CN109567786B - A kind of processing method of implantable flexible nerve microelectrode comb - Google Patents
A kind of processing method of implantable flexible nerve microelectrode comb Download PDFInfo
- Publication number
- CN109567786B CN109567786B CN201910063108.8A CN201910063108A CN109567786B CN 109567786 B CN109567786 B CN 109567786B CN 201910063108 A CN201910063108 A CN 201910063108A CN 109567786 B CN109567786 B CN 109567786B
- Authority
- CN
- China
- Prior art keywords
- comb
- flexible neural
- neural microelectrode
- microelectrode
- tooth
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000003672 processing method Methods 0.000 title claims abstract description 12
- 210000005036 nerve Anatomy 0.000 title abstract description 14
- 230000001537 neural effect Effects 0.000 claims abstract description 147
- 238000000034 method Methods 0.000 claims abstract description 46
- 239000007787 solid Substances 0.000 claims abstract description 19
- 244000126211 Hericium coralloides Species 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 22
- 238000012545 processing Methods 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 15
- 239000002202 Polyethylene glycol Substances 0.000 claims description 11
- 229920001223 polyethylene glycol Polymers 0.000 claims description 11
- 229920000642 polymer Polymers 0.000 claims description 11
- 238000001338 self-assembly Methods 0.000 claims description 8
- 108010022355 Fibroins Proteins 0.000 claims description 7
- 229920001661 Chitosan Polymers 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 4
- 102000008186 Collagen Human genes 0.000 claims description 2
- 108010035532 Collagen Proteins 0.000 claims description 2
- 108010010803 Gelatin Proteins 0.000 claims description 2
- 238000007605 air drying Methods 0.000 claims description 2
- 229920001436 collagen Polymers 0.000 claims description 2
- 229920000159 gelatin Polymers 0.000 claims description 2
- 239000008273 gelatin Substances 0.000 claims description 2
- 235000019322 gelatine Nutrition 0.000 claims description 2
- 235000011852 gelatine desserts Nutrition 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 238000002513 implantation Methods 0.000 abstract description 18
- 230000006378 damage Effects 0.000 abstract description 11
- 210000003792 cranial nerve Anatomy 0.000 abstract description 4
- 238000001514 detection method Methods 0.000 abstract description 4
- 238000007654 immersion Methods 0.000 abstract description 3
- 210000004556 brain Anatomy 0.000 description 14
- 239000000243 solution Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 7
- 210000005013 brain tissue Anatomy 0.000 description 6
- 210000001520 comb Anatomy 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 230000007774 longterm Effects 0.000 description 4
- 238000003466 welding Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 210000003625 skull Anatomy 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 208000014674 injury Diseases 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 238000007711 solidification Methods 0.000 description 2
- 230000008023 solidification Effects 0.000 description 2
- 238000012876 topography Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000010146 3D printing Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000002151 Microfilament Proteins Human genes 0.000 description 1
- 108010040897 Microfilament Proteins Proteins 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003479 dental cement Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001548 drop coating Methods 0.000 description 1
- 210000001951 dura mater Anatomy 0.000 description 1
- 239000007772 electrode material Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000003632 microfilament Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 210000004498 neuroglial cell Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
- A61B5/25—Bioelectric electrodes therefor
- A61B5/279—Bioelectric electrodes therefor specially adapted for particular uses
- A61B5/291—Bioelectric electrodes therefor specially adapted for particular uses for electroencephalography [EEG]
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B05—SPRAYING OR ATOMISING IN GENERAL; APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D—PROCESSES FOR APPLYING FLUENT MATERIALS TO SURFACES, IN GENERAL
- B05D3/00—Pretreatment of surfaces to which liquids or other fluent materials are to be applied; After-treatment of applied coatings, e.g. intermediate treating of an applied coating preparatory to subsequent applications of liquids or other fluent materials
- B05D3/007—After-treatment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B2562/00—Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
- A61B2562/02—Details of sensors specially adapted for in-vivo measurements
- A61B2562/0209—Special features of electrodes classified in A61B5/24, A61B5/25, A61B5/283, A61B5/291, A61B5/296, A61B5/053
Landscapes
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medical Informatics (AREA)
- Biophysics (AREA)
- Pathology (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Physics & Mathematics (AREA)
- Molecular Biology (AREA)
- Surgery (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
- Materials For Medical Uses (AREA)
Abstract
本发明提供了一种植入式柔性神经微电极梳的处理方法，所述处理方法包括将植入式柔性神经微电极梳中的实心结构、网格结构和梳齿状结构浸没于固化剂中，以及从固化剂中取出该植入式柔性神经微电极梳，使得网格结构和梳齿状结构发生弯曲，网格结构发生自组装，梳齿状结构自组装形成针状结构；本发明提供的处理方法可以将二维平面的柔性神经微电极梳组装成具有三维结构的柔性神经微电极梳，可以大大减小植入过程造成的损伤，与通过滴涂法对柔性神经微电极梳进行处理相比，使用浸没的方法处理得到的柔性神经微电极梳，组装后的结构更有序，形成的针状结构直径更小，表面更光滑，电极植入过程造成的损伤更小，更适用于作为脑神经检测元件使用。
The invention provides a processing method of an implantable flexible nerve microelectrode comb, the processing method comprising immersing the solid structure, the mesh structure and the comb-tooth-like structure in the implantable flexible nerve microelectrode comb in a curing agent, and taking out the implantable flexible nerve microelectrode comb from the curing agent, so that the grid structure and the comb-tooth-like structure are bent, the grid structure self-assembles, and the comb-tooth-like structure self-assembles to form a needle-like structure; The processing method can assemble a two-dimensional planar flexible neural microelectrode comb into a flexible neural microelectrode comb with a three-dimensional structure, which can greatly reduce the damage caused by the implantation process. Compared with the flexible neural microelectrode comb obtained by the immersion method, the assembled structure is more orderly, the needle-like structure formed has a smaller diameter and a smoother surface, and the damage caused by the electrode implantation process is smaller, which is more suitable for use as a needle-like structure. Use of cranial nerve detection element.
Description
Technical Field
The invention belongs to the field of medical electrode materials, and particularly relates to a processing method of an implanted flexible neural microelectrode comb.
Background
The brain nerve engineering is a research field which is active and rapidly developed at present, products of the brain nerve engineering such as brain-computer interfaces, nerve prostheses and the like are also receiving more and more attention, wherein the most critical component is a nerve electronic interface, namely a nerve electrode which is used as a key interface between nerve tissues and functional instruments, and the performance of the nerve electrode directly determines the achievable limit performance of the whole nerve activity recording system or nerve function reconstruction system.
The ideal implanted neural microelectrode needs to simultaneously meet a plurality of requirements of implantation damage as small as possible, effective recording or stimulating effect, long-term stability, excellent biocompatibility and the like, and the implanted neural microelectrode which is widely applied at present mainly has a microfilament neural electrode and a silicon-based neural electrode. The two electrodes are rigid electrodes, and when the electrodes are implanted into the brain, the electrodes are easy to move slightly with brain tissues, generate a large immune response to the brain, cause the proliferation of glial cells around the electrodes, block the signal transmission of recording sites and nerve cells, and cause the signal failure of long-term measurement.
In recent years, in order to meet the requirement of mechanical matching between a neural electrode and brain tissue and improve the quality of long-term signal measurement, it has been sought to manufacture a neural microelectrode having flexible characteristics so as to be capable of adapting to the surface topography of different neural tissues and to be well attached to a target neural tissue. The flexible nerve electrode is required to have mechanical strength matched with brain tissue, generates smaller acute injury when penetrating into the brain, can reduce micromotion of the nerve electrode and peripheral tissues after being implanted into the brain, has better biocompatibility, is not easy to generate inflammatory reaction and neuron injury to the brain, and can be used for long-term measurement of nerve signals. For example, chinese patent CN106667475A discloses an implantable flexible neural microelectrode comb, which discloses a method for solidifying the obtained flexible neural microelectrode comb, but only mentions that a molten solidified material is coated on the surface of the flexible neural microelectrode comb for solidification, and does not relate to a specific electrode solidification treatment method, and further improvement is needed.
Therefore, based on the prior art, those skilled in the art need to develop a more specific treatment method of the implanted flexible neural microelectrode comb, so that the implanted flexible neural microelectrode comb has a more stable surface structure, and the implanted damage is reduced and the function of the flexible neural electrode is improved.
Disclosure of Invention
In view of the defects in the prior art, the invention aims to provide a more specific treatment method of an implanted flexible neural microelectrode comb, so that the comb has a more stable surface structure, and the implanted damage is reduced and the function of a flexible neural electrode is improved.
To achieve the object, one of the objects of the present invention is to provide a processing method of an implantable flexible neural microelectrode comb, the processing method comprising the steps of:
selecting an implanted flexible neural microelectrode comb containing a solid structure, a grid structure and a comb-tooth-shaped structure, and immersing the solid structure, the grid structure and the comb-tooth-shaped structure in the implanted flexible neural microelectrode comb in a curing agent;
and (2) taking the implanted flexible neural microelectrode comb out of the curing agent, so that the grid structure and the comb-tooth-shaped structure are bent, the grid structure is self-assembled, the comb-tooth-shaped structure is self-assembled to form a needle-shaped structure, and the treated implanted flexible neural microelectrode comb is obtained.
According to the invention, the grid structure and the comb-tooth-shaped structure in the implanted flexible neural microelectrode comb are completely immersed in the curing agent and taken out, so that the grid structure and the comb-tooth-shaped structure are self-assembled due to the liquid surface tension and the elastic capillary force, and the obtained self-assembled structure can ensure the mechanical stability of the whole structure of the implanted flexible neural microelectrode comb.
Preferably, the grid structure is self-assembled to form a gourd-shaped structure or a cylindrical structure which are connected in series end to end.
Preferably, the implantable flexible neural microelectrode comb is an implantable flexible neural microelectrode comb having the structure of the implantable flexible neural microelectrode comb as described in CN 106667475A.
Preferably, the curing agent is a polymer melt or a polymer solution in a molten state.
The flexible neural microelectrode comb processed by the polymer has proper hardness on the surface, namely the stability of an electrode structure is ensured, the implantation process can be smoothly carried out, and the polymer on the surface has hydrophilicity or can be degraded, so that the flexible microelectrode comb after being processed recovers the flexible characteristic after being implanted into brain tissue, and has mechanical properties matched with the brain tissue.
The number average molecular weight of the polyethylene glycol is preferably 1000 to 10000, for example, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 55000, 6000, 6500, 7000, 7500, 8000, 9000, 9500, and the like, and more preferably 4000.
Preferably, the temperature of the polymer melt is 40 to 150 ℃, for example, 45 ℃, 55 ℃, 65 ℃, 75 ℃, 85 ℃, 95 ℃, 105 ℃, 115 ℃, 125 ℃, 135 ℃ or 145 ℃, and more preferably 120 ℃.
Preferably, the solid structure, the grid structure and the comb-tooth-shaped structure in the implantable flexible neural microelectrode comb in the step (1) are sequentially connected to fix the implantable flexible neural microelectrode comb.
Preferably, after the implantable flexible neural microelectrode comb is taken out from the solidifying agent in the step (2), air drying or freeze drying is performed, so that the solidifying agent is further solidified and molded.
Preferably, when the implanted flexible neural microelectrode comb is taken out in the step (2), the speed of taking out in the direction vertical to the liquid level of the curing agent is 0.1-3 mm/s, for example, 0.3mm/s, 0.6mm/s, 0.8mm/s, 1mm/s, 1.2mm/s, 1.4mm/s, 1.6mm/s, 1.8mm/s, 2mm/s, 2.2mm/s, 2.4mm/s, 2.6mm/s, 2.8mm/s, or the like, the implanted flexible neural microelectrode comb immersed in the curing agent is taken out at the speed of taking out, the smooth self-assembly process can be ensured, the structure of the microelectrode comb is easy to bend and deform at the high speed of taking out, solidified curing agent liquid drops appear on the surface, so that the implantation process causes a large trauma, it is further preferable that the withdrawal speed is 1.5 mm/s.
Preferably, the taking out is taking out along the extending direction of the comb teeth in the comb-tooth-shaped structure.
Preferably, the length of the comb-tooth-shaped structure in step (1) is 0.5-50 mm, such as 0.6mm, 1mm, 2mm, 5mm, 10mm, 15mm, 20mm, 25mm, 30mm, 35mm, 40mm, 45mm or 48 mm.
Preferably, the diameter of the needle-like structure formed by self-assembly of the comb-tooth-like structure in step (1) is 20-200 μm, such as 21 μm, 25 μm, 35 μm, 45 μm, 60 μm, 80 μm, 100 μm, 120 μm, 140 μm, 160 μm, 180 μm, or 190 μm.
The second purpose of the present invention is to provide an implantable flexible neural microelectrode comb processed by the method for processing an implantable flexible neural microelectrode comb as described above.
The recitation of numerical ranges herein includes not only the above-recited numerical values, but also any numerical values between non-recited numerical ranges, and is not intended to be exhaustive or to limit the invention to the precise numerical values encompassed within the range for brevity and clarity.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a processing method of a flexible neural microelectrode comb, which comprises the steps of immersing an implanted flexible neural microelectrode comb containing a solid structure, a grid structure and a comb-tooth structure in a curing agent and then taking out the comb, so that the grid structure and the comb-tooth structure are bent, the grid structure is self-assembled, and the comb-tooth structure is self-assembled to form a needle-shaped structure, the processing method can assemble the flexible neural microelectrode comb with a two-dimensional plane into the flexible neural microelectrode comb with a three-dimensional structure, the damage caused in the implantation process can be greatly reduced by assembling a high-density comb-tooth structure in the flexible neural microelectrode comb into a needle-shaped electrode with a smaller diameter, compared with the method of processing the surface of the flexible neural microelectrode comb by a dripping method, the flexible neural microelectrode comb obtained by using the immersion method has a more ordered structure after being assembled and a smaller diameter of the formed needle-shaped structure, the surface is smoother, the damage to the electrode implantation process is less, and the electrode is more suitable for being used as a cranial nerve detection element.
Drawings
Fig. 1 is a photograph of the process of treating the implantable flexible neural microelectrode comb in example 1 according to the embodiment of the present invention, which sequentially includes, from left to right, the implantable flexible neural microelectrode comb (a) obtained in example 2 of CN106667475A immersed in the melt, the process of taking out the solid structure and the mesh structure of the flexible neural microelectrode comb immersed in the melt (B), the process of taking out the comb-tooth-shaped structure of the flexible neural microelectrode comb immersed in the melt (C), and the treated implantable flexible neural microelectrode comb (D).
FIG. 2 is a microscopic photograph of the needle-like structure of the treated implanted flexible neural microelectrode comb obtained in example 1, wherein the ruler is 100 μm.
FIG. 3 is a microscopic photograph of the needle-like structure of the treated implanted flexible neural microelectrode comb in comparative example 1, wherein the ruler is 100 μm.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments.
Example 1
Treating an implanted flexible neural microelectrode comb by:
step (1), selecting the implanted flexible neural microelectrode comb structure described in embodiment 2 of CN106667475A as a processing object, wherein the implanted flexible neural microelectrode comb comprises a comb-tooth structure, a grid structure, a solid structure and a pad, which are connected in sequence, and the comb-tooth structure has a length of 5mm, an electrode site is arranged on the comb-tooth structure, and a welding point corresponding to the electrode is arranged on the pad;
step (2), placing a beaker filled with polyethylene glycol (PEG) with the number average molecular weight of 4000 on a hot plate at 120 ℃ to completely melt the beaker, fixing the pad part of the implanted flexible neural microelectrode comb in the step (1) on a fixing device after the molten liquid becomes clear, and completely immersing the solid structure, the grid structure and the comb-tooth-shaped structure in the flexible neural microelectrode comb in the molten liquid;
and (3) adjusting the fixing device in the step (2) to take out the flexible neural microelectrode comb immersed in the molten liquid, wherein the taking-out speed is 1.5mm/s in the direction vertical to the liquid level of the molten liquid, so that a grid structure and a comb-tooth-shaped structure in the microelectrode comb are bent, the grid structure is self-assembled into a gourd-shaped structure with heads and tails connected in series in sequence, the comb-tooth-shaped structure is self-assembled into a needle-shaped structure with the diameter of 55 mu m, and the completely taken-out flexible neural microelectrode comb is placed in the air at room temperature for 1min to be dried, so that the treated implanted flexible neural microelectrode comb is obtained.
Example 2
Treating an implanted flexible neural microelectrode comb by:
step (1), selecting the implanted flexible neural microelectrode comb structure described in embodiment 2 of CN106667475A as a processing object, wherein the implanted flexible neural microelectrode comb comprises a comb-tooth structure, a grid structure, a solid structure and a pad, which are connected in sequence, and the comb-tooth structure has a length of 0.5mm, the comb-tooth structure is provided with electrode sites, and the pad is provided with welding points corresponding to the electrodes;
step (2), preparing fibroin with the weight-average molecular weight of 100000 into a fibroin aqueous solution with the mass fraction of 15 wt%, fixing a pad part of the implanted flexible neural microelectrode comb in the step (1) on a fixing device, and completely immersing a solid structure, a grid structure and a comb-tooth-shaped structure in the flexible neural microelectrode comb into the fibroin aqueous solution;
and (3) adjusting the fixing device in the step (2) to take out the flexible neural microelectrode comb immersed in the fibroin solution, wherein the taking-out speed is 1.5mm/s in the direction vertical to the liquid level of the fibroin solution, so that a grid structure and a comb-tooth-shaped structure in the microelectrode comb are bent, the grid structure is self-assembled into a gourd-shaped structure with heads and tails connected in series in sequence, the comb-tooth-shaped structure is self-assembled into a needle-shaped structure with the diameter of 20 mu m, and the completely taken-out flexible neural microelectrode comb is placed in the air at room temperature for 1min to be dried, so that the treated implantable flexible neural microelectrode comb is obtained.
Example 3
Treating an implanted flexible neural microelectrode comb by:
step (1), the implanted flexible neural microelectrode comb structure obtained in embodiment 2 of CN106667475A is selected as a processing object, the implanted flexible neural microelectrode comb comprises a comb-tooth structure, a grid structure, a solid structure and a pad which are connected in sequence, the comb-tooth structure has a length of 50mm, an electrode site is arranged on the comb-tooth structure, and a welding point corresponding to the electrode is arranged on the pad;
preparing chitosan with the deacetylation degree of 75-85% and the weight-average molecular weight of 310000-375000 into a chitosan acetic acid solution with the concentration of 2 wt%, fixing a pad part of the implantable flexible neural microelectrode comb in the step (1) on a fixing device, and completely immersing a solid structure, a grid structure and a comb-tooth-shaped structure in the flexible neural microelectrode comb in the chitosan solution;
and (3) adjusting the fixing device in the step (2) to take out the flexible neural microelectrode comb immersed in the chitosan solution, wherein the taking-out speed is 1.5mm/s in the direction vertical to the liquid level of the chitosan solution, so that a grid structure and a comb-tooth-shaped structure in the microelectrode comb are bent, the grid structure is self-assembled into a gourd-shaped structure with heads and tails connected in series in sequence, the comb-tooth-shaped structure is self-assembled into a needle-shaped structure with the diameter of 200 mu m, the completely taken-out flexible neural microelectrode comb is placed in a freeze dryer at minus 20 ℃ for freeze drying, and after freeze drying, a sodium hydroxide-ethanol mixed solution with the same temperature is used for cleaning to remove residual solvent in the comb, so that the treated implantable flexible neural microelectrode comb is obtained.
Example 4
Treating an implanted flexible neural microelectrode comb by:
the only difference from example 1 is that the number average molecular weight of polyethylene glycol in step (2) was 1000 and the temperature on the hot plate was 40 ℃.
Example 5
Treating an implanted flexible neural microelectrode comb by:
the only difference from example 1 is that the number average molecular weight of polyethylene glycol in step (2) was 10000 and the temperature on a hot plate was 150 ℃.
Example 6
Treating an implanted flexible neural microelectrode comb by:
the only difference from example 1 is that the withdrawal speed in step (3) was 3 mm/s.
Example 7
Treating an implanted flexible neural microelectrode comb by:
the only difference from example 1 is that the withdrawal speed in step (3) was 0.5 mm/s.
Example 8
Treating an implanted flexible neural microelectrode comb by:
the only difference from example 1 is that the withdrawal speed in step (3) is 5 mm/s.
Example 9
Treating an implanted flexible neural microelectrode comb by:
the only difference from example 2 is that the fibroin in step (2) was replaced with a mixture of collagen and gelatin of the same molecular weight in a weight ratio of 1:1 and prepared in the same concentration as the aqueous solution.
Comparative example 1
Treating an implanted flexible neural microelectrode comb by:
step (1), the implanted flexible neural microelectrode comb structure obtained in embodiment 2 of CN106667475A is selected as a processing object, the implanted flexible neural microelectrode comb comprises a comb-tooth structure, a grid structure, a solid structure and a pad which are connected in sequence, the comb-tooth structure has a length of 5mm, an electrode site is arranged on the comb-tooth structure, and a welding point corresponding to the electrode is arranged on the pad;
step (2), immersing the solid structure, the grid structure and the comb-tooth-shaped structure in the flexible neural microelectrode comb in water, and then taking out the flexible neural microelectrode comb from the water, wherein the grid structure and the comb-tooth-shaped structure are subjected to self-assembly in the taking-out process, so that the grid structure and the comb-tooth-shaped structure in the flexible neural microelectrode comb are bent, the grid structure is subjected to self-assembly to form a cylindrical or gourd-shaped structure which is sequentially connected in series end to end, and the comb-tooth-shaped structure is subjected to self-assembly to form a needle-shaped structure;
step (3), polyethylene glycol (PEG) with the number average molecular weight of 4000 is placed on a hot plate at 120 ℃ to be completely melted, after the molten liquid becomes clear, the molten liquid is dripped on the flexible neural microelectrode comb which is self-assembled in the step (2) by a dropper, and after all structures of the flexible neural microelectrode comb are covered by the molten liquid, the dripping process is finished;
and (4) placing the dripped flexible neural microelectrode comb in the air at room temperature for 1min, and airing to obtain a treated implanted flexible neural microelectrode comb, wherein grid structures in the microelectrode comb are self-assembled into cylindrical or gourd-shaped structures which are sequentially connected in series end to end, but more curing agents are gathered at the junction of the grid structures and the comb-shaped structures, the comb-shaped structures are needle-shaped structures with the diameter of 90 micrometers, and a plurality of small drops of the curing agents are distributed on the needle-shaped structures, so that the treated implanted flexible neural microelectrode comb is obtained.
The surface appearances of the treated implanted flexible neural microelectrode combs obtained in the above examples 1 to 9 and the comparative example 1 were observed with a microscope, and the implantation performances were observed through a mouse brain implantation experiment.
The mouse brain implantation experiment is carried out by the following steps:
step (1), respectively packaging the treated implanted flexible neural microelectrode combs in a 3D printing holder, and placing the holder under an ultraviolet lamp for disinfection for 30 min;
fixing a mouse on a brain stereotaxic apparatus, cutting off a scalp, positioning a brain area to be implanted, opening a skull, removing a dura mater, fixing a packaged flexible neural microelectrode comb on a micromanipulation control rod of the stereotaxic apparatus, and implanting the flexible neural microelectrode comb into the specific brain area at the speed of 2mm/s respectively, wherein the implantation depth is 0.5-2 mm;
after the flexible neural microelectrode combs are implanted, infiltrating the flexible neural microelectrode combs exposed on the upper parts of the brains with cerebrospinal fluid, and then continuously moving the micro control rods downwards for about 1mm to reduce the relative displacement of the skull and the brains and reduce the tissue damage;
and (4) covering the operation part with a Kwik-Sil isolation adhesive, and fixing the packaged flexible neural microelectrode comb on the skull by using dental cement to complete the whole implantation experiment.
The surface topography and implantation properties of the treated implanted flexible neural microelectrode combs obtained in the above examples and comparative examples are shown in table 1 for comparison.
TABLE 1 comparison of surface morphology and Implantation Performance of treated implantable flexible neural microelectrode combs obtained in each of examples and comparative examples
From the comparison between the embodiment 1 and the embodiments 2 to 9, it can be seen that in the processing method of the present invention, the change of other factors has a small influence on the processing result of the flexible neural microelectrode comb, and the flexible neural microelectrode comb with a complete self-assembly structure can be obtained, and the change of the taking-out rate has a significant influence on the processing of the implanted flexible neural microelectrode comb, and the too fast taking-out rate easily causes the structure of the flexible neural microelectrode comb to bend and deform, and solidified curing agent droplets appear on the surface, which is not favorable for the implantation of the electrode.
Fig. 1 is a photograph showing the process of treating an implantable flexible neural microelectrode comb in example 1 of the present invention, which sequentially shows, from left to right, the implantable flexible neural microelectrode comb (a) obtained in example 2 of CN106667475A immersed in the melt, the process of taking out the solid structure and the mesh structure of the flexible neural microelectrode comb immersed in the melt (B), the process of taking out the comb-tooth structure of the flexible neural microelectrode comb immersed in the melt (C), and the treated implantable flexible neural microelectrode comb (D).
FIG. 2 is a microscopic photograph of the needle-like structure of the treated implantable flexible neural microelectrode comb obtained in example 1 of the present invention under a microscope, wherein the ruler is 100 μm.
FIG. 3 is a microscopic photograph of the needle-like structure of the treated implantable flexible neural microelectrode comb in comparative example 1 of the present invention under a microscope, wherein the ruler is 100 μm.
As can be seen from fig. 1 to 3 and the comparison between example 1 and comparative example 1, compared with the method of drop coating, in which a curing agent is coated on the surface of a microelectrode comb to treat the microelectrode comb, the microelectrode comb is immersed in the curing agent and then taken out to be treated, so that the self-assembly process of the microelectrode comb can be more completely ordered, the obtained needle-like structure is smaller, the surface is smoother, the treated flexible neural microelectrode comb has less damage to brain tissue during the implantation process, and the flexible neural microelectrode comb is more suitable for being used as a cranial nerve detection element.
In summary, the invention provides a method for processing a flexible neural microelectrode comb, which comprises immersing an implanted flexible neural microelectrode comb having a solid structure, a grid structure and a comb-tooth structure in a curing agent, and then taking out the implanted flexible neural microelectrode comb, so that the grid structure and the comb-tooth structure are bent, the grid structure is self-assembled, and the comb-tooth structure is self-assembled to form a needle-like structure, the method can assemble a two-dimensional plane flexible neural microelectrode comb into a flexible neural microelectrode comb having a three-dimensional structure, the damage caused by the implantation process can be greatly reduced by assembling a high-density comb-tooth structure in the flexible neural microelectrode comb into a needle-like electrode with a smaller diameter, compared with the method for processing the surface of the flexible neural microelectrode comb by a dropping coating method, the flexible neural microelectrode comb obtained by using the immersion method has a more ordered structure after the assembly, the formed needle-shaped structure has smaller diameter and smoother surface, causes less damage in the electrode implantation process, and is more suitable for being used as a cranial nerve detection element.
The applicant declares that the above description is only a specific embodiment of the present invention, but the scope of the present invention is not limited thereto, and it should be understood by those skilled in the art that any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are within the scope and disclosure of the present invention.
Claims (14)
1. A processing method of an implantable flexible neural microelectrode comb is characterized by comprising the following steps:
selecting an implanted flexible neural microelectrode comb containing a solid structure, a grid structure and a comb-tooth-shaped structure, and immersing the solid structure, the grid structure and the comb-tooth-shaped structure in the implanted flexible neural microelectrode comb in a curing agent;
step (2), taking out the implanted flexible neural microelectrode comb from the curing agent, so that the grid structure and the comb-tooth-shaped structure are bent, the grid structure is self-assembled, the comb-tooth-shaped structure is self-assembled to form a needle-shaped structure, and the treated implanted flexible neural microelectrode comb is obtained;
when the implanted flexible neural microelectrode comb is taken out in the step (2), the taking-out speed in the direction vertical to the liquid level of the curing agent is 0.1-3 mm/s;
and (3) taking out along the extending direction of the comb teeth in the comb-tooth-shaped structure.
2. The method for processing the implantable flexible neural microelectrode comb of claim 1, wherein the curing agent is a polymer melt or a polymer solution in a molten state.
3. The method for processing the implantable flexible neural microelectrode comb according to claim 2, wherein the polymer is one or a mixture of at least two of polyethylene glycol, chitosan, fibroin, collagen and gelatin.
4. The method for processing the implantable flexible neural microelectrode comb of claim 3, wherein the polymer is polyethylene glycol.
5. The treatment method of the implantable flexible neural microelectrode comb of claim 3, wherein the polyethylene glycol has a number average molecular weight of 1000 to 10000.
6. The method for processing the implantable flexible neural microelectrode comb of claim 5, wherein the polyethylene glycol has a number average molecular weight of 4000.
7. The treatment method of the implantable flexible neural microelectrode comb of claim 2, wherein the temperature of the polymer melt is 40-150 ℃.
8. The method for processing the implantable flexible neural microelectrode comb of claim 7, wherein the temperature of the polymer melt is 120 ℃.
9. The method for processing the implantable flexible neural microelectrode comb of claim 1, wherein the solid structure, the grid structure and the comb-tooth structure in step (1) are connected in sequence.
10. The method for processing the implantable flexible neural microelectrode comb according to claim 1, wherein in the step (2), after the implantable flexible neural microelectrode comb is taken out from the curing agent, the grid structure and the comb-tooth structure are bent, the grid structure is self-assembled, the comb-tooth structure is self-assembled to form a needle-like structure, and then air drying or freeze drying is performed to obtain the processed implantable flexible neural microelectrode comb.
11. The method for processing the implantable flexible neural microelectrode comb of claim 1, wherein the speed of taking out the implantable flexible neural microelectrode comb in the direction perpendicular to the liquid level of the solidifying agent is 1.5mm/s in the step (2).
12. The method for processing the implantable flexible neural microelectrode comb of claim 1, wherein the length of the comb-shaped structure in the step (1) is 0.5-50 mm.
13. The method for processing the implantable flexible neural microelectrode comb according to claim 1, wherein the diameter of the needle-like structure formed by self-assembly of the comb-shaped structure in the step (1) is 20-200 μm.
14. An implantable flexible neural microelectrode comb after being treated by the treatment method of the implantable flexible neural microelectrode comb according to any one of claims 1 to 13.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910063108.8A CN109567786B (en) | 2019-01-23 | 2019-01-23 | A kind of processing method of implantable flexible nerve microelectrode comb |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910063108.8A CN109567786B (en) | 2019-01-23 | 2019-01-23 | A kind of processing method of implantable flexible nerve microelectrode comb |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109567786A CN109567786A (en) | 2019-04-05 |
| CN109567786B true CN109567786B (en) | 2021-10-19 |
Family
ID=65917004
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910063108.8A Active CN109567786B (en) | 2019-01-23 | 2019-01-23 | A kind of processing method of implantable flexible nerve microelectrode comb |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109567786B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111450411B (en) * | 2020-04-09 | 2023-07-25 | 国家纳米科学中心 | A kind of composite nerve electrode and preparation method thereof |
| CN119970050B (en) * | 2025-01-20 | 2025-12-05 | 浙江大学 | A self-climbing, self-adhesive flexible electrode patch for neural monitoring |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3217290C2 (en) * | 1982-05-07 | 1985-06-20 | Dr.-Ing. Rudolf Hell Gmbh, 2300 Kiel | Method and device for producing an electrode comb |
| US6745079B2 (en) * | 2001-11-07 | 2004-06-01 | Medtronic, Inc. | Electrical tissue stimulation apparatus and method |
| US20030176908A1 (en) * | 2002-03-18 | 2003-09-18 | Hsin-Yi Lin | Water-impregnable electrode for electrical stimulation device |
| JP5502992B2 (en) * | 2009-05-26 | 2014-05-28 | カーディアック ペースメイカーズ， インコーポレイテッド | Lead assembly for implantable medical devices |
| EP2353636A1 (en) * | 2010-02-05 | 2011-08-10 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. | Neurological interfacing probe |
| CN101884530A (en) * | 2010-07-14 | 2010-11-17 | 中国科学院半导体研究所 | Flexible Probe Electrode and Its Implantation Tool for Recording Electrical Signals of Neural Activity |
| CN101912666B (en) * | 2010-08-18 | 2014-12-03 | 中国科学院上海微系统与信息技术研究所 | PDMS-based flexible implanted neural microelectrode and manufacturing method |
| CN102755158A (en) * | 2011-04-25 | 2012-10-31 | 有医科技股份有限公司 | Comb electrode |
| CN103035774B (en) * | 2012-12-31 | 2015-07-01 | 东南大学 | Single-light-source implantable nerve multipoint synchronous interaction chip and preparation method thereof |
| WO2015106378A1 (en) * | 2014-01-14 | 2015-07-23 | 无锡慧思顿科技有限公司 | Multifunctional medical mems microprobe |
| CN206228767U (en) * | 2016-07-28 | 2017-06-09 | 苏州大学 | Nerve electrode and preparation method thereof |
| CN106667475B (en) * | 2016-12-20 | 2019-05-07 | 国家纳米科学中心 | An implantable flexible nerve microelectrode comb and its preparation method and implantation method |
| CN107638175B (en) * | 2017-08-24 | 2020-12-01 | 国家纳米科学中心 | A flexible electrode array-fiber composite nerve electrode and preparation method thereof |
| CN108553755A (en) * | 2018-05-03 | 2018-09-21 | 国家纳米科学中心 | A kind of flexible 3 D nerve electrode and preparation method thereof |
| CN108801347B (en) * | 2018-06-07 | 2021-01-12 | 哈尔滨工业大学深圳研究生院 | Preparation method of transparent flexible multifunctional sensor |
| CN108853717B (en) * | 2018-06-19 | 2022-03-22 | 国家纳米科学中心 | A kind of flexible nerve electrode and implantation method of flexible nerve electrode |
-
2019
- 2019-01-23 CN CN201910063108.8A patent/CN109567786B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN109567786A (en) | 2019-04-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Fernandes et al. | Bioinspired three-dimensional magnetoactive scaffolds for bone tissue engineering | |
| Cointe et al. | Scalable batch fabrication of ultrathin flexible neural probes using a bioresorbable silk layer | |
| Yang et al. | Characterization of neural stem cells on electrospun poly (L-lactic acid) nanofibrous scaffold | |
| US7981353B2 (en) | Method for controlled electrospinning | |
| DE10312144B4 (en) | Carrier material for tissue and cell culture and the production of implant materials | |
| US10292656B2 (en) | Fabrication for ultra-compliant probes for neural and other tissues | |
| US10633766B2 (en) | Method and apparatus for collecting cross-aligned fiber threads | |
| Khilwani et al. | Ultra-miniature ultra-compliant neural probes with dissolvable delivery needles: design, fabrication and characterization | |
| CN109567786B (en) | A kind of processing method of implantable flexible nerve microelectrode comb | |
| Liu et al. | Recent progress of spider-silk-inspired adhesive materials | |
| CN108774327A (en) | It is used to prepare the method for PVA hydrogels, using the PVA hydrogels and composite material of its preparation | |
| WO2012145652A1 (en) | Dynamic silk coatings for implantable devices | |
| WO2015178980A2 (en) | Anisotropic muscular tissue devices with integrated electrical force readouts | |
| Lee et al. | Matrigel coatings for P arylene sheath neural probes | |
| Sivolella et al. | Nanostructured guidance for peripheral nerve injuries: a review with a perspective in the oral and maxillofacial area | |
| US20230386697A1 (en) | Viscoelastic conductive hydrogel | |
| WO2014063013A1 (en) | Apparatus and method for electrospinning a nanofiber coating on surfaces of poorly conductive three-dimensional objects | |
| Wu et al. | A multi-shank silk-backed parylene neural probe for reliable chronic recording | |
| Ma et al. | Bio-inspired low-cost fabrication of stretchable, adhesive, transparent, and multi-functionalized joint wound dressings | |
| Ando et al. | Filtration-processed biomass nanofiber electrodes for flexible bioelectronics | |
| KR101791896B1 (en) | Apparatus and method for making functional prostheses using 3D printing and EHD | |
| EP4223325B1 (en) | Surface treatment of polyaryletherketones | |
| WO2024153047A1 (en) | Permeable stretchable bioelectronic devices and methods of use and fabrication thereof | |
| PT110191B (en) | BIOMICROELECTROMECHANICAL SYSTEMS (BIOMEMS) FOR ADVANCED METALLIC IMPLANTS CONTROLLED BY FUNCTIONALIZED PIEZOELECTRIC COATINGS | |
| Hoshino et al. | Muscle-powered cantilever for microtweezers with an artificial micro skeleton and rat primary myotubes |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230414 Address after: Room 401, 4th Floor, South Building, Zhongke Resource Building, No. 6 South Third Street, Zhongguancun, Haidian District, Beijing, 100190 Patentee after: Beijing Zhiran Medical Technology Co.,Ltd. Address before: 100190 No. 11, north of Haidian District, Beijing, Zhongguancun Patentee before: NATIONAL CENTER FOR NANOSCIENCE AND TECHNOLOGY |
|
| TR01 | Transfer of patent right |