Injectable adhesive microcarrier with hierarchical structure, and preparation method therefor and use thereof

Abstract

An injectable adhesive microcarrier with a hierarchical structure, and a preparation method therefor and the use thereof. A hydrogel microcarrier is constructed by means of microfluidic technology, and the size of the microcarrier is adjusted by adjusting a flow rate and voltage; and polydopamine generated by means of the oxidative self-polymerization of dopamine is attached to the surface of the microcarrier, thereby obtaining an adhesive and responsive hierarchical microcarrier. The prepared microcarrier has a three-dimensional network structure and hydrophilic characteristics, which can provide sufficient space for the loading of various drugs. The photothermal conversion characteristics of the microcarrier are controlled by adjusting near-infrared irradiation, thereby realizing control over the drug release process. These characteristics enable the injectable adhesive microcarrier with a hierarchical structure to overcome the limitations of a delivery system for middle ear administration. The injectable adhesive microcarrier with a hierarchical structure has the advantages of reusability, low cost, easy operation, convenience and reliability, high biocompatibility, inner ear targeting, etc.

Description

A layered injectable adhesive microcarrier, its preparation method and application Technical Field

[0001] This invention belongs to the field of biomaterials, specifically relating to a layered injectable adhesive microcarrier, its preparation method, and its application. Background Technology

[0002] Hearing loss is one of the most common health defects among adults. According to the World Health Organization's (WHO) 2021 World Hearing Report, 1.5 billion people worldwide suffer from varying degrees of hearing loss, of which approximately 430 million have disabling hearing loss. Hearing loss causes more than US$979.6 billion in economic losses globally each year. The latest results of the Second National Sample Survey of Disabilities in my country show that people with hearing disabilities account for 24.2% of the total number of disabled people. Furthermore, my country faces severe and complex factors contributing to hearing impairment, particularly the increasing industrial noise pollution and the deepening aging of the population, making deafness an increasingly significant disease affecting national health and socio-economic development.

[0003] Currently, clinical inner ear drug delivery systems are mainly divided into two types: systemic administration and local inner ear administration, with the former being the most commonly used method. Many drugs enter the cochlea in very small quantities or cannot cross the blood labyrinth, limiting the application of systemic administration in inner ear treatment. In contrast, intratympanic injection can bypass these barriers, increasing drug concentration in the cochlea to enhance efficacy and reducing systemic drug exposure. However, due to the presence of the Eustachian tube, drugs are difficult to retain in the middle ear cavity, requiring repeated injections to achieve the desired therapeutic effect. To avoid damage caused by multiple injections and improve treatment efficacy, local drug delivery systems derived from various materials such as microcatheters, micropumps, hydrogels, and micro / nanoparticles have emerged. Despite significant progress, most of these carriers are controversial due to their simple structure, low biocompatibility, and easy degradation in vivo, resulting in less than satisfactory therapeutic effects. Furthermore, due to the unique anatomical structure of the inner ear, carriers without sufficient adhesion cannot remain in the middle ear cavity for extended periods, preventing drugs from continuously reaching the inner ear to exert their therapeutic effect. Therefore, developing multifunctional delivery vehicles with minimally invasive delivery and controllable manipulation characteristics, and finding safer and more effective inner ear drug delivery strategies are of great significance for the prevention and treatment of deafness. Summary of the Invention

[0004] Purpose of the invention: The technical problem to be solved by the present invention is to provide an injectable microcarrier for the middle ear with adhesiveness and responsive layering, and a method for preparing the same, in order to overcome the shortcomings of traditional inner ear drug delivery methods, such as poor targeting, low bioavailability, and poor biocompatibility.

[0005] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0006] A method for preparing a layered injectable adhesive microcarrier includes the following steps:

[0007] (1) A microfluidic device was constructed, and alginate aqueous solution was added dropwise to calcium chloride aqueous solution under the action of an electric field to obtain monodisperse alginate microcarriers;

[0008] (2) Dopamine was dissolved in Tris buffer to prepare a dopamine (DA) solution, and the reaction was carried out in the dark to obtain adhesive polydopamine (PDA) nanoparticles.

[0009] (3) The alginate microcarrier obtained in step (1) is immersed in the dopamine solution in step (2) for polymerization reaction, so that the polydopamine nanoparticles adhere to the surface of the alginate microcarrier, and the product is freeze-dried.

[0010] Specifically, in step (1), the alginate aqueous solution solute is sodium alginate with a concentration of 10-20 g / L.

[0011] Specifically, in step (1), the microfluidic device's dripping end is located under an electric field, causing the alginate aqueous solution droplets to form a Taylor cone shape through the electric field. The electric field voltage is 8-14KV, and the flow rate of the microfluidic device dripping the alginate aqueous solution is 80-120mL / h. By adjusting the voltage, height, and flow rate parameter on the peristaltic pump, the droplet size can be precisely controlled, dividing the liquid into droplets of different sizes. The droplet size decreases with increasing voltage and flow rate, and decreases with increasing height.

[0012] Specifically, in step (1), the concentration of the calcium chloride aqueous solution is 10-20 g / L; the obtained monodisperse alginate microcarrier is washed with pure water to remove residual calcium chloride from the surface.

[0013] Specifically, in step (1), the diameter of the monodisperse alginate microcarriers obtained is 80–95 μm.

[0014] Specifically, in step (2), the concentration of the Tris buffer is 10 mM, the pH value is 8.5, and the concentration of the dopamine solution prepared is 1-4 mg / mL.

[0015] Specifically, in step (2), the alginate microcarriers are reacted in a dopamine solution in the dark for more than 10 hours, resulting in adhesive polydopamine (PDA) nanoparticles with an average diameter of 100–140 nm. PDA is obtained through oxidative self-polymerization, and surface modification technology is used to graft polydopamine onto the surface of the microcarriers, thereby endowing them with good tissue adhesion and photothermal properties. Steps (2) and (3) can be carried out in the same step, and the generated polydopamine is attached to the surface of the microcarriers through the dopamine oxidative self-polymerization method, thus obtaining adhesive and responsive layered microcarriers. PDA can be rapidly loaded onto the surface of the microcarriers, and the loading rate can reach 24.24 ± 0.45% after 24 hours.

[0016] The lyophilized, adhesive, and responsive layered injectable microcarriers possess a three-dimensional network structure and hydrophilic properties, ensuring rapid expansion of the thermoresponsive hydrogel microspheres in solution and the adsorption of large amounts of liquid. The lyophilized thermoresponsive hydrogel microcarriers reached swelling equilibrium after immersion in PBS for 4 hours, exhibiting a swelling capacity exceeding 4000 times.

[0017] Furthermore, the adhesive and responsive stratified injectable microcarriers prepared by this invention exhibit adhesion at 1 W / cm². 2 It can be heated to 40°C after infrared irradiation. In five on / off cycles of exposure to near-infrared light, the sodium alginate microcarrier exhibited rapid heating to 40°C in each cycle when the near-infrared light was on, and immediate cooling back to its initial temperature after the near-infrared light was off, demonstrating controllable thermal properties.

[0018] Furthermore, the layered injectable adhesive microcarriers prepared by the above preparation method are also within the scope of protection of this invention, and the average diameter of the prepared injectable microcarriers is 82-95 μm.

[0019] Furthermore, the present invention also claims the use of the above-mentioned injectable microcarriers in loading antioxidant drugs, including but not limited to the universal antioxidant alpha-lipoic acid.

[0020] Furthermore, the present invention also claims protection for the application of the above-mentioned injectable microcarriers in middle ear drug delivery, specifically: preparing a drug solution, immersing the layered injectable adhesive microcarriers in the drug solution, so that the drug solution fully penetrates into the pores of the microcarriers, thereby achieving drug loading. Beneficial effects:

[0021] (1) Based on microfluidic technology, hydrogel microcarriers are constructed using microfluidic technology, and the size of the microcarriers is adjusted by regulating the flow rate and voltage. Polydopamine generated is then attached to the surface of the microcarriers via dopamine oxidative self-polymerization, resulting in layered injectable adhesive microcarriers. The prepared microcarriers possess a three-dimensional network structure and hydrophilic properties, providing ample space for the loading of various drugs. By adjusting near-infrared irradiation, the photothermal conversion characteristics of the microcarriers can be controlled, thereby controlling the drug release process. These characteristics enable the layered injectable adhesive microcarriers of this invention to overcome the limitations of middle ear drug delivery systems. This microfluidic-based preparation method has advantages such as low cost, simple operation, and high reliability.

[0022] (2) The layered injectable adhesive microcarrier prepared by this invention has a three-dimensional network structure and hydrophilic properties, which can provide sufficient space for the loading of various drugs. It can be used to treat deafness, and the photothermal conversion characteristics of the microcarrier can be controlled by adjusting near-infrared irradiation, thereby controlling the drug release process. Attached Figure Description

[0023] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0024] Figure 1 is a schematic diagram illustrating the preparation of layered injectable adhesive microcarriers and their application in inner ear delivery.

[0025] Figure 2 shows the optimization and adhesion properties of the layered injectable adhesive microcarriers. (a) Electron micrograph of PDA nanoparticles. (bc) Microscopic images of MCs and PDA@MCs. (de) Scanning electron micrograph of PDA@MCs. (f) Statistical analysis of PDA@MCs particle size at different voltages. (gh) Statistical size distribution of MCs and PDA@MCs (n = 150). (i) Swelling curve of PDA@MCs in PBS. (jk) Adhesion properties of MCs and PDA@MCs.

[0026] Figure 3 shows the drug loading rate and amount of the layered injectable adhesive microcarriers: (a) Confocal scan images of RHB-loaded PDA@MCs at different immersion times. (b) Standard curve of RHB in PBS. (c) Drug loading of PDA@MCs over 24 hours.

[0027] Figure 4 shows the distribution and metabolism of drugs loaded with layered injectable adhesive microcarriers in the cochlea. (a) In vivo cochlear fluorescence images at different time points over 11 consecutive days in the mouse middle ear injection group of PDA@MCs-Cy7. (b) In vitro cochlear fluorescence images at different time points over 11 consecutive days in the mouse middle ear injection group of PDA@MCs-Cy7. (c) In vivo cochlear images of mice in the control group injected with Cy7 at different time points over 4 consecutive days. (d) In vitro cochlear fluorescence images of mice in the control group injected with Cy7 at different time points over 4 consecutive days. (e) Relative fluorescence intensity of the in vivo cochlea of ​​mice injected with PDA@MCs-Cy7 at different time intervals. (f) Relative fluorescence intensity of the isolated cochlea of ​​mice injected with PDA@MCs-Cy7 at different time intervals. (g) Relative fluorescence intensity of the in vivo cochlea of ​​mice in the control group at different time intervals. (h) Relative fluorescence intensity of the isolated cochlea of ​​mice in the control group at different time intervals.

[0028] Figure 5 shows the in vivo photothermal effect study of the layered injectable adhesive microcarriers. (a) In vivo thermal imaging after injecting MCs and PDA@MCs into the middle ear of mice and irradiating with 1W / cm2 near-infrared radiation for 5 minutes. (b) Fluorescence intensity in the cochlea of ​​the control group without NIR and the experimental group with NIR. (c) Statistical analysis of the fluorescence intensity in the cochlea of ​​the two groups in (b).

[0029] Figure 6 shows the validation of the antagonistic effect of the layered injectable adhesive microcarrier on cisplatin ototoxicity in mice. (a) Injection timeline of PDA-MCs-ALA. (bd) Cochlear basilar membrane flaps of mice in the control group, cisplatin group, and PDA@MCs-ALA group. (e) Statistical analysis of OHC survival rate in each group. (fh) ABR results of mice in each group. Detailed Implementation

[0030] The present invention can be better understood from the following embodiments.

[0031] Example 1

[0032] Referring to Figure 1, the preparation method of the layered injectable adhesive microcarrier of the present invention includes the following steps:

[0033] (1) A microfluidic device was constructed, and alginate aqueous solution was added dropwise to calcium chloride aqueous solution under the action of an electric field to obtain monodisperse alginate microcarriers;

[0034] (2) Dopamine was dissolved in Tris buffer to prepare a dopamine (DA) solution, and the reaction was carried out in the dark to obtain adhesive polydopamine (PDA) nanoparticles.

[0035] (3) The alginate microcarrier obtained in step (1) is immersed in the dopamine solution in step (2) for polymerization reaction, so that the polydopamine nanoparticles adhere to the surface of the alginate microcarrier, and the product is freeze-dried.

[0036] The prepared layered injectable adhesive microcarriers (PDA@MCs) are immersed in a drug solution, allowing the drug solution to fully penetrate into the pores of the microcarriers, thus obtaining drug-loaded injectable microspheres. These microspheres can be administered to the middle ear via injection, effectively preventing and treating deafness.

[0037] Example 2

[0038] In this embodiment, polypamine is used to modify the surface of sodium alginate microcarriers. Adhesive polydopamine (PDA) can be produced by soaking dopamine (DA) in 10 mM Tris buffer (pH = 8.5) in the dark for 12 hours. The obtained PDA nanoparticles exhibit significant uniformity with an average diameter of 127 ± 7.44 nm (see Figure 2a). After polymerization with PDA, it is endowed with adhesiveness and responsive layering to form injectable hydrogel microcarriers.

[0039] Example 3

[0040] This embodiment provides a method for preparing layered injectable adhesive microcarriers (PDA@MCs), including the following steps:

[0041] Step S1: Construction of microcarriers

[0042] A microfluidic platform was constructed and monodisperse sodium alginate microcarriers were prepared: 20 g / L high-viscosity sodium alginate was dissolved and drawn into a syringe. A voltage generator was used to provide different voltages and generate an electric field. Under the action of the electric field, the droplets at the end of the channel transformed into Taylor cones, and then the droplets were collected in a container containing a 20 g / L calcium chloride (CaCl2) solution. By changing the flow rate and voltage in the microcontroller, the liquid was divided into droplets of different sizes. Then, the microcarriers were washed with pure water (repeated 3 times) to remove residual calcium chloride.

[0043] The microsphere size was adjusted according to requirements: the droplet size could be precisely controlled by adjusting the voltage, height, and flow rate (i.e., the flow rate parameter on the peristaltic pump). The droplet size decreased with increasing voltage and flow rate, and decreased with increasing height. Finally, a voltage of 12KV and a flow rate of 100mL / h were selected, and the diameter of the prepared microcarrier was 86.9±4.8μm (see b, g, f in Figure 2).

[0044] Step S2: Construction of PDA-modified adhesive and responsive stratified injectable microcarriers

[0045] Different concentrations of dopamine (DA) were weighed and dissolved in 10 mM Tris buffer (pH = 8.5). The prepared microcarriers were then immersed in the DA solution in the reaction. After reacting in the dark for 12 hours, polydopamine (PDA) was obtained. After the microcarriers were polymerized with PDA, the injectable hydrogel microcarriers (PDA@MCs) that were endowed with adhesion and responsive layering had a diameter of 87.6.6 ± 5.0 μm and were uniform in size (see ce,h in Figure 2).

[0046] Step S3: Adhesion properties of the prepared layered injectable adhesive microcarrier

[0047] Microcarriers (MCs) and PDA@MCs were adhered to the skin surface of mice, immersed in water, and shaken. After shaking, the PDA@MCs remained adhered to the mouse skin surface, while the MCs quickly slid off the skin surface (see jk in Figure 2). Thus, PDA imparts adhesive properties to microcarriers.

[0048] Example 4

[0049] Drug loading rate and drug capacity of the prepared layered injectable adhesive microcarriers (PDA@MCs):

[0050] The lyophilized porous PDA@MCs hydrogel microspheres were immersed in an alpha-lipoic acid (ALA) solution, and the drug was adsorbed into the three-dimensional network structure of the PDA@MCs through reabsorption swelling. To determine the drug loading behavior, Rhodamine B (RHB) was selected instead of ALA as the model drug. After drug loading was completed, the supernatant was collected, and the microcarriers were repeatedly washed with fresh PBS to remove excess drug from the surface. The washing solution was also collected and thoroughly mixed with the previously collected supernatant, and the volume was adjusted. 100 μL of the solution was aspirated into a 96-well plate, and the drug encapsulation efficiency and drug loading rate were calculated by measuring the drug absorbance using a microplate reader. In addition, the microcarriers were observed using a confocal microscope to determine the distribution of the drug in the microcarriers. From the laser confocal image, it can be observed that RHB with red fluorescence is uniformly distributed in the PDA@MCs, indicating that the drug was completely loaded after 12 hours of immersion (see Figure 3a). Next, the loading rate of polydopamine sodium alginate microcarriers was studied by the standard curve method. First, the standard curve of RHB in PBS was recorded. Then, the loading rate of PDA@MCs was calculated by measuring the absorbance of RHB in PBS. PDA@MCs could be loaded with approximately 23.62 ± 0.26% RHB after 10 minutes of soaking, and 24.24 ± 0.45% RHB after 24 hours, at which point the loading capacity of the photothermal microcarrier reached saturation. This result indicates that PDA@MCs have a rapid loading capacity, which may be related to their porous structure, facilitating their use.

[0051] Example 5

[0052] Distribution and metabolism of PDA@MCs-loaded drugs within the cochlea:

[0053] In vivo absorption and transport distribution are key aspects of in vivo evaluation of nanoloaded drug systems. Notably, Cy7, a commonly used near-infrared fluorescent dye, can generate signals in deep tissues and has therefore been used to mimic drug molecules for in vivo imaging system (IVIS) tracking. In this study, Cy7 fluorescent dye was used instead of ALA for in vivo tracking observation, and IVIS was used to observe the distribution of PDA@MCs in the cochlea after intratympanic administration. Cy7 was loaded into PDA@MCs, and continuous observation was performed using IVIS, with fluorescence results statistically analyzed. The results showed that the fluorescence signal of PDA@MCs-Cy7 injection persisted for more than 11 days and showed a slow decreasing trend (Figure 4a, e). Furthermore, 11 days after PDA@MCs-Cy7 injection into the middle ear, fluorescence signals were observed in the isolated cochlea of ​​mice in the PDA@MCs-Cy7 group, demonstrating that the drug can passively penetrate into the inner ear via the RWM (see Figure 4b, f). In contrast, the fluorescent signal of the control group (directly injected Cy7) lasted only about 4 days (see Figure 4c, g), and there was almost no fluorescence in the cochlea of ​​the inner ear after 4 days (see Figure 4d, h). These results indicate that PDA@MCs have significant adhesiveness, increasing the retention time of drug microspheres in the middle ear cavity and improving drug bioavailability.

[0054] Example 6

[0055] In vivo photothermal effects and drug release of PDA@MCs

[0056] In vitro studies showed that the photothermal heating properties of PDA@MCs could be controlled by adjusting near-infrared irradiation. Building on this, to further verify the photothermal properties of PDA@MCs and accelerate drug release without burning the in vivo skin, we injected PDA@MCs into the middle ear of mice. PDA@MCs heated effectively under near-infrared radiation, reaching 42°C within 5 minutes of exposure, indicating appropriate in vivo heating capacity (see Figure 5a).

[0057] In thermoresponsive microcarriers, the added PDA can be released in a controlled manner via near-infrared stimulation. When PDA-doped hydrogel microparticles are exposed to near-infrared light, the local temperature rises, and drug molecules undergo faster molecular motion, thereby accelerating drug release. Once the near-infrared light is turned off, the temperature gradually returns to room temperature, and drug release slows down. To further evaluate the effect of photothermal stimulation on drug delivery to the inner ear, we heated PDA@MCs-Cy7 injected into the middle ear with near-infrared light. The control group was not heated, and the fluorescence intensity of the cochlea in both groups was observed at the same time point to evaluate whether near-infrared stimulation accelerates drug delivery to the inner ear. The study found that the fluorescence intensity of the cochlea at different time points after photothermal stimulation was higher than that of the control group (see Figure 5b, c). Therefore, it is shown that Cy7 is released from the microparticles, and near-infrared irradiation can promote drug delivery to the inner ear. This study provides important technical guidance and theoretical basis for the construction and functional modification of microcarriers in this project.

[0058] Example 7

[0059] Statistical results of mouse basement membrane outer hair cells (OHCs) and hearing loss assessment

[0060] The hearing-protective effect of PDA@MCs-ALA against cisplatin (CDDP) ototoxicity was evaluated using an adult mouse model. Middle ear injection in mice is a prerequisite for inner ear treatment. PDA@MCs, with their small diameter and ease of injection, are excellent biomaterials for middle ear administration. The mouse tympanic membrane was exposed under a microscope, and then PDA@MCs-ALA was injected into the middle ear. To further investigate the pre-protective effect of PDA@MCs-ALA, the following animal experiments were conducted: 40-day-old mice were divided into a control group, a CDDP group, and a PDA@MCs-ALA group. In the control group, a tympanic membrane perforation model was established in the ear only. In the CDDP group, after establishing the tympanic membrane perforation model in the ear, mice were injected intraperitoneally with 25 mg / kg of CDDP. In the PDA@MCs-ALA group, PDA@MCs-ALA was first injected into the ear, followed by an intraperitoneal injection of 25 mg / kg of CDDP the next day (see Figure 6a).

[0061] Statistical results of outer hair cells (OHCs)

[0062] To observe the ototoxicity of CDDP, cochlear outer hair cells were statistically analyzed in the control group, CDDP group, and PDA@MCs-ALA group. The study found that, compared to the control group (see Figure 6b), CDDP caused severe damage to the basal and middle loops of OHCs (see Figure 6c). Compared to the control group, the PDA@MCs-ALA group showed a more significant protective effect against OHCs (see Figure 6d). It is well known that the cochlea is a vital organ for sound perception, and the different forms of basilar membrane vibration caused by different frequencies of sound are considered the basis for the cochlea's ability to distinguish different sound frequencies. Experiments involving damage to the basilar membrane in different parts of animals and clinical studies on different types of hearing loss have confirmed this conclusion: damage to the basal cochlea primarily affects high-frequency hearing, while damage to the apex of the cochlea primarily affects low-frequency hearing. These results indicate that the prepared PDA@MCs-ALA group effectively delivered drugs to the inner ear and provided good protection against OHCs.

[0063] Auditory brainstem response (ABR) is a commonly used electrophysiological indicator in hearing testing and has been routinely used in basic auditory research to objectively assess hearing in small animals. ABR thresholds were measured 3 days before treatment and 10 days after injection. Results showed that hearing in the control group remained unchanged (see Figure 6f), indicating that 10 days after tympanic membrane perforation modeling, hearing in mice was not impaired. However, the ABR threshold in the CDDP group changed significantly 10 days after CDDP treatment, showing obvious hearing loss (see Figure 6g). In contrast, the ABR threshold in the PDA@MCs-ALA group showed a slight change compared to before CDDP treatment (see Figure 6h). These results indicate that PDA@MCs successfully delivered the loaded ALA to the inner ear and protected against CDDP-induced hearing loss. These results demonstrate that PDA@MCs-ALA significantly prevents CDDP-induced hearing loss in mice.

[0064] This invention provides a layered injectable adhesive microcarrier, its preparation method, and its application. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for preparing a layered injectable adhesive microcarrier, characterized in that, Includes the following steps: (1) A microfluidic device was constructed, and alginate aqueous solution was added dropwise to calcium chloride aqueous solution under the action of an electric field to obtain monodisperse alginate microcarriers; (2) Dopamine was dissolved in Tris buffer to prepare a dopamine solution, and the reaction was carried out in the dark to obtain adhesive polydopamine nanoparticles. (3) The alginate microcarrier obtained in step (1) is immersed in the dopamine solution in step (2) for polymerization reaction, so that the polydopamine nanoparticles adhere to the surface of the alginate microcarrier, and the product is freeze-dried.

2. The method for preparing a layered injectable adhesive microcarrier according to claim 1, characterized in that, In step (1), the alginate aqueous solution solute is sodium alginate with a concentration of 10-20 g / L.

3. The method for preparing a layered injectable adhesive microcarrier according to claim 1, characterized in that, In step (1), the microfluidic device is placed under an electric field at the tip of the droplet, and the droplets of alginate aqueous solution are formed into Taylor cones by the action of the electric field. The electric field voltage is 8-14KV, and the flow rate of the microfluidic device dropping alginate aqueous solution is 80-120mL / h.

4. The method for preparing a layered injectable adhesive microcarrier according to claim 1, characterized in that, In step (1), the concentration of the calcium chloride aqueous solution is 10-20 g / L; the obtained monodisperse alginate microcarrier is washed with pure water to remove residual calcium chloride from the surface.

5. The method for preparing a layered injectable adhesive microcarrier according to claim 1, characterized in that, In step (1), the diameter of the monodisperse alginate microcarriers obtained is 80-95 μm.

6. The method for preparing a layered injectable adhesive microcarrier according to claim 1, characterized in that, In step (2), the concentration of the Tris buffer is 10 mM, the pH value is 8.5, and the concentration of the dopamine solution prepared is 1-4 mg / mL.

7. The method for preparing a layered injectable adhesive microcarrier according to claim 1, characterized in that, In step (2), the alginate microcarriers are reacted in dopamine solution in the dark for more than 10 hours, and the average diameter of the adhesive polydopamine nanoparticles is 100-140 nm.

8. The layered injectable adhesive microcarrier prepared by the preparation method according to any one of claims 1 to 7, characterized in that, The average diameter of the injectable microcarriers is 82–95 μm.

9. The use of the injectable microcarrier of claim 8 in loading antioxidant drugs, characterized in that, The antioxidant drug mentioned is the universal antioxidant alpha-lipoic acid.

10. The use of the injectable microcarrier of claim 8 in middle ear drug delivery.

Images