CN111939472A - Intracranial stimulation recording system and preparation method thereof - Google Patents
Intracranial stimulation recording system and preparation method thereof Download PDFInfo
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- CN111939472A CN111939472A CN202010795035.4A CN202010795035A CN111939472A CN 111939472 A CN111939472 A CN 111939472A CN 202010795035 A CN202010795035 A CN 202010795035A CN 111939472 A CN111939472 A CN 111939472A
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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
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
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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
- A61N1/0534—Electrodes for deep brain stimulation
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0601—Apparatus for use inside the body
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/067—Radiation therapy using light using laser light
Abstract
The invention discloses an intracranial stimulation recording system which comprises a flexible optical fiber, a laser and a flexible deep brain electrode, wherein the flexible optical fiber is connected with the laser, and the flexible deep brain electrode is fixed on the flexible optical fiber through a clamp. Correspondingly, the invention also discloses a method for preparing the intracranial stimulation recording system. According to the invention, the flexible deep brain electrode is attached to the surface of the flexible optical fiber, the laser is used as a light source, the functions of optical pulse nerve stimulation and nerve electrophysiological signal acquisition can be integrated, meanwhile, optogenetic excitation and inhibition are realized, and the damage to brain tissues caused by heating of the LED chip when the LED chip is used as the light source can be avoided; the fibroin is adopted as the main materials of the substrate layer, the insulating layer and the packaging layer of the flexible deep brain electrode, and the flexible optical fiber material is combined, so that the mechanical compliance of the implanted device to brain tissues can be greatly improved, the neuroinflammation caused by the long-term in vivo implantation of the device is reduced, and the long-term in vivo stimulation and recording are realized.
Description
Technical Field
The invention relates to the technical field of neuroscience, in particular to an intracranial stimulation recording system and a preparation method thereof.
Background
The brain is the most complex and highest-level biological organ of the known universe, and neurons, as the basic structure of the brain, are responsible for transmitting neural information. Neurons of different nature and function form neural circuits through various forms of complex connections. The neural circuit is a bridge between the function of the connected molecular cells and the function of the whole behavior, and the research of the neural circuit with specific function is beneficial to understanding the formation and modification of the neural circuit, information coding, the relation between the information coding and the behavior and the like, thereby being capable of understanding the working principle of the brain more deeply.
Neuromodulation is an effective means of studying neural circuits. Common nerve regulation means comprise drug interference, electrical stimulation and the like, but the drug interference has the problems of slow onset time and large side effect; electrical stimulation lacks specificity and spatial selectivity, limiting its application in neural circuit studies.
The optogenetic technology provides a personality-changing research means for the research of the neural circuit, can realize the regulation and control of specific types of neuron activities, reveals the connection and mechanism between animal behavior activities and the neural circuit, and can become a more effective neural regulation and control means than electrical stimulation in the future.
At present, optogenetics mainly adopts the following two technical schemes: the first technical scheme is that an LED chip is additionally arranged near a detection electrode to be used as a light source to realize light stimulation; the second technical scheme is that a waveguide is manufactured on a substrate electrode to conduct light from the rear end of the device to the vicinity of a detection electrode at the front end of the device so as to realize optical stimulation. However, the heating of the LED chip in the first technical solution may cause damage to brain tissue; the second technical scheme is that the hard silicon substrate is mostly processed, the Young modulus difference between the hard probe of the silicon substrate and brain tissue is very large, and neuroinflammation is easily caused in a human body for a long time after the device is implanted, so that an experimental body is damaged.
Disclosure of Invention
The invention aims to provide an intracranial stimulation recording system and a preparation method thereof, so as to solve the technical problems in the prior art.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides an intracranial stimulation recording system which comprises a flexible optical fiber, a laser and a flexible deep brain electrode, wherein the flexible optical fiber is connected with the laser, and the flexible deep brain electrode is fixed on the flexible optical fiber through a clamp.
Preferably, the flexible deep brain electrode is attached to the surface of the flexible optical fiber by capillary tension.
Preferably, the flexible deep brain electrode comprises a metal wiring layer, an insulating layer and a metal electrode layer which are sequentially arranged,
the metal wiring layer is provided with a lead structure for connecting the metal electrode layer positioned at the front end of the flexible deep brain electrode with the rear end of the flexible deep brain electrode through the lead structure,
the insulating layer is used for isolating the metal wiring layer from the metal electrode layer,
the metal electrode layer is used for recording electrophysiological signals generated by nerve cells.
Preferably, the flexible deep brain electrode further comprises an encapsulation layer,
the packaging layer is arranged above the metal electrode layer, and hollow holes used for exposing the metal electrode layer are formed in the packaging layer.
Preferably, the flexible deep brain electrode further comprises a backing layer,
the substrate layer is arranged below the metal wiring layer and used for supporting the metal wiring layer, the insulating layer, the metal electrode layer and the packaging layer.
Preferably, the substrate layer, the insulating layer and the packaging layer are all made of fibroin.
In another aspect of the present invention, there is provided a method of making the intracranial stimulation recording system described above, the method comprising the steps of:
s1: preparing a clean substrate for later use;
s2: preparing a nickel sacrificial layer on the substrate prepared in the step S1;
s3: preparing a substrate layer on the nickel sacrificial layer obtained in the step S2;
s4: forming a metal wiring layer on the substrate layer prepared in step S3;
s5: preparing an insulating layer on the metal wiring layer formed at step S4;
s6: forming a metal electrode layer on the insulating layer prepared in step S5;
s7: preparing an encapsulation layer on the metal electrode layer formed in step S6;
s8: etching to remove the nickel sacrificial layer on the structure obtained in the step S7, and releasing the etched structure from the substrate to obtain the flexible deep brain electrode;
s9: and (5) fixing the flexible deep brain electrode obtained in the step (S8) on a flexible optical fiber through a clamp, and connecting the flexible optical fiber with a laser to obtain the intracranial stimulation recording system.
Preferably, the substrate is a single polished silicon wafer.
Preferably, the step S2 includes: and patterning the photoresist on the single-polished silicon wafer prepared in the step S1 through photoetching, preparing a layer of metal nickel with the thickness of 50-150nm through a thermal evaporation deposition process, and carrying out stripping process patterning on the metal nickel to obtain a nickel sacrificial layer.
Preferably, the step S3 includes: and spin-coating the fibroin solution on the nickel sacrificial layer obtained in the step S2 at the rotating speed of 2000-4000r/min for 20-40S to prepare a layer of fibroin film with the thickness of 400-600nm to obtain the substrate layer.
Preferably, the step S4 includes: preparing a chromium/gold alloy layer with the thickness of 5nm/50nm-10nm/100nm on the substrate layer prepared in the step S3 through photoetching patterning and thermal evaporation deposition processes, and carrying out stripping process patterning on the chromium/gold alloy layer to obtain the metal wiring layer.
Preferably, the step S5 includes: and spin-coating the fibroin solution on the metal wiring layer formed in the step S4 at the rotating speed of 2000-4000r/min for 10-20S, preparing a fibroin film with the thickness of 200-400nm, and exposing the metal wiring layer on the fibroin film to form a wire structure for connecting the metal electrode layer to obtain the insulating layer.
Preferably, the step S6 includes: preparing a chromium/gold alloy layer with the thickness of 5nm/50nm-10nm/100nm on the insulating layer prepared in the step S5 through photoetching patterning and thermal evaporation deposition processes, and carrying out stripping process patterning on the chromium/gold alloy layer to obtain the metal electrode layer.
Preferably, the step S7 includes: and spin-coating the fibroin solution on the metal electrode layer formed in the step S6 at the rotating speed of 2000-4000r/min for 20-40S to prepare a fibroin film with the thickness of 400-600nm, and obtaining the packaging layer through photoetching patterning.
Preferably, the step S8 includes: and (4) removing the nickel sacrificial layer on the structure obtained in the step (S7) by using metal corrosive liquid, and releasing the etched structure from the substrate to obtain the flexible deep brain electrode.
Compared with the prior art, the invention has the following beneficial effects:
1. according to the intracranial stimulation recording system, the flexible deep brain electrode is attached to the surface of the flexible optical fiber, the laser is used as a light source, the functions of optical pulse nerve stimulation and nerve electrophysiological signal acquisition can be integrated, meanwhile, optogenetic excitation and inhibition are realized, and the damage to brain tissues caused by heating of an LED chip when the LED chip is used as the light source can be avoided;
2. the intracranial stimulation recording system provided by the invention adopts fibroin as main materials of the substrate layer, the insulating layer and the packaging layer of the flexible deep brain electrode, and combines with the flexible optical fiber material, so that the mechanical compliance of an implanted device to brain tissue can be greatly improved, the neuroinflammation caused by long-term in vivo after the device is implanted is reduced, and long-term in vivo stimulation and recording are realized.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
Fig. 1 is a schematic structural diagram of an intracranial stimulation recording system according to an embodiment of the invention;
FIGS. 2 a-2 h are schematic diagrams illustrating a process for preparing a flexible deep electroencephalogram according to a second embodiment of the present invention;
in the figure: the device comprises 1-flexible optical fiber, 2-flexible deep brain electrode, 3-laser, 4-clamp, 5-substrate layer, 6-metal wiring layer, 7-insulating layer, 8-metal electrode layer, 9-packaging layer, 10-substrate and 11-nickel sacrificial layer.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be described in further detail with reference to the accompanying drawings in conjunction with the following detailed description. It should be understood that the description is intended to be exemplary only, and is not intended to limit the scope of the present invention.
Example one
The present embodiment provides an intracranial stimulation recording system, as shown in fig. 1, which includes a flexible optical fiber 1, a flexible deep brain electrode 2, and a laser 3. The flexible deep brain electrode 2 is fixed at the front end of the flexible optical fiber 1 through a clamp 4, and the flexible part of the flexible deep brain electrode 2 naturally droops under the action of gravity and is attached to the surface attached to the flexible optical fiber 1 under the action of capillary tension. The laser 3 is connected with the rear end of the flexible optical fiber 1 and used as a light source for light stimulation.
As shown in fig. 2h, the flexible deep brain electrode includes a substrate layer 5, a metal wiring layer 6, an insulating layer 7, a metal electrode layer 8, and an encapsulation layer 9, which are provided from the bottom up. Preferably, the substrate layer 5 is made of fibroin and is used for supporting the metal wiring layer 6, the insulating layer 7, the metal electrode layer 8 and the packaging layer 9. The metal wiring layer 6 is provided with a lead structure through which the metal electrode layer 8 positioned at the front end of the flexible deep brain electrode 2 is connected to the rear end of the flexible deep brain electrode. The metal electrode layer 8 is provided with a plurality of electrode sites (not shown in the figure) which are used for directly contacting with nerve cells to record the generated electrophysiological signals. Preferably, the insulating layer 7 is made of fibroin and used for isolating the metal wiring layer 6 from the metal electrode layer 8. Preferably, the packaging layer 9 is made of fibroin, and hollow holes for exposing the electrode sites on the metal electrode layer 8 are formed in the packaging layer 9.
Example two
This embodiment provides a method of making the intracranial stimulation recording system described above, the method comprising the steps of:
s1: a clean substrate 10 is prepared for use.
Preferably, the substrate 10 is a single polishing silicon wafer with a thickness of 300-500 μm (for example, 450 μm), and the single polishing silicon wafer is cleaned for use (see fig. 2 a).
S2: a nickel sacrificial layer 11 is prepared on the prepared substrate 10 at step S1.
Specifically, a photoresist (for example, SU-8 photoresist) is patterned by photolithography on the prepared substrate 10 in step S1, a layer of metal nickel with a thickness of 50-150nm (for example, 100nm) is prepared on the photoresist by a thermal evaporation deposition process, and the metal nickel is patterned by a stripping process to obtain a nickel sacrificial layer 11, wherein the nickel sacrificial layer 11 is used for subsequently releasing the flexible deep brain electrode from the substrate 10 (see fig. 2 b).
S3: a substrate layer 5 is prepared on the nickel sacrificial layer 11 obtained in step S2.
Specifically, the fibroin solution is spin-coated on the nickel sacrificial layer 11 obtained in step S2 at a rotation speed of 2000-4000r/min (e.g. 3000r/min), the spin-coating time is 20-40S (e.g. 30S), and a fibroin film with a thickness of 400-600nm (e.g. 500nm) is prepared, so as to obtain the substrate layer 5 (see fig. 2 c).
S4: a metal wiring layer 6 is formed on the substrate layer 5 prepared in step S3.
Specifically, after the surface of the substrate layer 5 prepared in step S3 is patterned by photolithography, a chromium/gold alloy layer with a thickness of 5nm/50nm-10nm/100nm (e.g., 10nm/100nm) is prepared by a thermal evaporation deposition process, and the chromium/gold alloy layer is patterned by a lift-off process to obtain the metal wiring layer 6 (see fig. 2 d).
S5: an insulating layer 7 is prepared on the metal wiring layer 6 formed in step S4.
Specifically, the surface of the metal wiring layer 6 formed in step S4 is spin-coated with a fibroin solution at a rotation speed of 2000-4000r/min (e.g., 3000r/min) for 10-20S (e.g., 18S), a fibroin film with a thickness of 200-400nm (e.g., 300nm) is prepared, and the metal wiring layer 6 is exposed on the fibroin film for connecting with the wire structure of the metal electrode layer, so as to obtain the insulating layer 7 (see fig. 2 e).
S6: a metal electrode layer 8 is formed on the insulating layer 7 prepared in step S5.
Specifically, after the surface of the insulating layer 7 prepared in step S5 is patterned by photolithography, a chromium/gold alloy layer having a thickness of 5nm/50nm to 10nm/100nm (e.g., 10nm/100nm) is prepared by a thermal evaporation deposition process, and the chromium/gold alloy layer is patterned by a lift-off process to obtain the metal electrode layer 8 (see fig. 2 f).
S7: an encapsulation layer 9 is prepared on the metal electrode layer 8 formed at step S6.
Specifically, the surface of the metal electrode layer 8 formed in step S6 is spin-coated with a fibroin solution at a rotation speed of 2000-4000r/min (e.g., 3000r/min) for 20-40S (e.g., 30S), a fibroin film with a thickness of 400-600nm (e.g., 500nm) is prepared, the fibroin film is patterned by photolithography to obtain an encapsulation layer 9, and the electrode sites on the metal electrode layer 8 are exposed from the hollow holes on the encapsulation layer 9 (see fig. 2 g).
S8: and (5) etching and removing the nickel sacrificial layer 11 on the structure obtained in the step (S7), and releasing the etched structure from the substrate 10 to obtain the flexible deep brain electrode.
Specifically, the use formula is I2:KI:H2And (3) etching and removing the nickel sacrificial layer 11 on the structure obtained in the step S7 by using a metal etching solution with the volume ratio of O being 1:4:40, and releasing the etched structure from the single-polished silicon wafer to obtain the flexible deep brain electrode (see fig. 2 h).
S9: and (5) fixing the flexible deep brain electrode obtained in the step (S8) on a flexible optical fiber through a clamp, and connecting the flexible optical fiber with a laser to obtain the intracranial stimulation recording system.
Specifically, the flexible deep brain electrode 2 obtained in step S8 is fixed to a flexible optical fiber 1 by a jig 4, the flexible portion of the flexible deep brain electrode 2 is attached to the surface of the flexible optical fiber 1 by capillary tension, and a laser 3 is connected to the rear end of the flexible optical fiber 1 as a light source, so as to obtain the intracranial stimulation recording system (see fig. 1).
The intracranial stimulation recording system provided by the invention has the following advantages:
1. according to the intracranial stimulation recording system, the flexible deep brain electrode is attached to the surface of the flexible optical fiber, the laser is used as a light source, the functions of optical pulse nerve stimulation and nerve electrophysiological signal acquisition can be integrated, meanwhile, optogenetic excitation and inhibition are realized, and the damage to brain tissues caused by heating of an LED chip when the LED chip is used as the light source can be avoided;
2. the intracranial stimulation recording system provided by the invention adopts fibroin as main materials of the substrate layer, the insulating layer and the packaging layer of the flexible deep brain electrode, and combines with the flexible optical fiber material, so that the mechanical compliance of an implanted device to brain tissue can be greatly improved, the neuroinflammation caused by long-term in vivo after the device is implanted is reduced, and long-term in vivo stimulation and recording are realized.
It should be noted that the above examples are only for illustrative purposes and should not be construed as limiting the scope of the present invention. While the invention has been described with reference to a preferred embodiment, those skilled in the art will appreciate that various changes can be made in the invention without departing from the spirit and scope of the invention, and all such changes are intended to be within the scope of the invention as defined and equivalents thereof.
Claims (15)
1. The intracranial stimulation recording system is characterized by comprising a flexible optical fiber (1), a laser (3) and a flexible deep brain electrode (2), wherein the flexible optical fiber (1) is connected with the laser (3), and the flexible deep brain electrode (2) is fixed on the flexible optical fiber (1) through a clamp (4).
2. The intracranial stimulation recording system as recited in claim 1, wherein the flexible deep brain electrode (2) is attached to the surface of the flexible optical fiber (1) by capillary tension.
3. The intracranial stimulation recording system according to claim 1, wherein the flexible deep brain electrode (2) comprises a metal wiring layer (6), an insulating layer (7), and a metal electrode layer (8) that are sequentially provided,
the metal wiring layer (6) is provided with a lead structure for connecting the metal electrode layer (8) positioned at the front end of the flexible deep brain electrode (2) with the rear end of the flexible deep brain electrode (2) through the lead structure,
the insulating layer (7) is used for isolating the metal wiring layer (6) from the metal electrode layer (8),
the metal electrode layer (8) is used for recording electrophysiological signals generated by nerve cells.
4. The intracranial stimulation recording system as recited in claim 3, wherein the flexible deep brain electrode (2) further comprises an encapsulation layer (9),
the packaging layer (9) is arranged above the metal electrode layer (8), and hollow holes for exposing the metal electrode layer (8) are formed in the packaging layer (9).
5. The intracranial stimulation recording system as recited in claim 4, wherein the flexible deep brain electrode (2) further comprises a backing layer (5),
the substrate layer (5) is arranged below the metal wiring layer (6), and the substrate layer (5) is used for supporting the metal wiring layer (6), the insulating layer (7), the metal electrode layer (8) and the packaging layer (9).
6. Intracranial stimulation recording system according to claim 5, wherein the substrate layer (5), the insulating layer (7) and the encapsulation layer (9) are all made of fibroin.
7. A method of making the intracranial stimulation recording system as recited in any one of claims 1-6, comprising the steps of:
s1: preparing a clean substrate (10) for use;
s2: preparing a nickel sacrificial layer (11) on the substrate (10) prepared in step S1;
s3: preparing a substrate layer (5) on the nickel sacrificial layer (11) obtained in the step S2;
s4: forming a metal wiring layer (6) on the substrate layer (5) prepared in step S3;
s5: preparing an insulating layer (7) on the metal wiring layer (6) formed in step S4;
s6: forming a metal electrode layer (8) on the insulating layer (7) prepared in step S5;
s7: preparing an encapsulation layer (9) on the metal electrode layer (8) formed in step S6;
s8: etching and removing the nickel sacrificial layer (11) on the structure obtained in the step S7, and releasing the etched structure from the substrate (10) to obtain the flexible deep brain electrode (2);
s9: and (5) fixing the flexible deep brain electrode (2) obtained in the step (S8) on a flexible optical fiber (1) through a clamp (4), and connecting the flexible optical fiber (1) with a laser (3) to obtain the intracranial stimulation recording system.
8. The method of manufacturing an intracranial stimulation recording system as recited in claim 7, wherein the substrate (10) is a single-polished silicon wafer.
9. The method for preparing an intracranial stimulation recording system as recited in claim 8, wherein the step S2 includes: and patterning the photoresist on the single-polished silicon wafer prepared in the step S1 by photoetching, preparing a layer of metal nickel with the thickness of 50-150nm by a thermal evaporation deposition process, and patterning the metal nickel by a stripping process to obtain the nickel sacrificial layer (11).
10. The method for preparing an intracranial stimulation recording system as recited in claim 9, wherein the step S3 includes: and spin-coating the fibroin solution on the nickel sacrificial layer (11) obtained in the step S2 at the rotating speed of 2000-4000r/min for 20-40S to prepare a fibroin film with the thickness of 400-600nm to obtain the substrate layer (5).
11. The method for preparing an intracranial stimulation recording system as recited in claim 10, wherein the step S4 includes: preparing a chromium/gold alloy layer with the thickness of 5nm/50nm-10nm/100nm on the substrate layer (5) prepared in the step S3 through photoetching patterning and thermal evaporation deposition processes, and carrying out stripping process patterning on the chromium/gold alloy layer to obtain the metal wiring layer (6).
12. The method for preparing an intracranial stimulation recording system as recited in claim 11, wherein the step S5 includes: and spin-coating the fibroin solution on the metal wiring layer (6) formed in the step S4 at the rotating speed of 2000-4000r/min for 10-20S, preparing a fibroin film with the thickness of 200-400nm, and exposing a wire structure of the metal wiring layer (6) for connecting the metal electrode layer (8) on the fibroin film to obtain the insulating layer (7).
13. The method for preparing an intracranial stimulation recording system as recited in claim 12, wherein the step S6 includes: preparing a chromium/gold alloy layer with the thickness of 5nm/50nm-10nm/100nm on the insulating layer (7) prepared in the step S5 through photoetching patterning and thermal evaporation deposition processes, and carrying out stripping process patterning on the chromium/gold alloy layer to obtain a metal electrode layer (8).
14. The method for preparing an intracranial stimulation recording system as recited in claim 13, wherein the step S7 includes: and spin-coating the fibroin solution on the metal electrode layer (8) formed in the step S6 at the rotating speed of 2000-4000r/min for 20-40S to prepare a fibroin film with the thickness of 400-600nm, and obtaining the packaging layer (9) through photoetching patterning.
15. The method for preparing an intracranial stimulation recording system as recited in claim 14, wherein the step S8 includes: and (3) removing the nickel sacrificial layer (11) on the structure obtained in the step (S7) by etching by using a metal corrosive liquid, and releasing the etched structure from the substrate (10) to obtain the flexible deep brain electrode (2).
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