An ultrasonic-triggered controllable drug release carrier based on 3D printing microsphere array, system and preparation method and application thereof

Abstract

The present application relates to the field of biomedical engineering and drug delivery, and particularly relates to an ultrasound-triggered controllable drug release carrier based on 3D printed microsphere array, a system, and a preparation method and application thereof. The ultrasound-triggered controllable drug release system comprises a porous hollow microsphere array and a hydrogel matrix encapsulating the array, the porous hollow microsphere has a hollow cavity and a porous shell layer covering the hollow cavity, and the hydrogel matrix is a biocompatible thermosensitive hydrogel matrix. The present application can realize high customization according to clinical requirements by using two-photon polymerization (2PP) technology, and precisely design the size, pore size and array configuration of the microsphere, and in combination with high-intensity focused ultrasound (HIFU) technology, the microstructure of the porous hollow microsphere is changed by ultrasound to realize the precise spatiotemporal controllable drug release.

Description

Technical Field

[0001] This invention belongs to the field of drug delivery technology, specifically relating to an ultrasonically triggered controlled-release drug carrier based on a 3D-printed microsphere array, a system, its preparation method, and its application. Background Technology

[0002] In recent years, with the popularization of the concept of precision medicine, developing advanced platforms that can achieve personalized drug delivery to meet specific patient needs has become a research hotspot in the biomedical field. Controlled drug delivery systems can encapsulate therapeutic drugs in carriers, maintaining drug concentrations within the therapeutic window and confining their diffusion to the vicinity of target tissues, thereby improving efficacy while minimizing systemic toxicity.

[0003] Among various drug delivery systems, micron-sized spheres have attracted widespread attention due to their flexible drug loading capacity and good compatibility with a variety of active ingredients. However, traditional microsphere manufacturing methods (such as emulsification and spray drying) often suffer from insufficient structural control, making it difficult to produce microspheres with precisely defined pore structures and strict size control. This structural uncertainty directly leads to fluctuations in drug release profiles, making it difficult for researchers to accurately predict and control drug release kinetics, thus limiting their application in complex clinical scenarios.

[0004] To overcome the limitations of traditional manufacturing processes, two-photon polymerization (TPP) high-precision 3D micro / nano printing technology has emerged as a promising approach. TPP technology can fabricate complex microstructures at sub-micron resolution, allowing for the design and fabrication of hollow microspheres with precisely engineered, tunable surface pore sizes. While such precise structures offer the possibility of stable drug encapsulation, integrating these isolated microspheres into clinically applicable implantable devices requires embedding them in a suitable matrix material. Hydrogels, due to their high water content, extracellular matrix-like properties, and good biocompatibility, have become ideal matrices for encapsulating micro / nano devices.

[0005] In particular, hydrogels with thermosensitive properties can undergo a sol-gel transition at physiological temperatures, thereby forming a gel in situ at the implantation site and achieving efficient fixation of the microstructure array. Furthermore, the hydrogel network can also act as an additional physical diffusion barrier, significantly mitigating the initial "burst release" phenomenon of drugs and prolonging the effective treatment time.

[0006] Furthermore, static structures alone are insufficient to achieve true "on-demand release," requiring the drug delivery system to be able to combine with external stimuli to achieve remote release control.

[0007] Therefore, there is an urgent need for an integrated platform that combines precision-printed microarchitecture with a multi-element hydrogel matrix to achieve high-precision, on-demand drug release through non-invasive stimulation, meeting the application requirements of implantable bioelectronics and intelligent drug delivery systems. In particular, a platform that can balance the fidelity of complex microstructures, physiological stability, and efficient remote actuation capabilities is needed to meet the application requirements of next-generation precision medicine for controlled drug release. Summary of the Invention

[0008] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide an ultrasonically triggered controlled-release drug carrier, system and preparation method based on 3D printed microsphere array, to solve the problems of low manufacturing precision of drug carriers, difficulty in accurately controlling release kinetics and lack of non-invasive on-demand driving means in the prior art.

[0009] This carrier is printed with an array of hollow microspheres with adjustable surface pore size using two-photon polymerization and integrated into a biocompatible thermosensitive hydrogel. The microstructure is induced by ultrasonic stimulation to achieve efficient and precise on-demand drug release.

[0010] To achieve the above and other related objectives, the first aspect of this application provides an ultrasonically triggered controlled-release drug carrier based on a 3D-printed microsphere array. The carrier comprises a porous hollow microsphere array and a hydrogel matrix encapsulating the array. The porous hollow microsphere array is composed of a uniform arrangement of porous hollow microspheres. Each porous hollow microsphere has a hollow cavity and a porous shell covering the hollow cavity. The hollow cavity of the porous hollow microsphere is suitable for loading functional loading components.

[0011] A second aspect of the present invention provides a method for preparing the above-mentioned carrier, the method comprising the following steps:

[0012] 1) Hollow microspheres are printed on a substrate using 3D printing technology. After development and rinsing, a porous hollow microsphere array with micropores and uniformly arranged microspheres is obtained.

[0013] 2) Load the hollow microspheres from step 1) with functional loading components using the permeation method to obtain a drug-loaded microsphere array;

[0014] 3) The drug-loaded microsphere array is embedded in a thermosensitive hydrogel matrix and induced to form a gel to obtain an ultrasound-triggered controlled-release drug carrier.

[0015] In summary, this invention provides an ultrasonically triggered controlled-release drug carrier, system, preparation method, and application based on a 3D-printed microsphere array, and achieves the following beneficial effects:

[0016] 1) 2PP technology can be used to achieve a high degree of customization according to clinical needs, and to precisely design the hollow size, pore size and array configuration of microspheres;

[0017] 2) It uses materials with good biocompatibility, such as chitosan, which are suitable for implantable medical applications;

[0018] 3) Combining high-intensity focused ultrasound (HIFU) technology, an array of acoustic energy is non-invasively focused on the lesion. By adjusting ultrasound parameters (such as pulsed wave (PW) or continuous wave (CW) modes), the fracture of the microsphere interconnected scaffold or the structural rupture of the shell can be precisely induced, achieving precise spatiotemporal control of drug release;

[0019] 4) By adjusting the ultrasonic parameters, the release dynamics of different intensities can be regulated. Attached Figure Description

[0020] Figure 1 The image shows a scanning electron microscope (SEM) image of porous hollow microspheres with different micropore sizes (2 μm and 4 μm) in Example 1.

[0021] Figure 2 This is an optical microscope image of the 3×3×4 porous hollow microsphere array in Example 1.

[0022] Figure 3 This is a scanning electron microscope image of the porous microstructure of the hydrogel matrix cross-section in Example 2.

[0023] Figure 4 The graph shows the rheological characterization curves of the storage modulus (G') and loss modulus (G'') of the thermosensitive hydrogel in Example 2 as a function of temperature.

[0024] Figure 5 A schematic diagram illustrating the preparation and drug loading process of the ultrasonically triggered controlled drug release system based on a 3D-printed microsphere array in Example 3.

[0025] Figure 6 This is a comparison of the cumulative drug release curves of microsphere arrays with and without thermosensitive hydrogel encapsulation under simulated physiological conditions (37℃, 200 rpm).

[0026] Figure 7 This is a schematic diagram of the process of using ultrasound to achieve ultrasound-triggered controlled drug release in Example 3.

[0027] Figure 8 This is a comparison of the cumulative drug release kinetic curves of the microsphere array under different triggering conditions (continuous wave, pulse wave, static control, and pure heating) in Example 3. Detailed Implementation

[0028] The technical solution of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] Before further describing specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of the present invention is for describing specific embodiments and not for limiting the scope of protection of the present invention; in the specification and claims of the present invention, unless otherwise expressly stated in the text, the singular forms "a", "an" and "this" include the plural forms.

[0030] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this invention may be used to implement the present invention.

[0031] This application first provides an ultrasonically triggered controlled-release drug carrier based on a 3D-printed microsphere array. The carrier comprises a porous hollow microsphere array and a hydrogel matrix encapsulating the array. The porous hollow microsphere array is composed of a uniform arrangement of porous hollow microspheres. The porous hollow microspheres have a hollow cavity and a porous shell covering the hollow cavity. The hollow cavity of the porous hollow microspheres is suitable for loading functional loading components.

[0032] In this invention, the hollow cavity of the porous hollow microspheres is loaded with a functional loading component. Preferably, the functional loading component includes: a drug or protein factor, or a biological carrier; the functional loading component is used to achieve a therapeutic or release function under ultrasonic excitation.

[0033] In some embodiments of the present invention, the drugs or protein factors include, but are not limited to, antibacterial drugs, antitumor drugs, anti-inflammatory drugs, hemostatic and procoagulant components, and growth factors (such as VEGF, EGF, bFGF, etc.) for local repair and inflammation control. The biological carriers include, but are not limited to, exosomes, stem cell-derived secretions, and nucleic acid molecules (such as siRNA, mRNA), which are suitable for tissue regeneration or regulation of local immune responses.

[0034] In some embodiments, the mass ratio of the functional loading component to the porous hollow microspheres is 1:3 to 6. Preferably, the mass ratio of the functional loading component to the porous hollow microspheres can be 1:3, 1:4, 1:5, or 1:6.

[0035] In some embodiments, the mass percentage of the hydrogel matrix is ​​10% to 20% based on an ultrasound-triggered controlled-release drug carrier.

[0036] In some embodiments, the raw material for the porous shell comprises a polymeric material. Preferably, the polymeric material is selected from natural polymeric materials and / or artificially synthesized polymeric materials.

[0037] More preferably, the natural polymer material is selected from one or more of chitin, chitosan, alginate, and cyclodextrin.

[0038] More preferably, the synthetic polymer material is selected from one or more of the following: photosensitive resin (such as IP-S series photoresist), polyethylene glycol diacrylate (PEGDA), polylactic acid, polylactic acid-glycolic acid copolymer, polyisopropylacrylamide, polyvinylpyrrolidone, and polyethylene glycol-cholesterol copolymer.

[0039] In this application, the hollow inner cavity refers to the internal space surrounded by a shell (porous shell layer) made of polymer material.

[0040] In some embodiments, the diameter of the hollow inner cavity is 70~90 μm, which can be 70 μm, 80 μm, or 90 μm, preferably 80 μm.

[0041] In some embodiments, the outer diameter of the porous shell is 90~110 μm, which can be 90 μm, 100 μm, or 110 μm, preferably 100 μm.

[0042] In some embodiments, the pore size in the porous shell is 1 μm to 5 μm, and can be 1 μm, 2 μm, 3 μm, 4 μm, or 5 μm. Further, the porosity of the porous shell is 10% to 90%, preferably 45% to 85%.

[0043] In some embodiments, the specific surface area of ​​the porous hollow microspheres is 0.1~0.2 m². 2 / g. Preferably, the specific surface area of ​​the porous hollow microspheres can be 0.1~0.12m². 2 / g, 0.12~0.14m 2 / g, 0.14~0.16m 2 / g, 0.16~0.18m 2 / g, 0.18~0.2m 2 / g; more preferably, the specific surface area of ​​the porous hollow microspheres can be 0.168 m². 2 / g.

[0044] In some embodiments, the raw materials of the biocompatible thermosensitive hydrogel matrix include one or more combinations of methylcellulose (MC), quaternized chitosan (QCS), collagen hydrogel, chitosan, and β-glycerophosphate (β-GP).

[0045] Preferably, the biocompatible thermosensitive hydrogel matrix can be a methylcellulose (MC) / quaternized chitosan (QCS) composite hydrogel, collagen hydrogel, or chitosan / β-glycerophosphate (β-GP) composite hydrogel.

[0046] In this invention, the aforementioned hydrogel matrix can transform from a liquid state to a solid gel under physiological conditions, thereby achieving in-situ fixation and mechanical support for the microsphere array at the implantation site. It also acts as an additional physical diffusion barrier, effectively mitigating the initial burst release of drugs and prolonging the therapeutic window. Furthermore, the use of biocompatible materials enhances the self-degradation capacity of the drug delivery system, reducing the risk of inflammatory reactions caused by long-term placement in the human body.

[0047] In this invention, porous hollow microspheres are prepared by 3D printing of polymer materials. High-intensity focused ultrasound (HIFU) can be used as a non-invasive external triggering method to drive drug release by disrupting the pore structure of the porous hollow microspheres through acoustic stimulation. Acoustic stimulation induces significant rupture, gap formation, or displacement of the pore structure of the porous shell of the porous hollow microspheres, enabling on-demand and accelerated drug release through integrated ultrasound.

[0048] This invention also provides a method for preparing the above-mentioned drug delivery carrier, the method comprising the following steps:

[0049] 1) A porous hollow microsphere substrate was printed using 3D micro-nano printing technology. After development and rinsing, a porous hollow microsphere array with micropores and uniformly arranged microspheres was obtained.

[0050] 2) Load the porous hollow microspheres from step 1) with functional loading components using a permeation method to obtain drug-loaded microspheres;

[0051] 3) Drug-loaded microspheres are embedded in an array into a thermosensitive hydrogel matrix and induced to form a gel to obtain an ultrasound-triggered controlled-release drug carrier.

[0052] In this invention, in step 1), the porous hollow microsphere substrate is made of polymer material.

[0053] Preferably, the polymer material is selected from natural polymer materials and / or artificially synthesized polymer materials.

[0054] More preferably, the natural polymer material is selected from one or more of chitin, chitosan, alginate, and cyclodextrin.

[0055] More preferably, the synthetic polymer material is selected from one or more of the following: photosensitive resin (such as IP-S series photoresist), polyethylene glycol diacrylate (PEGDA), polylactic acid, polylactic acid-glycolic acid copolymer, polyisopropylacrylamide, polyvinylpyrrolidone, and polyethylene glycol-cholesterol copolymer.

[0056] In some embodiments, the 3D micro / nano printing technology can be two-photon polymerization technology. The method for preparing the porous hollow microspheres includes: cleaning the substrate (such as a glass slide) and treating it with oxygen plasma to increase the surface energy, then coating it with photoresist, performing three-dimensional exposure printing using a two-photon laser direct writing system, then washing away the uncured resin with a developer, and finally drying to obtain porous hollow microspheres.

[0057] Furthermore, the laser power of the 3D micro-nano printing is 100-140 mW, which can be 100 mW, 110 mW, 120 mW, 130 mW, or 140 mW; the scanning speed is 40000-60000 mm / s, which can be 40000 mm / s, 50000 mm / s, or 60000 mm / s.

[0058] Furthermore, the cleaning of the porous hollow microsphere substrate is performed using isopropanol, and the oxygen plasma treatment time is 200~400s, which can be 200s, 250s, 300s, 350s, or 400s.

[0059] Furthermore, development was performed using PGMEA (propylene glycol methyl ether acetate) developer for 15 minutes, followed immediately by rinsing with isopropanol to terminate the reaction and drying with nitrogen. In this application, PGMEA was used to remove uncured porous hollow microsphere substrate.

[0060] In this invention, in step 2), the permeation method can be a vacuum-assisted permeation method. Preferably, the vacuum-assisted permeation method specifically involves immersing porous hollow microspheres in a functional loading component solution, connecting a vacuum pump to perform multiple "vacuum-maintain-release" cycles to completely remove air from the porous hollow microsphere cavity and allow the drug solution to enter.

[0061] Furthermore, the functional loading components include: drugs, protein factors, or biological carriers.

[0062] Furthermore, the functional loading component can be a fluorescent tracer (such as rhodamine B), an antitumor drug (such as paclitaxel or doxorubicin), an anti-inflammatory drug, an anesthetic drug, or a tissue growth factor, etc.

[0063] Furthermore, the mass ratio of the functional loading component to the porous hollow microspheres is 1:3 to 6. Preferably, the mass ratio of the functional loading component to the porous hollow microspheres can be 1:3, 1:4, 1:5, or 1:6.

[0064] In this invention, in step 3), the raw materials of the thermosensitive hydrogel matrix include one or more combinations of methylcellulose (MC), quaternized chitosan (QCS), collagen hydrogel, chitosan, and β-glycerophosphate (β-GP).

[0065] Preferably, the biocompatible thermosensitive hydrogel matrix can be a methylcellulose (MC) / quaternized chitosan (QCS) composite hydrogel matrix, a collagen hydrogel matrix, or a chitosan / β-glycerophosphate composite hydrogel matrix.

[0066] In some embodiments, in the methylcellulose (MC) / quaternized chitosan (QCS) composite hydrogel matrix, the mass ratio of methylcellulose to quaternized chitosan can be 1~5:5~1; preferably, it can be 1:5, 2:4, 3:3, 4:2, or 5:1. Preferably, the solvent for the methylcellulose / quaternized chitosan composite hydrogel matrix is ​​PBS solution.

[0067] In some embodiments, the collagen in the collagen hydrogel matrix is ​​1% to 5% by mass. Preferably, the solvent for the collagen hydrogel matrix is ​​PBS solution.

[0068] In some embodiments, the mass ratio of chitosan to β-glycerophosphate (β-GP) composite hydrogel matrix is ​​1:2 to 5. Preferably, it can be 1:2, 1:3, 1:4, or 1:5.

[0069] Preferably, the solvent for the chitosan / β-glycerol phosphate (β-GP) composite hydrogel matrix is ​​a 0.5% (v / v) acetic acid solution.

[0070] More preferably, the amount of chitosan / β-glycerophosphate (β-GP) composite hydrogel matrix added is 90%~99% based on the total mass of the ultrasonically triggered controlled-release drug carrier.

[0071] In some embodiments, the temperature for inducing gelation is selected from 35~40°C, and can be 35°C, 36°C, 37°C, 38°C, 39°C, or 40°C.

[0072] The present invention also provides the use of the above-mentioned drug delivery carrier in the preparation of implantable medical products.

[0073] Preferably, the implantable medical product can release the drug it carries under the action of ultrasound.

[0074] Specifically, under physiological conditions, the drug delivery carrier can slowly release drugs; while under ultrasonic radiation, the porous shell structure of the porous hollow microspheres undergoes significant rupture, gap formation, or displacement, causing changes in the porosity of the porous hollow microspheres, thereby achieving local drug release by the ultrasound-controlled drug delivery system.

[0075] The present invention also provides an ultrasound-triggered controlled drug release system, the system comprising the above-mentioned ultrasound-triggered controlled drug release carrier and ultrasound generator, wherein the hollow cavity of the system is loaded with a functional loading component.

[0076] In some embodiments, the ultrasound generator is used to apply ultrasonic vibrations to the ultrasound-triggered controlled-release drug carrier. Preferably, the ultrasound generator includes, but is not limited to, an ultrasound therapy device or a high-energy focused ultrasound device.

[0077] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0078] Example 1

[0079] This embodiment prepared a porous hollow microsphere array, and characterized and analyzed its structure. The preparation method includes the following steps:

[0080] First, the substrate was sequentially cleaned with isopropanol and then subjected to 300-second oxygen plasma treatment. Subsequently, a commercial two-photon polymerization (TPP) system was used, with a laser power of 120 mW and a plasma density of 50 × 10⁻⁶. 3 At a scanning speed of mm / s, a 3×3×4 hollow microsphere array with an outer diameter of 100 μm and an inner diameter of 80 μm was printed on a substrate using IP-S photoresist. After printing, the sample was placed in a propylene glycol methyl ether acetate (PGMEA) solution for 15 minutes to remove uncured resin, followed by rinsing with isopropanol and drying with nitrogen.

[0081] The resulting arrays of microspheres with different micropore sizes (2 μm and 4 μm) were sputter-coated with gold and observed using a scanning electron microscope. Figure 1 It is known that the surface of the microspheres has pores of uniform size and adjustable dimensions. Different pore sizes can meet the requirements of different drug loading and release rates. A 3×3×4 microsphere array, such as... Figure 2 As shown.

[0082] Example 2

[0083] This embodiment prepared three types of thermosensitive hydrogels for encapsulating microsphere arrays. The specific process includes the following steps:

[0084] The first type is a methylcellulose (MC) composite hydrogel. Methylcellulose (MC) and quaternized chitosan (QCS) are added to 0.005 M PBS buffer at a mass ratio of 1:2. The mixture is stirred at 60°C until the solutes are completely dissolved. The solution is then cooled overnight at 4°C to obtain a stable hydrogel.

[0085] The second type is collagen hydrogel. Type I rat tail collagen (A1048301, Gibco) is mixed with 1 N sodium hydroxide solution and 10x PBS buffer. 300 μL of the mixture is added to each well of a 24-well plate and cultured at 37°C to induce gelation.

[0086] The third type is a chitosan / β-glycerophosphate (β-GP) thermosensitive hydrogel. 300 mg of chitosan was dissolved in 15 mL of 0.5% (v / v) acetic acid solution. A 20% (w / v) β-GP aqueous solution was added dropwise under ice bath conditions with continuous stirring to prevent premature gelation. The thermal response of the chitosan / β-GP hydrogel was characterized.

[0087] The prepared thermosensitive hydrogel was freeze-dried, sliced, and sputter-coated with gold for 20 seconds. Scanning electron microscopy was used to obtain its cross-sectional porous structure image. The chitosan / β-GP thermosensitive hydrogel is shown below. Figure 3 As shown.

[0088] Depend on Figure 4 The rheological temperature control characterization curves show that the storage modulus (G') and loss modulus (G'') of the chitosan / β-GP thermosensitive hydrogel cross at about 37°C, further confirming that the prepared thermosensitive hydrogel loses its fluidity and transforms into a solid when heated to physiological temperature, proving its gelling properties.

[0089] Example 3: Preparation of an ultrasound-triggered controlled-release drug carrier and detection of ultrasound-triggered release

[0090] In this embodiment, an ultrasound-triggered controlled-release drug carrier was prepared, and drug loading and high-intensity focused ultrasound (HIFU) triggered release experiments were conducted. The specific process is as follows:

[0091] Drug loading was performed using a vacuum-assisted permeation method. The microsphere array obtained in Example 1 was immersed in a container filled with a saturated solution of Rhodamine B (SRB). Rhodamine B (SRB, concentration 10 mg / mL) was selected as the model drug. 2 μL of SRB solution was added dropwise to completely immerse each 3×3×4 microsphere array. The sample was connected to a vacuum pump, and vacuum was applied for 2 minutes and maintained for 10 minutes. This "vacuum-maintain-release" cycle was repeated three times to thoroughly remove air from the internal cavity of the microspheres and aspirate the drug solution (see flowchart). Figure 5 ).

[0092] Excess dye adsorbed on the surface of the microspheres was then washed with pre-cooled (-20°C) isopropanol and vacuum dried at room temperature. Fluorescence microscopy confirmed that SRB was successfully encapsulated inside the microspheres (e.g., Figure 7 (As shown). After loading, the drug-loaded microsphere array was immersed in 2 mL of the thermosensitive hydrogel solution prepared in Example 2, and the temperature was raised to 37°C to induce gelation, achieving in-situ encapsulation of the array in the matrix. The weight of the thermosensitive hydrogel was 96% of the weight of the ultrasonically triggered controlled-release drug carrier. The encapsulated ultrasonically triggered controlled-release drug carrier was placed in a constant temperature shaker at 37°C and 300 rpm, and immersed in PBS buffer to simulate the in vivo fluid environment. Samples were taken at set time points (20 min, 40 min, 60 min, and 80 min), and the absorbance at 564 nm was measured using a microplate reader (SpectraMax i3x) to calculate the drug release amount.

[0093] Depend on Figure 6 It can be seen that the three thermosensitive hydrogels, acting as an additional barrier during diffusion, effectively mitigated the initial burst release of the drug. All three thermosensitive hydrogels significantly reduced the initial drug release compared to the hydrogel-free microsphere array, significantly prolonging the effective therapeutic window. Figure 8 It can be seen that the use of focused ultrasound technology has enabled the remote, on-demand accelerated release of drugs from controlled-release drug carriers triggered by ultrasound.

[0094] In summary, the ultrasound-triggered controlled-release drug delivery system of this application exhibits excellent loading capacity and sustained-release effect under simulated physiological conditions. The thermosensitive hydrogel matrix, acting as an additional physical barrier, effectively delays the initial burst release of the drug, while the porous hollow microspheres enable on-demand and accelerated drug release under ultrasound control. This invention, by combining precision 3D printing technology with the selection of a thermosensitive hydrogel matrix, provides a highly customizable material platform for remote controlled drug delivery in precision medicine, demonstrating broad application potential in areas such as local drug delivery and personalized medicine.

[0095] In summary, the above description is merely a preferred embodiment of the present invention and does not constitute any limitation on the present invention in any form or substance. It should be noted that those skilled in the art can make various improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention. Any modifications, alterations, and equivalent changes made by those skilled in the art based on the above-disclosed technical content without departing from the spirit and scope of the present invention are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and evolutions made to the above embodiments based on the essential technology of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. An ultrasonically triggered controlled-release drug carrier based on a 3D-printed microsphere array, characterized in that, The carrier comprises a porous hollow microsphere array and a hydrogel matrix encapsulating the array. The porous hollow microsphere array is composed of a uniform arrangement of porous hollow microspheres. Each porous hollow microsphere has a hollow inner cavity and a porous shell covering the hollow inner cavity. The hollow inner cavity of the porous hollow microsphere is suitable for loading functional load components.

2. The ultrasound-triggered controlled-release drug carrier according to claim 1, characterized in that, Based on an ultrasound-triggered controlled-release drug carrier, the hydrogel matrix comprises 90% to 99% by mass; and / or, the hydrogel matrix is ​​a biocompatible thermosensitive hydrogel matrix, the raw materials of which include one or more combinations of methylcellulose, quaternized chitosan, collagen hydrogel, chitosan, β-glycerophosphate, and poloxamer; and / or, the hollow cavities of the porous hollow microspheres are loaded with functional loading components, the mass ratio of the functional loading components to the porous hollow microspheres being 1:3 to 6; and / or, the functional loading components include: drugs, protein factors, or biological carriers.

3. The ultrasound-triggered controlled-release drug carrier according to claim 1, characterized in that, The raw material of the porous shell layer includes a polymer material, which is selected from natural polymer materials and / or artificially synthesized polymer materials. Preferably, the natural polymer material is selected from one or more of chitin, chitosan, alginate and cyclodextrin, and the artificially synthesized polymer material is selected from one or more of photosensitive resin, polyethylene glycol diacrylate, polylactic acid, polylactic acid-glycolic acid copolymer, polyisopropylacrylamide, polyvinylpyrrolidone and polyethylene glycol-cholesterol copolymer.

4. The ultrasound-triggered controlled-release drug carrier according to claim 1, characterized in that, It also includes one or more of the following features: A1) The diameter of the hollow inner cavity is 70~90 μm; A2) The outer diameter of the porous shell is 90~110 μm; A3) The pore size in the porous shell is 1μm~5μm; A4) The porosity of the porous shell is 10%~90%; A5) The specific surface area of ​​the porous hollow microspheres is 0.1~0.2 m². 2 / g.

5. The ultrasound-triggered controlled-release drug carrier according to claim 2, characterized in that, The thermosensitive hydrogel matrix is ​​any one of methylcellulose / quaternized chitosan composite hydrogel matrix, collagen hydrogel matrix, or chitosan / β-glycerophosphate composite hydrogel matrix.

6. The method for preparing an ultrasound-triggered controlled-release drug carrier according to any one of claims 1 to 5, the method comprising the following steps: 1) A porous hollow microsphere substrate is printed on a substrate using 3D micro-nano printing technology. After development and rinsing, a porous hollow microsphere array with micropores and uniformly arranged microspheres is obtained. 2) Load the porous hollow microspheres from step 1) with functional loading components using a permeation method to obtain a drug-loaded microsphere array; 3) The drug-loaded microsphere array is embedded in a thermosensitive hydrogel matrix and induced to form a gel to obtain an ultrasound-triggered controlled-release drug carrier.

7. The preparation method according to claim 6, characterized in that, The method also includes one or more of the following features: a. The laser power of the 3D micro-nano printing is 100~140 mW, and the scanning speed is 20×10³~50×10³ mm / s; b. The development is performed using PGMEA developer for 10-20 minutes, followed by rinsing with isopropanol to terminate the reaction and drying with nitrogen. c. The permeation method is a vacuum-assisted permeation method; d. The temperature for inducing gelation is 35~38℃; e. The functional loading component includes a drug, protein factor, or biological carrier; f. The thermosensitive hydrogel matrix is ​​selected from any one of the following: methylcellulose / quaternized chitosan composite hydrogel matrix, collagen hydrogel matrix, or chitosan / β-glycerophosphate composite hydrogel matrix.

8. The preparation method according to claim 6, characterized in that: In the methylcellulose / quaternized chitosan composite hydrogel matrix, the mass ratio of methylcellulose to quaternized chitosan is 1~5:5~1; And / or, the collagen in the collagen hydrogel matrix is ​​1% to 10% by mass; And / or, in the chitosan / β-glycerophosphate composite hydrogel matrix, the mass ratio of chitosan to β-glycerophosphate is 1:2~5.

9. The use of the ultrasound-triggered controlled-release drug carrier as described in any one of claims 1 to 5 in the preparation of implantable medical products.

10. An ultrasound-triggered controlled release drug delivery system, the system comprising an ultrasound-triggered controlled release drug delivery carrier and an ultrasound generator as described in any one of claims 1 to 5, wherein the hollow cavity of the system is loaded with a functional loading component.

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