Electropolymerized conductive polymer drug-loaded cochlear implant electrode and its manufacturing method

Abstract

The present invention discloses an electropolymerized conductive polymer drug-loaded cochlear implant electrode and a manufacturing method thereof, comprising a flexible electrode head, n stimulation electrodes, m drug film electrodes, a silica gel, a first booster ring, a second booster ring, an implant fin, a wavy lead bundle, a spiral lead bundle, a loop electrode, a film electrode lead, a stimulation lead and a loop lead, wherein the drug film electrode is based on an inert metal, and an electropolymerization chemical reaction solidifies the ear drug and the conductive high molecular polymer on the substrate, and the release of the ear drug is controlled by the amount of electricity applied to the drug film electrode. The release of the ear drug on the drug film electrode of the present invention is carried out by a potential-controlled or current-controlled triangle wave, square wave, sine wave cyclic scanning potential method, and the amount of drug released is proportional to the amount of electricity applied to the drug film electrode.

Description

Technical Field

[0001] The present invention relates to the field of electronic medical treatment, and in particular to an electropolymerized conductive polymer drug-loaded cochlear implant electrode and a manufacturing method thereof. Background Art

[0002] According to the World Health Organization, there are about 280 million people with disabling hearing loss in the world. There are 27.8 million hearing-impaired people in China, of which 8 million are severely deaf. In addition to infectious causes such as meningitis, measles, mumps and chronic ear infections, hearing loss is usually caused by exposure to excessive noise, head and ear injuries, aging and the use of ototoxic drugs.

[0003] Drug therapy has always been the first choice for the treatment of inner ear diseases. Other treatment options are considered only when drug therapy is ineffective. Intravenous, intramuscular or oral administration is still the main way to treat inner ear diseases. Because there is a blood-labyrinth barrier between the inner ear and the systemic blood circulation, it is similar to the blood-brain barrier in anatomy and function. Therefore, for many drugs, systemic treatment is not feasible, and local administration has advantages. In addition, systemic administration may cause adverse reactions to other organs in the body, or some patients with systemic diseases have contraindications to drugs, such as patients with diabetes, hypertension, and gastric ulcers cannot be given systemic hormone therapy. The inner ear includes the cochlea and vestibule, which has a delicate and complex structure. The cochlea is a small spiral tube (about 35 mm in length). In the cochlea, most target tissues are immersed in about 76 mL of peripheral lymph, which is similar to cerebrospinal fluid. Studies have shown that local administration of drugs to the inner ear allows the drugs to cross the blood-labyrinth barrier and directly enter the inner ear. The drug concentration achieved in the inner ear is more than 100 times that of systemic administration, thereby reducing the dosage of the drug while avoiding the adverse reactions of systemic medication, overcoming the disadvantage of uneven distribution in the cochlea when administering drugs through the round window membrane, and improving the local efficacy of the drug in the inner ear.

[0004] Local drug delivery to the inner ear has been clinically used for a long time. The main method at present is tympanic perfusion, followed by sustained release / controlled release through the round window membrane. Both are based on the permeability of the inner ear round window membrane. The drug molecules that reach the middle ear cavity penetrate into the inner ear through the round window membrane to exert their effects. The permeability of the round window membrane is affected by many factors, such as the size, configuration, concentration, lipid solubility, charge and thickness of the round window membrane. The permeability diameter of the round window membrane is less than 2μm, and particles with a diameter of 3μm or more cannot pass through.

[0005] Since the sensory cells of the inner ear of mammals only develop during embryogenesis and cannot regenerate postnatally, hearing can only be restored by implanting a cochlear implant when drug treatment is ineffective. The cochlear implant system is an implantable electronic device that can provide functional hearing for patients with severe and profound sensorineural hearing loss. It is also the only effective treatment for sensorineural hearing loss in clinical practice. Cochlear implant technology stimulates spiral ganglion neurons (SGNs) through electrodes implanted in the cochlea to provide hearing for patients with severe to profound sensorineural hearing loss. The cochlear implant passes over the outer ear, middle ear, and inner ear of the human body, and directly stimulates the auditory nerve with electrical pulses carrying sound information to produce hearing. It usually consists of an external device and an implantable internal device.

[0006] The external device is called a cochlear implant speech processor (abbreviated as: speech processor). The main principle is that the microphone on the speech processor picks up the sound signal, processes and encodes the collected sound signal, and then transmits it to the implant wirelessly. The internal device is called a cochlear implant (abbreviated as: implant). Its principle is to receive the sound signal processed by the speech processor in the form of radio frequency, and convert it into current pulses after decoding; the current pulses stimulate the remaining auditory nerves in the cochlea through the electrode array, so that the brain of patients with severe and profound sensorineural hearing loss can perceive the sound.

[0007] After cochlear implant surgery, residual hearing and hearing produced by the cochlear implant are often affected by the growth of fibroblasts and delayed degeneration of neuronal tissue in the cochlea after surgery. Histological evaluation of the temporal bones of patients with cochlear implants showed that fibrous tissue hyperplasia was formed in nearly 60% of the cases examined. The formation of fibrous tissue hyperplasia is believed to be caused by mechanical damage to the fine structure of the cochlea caused by electrode insertion and the body's rejection of the implant. The formation of fibrous tissue between the electrode and the cochlea leads to damage to hair cells and spiral ganglion cells. At the same time, the proliferation of fibrous tissue around the electrode increases the electrode impedance, which affects the effectiveness of electrical stimulation of the auditory nerve in the cochlea, reduces the dynamic range of the threshold, and reduces the speech perception effect and the function of the cochlear implant itself. Fibrous tissue hyperplasia mainly occurs in the first 4 weeks of implantation, which can be clinically judged by the increase in the electrode impedance of the cochlear implant.

[0008] Recent advances in cochlear implant technology have led to the development of a new generation of less invasive electrodes that minimize damage to the inner ear during electrode insertion. This is particularly true for those with residual hearing who may benefit from emerging stimulation strategies that employ combined acoustic and electrical stimulation. In addition, insertion trauma may also result in scarring and fibrous tissue formation, which can lead to increased impedance and reduced residual hearing. Two surgical strategies have been used to reduce insertion trauma: soft surgery and targeted drug delivery. However, even with the introduction of minimally invasive “soft” surgical techniques and modifications to the electrodes to reduce intracochlear damage during insertion, one-third of cases still experience loss or incomplete preservation of residual hearing. Residual hearing preservation has been achieved by applying protective pharmacology to the inner ear during cochlear implant surgery, but this effect is only temporary due to the limited amount of drug delivery. Using the electrode array in the cochlear implant as a carrier to deliver drugs to the inner ear is an effective approach due to the close proximity of the electrode array to the spiral neurons in the cochlear implant.

[0009] Advanced drug delivery systems (DDS) have brought immeasurable benefits to drug administration. In the past three decades, new approaches have been proposed to develop novel carriers for drug delivery.

[0010] Dexamethasone (DXMS) is a synthetic corticosteroid with a chemical formula of C22H29FO5. Dexamethasone, like other glucocorticoids, has anti-inflammatory effects, can reduce and prevent tissue responses to inflammation, and has pharmacological effects such as anti-endotoxin, immunosuppressive, anti-shock, and enhanced stress response. Studies have shown that topically applied glucocorticoid receptor agonists (such as dexamethasone) can inhibit inflammation of the inner ear, thereby preventing the expansion of connective tissue, cell degeneration, and residual hearing loss associated with fibrosis. Due to the relative difficulty of entering the inner ear, it has been problematic to maintain adequate therapeutic levels of this agent for a long time.

[0011] Laminin, also known as laminin, is a non-collagenous sugar that constitutes the intercellular matrix and, together with collagen, constitutes the component of the cochlear basement membrane. Studies have shown that administration through electrode adsorption and promoting the survival of spiral nerve neurons after electrode insertion trauma have the ability to reduce the threshold of acoustic brainstem response and electrically evoked auditory brainstem response (i.e., eCAP and eABR).

[0012] Results from local application of insulin-like growth factor 1 (IGF1) and hepatocyte growth factor (HGF)-containing hydrogels implanted in guinea pig ears suggest that the growth factors can protect hearing, thereby significantly improving hearing hair cells (HCs) from damage caused by intense noise exposure, drug-induced hearing loss, or ischemic injury, without adverse events. IGF1 inhibits apoptosis and promotes cell cycle progression to maintain the value of residual hair cells in the damaged cochlea. In addition, human clinical trials have shown that IGF1 hydrogel treatment is effective for patients with sudden sensorineural hearing loss that is refractory to glucocorticoid therapy.

[0013] The drug delivery cochlear implant electrodes in the prior art mainly involve drug loading in the silicone body or hydrogel body of the electrode. Since the loading will affect the quality of the silicone, the surface of the silicone will be damaged after the drug is dissolved, which will affect the functionality and long-term reliability of the electrode. In addition, drug loading in the silicone or hydrogel body is a physical adsorption, and the release of the drug is affected by free diffusion and cannot be controlled. Summary of the invention

[0014] The present invention arranges a metal film as a substrate on the silica gel of the artificial cochlear electrode array, and solidifies ear medicine and conductive high molecular polymer onto the surface of the film electrode substrate through electropolymerization chemical reaction.

[0015] In order to achieve the above-mentioned purpose, the technical scheme of the present invention is as follows: an electropolymerized conductive polymer drug-loaded cochlear implant electrode, comprising a flexible electrode head, n stimulation electrodes, m drug film electrodes, a silicone body, a first booster ring, a second booster ring, an implant fin, a wavy lead bundle, a spiral lead bundle, a loop electrode, a film electrode lead, a stimulation lead and a loop lead, wherein the drug film electrode is based on an inert metal, and the electropolymerization chemical reaction solidifies the ear drug and the conductive polymer on the substrate, and the release of the ear drug is controlled by the amount of electricity applied to the drug film electrode; the flexible electrode head is arranged at the front end, the n stimulation electrodes and the m drug film electrodes are all arranged on the silicone body, the n stimulation electrodes and the m drug film electrodes are relatively co-located or relatively staggered, the first booster ring, the second booster ring and the implant fin are arranged behind the two, the loop electrode is arranged at the end of the silicone body, the stimulation electrode is connected to the stimulation lead, the drug film electrode is connected to the film electrode lead, the loop electrode is connected to the loop lead, and the film electrode lead and the stimulation lead form a wavy lead bundle and a spiral lead bundle in the silicone body.

[0016] Preferably, the ear drug comprises a glucocorticoid receptor agonist, laminin, insulin-like growth factor or hepatocyte growth factor.

[0017] Preferably, the conductive high molecular polymer includes polypyrrole, a derivative of polypyrrole, polythiophene or a derivative of polythiophene.

[0018] Preferably, the glucocorticoid receptor agonist is dexamethasone.

[0019] Preferably, the polythiophene derivative is polyethylenedioxythiophene.

[0020] Based on the above purpose, the present invention also provides a method for preparing an electropolymerized conductive polymer drug-loaded cochlear implant electrode, comprising the following steps:

[0021] Making drug thin film electrodes;

[0022] Making stimulation electrodes;

[0023] Making thin film electrode leads and stimulation leads, welding the thin film electrode leads to the drug thin film electrode, welding the stimulation electrode to the stimulation lead, ultrasonic cleaning and plasma treatment;

[0024] Injection molding with silicone;

[0025] Manufacturing loop electrodes and loop leads, welding the loop electrodes and loop leads, ultrasonic cleaning and plasma treatment;

[0026] It is fixed in the mold together with the spiral lead bundle, and silicone injection molding is added, and the surface is coated with self-lubricating silicone;

[0027] The manufacturing of the drug film electrode comprises the following steps:

[0028] An inert metal sheet is used as a working electrode, a calomel electrode or silver or silver chloride is used as a reference electrode, and platinum is used as an auxiliary electrode, and they are connected to an electrochemical workstation respectively;

[0029] The electrolytic cell is placed, wherein the electrolytic cell contains a deposition solution, wherein the deposition solution includes an ear medicine and a conductive high molecular polymer;

[0030] The electrolytic cell is placed on a magnetic stirrer, and the magnet is placed in the center of the bottom of the electrolytic cell;

[0031] Turn on the electrochemical workstation and magnetic stirrer to deposit the ear drug and conductive polymer on the working electrode.

[0032] Preferably, the manufacturing of the stimulation electrode comprises the following steps:

[0033] Annealing the platinum-iridium alloy billet and rolling it into a platinum-iridium alloy sheet;

[0034] After laser cutting, the platinum-iridium alloy sheet is punched into shape;

[0035] The manufacturing of the thin film electrode leads and the stimulation leads comprises the following steps:

[0036] The platinum-iridium alloy billet is annealed, cold drawn and straightened into a platinum-iridium alloy wire;

[0037] Platinum-iridium alloy wire is coated and wavy and spiraled;

[0038] Cut the platinum-iridium alloy wire and remove the coating at both ends;

[0039] The manufacturing of the loop electrode comprises the following steps:

[0040] The platinum-iridium alloy blank is annealed, cold drawn, straightened, and ground into an annular platinum-iridium alloy sheet;

[0041] Perform laser cutting and deburring;

[0042] The manufacturing of the loop lead comprises the following steps:

[0043] The platinum-iridium alloy billet is annealed, cold drawn and straightened into a platinum-iridium alloy wire;

[0044] The platinum-iridium alloy wire is coated, cut, and the coating is removed at both ends.

[0045] Preferably, the ear drug comprises a glucocorticoid receptor agonist, laminin, insulin-like growth factor or hepatocyte growth factor.

[0046] Preferably, the conductive high molecular polymer includes polypyrrole, a derivative of polypyrrole, polythiophene or a derivative of polythiophene.

[0047] Preferably, the deposition is carried out by constant current deposition with a current density of 0.1-0.9 mA / cm 2 , the deposition time does not exceed 500s.

[0048] The present invention includes at least the following beneficial effects: conductive high molecular polymer is a type of polymer material that is a polymer with conjugated π-bonds, which is converted from a non-conductor to a conductor by chemical or electrochemical "doping". When in use, the cochlear implant system applies electricity to the drug film electrode of the conductive high molecular polymer containing the ear drug as needed to control the release of the drug. Since the ear drug is fixed on the surface of the electrode array through an electropolymerization chemical reaction, the release of the ear drug will not diffuse freely, nor will it affect the physical and chemical properties of the electrode array silica gel, and thus will not affect the functionality and reliability of the cochlear implant electrode. BRIEF DESCRIPTION OF THE DRAWINGS

[0049] Figure 1 This is a schematic structural diagram of an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to Example 1 of the present invention;

[0050] Figure 2 This is a schematic diagram of the drug film electrode structure of the electropolymerized conductive polymer drug-loaded cochlear implant electrode according to Example 1 of the present invention;

[0051] Figure 3This is a schematic diagram of the drug film electrode structure of the electropolymerized conductive polymer drug-loaded cochlear implant electrode in Example 2 of the present invention;

[0052] Figure 4 This is a schematic diagram of the drug film electrode structure of the electropolymerized conductive polymer drug-loaded cochlear implant electrode in Example 3 of the present invention;

[0053] Figure 5 This is a schematic structural diagram of an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to Example 4 of the present invention;

[0054] Figure 6 This is a schematic diagram of the drug film electrode structure of the electropolymerized conductive polymer drug-loaded cochlear implant electrode according to Example 4 of the present invention;

[0055] Figure 7 This is a schematic structural diagram of an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to Example 5 of the present invention;

[0056] Figure 8 This is a cross-sectional view of the electropolymerized conductive polymer drug-loaded cochlear implant electrode according to Example 1 of the present invention;

[0057] Fig. 9 It is a schematic diagram of the structure of a deposition device of a method for manufacturing an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to an embodiment of the present invention;

[0058] Fig.10 This is a curve diagram of the release of ear drugs controlled by the electrochemical reaction of the electropolymerized conductive polymer drug-loaded cochlear implant electrode according to an embodiment of the present invention. DETAILED DESCRIPTION

[0059] Example 1

[0060] See also Figure 1As shown, an electropolymerized conductive polymer drug-loaded cochlear implant electrode comprises a flexible electrode head 1, n stimulation electrodes 2, m drug film electrodes 3, a silica gel body 4, a first booster ring 5, a second booster ring 6, an implant fin 7, a wavy lead bundle 8, a spiral lead bundle 9, a loop electrode 10, a film electrode lead 11, a stimulation lead 12 and a loop lead 13, wherein the drug film electrode 3 is based on an inert metal, and an electropolymerization chemical reaction solidifies the ear drug and the conductive polymer on the substrate, and the release of the ear drug is controlled by the amount of electricity applied to the drug film electrode; The pole head 1 is arranged at the front end, n stimulation electrodes 2 and m drug film electrodes 3 are all arranged on the silicone body 4, the n stimulation electrodes 2 and m drug film electrodes 3 are arranged in relatively the same position, a first booster ring 5, a second booster ring 6 and an implant fin 7 are arranged behind the two, a loop electrode 10 is arranged at the end of the silicone body 4, the stimulation electrode 2 is connected to the stimulation lead 12, the drug film electrode 3 is connected to the film electrode lead 11, the loop electrode 10 is connected to the loop lead 13, and the film electrode lead 11 and the stimulation lead 12 form a wavy lead bundle 8 and a spiral lead bundle 9 in the silicone body 4.

[0061] The ear drugs include glucocorticoid receptor agonists, laminin, insulin-like growth factor or hepatocyte growth factor, and the conductive high molecular polymer includes polypyrrole, polypyrrole derivatives, polythiophene or polythiophene derivatives.

[0062] In a specific embodiment, the ear drug is dexamethasone, and the conductive polymer is polypyrrole. Figure 2 The drug film electrode 3-1 exposed outside the silicone body is circular and opposite to the stimulation electrode cross section. Figure 8 The drug film electrode is divided into two layers, the bottom layer is the substrate 14, and the upper layer is the polymer layer 15. The polymer layer 15 is a combination of ear drugs and conductive high molecular polymers.

[0063] The drug film electrode 3 has the following embodiments

[0064] Example 2

[0065] See also Figure 3 The n stimulation electrodes 2 and the m drug film electrodes 3-2 are arranged at the same position relative to each other. The drug film electrodes 3-2 are elliptical, which increases the exposure area and improves the amount of drug released in the ear.

[0066] Example 3

[0067] See also Figure 4 The n stimulation electrodes 2 and the m drug film electrodes 3-3 are arranged at the same position relative to each other. The drug film electrodes 3-3 are arc-shaped, which also increases the exposure area and improves the amount of drug released in the ear.

[0068] Example 4

[0069] See also Figure 5-Figure 6 , n stimulation electrodes 2 and m drug film electrodes 3-4 are arranged in relatively staggered positions. The drug film electrodes 3-4 are semi-circular, which further increases the exposure area and improves the amount of drug released in the ear. They are staggered so that the stimulation electrodes 2 are not affected by the increase in the area of ​​the drug film electrodes 3-4 exposed to the silica gel.

[0070] Example 5

[0071] See also Figure 7 , n stimulation electrodes 2 and m drug film electrodes 3-5 are arranged at intervals, and the drug film electrodes 3-5 are fully annular, so that the exposure area is increased to the extreme. Similarly, the amount of ear drug release is similar. This embodiment is suitable for users with high risk of ear fibrous tissue hyperplasia assessment.

[0072] Based on the above purpose, the present invention also provides a method for preparing an electropolymerized conductive polymer drug-loaded cochlear implant electrode, comprising the following steps:

[0073] Making drug thin film electrodes;

[0074] Making stimulation electrodes;

[0075] Making thin film electrode leads and stimulation leads, welding the thin film electrode leads to the drug thin film electrode, welding the stimulation electrode to the stimulation lead, ultrasonic cleaning and plasma treatment;

[0076] Injection molding with silicone;

[0077] Manufacturing loop electrodes and loop leads, welding the loop electrodes and loop leads, ultrasonic cleaning and plasma treatment;

[0078] It is fixed in the mold together with the spiral lead bundle, and silicone injection molding is added, and the surface is coated with self-lubricating silicone;

[0079] The preparation of the drug thin film electrode comprises the following steps:

[0080] An inert metal sheet is used as a working electrode, a calomel electrode or silver or silver chloride is used as a reference electrode, and platinum is used as an auxiliary electrode, and they are connected to an electrochemical workstation respectively;

[0081] The electrolytic cell is placed, wherein the electrolytic cell contains a deposition solution, wherein the deposition solution includes an ear medicine and a conductive high molecular polymer;

[0082] The electrolytic cell is placed on a magnetic stirrer, and the magnet is placed in the center of the bottom of the electrolytic cell;

[0083] Turn on the electrochemical workstation and magnetic stirrer to deposit the ear drug and conductive polymer on the working electrode.

[0084] Of course, it can also be produced by vapor phase precipitation, solid phase precipitation, electroless chemical plating, etc. The thickness of the inert metal sheet is 0.3 μm-1 μm, and the inert metal can be any biocompatible inert metal, such as gold, platinum, iridium, ruthenium, palladium and their alloys.

[0085] The device structure for making drug thin film electrodes can be found in Fig. 9 The electrochemical synthesis used a three-electrode electrolytic cell device. The electrolytic cell 24 was a 50 ml glass cuvette. The constant temperature water inlet 25 was located at the low side, and the constant temperature water outlet 26 was located at the high side. The electrolytic cell 24 contained a working electrode (i.e., an inert metal sheet to be plated, which became a drug film electrode 3 after plating), a platinum auxiliary electrode 23, and a calomel electrode (SCE) or a silver / silver chloride (Ag / AgCl) reference electrode 22. During the electropolymerization process, the working electrode served as the anode of the electrolytic cell 24, and an oxidation reaction occurred. The electrochemical workstation 21 was used for control. The deposition solution (15 ml) contained 0.2 M polypyrrole (PPy, molecular formula C4H5N) and 0.3 M dexamethasone disodium phosphate. The actual electrode area in the deposition solution, i.e., the area covered by the generated polymer drug film, was 100-300 mm. 2 In the constant potential chronoamperometric static mode, a constant potential of 1.0 V (0.5-1.5 V range) relative to the reference electrode is used. The amount of material deposited on the surface of the working electrode 3 is controlled by the total charge during the deposition process over time, and the deposited charge density is 10-100 mC / cm 2 , of which 25-50mC / cm 2 Optimal in terms of film stability and release efficiency.

[0086] The basic principle of one-step electropolymerization of polypyrrole and dexamethasone is as follows:

[0087]

[0088] In the presence of A- (anion or negatively charged biomolecule or drug), the pyrrole monomer is oxidized and electropolymerized, and the resulting polymer is deposited on the anode. Since the polymer backbone is positively charged, the negatively charged drug ions are incorporated to maintain charge neutrality. The negatively charged otic drug is dexamethasone disodium phosphate (DXMS). The presence of phosphate groups on the dexamethasone steroid ring structure creates a negative charge on the drug, allowing it to be synthesized into polypyrrole after electropolymerization.

[0089] A Philips XL-30 field emission scanning electron microscope (SEM) was used to examine the morphology of the PPy / DXMS thin film coating. To improve the clarity of the SEM image, a thin layer of gold film (about 10 nanometers) was sputtered onto the electrode surface. The gold film was sputtered using a Hummer-600 sputtering system. The SEM scanning electron microscope was used to observe the surface of the PPy / DXMS film, which was micron-sized conductive polymer particles. The surface of the conductive polymer was observed to be uniform and free of cracks.

[0090] Taking polyethylene dioxythiophene, a derivative of a conductive polymer polythiophene, namely PEDOT, as a specific example, the ear drug is the glucocorticoid dexamethasone (DXMS), and the inert metal sheet is gold. The conductive polymer of dexamethasone (DXMS) and polythiophene (PEDOT) is grown on the inert metal sheet in a constant current manner.

[0091] PEDOT uses 3,4-ethylenedioxythiophene (EDOT) as a monomer. PEDOT has dioxyethylene bridging groups at the 3 and 4 positions of the heterocyclic ring, which can prevent the possibility of coupling, thereby providing excellent electrochemical stability and good conductivity. The equation for the one-step electropolymerization of 3,4-ethylenedioxythiophene EDOT monomer and dexamethasone cation deposition on the electrode surface is:

[0092]

[0093] The inert metal sheet is made by gold plating process, and the exposed surface diameter is 100-500 microns. The surface of the inert metal sheet is electrochemically cleaned before depositing PEDOT / DXMS.

[0094] Specifically, PEDOT / DXMS was electropolymerized from an aqueous solution of EDOT and dexamethasone disodium phosphate, where the concentration of EDOT was 0.1 M and the concentration of dexamethasone disodium phosphate was 0.2 M. Compared with constant potential deposition, constant current deposition can provide more stable and uniform PEDOT / DXMS films. The current density used for electropolymerization was 0.64 mA / cm 2 , can be 0.1-0.9mA / cm 2 The deposition time varies from 10, 50, 100, 190, 300, 410, 500 s with different deposition amount and film thickness. The current output is controlled by the electrochemical workstation 21, and the timing of each deposition is recorded. The entire electropolymerization reaction is completed in the three-electrode electrolytic cell 24.

[0095] As the film grows, the potential on the working electrode 3 drops rapidly, then slows, but continues to drop for up to 500 s. The potential drop is considered an indication of changes in electrode impedance. The initial sharp drop indicates a significant impedance difference between the gold electrode / electrolyte interface and the PEDOT / electrolyte interface. Once the electrode is completely covered with the PEDOT coating, the impedance decreases significantly because the effective surface area of ​​the thicker film increases. Over 500 s, the potential is still gradually decreasing, however, the growth of the PEDOT coating exceeds the defined area of ​​the gold electrode surface. Such coatings are easy to fall off, and the effective electrode surface area is difficult to define.

[0096] As mentioned above, the morphology of the PEDOT / DXMS film coating was examined using a Philips XL-30 field emission scanning electron microscope (SEM). To improve the clarity of the SEM image, a thin layer of gold film (about 10 nanometers) was sputtered onto the electrode surface. The gold film was sputtered using a Hummer-600 sputtering system. The surface of the PEDOT / DXMS film was observed using a SEM scanning electron microscope, which showed micrometer-sized conductive polymer particles. The surface of the conductive polymer was observed to be uniform and free of cracks.

[0097] The specific embodiment of the controlled drug release of conductive polymer drug carriers using electrical stimulation is dexamethasone and PPy deposited on the electrode. The selected stimulation waveform type is triangular wave cyclic voltametry (CV), that is, the potential is periodically cycled between positive and negative values, and the released drug is quantified using ultraviolet spectroscopy. Triangular wave cyclic voltametry (CV) is performed using a Gamry FAS2 / Femostat (Gamostat) potentiostat under the control of the Gamry software framework. The triangular wave cyclic voltametry is completed in a 100 ml two-electrode electrolytic cell, the electrolyte is pH 7.4, 100 mM phosphate buffered saline (PBS), the loop electrode 10 is a tubular platinum electrode or a flat platinum electrode outside the cochlea, and the voltage is scanned from -0.7 V to +1.3 V at a scan rate of 100 mV / s, and then scanned back to -0.7 V to form a cycle.

[0098] The dexamethasone release from the solution was quantified by UV absorbance to determine the concentration of dexamethasone released. The released drug was detected using an ultraviolet spectrometer (UV757CRT UV-visible spectrophotometer, Shanghai Precision Scientific Instrument Co., Ltd.), and the characteristic absorption band reading of dexamethasone was taken at 242 nm. Before starting the cyclic voltanomic scan, the drug film electrode 3 was soaked in distilled water to remove any dexamethasone that might be loosely attached to the surface. This ensured that the release of dexamethasone was mainly caused by the potential cycling stimulation. Phosphate buffered saline was used as a blank, and the readings of phosphate buffered saline were subtracted from the readings of the release samples. A standard calibration curve for dexamethasone was plotted to define the quantitative relationship between the observed dexamethasone absorbance and concentration. The standard calibration curve for the release amount triggered by the cyclic voltanomic scan stimulation is shown in Figure 2. Fig.10 It is obvious that the release of dexamethasone is approximately linear (R 2 =0.989) is related to the number of stimulations for a given cyclic voltammogram. As a control, UV readings were taken from coated electrodes immersed in PBS without applying electrical stimulation. These control samples did not significantly release dexamethasone by diffusion. Since diffusion is a time-dependent process, control samples were also read after 24 hours, and no significant release of dexamethasone was seen. The above shows that the drug film electrode is a true electrically controlled release system.

[0099] Previous studies have shown that dexamethasone is effective at concentrations of 0.2-0.7 μM, and around this local concentration, a significant reduction in inflammatory tissue response can be seen around neural implants. The present invention is able to release 0.0823 μg / cm after each cyclic voltammogram scan cycle. 2 Dexamethasone, and released a total of nearly 23 μg / cm after 300 cyclic voltametry cycles. 2 According to most histological studies, the reactive area represented by enhanced glial fibrillary acidic protein (GFAP), a key intermediate filament, around the cochlear nerve electrode array has an active radius of less than 500 μm, 0.0823 μg / cm 2 The release of dexamethasone would result in an average dexamethasone concentration of 0.67 μM within a 500 μm radius of the electrode. Thus, the dose triggered by 1 cyclic voltametric scan cycle would achieve an effective concentration around the electrode array sufficient to reduce inflammation.

[0100] In a specific embodiment, making the stimulation electrode comprises the following steps:

[0101] Annealing the platinum-iridium alloy billet and rolling it into a platinum-iridium alloy sheet;

[0102] The platinum-iridium alloy sheet is laser cut and then punched into shape.

[0103] The production of thin film electrode leads and stimulation leads includes the following steps:

[0104] The platinum-iridium alloy billet is annealed, cold drawn and straightened into a platinum-iridium alloy wire;

[0105] Platinum-iridium alloy wire is coated and wavy and spiraled;

[0106] Cut the platinum-iridium alloy wire and remove the coating at both ends;

[0107] The manufacturing of the loop electrode comprises the following steps:

[0108] The platinum-iridium alloy blank is annealed, cold drawn, straightened, and ground into an annular platinum-iridium alloy sheet;

[0109] Laser cutting and deburring are performed.

[0110] Making a loop lead involves the following steps:

[0111] The platinum-iridium alloy billet is annealed, cold drawn and straightened into a platinum-iridium alloy wire;

[0112] The platinum-iridium alloy wire is coated, cut, and the coating is removed at both ends.

[0113] Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that various changes can be made in form and details without departing from the scope defined by the claims of the present invention.

Claims

1. An electropolymerized conductive polymer drug-loaded cochlear implant electrode, characterized in that: It comprises a flexible electrode head, n stimulation electrodes, m drug film electrodes, a silicone body, a first booster ring, a second booster ring, an implant fin, a wavy lead bundle, a spiral lead bundle, a loop electrode, a film electrode lead, a stimulation lead and a loop lead, wherein the drug film electrode is based on an inert metal, and an electropolymerization chemical reaction solidifies the ear drug and a conductive high molecular polymer on the substrate, and the release of the ear drug is controlled by the amount of electricity applied to the drug film electrode; the flexible electrode head is arranged at the front end, the n stimulation electrodes and the m drug film electrodes are all arranged on the silicone body, the n stimulation electrodes and the m drug film electrodes are relatively co-located or relatively staggered, a first booster ring, a second booster ring and an implant fin are arranged behind the two, the loop electrode is arranged at the end of the silicone body, the stimulation electrode is connected to the stimulation lead, the drug film electrode is connected to the film electrode lead, the loop electrode is connected to the loop lead, and the film electrode lead and the stimulation lead form a wavy lead bundle and a spiral lead bundle in the silicone body.

2. The electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 1, characterized in that: The ear drugs include glucocorticoid receptor agonists, laminin, insulin-like growth factor or hepatocyte growth factor.

3. The electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 1, characterized in that: The conductive high molecular polymer includes polypyrrole, a derivative of polypyrrole, polythiophene or a derivative of polythiophene.

4. The electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 2, characterized in that: The glucocorticoid receptor agonist is dexamethasone.

5. The electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 3, characterized in that: The polythiophene derivative is polyethylene dioxythiophene.

6. A method for manufacturing the electropolymerized conductive polymer drug-loaded cochlear implant electrode according to any one of claims 1 to 5, characterized in that: The following steps are involved: Making drug thin film electrodes; Making stimulation electrodes; Manufacturing thin film electrode leads and stimulation leads, welding the thin film electrode leads to the drug thin film electrode, welding the stimulation electrode to the stimulation lead, ultrasonic cleaning and plasma treatment; Injection molding with silicone; Manufacturing loop electrodes and loop leads, welding the loop electrodes and loop leads, ultrasonic cleaning and plasma treatment; It is fixed in the mold together with the spiral lead bundle, and silicone injection molding is added, and the surface is coated with self-lubricating silicone; The manufacturing of the drug film electrode comprises the following steps: An inert metal sheet is used as a working electrode, a calomel electrode or silver or silver chloride is used as a reference electrode, and platinum is used as an auxiliary electrode, and they are connected to an electrochemical workstation respectively; The electrolytic cell is placed, wherein the electrolytic cell contains a deposition solution, wherein the deposition solution includes an ear medicine and a conductive high molecular polymer; The electrolytic cell is placed on a magnetic stirrer, and the magnet is placed in the center of the bottom of the electrolytic cell; Turn on the electrochemical workstation and magnetic stirrer to deposit the ear drug and conductive polymer on the working electrode.

7. The method for manufacturing an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 6, characterized in that: The manufacturing of the stimulation electrode comprises the following steps: Annealing the platinum-iridium alloy billet and rolling it into a platinum-iridium alloy sheet; After laser cutting, the platinum-iridium alloy sheet is punched into shape; The manufacturing of the thin film electrode leads and the stimulation leads comprises the following steps: The platinum-iridium alloy billet is annealed, cold drawn and straightened into a platinum-iridium alloy wire; Platinum-iridium alloy wire is coated and wavy and spiraled; Cut the platinum-iridium alloy wire and remove the coating at both ends; The manufacturing of the loop electrode comprises the following steps: The platinum-iridium alloy blank is annealed, cold drawn, straightened, and ground into an annular platinum-iridium alloy sheet; Perform laser cutting and deburring; The manufacturing of the loop lead comprises the following steps: The platinum-iridium alloy billet is annealed, cold drawn and straightened into a platinum-iridium alloy wire; The platinum-iridium alloy wire is coated, cut, and the coating is removed at both ends.

8. The method for manufacturing an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 6, characterized in that: The ear drugs include glucocorticoid receptor agonists, laminin, insulin-like growth factor or hepatocyte growth factor.

9. The method for manufacturing an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 6, characterized in that: The conductive high molecular polymer includes polypyrrole, a derivative of polypyrrole, polythiophene or a derivative of polythiophene.

10. The method for manufacturing an electropolymerized conductive polymer drug-loaded cochlear implant electrode according to claim 6, characterized in that: The deposition is carried out by constant current deposition with a current density of 0.1-0.9 mA / cm 2 , the deposition time does not exceed 500s.

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