve electrode is connected with a 128-channel neuroelectrophysiological recording system to record nerve signals (including local field potential and action potential).
It is to be noted that the foregoing is only illustrative of the preferred embodiments of the present invention and the technical principles employed. It will be understood by those skilled in the art that the present invention is not limited to the particular embodiments described herein, but is capable of various obvious changes, rearrangements and substitutions as will now become apparent to those skilled in the art without departing from the scope of the invention. Therefore, although the present invention has been described in greater detail by the above embodiments, the present invention is not limited to the above embodiments, and may include other equivalent embodiments without departing from the spirit of the present invention, and the scope of the present invention is determined by the scope of the appended claims.
Claims (12)
1. A flexible neural electrode, comprising:
the flexible circuit board comprises a flexible substrate, a flexible insulating layer, and a conductive layer and a magnetic material layer which are positioned between the flexible substrate and the flexible insulating layer;
wherein the conductive layer comprises at least one conductive line comprising an interconnection wire and recording sites and pads at both ends of the interconnection wire, respectively;
the flexible nerve electrode comprises a probe area, an auxiliary area and a connecting area, the recording sites and a first part of interconnection leads connected with the recording sites are located in the probe area, a second part of interconnection leads except the first part of interconnection leads are located in the auxiliary area, and welding spots are located in the connecting area;
the magnetic material layer comprises a plurality of magnetic material parts, the magnetic material parts correspond to the first part interconnection lead one by one, and the magnetic material parts are arranged in a laminating mode corresponding to the first part interconnection lead in the laminating direction of the flexible substrate and the flexible insulating layer;
the flexible insulating layer at least covers the conducting layer and the magnetic material layer, at least one through hole is formed in the flexible insulating layer, the through holes correspond to the recording sites one to one, and the through holes penetrate through the flexible insulating layer and are exposed out of the flexible insulating layer and correspond to the recording sites;
the flexible substrate in the probe region comprises a plurality of strip-shaped structures which correspond to the conductive wires one by one;
the magnetic force generated by the magnetic field generating component plays a role in traction on the probe area of the flexible nerve electrode.
2. The flexible neural electrode of claim 1, wherein the material of the flexible substrate is any one of polyimide, parylene and SU8 photoresist or a combination of any at least two of the foregoing;
the thickness value range of the flexible substrate is 0.5-4 um.
3. The flexible neural electrode of claim 1, wherein the material of the flexible insulating layer is any one or a combination of at least two of polyimide, parylene and SU8 photoresist;
the thickness value range of the flexible insulating layer is 0.5-4 um.
4. The flexible neural electrode of claim 1, wherein the material of the conductive layer is any one or a combination of at least two of gold, platinum and iridium;
the thickness range of the conducting layer is 20-500 nm.
5. The flexible neural electrode of claim 1, wherein when the number of the conductive wires is greater than 1, the conductive wires are arranged in parallel;
the number of the conductive wires ranges from 1 to 500.
6. The flexible neural electrode of claim 1, wherein the width of the interconnection lead is in the range of 2-100 um.
7. The flexible neural electrode of claim 1, wherein an adhesion layer is disposed between the flexible substrate and the conductive layer;
the material of the adhesion layer is chromium or titanium;
the thickness range of the adhesion layer is 5-60 nm.
8. The flexible neural electrode of claim 1, wherein the layer of magnetic material is on a side of the conductive layer remote from the flexible substrate;
the magnetic material layer is formed through an electroplating process;
the magnetic material layer is made of one or the combination of at least two of FeNi, FePt and CoPt;
the thickness value range of the magnetic material layer is 0.5-4 um.
9. The flexible neural electrode of claim 8, wherein the temperature adopted in the electroplating process ranges from 20 ℃ to 70 ℃, the electroplating time ranges from 1min to 15min, and the current density ranges from 50A/m to 600A/m2。
10. The flexible neural electrode of claim 1, wherein the width of the magnetic material portion ranges from 2um to 90 um;
the magnetic material portion is strip-shaped or comprises at least two discrete sub-portions arranged along the extending direction of the conductive wire.
11. The flexible neural electrode of claim 1, wherein the length of the strip-shaped structure ranges from 1 mm to 15 mm;
the width value range of the strip-shaped structure is 5-100 um;
when the number of the strip-shaped structures is larger than 1, the range of the distance between the adjacent strip-shaped structures is 20-1000 um.
12. The flexible neural electrode of claim 1, wherein the recording sites are circular in shape;
the diameter range of the recording sites is 5-30 um.
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| WO2020107345A1 (en) * | 2018-11-29 | 2020-06-04 | 深圳先进技术研究院 | Functionalized implantable flexible electrode and application thereof |
| CN109567786B (en) * | 2019-01-23 | 2021-10-19 | 国家纳米科学中心 | Processing method of implantable flexible neural microelectrode comb |
| US20210260368A1 (en) * | 2019-07-09 | 2021-08-26 | Shenzhen Institutes Of Advanced Technology | Microelectrode, preparation method thereof and neural prosthesis |
| CN111053554A (en) * | 2019-11-28 | 2020-04-24 | 开封市学国生物科技有限公司 | Ultramicro flexible linear deep brain electrode |
| CN111450411B (en) * | 2020-04-09 | 2023-07-25 | 国家纳米科学中心 | Composite nerve electrode and preparation method thereof |
| CN111698802A (en) * | 2020-06-28 | 2020-09-22 | 苏州捷迪纳米科技有限公司 | Flexible electrode and surface heater with same |
| CN112244850B (en) * | 2020-09-29 | 2022-03-25 | 中国科学院上海微系统与信息技术研究所 | Intracranial deep electrode recording device and preparation method and system thereof |
| CN112641448B (en) * | 2020-12-18 | 2023-02-24 | 浙江大学 | Flexible magnetic compatible implanted electroencephalogram electrode array and preparation method thereof |
| CN115054265A (en) * | 2022-06-17 | 2022-09-16 | 中国科学院脑科学与智能技术卓越创新中心 | Flexible electrode assembly for bonding with SEEG electrode and method for manufacturing same |
| CN115054261A (en) * | 2022-06-17 | 2022-09-16 | 中国科学院脑科学与智能技术卓越创新中心 | Flexible electrode and manufacturing method thereof |
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