CN111053535A - Flexible stretchable nerve probe for bioimplantation and method of preparing the same - Google Patents
Flexible stretchable nerve probe for bioimplantation and method of preparing the same Download PDFInfo
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- CN111053535A CN111053535A CN201911306298.8A CN201911306298A CN111053535A CN 111053535 A CN111053535 A CN 111053535A CN 201911306298 A CN201911306298 A CN 201911306298A CN 111053535 A CN111053535 A CN 111053535A
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/40—Detecting, measuring or recording for evaluating the nervous system
- A61B5/4058—Detecting, measuring or recording for evaluating the nervous system for evaluating the central nervous system
- A61B5/4064—Evaluating the brain
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
- A61B5/685—Microneedles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
- A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
- A61B5/6867—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive specially adapted to be attached or implanted in a specific body part
- A61B5/6868—Brain
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B81—MICROSTRUCTURAL TECHNOLOGY
- B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
- B81C1/00—Manufacture or treatment of devices or systems in or on a substrate
- B81C1/00015—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems
- B81C1/00134—Manufacture or treatment of devices or systems in or on a substrate for manufacturing microsystems comprising flexible or deformable structures
- B81C1/00166—Electrodes
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- 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
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- 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
- A61B2562/12—Manufacturing methods specially adapted for producing sensors for in-vivo measurements
- A61B2562/125—Manufacturing methods specially adapted for producing sensors for in-vivo measurements characterised by the manufacture of electrodes
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- 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
- A61B2562/16—Details of sensor housings or probes; Details of structural supports for sensors
- A61B2562/164—Details of sensor housings or probes; Details of structural supports for sensors the sensor is mounted in or on a conformable substrate or carrier
Abstract
The present invention provides a flexible stretchable nerve probe for bioimplantation and a method for preparing the same, comprising: a first flexible polymer layer, a metal wire layer, and a second flexible polymer layer; the metal wire layer is wrapped between the first flexible polymer layer and the second flexible polymer layer, and the electrode points and the connection points of the metal wire layer are exposed on the surface of the first flexible polymer layer or the second flexible polymer layer; the first flexible polymer layer and the second flexible polymer layer are provided with regularly arranged slits. The probe not only has flexibility, but also is provided with regularly arranged slits on the flexible polymer layer, so that the film has large stretchability, and meanwhile, the slits on the flexible polymer layer enable biological body fluid on two sides of the probe to circulate, thereby enhancing the biocompatibility of the implanted probe.
Description
Technical Field
The invention relates to a neural microelectrode in the technical field of biomedical engineering, in particular to a flexible stretchable neural probe for bioimplantation and a preparation method thereof.
Background
The implanted electrode plays a very important role in brain science research and brain disease diagnosis. Nowadays, they have been successfully used not only in the diagnosis and treatment of some brain diseases such as epilepsy, parkinson's disease and obsessive-compulsive disorder, but also in the field of neuroscience to detect neuroelectrical signals and perform stimulation of specific neurons, thereby enabling related researchers to study the functions of different neurons.
The traditional nerve probe is usually made of silicon-based, metal or glass materials with high Young modulus (50-500 Gpa), the Young modulus of biological soft tissue does not exceed 1Gpa, particularly, brain tissue is one of tissues with the lowest modulus (1Kpa) in human tissue, the brain tissue is in a micro-motion state in respiration and blood vessel expansion and contraction matrix of a human body, and the high modulus of an implanted probe electrode relative to the brain tissue can cause the electrode to continuously rub and shear the brain tissue due to the micro-motion, so that inflammatory reaction and colloid coating are aggravated, and the recording capacity of the electrode is reduced. The flexible flat cable and the microelectrode are welded, so that the electrode can slightly move along with brain tissue after being implanted, and inflammatory reaction caused by shearing the tissue by the electrode is effectively reduced; the modulus of the whole probe can be reduced by changing the substrate material of the traditional probe electrode, so that the biocompatibility of the probe is better.
According to the search discovery of the prior art, Philippie Renaud et al published a "monitoring of clinical recording and reduced in-plane response using flexible polymer probe with platinum as a metal wire layer material using polyimide as a base insulating material in IEEE Micro Electro Mechanical Systems 2007 conference," and successfully obtained the local field potential and the action potentials of single and multiple neurons after being implanted into the brain of a mouse. Polyimide and platinum metal are inert materials, and the modulus of the material is smaller than that of silicon base, so that the material has smaller damage to the organism during and after implantation, and causes smaller rejection reaction.
The scientific Advance,2017,3: e1601966 of "ultra flexible electronic probes for a usable, and a nanowire neural probe electrode having an ultra-small line width and using a flexible SU-8 polymer as a substrate insulating material is provided, because the flexible polymer material is used, the modulus is lower than that of silicon-based or glass, and the width of the electrode is only 50 micrometers, the invasiveness of the whole electrode is reduced, and the electrode can continuously and stably record neural activity in the brain of a mouse for a plurality of months for a long time.
The Ji Liu, Tian-Ming Fu of the Harvard university of America, combined with Zengguang Cheng, Square-English et al, Nature nanotechnology, 2015,10, written by Syring-objectable electronics, proposes a mesh SU-8 polymer flexible electrode array injected into organism tissue by using an injector, wherein the mesh SU-8 polymer flexible electrode array is provided with regularly arranged meshes on a flexible substrate, and after the mesh SU-8 polymer flexible electrode array is implanted, the organism tissue is interpenetrated and grown between the meshes of the nerve electrode, so that the nerve tissue and the flexible electrode are interpenetrated, and the relative motion between the organism tissue and the electrode is reduced while the good fit between the nerve electrode and the organism tissue is ensured, thereby causing smaller rejection reaction.
In addition, Wen Shen, MarkG, Allen, Inc. of electronics and nanotechnology research, Inc. of Georgia, USA, under Microsystems & Nanoengineering (2015)1, "Extracellular matrix-based microelectronics," heated a micro-machined neural interface based natural materials, "provides a flexible probe that uses a hydrogel as the probe substrate, which has a modulus that decreases from 3.4GPa to 2.6MPa after hydration, a relatively large modulus before implantation that facilitates electrode implantation, and a decrease in the overall modulus of the probe due to absorption of water in the tissue after implantation that increases biocompatibility. However, hydrogels have not been well microfabricated and are difficult to pattern in small dimensions.
In summary, flexible probe electrodes with small size and large opening hole of flexible polymer are more biocompatible than silicon-based probes and cause less rejection reaction after implantation, but such electrodes are mostly flexible and can swing along the side direction of the tissue without having the stretchable characteristic in the longitudinal direction. Although hydrogel materials are deformable in both lateral and longitudinal directions, no mature micro-processing method is available so far, and small-size patterning is impossible, so that a probe electrode which is flexible and stretchable and has good processing characteristics is required to be applied to biological tissues.
Disclosure of Invention
In view of the drawbacks of the prior art, it is an object of the present invention to provide a flexible and stretchable nerve probe for bioimplantation and a method for preparing the same.
According to a first aspect of the present invention, there is provided a flexible stretchable nerve probe for bioimplantation, comprising: a first flexible polymer layer, a metal wire layer, and a second flexible polymer layer; wherein the content of the first and second substances,
the metal wire layer is wrapped between the first flexible polymer layer and the second flexible polymer layer, and electrode points of the metal wire layer are exposed on the surface of the first flexible polymer layer or the second flexible polymer layer;
the first flexible polymer layer and the second flexible polymer layer are provided with regularly arranged slits.
Preferably, the device further comprises a connection port and an implantation hole, wherein the connection port is positioned at one end of the probe and is used for electrically connecting an external circuit; the implantation hole is positioned at the other end of the probe and is used for penetrating a steel needle so as to implant the probe to a required position.
Preferably, the connection port is located on the metal wire layer and exposed on the surface of the first flexible polymer layer or the second flexible polymer layer;
the implantation hole is formed in the first flexible polymer layer and the second flexible polymer layer, that is, a through hole is formed in the first flexible polymer layer and the second flexible polymer layer.
Preferably, the first flexible polymer layer and the second flexible polymer layer are provided with horseshoe-shaped grooves, and the horseshoe-shaped grooves are located around the electrode points to form floating electrodes.
Preferably, the wires of the metal wire layer are bent wires.
Preferably, the material of the first flexible polymer layer and the second flexible polymer layer is any one of non-photosensitive polyimide, photosensitive polyimide or parylene;
the thickness of the first flexible polymer layer and the thickness of the second flexible polymer layer are 2-25 micrometers.
Preferably, the metal wire layer includes an adhesion layer disposed on an upper surface of the first flexible polymer layer and a conductive layer disposed on an upper surface of the adhesion layer.
Preferably, the material of the adhesion layer is any one of titanium, chromium or titanium-tungsten alloy;
the material of the conducting layer is any one of gold, platinum and titanium;
the thickness of the adhesion layer is 10-100 nanometers;
the thickness of the conducting layer is 200-500 nanometers.
Preferably, the slit is a composite structure of any one or more than two of a long-strip slit, an elliptical groove or a square groove.
In a second aspect of the present invention, there is provided a method for preparing a flexible and stretchable nerve probe for bioimplantation, comprising:
preparing a first flexible polymer layer on a substrate;
sequentially sputtering or evaporating a metal adhesion layer and a metal conducting layer on the first flexible polymer layer, spin-coating a positive photoresist on the metal conducting layer to be used as a mask, and performing prebaking, exposure, development and postbaking, and performing ion beam etching or wet etching to obtain a patterned metal wire layer, namely forming metal electrode points and wires with bent wires;
preparing a second flexible polymer layer over the patterned metal wire layer;
preparing graphical regularly arranged slits on the first flexible polymer layer and the second flexible polymer layer;
and the second flexible polymer layer is provided with an electrode hole for exposing an electrode point below the second flexible polymer layer.
Compared with the prior art, the invention has at least one of the following beneficial effects:
according to the structure, the biocompatible flexible polymer is used as a substrate material of the electrode, and the electrode can be patterned in a small size; in addition, slits which are regularly arranged are introduced on the flexible polymer substrate, so that the circulation of biological fluid on two sides of the probe can be increased, the whole structure has stretchability, and the maximum stretchability can reach 11%.
Furthermore, the stretchability of the metal wire in the wire running direction is increased by adopting a bent wire running mode for the biocompatible metal wire layer, and the generation of cracks during stretching can be reduced by bending the wire running, so that the increase of impedance is controlled to a certain extent, and the possibility of metal fracture of the polymer film during stretching is reduced.
According to the method, the stretchable probe is prepared by adopting an MEMS (micro-electromechanical systems) process, and has high reproducibility.
Drawings
Other features, objects and advantages of the invention will become more apparent upon reading of the detailed description of non-limiting embodiments with reference to the following drawings:
FIG. 1 is an exploded view of a stretchable nerve probe according to one embodiment of the present invention;
FIG. 2 is an enlarged view of a portion of FIG. 1 at A;
FIG. 3 is a process flow diagram of a stretchable nerve probe according to one embodiment of the present invention;
FIG. 4 is a surface topography in centimeters of scale for a stretchable nerve probe according to an embodiment of the present invention at different stretch ratios;
FIG. 5 is an AC impedance and change in impedance at 1000Hz for various stretch ratios for a stretchable neural probe in accordance with an embodiment of the present invention;
FIG. 6 is a graph showing the change in impedance after different stretching times and the change in impedance at 1000Hz for a stretchable neural probe in accordance with an embodiment of the present invention.
The scores in the figure are indicated as: 1 is a first flexible polymer layer, 2 is a second flexible polymer layer, 3 is a metal wire layer, 4 is a slit, 5 is an electrode hole, 6 is an electrode point, 7 is a horseshoe-shaped groove, 8 is a connecting port, and 9 is an implantation hole.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Referring to fig. 1, there is shown an exploded view of a flexible and stretchable nerve probe for bioimplantation according to an embodiment of the present invention, including: a first flexible polymer layer 1, a metal wire layer 3 and a second flexible polymer layer 2; the metal wire layer 3 is wrapped between the first flexible polymer layer 1 and the second flexible polymer layer 2, namely the first flexible polymer layer 1 is located at the bottommost layer, the metal wire layer 3 is located at the middle layer, the second flexible polymer layer 2 is located at the top layer, the second flexible polymer layer 2 is provided with an electrode hole 5, and an electrode point 6 of the metal wire layer 3 is exposed on the surface of the second flexible polymer layer 2. Referring to fig. 1 and 2, the first flexible polymer layer 1 and the second flexible polymer layer 2 are provided with regularly arranged and uniformly distributed slits 4, and the regularly arranged slits 4 are introduced to increase the circulation of biological fluid on both sides of the probe, so that the whole structure has stretchability.
The slits 4 of the first flexible polymer layer 1 are identical in shape and position to the slits 4 of the second flexible polymer layer 2.
In other partially preferred embodiments, referring to fig. 1, the first flexible polymer layer 1 and the second flexible polymer layer 2 are provided with horseshoe-shaped grooves 7, the horseshoe-shaped grooves 7 are correspondingly arranged above and below the first flexible polymer layer 1 and the horseshoe-shaped grooves 7 of the second flexible polymer layer 2, and the horseshoe-shaped grooves 7 are arranged around the electrode points 6 to form floating electrodes. The floatable electrode ensures that the electrode point 6 is slightly moved along with the brain after being implanted to ensure the attaching tightness.
In other preferred embodiments, the probe further comprises a connection port 8 and an implantation hole 9 from the aspect of device function, wherein the connection port 8 is positioned at one end of the probe and is used for electrically connecting an external circuit; an implantation hole 9 is formed at the other end of the probe for inserting a steel needle so that the probe is implanted at a desired position. The connection port 8 is positioned on the metal wire layer 3 and exposed on the surface of the first flexible polymer layer 1 or the second flexible polymer layer 2; the implant holes 9 are provided in the first flexible polymer layer 1 and the second flexible polymer layer 2, i.e., through holes are formed in the first flexible polymer layer 1 and the second flexible polymer layer 2.
In some other preferred embodiments, the materials of the first flexible polymer layer 1 and the second flexible polymer layer 2 are biocompatible flexible polymers, and biocompatible means that the materials have low toxicity relative to organisms, and can effectively perform corresponding functions in specific organism applications.
The biocompatible flexible polymer comprises but is not limited to non-photosensitive or photosensitive polyimide, or colorless and transparent insulating polymer film materials such as parylene, and the flexible polymer layer is processed in two steps in the processing process, wherein the bottom polymer film (the first flexible polymer layer 1) is processed firstly, and the top polymer film (the second flexible polymer layer 2) is processed secondly, and the whole thickness range of the flexible polymer layer is 2-25 micrometers.
In other partially preferred embodiments, the metal wire layer 3 includes an adhesion layer and a conductive layer. The material of the adhesion layer includes but is not limited to any one of titanium, chromium or titanium-tungsten alloy; the thickness of the adhesion layer is 10-100 nanometers. The material of the conductive layer includes, but is not limited to, any one of gold, platinum, titanium, etc. biocompatible metal, and the thickness of the conductive layer is 200-500 nm. The metal wire layer 3 is located in-process in sequence after the processing of the bottom polymer film (first flexible polymer layer 1), between the top polymer film (second flexible polymer layer 2) and the bottom polymer film (first flexible polymer layer 1).
In some other preferred embodiments, the wires of the metal wire layer 3 are arranged in a curved track manner to increase the stretchability in the conducting direction, and the geometric parameters of the curve can be changed according to the size of the slit 4 on the actual polymer film and the required stretchability.
In other preferred embodiments, the second flexible polymer layer 2 is provided with electrode holes 5 for exposing the electrode points 6 below, the diameter of the electrode holes 5 is 10-200 micrometers, and the positions of the flexible probes where the electrode points 6 are located and the number of the electrode points 6 can be adjusted according to actual needs.
In other preferred embodiments, the slits 4 regularly arranged on the flexible polymer refer to openings on the surface of the polymer film, and include not only elongated slits, but also oval, square, and multiple-shaped composite grooves, and the shape, size, and arrangement of the grooves can be adjusted according to the stretching effect required by the actual probe.
The following is a description of the method of preparing the above flexible stretchable probe using two different polymer films.
In one embodiment, there is provided a flexible stretchable nerve probe for bioimplantation using polyimide as a flexible polymer layer and a method for preparing the same, comprising the steps of:
a common single-side polished silicon wafer is used as a substrate material of an electrode, the silicon wafer is respectively put into acetone, ethanol and deionized water for ultrasonic cleaning for 5 minutes, and then the silicon wafer is dried by nitrogen and then is put into an oven at 180 ℃ for baking for 3 hours.
Evaporating a layer of aluminum with the thickness of 400nm on the cleaned silicon wafer to be used as sacrificial layer metal, as shown in a in figure 3, spin-coating photosensitive polyimide Durimide 7505 on the sacrificial layer metal, and obtaining an electrode bottom polymer layer (namely, a first flexible polymer layer 1) with the thickness of 2.5 microns after exposure, development and curing; as shown in fig. 3 b, horseshoe-shaped grooves 7 are formed in the bottom polymer layer, the horseshoe-shaped grooves 7 are positioned around the electrode points 6 to obtain floating electrode points 6, the floating electrode points 6 can follow the micro-motion of the brain after being implanted, and in addition, slits 4 with the length of 700 microns are regularly arranged on the bottom polymer layer.
As shown in fig. 3 c, 30nm chromium (adhesion layer) and 300nm gold (conductive layer) were sputtered in that order on the underlying polyimide.
As shown in d in fig. 3, a positive photoresist AZ4620 with a thickness of 5 μm is spin-coated on the conductive layer, and a patterned photoresist mask is obtained through pre-baking, photolithography, development and post-baking. And patterning the metal layer after patterning by using ion beam etching or wet etching, and removing the positive photoresist mask by using acetone. This step forms 4 electrode points 6 and the corresponding meandering lines of the conductor lines, as shown in fig. 3 e.
And spin-coating photosensitive polyimide on the patterned metal layer, exposing, developing and curing to obtain a top polyimide layer (i.e. a second flexible polymer layer 2) with a thickness of 5 μm, wherein as shown in f in fig. 3, the top polyimide layer has slits 4 regularly arranged as the bottom layer, and also includes horseshoe-shaped grooves around electrode points 6, the shape and position of the horseshoe-shaped grooves are the same as those of the bottom polyimide layer, and in addition, each electrode point 6 is provided with an electrode hole 5 concentric with the electrode point 6, so that the electrode points 6 are exposed out of the top polyimide layer.
Finally, the sacrificial layer of aluminum is etched electrochemically or with dilute hydrochloric acid to release the electrode, as shown in figure 3 g.
In another embodiment, there is provided a flexible stretchable nerve probe for bioimplantation using Parylene (Parylene) as a flexible polymer layer, and a method for preparing the same, comprising the steps of:
a common 3-inch round glass sheet is used as a substrate material of an electrode, the glass sheet is respectively put into acetone, ethanol and 1 deionized water for ultrasonic cleaning for 5 minutes, and then the glass sheet is dried by nitrogen and then is put into an oven at 180 ℃ for baking for 3 hours.
5 μm parylene C was deposited on the glass sheet as the bottom insulating layer of the electrode (i.e. the first flexible polymer layer 1) using a chemical vapor deposition system (CVD).
And sequentially sputtering a Cr layer and an Au layer on the bottom insulating layer to form a metal conducting layer, wherein the Cr layer is an adhesion layer and has a thickness of 30nm, and the Au layer is a conducting layer and has a thickness of 300 nm.
And throwing positive glue (AZ4620)5 microns on the conductive layer, developing after exposure, post-baking, and then forming metal wires and electrode points 6 of the bent wires by using wet etching.
Again using a chemical vapour deposition system (CVD) 5 μm parylene C was deposited on the glass sheet as the top insulating layer of the electrode (i.e. the second flexible polymer layer 2).
Throwing positive glue (AZ4620) with the thickness of 10 mu m on the top insulating layer, developing after photoetching and baking for 30 minutes on a hot plate with the temperature of 60 ℃, wherein the regularly arranged slits 4, electrode holes 5, horseshoe-shaped grooves 7 and the whole contour line of the electrode are exposed on the top insulating layer, and the horseshoe-shaped grooves 7 correspond to the positions of the lower electrode points 6 and are positioned around the lower electrode points 6; and meanwhile, the slits 4 and the U-shaped grooves 7 which are regularly arranged and are the same as the top insulating layer are exposed out of the bottom insulating layer, and the U-shaped grooves 7 correspond to the upper electrode points 6 and are positioned around the upper electrode points 6.
Etching the slit 4, the electrode point 6, the horseshoe-shaped groove 7 and the whole outline of the electrode, which are not covered by the positive glue, by using oxygen plasma etching equipment, wherein the etching time and power are controlled well during the etching step, if the etching is not enough, the electrode is not conducted, and the electrode is not shaped; such as over-etching, will result in the top insulating layer being etched away and not functioning as an insulator.
Finally, the formed electrode was slowly peeled off from the glass substrate with tweezers.
The flexible and stretchable nerve probe realized by the above two different process modes has the same structure and similar functions, and the characteristics of the flexible and stretchable nerve probe are further explained below:
to further illustrate the advantages of the flexible, stretchable nerve probe for bioimplantation of the above embodiments over conventional flexible probes, changes in surface topography were observed at different stretch ratios. As shown in fig. 4, the polyimide substrate with regular slits 4 distributed on the surface makes the whole polyimide substrate have stretchability, the maximum stretching degree can reach 11%, and in the stretching process, the slits 4 regularly arranged bend and fold out of the plane where the polyimide is located, and generate out-of-plane deformation, which is also the reason that a common non-stretchable film can be stretched to achieve large deformation. The scale units in the figures are centimeters. In addition, the corresponding maximum deformation amount can be controlled by controlling the geometric dimension and the arrangement mode of the slits 4, and the adjustment can be carried out according to the actual requirement.
In the process of neuroelectrophysiology detection, the impedance of a nerve probe is a key index influencing the quality of a final detection signal, the sampling frequency used for generally collecting cerebral cortex electricity is 1000Hz, the impedance of 10-10000 Hz under the condition of different stretching ratios is separately tested and analyzed, and the impedance at the position of 1kHz is extracted. As shown in fig. 5, the flexible probe has an overall increasing impedance at 10 to 10000Hz as the stretching ratio increases, which is mainly due to cracks generated in the metal wire during stretching, and the larger the stretching ratio, the larger the crack size. Bending the wired conductor reduces the occurrence of such cracks, thereby controlling the increase in impedance to some extent. Similarly, the impedance of 1kHz is increased, but the whole impedance is kept below 15k omega, thereby meeting the requirement of recording impedance.
After the flexible and stretchable nerve probe is implanted, the biological tissue will continuously deform along with the respiration, heartbeat and muscle movement of the organism, so that the impedance characteristics of the flexible nerve probe need to be evaluated under a static condition, and the impedance change of the flexible nerve probe after the flexible nerve probe is subjected to stretching deformation for many times needs to be tested. As shown in fig. 6, two ends of the stretchable flexible probe are fixed, a stepping motor is used for a cyclic stretching test, the stretching ratio of each time is 10%, impedance spectrum analysis of 10-10000 Hz is performed after 100 times, 300 times and 500 times of stretching, and the result shows that the impedance at the frequency is increased as the stretching times are increased, and the impedance at 1kHz is also increased from 3.8k Ω to 5.2k Ω within the same order of magnitude.
In general, the flexible and stretchable nerve probe for bioimplantation of the invention can keep low impedance characteristics in a stretching state or after repeated stretching, and meets the requirement of neuroelectricity recording in a living body.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes and modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (10)
1. A flexible, stretchable nerve probe for bioimplantation, comprising: a first flexible polymer layer, a metal wire layer, and a second flexible polymer layer; wherein the content of the first and second substances,
the metal wire layer is wrapped between the first flexible polymer layer and the second flexible polymer layer, and electrode points of the metal wire layer are exposed on the surface of the first flexible polymer layer or the second flexible polymer layer;
the first flexible polymer layer and the second flexible polymer layer are provided with regularly arranged slits.
2. The flexible stretchable nerve probe for bioimplantation according to claim 1, further comprising a connection port and an implantation hole, wherein the connection port is located at one end of the probe for electrically connecting an external wiring; the implantation hole is positioned at the other end of the probe and is used for penetrating a steel needle so as to implant the probe to a required position.
3. A flexible stretchable neural probe for bioimplantation according to claim 2,
the connecting port is positioned on the metal wire layer and exposed out of the surface of the first flexible polymer layer or the second flexible polymer layer;
the implantation hole is formed in the first flexible polymer layer and the second flexible polymer layer, that is, a through hole is formed in the first flexible polymer layer and the second flexible polymer layer.
4. A flexible stretchable neural probe for bioimplantation according to claim 1,
the first flexible polymer layer and the second flexible polymer layer are respectively provided with a horseshoe-shaped groove, and the horseshoe-shaped grooves are located around the electrode points to form floating electrodes.
5. The flexible and stretchable nerve probe for bioimplantation according to claim 1, wherein the wires of the metal wire layer are curved runs.
6. The flexible stretchable nerve probe for bioimplantation according to claim 1, wherein the material of the first flexible polymer layer, the second flexible polymer layer is any one of non-photosensitive polyimide, photosensitive polyimide or parylene; the thickness of the first flexible polymer layer and the thickness of the second flexible polymer layer are 2-25 micrometers.
7. A flexible stretchable nerve probe for bioimplantation according to claim 1, wherein the metal wire layer comprises an adhesive layer disposed on an upper surface of the first flexible polymer layer and a conductive layer disposed on an upper surface of the adhesive layer.
8. A flexible stretchable nerve probe for bioimplantation according to claim 7, wherein the material of the adhesion layer is any one of titanium, chromium or titanium tungsten alloy; the thickness of the adhesion layer is 10-100 nanometers;
the conducting layer is made of one or more than two metal alloys of gold, platinum or titanium; the thickness of the conducting layer is 200-500 nanometers.
9. The flexible and stretchable nerve probe for bioimplantation according to claim 1, wherein the slit is a composite structure of any one or more of a long slit, an elliptical groove or a square groove.
10. A method of making a flexible, stretchable nerve probe for bioimplantation, comprising:
preparing a first flexible polymer layer on a substrate;
sequentially sputtering or evaporating a metal adhesion layer and a metal conducting layer on the first flexible polymer layer, spin-coating a positive photoresist on the metal conducting layer to be used as a mask, and performing prebaking, exposure, development and postbaking, and performing ion beam etching or wet etching to obtain a patterned metal wire layer, namely forming metal electrode points and wires with bent wires;
preparing a second flexible polymer layer over the patterned metal wire layer;
preparing graphical regularly arranged slits on the first flexible polymer layer and the second flexible polymer layer;
and the second flexible polymer layer is provided with an electrode hole for exposing an electrode point below the second flexible polymer layer.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911306298.8A CN111053535A (en) | 2019-12-18 | 2019-12-18 | Flexible stretchable nerve probe for bioimplantation and method of preparing the same |
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| CN201911306298.8A CN111053535A (en) | 2019-12-18 | 2019-12-18 | Flexible stretchable nerve probe for bioimplantation and method of preparing the same |
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| CN112244839A (en) * | 2020-09-29 | 2021-01-22 | 中国科学院上海微系统与信息技术研究所 | Flexible electrode probe for long-term implantation and preparation method and equipment thereof |
| CN113041496A (en) * | 2021-03-19 | 2021-06-29 | 国家纳米科学中心 | Nerve electrical stimulation electrode, preparation method and implantation method thereof |
| CN114699087A (en) * | 2022-05-23 | 2022-07-05 | 国家纳米科学中心 | Nerve electrode structure and implantation method and manufacturing method thereof |
| CN115285930A (en) * | 2022-07-25 | 2022-11-04 | 武汉衷华脑机融合科技发展有限公司 | Micro-needle and flat cable inverse welding connecting structure and preparation process thereof |
| EP4091662A1 (en) * | 2021-05-21 | 2022-11-23 | ReVision Implant NV | Flexible neural implant with improved insertion and fixation characteristics |
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| CN113041496A (en) * | 2021-03-19 | 2021-06-29 | 国家纳米科学中心 | Nerve electrical stimulation electrode, preparation method and implantation method thereof |
| EP4091662A1 (en) * | 2021-05-21 | 2022-11-23 | ReVision Implant NV | Flexible neural implant with improved insertion and fixation characteristics |
| WO2022242916A1 (en) * | 2021-05-21 | 2022-11-24 | Revision Implant Nv | Flexible neural implant with improved insertion and fixation characteristics |
| CN114699087A (en) * | 2022-05-23 | 2022-07-05 | 国家纳米科学中心 | Nerve electrode structure and implantation method and manufacturing method thereof |
| CN114699087B (en) * | 2022-05-23 | 2023-01-10 | 国家纳米科学中心 | Nerve electrode structure and implantation method and manufacturing method thereof |
| CN115285930A (en) * | 2022-07-25 | 2022-11-04 | 武汉衷华脑机融合科技发展有限公司 | Micro-needle and flat cable inverse welding connecting structure and preparation process thereof |
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Application publication date: 20200424 |