Focused ultrasound controllable degradation nerve stimulation electrode and preparation method thereof

Abstract

The application discloses a kind of focused ultrasound controllable degradation nerve stimulation electrode and preparation method thereof, comprising the following steps: 1) making polycaprolactone film;2) the front surface of polycaprolactone film is pasted with metal mask, then magnetron sputtering is carried out, and titanium adhesion layer and molybdenum conductor layer are sequentially deposited on the front surface of polycaprolactone film, then the metal mask is removed, and sample 1 is obtained;3) polycaprolactone-thiophene / bismaleimide spin coating working solution is spin-coated on the front surface of sample 1, dried, vacuum overnight, and sample 2 is obtained;4) sample 2 is turned over, so that the back surface of polycaprolactone film faces upwards, the metal site is exposed by laser windowing on polycaprolactone film by laser, then activated, then drop-coated modification material, then film forming, and a focused ultrasound controllable degradation nerve stimulation electrode is obtained.The nerve stimulation electrode prepared by the method can realize non-invasive triggering, and the predictability and safety of the failure process are relatively high.

Description

Technical Field

[0001] This invention belongs to the field of biomedical engineering and relates to a focused ultrasound-controlled degradable nerve stimulation electrode and its preparation method. Background Technology

[0002] High-performance implantable stimulating electrodes face two conflicting demands when used in vivo: on the one hand, they need to maintain a stable, low-impedance electrode interface and reliable interconnection during long-term operation. More importantly, the encapsulation / insulation layer must remain intact for a long time to prevent body fluids from seeping in along the wiring, causing lateral leakage, impedance drift, or even short circuits. On the other hand, many applications do not require permanently placed devices. If they cannot safely degrade after the therapeutic or invention window ends, it may lead to long-term foreign body reactions, infection risks, and the burden of secondary removal surgery. Traditional biodegradable polymers often degrade too slowly in vivo and are greatly affected by the environment, making their failure time difficult to program. Furthermore, the failure of conventional encapsulation systems is mostly random, unlocatable, and unmeasurable, making it difficult to meet the system-level goals of high-performance operation and controllable failure.

[0003] CN120837834A discloses a flexible array-type external field programmable neurostimulation device, its fabrication method, and its application. The device includes a flexible substrate layer and a stimulation-responsive fiber array layer. The stimulation-responsive fiber array layer is made of functional materials capable of converting external field energy such as ultrasound, magnetism, and light into electrical energy, and is integrated onto the flexible substrate layer in an array arrangement. Due to the highly flexible substrate layer, conformal matching with the surface of the nerve target tissue can be achieved. The stimulation-responsive fiber array layer integrated onto the flexible substrate layer in an array arrangement can meet the spatial resolution of stimulation at the neuronal and even subneuronal precision. It possesses excellent flexibility, biocompatibility, and passive / wireless characteristics. It can not only provide high spatial resolution neuroelectric stimulation signals but also conformally fit the irregular surface of nerve soft tissue, making it suitable for high-resolution neuroelectric stimulation applications in different locations such as the eye, brain, and peripheral nerves.

[0004] Existing implantable stimulation electrode technologies have three main areas for improvement: While passive biodegradable / absorbable devices can avoid secondary removal, their degradation / failure is often dominated by in vivo hydrolysis and environmental conditions. The time window is difficult to program precisely, there are large individual differences, and failure often manifests as random package breakage or interface leakage. They lack spatial selectivity and are prone to stimulation parameter drift and unpredictable electrical risks. Traditional non-degradable encapsulation systems can achieve a long lifespan, but once pinholes, microcracks, or interface peeling occur, leakage failure caused by bodily fluids invading along the traces is random, unlocatable, and immeasurable. It is difficult to provide early warning and cannot proactively fail when needed. In addition, traditional high-performance non-degradable stimulation electrodes require a second surgery to remove them, which may cause serious secondary trauma. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of the prior art and provide a focused ultrasound-controlled degradable neurostimulation electrode and its preparation method. The neurostimulation electrode prepared by this method can achieve non-invasive triggering, and the failure process has high predictability and safety.

[0006] To achieve the above objectives, this invention discloses a method for preparing a focused ultrasound-controlled degradable neurostimulation electrode, comprising the following steps: 1) Fabrication of polycaprolactone film; 2) A metal mask is attached to the front side of the polycaprolactone film, and then a titanium adhesion layer and a molybdenum conductor layer are sequentially deposited on the front side of the polycaprolactone film by magnetron sputtering. Then the metal mask is removed to obtain sample 1. 3) Spin-coating the polycaprolactone-thiophene / bismaleimide working solution onto the front side of sample 1, drying and vacuum overnight to obtain sample 2; 4) Flip sample 2 so that the back side of the polycaprolactone film is facing up. Use a laser to open windows on the polycaprolactone film to expose metal sites, then activate it, then drop-coat the modification material, and then form a film to obtain a focused ultrasound-controlled degradable neurostimulation electrode.

[0007] Further, the specific operation of step 1) is as follows: take a glass substrate, cover the glass substrate with a layer of pressure-sensitive adhesive as a temporary carrier adhesive layer, then flatly attach the polycaprolactone film onto the pressure-sensitive adhesive, then remove the glass substrate and the pressure-sensitive adhesive, and finally wipe the surface of the polycaprolactone film with a lint-free cloth.

[0008] Furthermore, the specific operation of step 2) is as follows: A metal mask was attached to the front side of the polycaprolactone film, and then the whole thing was placed in a magnetron sputtering device and vacuumed. Then, the titanium adhesive layer was sputtered first, followed by the molybdenum conductor layer. Finally, the metal mask was removed to obtain sample 1.

[0009] Furthermore, the titanium adhesive layer has a thickness of 10 nanometers, and the molybdenum conductor layer has a thickness of 300 nanometers.

[0010] Furthermore, the specific operation of step 3) is as follows: Bismaleimide was dissolved in dimethylformamide to obtain solution B. Polycaprolactone-thiophene was dissolved in dimethylformamide to obtain solution A. Solution B was poured into solution A and stirred at room temperature to obtain a polycaprolactone-thiophene / bismaleimide spin-coating working solution. The polycaprolactone-thiophene / bismaleimide spin-coating working solution was spin-coated onto the front side of sample 1, then dried at 50°C for 10 min, and then vacuum-treated at 50°C overnight to remove dimethylformamide and continue crosslinking to obtain sample 2.

[0011] Furthermore, the concentration of bismaleimide in solution B is 0.15 mmol / L, and the concentration of polycaprolactone-thiophene in solution A is 0.15 mmol / L.

[0012] Furthermore, during the spin coating process, the spin coating is first performed at a speed of 500 rpm for 10 seconds, and then at a speed of 2000 rpm for 30 seconds.

[0013] Furthermore, the specific operation of step 4) is as follows: Sample 2 was flipped so that the back side of the polycaprolactone film was facing up. The center of the electrode pad was positioned by the alignment mark on the circuit. Then, the molybdenum inside the window was activated by laser windowing. Subsequently, the modification material was drop-coated and heated at 60°C for 5 minutes to form a film, thus obtaining a focused ultrasound-controlled degradable neurostimulation electrode.

[0014] This invention discloses a focused ultrasound-controlled degradable neurostimulation electrode, which is prepared based on the preparation method of the focused ultrasound-controlled degradable neurostimulation electrode.

[0015] Furthermore, when failure is required, the process is triggered by multiple short-segment focused ultrasound cycles and controlled in real time by impedance / leakage monitoring. Once the threshold is reached, the process stops, thus simultaneously satisfying the stability requirements of high-performance stimulation and the controllability and safety boundaries of on-demand failure in vivo.

[0016] The present invention has the following beneficial effects: The focused ultrasound-controlled degradable neurostimulation electrode and its preparation method described in this invention, in specific operation, construct a cross-linked network through thiophene / furandiene and bismaleimide (Diesel-Alder reversible cross-linking). Under focused ultrasound stimulation, a reverse reaction and network reconstruction are triggered, exhibiting a repeatable and cumulative response. Simultaneously, spatial focusing and alignment monitoring can be achieved under imaging guidance. The thiophene-type cross-linking is relatively milder and slower, making it more suitable for the desired "gradual leakage failure" rather than instantaneous perforation damage, thus achieving on-demand, gradual, and monitorable leakage failure at the site. Furthermore, the geometric isolation of "back-side windowing + front-side full-coverage insulation" confines the failure to the target area, preventing premature exposure of wiring and sidewalls, and improving the predictability and safety of the failure process.

[0017] Furthermore, the focused ultrasound-controlled degradation neurostimulation electrode of the present invention maintains high integrity during normal operation, while under the action of external focused ultrasound, cross-linking disintegration and network recombination occur in a designated area, thereby achieving "on-demand, gradual, and monitorable degradation", transforming the electrode failure process from a passive random failure to an active and controllable process. Attached Figure Description

[0018] To more clearly illustrate the technical solutions of the embodiments of this application, the drawings used in the description of the embodiments of this application will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0019] Figure 1 This is a flowchart of the method of the present invention; Figure 2 These are diagrams showing the state of the electrode before and after ultrasound as described in this invention. Detailed Implementation

[0020] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0021] In the description of this invention, it should be understood that the terms "comprising" and "including" indicate the presence of the described features, integrals, steps, operations, elements and / or components, but do not exclude the presence or addition of one or more other features, integrals, steps, operations, elements, components and / or collections thereof.

[0022] It should also be understood that the terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” are intended to include the plural forms unless the context clearly indicates otherwise.

[0023] It should also be further understood that the term "and / or" as used in this specification and the appended claims refers to any combination and all possible combinations of one or more of the associated listed items, and includes such combinations. For example, A and / or B can represent three cases: A alone, A and B simultaneously, and B alone. Additionally, the character " / " in this invention generally indicates that the preceding and following objects have an "or" relationship.

[0024] It should be understood that although terms such as first, second, third, etc., may be used in the embodiments of the present invention to describe the preset range, these preset ranges should not be limited to these terms. These terms are only used to distinguish the preset ranges from one another. For example, without departing from the scope of the embodiments of the present invention, the first preset range may also be referred to as the second preset range, and similarly, the second preset range may also be referred to as the first preset range.

[0025] Depending on the context, the word "if" as used here can be interpreted as "when," "when," "in response to determination," or "in response to detection." Similarly, depending on the context, the phrase "if determination" or "if detection (of the stated condition or event)" can be interpreted as "when determination," "in response to determination," "when detection (of the stated condition or event)," or "in response to detection (of the stated condition or event)."

[0026] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. The components of the embodiments of the present invention described and shown in the accompanying drawings can generally be arranged and designed in various different configurations. Therefore, the following detailed description of the embodiments of the present invention provided in the accompanying drawings is not intended to limit the scope of the claimed invention, but merely to illustrate selected embodiments of the invention. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention.

[0027] The accompanying drawings illustrate various structural schematic diagrams according to embodiments disclosed in this invention. These drawings are not to scale, and some details have been enlarged for clarity, and some details may have been omitted. The shapes of the various regions and layers shown in the drawings, as well as their relative sizes and positional relationships, are merely exemplary and may deviate from reality due to manufacturing tolerances or technical limitations. Furthermore, those skilled in the art can design regions / layers with different shapes, sizes, and relative positions as needed.

[0028] Example 1 refer to Figure 1 The preparation method of the focused ultrasound controllable degradation neurostimulation electrode of the present invention includes the following steps: 1) Fabricate a polycaprolactone film on a glass substrate, then remove the glass substrate and clean the surface of the polycaprolactone film. Specifically, take a clean glass substrate, cover the glass substrate with a layer of pressure-sensitive adhesive as a temporary carrier adhesive layer, then smoothly attach the polycaprolactone film onto the pressure-sensitive adhesive to avoid bubbles and wrinkles, then remove the glass substrate and pressure-sensitive adhesive, and finally wipe the surface of the polycaprolactone film with a lint-free cloth.

[0029] 2) A metal mask is attached to the front side of the polycaprolactone film, and then a titanium adhesion layer and a molybdenum conductor layer are sequentially deposited on the front side of the polycaprolactone film by magnetron sputtering. Then the metal mask is removed to obtain sample 1. Specifically, a metal mask is attached to the front side of the polycaprolactone film, and then the whole thing is placed in a magnetron sputtering device and vacuumed. Then, a 10-nanometer-thick titanium adhesive layer is sputtered first, followed by a 300-nanometer-thick molybdenum conductor layer. Finally, the metal mask is removed to obtain sample 1.

[0030] 3) Spin-coating the polycaprolactone-thiophene / bismaleimide working solution onto the front side of sample 1, drying and vacuum overnight to obtain sample 2; Specifically, bismaleimide was dissolved in 0.25 mL of dimethylformamide to obtain solution B, and polycaprolactone-thiophene was dissolved in 1.25 mL of dimethylformamide to obtain solution A. The concentration of bismaleimide in solution B was 0.15 mmol / L, and the concentration of polycaprolactone-thiophene in solution A was also 0.15 mmol / L. Solution B was poured into solution A and stirred at room temperature for 1-2 minutes to obtain the polycaprolactone-thiophene / bismaleimide spin-coating working solution. This working solution was then immediately spin-coated onto the front side of sample 1. It was subsequently dried at 50°C for 10 minutes to evaporate some of the dimethylformamide and reduce bubbling. Then, it was vacuum-treated overnight at 50°C to remove the dimethylformamide and continue cross-linking, improving insulation density to obtain sample 2. During the spin-coating process, the spin-coating speed was first 500 rpm for 10 seconds, followed by a spin-coating speed of 2000 rpm. Spin coat at a speed of 30 revolutions per minute for 30 seconds; 4) Flip sample 2 so that the back side of the polycaprolactone film is facing up. Use a laser to open windows on the polycaprolactone film to expose metal sites, then activate it, then drop-coat the modification material, and then form a film to obtain a focused ultrasound-controlled degradable neurostimulation electrode.

[0031] Specifically, sample 2 was flipped so that the back side of the polycaprolactone film was facing up. The center of the electrode pads was positioned by the alignment mark on the circuit. Then, the polycaprolactone film was exposed by laser windowing through multiple low-energy, layer-by-layer etches. After each etch, the process was stopped and examined with a microscope until the metal sites were exposed. The molybdenum inside the window was then lightly surface-activated. Subsequently, a modification material was drop-coated, and the film was heated at 60°C for 5 minutes to form a film.

[0032] Example 2 The implantation method of the focused ultrasound controllable degradation neurostimulation electrode of the present invention includes the following steps: 1) Animal anesthesia, skin preparation, and aseptic implantation; Anesthesia and analgesia were administered in accordance with ethical protocols. The surgical area was shaved, disinfected, and draped. Implantation site selection: as superficial as possible (to facilitate ultrasound energy delivery, ensure stable alignment, and reduce tissue attenuation), away from major blood vessels and high-risk organs (to reduce the risk of accidental thermal / mechanical damage), and fix the focused ultrasound controllable degradable nerve stimulation electrode (fixed at the suture point or tissue bag) to avoid displacement during subsequent ultrasound irradiation, which could lead to "misalignment".

[0033] 2) Preparation and coupling of the focused ultrasound system; Shave, clean, and apply coupling adhesive thoroughly, avoiding any air gaps.

[0034] Coupling stability is achieved by using a degassed water bladder to form a stable acoustic channel (muscle areas rely more on stable coupling). Enable real-time ultrasound imaging, coaxial imaging, for monitoring cavitation activity and alignment.

[0035] 3) Location and dosage calibration; Zero-power positioning: First, image without outputting energy to confirm that the focal point covers the area of ​​the implanted electrode site.

[0036] By using repeated irradiation to accumulate the effect, we can avoid adopting a high mechanical effect scheme that emphasizes cavitation from the outset.

[0037] Subcutaneous administration using a minimum dose closed-loop method can establish a dose-leakage curve. Muscles are prioritized for enhanced fixation and coupling stability, followed by cumulative effects based on "number of times / total duration". Paraneural ultrasound administration further reduces single-segment ultrasound time and power, and intensifies monitoring; any abnormal neurological function is immediately stopped.

[0038] 4) In vivo triggered irradiation detection; Closed-loop rhythm: Stimulate a short segment, immediately measure site impedance; if the change is slight, proceed to the next segment. If the change is too rapid or abnormalities occur (skin redness, significant temperature rise, animal stress response), stop immediately and record.

[0039] Temperature rise / thermal effect monitoring was performed, and the process was paused when an external temperature rise of approximately 2 degrees Celsius was detected.

[0040] It should be noted that the present invention has the following characteristics: The crosslinking bond of this invention is a reversible cycloaddition of "diene + dienophile". When the system gains energy, a reverse Diels-Alder reaction occurs, resulting in a "reverse reaction". The crosslinking points are unlinked, returning to the original reactants. The process involves sputtering a titanium adhesive layer and a molybdenum conductor layer onto a polycaprolactone film, spin-coating a crosslinked insulation layer, laser opening on the back side, and local modification of the site. The process is simple.

[0041] This invention employs a reversible cross-linked network formed by polycaprolactone-thiophene / bismaleimide as the insulating layer. Under focused ultrasound, this network primarily undergoes network reorganization due to a gentle thermal effect, resulting in a segmented irradiation-gradual leakage adjustable failure process, rather than a one-time perforation failure. Furthermore, a controllable failure time window and dose-response relationship are achieved through multiple low-power accumulations, meeting the design goal of on-demand failure in vivo.

[0042] This invention employs focused ultrasound, performed in segments. By observing the rise in impedance, the degradation of the electrodes is determined, and a closed-loop control for the next ultrasound session is initiated. Combined with temperature rise monitoring and site-specific strategies (subcutaneous / muscle / paraneural), this invention achieves a quantifiable, reproducible, and safely convergent in vivo triggering scheme.

[0043] It should be noted that transient molybdenum-based electrodes typically rely on the passive dissolution of the material in body fluids and the integrity of the encapsulation to determine their lifetime window. Degradation time is significantly affected by individual environmental factors and local defects, and failure often occurs in a randomly accelerated manner. On the other hand, while commercial platinum / iridium systems offer long-term reliability, they are essentially "permanent device paradigms," and once pinholes or interface peeling occur in the encapsulation, unpredictable random leakage often results. This invention, through a system design of "polycaprolactone substrate + titanium / molybdenum circuitry + polycaprolactone-thiophene reversible cross-linked insulating layer + back-side laser micro-windowing + focused ultrasound segmented closed-loop triggering," upgrades electrode failure from passive, random dissolution or encapsulation failure to a non-invasive, image-alignable, spatially selective, and metered closed-loop-progressive "gradual leakage failure" process. During the working period, the site is strictly defined, and the wiring and sidewalls are fully covered by an insulating layer for long-term protection. When failure is required, multiple short-segment focused ultrasound triggers are used, and the process is controlled in real-time by impedance / leakage monitoring. The failure can be stopped after reaching a threshold, thus simultaneously meeting the stability requirements of high-performance stimulation and the controllability and safety boundaries of on-demand failure in vivo.

[0044] Other embodiments of the invention will readily occur to those skilled in the art upon consideration of the specification and disclosure of the invention. This application is intended to cover any variations, uses, or adaptations of the invention that follow the general principles of the invention and include common knowledge or customary techniques in the art not disclosed herein. The specification and examples are to be considered exemplary only, and the true scope and spirit of the invention are indicated by the following claims.

[0045] It should be understood that the present invention is not limited to the precise structure described above and shown in the accompanying drawings, and various modifications and changes can be made without departing from its scope. The scope of the invention is limited only by the appended claims.

[0046] The above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the present invention. Any simple modifications, alterations, or equivalent structural changes made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A method for preparing a focused ultrasound-controlled degradable neurostimulation electrode, characterized in that, Includes the following steps: 1) Fabrication of polycaprolactone film; 2) A metal mask is attached to the front side of the polycaprolactone film, and then a titanium adhesion layer and a molybdenum conductor layer are sequentially deposited on the front side of the polycaprolactone film by magnetron sputtering. Then the metal mask is removed to obtain sample 1. 3) Spin-coating the polycaprolactone-thiophene / bismaleimide working solution onto the front side of sample 1, drying and vacuum overnight to obtain sample 2; 4) Flip sample 2 so that the back side of the polycaprolactone film is facing up. Use a laser to open windows on the polycaprolactone film to expose metal sites, then activate it, then drop-coat the modification material, and then form a film to obtain a focused ultrasound-controlled degradable neurostimulation electrode.

2. The method for preparing a focused ultrasound-controlled degradable neurostimulation electrode according to claim 1, characterized in that, Step 1) is as follows: Take a glass substrate, cover the glass substrate with a layer of pressure-sensitive adhesive as a temporary carrier adhesive layer, then flatly attach the polycaprolactone film onto the pressure-sensitive adhesive, then remove the glass substrate and the pressure-sensitive adhesive, and finally wipe the surface of the polycaprolactone film with a lint-free cloth.

3. The method for preparing a focused ultrasound-controlled degradable neurostimulation electrode according to claim 1, characterized in that, The specific operation of step 2) is as follows: A metal mask was attached to the front side of the polycaprolactone film, and then the whole thing was placed in a magnetron sputtering device and vacuumed. Then, the titanium adhesive layer was sputtered first, followed by the molybdenum conductor layer. Finally, the metal mask was removed to obtain sample 1.

4. The method for preparing a focused ultrasound-controlled degradable neurostimulation electrode according to claim 3, characterized in that, The titanium adhesive layer is 10 nanometers thick, and the molybdenum conductor layer is 300 nanometers thick.

5. The method for preparing a focused ultrasound-controlled degradable neurostimulation electrode according to claim 1, characterized in that, The specific operation of step 3) is as follows: Bismaleimide was dissolved in dimethylformamide to obtain solution B. Polycaprolactone-thiophene was dissolved in dimethylformamide to obtain solution A. Solution B was poured into solution A and stirred at room temperature to obtain a polycaprolactone-thiophene / bismaleimide spin-coating working solution. The polycaprolactone-thiophene / bismaleimide spin-coating working solution was spin-coated onto the front side of sample 1, then dried at 50°C for 10 min, and then vacuum-treated at 50°C overnight to remove dimethylformamide and continue crosslinking to obtain sample 2.

6. The method for preparing a focused ultrasound-controlled degradable neurostimulation electrode according to claim 5, characterized in that, The concentration of bismaleimide in solution B is 0.15 mmol / L, and the concentration of polycaprolactone-thiophene in solution A is 0.15 mmol / L.

7. The method for preparing a focused ultrasound-controlled degradable neurostimulation electrode according to claim 5, characterized in that, During the spin coating process, spin coating is first performed at a speed of 500 rpm for 10 seconds, and then at a speed of 2000 rpm for 30 seconds.

8. The method for preparing a focused ultrasound-controlled degradable neurostimulation electrode according to claim 1, characterized in that, The specific operation of step 4) is as follows: Sample 2 was flipped so that the back side of the polycaprolactone film was facing up. The center of the electrode pad was positioned by the alignment mark on the circuit. Then, the molybdenum inside the window was activated by laser windowing. Subsequently, the modification material was drop-coated and heated at 60°C for 5 minutes to form a film, thus obtaining a focused ultrasound-controlled degradable neurostimulation electrode.

9. A focused ultrasound-controlled degradable nerve stimulation electrode, characterized in that, It is prepared based on the preparation method of the focused ultrasound controllable degradation neurostimulation electrode according to any one of claims 1-8.

10. The focused ultrasound controllable degradable nerve stimulation electrode according to claim 9, characterized in that, When failure is required, the process is triggered by multiple short-segment focused ultrasound cycles and controlled in real time by impedance / leakage monitoring. Once the threshold is reached, the process stops, thus simultaneously satisfying the stability requirements of high-performance stimulation and the controllability and safety boundaries of on-demand failure in vivo.

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