Personalized auxiliary implant for precisely delivering medicine to round window niche

Abstract

The invention discloses a personalized auxiliary implant for precisely delivering drugs to a round window niche. The personalized auxiliary implant comprises a main structure arranged in an external auditory canal; one bottom surface of the main structure is positioned in the middle of a bony external auditory canal and faces a tympanic membrane and a middle ear, and the other bottom surface is positioned at an opening of the external auditory canal; the shape contour of the side surface of the main structure is matched with and mechanically and fixedly connected with an anatomical structure of an external auditory canal of a patient; a hollow linear conveying channel is arranged between the two bottom faces of the main structure, and the extension line of the conveying channel is aligned with the round window niche of the inner ear structure. The main structure is made of a biocompatible flexible material. The problems of individual operation difference, dissection complexity influence and drug loss risk due to dependence on manual operation of doctors on tympanic membrane injection administration under guidance of a traditional endoscope can be solved, and the device can be widely applied to the fields of drug delivery, contrast agent and local anesthetic injection, gene therapy, biosensor or microelectrode implantation and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of personalized medicine, precision treatment, and otological implants, and particularly relates to a personalized auxiliary implant for precisely delivering drugs to the round window niche. Background Art

[0002] Existing treatment strategies for inner ear diseases usually rely on systemic drug administration or local drug administration through the middle ear. However, these methods have obvious limitations. For example, systemic drug administration (such as oral or intravenous injection) often makes it difficult for drugs to effectively reach the inner ear target area due to the existence of the blood-labyrinth barrier. At the same time, increasing the drug dose may cause systemic side effects. Direct injection of drugs into the middle ear cavity (such as tympanocentesis or intratympanic injection) can increase the local drug concentration. However, due to the complexity of the anatomical structure, the variability of the drug delivery route, and the instability of drug retention, it may lead to uneven diffusion of drugs in the middle ear cavity, thereby affecting the effect of penetration into the inner ear. In addition, traditional intratympanic injection drug administration also has problems such as drug loss through the eustachian tube, high dependence on the professionalism of operators, and repeated operations may cause damage to middle ear tissues (such as ossicles and chorda tympani nerve damage). The round window niche (Round Window Niche, RWN) is an important channel for drugs to enter the inner ear. However, due to large individual anatomical differences, it is difficult to ensure that drugs accurately reach the round window membrane during clinical operations, thus affecting the efficiency of drugs penetrating into the inner ear through the round window membrane. Therefore, how to establish a standardized, stable, and precise drug delivery path so that drugs can efficiently reach the round window niche and penetrate into the inner ear through the round window membrane is the key challenge in current otological precision drug delivery technology. Summary of the Invention

[0003] The main object of the present invention is to overcome the disadvantages and deficiencies of the prior art, and provide a personalized auxiliary implant for precisely delivering drugs to the round window niche, which is used to establish a stable drug delivery channel so as to achieve effective drug delivery to the inner ear through the round window membrane. It can be applied to the diagnosis and treatment of inner ear diseases, optimize the otological drug delivery method, and improve the precision and stability of the inner ear drug delivery strategy.

[0004] To achieve the above object, the present invention adopts the following technical solutions: In one aspect of the present invention, there is provided a personalized auxiliary implant for precisely delivering drugs to the round window niche, including a main structure disposed in the external auditory canal; One bottom surface of the main structure is located in the middle of the bony external auditory canal, facing the tympanic membrane and the middle ear, and the other bottom surface is located at the opening of the external auditory canal; the shape profile of the side surface of the main structure is adapted to the anatomical structure of the patient's external auditory canal and is mechanically fixedly connected; A hollow linear delivery channel is provided between the two bottom surfaces of the main structure, and the extension line of the delivery channel is aligned with the round window niche of the inner ear structure; The main structure is made of a biocompatible flexible material.

[0005] As a preferred technical solution, the delivery channel is made of a rigid material.

[0006] As a preferred technical solution, the biocompatible flexible material includes silica gel, TPU, hydrogel, and flexible resin.

[0007] As a preferred technical solution, the main structure is coated with a silver ion and / or antibacterial polymer coating.

[0008] As a preferred technical solution, it further includes a handle structure for positioning and clamping, and the handle structure is arranged at the bottom surface of the main structure located at the opening of the external auditory canal, or at the side surface close to one end of the bottom surface located at the opening of the external auditory canal and fitting the concha.

[0009] As a preferred technical solution, the space between the outer surface of the main structure and the delivery channel is a hollow grid structure.

[0010] As a preferred technical solution, the outer surface of the main structure has a microstructure or nanoscale roughness.

[0011] Another aspect of the present invention further provides a preparation method of a personalized auxiliary implant for precisely delivering drugs to the round window niche as described above, including the following steps: Obtain the anatomical data of the patient's external auditory canal, middle ear, and round window niche through medical imaging; Generate a three-dimensional model of the patient's external auditory canal, tympanic membrane, ossicles, and round window niche according to the anatomical data of the patient's external auditory canal, middle ear, and round window niche; Calculate the optimal path of the drug delivery channel according to the patient's anatomical data, and generate a three-dimensional model of the main structure according to the path. Adjust the shape, length of the main structure, and the angle of the drug delivery channel so that the outer surface of the main structure completely fits the external auditory canal, the length of the main structure matches the shape of the ear canal, and the channel angle is suitable for drug delivery; Perform mesh optimization on the three-dimensional model of the main structure, smooth the surface and reduce the number of redundant triangles to adapt to 3D printing; Slice the three-dimensional model of the main structure, and set the layer thickness, support structure, and exposure parameters suitable for stereolithography; Select the printing material of the main structure for 3D printing.

[0012] Another aspect of the present invention further provides an implantation method of a personalized auxiliary implant for precisely delivering drugs to the round window niche as described above, including the following steps: Using a microscope or an otoscope, hold the main structure with tissue forceps under direct vision. With the assistance of an otological dissector, place the main structure through the external auditory meatus along the external auditory canal to the predetermined position, and determine the placement orientation of the main structure through the auxiliary positioning points. Rely on the morphological structure of the side of the main structure adapted to the external auditory canal wall to achieve mechanical fixation. Calibrate through intraoperative CT or endoscope, specifically: observe whether the placement position of the main structure is accurate and whether the extension line of the delivery channel is aligned with the round window niche.

[0013] Another aspect of the present invention also provides an application of the personalized auxiliary implant for precisely delivering drugs to the round window niche as described above in the injection of sustained-release drug carriers, drugs, contrast agents, and local anesthetics, as well as in the delivery of gene therapy vectors, and in the implantation of biosensors or microelectrodes.

[0014] Compared with the prior art, the present invention has the following advantages and beneficial effects: (1) The present invention uses patient-specific anatomical image data (such as CBCT, MR, etc.) for personalized computational modeling to ensure that the implant precisely fits the anatomical structures of the individual external auditory canal and round window niche. Through optimized design, while the implant is fixed in the ear canal, the precise alignment of the drug delivery channel is maintained, ensuring the stability and repeatability of the delivery channel, reducing drug spillage, and improving the efficiency of drug penetration through the round window membrane into the inner ear. It can significantly reduce the problems of individual operation differences, anatomical complexity effects, and drug loss risks in the traditional endoscopic-guided intratympanic injection administration, which is particularly important in the more difficult middle ear and inner ear treatment fields, and can improve the promotion feasibility of this technology by medical institutions. (2) The present invention uses non-invasive ear canal fixation, avoiding the risks of non-healing tympanic membrane perforation, ossicular chain injury, chorda tympani nerve stimulation, etc. caused by potential additional injuries due to instability, enhancing safety. Since the implant provides a fixed drug delivery path, it can reduce the repeated interference with the ear canal and middle ear tissues during the operation process, reducing the possibility of inflammation or other adverse reactions. (3) The delivery channel of the present invention is compatible with various delivery methods such as micro-syringes, micropumps, pressure-driven devices, etc., suitable for different drug delivery requirements, and realizes the placement of minimally invasive round window niche implants. In addition to drug delivery, the present invention can also be used for contrast agent delivery (for MRI diagnosis of Meniere's disease), gene therapy, stem cell delivery and other high-precision treatments, as well as the physiological function detection of the inner ear, with broad clinical application prospects and high value. Description of the Drawings

[0015] Figure 1 It is a schematic structural diagram of a personalized auxiliary implant for precisely delivering drugs to the round window niche according to an embodiment of the present invention. Figure 2 It is a schematic diagram of the anatomical adaptation of the personalized auxiliary implant in the ear canal according to an embodiment of the present invention; Explanation of reference numerals: 1, main structure; 2, delivery channel; 3, external auditory canal; 4, tympanic membrane; 5, ossicular chain; 6, round window niche. Detailed implementation manners

[0016] In order to enable those skilled in the art of the present technology to better understand the solutions of the present application, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the accompanying drawings in the embodiments of the present application. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative efforts fall within the scope of protection of the present application.

[0017] Embodiment 1: As Figure 1 shown, this embodiment provides a personalized auxiliary implant for precisely delivering drugs to the round window niche, including a main structure 1 made of biocompatible flexible material and disposed in the external auditory canal 3; One bottom surface of the main structure 1 is located in the middle of the bony external auditory canal and faces the tympanic membrane 4 and the middle ear (i.e., the implant outlet), and the other bottom surface is located at the opening of the external auditory canal 3 (i.e., the implant inlet); The shape profile of the side surface of the main structure is designed based on the imaging data (CT, CBCT, MRI, PET-CT or ultrasound) of the patient, and can be adapted to the anatomical structure of the patient's external auditory canal 3 to achieve mechanical self-adaptive fixation without additional adhesion materials.

[0018] A hollow linear delivery channel 2 is provided between the two bottom surfaces of the main structure 1, and the extension line of the delivery channel is aligned with the round window niche 6 of the inner ear structure. The diameter range of the delivery channel 2 can be adjusted according to the drug delivery method and treatment needs to be compatible with the use of micro syringes, micropumps, microelectrodes, etc.

[0019] The positional relationship among the main structure 1, the delivery channel 2, the external auditory canal 3, the tympanic membrane 4, the ossicular chain 5, and the round window niche 6 is as Figure 1 shown.

[0020] In one or more preferred embodiments, the biocompatible flexible material includes silicone, TPU, hydrogel, and flexible resin, and can also be a medical-grade polymer or a biodegradable material.

[0021] In one or more preferred embodiments, the main structure 1 and the delivery channel 2 are provided in a split manner, specifically: The delivery channel 2 is made of rigid materials such as ceramics, hard resins, metals, etc.; other parts of the main structure 1 are made of biocompatible flexible materials such as flexible resins, silica gels, TPU, hydrogels, etc. Among them, the rigidity of the delivery channel 2 can ensure the stability of the drug delivery process; other parts of the main structure 1 are made of flexible materials with an elastic modulus within a controllable and appropriate range, which can ensure easy implantability and comfort while providing sufficient support. Furthermore, the space between the outer surface of the main structure 1 and the delivery channel 2 is a hollow grid structure for easy clamping and implantation.

[0022] In one or more preferred embodiments, the main structure 1 is coated with a biocompatible coating (such as an antibacterial coating, a hydrogel coating, a bioactive drug coating) to improve biocompatibility. Among them, the antibacterial coating includes antibacterial components to reduce the risk of postoperative infection.

[0023] In one or more preferred embodiments, the inner wall of the delivery channel 2 is treated with a hydrophilic coating to improve drug delivery efficiency and reduce drug retention during delivery.

[0024] In one or more preferred embodiments, the inner wall of the delivery channel 2 is treated with an insulating coating to improve the working efficiency of electrodes and biosensors during implantation.

[0025] In one or more preferred embodiments, the surface of the main structure 1 has microstructures or nano-scale roughness to increase friction, thereby enhancing stability in the ear canal and reducing the risk of displacement; the microstructures are obtained by surface sandblasting or surface engraving of micro-grooves (diameter 1 - 100 μm).

[0026] In one or more preferred embodiments, a handle structure for positioning and clamping is also provided, and the handle structure is provided at the bottom surface of the implant inlet or at the place where the implant inlet fits the concha.

[0027] The personalized auxiliary implant of the present invention is not only applicable to the delivery of drugs or other bioactive substances, but can also be extended to a variety of otological clinical applications, including but not limited to: Inner ear contrast agent injection: By injecting a gadolinium-based contrast agent (such as gadopentetic acid) through this channel, the contrast agent can penetrate through the round window membrane into the inner ear, and then magnetic resonance imaging (MRI) is performed to assist in the diagnosis of diseases such as Meniere's disease and endolymphatic hydrops of the inner ear.

[0028] Local gene therapy or stem cell delivery: As a gene therapy vector, it can be used to deliver gene editing tools (such as CRISPR-Cas9) or stem cells to inner ear hair cells or spiral ganglion to promote the recovery of auditory function.

[0029] Biosensor or microelectrode implantation: The channel can be used for the precise implantation of micro-sensors or electrodes to monitor inner ear environmental parameters (such as pH value, oxygen concentration), or for cochlear nerve stimulation therapy.

[0030] Local anesthesia or anti-inflammatory treatment: Used before and after inner ear surgery to precisely deliver local anesthetics or anti-inflammatory drugs, reducing postoperative discomfort and inflammatory responses.

[0031] Nanodrug, long-acting drug or sustained-release carrier delivery: Can be used to deliver sustained-release preparations or nanoparticle drugs to achieve long-term and stable inner ear treatment, reducing the need for repeated drug administration and improving patient compliance.

[0032] Example 2: This example expands on the preparation and implantation method of a personalized auxiliary implant for precisely delivering drugs to the round window niche described in Example 1, so that those skilled in the art can more easily and clearly understand the technical solution of this application.

[0033] (1) The design and preparation method of the personalized auxiliary implant for precisely delivering drugs to the round window niche includes the following steps: S1. Personalized design. Based on the patient's imaging data (CT, CBCT, MRI, PET-CT or ultrasound), a 3D model of the external auditory canal, tympanic membrane, middle ear (ossicles) and round window niche is established, and the implant is customized to ensure its stable fixation and precise alignment with the round window niche. Among them, the anatomical adaptation of the implant in the ear canal is as Figure 2 shown by the white arrow.

[0034] S1.1. Data acquisition: Obtain the anatomical data of the patient's external auditory canal, middle ear (ossicles) and round window niche through high-resolution imaging data (resolution voxel size 0.25 - 0.5 mm).

[0035] S1.2. 3D modeling: Use the computer-aided design software 3D Slicer to generate three-dimensional models of the external auditory canal, tympanic membrane, ossicles, and round window niche.

[0036] S1.3. Personalized design: According to the patient's specific anatomical data, use the built-in python auxiliary function of 3D Slicer, use the code to calculate the most suitable passage path, generate the implant according to the passage path, adjust the shape (especially the length) of the implant and the angle of the channel to ensure that the outer surface of the implant fits completely with the ear canal, the length of the implant matches the ear canal morphology (crossing the isthmus of the external auditory canal) and the channel angle is suitable for drug administration.

[0037] S1.4. Model Optimization: Use printer software such as PreForm, MeshLab, or Blender for mesh optimization, smooth the surface, reduce the number of redundant triangles, and optimize the model file to fit 3D printing.

[0038] S1.5. Model Slicing: Use PreForm or Chitubox for model slicing, and set layer thickness, support structure, and exposure parameters suitable for stereolithography 3D printing.

[0039] As a preferred embodiment, the 3D printing method can also use laser printing or FDM.

[0040] S2. Materials and Manufacturing Processes.

[0041] S2.1. Material Selection: In this embodiment, the implant uses 50A flexible resin material, which has a tensile strength of 3.2 MPa and a Shore hardness of 50A, and has elasticity, ductility, and low elongation for easy implantation, while maintaining structural rigidity to ensure the shape stability of the delivery channel.

[0042] S2.2. Additive Manufacturing: In this embodiment, the following equipment and parameter settings are used: Equipment: Use a Formlabs Form4 stereolithography 3D printer for printing.

[0043] Printing Parameters: The layer thickness is 100 μm, and the support type is adjusted according to the shape of the implant.

[0044] Post-processing: Use isopropyl alcohol to wash for 20 minutes to remove residual uncured resin, and perform secondary photocuring (curing time 30 min, curing temperature 70 °C) to ensure stable material properties.

[0045] S2.3. As a preferred embodiment, optimize the surface of the implant, including: Microstructure: Introduce a microstructure on the surface of the implant (such as surface sandblasting or surface engraving of micro-grooves with a diameter of 1 - 100 μm) to increase surface roughness and friction, thereby enhancing the stability of the implant.

[0046] Coating Treatment: Coat a biocompatible coating (such as an antibacterial coating, a hydrogel coating, a bioactive drug coating) on the surface of the implant to improve biocompatibility.

[0047] (2) The implantation and fixation method of the personalized auxiliary implant for precisely delivering drugs to the round window niche includes the following steps: S3. Implantation.

[0048] S3.1. Preoperative preparation: Design and print a personalized implant according to the patient's ear canal anatomical data to ensure that the delivery channel is aligned with the round window niche.

[0049] S3.2. Implantation process: A. Guided implantation: Use a microscope or otoscope to directly visualize and hold the implant with tissue forceps. Under the assistance of an otological dissector, place the implant through the external auditory meatus along the ear canal to the predetermined position (i.e., the middle of the bony ear canal), and determine the placement orientation of the implant through the auxiliary positioning points (positioning marks that fit the concha).

[0050] B. Fixation: Mechanical adaptation: Rely on the morphological characteristics of the implant itself to adapt to the ear canal wall to achieve mechanical fixation without additional adhesive materials.

[0051] Friction force analysis: The close fit between the surface of the implant and the ear canal skin provides appropriate friction force to prevent displacement.

[0052] C. Delivery channel calibration: Ensure that the delivery channel of the implant is accurately aligned with the round window niche to avoid deviation or blockage. The channel diameter is set to 0.4 mm - 2 mm (adjustable according to specific usage scenarios), and the angle is 20° to 70° (angle adjustment is mainly based on the patient's personalized anatomical structure to ensure accurate angle and meet the needs of personalized medicine).

[0053] S3.3. Intraoperative evaluation: Imaging verification: Observe whether the position of the implant is accurate and whether the extension line of the delivery channel is aligned with the round window niche through intraoperative CT, microscope or endoscope to ensure that the delivery channel is unobstructed.

[0054] S4. Drug delivery method and precision analysis.

[0055] S4.1. Drug delivery method: The implant of the present invention does not contain drugs itself, but provides a precise delivery channel, which can be applicable to various drug delivery methods / therapeutic uses, including but not limited to: Micro syringe delivery: The drug is directly delivered to the round window niche through a micro syringe (needle diameter 0.4 mm - 1.6 mm), improving the delivery precision and avoiding drug loss or diffusion to non-target areas.

[0056] Application scenarios: It can be used for injecting sustained-release drug carriers (such as drug-loaded hydrogels).

[0057] Local anti-inflammatory treatment (slowly inject anti-inflammatory drugs using a pump, and the drug concentration required by the patient can be adjusted according to the specific condition).

[0058] Contrast agent injection (injecting gadolinium-based contrast agent into the round window niche, permeating through the round window membrane into the inner ear lymphatic circulation, and then performing MRI examination to diagnose Meniere's disease).

[0059] Gene therapy vector delivery (directly injecting a gene vector with a certain adhesiveness into the round window niche through a channel, enabling the gene vector to be released into the inner ear directionally for targeted gene therapy).

[0060] Implantation of microelectrodes (implanting microelectrodes into the round window membrane through a channel to perform non-invasive monitoring and detection of the physiological functions of the inner ear).

[0061] Biosensor (placing a biosensor on the round window membrane or cochlear bone through a channel to perform early preventive detection of inner ear diseases, specifically including: detecting through the physiological and biochemical reactions of the cochlear bone, or detecting through the lymphatic fluid circulation, or detecting through the vibration of the round window membrane, or detecting the inner ear lymphatic fluid by micro-needle penetrating the round window membrane).

[0062] S4.2, Drug flow path and accuracy: Through the preset delivery channel of the implant, the drug can be accurately delivered to the round window niche and the diffusion of the drug in the ear canal can be reduced. The treatment effect can be analyzed by software simulation before surgery, and the specific drug flow path can be verified by imaging to ensure the delivery accuracy.

[0063] Hydrodynamics simulation: Using computational fluid dynamics (CFD) to simulate and analyze the drug flow path.

[0064] Evaluating the drug flow rate and diffusion range according to specific application scenarios.

[0065] Imaging verification: Observing the drug diffusion path through MRI or CT (when using a micropump to control sustained-release drug delivery, qualitative monitoring can be performed while administering the drug).

[0066] Ensuring that the drug effectively covers the target area of the round window niche within a short time.

[0067] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A personalized auxiliary implant for accurately delivering drugs to the round window niche, characterized in that: It includes a main structure disposed in the external auditory canal; One bottom surface of the main structure is located in the middle of the bony external auditory canal, facing the tympanic membrane and the middle ear, and the other bottom surface is located at the opening of the external auditory canal; the shape contour of the side surface of the main structure is adapted to the anatomical structure of the patient's external auditory canal and is mechanically fixedly connected; A hollow linear delivery channel is provided between the two bottom surfaces of the main structure, and the extension line of the delivery channel is aligned with the round window niche of the inner ear structure; The main structure is made of biocompatible flexible material.

2. A personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 1, characterized in that: The conveying channel is made of rigid material.

3. A personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 1, characterized in that: The biocompatible flexible material includes silicone, TPU, hydrogel and flexible resin.

4. A personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 3, characterized in that: The primary structure is coated with silver ions and / or an antimicrobial polymer coating.

5. The personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 1, characterized in that: It also includes a handle structure for positioning and clamping, which is arranged on the bottom surface of the main structure located at the external auditory canal opening, or on the side close to one end of the bottom surface located at the external auditory canal opening where the concha cavity is attached.

6. The personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 1, characterized in that: The space between the outer surface of the main structure and the conveying channel is a hollow grid structure.

7. The personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 1, characterized in that: The outer surface of the main structure has a microstructure or nanoscale roughness.

8. The method for preparing a personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 1, characterized in that: The following steps are involved: Obtain the anatomical data of the patient's external auditory canal, middle ear, and round window niche through medical imaging; generating a three-dimensional model of the patient's external auditory canal, tympanic membrane, ossicles and round window niche according to the patient's anatomical data of the patient's external auditory canal, middle ear and round window niche; The optimal path of the drug delivery channel is calculated according to the patient's anatomical data, and a three-dimensional model of the main structure is generated according to the path, and the shape, length and angle of the main structure and the drug delivery channel are adjusted so that the outer surface of the main structure fits perfectly with the external auditory canal, the length of the main structure matches the morphology of the auditory canal, and the angle of the channel is suitable for drug delivery; Optimize the mesh of the 3D model of the main structure, smooth the surface and reduce the number of redundant triangles to adapt to 3D printing; Slice the 3D model of the main structure and set the layer thickness, support structure and exposure parameters suitable for photocuring; Select the printing material of the main structure for 3D printing.

9. The method for implanting a personalized auxiliary implant for accurately delivering drugs to the round window niche according to claim 1, characterized in that: The following steps are involved: Use a microscope or an otoscope to clamp the main structure with tissue forceps under direct vision, and with the assistance of an otological dissector, place the main structure through the external auditory canal opening along the external auditory canal to the predetermined position, and determine the placement orientation of the main structure using the auxiliary positioning points; Mechanical fixation is achieved by relying on the adaptive morphological structure of the side of the main structure and the wall of the external auditory canal; Calibration is performed through intraoperative CT or endoscopy, specifically observing whether the placement of the main structure is accurate and whether the extension line of the delivery channel is aligned with the round window niche.

10. A personalized auxiliary implant for precisely delivering drugs to the round window niche as described in any one of claims 1 to 7, its use in the injection of sustained-release drug carriers, drugs, contrast agents and local anesthetics, its use in the delivery of gene therapy vectors, and its use in biosensor or microelectrode implantation.

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