Magnetic control targeted inner ear drug delivery method in cochlea

Abstract

The invention provides an inner ear drug delivery method in a magnetic control targeting cochlea, and relates to the technical field of magnetic material application, and the method comprises the following steps: preparing a novel magnetic material carrier; the method comprises the following steps: after anesthetizing a rat, identifying occipital bone and positioning semicircular canals of the rat under an operating microscope, performing minimally invasive drilling by adopting a 1mL injector, and injecting a novel magnetic material carrier loaded with a target inner ear medicine into the semicircular canals of the rat; when the rat semicircular canal administration meets a preset time threshold value, the rat is placed in a 9.4 T magnetic resonance magnetic field, the magnetic field direction is from the bottom of the cochlea to the top of the cochlea, the target inner ear medicine is driven to move in the cochlea lymph, and target area release is executed. According to the invention, the technical problem that the medicine is difficult to uniformly and accurately distribute in the inner ear due to the fact that the medicine can only passively move along with cochlea lymph fluid and cannot be administrated to a specific part in the cochlea in a traditional inner ear local administration method is solved.

Description

Technical Field

[0001] The present invention relates to the technical field of magnetic material application, and in particular to a method for delivering inner ear drugs by magnetically controlling and targeting the interior of the cochlea. Background Art

[0002] The structure of the inner ear is delicate and complex, consisting of the cochlea, vestibule, etc., and is responsible for the functions of hearing and balance. However, due to the existence of the blood-labyrinth barrier, traditional drug delivery methods (such as systemic administration, local injection, etc.) have many defects. During systemic administration, the drug needs to pass through the blood circulation, and a large amount of the drug is distributed in the tissues of the whole body. Only a small amount can reach the target site of the inner ear, resulting in low drug utilization and easy to cause systemic side effects; although local injection can increase the concentration of drugs in the inner ear to a certain extent, there is a drug concentration gradient in the cochlea, and only the basal turn of the cochlea is more distributed, resulting in uneven drug dispersion. In addition, the traditional method of local drug delivery in the inner ear can only make the drug move passively with the cochlear lymph fluid, and cannot achieve drug delivery to a specific part of the cochlea. Therefore, there is an urgent need for a safe, efficient and accurate inner ear drug delivery technology. Summary of the Invention

[0003] The present application provides a method for delivering inner ear drugs by magnetically controlling and targeting the interior of the cochlea, aiming to solve the technical problem that traditional methods of local drug delivery in the inner ear can only allow the drug to move passively with the cochlear lymph, but cannot achieve drug delivery to specific parts of the cochlea, resulting in difficulty in uniform and accurate distribution of drugs in the inner ear.

[0004] The present application discloses a method for delivering inner ear drugs to the interior of the cochlea through magnetically controlled targeting, the method comprising: preparing a novel magnetic material carrier, wherein the novel magnetic material carrier is composed of hollow mesoporous ferrosoferric oxide, the surface of the novel magnetic material carrier is modified with polyethylene glycol, and the novel magnetic material carrier is loaded with a target inner ear drug; after anesthetizing a rat, identifying the rat's occipital bone under a surgical microscope, locating the semicircular canals, and using a 1 mL syringe for minimally invasive drilling, injecting the novel magnetic material carrier loaded with the target inner ear drug into the rat's semicircular canals using a microinjection pump; when the rat's semicircular canals have been administered for a predetermined time threshold, the rat is placed in a 9.4 T magnetic resonance magnetic field, wherein the magnetic field direction of the magnetic resonance magnetic field is from the base of the cochlea toward the apex of the cochlea, and the target inner ear drug is driven to move in the cochlear lymph based on the magnetic response characteristics of the novel magnetic material carrier, thereby performing target area release.

[0005] One or more technical solutions provided in this application have at least the following beneficial effects:

[0006] By adopting a new magnetic material carrier composed of hollow mesoporous ferrosoferric oxide, the specific surface area and drug loading capacity of the carrier are significantly improved, achieving efficient drug loading and sustained release performance. The surface of the new magnetic material carrier is modified with polyethylene glycol, which gives the carrier good water solubility and biocompatibility, effectively reduces the nonspecific adsorption and immune recognition of the carrier, and improves the stability and circulation time of the carrier in the body; using a surgical microscope to accurately identify anatomical structures, including the rat occipital bone and rat semicircular canals, to ensure the accurate positioning of the drug delivery site, improve the repeatability and stability of the drug delivery operation, use a 1mL syringe for minimally invasive drilling, and combine with a microinjection pump to achieve the new magnetic material carrier Precise infusion reduces the risk of tissue damage and fluid overflow. The drug administration method of injection into the semicircular canal allows the drug to directly enter the cochlear lymph system, shortens the path of the drug from the administration point to the target area, and improves delivery efficiency. Rats are placed in a 9.4T magnetic resonance magnetic field, and the direction of the magnetic field is adjusted from the base of the cochlea to the apex of the cochlea to effectively stimulate the magnetic response characteristics of the carrier, drive the new magnetic material carrier and the loaded drug to produce directional movement in the inner ear lymph, and use the controllability of the magnetic field to achieve precise positioning and motion trajectory control of the new magnetic material carrier in a complex microenvironment, breaking through the limitations of traditional passive diffusion and realizing dynamic adjustment and precise control of the inner ear delivery system.

[0007] The above description is only an overview of the technical solution of the present application. In order to more clearly understand the technical means of the present application, it can be implemented in accordance with the contents of the specification. In order to make the above and other purposes, features and advantages of the present application more obvious and easy to understand, the specific implementation methods of the present application are listed below. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 A schematic flow chart of a method for delivering inner ear drugs by magnetically controlling and targeting the interior of the cochlea is provided for an embodiment of the present application.

[0009] Figure 2 The present invention provides a schematic diagram of the process for preparing a novel magnetic material carrier in a method for delivering inner ear drugs with magnetically controlled targeting to the cochlea in an embodiment of the present application.

[0010] Figure 3 The present invention provides a schematic diagram of the quantitative change trend of MRI signal intensity in the lymphatic fluid area of ​​the animal experimental results in the inner ear drug delivery method of magnetically controlled targeting inside the cochlea for the embodiment of the present application. DETAILED DESCRIPTION

[0011] The embodiments of the present application provide a method for delivering inner ear drugs with magnetically controlled targeting to the interior of the cochlea, which solves the technical problem that traditional local drug delivery methods in the inner ear can only allow the drug to move passively with the cochlear lymph, and cannot achieve drug delivery to specific parts of the cochlea, resulting in difficulty in uniform and accurate distribution of drugs in the inner ear.

[0012] After introducing the basic principles of this application, various non-limiting embodiments of this application will be specifically introduced in conjunction with the accompanying drawings of the specification. It should be noted that the technical solution described in this application mainly relates to an inner ear drug delivery system and a magnetically controlled driving method thereof, focusing on technical means for realizing the preparation, precise positioning and controlled release of drug carriers, aiming to improve the spatial and temporal controllability of drug delivery. This application does not involve the treatment plan or effect of a specific disease, but only provides a physical and engineering drug delivery technology platform.

[0013] like Figure 1 As shown, the embodiment of the present application provides a method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea, the method comprising:

[0014] A novel magnetic material carrier is prepared, wherein the novel magnetic material carrier is composed of hollow mesoporous ferrosoferric oxide, the surface of the novel magnetic material carrier is modified with polyethylene glycol, and the novel magnetic material carrier is loaded with a target inner ear drug.

[0015] The new magnetic material carrier is composed of hollow mesoporous ferroferric oxide (Fe3O4). The ferroferric oxide serves as a drug carrier and magnetically responsive component, exhibiting excellent biocompatibility and tunable magnetic properties. The combination of the hollow and mesoporous structures provides a large specific surface area, facilitating effective drug loading and controlled release. To enhance the biocompatibility of the hollow mesoporous ferroferric oxide and reduce immune responses, the surface is modified with polyethylene glycol (PEG). PEG inhibits the aggregation of nanoparticles, further improving material stability and dispersibility. It also increases the time nanoparticles spend in lymphatic fluid and prevents nonspecific binding of nanoparticles to proteins. PEG modification enhances biocompatibility and circulatory stability, reduces the risk of macrophage phagocytosis, and potentially prolongs their retention time within the cochlear tissue, enhancing the directional transport effect under magnetic field control. During the preparation process, hollow mesoporous ferroferric oxide loads the target inner ear drug onto its surface by physical adsorption. The target inner ear drug is combined with the surface of the magnetic material by physical adsorption rather than chemical bonding, which can easily control the release of the drug and reduce side effects.

[0016] After the rats were anesthetized, the occipital bones of the rats were identified under a surgical microscope, the semicircular canals were located, and after minimally invasive drilling with a 1mL syringe, the new magnetic material carrier loaded with the target inner ear drug was injected into the rat semicircular canals based on a microinjection pump.

[0017] After anesthesia, the rat's occipital bone was first identified under a surgical microscope. Because the semicircular canals are adjacent to the occipital bone and surrounded by dense temporal bones, they cannot be directly observed with the naked eye. Therefore, the occipital bone can be used as an anatomical landmark to locate the specific position of the semicircular canals for minimally invasive drilling. Subsequently, under a surgical microscope, a 1 mL syringe needle was used to perform minimally invasive drilling in the middle of the temporal bone adjacent to the occipital bone. During the operation, a microscope was used to assist in ensuring the accuracy of positioning. When the lymph fluid flowed out clearly after drilling, it indicated that the semicircular canal had been entered. After drilling, a new magnetic material carrier loaded with the target inner ear drug was injected into the rat's semicircular canal using a microinjection pump. During the injection process, the operation must be delicate to avoid damaging the rat's inner ear structure.

[0018] When the rat's semicircular canal drug administration meets the predetermined time threshold, the rat is placed in a 9.4T magnetic resonance magnetic field. The magnetic field direction of the magnetic resonance magnetic field is from the base of the cochlea to the apex of the cochlea. Based on the magnetic response characteristics of the new magnetic material carrier, the target inner ear drug is driven to move in the cochlear lymph fluid and released in the target area.

[0019] After the drug was administered to the rat's semicircular canals and the predetermined time threshold was met, the rat was then placed in a 9.4T magnetic resonance magnetic field. 9.4T represents the magnetic field strength of the magnetic resonance device, which is commonly used for high-resolution imaging and magnetic field-driven experiments. The direction of the magnetic field is set to rotate from the base of the cochlea toward the top of the cochlea. This ensures that the new magnetic material carrier is pushed along this direction in the lymph fluid in the cochlea, helping the drug to reach the designated target area more accurately. The new magnetic material carrier has magnetic response characteristics, which enables them to move in a directional manner under the action of an external magnetic field. When the rat is in the magnetic field, the force of the magnetic field drives the new magnetic material carrier to move in a predetermined direction. The action of the magnetic field can not only promote the movement of the drug carrier, but also ensure that the drug is released in the target area in the cochlea. In this way, the drug can accurately reach the target area, avoid uneven distribution of the drug in the cochlea, and maximize the therapeutic effect of the drug.

[0020] Furthermore, if Figure 2 As shown, the preparation of the novel magnetic material carrier comprises:

[0021] Ferric chloride hexahydrate is dissolved in deionized water, and after magnetic stirring for 10 minutes, sodium citrate, polyacrylamide and urea are added. After continuous vigorous stirring for 30 minutes, the mixture is transferred to a hydrothermal reactor, reacted at 200°C for 12 hours, and washed to obtain ferroferric oxide; the prepared ferroferric oxide is dispersed in deionized water, triethoxysilane is added, stirred at room temperature, and then washed with deionized water to obtain amino-containing hollow ferroferric oxide; the amino-containing hollow ferroferric oxide is dispersed again in deionized water, polyethylene glycol-N-hydroxysuccinimide ester is added, and the reaction is continuously stirred to obtain PEGylated hollow ferroferric oxide; the PEGylated hollow ferroferric oxide is dispersed in deionized water, the target inner ear drug is dissolved in methanol to prepare a solution, and the target inner ear drug solution is dropwise added to the PEGylated hollow ferroferric oxide dispersion system to complete the preparation of a new magnetic material carrier loaded with the target inner ear drug.

[0022] Dissolve ferric chloride hexahydrate in deionized water. After dissolution, use a magnetic stirrer to stir for 10 minutes to ensure that the ferric chloride hexahydrate is completely dissolved to form a uniform solution. Sodium citrate, polyacrylamide and urea are added to the above uniform solution. Sodium citrate serves as a reducing agent and stabilizer, polyacrylamide helps to form a hollow structure, and urea participates in the reaction as a nitrogen source. Continue to stir vigorously for 30 minutes to ensure that all components are evenly mixed. The above mixture is transferred to a hydrothermal reactor and reacted at 200°C for 12 hours. The hydrothermal reaction helps to synthesize hollow ferrosoferric oxide nanoparticles under high temperature conditions. After the reaction is completed, the obtained ferrosoferric oxide needs to be washed several times with deionized water to remove unreacted chemical reagents and impurities.

[0023] The prepared ferroferric oxide nanoparticles are redispersed in deionized water, and triethoxysilane is added to the ferroferric oxide dispersion. This compound contains an amino functional group and can react with the hydroxyl groups on the surface of the ferroferric oxide to form an amino surface modification. The mixture is stirred at room temperature to allow the triethoxysilane to react with the ferroferric oxide to form an amino modification on its surface. After the reaction is completed, the mixture is washed with deionized water to remove the unreacted triethoxysilane to obtain an amino hollow ferroferric oxide.

[0024] The aminated hollow ferroferric oxide is redispersed in deionized water to form a uniform dispersion. Polyethylene glycol-N-hydroxysuccinimide ester (PEG-NHS) is added to the dispersion. PEG-NHS is a reagent used for polyethylene glycol modification, which can introduce polyethylene glycol chains onto the surface of ferroferric oxide, thereby improving the biocompatibility and stability of the particles. The reaction is stirred continuously. Through the reaction of PEG-NHS, polyethylene glycol is modified onto the surface of the aminated hollow ferroferric oxide, resulting in PEGylated hollow ferroferric oxide.

[0025] The PEGylated hollow ferroferric oxide was dispersed in deionized water, and the target inner ear drug (dexamethasone) was dissolved in methanol to prepare a target inner ear drug solution. Then, the target inner ear drug solution was added dropwise to the PEGylated hollow ferroferric oxide dispersion system. During the stirring process, the drug adhered to the surface of the ferroferric oxide through physical adsorption, thereby obtaining a novel magnetic material carrier loaded with the target inner ear drug.

[0026] Furthermore, the particle size of the novel magnetic material carrier ranges from 150 nanometers to 200 nanometers.

[0027] The particle size of the new magnetic material carrier ranges from 150 nanometers to 200 nanometers. This particle size range is selected to ensure that the magnetic nanoparticles can move stably in the magnetic field while maintaining drug loading capacity and biocompatibility. This particle size helps ensure that the nanoparticles can maintain good dispersion in the cochlear lymph fluid and avoid agglomeration, while having a large enough specific surface area to load drugs and ensure the stability of the drug release process.

[0028] Furthermore, after placing the rat in a 9.4T magnetic resonance magnetic field, the following steps are performed:

[0029] A 9.4T magnetic resonance scanner was used to provide the magnetic resonance magnetic field, and magnetic resonance imaging was performed synchronously. The rats were maintained in an anesthetized state using 2% to 2.5% isoflurane in the magnetic resonance magnetic field, and their respiratory rate was monitored. T2-weighted three-dimensional images were acquired using a magnetic resonance imaging system. The key acquisition parameters of the magnetic resonance imaging system included: voxel size of 0.08×0.08×0.35mm, bandwidth of 260Hz / pixel, repetition time of 2800ms, echo time of 48.16ms, echo chain length of 15, average acquisition times of 20, slice thickness of 0.35mm, readout field of view of 26mm, phase of 24mm, readout resolution of 312 points, and three consecutive scans with a predetermined duration for each scan.

[0030] A 9.4T MRI scanner generates a magnetic resonance magnetic field, a high-field strength suitable for high-resolution imaging and high-precision drug delivery monitoring. This strong magnetic field helps drive the precise movement of magnetic material carriers within the cochlea. During the drug delivery process, MRI imaging and magnetic field application are performed simultaneously, enabling researchers to monitor the movement, distribution, and positioning of the drug carrier within the cochlea in real time.

[0031] The rats were maintained in an anesthesia state using 2% to 2.5% isoflurane. Isoflurane is a commonly used volatile anesthetic that is effective in maintaining anesthesia depth, and its concentration can be adjusted to ensure that the rats maintain a stable anesthesia state throughout the experiment. By adjusting the concentration of isoflurane, the rats were ensured to be in an appropriate anesthesia state to avoid stress reactions due to discomfort during the scanning process. During anesthesia, the rats' respiratory rate was continuously monitored to ensure that the rats maintained a normal physiological state during anesthesia. This is crucial to ensuring the safety and effectiveness of the experiment, as abnormal respiratory rate indicates discomfort with the depth of anesthesia or physiological abnormalities.

[0032] Magnetic resonance imaging systems use T2-weighted image technology, which can effectively display the water distribution of tissues. They are particularly suitable for displaying the distribution of the cochlea and its lymphatic fluid. This type of imaging is used to monitor the process of drug delivery to the cochlea, because drugs may affect the hydration of lymphatic fluid or the water distribution of tissues.

[0033] The following are the key acquisition parameters of the MRI system, which help to obtain high-quality imaging results: voxel size is 0.08×0.08×0.35mm. The voxel size determines the spatial resolution of the imaging. A smaller voxel size helps to improve the image's ability to display details and helps to more clearly observe the distribution of drug carriers in the cochlea; the bandwidth is 260Hz / pixel. The bandwidth affects the signal-to-noise ratio of the imaging. A higher bandwidth helps to obtain clearer images; the repetition time is 2800ms. The repetition time is the time interval in a scan, which affects the quality and speed of the imaging; the echo time is 48.16ms. The echo time is the time it takes to acquire the echo signal. The echo train length is 15, which affects image scanning speed and resolution. The average acquisition count is 20, increasing the number of acquisitions to reduce noise and obtain more accurate images. The slice thickness is 0.35 mm. Thinner slices help improve image resolution, making details of the cochlea and surrounding structures clearer. The readout field of view is 26 mm, which determines the spatial extent of the image. A larger readout field of view can cover a wider area. The phase is 24 mm, which affects the phase encoding accuracy of the image and ensures coverage of the imaged area. The readout resolution is 312 points. The higher the readout resolution, the richer the imaging details. Three consecutive scans are performed, each with a predetermined duration of 18 minutes and 43 seconds. Continuous scanning helps identify the movement trajectory of drug carriers in the cochlea and provides researchers with real-time feedback.

[0034] Furthermore, the target inner ear drug is a glucocorticoid drug dexamethasone, and the target inner ear drug forms a stable complex with the novel magnetic material carrier through physical adsorption.

[0035] The target inner ear drug is the glucocorticoid drug dexamethasone, which is used to treat inner ear diseases such as sensorineural hearing loss and Meniere's disease. Specifically, dexamethasone forms a stable complex with a new magnetic material carrier through physical adsorption. The physical adsorption method has the advantages of simple operation, controllable loading amount, and adjustable drug release. Through physical adsorption, the target inner ear drug can be stably attached to the surface of the new magnetic material carrier and released when needed, thereby achieving precise delivery of the inner ear drug. This loading method will not destroy the chemical structure of the drug and helps to maintain the activity of the drug.

[0036] Furthermore, a novel magnetic material carrier loaded with a target inner ear drug is injected into the rat semicircular canal via a microinjection pump connected to a semicircular canal drug delivery device, wherein the semicircular canal drug delivery device comprises:

[0037] The glass microneedle has an inner diameter of 0.5 mm and an outer diameter of 1.14 mm; the polyimide tube has an inner diameter of 0.4 mm and an outer diameter of 0.46 mm, and the glass microneedle and the polyimide tube are connected by dental cement.

[0038] A microinjection pump is a precision device capable of injecting a novel magnetic material carrier at a precise flow rate and speed. In this step, the microinjection pump is used to control the injection of a novel magnetic material carrier loaded with a targeted inner ear drug into the rat's semicircular canals. The microinjection pump can precisely adjust the injection volume and speed of the drug carrier, ensuring that the drug enters the semicircular canals at the appropriate dose and rate. The semicircular canal drug delivery device consists of a glass microneedle and a polyimide tube.

[0039] The inner diameter of the glass microneedle is 0.5mm and the outer diameter is 1.14mm. These specifications enable the glass microneedle to accommodate the influx of trace drug carriers without damaging the structure of the semicircular canal. The inner diameter design can accurately control the flow rate of the drug carrier, and the outer diameter ensures that it can be smoothly inserted into the semicircular canal and ensures the non-invasiveness of the drug delivery process.

[0040] The polyimide tube has an inner diameter of 0.4mm and an outer diameter of 0.46mm. This specification helps further control the flow of the drug carrier and effectively connects with the glass microneedles. The inner diameter of the polyimide tube is slightly smaller than the outer diameter of the glass microneedles, which helps stabilize the flow of the drug carrier and avoids blockage or unsmooth flow within the tube. The glass microneedles and the polyimide tube are connected by dental cement, a highly adhesive material that provides a durable and secure connection. It effectively combines the two components, preventing loosening or breakage during drug administration, thereby ensuring smooth drug delivery.

[0041] Furthermore, after anesthetizing the rat, identifying the rat's occipital bone under a surgical microscope, locating the semicircular canals, using a 1 mL syringe for minimally invasive drilling, and then injecting the novel magnetic material carrier loaded with the target inner ear drug into the rat's semicircular canals using a microinjection pump, comprises:

[0042] Rats were generally anesthetized with 1% sodium pentobarbital, and the reflex stimulation method was used to assess the depth of anesthesia. When the preset anesthesia state was met, the rats were placed in a lateral position on the operating table with the operated ear facing upward. After skin preparation in the surgical ear area, the surgical area was locally anesthetized with 0.3 ml of 1% lidocaine. After a 0.7 cm to 0.9 cm arc-shaped incision was made on the posterior side of the auricle, the rat's occipital bone was located to complete the delivery of the new magnetic material carrier.

[0043] This operating procedure is the necessary experimental operation implemented as the inner ear drug delivery technology of the present invention, is intended to realize the accurate infusion and the positioning of magnetic material carrier, belongs to the technical method category, and is not for any disease or treatment purpose medical behavior.Particularly, 1% sodium pentobarbital (50mg / kg) is used to carry out general anesthesia to rat, sodium pentobarbital is a kind of commonly used anesthetic, can effectively allow rat to enter anesthetic state by injection, adopt reflex stimulation method, as tail pinching method, assess the degree of anesthesia of rat, if the degree of anesthesia is suitable, when pinching rat tail, rat can not produce any reaction, and this represents that the degree of anesthesia has reached predetermined anesthetic state.After anesthesia, rat is placed on operating table, ensures that it lies on its side, and with surgical ear upwards, this position is convenient to subsequent operation, and ensures that operating area can be fully exposed.

[0044] The surgical area of ​​the operative ear was prepared to ensure aseptic technique. This is a necessary preoperative step to prevent infection. Local anesthesia was administered with 1% lidocaine (0.3 mL) in the surgical area. This ensures local painlessness during surgery and reduces discomfort for the animal. An approximately 0.8 cm arcuate incision was made posterior to the auricle, directly exposing the rat's occipital bone and adjacent structures. Muscles were bluntly dissected with forceps, and skin retractors were used to stretch the skin and soft tissue until bone was exposed. Under the operating microscope, bone adjacent to the occipital head was observed, representing the temporal bone surrounding the semicircular canals. Through this step, the occipital bone of the rat can be accurately located using a surgical microscope. The accurate position of the occipital bone of the rat is crucial for subsequent operations. The occipital bone of the rat is closely related to the position of the semicircular canals. By locating the occipital bone of the rat, the surgeon can determine the position of the semicircular canals under a surgical microscope, providing accurate guidance for subsequent drug injections. Although this involves invasive operations, this application only involves the research and development of inner ear drug carrier delivery technology. The relevant operations are used to achieve the delivery and positioning of the carrier and do not constitute a treatment method for specific diseases.

[0045] Furthermore, after placing the rat in a 9.4T magnetic resonance magnetic field, the following steps are performed:

[0046] Magnetic resonance imaging detection is performed at predetermined time intervals to establish a signal intensity data set; directional movement verification is performed based on the signal intensity data set, and movement management of the new magnetic material carrier is performed based on the directional movement verification result.

[0047] After the rats were placed in a 9.4T magnetic resonance magnetic field, timed magnetic resonance imaging scans were performed. The time intervals between imaging scans were pre-set to regularly monitor the distribution and dynamic changes of the drug carrier in the cochlea. After each imaging scan, magnetic resonance signal data of the cochlear region were obtained. These data included signal intensity data at each scanning position. Changes in signal intensity can reflect the movement of the drug carrier in the cochlea. For example, as the carrier moves in the cochlea, the signal intensity in the local area will change. These changes can be used to infer the distribution and movement trajectory of the carrier. Through multiple imaging, combined with signal intensity data at different time points, a complete signal intensity dataset is established. This signal intensity dataset can provide detailed information about the carrier in the cochlea, such as movement speed, movement direction, and whether it has reached the predetermined target area.

[0048] Directional motion verification is performed by analyzing the signal intensity data set. That is, based on the changes in signal intensity, it is verified whether the new magnetic material carrier moves in the predetermined direction and position. For example, if the magnetic field is set from the base of the cochlea to the top of the cochlea, then the signal intensity should indicate that the direction of movement of the carrier conforms to this preset path. Based on the directional information provided by magnetic resonance imaging, it can be determined whether the carrier moves in the correct direction and whether it follows the expected influence of the magnetic field.

[0049] Through the results of directional motion verification, the strength or direction of the magnetic field can be adjusted in real time to optimize the movement of the new magnetic material carrier. For example, if the new magnetic material carrier is found to deviate from the predetermined path or stagnate in certain areas, corresponding adjustments can be made based on the directional motion verification to ensure that the carrier accurately reaches the target area. Motion management helps to ensure the efficiency and accuracy of drug delivery. Throughout the experiment, through continuous motion management, it can ensure that the drug carrier is distributed more evenly in the cochlea, avoiding excessive accumulation or uneven distribution of drugs in certain areas.

[0050] Furthermore, the magnetic resonance magnetic field can drive the novel magnetic material carrier to move and simultaneously perform magnetic resonance imaging monitoring.

[0051] Through a 9.4T magnetic resonance magnetic field, the new magnetic material carrier is driven to move in the lymph fluid of the cochlea in a preset direction and speed. The strength and direction of the magnetic field are precisely controlled to effectively promote the migration of the carrier to the target area, avoiding the uneven distribution of drugs caused by fluid flow or other factors in traditional drug delivery methods. At the same time, magnetic resonance imaging technology is used to monitor the movement of drug carriers in real time. Through magnetic resonance imaging, real-time imaging in the cochlea is obtained, showing the distribution and movement trajectory of the new magnetic material carrier in the cochlea. By performing simultaneous magnetic resonance imaging monitoring, it is possible not only to verify whether the drug carrier moves in the predetermined direction, but also to ensure that the distribution of the drug in the cochlea meets the treatment needs. Imaging technology provides visualization of the drug delivery process, increasing the controllability and accuracy of the treatment.

[0052] Furthermore, the hydrodynamic size of the unloaded new magnetic material carrier is 230.09±9.11nm, the PDI value is 0.21±0.006, and the zeta potential is -4.13±0.3mV.

[0053] The hydrodynamic size of the empty new magnetic material carrier is 230.09±9.11nm. The smaller particle size helps to improve the stability of the new magnetic material carrier in the physiological environment and helps to cross the biological barrier. The PDI value (polydispersity index) is 0.21±0.006. This value shows that the new magnetic material carrier has good monodispersity. The lower the PDI value, the more uniform the size distribution of the particles, which helps to improve the stability of the carrier. The zeta potential is -4.13±0.3mV. This value shows that the surface of the new magnetic material carrier has a weak negative charge. The weak negative charge helps to improve the dispersion of the particles and reduce the mutual aggregation between particles, thereby enhancing the stability of the material, especially the stability in physiological fluids, thereby improving the drug delivery effect driven by the magnetic field.

[0054] The results of cell experiments showed that the upper limit of the safe concentration of this material is 62.5μg / ml, and the dexamethasone drug it carries can enter the cells and locate in the cytoplasm and nuclear areas; the results of animal experiments showed that when an MRI scan was performed one day after surgery, cochlear imaging was performed when the animals were placed in the magnetic field for 20 minutes, 40 minutes, and 60 minutes. The MRI signal intensity of the top, middle, and bottom turns of the cochlea was statistically analyzed, and it was found that the signal intensity of the operated ear was lower than that of the non-operated ear, with a statistically significant difference. Figure 3The figure shows the quantitative trend of MRI signal intensity changes in the lymphatic fluid region from animal experiments. The MRI signal intensity at 20 minutes was set as the baseline, and the relative changes in MRI signal intensity in these regions at 40 and 60 minutes were calculated. This indicates that the superparamagnetic properties of ferroferric oxide cause a decrease in MRI signal intensity. The signal intensity in the apical and middle rotations was even lower at 60 minutes, suggesting that ferroferric oxide diffuses from the basal, middle, and apical rotations under the influence of the magnetic field. This suggests that under ultra-high field strengths, the magnetic field can cause the ferroferric oxide magnetic material to diffuse more evenly within the cochlea. Immunofluorescence experiments also showed that the distribution of dexamethasone in the magnetic field group was significantly wider than that in the control group that did not receive magnetic field treatment. This distribution pattern is consistent with the MRI signal attenuation pattern. Observations were made on the apical, middle, and basal regions of the cochlea. The results showed that one day after surgery, the distribution of dexamethasone in the apical, middle, and basal regions of the magnetic field group was more even, while a concentration gradient of dexamethasone existed in the cochlea of ​​the non-magnetic field group. This further confirmed that magnetic field drive can enable magnetic nanoparticles to actively move in the cochlear lymph, achieving efficient drug delivery throughout the cochlea.

[0055] In summary, the method for delivering inner ear drugs by magnetically controlling and targeting the inner part of the cochlea provided in the embodiments of the present application has the following technical effects:

[0056] By adopting a new magnetic material carrier composed of hollow mesoporous ferrosoferric oxide, the specific surface area and drug loading capacity of the carrier are significantly improved, achieving efficient drug loading and sustained release performance. The surface of the new magnetic material carrier is modified with polyethylene glycol, which gives the carrier good water solubility and biocompatibility, effectively reduces the nonspecific adsorption and immune recognition of the carrier, and improves the stability and circulation time of the carrier in the body; using a surgical microscope to accurately identify anatomical structures, including the rat occipital bone and rat semicircular canals, to ensure the accurate positioning of the drug delivery site, improve the repeatability and stability of the drug delivery operation, use a 1mL syringe for minimally invasive drilling, and combine with a microinjection pump to achieve the new magnetic material carrier Precise infusion reduces the risk of tissue damage and fluid overflow. The drug administration method of injection into the semicircular canal allows the drug to directly enter the cochlear lymph system, shortens the path of the drug from the administration point to the target area, and improves delivery efficiency. Rats are placed in a 9.4T magnetic resonance magnetic field, and the direction of the magnetic field is adjusted from the base of the cochlea to the apex of the cochlea to effectively stimulate the magnetic response characteristics of the carrier, drive the new magnetic material carrier and the loaded drug to produce directional movement in the inner ear lymph, and use the controllability of the magnetic field to achieve precise positioning and motion trajectory control of the new magnetic material carrier in a complex microenvironment, breaking through the limitations of traditional passive diffusion and realizing dynamic adjustment and precise control of the inner ear delivery system.

[0057] The above description of the disclosed embodiments is intended to enable one skilled in the art to implement or use the present application. Various modifications to these embodiments will be readily apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present application. Therefore, the present application is not limited to the embodiments shown herein, but is intended to conform to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea, characterized in that: The method comprises: Prepare a novel magnetic material carrier, wherein the novel magnetic material carrier is composed of hollow mesoporous ferrosoferric oxide, the surface of the novel magnetic material carrier is modified with polyethylene glycol, and the novel magnetic material carrier is loaded with a target inner ear drug; After the rats were anesthetized, the occipital bones were identified under a surgical microscope, and the semicircular canals were located. After minimally invasive drilling with a 1mL syringe, the novel magnetic material carrier loaded with the target inner ear drug was injected into the rat semicircular canals using a microinjection pump. When the rat's semicircular canal drug administration meets the predetermined time threshold, the rat is placed in a 9.4T magnetic resonance magnetic field. The magnetic field direction of the magnetic resonance magnetic field is from the base of the cochlea to the apex of the cochlea. Based on the magnetic response characteristics of the new magnetic material carrier, the target inner ear drug is driven to move in the cochlear lymph fluid and released in the target area.

2. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea according to claim 1, wherein: The preparation of the novel magnetic material carrier comprises: Dissolve ferric chloride hexahydrate in deionized water and stir magnetically for 10 minutes. Then add sodium citrate, polyacrylamide, and urea. Stir vigorously for 30 minutes. Transfer the mixture to a hydrothermal reactor and react at 200°C for 12 hours. Wash and obtain ferrosoferric oxide. The prepared ferrosoferric oxide was dispersed in deionized water, triethoxysilane was added and stirred at room temperature, and then washed with deionized water to obtain an amination-modified hollow ferrosoferric oxide. The aminated hollow ferrosoferric oxide was dispersed again in deionized water, polyethylene glycol-N-hydroxysuccinimide ester was added, and the mixture was stirred continuously to obtain polyethylene glycol-treated hollow ferrosoferric oxide. The PEGylated hollow ferroferric oxide was dispersed in deionized water, the target inner ear drug was dissolved in methanol to prepare a solution, and the target inner ear drug solution was added dropwise to the PEGylated hollow ferroferric oxide dispersion system to complete the preparation of a new magnetic material carrier loaded with the target inner ear drug.

3. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea according to claim 2, wherein: The particle size of the novel magnetic material carrier ranges from 150 nanometers to 200 nanometers.

4. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea according to claim 1, wherein: After placing the rat in a 9.4T magnetic resonance magnetic field, the method includes: A 9.4T magnetic resonance scanner was used to provide a magnetic resonance magnetic field and simultaneously perform magnetic resonance imaging; The rats were maintained in an anesthetized state using 2% to 2.5% isoflurane in the magnetic resonance field, and their respiratory rate was monitored; T2-weighted three-dimensional images were acquired with a magnetic resonance imaging system. The key acquisition parameters of the magnetic resonance imaging system were as follows: voxel size of 0.08 × 0.08 × 0.35 mm, bandwidth of 260 Hz per pixel, repetition time of 2800 ms, echo time of 48.16 ms, echo train length of 15, average acquisition times of 20, slice thickness of 0.35 mm, readout field of view of 26 mm, phase shift of 24 mm, readout resolution of 312 points, and three consecutive scans of a predetermined duration each.

5. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea as claimed in claim 1, wherein: The target inner ear drug is a glucocorticoid drug dexamethasone, and the target inner ear drug forms a stable complex with the novel magnetic material carrier through physical adsorption.

6. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea as claimed in claim 5, characterized in that: The novel magnetic material carrier loaded with the target inner ear drug is injected into the rat semicircular canal through a microinjection pump connected to a semicircular canal drug delivery device, wherein the semicircular canal drug delivery device comprises: Glass microneedles, wherein the inner diameter of the glass microneedles is 0.5 mm and the outer diameter is 1.14 mm; The polyimide tube has an inner diameter of 0.4 mm and an outer diameter of 0.46 mm. The glass microneedle is connected to the polyimide tube via dental cement.

7. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea as claimed in claim 1, wherein: After the rat is anesthetized, the occipital bone of the rat is identified under an operating microscope, the semicircular canals are located, a 1 mL syringe is used for minimally invasive drilling, and the novel magnetic material carrier loaded with the target inner ear drug is injected into the rat semicircular canals using a microinjection pump, comprising: Rats were anesthetized with 1% sodium pentobarbital. When the depth of anesthesia was assessed by reflex stimulation and the preset anesthesia state was met, the rats were placed in a lateral position on the operating table with the operated ear facing upwards. After preparing the skin of the surgical ear area, the surgical area was locally anesthetized with 0.3 ml of 1% lidocaine, and a 0.7 cm to 0.9 cm arc-shaped incision was made on the posterior side of the auricle. The occipital bone of the rat was then located to complete the delivery of the new magnetic material carrier.

8. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea as claimed in claim 1, characterized in that: After placing the rat in a 9.4T magnetic resonance magnetic field, the method includes: Performing magnetic resonance imaging at predetermined time intervals to establish a signal intensity data set; Directional movement verification is performed based on the signal strength data set, and movement management of the new magnetic material carrier is performed based on the results of the directed movement verification.

9. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea as claimed in claim 1, wherein: The magnetic resonance magnetic field can drive the novel magnetic material carrier to move and simultaneously perform magnetic resonance imaging monitoring.

10. The method for delivering inner ear drugs by magnetically controlling the inner part of the cochlea as claimed in claim 1, characterized in that: The hydrodynamic size of the unloaded new magnetic material carrier is 230.09±9.11nm, the PDI value is 0.21±0.006, and the zeta potential is -4.13±0.3mV.

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