阅读说明：本技术 一种可自卷曲的外周神经电极及其制备方法 (Self-curling peripheral nerve electrode and preparation method thereof ) 是由 胡本慧 唐文杰 周宇轩 尹思梦 于 2020-11-19 设计创作，主要内容包括：本发明提供了一种可自卷曲的外周神经电极,所述可自卷曲的外周神经电极主要包括温度响应性的形状记忆基底薄膜、无生物毒性的柔性导电层和生物兼容性的封装层；本发明还提供了一种可自卷曲的外周神经电极制备方法,主要包括将所述神经电极放置于动物外周神经平面,等待3-5秒,所述神经电极在动物体温驱动下自动卷曲并紧密缠绕于外周神经,通过柔性引线将所述神经电极与信号处理装置或刺激装置连接,可获取神经电信号和/或刺激外周神经。本发明具有良好柔性特性,可以解决目前电极和神经的机械性能不匹配问题；采用三通道并行传输,可显著减少植入电极数量；本发明在温度驱动下可以快速自动卷曲并紧密缠绕于外周神经,手术易操作,具有很强的实用性。(The invention provides a self-crimpable peripheral nerve electrode, which mainly comprises a temperature-responsive shape memory substrate film, a nonbiotoxic flexible conductive layer and a biocompatible packaging layer; the invention also provides a preparation method of the self-curling peripheral nerve electrode, which mainly comprises the steps of placing the nerve electrode on the plane of the peripheral nerve of an animal, waiting for 3-5 seconds, automatically curling the nerve electrode under the drive of the body temperature of the animal and tightly winding the nerve electrode on the peripheral nerve, and connecting the nerve electrode with a signal processing device or a stimulation device through a flexible lead wire, so that a nerve electric signal can be obtained and/or the peripheral nerve can be stimulated. The invention has good flexibility, and can solve the problem of unmatched mechanical properties of the electrode and the nerve at present; three channels are adopted for parallel transmission, so that the number of implanted electrodes can be obviously reduced; the invention can be quickly and automatically curled and tightly wound on peripheral nerves under the drive of temperature, and the operation is easy to operate, thus having strong practicability.)

1. A self-crimpable peripheral nerve electrode characterized in that it comprises a temperature responsive shape memory base film (2), a non-biotoxic flexible conductive layer (1), a biocompatible encapsulation layer (3).

2. A self-crimpable peripheral nerve electrode according to claim 1, characterized in that it is provided in a three-layer structure, a temperature-responsive shape memory base film (2) is provided in the lower layer, and a layer of three nonbiotoxic flexible conductive layers (1) arranged in parallel is deposited on the upper part thereof, and the whole is encapsulated with a biocompatible encapsulating material.

3. The self-curling peripheral nerve electrode of claim 1, wherein the temperature-responsive shape memory substrate film (2) has temperature sensing and shape memory functions, and can be quickly and automatically curled into a pre-designed spiral structure under the driving of body temperature, so as to achieve the effect of tightly winding the peripheral nerve; the flexible conducting layer (1) without biotoxicity has good flexibility, can realize three-channel parallel transmission, can effectively reduce the number of implanted electrodes, and reduces operation difficulty and infection risk.

4. A method of making a self-crimpable peripheral nerve electrode comprising the steps of:

step 1: manufacturing a mask plate according to the designed pattern shape of the conducting layer, attaching a polymer film with certain adhesive force to one side of the mask plate, and forming a channel with specific patterning by the polymer film and the mask plate;

step 2: injecting a mixed solution of a conductive material and a flexible polymer into the channel, and heating to evaporate a solvent to form a flexible conductive layer (1);

and step 3: after drying, only the polymer film is taken down, and the flexible conducting layer (1) is reserved in a pattern gap of a mask plate;

and 4, step 4: pouring a precursor of a temperature-responsive shape memory polymer as a substrate on the other side of the mask plate, and heating and curing the substrate; taking the flexible conductive layer (1) and the shape memory substrate film (2) with temperature responsiveness off the mask plate, removing redundant substrates, and preparing a long-strip-shaped nerve electrode; the substrate is slightly larger than the flexible conducting layer (1), and two ends of the substrate are reserved as flexible lead connecting sites;

and 5: encapsulating the whole device by using a biocompatible polymer to form a biocompatible encapsulation layer (3);

step 6: winding the strip-shaped nerve electrode on the cylinder and fixing the strip-shaped nerve electrode to prepare a nerve electrode to be formed;

and 7: heating the nerve electrode to be molded and fixed on the cylinder to be equal to or higher than the plastic transition temperature of the shape memory substrate film; and continuously heating for 8-12min at constant temperature to prepare the self-crimpable permanent spiral nerve electrode, wherein the plastic transition temperature is 160-200 ℃.

5. The method for preparing a self-crimpable peripheral nerve electrode according to claim 4, wherein the step 2 further comprises:

pouring a precursor of the shape memory polymer on a substrate, and heating the precursor to a semi-cured polymer film;

placing a patterned mask plate on the polymer film, wherein the polymer film and the mask plate jointly form a patterned channel;

and injecting a mixed solution of the conductive material and the flexible polymer into the channel, and forming a flexible conductive layer (2) along with the evaporation of the solvent.

6. The method for preparing a self-crimpable peripheral nerve electrode according to claim 4, wherein the step 3 further comprises:

and pouring a precursor of the shape memory polymer on the substrate, and heating the polymer film in a semi-cured state.

And depositing the mixed solution of the conductive material and the flexible polymer to form a conductive film, and preparing different patterns by micromachining.

The patterned polymer film is transferred to a semi-cured shape memory polymer.

The predetermined shape of the mask plate is any one of a linear shape, a snake shape and an S shape. Three-channel flexible conductive layers (1) made of mask plates in various shapes are not communicated with each other and are parallel to each other, and the lengths of the three-channel flexible conductive layers are arranged in a T-degree distribution; the purpose is to ensure that the connecting line of the end points and the nerve are in the same straight line when the nerve electrode is wound on the nerve.

7. The method of claim 4, wherein the overall thickness of the nerve electrode is about 200 μm; a width that is less than or equal to a maximum value of the width that can be tightly spirally wound onto a nerve bundle; the length range is greater than or equal to the length that can wrap the nerve bundle for one turn.

8. A method for preparing a self-crimpable peripheral nerve electrode according to claim 4, characterized in that said flexible conductive layer (1) has a thickness of 20 μm or less; the cylinder used for preforming can be a prefabricated glass rod, a metal rod or a plastic rod, and the diameter of the cylinder is slightly smaller than that of the peripheral nerve bundle.

9. The method of claim 4, wherein the conductive material comprises metal nanowires, nanoparticles, carbon nanowires, nanotubes, graphene or conductive polymers; the flexible polymer composition comprises polyvinylidene fluoride (PVDF); the packaging layer (3) material comprises parylene.

10. The method for preparing a self-crimpable peripheral nerve electrode according to claim 4, wherein the method for detecting or stimulating the peripheral nerve electrode comprises the following steps:

step 1: heating the self-curled permanent spiral nerve electrode to be equal to or higher than the shape transition temperature of the shape memory substrate film, flattening by external force and cooling to prepare a temporary planar nerve electrode;

step 2: connecting the flexible lead connecting site of the temporary planar nerve electrode with external equipment through a flexible lead, and stimulating peripheral nerves or acquiring nerve electrical signals; the external device comprises an external stimulator or a signal processor;

and step 3: and placing the temporary planar nerve electrode on the peripheral nerve plane of the animal, waiting for 3-5 seconds, and automatically curling and rapidly winding the temporary planar nerve electrode on the peripheral nerve under the drive of body temperature.

Technical Field

The invention relates to the technical field of neuroscience and biomedical equipment, in particular to a self-curling peripheral nerve electrode and a preparation method thereof.

Background

Neural electrodes are an important component of the interface between biological tissue and mechanical devices. In peripheral nerve electrodes, because of the strong invasiveness of the nerve inner electrode, micro-invasive electrodes such as a Cuff electrode and a spiral electrode are common at present. The two types of electrodes are fixed on the surface of the nerve, so that the risks of nerve injury and infection are reduced, and the long-term use of the electrodes is promoted.

The nerve sizes are different and the nerve sizes have individual and time difference, so that the Cuff electrode has no universality and must be specifically customized according to a specific nerve type. On the other hand, the Cuff electrodes interact with adjacent contacting nerves, causing tissue inflammation and scarring effects, ultimately changing nerve diameter. The diameter of the pre-designed Cuff electrode in the current mainstream scheme is slightly larger than the target nerve, so that the influence is weakened, the contact between the Cuff electrode and the nerve is looser, and a series of problems of poor signal quality and the like are generated.

The spiral nerve electrode can realize effective contact between the electrode and a nerve bundle, and signal quality is improved. At present, when polyimide, Polydimethoxysiloxane (PDMS) and the like are used as substrate materials of the nerve electrode, the requirements of mechanical property and signal sensing are difficult to achieve, and the operation difficulty is large.

In summary, there is a need to find a design method of a neural electrode to solve the problems of mismatch of mechanical properties between the neural electrode and the nerve, poor signal sensing quality, and difficulty in surgical operation.

Disclosure of Invention

In view of the problems in the prior art, the invention designs a self-curling peripheral nerve electrode and a preparation method thereof, and the structure of the self-curling peripheral nerve electrode comprises: a temperature responsive shape memory substrate film, a non-biotoxic flexible conductive layer and a biocompatible encapsulation layer.

The peripheral nerve electrode designed by the invention has simple structure and easy preparation, and the used material has good biocompatibility. The detection/stimulation method of the peripheral nerve electrode comprises the steps of obtaining a nerve electric signal through the connection of a lead and a signal receiver so as to analyze the nerve activity of an organism; when the nerve electrode is connected with a constant voltage or constant current stimulator, electrical stimulation can be applied to peripheral nerves so as to treat diseases such as drug-resistant epilepsy, heart failure, major depression and the like. The technical scheme adopted by the invention for achieving the purpose is as follows:

a self-curling peripheral nerve electrode is provided as a three-layer structure, a temperature-responsive shape memory substrate film is provided at the lower layer, a layer of three nonbiotoxic flexible conductive layers arranged in parallel are placed on the substrate film, and the whole body is encapsulated by parylene. The flexible conducting layer without biotoxicity has good flexibility, is three-channel parallel transmission, and can effectively reduce the number of implanted electrodes. The shape memory substrate film with temperature responsiveness has a temperature sensing function, so that the peripheral nerve electrode can be quickly and automatically curled and wound on the peripheral nerve under the temperature driving.

A self-crimpable peripheral nerve electrode, said method of manufacture comprising the steps of:

step 1: and manufacturing a mask plate according to the designed pattern shape of the conducting layer, attaching a polymer film with certain adhesion to one side of the mask plate, and forming a channel with specific patterning by the polymer film and the mask plate together.

Step 2: and injecting a mixed solution of a conductive material and a flexible polymer into the channel, and heating to evaporate the solvent.

And step 3: after drying, only the polymer film is taken down, and the flexible conductive layer is remained in the pattern gap of the mask plate.

And 4, step 4: and pouring a precursor of the temperature-responsive shape memory polymer as a substrate on the other side of the mask plate, and heating and curing the substrate. And taking the flexible conductive layer and the temperature-responsive shape memory substrate film off the mask plate, removing the redundant substrate, and preparing the long-strip-shaped nerve electrode. The substrate is slightly larger than the flexible conducting layer, and two ends of the substrate are reserved as flexible lead connecting sites.

And 5: and encapsulating the whole device by using a biocompatible polymer to form a biocompatible encapsulation layer.

Step 6: and winding the strip-shaped nerve electrode on the cylinder and fixing to prepare the nerve electrode to be molded.

And 7: heating the nerve electrode fixed on the cylinder to be formed to be equal to or higher than the plastic transition temperature of the shape memory substrate film. Heating for 8-12min at constant temperature to obtain self-curling permanent spiral nerve electrode. The plastic transition temperature is 160-200 ℃.

For the above method, in one possible implementation, the method further includes:

and pouring a precursor of the shape memory polymer on the substrate, and heating to a semi-cured state.

And placing the patterned mask plate on the semi-solidified shape memory polymer substrate to form a patterned channel between the substrate and the mask plate.

And injecting a mixed solution of the conductive material and the flexible polymer into the channel, and forming a flexible conductive layer along with the evaporation of the solvent.

The substrate may be, but is not limited to, a glass plate, a metal plate or a plastic plate.

In one possible implementation of the method, the mask plate has a thickness of about 100 to 200 μm, the predetermined shape is any one of a straight line shape, a serpentine shape and an S-shape, and the shapes are not communicated with each other and are parallel, and the length of the nerve contacting end is different, so that when the mask plate is wound on a nerve, a connecting line of the end points and the nerve are in a straight line.

For the above method, in one possible implementation, the method further includes:

and pouring a precursor of the shape memory polymer on the substrate, and heating to be in a semi-cured state.

And pouring the conductive slurry into a template, preparing a flexible conductive film along with solvent evaporation, and patterning the conductive film through micromachining.

And transferring the patterned conductive film onto the semi-cured shape memory polymer, and firmly adhering the conductive film and the shape memory polymer substrate along with the continuous curing of the semi-cured shape memory polymer film.

Wherein the substrate may be a glass plate, a metal plate or a plastic plate.

With respect to the above method, in one possible implementation, the predetermined shape of the micro-machined pattern is any one of a linear shape, a serpentine shape, and an S-shape. Three-channel flexible conductive layers made of the mask plates in various shapes are not communicated with each other and are parallel to each other, and the lengths of the three-channel flexible conductive layers are arranged in a T-degree distribution manner. The purpose is to ensure that the connecting line of the end points and the nerve are in the same straight line when the nerve electrode is wound on the nerve.

For the method, the micro-processing method comprises etching, cutting and cutting.

For the above method, in one possible implementation, the conductive layer has a thickness of about 10-20 microns and the overall thickness of the spiral electrode is about 200 microns. The width is less than or equal to the minimum value of the width which can be tightly wound on the nerve bundle. The length is more than or equal to one circle of the nerve bundle.

The cylinder used for the pre-forming can be, but is not limited to, a pre-processed glass rod, a metal rod or a plastic rod, and the diameter of the cylinder is slightly smaller than that of the peripheral nerve bundle.

The conductive material of the conductive film can be metal nanowires/nanoparticles (such as gold, titanium, magnesium, zinc, and the like), carbon nanowires/nanotubes, conductive polymers, and other conductive materials. The flexible polymer composition includes, but is not limited to, polyvinylidene fluoride (PVDF). The encapsulation layer material includes, but is not limited to, parylene.

The application method comprises the following steps:

step 1: and heating the self-curled permanent spiral nerve electrode to be equal to or higher than the shape transition temperature of the shape memory substrate film, flattening by external force and cooling to prepare the temporary planar nerve electrode.

Step 2: and connecting the flexible lead connecting site of the temporary planar nerve electrode with an external device through a flexible lead, and stimulating peripheral nerves or acquiring nerve electrical signals. The external device includes an external stimulator or a signal processor.

And step 3: and placing the temporary planar nerve electrode on the peripheral nerve plane of the animal, waiting for 3-5 seconds, and automatically curling and rapidly winding the temporary planar nerve electrode on the peripheral nerve under the drive of body temperature.

The preparation method of the peripheral nerve electrode is simple and easy to implement. The nerve electrode has flexibility and high signal sensing quality, can be in conformal contact with nerve bundles, and cannot cause compression on nerves. The shape memory substrate film with temperature responsiveness has the functions of temperature sensing and shape memory, can be automatically curled into a pre-designed spiral structure only in 3-5 seconds under the drive of body temperature, and finally is tightly wound on peripheral nerves. The nerve electrode is easy to implant in operation and has good long-term stability.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate exemplary embodiments, features, and aspects of the disclosure and, together with the description, serve to explain the principles of the disclosure.

FIG. 1 is a flow chart of a method of making a self-curling peripheral nerve electrode according to an embodiment of the invention;

FIG. 2a is a schematic diagram of the structure of a self-crimpable peripheral nerve electrode according to an embodiment of the present invention;

FIG. 2b is a schematic structural diagram of a self-crimpable peripheral nerve electrode according to an embodiment of the present invention;

FIG. 3 is a schematic diagram of a self-curling peripheral nerve electrode according to an embodiment of the invention;

FIG. 4a is a first electrical signal recorded by a self-curling peripheral nerve electrode according to an embodiment of the invention;

FIG. 4b is a second electrical signal recorded by the self-curling peripheral nerve electrode according to the embodiment of the invention;

FIG. 5a is a graph of the action potential of Bullfrog at different voltages recorded by the self-curling peripheral nerve electrode according to one embodiment of the present invention;

FIG. 5b is a second action potential of a bullfrog at different voltages recorded by the self-curled peripheral nerve electrode according to the embodiment of the present invention;

fig. 6 is a diagram showing an application of the self-curled peripheral nerve electrode of the embodiment of the present invention on a human arm.

In the figure: 1. a non-biotoxic flexible conductive layer; 2. a temperature-responsive shape memory substrate film; 3. biocompatible encapsulation layer

Detailed Description

Embodiments of the present disclosure will be described in detail below with reference to the accompanying drawings:

referring to fig. 1, the present invention discloses a method for preparing a nerve electrode, which is implanted into a peripheral nerve of a mammal to collect nerve electrical signals and/or stimulate the peripheral nerve. The schematic structure diagram and the schematic structure diagram of the self-crimpable peripheral nerve electrode are given by fig. 2a and fig. 2b, respectively. The self-curling peripheral nerve electrode is of a three-layer structure, the temperature-responsive shape memory substrate film is arranged on the lower layer, the three parallel non-biotoxic flexible conductive layers are deposited on the upper part of the temperature-responsive shape memory substrate film, and the whole electrode is packaged by a biocompatible packaging material. The shape memory substrate film with temperature responsiveness has a temperature sensing function, so that the peripheral nerve electrode can be automatically coiled and wound on the peripheral nerve under the temperature driving. The flexible conducting layer without biotoxicity has good flexibility, and three channels are used for parallel transmission, so that the number of implanted electrodes can be effectively reduced.

The invention relates to a preparation method of a nerve electrode, which is characterized by comprising the following steps:

step 1: and manufacturing a mask plate according to the designed pattern shape of the conducting layer, attaching a polymer film with certain adhesion to one side of the mask plate, and forming a channel with specific patterning by the polymer film and the mask plate together. The thickness of the mask plate is 100-200 microns, and the pattern shape can be linear, serpentine or S-shaped, which is not limited herein.

Step 2: and injecting a mixed solution of a conductive material and a flexible polymer into the channel, and heating to evaporate the solvent. The conductive material includes, but is not limited to, metal nanowires/nanoparticles (e.g., gold, titanium, magnesium, zinc, etc.), carbon nanowires/nanotubes, and other conductive materials such as conductive polymers. The flexible polymer composition includes, but is not limited to, polyvinylidene fluoride (PVDF).

Wherein the main component of the shape memory precursor is three-arm polycaprolactone, and the preparation method is as follows:

step 1: 30-50 g of caprolactone, trimethylolpropane and stannous isooctanoate are added into a dry double-neck round-bottom flask and reacted for 12-24 h at the temperature of 80-120 ℃ in nitrogen atmosphere.

Step 2: after the reaction is finished, the obtained three-arm polycaprolactone is purified and separated out in methanol and is dried for 8-12 h in vacuum at the temperature of 60-80 ℃.

The preparation method of the temperature-responsive shape memory polymer comprises the following steps:

the three-arm polycaprolactone prepared by the method is melted at a high temperature of 80-100 ℃, and then 0.5-2 mL of butyl acetate, 200-400 mu L of hexamethylene diisocyanate and 0.3-0.6 wt% of stannous isooctanoate are added and stirred to form a uniform mixture.

And pouring the mixture into a mold, curing at 50-70 ℃ for 2-3 h, and finally putting the mold into a vacuum drying oven, and performing vacuum drying at 60-100 ℃ for 10-14 h to obtain the temperature-responsive shape memory polymer material.

And step 3: and after drying, taking down the polymer film, and keeping the flexible conductive layer in the gap of the mask plate.

And 4, step 4: and pouring a precursor of the temperature-responsive shape memory polymer as a substrate on the other side of the mask plate, and heating and curing the substrate. And taking the flexible conductive layer and the temperature-responsive shape memory substrate film off the mask plate, removing the redundant substrate, and preparing the long-strip-shaped nerve electrode.

And 5: and encapsulating the whole device by using a biocompatible polymer to form a biocompatible encapsulation layer.

Step 6: and winding the strip-shaped nerve electrode on the cylinder and fixing to prepare the nerve electrode to be molded.

And 7: heating the neural electrode to be formed to 160-200 ℃, keeping for 8-12min, cooling to room temperature, and taking down to prepare the permanent spiral neural electrode.

And 8: heating the spiral nerve electrode to a transition temperature (36-38 ℃), flattening by an external force and cooling to prepare the temporary planar nerve electrode.

And step 9: and connecting the lead connecting end of the temporary planar nerve electrode with an external device through a lead, wherein the external device comprises an external stimulator or a signal receiver. The aim is to stimulate the peripheral nerves to capture the neural electrical signals via the neural electrodes of the study vegetation. (as shown in FIGS. 4a, 4b, 5)

When in use, the temporary planar nerve electrode is contacted with the peripheral nerve, and the temporary planar nerve electrode curls under the drive of body temperature and automatically winds on the peripheral nerve (as shown in figures 3 and 6).

The above embodiment is only an example according to specific situations, and does not limit the scope of the present invention. It will be appreciated by those skilled in the art that the invention is still within the scope of the invention without substantial change in the innovations.