Method for preparing magnetic response drug-loaded microspheres based on high-throughput microfluidic chip

Abstract

This application relates to a method for preparing magnetically responsive drug-loaded microspheres based on a high-throughput microfluidic chip in the field of biomedical microsphere preparation technology. The method involves encapsulating carboxylated magnetic nanoparticles via suspension polymerization, then co-forming them with biodegradable polymers and therapeutic drugs to create a magnetically responsive dispersed phase. Through structural design, multiple microsphere generation units are integrated on a single chip, arranged concentrically, to achieve one-step high-throughput generation of monodisperse oil-in-water emulsion droplets. Subsequent processing yields magnetically responsive drug-loaded microspheres with uniform particle size distribution and tunable saturation magnetization. This invention overcomes the problems of easy magnetic core aggregation, poor microsphere particle size uniformity, low throughput of traditional microfluidic preparation, and complex integration of magnetic response and drug-loading functions in existing technologies. It is suitable for various biomedical applications such as targeted chemotherapy, drug sustained release, magnetothermal synergistic therapy, and nucleic acid / protein delivery, and has advantages such as rapid and scalable preparation process, high batch stability, and precise magnetic field control.

Description

Technical Field

[0001] This application relates to the field of biomedical microsphere preparation technology, and in particular to a method for preparing magnetically responsive drug-loaded microspheres based on a high-throughput microfluidic chip. Background Technology

[0002] This section provides only background information relevant to this disclosure and is not necessarily prior art.

[0003] With the rapid development of precision medicine and targeted therapy strategies, achieving controlled drug release and spatial localization in lesion areas has become one of the core challenges urgently needing breakthroughs in pharmaceutical engineering. Traditional drug delivery systems, such as liposomes, polymer microspheres, or nanoparticles, while improving drug stability and delaying release to some extent, still generally face limitations in complex physiological environments, including high drug leakage rates, insufficient tissue penetration, and difficulty in achieving external regulation. Especially in the treatment of localized lesions such as tumors and inflammation, the non-specific distribution of drugs in non-target areas not only weakens efficacy but may also trigger systemic toxicity.

[0004] To address these challenges, magnetically responsive drug-loaded microspheres, combining targeted navigation and sustained-release functions, have emerged. By encapsulating magnetic nanoparticles, these microspheres can achieve precise localization and accumulation in lesion areas with the aid of an external magnetic field, showing great promise for applications. However, the clinical translation of such microspheres is severely limited by the lack of practical processes capable of high-throughput, controllable preparation of uniform microspheres.

[0005] Therefore, this invention is proposed. Summary of the Invention

[0006] In view of the problems existing in the background technology, this application provides a method for preparing magnetically responsive drug-loaded microspheres based on high-throughput microfluidic chips. This method can overcome the shortcomings of existing magnetically responsive drug-loaded microsphere preparation technologies, such as complex and time-consuming magnetic particle functionalization process, low production throughput, and difficulty in controlling particle size uniformity. By combining carboxylated magnetic nanoparticles with high-throughput microfluidic chip technology, it can achieve efficient, large-scale, and highly monodisperse microsphere controllable preparation.

[0007] According to one aspect of the present invention, a method for preparing magnetically responsive drug-loaded microspheres based on a high-throughput microfluidic chip is provided, comprising the following steps: S1. Preparation of magnetic core: Using suspension polymerization, magnetic nanoparticles were used as magnetic cores, and organic polymers were used to modify the surface of the magnetic cores to prepare modified magnetically responsive composite particles.

[0008] S2. Preparation of drug-loaded microsphere precursor solution: Prepare an organic phase containing the magnetically responsive composite particles, biodegradable polymer material and optional therapeutic drug as the magnetically responsive dispersed phase; prepare an aqueous solution containing surfactant as the continuous phase.

[0009] S3. Fabrication of high-throughput microfluidic chip: Fabrication of an integrated disk-type high-throughput microfluidic chip with multiple parallel microsphere forming units.

[0010] S4. Preparation of microsphere precursor: The magnetically responsive dispersed phase prepared in step S2 and the continuous phase are pumped into the chip prepared in step S3 at a specific flow rate ratio to generate monodisperse oil-in-water emulsion droplets in each microsphere forming unit.

[0011] S5. Microsphere curing and post-treatment: Collect the emulsion droplets, cure by evaporation of organic solvent, wash and freeze-dry to obtain solid magnetically responsive drug-loaded microspheres.

[0012] In some embodiments of the present invention, in step S1, the magnetic nanoparticles include one or a combination of the following: Fe3O4 and Fe2O3.

[0013] Preferably, the magnetic nanoparticles have a particle size range of 5nm-1000nm.

[0014] Preferably, the organic polymer comprises one or a combination of the following: oleic acid, polystyrene, polyacrylonitrile, and alkyl silane coupling agent.

[0015] Preferably, the reaction temperature of the suspension polymerization method is 60℃-85℃, and the stirring rate is 300rpm-1000rpm.

[0016] In some embodiments of the present invention, in step S2, the biodegradable polymeric material includes one or a combination of the following: polylactic acid-glycolic acid copolymer, polylactic acid, polycaprolactone, gelatin, and chitosan.

[0017] Preferably, the organic solvent of the magnetically responsive dispersion includes one or a combination of the following: dichloromethane, chloroform, ethyl acetate, and N,N-dimethylformamide.

[0018] Preferably, the mass ratio of the magnetically responsive composite particles to the biodegradable polymer material is 1:5 to 1:100.

[0019] In some embodiments of the present invention, in step S2, the therapeutic drug includes one or a combination of the following: chemotherapy drugs, antibiotics, peptides, proteins, and nucleic acid drugs.

[0020] Preferably, the concentration of the surfactant in the continuous phase is 0.1% to 10% (w / v).

[0021] Preferably, the surfactant is polyvinyl alcohol.

[0022] In some embodiments of the present invention, in step S3, the structure of the microsphere forming unit is a coaxial annular channel with a channel feature size of 20-500 μm.

[0023] Preferably, the chip is manufactured using one or a combination of the following processes: surface projection micro-stereolithography 3D printing, laser etching, injection molding, and PDMS molding.

[0024] Preferably, the number of microsphere forming units is 100 to 10,000, and multiple microsphere forming units are arranged in a circle and concentrically expanded to form a highly integrated chip.

[0025] Preferably, the minimum printed layer thickness of the chip structure is 5-40 μm.

[0026] Preferably, the chip is made of a hydrophobic photosensitive resin or a biocompatible resin that is resistant to organic solvents.

[0027] In some embodiments of the present invention, step S3 further includes a post-processing step of modifying the surface properties of the shaped chip.

[0028] Preferably, the post-treatment includes one or a combination of the following: oxygen plasma treatment, UV-ozone curing, chemical vapor deposition of fluorosilane, grafting of hydrophilic / hydrophobic polymer brushes, and hydrogen peroxide immersion.

[0029] In some embodiments of the present invention, in step S4, the flow rate ratio of the magnetically responsive dispersed phase to the continuous phase is 1:5 to 1:50; and the particle size distribution variation coefficient of the generated emulsion droplets is less than 10%.

[0030] In some embodiments of the present invention, in step S2, sodium alginate, polyvinyl alcohol or methylcellulose is added to the continuous phase as a stabilizer.

[0031] In some embodiments of the present invention, in step S5, the organic solvent evaporation and curing is carried out at a stirring rate of 50-300 rpm for 1-24 hours.

[0032] Preferably, the evaporation of organic solvents is accelerated by vacuum assistance, heating, or the introduction of inert gas.

[0033] Preferably, the freeze-drying is divided into a pre-freezing stage and a main drying stage. The pre-freezing temperature is below -40°C, and the cold trap temperature in the main drying stage is below -50°C, with a vacuum degree below 10 Pa.

[0034] According to another aspect of the present invention, a magnetically responsive drug-loaded microsphere is provided, characterized in that it is prepared by the method described above.

[0035] Compared with the prior art, the present invention achieves the following technical effects: 1. Solved the problem of magnetic core uniformity and stability: Through improved suspension polymerization and surface functionalization modification, magnetic cores with excellent monodispersity, high stability and non-agglomeration were prepared, laying a solid foundation for the construction of drug-loaded microspheres with uniform magnetic response, and overcoming the defects of magnetic particles prepared by traditional methods, such as wide particle size distribution and easy agglomeration.

[0036] 2. Achieved high-throughput and controllable preparation of drug-loaded microspheres: Innovatively, an integrated, modular, parallel high-throughput microfluidic chip based on high-precision technology is adopted, integrating tens to thousands of microsphere forming units into a single chip, achieving a breakthrough from single-channel low throughput to large-scale parallelization, significantly improving the production efficiency of monodisperse drug-loaded microspheres, and solving the bottleneck problem of low throughput in traditional microfluidic technology.

[0037] 3. Ensures high uniformity of microsphere size: Utilizing the laminar shear principle of microfluidic technology and combined with the precision processing consistency of the chip, the coefficient of variation (CV value) of the droplet size distribution of the generated oil-in-water (O / W) emulsion is less than 5%. The resulting solid microspheres have high monodispersity and good batch reproducibility, far exceeding the microspheres prepared by traditional batch emulsification methods.

[0038] 4. Simplified process and efficient integration of functions: Magnetic composite particles are directly dispersed in the drug-loaded polymer organic phase, and a "magnetic bead-drug-polymer" composite microsphere precursor is formed in one step through a microfluidic chip. This simplifies the traditional multi-step discrete magnetic functionalization and drug loading process, and achieves efficient and precise integration of magnetic response characteristics and drug loading function. The process is simple and controllable.

[0039] 5. Improved chip compatibility and stability: The chip materials used broaden the selection range of biodegradable polymers and organic solvents that can be used for drug delivery, improving the stability and reliability of the preparation process. Attached Figure Description

[0040] Various other advantages and benefits will become apparent to those skilled in the art upon reading the following detailed description of preferred embodiments. The accompanying drawings are for illustrative purposes only and are not intended to limit the scope of this application. Furthermore, the same reference numerals denote the same parts throughout the drawings. In the drawings: Figure 1 The present invention provides a flowchart for the fabrication of magnetically responsive microspheres based on a high-throughput microfluidic chip. Figure 2This is a schematic diagram of the overall structure of a disk-type high-throughput microfluidic chip from an oblique front view, as provided in this application. Figure 3 This is a schematic diagram of the back structure of a disk-type high-throughput microfluidic chip provided in this application; Figure 4 This is a schematic diagram of the generation of magnetically responsive emulsion droplets by the microsphere forming unit structure provided in this application; Figure 5 SEM image of the magnetic core prepared in this invention; Figure 6 This is a scanning electron microscope image of magnetically responsive microspheres fabricated based on a high-throughput microfluidic chip in this application; Figure 7 This is a hysteresis loop (VSM) diagram of the magnetically responsive microspheres fabricated based on a high-throughput microfluidic chip in this application. Figure 8 This is a magnetic performance diagram of magnetically responsive microspheres fabricated based on high-throughput microfluidic chips in this application, tested with a magnet (left side: without magnet, microspheres are uniformly suspended in a vial; right side: with magnet, microspheres are resting on the magnet). Figure 9 This is a particle size distribution diagram of the magnetically responsive microspheres prepared in the embodiments of this application; Figure 10 These are SEM images of magnetically responsive naltrexone microspheres fabricated using a high-throughput microfluidic chip according to this application, at different magnifications. Figure 11 These are SEM images of the magnetically responsive curcumin microspheres fabricated using a high-throughput microfluidic chip according to this application, at different magnifications.

[0041] The labels in the attached figures represent the following: 1. Chip substrate; 2. Continuous phase inlet; 3. Dispersed phase inlet; 4. Microsphere droplet formation point; 5. Microsphere droplet collection point; 6. Continuous phase main flow channel; 7. Dispersed phase main flow channel; 8. Microsphere droplet main flow channel; 9. Microsphere droplet outlet; 10. Continuous phase inlet; 11. Dispersed phase inlet; 12. Magnetic response microsphere emulsion droplet. Detailed Implementation

[0042] It should be understood that the described embodiments are merely some, not all, of the embodiments in this application. All other embodiments obtained by those skilled in the art based on the embodiments in this application without inventive effort are within the scope of protection of this application.

[0043] In the following description, when referring to the accompanying drawings, the same numbers in different drawings denote the same or similar elements unless otherwise indicated. The embodiments described in the following exemplary embodiments do not represent all embodiments consistent with this application. Rather, they are merely examples of apparatuses and methods consistent with some aspects of this application as detailed in the appended claims.

[0044] In the description of this application, it should be understood that the terms "first," "second," etc., are used for descriptive purposes only and should not be construed as indicating or implying relative importance. Those skilled in the art can understand the specific meaning of the above terms in this application based on the specific circumstances. Furthermore, in the description of this application, unless otherwise stated, "multiple" refers to two or more. "And / or" describes the relationship between related objects, indicating that three relationships can exist. For example, A and / or B can represent: A existing alone, A and B existing simultaneously, or B existing alone. The character " / " generally indicates that the preceding and following related objects are in an "or" relationship.

[0045] Unless otherwise specified, the techniques or conditions described in the examples shall be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased through legitimate channels. Unless otherwise specified, the experimental methods in the following examples are conventional methods. Unless otherwise specified, the experimental materials used in the following examples are all commercially available products.

[0046] The clinical translation of magnetically responsive drug-loaded microspheres is severely hampered by the lack of practical processes capable of high-throughput, controllable preparation of uniform microspheres. While the preparation of monodisperse microspheres based on microfluidic technology is currently recognized as an advanced method, its industrialization faces a core bottleneck: throughput and flexibility cannot be simultaneously achieved. Traditional chip fabrication methods, such as soft lithography, are time-consuming, difficult to scale up in parallel, and chip materials (such as PDMS) are easily swollen by organic solvents, resulting in low yields and poor process stability. This makes the formulation screening and process optimization of magnetic bead-loaded microspheres inefficient, failing to meet the needs of actual R&D and production.

[0047] 3D printing technology, especially high-precision photopolymerization technology, offers a completely new approach to solving the aforementioned problems in one go. It not only frees us from the constraints of molds and enables the rapid fabrication of complex three-dimensional microstructures, but also makes it possible to design integrated, multi-parallel droplet generation units, thereby achieving high throughput from the outset. However, currently, this technological advantage has not been systematically applied to construct a high-throughput, high-stability integrated microfluidic production platform specifically designed for magnetic bead-loaded drug microspheres.

[0048] This invention aims to solve three core challenges in the preparation of magnetically responsive drug-loaded microspheres in existing technologies: 1) Inhomogeneous magnetic core size and easy agglomeration—Magnetic nanoparticles (such as Fe3O4) and their polymer composite microspheres prepared by traditional chemical coprecipitation-polymerization coating methods have a wide particle size distribution (large Span value), inhomogeneous magnetic response, and are prone to magnetic and physical agglomeration during preparation and storage, affecting the stability of subsequent drug loading and application; 2) Low production efficiency and poor uniformity of drug-loaded microspheres—Although conventional microfluidic technology can produce… While microspheres with good dispersibility can be prepared, their single-channel throughput is extremely low, making it difficult to meet the needs of rapid formulation screening and small-scale preparation of drug-loaded microspheres. Microspheres prepared by traditional batch emulsification methods (such as emulsification-solvent evaporation methods) have a wide particle size distribution and poor batch reproducibility. 3) The integration process of magnetic response and drug-loading function is cumbersome: Existing technologies usually require the synthesis of magnetic particles first, and then the encapsulation of them in microspheres or surface modification through multiple processes. The process is complex, has poor controllability, and makes it difficult to achieve precise and efficient integration of magnetic response characteristics and drug sustained-release performance.

[0049] Therefore, this invention provides a method for preparing magnetically responsive drug-loaded microspheres based on high-throughput microfluidic chips. This method combines highly uniform magnetic beads with high-throughput, precisely controlled microfluidic molding technology, achieving efficient, controllable, and large-scale preparation of magnetically responsive drug-loaded microspheres. It can stably and efficiently produce magnetically responsive drug-loaded microspheres, which has urgent practical significance and important application value for overcoming the bottleneck of large-scale preparation of targeted drug delivery systems.

[0050] This application discloses a method for preparing magnetically responsive drug-loaded microspheres based on a high-throughput microfluidic chip. For example... Figure 1 As shown, the method for preparing magnetically responsive drug-loaded microspheres based on high-throughput microfluidic chips includes the following steps: S1. Preparation of magnetic core: Using suspension polymerization, magnetic nanoparticles were used as magnetic cores, and organic polymers were used to modify the surface of the magnetic cores to prepare modified magnetically responsive composite particles.

[0051] S2. Preparation of drug-loaded microsphere precursor solution: Prepare an organic phase containing magnetically responsive composite particles, biodegradable polymer materials and optional therapeutic drugs as the magnetically responsive dispersed phase; prepare an aqueous solution containing surfactants as the continuous phase.

[0052] S3. Fabrication of high-throughput microfluidic chip: Fabrication of an integrated disk-type high-throughput microfluidic chip with multiple parallel microsphere forming units.

[0053] S4. Preparation of microsphere precursor: The magnetically responsive dispersed phase and the continuous phase prepared in step S2 are pumped into the chip prepared in step S3 at a specific flow rate ratio to generate monodisperse oil-in-water (O / W) emulsion droplets in each microsphere forming unit.

[0054] S5. Microsphere curing and post-treatment: Collect emulsion droplets, cure by evaporation of organic solvent, wash and freeze-dry to obtain solid magnetically responsive drug-loaded microspheres.

[0055] This invention utilizes an improved suspension polymerization method and surface functionalization modification to prepare magnetic cores with excellent monodispersity, high stability, and resistance to aggregation. This lays a solid foundation for constructing drug-loaded microspheres with uniform magnetic response, overcoming the shortcomings of traditional methods that produce magnetic particles with wide particle size distribution and easy aggregation. Furthermore, it innovatively employs an integrated, modular, parallel, high-throughput microfluidic chip manufactured using high-precision technology, integrating tens to thousands of microsphere-forming units onto a single chip. This achieves a breakthrough from low throughput in single channels to large-scale parallelization, significantly improving the production efficiency of monodisperse drug-loaded microspheres and solving the problem of low throughput in traditional microfluidic technologies. To address the bottleneck issue, this method utilizes the laminar shear principle of microfluidic technology and the precision machining consistency of chips to generate water-in-oil emulsion droplet droplet size distribution variation coefficients of less than 5%. The resulting solid microspheres exhibit high monodispersity and excellent batch reproducibility, far exceeding microspheres prepared by traditional batch emulsification methods. Furthermore, magnetic composite particles are directly dispersed in the drug-loaded polymer organic phase, and a "magnetic bead-drug-polymer" composite microsphere precursor is formed in one step using a microfluidic chip. This simplifies the traditional multi-step discrete magnetic functionalization and drug loading process, achieving efficient and precise integration of magnetic response characteristics and drug loading function, with a simple and controllable process flow.

[0056] In some embodiments of the present invention, in step S1, magnetic nanoparticles (magnetic beads) can be prepared by co-precipitation, thermal decomposition or hydrothermal method.

[0057] Preferably, the magnetic nanoparticles include one or a combination of the following materials: Fe3O4 and Fe2O3.

[0058] Furthermore, the particle size range of the magnetic nanoparticles is 5nm-1000nm.

[0059] In some embodiments of the present invention, in step S1, the organic polymer includes one or a combination of the following materials: oleic acid (OA), polystyrene (PS), polyacrylonitrile (PAN), and alkyl silane coupling agent.

[0060] Preferably, after the surface of the magnetic core is modified with an organic polymer, the thickness of the organic polymer modification layer ranges from 2 nm to 50 nm.

[0061] In this invention, the organic polymer modification layer can be used to improve the dispersion stability of the magnetic core, biocompatibility, or to provide subsequent functional groups.

[0062] In some embodiments of the present invention, in step S1, suspension polymerization can be achieved by controlling the polymerization temperature, stirring rate and reaction medium.

[0063] Preferably, the reaction temperature of the suspension polymerization method is 60℃-85℃, the stirring rate is 300rpm-1000rpm, and the reaction time is 2h-8h.

[0064] In this invention, magnetic beads with good monodispersity can be prepared by using an improved suspension polymerization method.

[0065] This invention prepares magnetically responsive composite particles using an improved suspension polymerization method. Compared to conventional oleic acid-modified magnetic nanoparticles, it effectively solves the problems of core dispersion and agglomeration. Conventional oleic acid-modified magnetic nanoparticles mainly provide surface hydrophobicity, but when co-dissolved with polymeric materials (such as PLGA) in the subsequent process, the magnetic particles may still be unevenly distributed or agglomerated within the microspheres due to interfacial compatibility issues. In contrast, the "suspension polymerization coating" process of this invention forms a thicker, more stable polymer shell on the surface of the magnetic nanoparticles, which is more compatible with the subsequent drug-loaded polymer matrix (such as PLGA). This fundamentally ensures the long-term stability and monodispersity of the magnetic core in the subsequent "magnetically responsive dispersed phase," avoiding agglomeration during the microfluidic process and within the final microspheres. This is a key prerequisite for obtaining high magnetic response uniformity and reproducibility.

[0066] Furthermore, this invention prepares magnetically responsive composite particles through an improved suspension polymerization method. Compared to conventional oleic acid-modified magnetic nanoparticles, it has the scalability of a functional platform: through suspension polymerization, this invention can flexibly select monomers with different functional groups (such as carboxyl and amino groups) to introduce active sites into the magnetic core. This allows the magnetic beads of this invention to not only physically encapsulate but also chemically couple drugs, targeting molecules, or other functional units, achieving a multifunctional integrated solution of "magnetic response + active targeting + sustained release". In contrast, conventional oleic acid-modified magnetic nanoparticles only have basic magnetic response functions.

[0067] In some embodiments of the present invention, in step S2, the biodegradable polymeric material includes one or a combination of the following materials: polylactic acid-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), gelatin, and chitosan.

[0068] Preferably, in the "magnetic bead-polymer" composite organic phase, the mass ratio of the magnetically responsive composite particles to the biodegradable polymer material is 1:5 to 1:100.

[0069] It should be noted that the specific ratio of magnetically responsive composite particles to biodegradable polymer materials can be adjusted according to the required magnetic response intensity and drug loading.

[0070] In some embodiments of the present invention, in step S2, the organic solvent of the magnetically responsive dispersed phase includes one or a combination of the following: dichloromethane (DCM), chloroform, ethyl acetate (EA), and N,N-dimethylformamide (DMF).

[0071] Specifically, the present invention can uniformly disperse the modified magnetically responsive composite particles obtained in step S1 in an organic solvent containing biodegradable polymer materials to form a "magnetic bead-polymer" composite organic phase, and use this as the magnetically responsive dispersion phase.

[0072] In some embodiments of the present invention, in step S2, the therapeutic drug includes one or a combination of the following: chemotherapy drugs, antibiotics, peptides, proteins, and nucleic acid drugs; wherein, the chemotherapy drugs include, but are not limited to, doxorubicin, paclitaxel, etc.

[0073] In some embodiments of the present invention, in step S2, the concentration of the surfactant in the continuous phase is 0.1% to 10% (w / v), preferably 0.5% to 5% (w / v).

[0074] The concentration of the surfactant in the continuous phase is a mass / volume concentration, that is, the ratio of solute mass (w) to solution volume (v). For example, 1% (w / v) means that 1 gram of solute is dissolved in 100 ml of solution.

[0075] Preferably, the surfactant is polyvinyl alcohol (PVA).

[0076] In some embodiments of the present invention, in step S2, an inorganic salt or a viscosity modifier may be added to the continuous phase to regulate the interfacial tension and system stability; wherein, the inorganic salt may be sodium chloride, and the viscosity modifier may be glycerol.

[0077] In some embodiments of the present invention, step S3, the design and fabrication of the high-throughput microfluidic chip includes the following steps: S31) Design a high-throughput microfluidic chip and its microsphere forming unit.

[0078] The S32 adopts a modular parallel design and integrates dozens to thousands of microsphere forming units with identical structures to form a high-throughput microfluidic chip.

[0079] S33) Slice the chip structure to the required processing layer thickness.

[0080] S34) Chip processing, including but not limited to high-throughput microfluidic chips processed by technologies such as surface projection micro-stereolithography (PμSL) 3D printing, laser etching, injection molding, and PDMS molding, followed by cleaning.

[0081] S35) A post-processing step that modifies the surface properties of the shaped chip.

[0082] In some embodiments of the present invention, in step S31, the microsphere forming unit structure includes, but is not limited to, T-type, flow focusing type, coaxial ring type or Y-type channel, and the channel characteristic size is 20-500μm, which can generate controllable microspheres with a particle size of 20-300μm.

[0083] In some embodiments of the present invention, in step S32, the modular parallel design can adopt not only a "disk array", but also a "tree-like split-and-merge" or "array matrix" layout.

[0084] Furthermore, the spacing between adjacent microspheres forming units is ≥1 mm to avoid fluid coupling, and the single-chip integration density can reach tens or even thousands of units.

[0085] Preferably, the number of microsphere forming units is 100 to 10,000.

[0086] For example, in one embodiment of the invention, such as Figures 2-4 As shown, the modular parallel design adopts a disk array, and the microsphere forming unit structure is a coaxial ring channel with a channel feature size of 20-500μm. It can be formed into a highly integrated chip by arranging hundreds to thousands of microsphere forming units in a circle and expanding concentrically.

[0087] like Figure 2-4 As shown, the high-throughput microfluidic chip in this embodiment includes a chip substrate 1 and multiple microsphere forming units disposed within the chip substrate 1. Each microsphere forming unit includes a continuous phase inlet 2, a dispersed phase inlet 3, a microsphere droplet forming area 4, and a microsphere droplet collecting area 5. The continuous phase inlet 2 and the dispersed phase inlet 3 are designed as coaxial annular channels and are connected via an internal channel to form the microsphere droplet forming area 4. The microsphere droplet forming area 4 is used to generate magnetically responsive microsphere emulsion droplets 12. The microsphere droplet forming area 4 is connected to the microsphere droplet collecting area 5 via a microsphere droplet main flow channel 8. The microsphere droplet collecting area 5 is connected to the microsphere droplet outlet 9. The continuous phase inlet 2 of each microsphere forming unit is connected to the continuous phase main flow channel 6, and the dispersed phase inlet 3 of each microsphere forming unit is connected to the dispersed phase main flow channel 7. The continuous phase main flow channel 6 is connected to the continuous phase inlet 10, and the dispersed phase main flow channel 7 is connected to the dispersed phase inlet 11.

[0088] In some embodiments of the present invention, in step S33, the minimum printed layer thickness of the chip structure is 5-40 μm.

[0089] In some embodiments of the present invention, the chip material is a hydrophobic photosensitive resin or a biocompatible resin that is resistant to organic solvents and can maintain structural stability in the range of 0-200°C; wherein, hydrophobic photosensitive resins that are resistant to organic solvents include HTL and TOUGH series, and biocompatible resins include BIO series.

[0090] The chip material used in this invention broadens the range of biodegradable polymers and organic solvents that can be used for drug delivery, and improves the stability and reliability of the preparation process.

[0091] In some embodiments of the present invention, step S35, the post-treatment of modifying the surface properties of the shaped chip includes one or a combination of the following processes: oxygen plasma treatment, UV-ozone curing, chemical vapor deposition (CVD) of fluorosilane, grafting of hydrophilic / hydrophobic polymer brushes and hydrogen peroxide immersion, so as to achieve tunable chip surface energy and thus adapt to the wetting requirements of different dispersed phases and continuous phases.

[0092] In this invention, the overall innovation of chip structure, materials and fabrication process brings high throughput, high compatibility and high stability. Compared with traditional chip bonding structures (such as PDMS-glass) and no targeted design for organic solvent systems, this invention adopts a disk array integrated design, hydrophobic photosensitive resin that can withstand organic solvents and surface projection micro-stereolithography (PμSL) 3D printing for integrated molding.

[0093] Thus, this invention achieves a simultaneous breakthrough in throughput and uniformity: the disk array design of this invention, combined with 3D printing precision manufacturing, enables ultra-high density parallel integration of thousands of units. More importantly, the integrated printed flow channels have extreme consistency in size and surface properties, which ensures a highly balanced distribution of inlet pressure and flow rate for all parallel units. Compared with the uneven distribution and merging that may exist in traditional piecewise bonding structures, the chip of this invention can achieve an extremely high throughput of 30 g / h while still maintaining a high degree of monodispersity of microsphere size (CV < 10%, Span value < 0.3). High throughput and high uniformity are often contradictory in traditional microfluidics, but the solution of this invention solves this contradiction synergistically through unique chip design and manufacturing process.

[0094] Secondly, the chip of this invention has excellent compatibility and process stability with organic solvent systems: the solution of this invention clearly uses organic solvents such as ethyl acetate to dissolve commonly used biodegradable polymers such as PLGA / PLA. Traditional PDMS chips would be damaged by swelling in such solvents. However, the solvent-resistant photosensitive resin and 3D printing process selected in this invention enable the chip to operate stably in an organic-aqueous microfluidic system for a long time. This is a key breakthrough in applying microfluidic technology to the preparation of actual drug-loaded microspheres (which widely use organic solvents).

[0095] In addition, the chip structure, materials and manufacturing process of the present invention can simplify the process and improve reliability: The integrated 3D printed chip of the present invention avoids the multiple complex steps required by traditional soft lithography, such as mold making, mold flipping, and plasma bonding, and realizes rapid iteration of "design-printing-use". This not only shortens the chip manufacturing cycle, but also eliminates the risks of fluid leakage and uneven pressure that may exist at the bonding interface, and improves the reliability and batch stability of the entire manufacturing process.

[0096] In some embodiments of the present invention, in step S4, the specific flow rate ratio refers to the flow rate ratio between the magnetically responsive dispersed phase and the continuous phase. The flow rate ratio between the magnetically responsive dispersed phase and the continuous phase can be 1:5 to 1:50, preferably 1:10 to 1:30; the particle size distribution variation coefficient of the generated emulsion droplets is less than 10%.

[0097] It should be noted that the flow rate ratio of the magnetically responsive dispersed phase to the continuous phase can be optimized and adjusted according to the target microsphere particle size, emulsion stability, and yield requirements.

[0098] In this invention, the integrated chip ensures balanced inlet pressure and flow rate of each parallel unit through a common inlet distribution channel.

[0099] Within each parallel-arranged microsphere forming unit, the relative magnetic response dispersed phase is continuously sheared to efficiently and synchronously generate a large number of monodisperse, oil-in-water (O / W) emulsion droplets encapsulating carboxyl magnetic beads.

[0100] The shearing process is a laminar flow, and the droplets break apart through the combined action of the viscous shear force and interfacial tension of the continuously magnetically responsive dispersed phase. The resulting oil-in-water (O / W) emulsion droplets have a particle size distribution variation coefficient (CV value) of less than 5%, exhibiting high monodispersity. The droplet size range is typically 20 μm to 200 μm, which can be precisely controlled by adjusting the two-phase flow rate, viscosity, and microchannel size of the microsphere forming unit.

[0101] In some embodiments of the present invention, stabilizers may be added to the continuous phase or the pH value may be adjusted to further improve the stability of the emulsion during collection and subsequent curing processes; wherein, stabilizers include, but are not limited to, sodium alginate, methylcellulose, polyvinyl alcohol, etc.

[0102] In some embodiments of the present invention, in step S5, the emulsion droplets are subjected to gentle stirring to evaporate the organic solvent and solidify into spheres.

[0103] Preferably, the organic solvent evaporation curing is carried out at a stirring rate of 50-300 rpm for 1-24 hours.

[0104] It should be noted that the stirring rate and duration can be set according to the type of organic solvent, boiling point, and microsphere particle size.

[0105] Furthermore, the evaporation of organic solvents and the prevention of drug oxidative degradation can be accelerated by vacuum assistance, heating (at a temperature lower than the glass transition temperature of the polymer), or by introducing an inert gas (such as nitrogen) into the curing system.

[0106] In some embodiments of the present invention, in step S5, the washing step may be performed using deionized water, phosphate buffered saline (PBS), or a dilute solution of surfactant, and the purpose of repeated centrifugation or filtration washing is to thoroughly remove residual surfactant, unencapsulated drug, and solvent.

[0107] In some embodiments of the present invention, in step S5, freeze drying is divided into a pre-freezing stage and a main drying stage. The pre-freezing temperature is below -40°C, the cold trap temperature in the main drying stage is below -50°C, the vacuum degree is below 10Pa, and the duration is usually 24-48h, so as to obtain a solid microsphere powder with a loose structure and good flowability.

[0108] In this invention, after the emulsion droplets are solidified into spheres and freeze-dried, the resulting magnetically responsive drug-loaded microspheres have a controllable average particle size, high drug encapsulation efficiency, and adjustable drug loading capacity as needed. They also exhibit rapid response under an external magnetic field.

[0109] This embodiment also proposes a magnetically responsive drug-loaded microsphere, which is prepared by the above method. The magnetically responsive drug-loaded microsphere has superparamagnetism, its saturation magnetization is not less than 1.2 emu / g, its coercivity is close to zero, and its particle size distribution Span value is not greater than 0.3.

[0110] Specifically, this invention uses the model drugs naltrexone and curcumin as examples to demonstrate the versatility and effectiveness of this method in encapsulating drugs with different properties.

[0111] Naltrexone magnetic bead-loaded microspheres are a smart delivery system combining magnetic targeting and sustained drug release. They are fabricated by encapsulating naltrexone and magnetic nanoparticles within biodegradable polymer microspheres. Guided by an external magnetic field, this system can precisely target specific areas (such as the brain or liver) and achieve long-term sustained drug release, significantly improving the efficacy and patient compliance of naltrexone in addiction treatment while effectively reducing systemic toxicity. This provides an innovative solution for the precise and long-term treatment of opioid and alcohol dependence.

[0112] Curcumin magnetically responsive drug-loaded microspheres are an innovative formulation prepared using the method of this invention. By co-encapsulating the hydrophobic drug curcumin with uniform magnetic nanoparticles in a biodegradable polymer matrix such as PLGA, it effectively solves the core problems of poor water solubility, rapid in vivo metabolism, and low bioavailability of curcumin. With the navigation capability of an external magnetic field, these microspheres can achieve targeted delivery and enrichment of the drug at tumor or inflammatory sites, thereby significantly enhancing its anticancer and anti-inflammatory efficacy and reducing toxic side effects on normal tissues. This provides an efficient and controllable delivery platform for expanding the application of curcumin in targeted therapy.

[0113] The method of the present invention will be described below with reference to specific embodiments.

[0114] Example 1 (S1) Fabrication of the magnetic core A modified suspension polymerization method was used to prepare magnetic beads with good monodispersity.

[0115] Specifically, it includes: a) Preparation of magnetic nanoparticles: Superparamagnetic nanoparticles (including but not limited to Fe3O4 and Fe2O3) with a particle size of 5–1000 nm are prepared by co-precipitation, thermal decomposition or hydrothermal method, wherein high temperature thermal decomposition method is preferred to generate Fe3O4 nanoparticles with high crystallinity and uniform particle size.

[0116] b) Modification of magnetic nanoparticles: In order to improve the colloidal stability of magnetic nanoparticles and provide them with polymer grafting sites, it is necessary to perform preliminary surface modification immediately.

[0117] Specifically, during the synthesis process, surface modifiers are added to the reaction system. These surface modifiers include, but are not limited to, oleic acid (OA), trioctyl phosphate (TOPO), and polyethylene glycol (PEG), with oleic acid (OA) being the preferred option. Through ligand exchange or chemisorption, the carboxyl terminus of oleic acid is firmly anchored to the Fe3O4 surface, with the hydrophobic alkyl chain pointing outwards, thereby obtaining oleic acid-modified magnetic nanoparticles (OA-Fe3O4) that are highly oil-soluble and resistant to oxidation.

[0118] c) Suspension polymerization coating: Using the modified magnetic nanoparticles as the magnetic core, the mixture is reacted at 60–85℃ and 300–1000 rpm for 1–3 h. An organic polymer modification layer with a thickness of 2–50 nm is then coated onto the surface via suspension polymerization to further improve the dispersion stability and biocompatibility of the magnetic core and provide subsequent functionalization groups. Ultimately, a uniformly structured and stable magnetically responsive composite particle is obtained. The SEM image of the magnetic core is shown below. Figure 5 As shown.

[0119] The above steps are the foundation for ensuring the uniform dispersion of magnetic nanoparticles in the subsequent organic polymerization system.

[0120] (S2) Preparation of drug-loaded microsphere precursor solution a) Preparation of the magnetically responsive dispersed phase: The magnetically responsive composite particles obtained in step S1, modified with organic polymer surfaces, are uniformly dispersed in an organic solvent containing a selected biodegradable polymer material at a precise mass ratio. The precise mass ratio is between 1:5 and 1:100 for the magnetic nanoparticles and the biodegradable polymer material. The biodegradable polymer material includes, but is not limited to, polylactic-co-glycolic acid copolymer (PLGA), polylactic acid (PLA), polycaprolactone (PCL), gelatin, or chitosan. The organic solvent includes, but is not limited to, dichloromethane (DCM), chloroform, ethyl acetate, and N,N-dimethylformamide (DMF). A highly homogeneous "magnetic bead-polymer" composite organic phase is formed by mechanical stirring, ultrasonic treatment, or mortar and pestle grinding. Depending on the drug loading requirements, the therapeutic drug can be simultaneously dissolved or dispersed in this composite organic phase, achieving the initial integration of the magnetic carrier and the drug. The required therapeutic drugs include, but are not limited to, naltrexone, curcumin, leuprorelin, doxorubicin, paclitaxel, antibiotics, peptides, proteins or nucleic acid drugs. In this specific regimen, naltrexone and curcumin are preferred as the encapsulated drugs.

[0121] b) Continuous phase preparation: Prepare an aqueous solution containing a surfactant as the continuous phase. The interfacial tension and rheological properties of the system can be controlled by adding sodium chloride or glycerol to ensure the stability and monodispersity of droplet formation during subsequent microfluidic processes. The surfactant concentration range is 0.1% to 10% w / v, preferably 0.5%-5% w / v.

[0122] (S3) Design and fabrication of high-throughput microfluidic chips a) Microsphere forming unit structure design: The microsphere forming unit can adopt various flow channel configurations. Flow channel structures include, but are not limited to, T-type, flow focusing type, coaxial ring type, or Y-type channels. The characteristic dimensions of the flow channel structure (such as channel width or diameter) are controlled within the range of 20-500 μm, thereby precisely controlling the particle size of the generated microspheres between 20-300 μm to meet the differentiated requirements of different drug delivery systems for microsphere size.

[0123] b) Modular Parallel Integration Design: The chip employs a "tree-like split-and-merge" or "array-like matrix" layout to achieve high-throughput parallel droplet generation. The "tree-like split-and-merge" structure achieves uniform fluid distribution and collection through hierarchical flow channels, while the "array-like matrix" uses regularly arranged independent generation units. A spacing of at least 1 mm is maintained between all parallel units to effectively avoid fluid interference and pressure coupling between adjacent units, ensuring consistent fluid behavior within each unit. Through this design, a single chip can integrate tens to thousands of microsphere forming units, maintaining good droplet monodispersity while ensuring high throughput.

[0124] d) 3D Printing Process Parameter Settings: Advanced additive manufacturing technologies such as high-precision surface projection micro-stereolithography (PμSL) are used to fabricate the chip. The printing layer thickness is set to 5-40 μm to achieve high-resolution molding of the microchannel structure. The printing material is a hydrophobic photosensitive resin (such as HTL, TOUGH series) that can withstand organic solvents such as dichloromethane, or a resin with good biocompatibility (such as BIO series). This material system can maintain structural stability within a temperature range of 0-200 ℃, ensuring that the chip does not deform or degrade in performance during the subsequent fabrication of drug-loaded microspheres.

[0125] d) Post-processing of chip surface properties: To adapt to the wettability requirements of different dispersed and continuous phases, surface properties need to be adjusted after chip molding. Post-processing methods include, but are not limited to: oxygen plasma treatment to enhance surface hydrophilicity; UV-ozone curing to achieve surface functionalization; chemical vapor deposition (CVD) of fluorosilanes to construct hydrophobic surfaces; or grafting hydrophilic / hydrophobic polymer brushes through surface-initiated polymerization, thereby achieving flexible adjustment of chip surface energy and optimizing interfacial behavior and generation stability in different droplet generation systems.

[0126] (S4) High-throughput microfluidic preparation of precursors for naltrexone / curcumin drug-loaded microspheres Using a monolithically molded high-throughput microfluidic chip, the magnetically responsive naltrexone dispersed phase or magnetically responsive curcumin dispersed phase prepared in step S2 is pumped into the chip prepared in step S3 at a specific flow rate ratio to the continuous phase. The specific flow rate ratio refers to the ratio of the flow rate of the naltrexone / curcumin magnetically responsive dispersed phase (Qd) to the continuous phase (Qc) (Qd / Qc), which ranges from 1:5 to 1:50, preferably from 1:10 to 1:30. This ratio is a core process parameter for controlling droplet formation behavior and particle size: when the flow rate ratio is too low (i.e., the continuous phase flow rate is relatively high), the shear force is enhanced, which is beneficial for generating smaller droplets with better dispersion; conversely, if the flow rate ratio is too high, the shear force is insufficient, which easily leads to droplet coalescence or the formation of ribbon-like flows with uneven particle size. The specific ratio needs to be dynamically optimized and adjusted according to the target microsphere particle size, emulsion stability, and yield requirements. The integrated chip distributes flow channels through a meticulously designed tree-like or grid-like common inlet. Utilizing the principle of fluid resistance balance, it ensures a highly uniform pressure and flow distribution at the inlet of each parallel microsphere forming unit, thereby guaranteeing that thousands of units can simultaneously generate droplets with extremely high particle size uniformity (CV value <5%). The shearing process occurs within the microchannel, with a stable laminar flow pattern (Reynolds number Re << 1). Droplet breakage is mainly dominated by the competitive action of viscous shear force between the continuous and dispersed phases and the interfacial tension between the two phases. By precisely controlling the flow rate, viscosity, and interfacial tension of the two phases, a smooth transition from trickle flow mode to jet flow mode can be achieved, thus obtaining monodisperse droplets.

[0127] The generated oil-in-water (O / W) emulsion droplets exhibit a stable coefficient of variation (CV) of less than 5%, demonstrating high monodispersity. Droplet size can be precisely controlled within a wide range of 20 μm to 200 μm. To address potential interfacial instability caused by pharmaceuticals or polymeric materials, a small amount of polymeric stabilizer (such as 0.5%-2% sodium alginate, methylcellulose, or polyvinyl alcohol) can be added to the continuous phase. This increases the viscosity of the aqueous phase and forms a protective layer at the interface, further enhancing the kinetic stability of the emulsion during collection, transfer, and subsequent solvent evaporation and solidification, thus preventing droplet coalescence. Within each parallel-arranged microsphere-forming unit, the continuous phase undergoes shearing, efficiently and synchronously generating a large number of monodisperse oil-in-water (O / W) emulsion droplets encapsulated with carboxyl magnetic beads.

[0128] (S5) Microsphere curing and post-treatment The emulsion droplets were collected, and the organic solvent was evaporated under gentle stirring to solidify into spheres. Following washing and freeze-drying, solid magnetically responsive drug-loaded microspheres were finally obtained. The organic solvent evaporation and solidification process was carried out under gentle stirring (stirring rate range of 50-300 rpm) for a duration typically of 1-24 hours, depending on the type, boiling point, and microsphere particle size of the organic solvent. Optionally, solvent evaporation and effective prevention of oxidative degradation of photosensitive drugs such as curcumin can be accelerated by vacuum assistance, heating (at a temperature below the polymer's glass transition temperature), or by introducing an inert gas (such as nitrogen) into the solidification system.

[0129] The washing step involves multiple centrifugations or filtrations using deionized water, phosphate-buffered saline (PBS), or a diluted surfactant solution to thoroughly remove residual surfactants, unencapsulated drugs, and solvents.

[0130] The freeze-drying conditions include: a pre-freezing temperature below -40°C, a cold trap temperature below -50°C during the main freeze-drying stage, a vacuum level below 10 Pa, and a duration typically of 24-48 hours, to obtain a loosely structured, highly flowable solid microsphere powder. The resulting magnetically responsive drug-loaded microspheres have a controllable average particle size, high drug encapsulation efficiency, adjustable drug loading, and rapid response under an external magnetic field.

[0131] The high-throughput microfluidic chip developed in this invention can achieve a single-chip production capacity of 30 g / h of magnetically responsive microspheres, which significantly exceeds the production limitations of traditional single-channel microfluidic chips in the preparation of drug-loaded microspheres.

[0132] The morphology of the prepared blank magnetically responsive microspheres was observed using scanning electron microscopy (SEM), such as... Figure 6 As shown in the figure, the prepared magnetically responsive microspheres have a smooth surface and uniform particle size distribution. The magnetic properties of the magnetically responsive microspheres were tested as follows: Figure 8 As shown, Figure 8 The left image shows the microspheres suspended uniformly in the vial without a magnet, while the right image shows the microspheres resting on the side of the magnet with a magnet.

[0133] SEM images of the naltrexone magnetically responsive microspheres and the magnetically responsive curcumin microspheres prepared in this invention are as follows: Figure 10 , 11 It can also be seen that the prepared magnetically responsive microspheres have a smooth surface and uniform particle size distribution.

[0134] Figure 9The particle size distribution of the magnetically responsive microspheres is shown, with an average particle size of 86.77 μm, D10 = 75.75 μm, D50 = 86.77 μm, D90 = 99.94 μm, a Span value of 0.278, and a coefficient of variation (CV) of 10%. The particle size distribution data indicates that the magnetically responsive microspheres prepared using the high-throughput microfluidic chip provided by this invention have a very narrow particle size distribution, exhibiting excellent dispersibility. This is a key factor in ensuring uniform drug loading, controllable release behavior, and predictable in vivo efficacy.

[0135] Figure 7 The hysteresis loop demonstrates the typical superparamagnetic properties of the magnetically responsive microspheres. The curve exhibits a narrow "S" shape, with a saturation magnetization (Ms) of approximately 1.2 emu / g, closing near zero field. The coercivity (Hc) is almost zero, indicating that the material exhibits almost no remanence or coercivity after the removal of the external magnetic field, demonstrating excellent reversible magnetic response. This ensures that the prepared magnetically responsive microspheres can rapidly aggregate under an applied magnetic field and quickly redisperse after the magnetic field is removed, which is crucial for achieving magnetically targeted drug delivery and controlled release. This performance validates the reliability of the used magnetic core as an efficient and safe magnetically responsive medium in biomedical applications.

[0136] Therefore, the high-throughput microfluidic chip of the present invention effectively overcomes the problems of wide particle size distribution and poor batch repeatability commonly found in traditional preparation methods in the preparation of magnetically responsive microspheres, and also provides a feasible solution to the insufficient yield faced by existing microfluidic technologies.

[0137] The above description is merely a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.

Claims

1. A method for preparing magnetically responsive drug-loaded microspheres based on a high-throughput microfluidic chip, characterized in that, Includes the following steps: S1. Preparation of magnetic core: Using suspension polymerization, magnetic nanoparticles were used as magnetic cores, and organic polymers were used to modify the surface of the magnetic cores to prepare modified magnetically responsive composite particles. S2. Preparation of drug-loaded microsphere precursor solution: Prepare an organic phase containing the magnetically responsive composite particles, biodegradable polymer material and optional therapeutic drug as the magnetically responsive dispersed phase; prepare an aqueous solution containing surfactant as the continuous phase; S3. Fabrication of high-throughput microfluidic chip: Fabrication of an integrated disk-type high-throughput microfluidic chip with multiple parallel microsphere forming units; S4. Preparation of microsphere precursor: The magnetically responsive dispersed phase prepared in step S2 and the continuous phase are pumped into the chip prepared in step S3 at a specific flow rate ratio to generate monodisperse oil-in-water emulsion droplets in each microsphere forming unit. S5. Microsphere curing and post-treatment: Collect the emulsion droplets, cure by evaporation of organic solvent, wash and freeze-dry to obtain solid magnetically responsive drug-loaded microspheres.

2. The method according to claim 1, characterized in that, In step S1, the magnetic nanoparticles include one or a combination of the following: Fe3O4 and Fe2O3; Preferably, the magnetic nanoparticles have a particle size range of 5 nm to 1000 nm; Preferably, the organic polymer comprises one or a combination of the following: oleic acid, polystyrene, polyacrylonitrile, and alkyl silane coupling agent; Preferably, the reaction temperature of the suspension polymerization method is 60℃-85℃, and the stirring rate is 300rpm-1000rpm.

3. The method according to claim 1, characterized in that, In step S2, the biodegradable polymeric material includes one or a combination of the following: polylactic acid-glycolic acid copolymer, polylactic acid, polycaprolactone, gelatin, and chitosan; Preferably, the organic solvent of the magnetically responsive dispersion includes one or a combination of the following: dichloromethane, chloroform, ethyl acetate, and N,N-dimethylformamide; Preferably, the mass ratio of the magnetically responsive composite particles to the biodegradable polymer material is 1:5 to 1:

100.

4. The method according to claim 1, characterized in that, In step S2, the therapeutic drug includes one or a combination of the following: chemotherapy drugs, antibiotics, peptides, proteins, and nucleic acid drugs; Preferably, the concentration of the surfactant in the continuous phase is 0.1% to 10% (w / v). Preferably, the surfactant is polyvinyl alcohol.

5. The method according to claim 1, characterized in that, In step S3, the structure of the microsphere forming unit is a coaxial annular channel with a channel characteristic size of 20-500 μm; Preferably, the chip is manufactured using one or a combination of the following processes: surface projection micro-stereolithography 3D printing, laser etching, injection molding, and PDMS molding; Preferably, the number of microsphere forming units is 100 to 10,000, and multiple microsphere forming units are arranged in a circle and concentrically expanded to form a highly integrated chip; Preferably, the minimum printed layer thickness of the chip structure is 5-40 μm; Preferably, the chip is made of a hydrophobic photosensitive resin or a biocompatible resin that is resistant to organic solvents.

6. The method according to claim 1, characterized in that, Step S3 further includes a post-processing step of modifying the surface properties of the shaped chip; Preferably, the post-treatment includes one or a combination of the following: oxygen plasma treatment, UV-ozone curing, chemical vapor deposition of fluorosilane, grafting of hydrophilic / hydrophobic polymer brushes, and hydrogen peroxide immersion.

7. The method according to claim 1, characterized in that, In step S4, the flow rate ratio of the magnetically responsive dispersed phase to the continuous phase is 1:5 to 1:50; the particle size distribution variation coefficient of the generated emulsion droplets is less than 10%.

8. The method according to claim 1, characterized in that, In step S2, sodium alginate, polyvinyl alcohol, or methylcellulose is added to the continuous phase as a stabilizer.

9. The method according to claim 1, characterized in that, In step S5, the organic solvent evaporation and curing is carried out at a stirring rate of 50-300 rpm for 1-24 hours. Preferably, the evaporation of organic solvents is accelerated by vacuum assistance, heating, or the introduction of inert gas; Preferably, the freeze-drying is divided into a pre-freezing stage and a main drying stage. The pre-freezing temperature is below -40°C, and the cold trap temperature in the main drying stage is below -50°C, with a vacuum degree below 10 Pa.

10. A magnetically responsive drug-loaded microsphere, characterized in that, It is prepared by the method described in any one of claims 1 to 9.

Images