CN113545790B - Preparation method of magnetic compatible nerve probe - Google Patents
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- 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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Abstract
The invention discloses a preparation method of a magnetic compatible nerve probe, which comprises the following steps: the method comprises the steps of sequentially coating a first biomedical polymer film layer on a substrate, covering a first metal layer, covering a second biomedical polymer film layer, sputtering a second metal layer and a third metal layer to serve as a metal circuit structure layer substrate, preparing a metal circuit structure layer comprising at least one electrode point, at least two connection points, at least one reference electrode point and a metal circuit used for connecting the electrode point or the reference electrode point with the connection point, spraying a third biomedical polymer film layer, modifying the electrode point, the reference electrode point and the connection point, and forming a nerve probe according to an outer contour pattern. The magnetic compatible nerve probe prepared by the invention can be used for detecting the nerve signals in the brain and performing electrical stimulation, is particularly suitable for being synchronously used with a magnetic resonance imager, can stably detect the change of the nerve signals in the brain, and can be synchronously recorded with magnetic resonance imaging.
Description
Technical Field
The invention belongs to the technical field of bioengineering, and particularly relates to a preparation method of a magnetic compatible nerve probe.
Background
The traditional nerve probe is widely applied to research on electrophysiological functions of cranial nerves, however, the traditional microelectrode probe developed at present is still not easy to reliably detect the activity of nerve cells during nuclear magnetic resonance, and the traditional microelectrode probe is mainly attributed to that the electrode made of metal materials is used for multiple purposes at present, so that the impedance is high in a low-frequency section, and the recording intensity and range of electrophysiological signals are weakened; in nuclear magnetic resonance examination, the metal portion may generate an eddy current electrocautery effect under a change in a high-intensity magnetic field, and may be displaced by a magnetic force even under a static magnetic field to damage nerve tissue. In addition, common metal components contained in common nerve electrodes and probes can distort and artifact images to different degrees during magnetic resonance imaging, and the application range of the nerve electrodes and the probes is greatly limited. As shown in fig. 13, when a tungsten electrode 91 (having a total diameter of about 100 micrometers) composed of 2 monofilaments or a two-channel platinum-iridium electrode 92 (having a total diameter of 150 micrometers) is used for mri, a large area of black image is generated at the electrode, which affects the judgment.
The technique of nerve implantation began in the 1960 s. At that time, neurologists and neurosurgeons attempted to electrically stimulate nerves using microelectrodes to locate specific sites in the brain, while using a signal processor to analyze changes in neuronal activity. Meanwhile, it was found that electrical stimulation of certain structures in the brain results in suppression of symptoms of neurological diseases, such as tremor and parkinson's disease. Researchers have therefore developed multichannel Neural implant devices to understand how brain neurons can Neural code specific behavioural movements, starting with simultaneous recording of neuronal activity in different brain regions, in an attempt to understand the meaning of Neural languages. The technology simultaneously records the information of the neuron cell activities of a plurality of brain areas in the brain, so that researchers can obtain the knowledge of how neurons communicate and process information, the knowledge can be used for solving a plurality of important problems in neurobiology, ethology and cognitive science, and the technology is a breakthrough in the research of neuroscience methodology.
Some of the conventional probes are silicon-based multi-channel microelectrode arrays, which are typically called Michigan electrode arrays (Michigan electrode array) and have a plurality of microelectrodes disposed on a handle-like structure, which also provide high spatial resolution for more complete neural signal recording. However, because the brain is complicated and is full of nerves, extra care needs to be taken when performing relevant invasive tests, especially when using a nerve probe to capture the information of nerve activity in a specific brain region. How to increase the detection range of a single nerve probe and reduce the occurrence of signal strength misjudgment is a problem that needs to be overcome at present.
In view of the above, the inventor of the present invention invests in many research and development energies and spirits, and continuously breaks through and innovates in the field, and intends to solve the conventional deficiencies by a novel technical means, thereby not only bringing better products to the society, but also promoting the industrial development.
Disclosure of Invention
The invention aims to provide a preparation method of a magnetic compatible nerve probe, which can be applied to the detection of current in a brain, is particularly suitable for being synchronously used with a detection instrument with high magnetic flux, can stably detect the current state in the brain and stimulate nerve cells with current or voltage, has no high impedance in a low-frequency section, and cannot be synchronously recorded with the detection instrument due to the limitation of metal substances.
The invention comprises the following technical scheme:
a method of making a magnetically compatible nerve probe, the method comprising the steps of:
(1) coating a first biomedical polymer film layer on a substrate, and covering a first metal layer on the first biomedical polymer film layer, wherein the first metal layer completely covers the first biomedical polymer film layer, and the first metal layer is made into the shape of a nerve probe;
(2) covering a second biomedical polymer film layer on the first metal layer, and sputtering a second metal layer and a third metal layer on the second biomedical polymer film layer in sequence to serve as a metal circuit structure layer substrate; etching a metal circuit structure layer on the metal circuit structure layer substrate through a metal circuit photomask, wherein the metal circuit structure layer comprises at least one electrode point, at least two connection points, at least one reference electrode point and a metal circuit for connecting the electrode point or the reference electrode point and the connection points;
(3) spraying a third biomedical polymer film layer on the metal circuit structure layer, arranging patterns at the electrode points, the reference electrode points and the connection points on the third biomedical polymer film layer, and exposing the electrode points, the reference electrode points and the connection points by etching;
(4) electroplating a gold layer or a silver layer on the electrode point, the reference electrode point and the connection point, wherein the heights of the electrode point, the reference electrode point and the connection point after electroplating the gold layer or the silver layer are greater than that of the third biomedical polymer film layer;
(5) modifying the electrode point and the reference electrode point by using iridium oxide in an electrochemical mode;
(6) separating the substrate and forming the nerve probe according to the outline pattern.
In step (6), the nerve probe is formed by cutting the outline pattern with a laser after separating the substrate.
Preferably, in the step (5), the parylene layer is coated on the third biomedical polymer film layer except for the electrode point, the reference electrode point and the connection point; and modifying the electrode point and the reference electrode point by using iridium oxide in an electrochemical mode, and then removing the parylene layer. In the step (6), the outline pattern of the nerve probe is arranged on the third biomedical polymer film layer, and the parts, outside the outline pattern, of the first biomedical polymer film layer, the second biomedical polymer film layer and the third biomedical polymer film layer are removed through etching; the neural probe is formed after the base material is separated.
In the present invention, the etching technique may be an oxygen plasma etching technique.
The base material is a glass sheet or a silicon wafer.
The first biomedical polymer film, the second biomedical polymer film and the third biomedical polymer film are made of materials selected from polyimide, polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene, polyacrylate, polymethacrylic acid, polyethylene terephthalate, polycarbonate, and parylene or a combination of more than two of the materials.
The first metal layer and the second metal layer are made of materials selected from titanium, copper, chromium, gold and silver.
The third metal layer is made of copper, gold or silver.
The thickness of the first biomedical polymer film layer and the second biomedical polymer film layer is between 10 micrometers and 60 micrometers; the thickness of the first metal layer is between 100 nanometers and 500 nanometers; the thickness of the second metal layer is between 50 nanometers and 400 nanometers; the thickness of the third biomedical polymer film layer is between 1 micron and 20 microns. Preferably, the thickness of the first biomedical polymer film layer and the second biomedical polymer film layer is 30 microns optimally; the thickness of the first metal layer is 200 nanometers; the thickness of the second metal layer is 100 nanometers; the thickness of the third biomedical polymer film layer is 3.2 microns.
The thickness of the third metal layer is between 500 nanometers and 1000 nanometers; the thickness of the gold or silver layer is between 2 and 20 microns. Preferably, the thickness of the third metal layer is 700 nm; the thickness of the gold layer or the silver layer is 5 microns.
The magnetic compatible nerve probe prepared by the preparation method sequentially comprises a first biomedical polymer film layer, a first metal layer and a second biomedical polymer film layer; the first metal layer is in the shape of a nerve probe; a metal circuit structure layer is arranged on the second biomedical polymer film layer; the metal circuit structure layer comprises at least one electrode point, at least two connecting points, at least one reference electrode point and a metal circuit for connecting the electrode point or the reference electrode point and the connecting points; a third biomedical polymer film layer is arranged on the second biomedical polymer film layer except for the electrode point, the reference electrode point and the connection point; a gold layer or a silver layer and an iridium oxide modification layer are sequentially covered on the electrode point and the reference electrode point, and the gold layer or the silver layer is covered on the connection point; the height of the electrode point, the height of the reference electrode point and the height of the connection point are higher than that of the third biomedical polymer film layer.
The thickness of the first biomedical polymer film layer and the second biomedical polymer film layer is between 10 micrometers and 60 micrometers; the thickness of the first metal layer is between 100 nanometers and 500 nanometers; the thickness of the second metal layer is between 50 nanometers and 400 nanometers; the thickness of the third biomedical polymer film layer is between 1 micron and 20 microns. Preferably, the thickness of the first biomedical polymer film layer and the second biomedical polymer film layer is 30 microns optimally; the thickness of the first metal layer is 200 nanometers; the thickness of the second metal layer is 100 nanometers; the thickness of the third biomedical polymer film layer is 3.2 microns.
The thickness of the third metal layer is between 500 nanometers and 1000 nanometers; the thickness of the gold or silver layer is between 2 and 20 microns. Preferably, the thickness of the third metal layer is 700 nm; the thickness of the gold layer or the silver layer is 5 microns.
The area of the reference electrode point is more than 10 times of the area of the electrode point. Preferably, the area of the reference electrode point is 20 times or more the area of the electrode point.
The nerve probe provided by the invention integrates the traditional reference/ground wire function depending on the metal nail and the lead on the metal circuit structure layer on the basis of abandoning ferromagnetic materials and reducing metal components as much as possible, can not be influenced by magnetic force when being in a nuclear magnetic resonance environment, simultaneously carries out corresponding current detection, and overcomes the problem of image defects caused by the prior art. The neural probe provided by the invention can be used for signal recording of single or multiple neurons in the brain, can also be used for giving electrical stimulation to a specific brain region to inhibit or promote corresponding neuron activity, and can also be used for simultaneously carrying out electrical stimulation and signal measurement. The electrophysiological signals recorded by the neural probe in the specific brain area can be analyzed for diagnosing epilepsy, migraine, Alzheimer's disease, etc., and can be used for providing electrical stimulation to the specific brain area or neuron to achieve specific therapeutic purposes.
Drawings
FIG. 1 is a schematic structural diagram of a first biomedical polymer film layer covered with a first metal layer;
FIG. 2 is another schematic structural diagram of a first biomedical polymer film layer covered with a first metal layer;
FIG. 3 is a schematic structural diagram of a second biomedical polymer film layer covered on the first metal layer;
FIG. 4 is a schematic structural view of a metal wiring structure layer etched;
FIG. 5 is a schematic structural view illustrating a third biomedical polymer film layer sprayed on a metal circuit structure layer;
FIG. 6 is a schematic view of a structure in which a gold or silver layer is electroplated onto the electrode points, the reference electrode points and the connection points;
FIG. 7 is a schematic structural diagram of a parylene layer covering a third biomedical polymer film layer except for an electrode point, a reference electrode point and a connection point;
FIG. 8 is a schematic structural diagram of an electrode point and a reference electrode point electrochemically modified with iridium oxide;
FIG. 9 is a schematic structural diagram of a portion of the first biomedical polymer film layer, the second biomedical polymer film layer and the third biomedical polymer film layer outside the outline pattern being removed by etching;
FIG. 10 is a schematic structural view of a nerve probe formed after separation of a base material;
FIG. 11 is a schematic diagram of a magnetically compatible nerve probe;
FIG. 12 is a diagram illustrating the MRI operation of the present invention;
fig. 13 is a diagram illustrating a state in which the prior art is applied to MRI.
Detailed Description
The nerve probe provided by the embodiment of the invention can be suitable for synchronous detection and electric stimulation with a magnetic resonance imager, can stably detect the change of nerve signals in a brain, and cannot be synchronously recorded with the magnetic resonance imager due to the influence limitation of a magnetic field.
In order to easily understand the structure and the manufacturing method of the magnetic compatible nerve probe of the present invention, the following description will be made in conjunction with the manufacturing method and the drawings.
As shown in fig. 1 to 10, the present embodiment provides a magnetic compatible nerve probe: the electrode structure sequentially comprises a first biomedical polymer film layer 10, a first metal layer 11 and a second biomedical polymer film layer 20, wherein the first metal layer 11 is in the shape of a nerve probe, a metal circuit structure layer 22 is arranged on the second biomedical polymer film layer 20, and the metal circuit structure layer 22 comprises 2 electrode points 222, three connection points 221, a reference electrode point R and a metal circuit 223 for connecting the electrode points 222 or the reference electrode point R with the connection points 221; a third biomedical polymer film layer 30 is arranged on the second biomedical polymer film layer 10 except for the electrode point 222, the reference electrode point R and the connection point 221; the electrode point 222 and the reference electrode point R are sequentially covered with a gold layer or silver layer 31 and an iridium oxide modification layer 50; the connection points 221 are covered with a gold or silver layer 31. The preparation method of the magnetic compatible nerve probe comprises the following steps:
s1, as shown in fig. 1, the first biomedical polymer film layer 10 is disposed on the substrate B, and the first biomedical polymer film layer 10 is covered with the first metal layer 11. The substrate B may be glass or silicon wafer. In addition, as shown in fig. 2, the first metal layer 11 may be laid in a probe shape. In the present embodiment, the first metal layer 11 is etched into a nerve probe shape. The first metal layer 11 may reinforce the mechanical strength of the entire probe.
S2, as shown in fig. 3, the second biomedical polymer film layer 20 is covered on the first metal layer 11 having the shape of the probe, the second metal layer and the third metal layer are disposed on the second biomedical polymer film layer 20 as the metal circuit structure layer substrate 21, and the metal circuit structure layer substrate 21 can be combined and covered on the second biomedical polymer film layer 20 by sputtering.
Wherein the thickness of the first biomedical polymer film layer 10 and the second biomedical polymer film layer 20 is between 10 microns and 60 microns, and preferably 30 microns. The thickness of the first metal layer is between 100 nm and 500 nm, preferably 200 nm; the thickness of the second metal layer is between 50 nm and 400 nm, preferably 100 nm; the thickness of the third metal layer is between 500 nm and 1000 nm, preferably 700 nm. Wherein the first biomedical polymer film layer, the second biomedical polymer film layer, and the third biomedical polymer film layer can be polyimide, polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene, polyacrylate, polymethacrylic acid, polyethylene terephthalate, polycarbonate, or parylene, or a combination thereof. The first metal layer may be chromium, copper, titanium, gold, or silver. The second metal layer and the third metal layer can be copper, gold or silver.
S3, as shown in fig. 4, the metal circuit pattern includes at least one electrode point, at least two connection points, at least one reference electrode point and at least two metal circuits, the metal circuit pattern is disposed (mask etching printing technology) on the metal circuit structure layer substrate 21 through a metal circuit mask, and then the metal circuit structure layer substrate 21 not covered by the metal circuit pattern is etched to form the metal circuit structure layer 22 on the second biomedical polymer film layer 20. The metal line structure layer 22 includes at least one electrode point 222, at least two connection points 221, a reference electrode point R, and at least two metal lines 223, wherein the metal lines 223 are electrically connected to the electrode point 222, the reference electrode point R, and the connection points 221. In the present embodiment, the metal circuit structure layer 22 includes 2 electrode points 222, three connection points 221, a reference electrode point R, and three metal circuits 223 respectively connecting the electrode points 222, the reference electrode point R, and the connection points 221.
S4, as shown in fig. 5, the third biomedical polymer thin film layer 30 is disposed on the metal circuit structure layer 22 by spraying, then the patterned mask corresponding to the electrode point 222, the connection point 221 and the reference electrode point R is disposed on the third biomedical polymer thin film layer 30, and the electrode point 222, the reference electrode point R and the connection point 221 are exposed by using oxygen plasma etching technique.
S5, as shown in fig. 6, the gold layer 31 (or silver layer) is electroplated on the electrode point 222, the reference electrode point R and the connection point 221, and the height of the electrode point 222, the reference electrode point R and the connection point 221 after the gold layer 31 is electroplated is higher than that of the third biomedical polymer thin film layer 30.
Wherein: the thickness of the third biomedical polymer film layer is between 1 micron and 20 microns, preferably 3.2 microns; the thickness of the gold layer (or silver layer) is between 2 microns and 20 microns, with 5 microns being most preferred.
S6, as shown in fig. 7, the parylene layer 40 is covered on the third biomedical polymer thin film layer 30, except for the gold layer 31 (or silver layer) corresponding to the electrode point 222, the reference electrode point R and the connection point 221, so as to protect the third biomedical polymer thin film layer 30 from being damaged in the subsequent modification process of the electrode point and the reference electrode point.
S7, as shown in fig. 8 to 10, after electrochemically modifying the electrode point 221 and the reference electrode point R with the iridium oxide 50 (i.e., covering the electrode point 221 and the gold layer 31 (or silver layer) corresponding to the reference electrode point R), removing the parylene layer 40; the outline pattern of the probe is printed on the third biomedical polymer film layer 30, and the oxygen plasma etching technology is used to remove the parts of the first biomedical polymer film layer 10, the second biomedical polymer film layer 20 and the third biomedical polymer film layer 30 outside the outline pattern. And finally, separating the substrate B to form the magnetic compatible nerve probe N.
Wherein, the step S6 and the step S7 can be replaced by the step S40 of forming the nerve probe by laser cutting the outline pattern after modifying the electrode points and the reference electrode points and separating the substrate material on the third biomedical polymer film layer 30 without covering the parylene layer. Thereby increasing the manufacturing speed and the dimensional accuracy.
The area of the reference electrode point R of the magnetic compatible nerve probe provided by the invention is more than ten times of the area of the electrode point 222, wherein more than twenty times is optimal.
Fig. 11 is a partially enlarged schematic view of a magnetic compatible nerve probe N according to the present invention, wherein a plurality of electrode points 222 are disposed on the magnetic compatible nerve probe N, and the electrode points 222 are used for contacting a region to be measured after being inserted into a brain. And a reference electrode point R is arranged near the tail end of the probe, and the reference electrode point R cannot contact the area to be detected, so that the potential value outside the area to be detected can be obtained and used as a reference potential. By setting the reference electrode point R in this embodiment, the magnetic-compatibility nerve probe N can be used as a reference potential after being inserted into the brain, so as to replace the measure in the prior art that a metal nail needs to be connected to the surface of the brain (or the skull), thereby overcoming the disadvantage that the nerve probe in the prior art cannot be synchronously detected by the magnetic resonance imager. As shown in fig. 12, the magnetic-compatible nerve probe N of the present invention is inserted into the brain and then detected by the magnetic resonance imager, so that the magnetic-compatible nerve probe N can continuously detect the neural signals in the brain and perform electrical stimulation without being influenced by magnetic force during imaging, and the shadow area is reduced to be inconspicuous, thereby overcoming the conventional problems.
The neural probe can be used for signal recording of single or multiple neurons in the brain, can also be used for giving electrical stimulation to a specific brain region to inhibit or promote corresponding neuron activity, and can also be used for simultaneously carrying out electrical stimulation and signal measurement. The electrophysiological signals recorded by the neural probe in the specific brain region can be analyzed for diagnosing epilepsy, migraine, Alzheimer's disease, Parkinson's disease, etc., and can be further used for applying electrical stimulation to the specific brain region or neurons to achieve specific therapeutic purposes.
Claims (7)
1. A preparation method of a magnetic compatible nerve probe is characterized by comprising the following steps:
(1) coating a first biomedical polymer film layer on a substrate, covering a first metal layer on the first biomedical polymer film layer, wherein the first metal layer completely covers the first biomedical polymer film layer, and etching the first metal layer into the shape of a nerve probe;
(2) covering a second biomedical polymer film layer on the first metal layer, and sputtering a second metal layer and a third metal layer on the second biomedical polymer film layer in sequence to serve as a metal circuit structure layer substrate; etching a metal circuit structure layer on the metal circuit structure layer substrate through a metal circuit photomask, wherein the metal circuit structure layer comprises at least one electrode point, at least two connection points, at least one reference electrode point and a metal circuit for connecting the electrode point or the reference electrode point and the connection points; the reference electrode point is arranged at the tail end close to the magnetic compatible nerve probe, and the area of the reference electrode point is larger than that of the electrode point; the reference electrode point does not contact the region to be detected and is used for obtaining the potential value outside the region to be detected;
(3) spraying a third biomedical polymer film layer on the metal circuit structure layer, then arranging patterns of the electrode point, the reference electrode point and the connection point on the third biomedical polymer film layer, and exposing the electrode point, the reference electrode point and the connection point by etching;
(4) electroplating a gold layer or a silver layer on the electrode point, the reference electrode point and the connection point, wherein the heights of the electrode point, the reference electrode point and the connection point after electroplating the gold layer or the silver layer are greater than that of the third biomedical polymer film layer;
(5) modifying the electrode point and the reference electrode point by using iridium oxide in an electrochemical mode;
(6) separating the substrate and forming the nerve probe according to the outline pattern.
2. The method of claim 1, wherein the substrate is a glass sheet or a silicon wafer.
3. The method as claimed in claim 1, wherein the first, second and third biomedical polymer films are made of polyimide, polyethylene, polypropylene, polyvinyl chloride, polytetrafluoroethylene, polyacrylate, polymethacrylic acid, ethylene terephthalate, polycarbonate, parylene, or a combination thereof.
4. The method of claim 1, wherein the first and second metal layers are made of a material selected from the group consisting of titanium, copper, chromium, gold, and silver.
5. The method of claim 1, wherein the third metal layer is selected from the group consisting of copper, gold, and silver.
6. The method for preparing a magnetic compatible nerve probe according to claim 1, wherein the thickness of the first biomedical polymer film layer and the second biomedical polymer film layer is between 10 microns and 60 microns; the thickness of the first metal layer is between 100 nanometers and 500 nanometers; the thickness of the second metal layer is between 50 nanometers and 400 nanometers; the thickness of the third metal layer is between 500 nanometers and 1000 nanometers; the thickness of the third biomedical polymer film layer is between 1 micron and 20 microns.
7. The method of claim 1, wherein the gold or silver layer has a thickness of between 2 and 20 microns.
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| CN101884530A (en) * | 2010-07-14 | 2010-11-17 | 中国科学院半导体研究所 | Flexible probe electrode used for recording electric signal of neural activity and implanting tool thereof |
| CN102626309A (en) * | 2011-03-27 | 2012-08-08 | 西安富德医疗电子有限公司 | Electrode for nerve electrophysiology monitoring in high field intensity magnetic resonance compatible technology |
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