Degradable microspheres with controllable degradation and preparation method thereof

Abstract

The application discloses a kind of degradable microspheres with controllable and preparation method thereof, belong to the technical field of biomedical materials.The base material of the microspheres is methacrylated gelatin, and the degradation time of the microspheres is controlled by regulating the degree of substitution of methacrylated gelatin.The microspheres are prepared by microfluidic and photopolymerization technology, and have uniform size with particle size of 10 μm to 1000 μm.The methacrylated gelatin microspheres with controllable degradation provided by the application can be used for interventional recanalization embolization therapy of substantial organ hemorrhage, realize the time sequence regulation of "hemostasis-degradation-recanalization", and have good clinical transformation value.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a microsphere with controllable degradation and its preparation method. Background Technology

[0002] Appropriately sized microspheres can be used for vascular embolization to treat diseases such as bleeding. Taking renal artery hemorrhage as an example, superselective renal artery embolization (SRAE) is its core treatment method, which can precisely stop bleeding and reduce tissue damage.

[0003] Existing embolization materials mainly include gelatin sponges, microcoils, polyvinyl alcohol (PVA) particles, and butyl cyanoacrylate (NBCA) adhesive, all of which have many drawbacks. Gelatin sponges degrade uncontrollably, easily leading to vascular recanalization and recurrent bleeding; permanent embolization materials such as microcoils and PVA particles remain in the body for a long time, causing vascular damage, non-targeted embolization, renal tissue necrosis, and long-term complications.

[0004] Existing embolization materials fail to simultaneously meet the three core requirements of effective hemostasis, controllable degradation, and biosafety: either they degrade too rapidly, leading to hemostasis failure, or they remain permanently, causing irreversible kidney damage. Furthermore, their poor size uniformity makes them unsuitable for precise embolization. Therefore, developing biodegradable embolization microspheres with uniform size and precisely controllable degradation rates to achieve rapid and effective embolization of renal artery bleeding has significant clinical and commercial value. Simultaneously, the materials must possess excellent biocompatibility and blood compatibility, be non-cytotoxic, suitable for clinical interventional embolization procedures, spontaneously degrade after hemostasis, and restore vascular recanalization, avoiding permanent tissue damage. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a microsphere with controllable degradation and its preparation method. By adjusting the degree of substitution (DS) of methacrylate in gelatin, the degradation time of the microsphere can be precisely controlled, thereby solving the problem of uncontrollable degradation or permanent retention of existing embolization materials and realizing an integrated treatment of "rapid hemostasis + time-sequential degradation + renal function protection".

[0006] To achieve the above objectives, the present invention provides the following technical solution: A degradation-controllable microsphere, wherein the matrix material of the microsphere is methacrylated gelatin, the degree of substitution of the methacrylated gelatin is 10% to 90%, and the degradation time of the microsphere is controlled by the degree of substitution.

[0007] Furthermore, the particle size of the microspheres is 10 μm to 1000 μm.

[0008] Furthermore, the degree of substitution is 20% to 80%.

[0009] Furthermore, the methacrylated gelatin is prepared by reacting gelatin with methacrylic anhydride or methacryloyl chloride.

[0010] The “degree of substitution (DS)” mentioned in this invention refers to the proportion of reactive amino residues in a gelatin molecule that are modified by methacryloyl groups. For example, a degree of substitution of 30% means that about 30% of the reactive amino residues in the gelatin molecule are modified by methacryloyl groups.

[0011] This invention also provides a method for preparing degradable microspheres, comprising the following steps: Step 1: Dissolve gelatin in water, add methacrylic anhydride or methacryloyl chloride to react, purify by dialysis, and freeze dry to obtain methacrylated gelatin powder; Step 2: Prepare an aqueous solution of the methacrylated gelatin powder obtained in Step 1, and add a photoinitiator; separately prepare an organic phase containing a surfactant. Step 3 uses a microfluidic chip to generate monodisperse droplets from the aqueous phase and the organic phase in a microfluidic system. After UV crosslinking, washing, and resuspending, methacrylated gelatin microspheres are obtained. The degradation time of the microspheres is controlled by the degree of substitution of the methacrylated gelatin.

[0012] Furthermore, the reaction temperature in step 1 is 50~70℃, and the reaction time is 1~3 hours.

[0013] Furthermore, the surfactant is selected from one or more of vitamin E polyethylene glycol succinate (VE-TPGS), sorbitan fatty acid ester (Span), polyoxyethylene-polyoxypropylene polymer (Pluronic), and hexadecyltrimethylammonium chloride (CTAB).

[0014] Furthermore, the photoinitiator is selected from one or more of TPO, 907, 1173, DBK, 2959, LAP, ITX, EDB, and CBP.

[0015] Furthermore, the organic phase is selected from one or more of liquid paraffin, chloroform, tetrahydrofuran, and ethyl acetate.

[0016] The beneficial effects of this invention are: 1. By adjusting the degree of substitution of methacrylated gelatin, the degradation time of microspheres can be precisely controlled, overcoming the defect of uncontrollable degradation of existing gelatin sponges; 2. The microspheres are prepared using microfluidic technology combined with photopolymerization, resulting in uniform microsphere size (10 μm~1000 μm), which meets the requirements for precise embolization. 3. The material has good biocompatibility and blood compatibility, is non-cytotoxic, and can spontaneously degrade and restore blood flow after hemostasis, thus avoiding permanent tissue damage. Attached Figure Description

[0017] To more clearly illustrate the technical solutions in this invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, those skilled in the art can obtain other drawings based on these drawings without creative effort.

[0018] Figure 1 This is a schematic diagram illustrating the characterization of the controllable degradation microspheres of the present invention. Detailed Implementation

[0019] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. It should also be noted that, to make the embodiments more comprehensive, the following embodiments are the best and preferred embodiments, and those skilled in the art can use other alternative methods to implement some well-known technologies; moreover, the accompanying drawings are only for more specific description of the embodiments and are not intended to specifically limit the present invention.

[0020] Example 1 Take 100 mL of pure water, add 10 g of gelatin, and stir at 60 °C until dissolved. Add 1 mL of methacrylic anhydride dropwise, and react at 60 °C for 1.5 h. Dialyze to purify until the conductivity is <1 μS / cm, and freeze-dry to obtain methacrylated gelatin powder.

[0021] A 5% aqueous solution of the above-mentioned methacrylated gelatin was prepared, and the photoinitiator LAP was added. A liquid paraffin organic phase containing 1% polyoxyethylene-polyoxypropylene polymer (Pluronic) was also prepared. Using a microfluidic chip with a flow channel diameter of 200 μm, the aqueous and organic phases were mixed to form monodisperse droplets in the microfluidic system. After UV crosslinking, washing, resuspending in sterile physiological saline, and UV sterilization, methacrylated gelatin microspheres were obtained.

[0022] The methacrylated gelatin obtained in this example was found to have a degree of substitution of 24.64%, a microsphere size of 175±4 μm, and a degradation time of 16±1 days.

[0023] Example 2 Take 100 mL of pure water, add 10 g of gelatin, and stir at 60 °C until dissolved. Add 4 mL of methacrylic anhydride dropwise, and react at 60 °C for 1.5 h. Dialyze to purify until the conductivity is <1 μS / cm, and freeze-dry to obtain methacrylated gelatin powder.

[0024] A 5% aqueous solution of the above-mentioned methacrylated gelatin was prepared, and the photoinitiator LAP was added. A liquid paraffin organic phase containing 1% polyoxyethylene-polyoxypropylene polymer (Pluronic) was also prepared. Using a microfluidic chip with a flow channel diameter of 200 μm, the aqueous and organic phases were mixed to form monodisperse droplets in the microfluidic system. After UV crosslinking, washing, resuspending in sterile physiological saline, and UV sterilization, methacrylated gelatin microspheres were obtained.

[0025] The methacrylated gelatin obtained in this example was found to have a degree of substitution of 72.29%, a microsphere size of 185±5 μm, and a degradation time of 28±2 days.

[0026] Performance testing The performance of the methacrylated gelatin microspheres prepared in Examples 1 and 2 was tested, and the results are shown in Table 1.

[0027] Table 1 Performance parameters of microspheres in Examples 1-2 As shown in Table 1, the degradation time of the microspheres significantly increased with the increase of the degree of substitution of methacrylated gelatin. When the degree of substitution was 24.64%, the degradation time was approximately 16 days; when the degree of substitution increased to 72.29%, the degradation time extended to approximately 28 days. This indicates that the degradation time of the microspheres can be effectively controlled by adjusting the degree of substitution of the methacrylated gelatin. A schematic diagram of the microsphere characterization is shown below. Figure 1 As shown.

[0028] This invention encompasses any substitutions, modifications, equivalent methods, and solutions made within the spirit and scope of this invention. To provide the public with a thorough understanding of this invention, specific details are described in detail in the following preferred embodiments; however, those skilled in the art will fully understand the invention even without these details. Furthermore, to avoid unnecessary misunderstanding of the essence of this invention, well-known methods, processes, procedures, components, and circuits are not described in detail.

[0029] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A microsphere with controllable degradation, characterized in that, The matrix material of the microspheres is methacrylated gelatin, and the degree of substitution of the methacrylated gelatin is 10% to 90%. The degradation time of the microspheres is controlled by the degree of substitution.

2. The microspheres according to claim 1, characterized in that, The microspheres have a particle size of 10 μm to 1000 μm.

3. The microspheres according to claim 1, characterized in that, The degree of substitution is 20% to 80%.

4. The microspheres according to claim 1, characterized in that, The methacrylated gelatin is prepared by reacting gelatin with methacrylic anhydride or methacryloyl chloride.

5. A method for preparing degradable microspheres, characterized in that, Includes the following steps: Step 1: Dissolve gelatin in water, add methacrylic anhydride or methacryloyl chloride to react, purify by dialysis, and freeze dry to obtain methacrylated gelatin powder; Step 2: Prepare an aqueous solution of the methacrylated gelatin powder obtained in Step 1, and add a photoinitiator; separately prepare an organic phase containing a surfactant. Step 3 uses a microfluidic chip to generate monodisperse droplets from the aqueous phase and the organic phase in a microfluidic system. After UV crosslinking, washing, and resuspending, methacrylated gelatin microspheres are obtained. The degradation time of the microspheres is controlled by the degree of substitution of the methacrylated gelatin.

6. The preparation method according to claim 5, characterized in that, The reaction temperature in step 1 is 50~70℃, and the reaction time is 1~3 hours.

7. The preparation method according to claim 5, characterized in that, The surfactant is selected from one or more of the following: vitamin E polyethylene glycol succinate, sorbitan fatty acid ester, polyoxyethylene-polyoxypropylene polymer, and hexadecyltrimethylammonium chloride.

8. The preparation method according to claim 5, characterized in that, The photoinitiator is selected from one or more of TPO, 907, 1173, DBK, 2959, LAP, ITX, EDB, and CBP.

9. The preparation method according to claim 5, characterized in that, The organic phase is selected from one or more of liquid paraffin, chloroform, tetrahydrofuran, and ethyl acetate.

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