Porous biological scaffold and preparation method thereof

Abstract

The invention provides a porous biological scaffold and a preparation method thereof, and the porous biological scaffold is prepared by pre-freezing and freeze-drying a mixed solution formed by a hydrophobic polyester material and a hydrophilic polymer material, the stent has a three-dimensional porous structure, can be compressed to be smaller than the original volume in a dry state, and can recover to the original volume after being released from a compressed state. According to the invention, the hydrophobic polyester material and the hydrophilic polymer material cooperate with each other, so that the material has unique dynamic response performance, specifically, the material has good compressibility in a dry state, can be compressed to be smaller than the original volume so as to be conveyed into a body, and can be recovered to the original volume before compression after being implanted into the body; and plugging, filling or mechanical supporting functions are realized.

Description

Technical Field

[0001] This invention relates to the field of biomedical materials technology, and in particular to a porous biological scaffold and its preparation method. Background Technology

[0002] Vascular embolism and skull base bone defects are two pathological conditions that pose significant clinical challenges.

[0003] Vascular embolism refers to the pathological process of blood flow interruption caused by the blockage of a blood vessel lumen by a thrombus, foreign body, or abnormal material. Currently, most existing vascular embolization methods use porous materials such as gelatin sponge particles and polyvinyl alcohol microspheres. While gelatin sponge particles can absorb blood in the short term, their softness makes them unable to provide support, and they are easily dispersed by blood flow, maintaining an embolic effect for only 1-2 weeks. Although polyvinyl alcohol microspheres can achieve permanent embolism, they cannot be metabolized and absorbed by the body. Long-term retention in the body may cause chronic inflammation, foreign body reactions, or tissue hyperplasia around the embolization site.

[0004] Skull base bone defects refer to the interruption or absence of continuity in the skull base bone structure, usually caused by trauma, tumors, or surgery. Currently, existing skull base bone repair methods mostly use autologous tissue, fat, fascia, or absorbent cotton for support and filling. However, these materials cannot simultaneously meet the dual requirements of good support performance and promoting bone repair.

[0005] Although porous materials are widely used in biomedical materials, most existing porous materials cannot meet the specific requirements of the aforementioned scenarios of vascular embolization and skull base bone repair. Furthermore, most existing porous materials rely on porogens to form porous structures, but this method requires additional elution of the porogen. On the one hand, the introduction of porogens and subsequent elution steps not only make it difficult to control the microstructure such as pore size, pore diameter distribution, and pore connectivity, but may also damage the integrity of the material matrix during repeated processing, causing uneven stress distribution within the material and ultimately leading to insufficient mechanical strength and poor structural stability. On the other hand, porogens are often difficult to completely remove, and residual components can easily have toxic effects on cells, thereby interfering with the normal repair process of tissues and affecting tissue healing.

[0006] Therefore, there is an urgent need to provide a porous biological scaffold and its preparation method. Summary of the Invention

[0007] This invention provides a porous biological scaffold and its preparation method, which can solve the problems of insufficient mechanical strength and structural instability of existing porous materials, and the inability to meet the needs of vascular embolization and skull base bone repair.

[0008] In a first aspect, the present invention provides a porous biological scaffold, which is prepared by pre-freezing and freeze-drying a mixture comprising a hydrophobic polyester material and a hydrophilic polymer material; wherein the scaffold has a three-dimensional porous structure, can be compressed to a size smaller than its original volume in a dry state, and can recover to its original volume after being released from the compressed state.

[0009] Preferably, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~15):1.

[0010] Preferably, the hydrophobic polyester material is at least one of poly(L-lactic acid-caprolactone copolymer), polytrimethylene carbonate, or polybutylene adipate-terephthalate.

[0011] Preferably, the hydrophilic polymer material is at least one of gelatin, chitosan, starch, sodium hyaluronate, regenerated oxidized cellulose, carboxymethyl cellulose, alginate, or starch polysaccharide.

[0012] Preferably, the solvent of the mixture is hexafluoroisopropanol.

[0013] More preferably, the intrinsic viscosity of the hydrophobic polyester material is 1.0~3.0 dL / g.

[0014] Preferably, the hydrophobic polyester material is a poly(L-lactic acid-caprolactone) copolymer.

[0015] Preferably, in the poly-L-lactic acid-caprolactone copolymer, the mass ratio of lactide to caprolactone is (50~80):(20~50).

[0016] Preferably, the porous biological scaffold has an average pore size of 10-80 μm and a porosity of 40-90%; and / or the porous biological scaffold has a peak load of 30-100 N, an elastic modulus of 1-10 MPa, a liquid absorption rate of 200-480%, and a degradation period of 1-12 months in a dry state.

[0017] Preferably, the porous biological scaffold is configured to be compressible in a dry state and delivered to the target site via a tubular instrument, and after implantation into the target site, it can return to its original volume before compression, thereby achieving closure or filling of the target site.

[0018] More preferably, the porous biological scaffold is configured as a vascular embolization material to block blood vessels; or the porous biological scaffold is configured as a skull base bone repair material to fill the skull base bone area.

[0019] Preferably, when the porous bio-scaffold is configured as a vascular embolization material, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~9):1.

[0020] Preferably, when the porous biological scaffold is configured as a skull base bone repair material, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~8):1.

[0021] More preferably, when the porous scaffold is configured as a skull base bone repair material, the material used to prepare the porous biological scaffold further includes modified inorganic particles.

[0022] More preferably, the mass ratio of the hydrophobic polyester material, the hydrophilic polymer material and the modified inorganic particles is (5~12):(0.2~3):(0.1~3); more preferably, it is (6~10):(0.5~2):(0.5~2).

[0023] Preferably, the modified inorganic particles are obtained by modifying inorganic particles with a surface modifier.

[0024] More preferably, the inorganic particles include at least one of hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, calcium dihydrogen phosphate, anhydrous calcium dihydrogen phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, octacalcium phosphate, calcium carbonate, calcium citrate, or calcium sulfate.

[0025] More preferably, the inorganic particles have a particle size of less than 70 μm.

[0026] Preferably, the surface modifier comprises a small molecule modifier or a polymer modifier; the small molecule modifier comprises at least one of oleic acid, dopamine, and silane coupling agent, and the polymer modifier comprises polydopamine and / or polyethyleneimine.

[0027] More preferably, the mass ratio of the small molecule modifier to the inorganic particles is 1:(50~300), and the mass ratio of the polymer modifier to the inorganic particles is 1:(15~50).

[0028] Secondly, embodiments of the present invention also provide a method for preparing the porous biological scaffold described in any of the first aspects above, the method comprising the following steps: (1) Add the hydrophobic polyester material and the hydrophilic polymer material to the solvent and stir to mix them to obtain a mixture; (2) The mixture is poured into a mold, and after pre-freezing and freeze-drying, the porous biological scaffold is obtained.

[0029] Preferably, the mixture further includes modified inorganic particles.

[0030] Preferably, in the mixture, the mass-volume concentration of the hydrophobic polyester material is 0.01~0.1 g / mL, the mass-volume concentration of the hydrophilic polymer material is 0.001~0.06 g / mL, and the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~15):1.

[0031] When the mixture includes modified inorganic particles, the mass-volume concentration of the modified inorganic particles is 0.001~0.02 g / mL, and the mass ratio of the hydrophobic polyester material, the hydrophilic polymer material and the modified inorganic particles is (5~12):(0.2~3):(0.1~3).

[0032] Preferably, in step (1), the stirring speed is 200~1000 rpm and the time is 10~24h.

[0033] Preferably, in step (2), the pre-freezing temperature is -80~-10℃ and the time is 0.5~5h; the freeze-drying temperature is -80~-40℃ and the time is 48~72h.

[0034] Preferably, the method for preparing the modified inorganic particles includes the step of mixing a surface modifier with inorganic particles to modify the inorganic particles. Preferably, before pre-freezing, the mixture is further subjected to a quick-freezing step; wherein the quick-freezing temperature is -25~-20℃ and the time is 1~2h.

[0035] Compared with the prior art, the present invention has at least the following beneficial effects: In this invention, a porous biological scaffold with a three-dimensional porous structure is prepared by pre-freezing and freeze-drying a mixture comprising hydrophobic polyester material and hydrophilic polymer material. Through the synergistic interaction between the hydrophobic polyester material and the hydrophilic polymer material, it possesses unique dynamic response properties. Specifically, it has good compressibility in the dry state and can be compressed to a size smaller than its original volume for delivery into the body via a tubular device. After implantation, it can return to its original volume before compression, thus achieving functions of occlusion, filling, or mechanical support.

[0036] The porous biological scaffold of this invention has good compressibility, fluid absorption, mechanical properties and good biocompatibility. After implantation, it can recover to its original volume before compression and has the advantage of small volume change after fluid absorption. It also has the advantages of easy storage and convenient use, and is suitable for interventional surgery.

[0037] The porous biological scaffold of this invention is simple to prepare, and can be formed by pre-freezing and freeze-drying without the need for additional foaming agents or pore-forming agents. This not only avoids the biocompatibility risks caused by chemical residues, but also significantly reduces the cost of raw materials and the complexity of the process, making it suitable for large-scale industrial production. Attached Figure Description

[0038] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0039] Figure 1 This is a product image of a porous biological scaffold provided in Embodiment 1 of the present invention; Figure 2 This is a product image of a porous biological scaffold provided in Embodiment 5 of the present invention; Figure 3 This is a scanning electron microscope image of a porous biological scaffold provided in Embodiment 1 of the present invention; Figure 4 This is a scanning electron microscope image of a porous biological scaffold provided in Embodiment 5 of the present invention; Figure 5 This is a scanning electron microscope image of a porous biological scaffold provided in Comparative Example 4 of the present invention; Figure 6 This is a microscope image of a porous biological scaffold provided in Embodiment 3 of the present invention; Figure 7 A microscope image of a porous biological scaffold provided in Comparative Example 5 of the present invention; Figure 8 This is a diagram of a porous biological scaffold used via a long catheter (the catheter contains bismuth oxide contrast agent) provided in Embodiment 2 of the present invention. Figure 9 This is a comparison image of a porous biological scaffold provided in Embodiment 8 of the present invention before and after compression; Figure 10 This is a comparison image of a porous biological scaffold in its dry state and after liquid absorption, as provided in Embodiment 5 of the present invention; Figure 11 This is a comparison image of a porous biological scaffold provided in Embodiment 7 of the present invention before and after liquid absorption after being cut; Figure 12 This is a comparison image of a porous biological scaffold provided in Comparative Example 4 of the present invention before and after liquid absorption after being cut. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0041] This invention provides a porous biological scaffold, which is prepared by pre-freezing and freeze-drying a mixture comprising a hydrophobic polyester material and a hydrophilic polymer material. The scaffold has a three-dimensional porous structure, can be compressed to a size smaller than its original volume in a dry state, and can recover to its original volume after being released from the compressed state.

[0042] In this embodiment of the invention, a porous biological scaffold with a three-dimensional porous structure is prepared by pre-freezing and lyophilizing a mixture comprising hydrophobic polyester material and hydrophilic polymer material. Through the synergistic interaction between the hydrophobic polyester material and the hydrophilic polymer material, it possesses unique dynamic response properties. Specifically, it has good compressibility in the dry state and can be compressed to a size smaller than its original volume for delivery into the body via a tubular device. After implantation, it can recover to its original volume before compression and can rapidly absorb liquid in the body fluid environment, thereby achieving stable occlusion, filling, or mechanical support functions.

[0043] The porous biological scaffold in this invention has the advantages of good compressibility, good elasticity, strong liquid absorption capacity, good biocompatibility, and small volume change after liquid absorption. It also has the advantages of easy storage and convenient use, and is suitable for interventional surgery.

[0044] According to some preferred embodiments, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~15):1 (for example, it can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 11:1, 12:1, 13:1, 14:1 or 15:1).

[0045] According to some preferred embodiments, the hydrophobic polyester material is at least one of poly(L-lactic acid-caprolactone copolymer), polytrimethylene carbonate, or polybutylene adipate-terephthalate; the hydrophilic polymer material is at least one of gelatin, chitosan, starch, sodium hyaluronate, regenerated oxidized cellulose, carboxymethyl cellulose, alginate, or starch polysaccharide; and the solvent of the mixture is hexafluoroisopropanol.

[0046] In this embodiment of the invention, screening hydrophobic polyester materials and hydrophilic polymer materials helps to fully leverage their synergistic and complementary effects. Hydrophobic polyester materials provide good mechanical strength and toughness, while hydrophilic polymer materials impart excellent liquid absorption performance and biocompatibility to the scaffold. Furthermore, using hexafluoroisopropanol as a solvent allows both materials to dissolve simultaneously and form a uniform and stable mixture, ensuring a uniform three-dimensional porous structure during subsequent freeze-drying. Simultaneously, optimizing the ratio of the two components helps ensure that the porous biological scaffold possesses good liquid absorption capacity, compressibility, mechanical support performance, biocompatibility, and a controllable degradation cycle. It also exhibits minimal volume change after liquid absorption, allowing for delivery to the target site via tubular instruments for occlusion or filling, making it suitable for interventional procedures. Other hydrophobic polyester materials, such as polycaprolactone, polylactic-co-glycolic acid copolymer, polydioxanone, and polybutylene succinate, suffer from poor toughness, resulting in porous biological scaffolds with poor compressibility and mechanical support performance when combined with hydrophilic polymer materials, making them unsuitable for clinical use.

[0047] According to some preferred embodiments, the intrinsic viscosity of the hydrophobic polyester material is 1.0~3.0 dL / g.

[0048] In this embodiment of the invention, the intrinsic viscosity of the hydrophobic polyester material is a key parameter affecting the performance of the scaffold. Controlling it within a suitable range allows the material to balance processability, mechanical properties, and a suitable degradation rate. If its intrinsic viscosity is too high, it not only increases the difficulty of material synthesis but also significantly reduces the solubility when blended with hydrophilic polymers, and the degradation cycle may be extended to 1-2 years, failing to meet the short-term degradation application requirements. Conversely, if its intrinsic viscosity is too low, the material is difficult to mold and lacks sufficient mechanical strength, making it difficult to maintain a stable support structure in specific locations within the body.

[0049] According to some preferred embodiments, the hydrophobic polyester material is a poly(L-lactic acid-caprolactone) copolymer; in the poly(L-lactic acid-caprolactone) copolymer, the mass ratio of lactide to caprolactone is (50~80):(20~50) (for example, it can be 50:50, 60:40, 70:30 or 80:20).

[0050] In this embodiment of the invention, the hydrophobic polyester material is preferably a poly(L-lactic acid)-caprolactone copolymer. By further controlling the mass ratio of lactide and caprolactone, the scaffold can achieve good mechanical support, compressibility, and degradation compatibility. Considering that polylactic acid (monomer lactide) has a high glass transition temperature, approximately 55-60°C, and is in a glassy state at body temperature (37°C), it can provide the necessary structural strength and rigid support for the scaffold. In contrast, polycaprolactone (monomer caprolactone) has a low glass transition temperature (approximately ~60°C), and is in a highly elastic state at body temperature, exhibiting a soft yet tough rubber-like material. Therefore, setting the lactide content to be no less than the caprolactone content can improve the compressibility and resilience of the scaffold while ensuring good support function. Furthermore, at the same molecular weight, polycaprolactone typically has a longer degradation cycle (approximately 2-4 years), while polylactic acid degrades relatively quickly (approximately several months to 1-2 years). Introducing more polylactic acid segments can effectively regulate the overall degradation rate of the copolymer, matching it with the tissue repair cycle.

[0051] According to some preferred embodiments, the porous biological scaffold has an average pore size of 10-80 μm and a porosity of 40-90%; and / or the porous biological scaffold has a peak load of 30-100 N, an elastic modulus of 1-10 MPa, a liquid absorption rate of 200-480%, and a degradation cycle of 1-12 months in a dry state.

[0052] According to some preferred embodiments, the porous biological scaffold is configured to be compressible in a dry state and delivered to the target site via a tubular instrument, and after implantation into the target site, it can return to its original volume before compression, thereby achieving closure or filling of the target site.

[0053] According to some preferred embodiments, the porous bio-scaffold is configured as a vascular embolization material to block blood vessels; or the porous scaffold is configured as a skull base bone repair material to fill the skull base bone area.

[0054] In some embodiments, the porous biological scaffold of the present invention can be compressed and delivered to the target site through tubular instruments such as interventional catheters. Especially in the application of vascular occlusion or filling of the skull base, the scaffold has a small volume change after absorbing liquid, so that it can effectively achieve the function of embolization or filling while avoiding compression damage to surrounding blood vessels or tissues due to expansion, and at the same time maintaining the structural stability and support effect after implantation.

[0055] It should be noted that the above implantation methods and sites are only examples. This porous biological scaffold is also applicable to other tissue sites that need to be blocked, supported or filled through minimally invasive methods.

[0056] According to some preferred embodiments, when the porous bioscaffold is configured as a vascular embolization material, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~9):1 (for example, it can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1 or 9:1).

[0057] According to some preferred embodiments, when the porous bioscaffold is configured as a skull base bone repair material, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~8):1 (for example, it can be 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1 or 8:1).

[0058] In this embodiment of the invention, the ratio of hydrophobic polyester material to hydrophilic polymer material in the porous biological scaffold can be adjusted to meet the specific needs of different application scenarios. When applied to vascular embolization, the scaffold needs to be delivered in a wet-compressed form through a thin interventional catheter and quickly absorb fluid within the blood vessel to complete the occlusion. In this case, the scaffold needs to have excellent fluid absorption performance, while the requirement for support strength is relatively general. Therefore, by increasing the content of hydrophilic polymer material, excellent fluid absorption performance is ensured, and the degradation period is controlled within 1-12 months to match the requirements of vascular embolization applications. When applied to skull base bone repair, the scaffold needs to have stable mechanical support and be able to guide bone growth, while the requirements for fluid absorption and compressibility are reduced. A thicker catheter is usually used for intervention. Therefore, by increasing the proportion of hydrophobic polyester material, structural stability is ensured, and the degradation time is controlled within 3-12 months to match the skull base bone tissue repair process.

[0059] According to some preferred embodiments, when the porous biological scaffold is configured as a skull base bone repair material, the material used to prepare the porous biological scaffold further includes modified inorganic particles; the mass ratio of the hydrophobic polyester material, the hydrophilic polymer material, and the modified inorganic particles is (5~12):(0.2~3):(0.1~3) (for example, it can be 5:0.2, 0.1, 5:1:1, 5:2:1, 5:2:3, 5:3:3, 6:0.5:0.5, 6:1:1, 6:2:1, 6:3:1, 6:3). :2, 6:3:3, 8:0.2:0.1, 8:1:1, 8:2:1, 8:3:1, 8:2:2, 8:2:3, 8:3:3, 10:1:1, 10:2:1, 10:2:3, 10:3:1, 10:3:3, 12:0.2:0.1, 12:1:1, 12:2:1, 12:2:3, 12:2:1, 12:3:1, 12:2:2, 12:2:3 or 12:3:3); more preferably (6~10):(0.5~2):(0.5~2).

[0060] According to some preferred embodiments, the inorganic particles include at least one of hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, calcium dihydrogen phosphate, anhydrous calcium dihydrogen phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, octacalcium phosphate, calcium carbonate, calcium citrate, or calcium sulfate; more preferably, the particle size of the inorganic particles is less than 70 μm. When the particle size of the inorganic particles is less than 70 μm, the modified inorganic particles are more evenly distributed on the surface and inside the porous biological scaffold, which is more conducive to promoting bone repair.

[0061] In this embodiment of the invention, when the scaffold is used for skull base bone repair, the above-mentioned modified inorganic particles are further added to mix with hydrophobic polyester materials and hydrophilic polymer materials. This not only helps to further improve the mechanical strength of the scaffold, making it better match the mechanical properties and degradation cycle of the skull base bone repair scaffold, but also the addition of modified inorganic particles helps to induce osteogenic differentiation of cells, thereby promoting the repair of skull base bone tissue.

[0062] According to some preferred embodiments, the modified inorganic particles are obtained by modifying inorganic particles with a surface modifier; the surface modifier includes a small molecule modifier or a polymer modifier; the small molecule modifier includes at least one of oleic acid, dopamine, and silane coupling agent, and the polymer modifier includes polydopamine and / or polyethyleneimine.

[0063] According to some preferred embodiments, the mass ratio of the small molecule modifier to the inorganic particles is 1:(50~300) (for example, it can be 1:50, 1:100, 1:150, 1:200, 1:250 or 1:300), and the mass ratio of the polymer modifier to the inorganic particles is 1:(15~50) (for example, it can be 1:15, 1:20, 1:25, 1:30, 1:45 or 1:50).

[0064] In this embodiment of the invention, surface modification of inorganic particles using an appropriate amount of surface modifier can effectively improve their interfacial compatibility with hydrophobic polyester materials and hydrophilic polymer materials, enabling the modified inorganic particles to be stably dispersed in the mixture, avoiding agglomeration, and thus improving the uniform distribution of the modified inorganic particles in the final scaffold. If the surface modifier content is too high, the surface modifier will completely coat the surface of the inorganic particles, affecting the interfacial compatibility between the inorganic particles and the hydrophobic polyester materials and hydrophilic polymer materials; if the surface modifier content is too low, the interfacial compatibility is also poor.

[0065] This invention also provides a method for preparing the porous biological scaffold described in any one of the above claims, the method comprising the following steps: (1) Add the hydrophobic polyester material and the hydrophilic polymer material to the solvent and stir to mix them to obtain a mixture; (2) The mixture is poured into a mold, and after pre-freezing and freeze-drying, the porous biological scaffold is obtained.

[0066] The preparation method of the biological scaffold in the embodiments of the present invention is simple. It can be formed by pre-freezing and freeze-drying without the need for additional foaming agents or pore-forming agents. This not only avoids the biocompatibility risks caused by chemical residues, but also significantly reduces the cost of raw materials and the complexity of the process, making it suitable for large-scale industrial production.

[0067] It should be noted that the mold used in the preparation process can be designed into any shape according to the final application requirements; when the mold is a slender catheter, a strip-shaped porous biological scaffold can be directly formed, which is convenient for delivery through interventional catheters for minimally invasive implantation.

[0068] In some preferred embodiments, such as when using a porous biological stent for vascular embolization, when implanting the porous biological stent using an interventional catheter, a contrast agent can be injected into the catheter containing the porous biological stent first, so that the stent can fully absorb the contrast agent before being pushed to the target vascular embolization site. This facilitates real-time imaging and positioning during implantation, ensuring accurate stent release.

[0069] For different types of contrast agents, corresponding pretreatment methods can be used to load the porous biological scaffold with the contrast agent before implantation, so as to achieve contrast localization during implantation. Specifically, when the contrast agent is iodized oil, before use, iodized oil is first injected into the microcatheter carrying the scaffold, allowing the scaffold to soak in the iodized oil for 10-20 minutes to fully absorb the iodized oil, and then the surface of the scaffold is rinsed off with physiological saline to remove any unloaded free iodized oil; when the contrast agent is an iodine contrast agent (such as iohexol, iopamidol, etc.), before use, it is mixed with physiological saline at a volume ratio of 1:1 to form a dilution, and then the dilution is injected into the microcatheter carrying the scaffold, allowing the scaffold to soak in the solution for 2-3 minutes before use; when the contrast agent is a powder contrast agent (such as tantalum powder, metal oxide, etc.), before use, it is first mixed with physiological saline at a mass ratio of 1:3 to form a uniform suspension, and then the suspension is injected into the microcatheter carrying the scaffold, allowing the scaffold to soak in the suspension for 3-5 minutes before use.

[0070] According to some preferred embodiments, when the porous bioscaffold is configured as a skull base bone repair material, the mixture further includes modified inorganic particles; According to some preferred embodiments, in the mixture, the mass-volume concentration of the hydrophobic polyester material is 0.01~0.1 g / mL (e.g., 0.01 g / mL, 0.03 g / mL, 0.05 g / mL, 0.08 g / mL, or 0.1 g / mL), and the mass-volume concentration of the hydrophilic polymer material is 0.001~0.06 g / mL (e.g., 0.001 g / mL, 0.003 g / mL, 0.005 g / mL, 0.008 g / mL, 0.01 g / mL, 0.03 g / mL, 0.05 g / mL, or 0.06 g / mL). The mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~15):1; when the mixture includes modified inorganic particles, the mass volume concentration of the modified inorganic particles is 0.001~0.02g / mL (for example, it can be 0.001g / mL, 0.005g / mL, 0.01g / mL, 0.015g / mL or 0.02g / mL), and the mass ratio of the hydrophobic polyester material, the hydrophilic polymer material to the modified inorganic particles is (5~12):(0.2~3):(0.1~3).

[0071] In this embodiment of the invention, by controlling the concentration and mass ratio of hydrophobic polyester material to hydrophilic polymer material in the mixture, or by controlling the concentration and mass ratio of hydrophobic polyester material, hydrophilic polymer material and modified inorganic particles, it is beneficial to form a uniform and stable mixture, avoid excessive viscosity of the solution due to excessive concentration, thereby affecting the processability, and make the finally prepared porous biological scaffold have good compressibility, liquid absorption performance, mechanical properties, and good biocompatibility.

[0072] According to some preferred embodiments, in step (1), the stirring speed is 200~1000 rpm (e.g., 200 rpm, 500 rpm, 600 rpm, 800 rpm or 1000 rpm), and the time is 10~24h (e.g., 10h, 12h, 15h, 18h, 20h or 24h); in step (2), the pre-freezing temperature is -80~-10℃ (e.g., -8... The freeze-drying temperature is -80 to -40°C (e.g., -80°C, -70°C, -60°C, -50°C, or -40°C), and the time is 0.5 to 5 hours (e.g., 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); the freeze-drying temperature is -80 to -40°C (e.g., -80°C, -70°C, -60°C, -50°C, or -40°C), and the time is 48 to 72 hours (e.g., 48 hours, 50 hours, 55 hours, 60 hours, 65 hours, 70 hours, or 72 hours).

[0073] According to some preferred embodiments, the method for preparing the modified inorganic particles includes the step of mixing a surface modifier with inorganic particles to modify the inorganic particles.

[0074] Furthermore, the surface modifier includes a small molecule modifier or a polymer modifier; the small molecule modifier includes at least one of oleic acid, dopamine, and silane coupling agent, and the polymer modifier includes polydopamine and / or polyethyleneimine.

[0075] In some specific implementations, when using small molecule modifiers as surface modifiers, modified inorganic particles can be prepared in advance. Specifically, the preparation method of the modified inorganic particles includes the following steps: Inorganic particles are mixed with alcohol solvents, and then modified with small molecule modifiers to obtain modified products. The modified product is then post-processed to obtain modified inorganic particles.

[0076] In some specific implementations, the modification temperature is 50-120°C, the modification pH is 8-12, and the modification time is 3-9 hours. To obtain modified inorganic particles with superior performance, stirring or ultrasound can be used. The stirring speed can be 100-800 rpm. More specifically, when using a silane coupling agent for modification, the modification pH is 8-12, and the modification is carried out under nitrogen protection; when using other small molecule modifiers such as oleic acid or dopamine for modification, it is not necessary to adjust the pH of the solution or carry out the modification under nitrogen protection.

[0077] In some specific embodiments, the post-processing includes precipitating the modified product to obtain a particulate product; further washing and drying the particulate product to obtain modified inorganic particles.

[0078] Furthermore, the particulate product can be washed with a polar solvent, such as water or alcohol solvents. Afterwards, solid-liquid separation is performed, followed by drying to obtain modified inorganic particles. The method of solid-liquid separation is not particularly limited in this invention and can include centrifugation, filtration, or vacuum filtration. The drying temperature and time are not particularly limited in this invention, as long as the modified inorganic particles are dried. Specifically, the drying temperature can be 35-45°C, and the drying time can be 12-36 hours.

[0079] In some specific implementation schemes, when using macromolecular modifiers for modification, the macromolecular modifiers, inorganic particles, hydrophobic polyester materials, and hydrophilic polymer materials are directly added to the solvent and stirred until homogeneous.

[0080] In some specific implementations, the mass ratio of the small molecule modifier to the inorganic particles is 1:(50~300), and the mass ratio of the polymer modifier to the inorganic particles is 1:(15~50).

[0081] According to some preferred embodiments, before pre-freezing, the mixture is further subjected to a quick-freezing step; wherein the quick-freezing temperature is -25~-20℃ (for example, it can be -25℃, -22℃ or -20℃), and the time is 1~2h (for example, it can be 1h, 1.5h or 2h).

[0082] In this embodiment of the invention, before pre-freezing, the mixture is first quick-frozen at a certain temperature, which helps to shorten the subsequent freeze-drying time, reduce the running time of the freeze dryer, and thus reduce equipment energy consumption and long-term wear and tear.

[0083] To more clearly illustrate the technical solution and advantages of the present invention, a porous biological scaffold and its preparation method are described in detail below through embodiments.

[0084] Example 1 (1) Take 1.6g of hydrophobic polyester material (poly-L-lactic acid-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, with a mass ratio of lactide to caprolactone of 70:30) and 0.4g of hydrophilic polymer material (gelatin) in a beaker, then add 20mL of hexafluoroisopropanol, stir and mix at 300rpm for 10h until clear to obtain a mixture; wherein, in the mixture, the mass volume concentration of hydrophobic polyester material is 0.08g / mL, and the mass volume concentration of hydrophilic polymer material is 0.02g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 1 cm and a height of 0.38 mm, quickly place it in a -20℃ freezer for 1 hour, then transfer it to a -80℃ freezer for 2 hours to pre-freeze, and then place it in a freeze dryer for 72 hours to freeze dry. The freeze dryer is set to a vacuum temperature of -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0085] Example 2 (1) Take 0.8g of hydrophobic polyester material (polytrimethylene carbonate with intrinsic viscosity of 1.5~2.0 dL / g) and 0.4g of hydrophilic polymer material (gelatin) in a beaker, then add 10mL of hexafluoroisopropanol, stir and mix at 400rpm for 12h until clear, and obtain a mixture; wherein, in the mixture, the mass volume concentration of hydrophobic polyester material is 0.08g / mL, and the mass volume concentration of hydrophilic polymer material is 0.04g / mL; (2) Pour the mixture into a 0.25 mm diameter conduit mold, quickly place it in a -20 °C freezer for 2 hours, then transfer it to a -80 °C freezer for 2 hours to pre-freeze, and then place it in a freeze dryer for 72 hours to freeze dry. The freeze dryer is set to a vacuum temperature of -80 °C. After demolding, a strip-shaped porous biological scaffold is obtained.

[0086] Before use, bismuth oxide and physiological saline are mixed at a mass ratio of 1:3 to obtain a suspension. This suspension is then injected into a microcatheter carrying the strip-shaped sample. The porous scaffold is immersed in the suspension for 3-5 minutes to obtain a porous biological scaffold loaded with bismuth oxide contrast agent. Figure 8 As shown.

[0087] Example 3 (1) Take 1.8g of hydrophobic polyester material (poly-L-lactic acid-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, with a mass ratio of lactide to caprolactone of 75:25) and 0.2g of hydrophilic polymer material (chitosan) in a beaker, then add 20mL of hexafluoroisopropanol, stir and mix at 400rpm for 24h until clear to obtain a mixture; wherein, in the mixture, the mass volume concentration of hydrophobic polyester material is 0.09g / mL, and the mass volume concentration of hydrophilic polymer material is 0.01g / mL; (2) Pour the mixture into a 50mL centrifuge tube (mold), quickly place it in a -20℃ freezer for 2 hours, then transfer it to a -80℃ freezer for 2 hours, and then freeze-dry it in a freeze dryer for 72 hours. The freeze dryer is set to a vacuum temperature of -80℃. After demolding, a rod-shaped porous biological scaffold is obtained.

[0088] Example 4 (1) Take 0.4g of hydrophobic polyester material (poly-L-lactic acid-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, and the mass ratio of lactide to caprolactone is 80:20) and 0.4g of hydrophilic polymer material (gelatin) in a beaker, then add 10mL of hexafluoroisopropanol solvent, stir and mix at 300rpm for 10h until clear to obtain a mixture; wherein, in the mixture, the mass volume concentration of hydrophobic polyester material is 0.04g / mL, and the mass volume concentration of hydrophilic polymer material is 0.04g / mL; (2) Pour the mixture into a 0.38 mm diameter conduit mold, quickly place it in a -20 °C freezer for 1 hour, then transfer it to a -80 °C freezer for 2 hours to pre-freeze, and then freeze-dry it in a freeze dryer for 72 hours. The freeze dryer is set to a vacuum temperature of -80 °C. After demolding, a strip-shaped porous biological scaffold is obtained.

[0089] Example 5 (1) 0.175 g of silane coupling agent (KH550) was added to an anhydrous ethanol solution containing 35 g of inorganic particles (hydroxyapatite) (hydroxyapatite mass fraction was 0.5%), and the temperature was controlled at 85 °C. Then the pH was adjusted to 11.0, and the reaction was stirred at 300 rpm for 6 h under nitrogen protection. After that, the product was washed three times with deionized water to remove residual solvent. After filtration, the filtered product was placed in an oven at 37 °C for 24 h, and the product was collected to obtain modified inorganic particles (KH550 modified hydroxyapatite). Take 0.8 g of hydrophobic polyester material (poly-L-lactic acid-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, with a lactide to caprolactone mass ratio of 75:25), 0.1 g of hydrophilic polymer material (gelatin), and 0.1 g of modified inorganic particles (KH550 modified hydroxyapatite) in a beaker, then add 20 mL of hexafluoroisopropanol, and stir at 500 rpm for 12 h to obtain a mixture; wherein, in the mixture, the mass-volume concentration of hydrophobic polyester material is 0.04 g / mL, the mass-volume concentration of hydrophilic polymer material is 0.005 g / mL, and the mass-volume concentration of modified inorganic particles is 0.005 g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 1 cm and a height of 10 cm, quickly place it in a -80℃ freezer for 4 hours, and then freeze-dry it in a freeze dryer for 72 hours. The vacuum temperature of the freeze dryer is set to -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0090] Example 6 Take 0.6 g of hydrophobic polyester material (polybutylene adipate terephthalate with an intrinsic viscosity of 2.3~2.8 dL / g), 0.2 g of hydrophilic polymer material (carboxymethyl cellulose), 0.01 g of polyethyleneimine, and 0.2 g of calcium carbonate in a beaker, then add 20 mL of hexafluoroisopropanol solvent, and stir at 500 rpm for 24 h to obtain a mixture; wherein, in the mixture, the mass-volume concentration of hydrophobic polyester material is 0.03 g / mL, the mass-volume concentration of hydrophilic polymer material is 0.01 g / mL, and the mass-volume concentration of modified inorganic particles is 0.01 g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 1 cm and a height of 2 cm, quickly place it in a -80℃ freezer for 4 hours, and then freeze-dry it in a freeze dryer for 72 hours. The vacuum temperature of the freeze dryer is set to -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0091] Example 7 (1) 0.16 g of silane coupling agent (KH550) was added to an anhydrous ethanol solution containing 20 g of inorganic particles (β-tricalcium phosphate) (the mass fraction of β-tricalcium phosphate was 0.8%), and the temperature was controlled at 85 °C. Then the pH was adjusted to 11.0, and the reaction was stirred at 300 rpm for 6 h under nitrogen protection. After washing with deionized water three times to remove residual solvent, the product was filtered and placed in an oven at 37 °C for 24 h. The product was collected to obtain modified inorganic particles (KH550 modified β-tricalcium phosphate). Take 0.7 g of hydrophobic polyester material (poly(L-lactic acid)-caprolactone copolymer with intrinsic viscosity of 2.0~3.0 dL / g, with a lactide to caprolactone mass ratio of 50:50), 0.15 g of hydrophilic polymer material (gelatin), and 0.15 g of modified inorganic particles (KH550 modified β-tricalcium phosphate) in a beaker, then add 20 mL of hexafluoroisopropanol, and stir at 500 rpm for 12 h to obtain a mixture; wherein, in the mixture, the mass-volume concentration of hydrophobic polyester material is 0.035 g / mL, the mass-volume concentration of hydrophilic polymer material is 0.0075 g / mL, and the mass-volume concentration of modified inorganic particles is 0.0075 g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 2cm and a height of 5cm, quickly place it in a -80℃ freezer for 4 hours, and then freeze-dry it in a freeze dryer for 72 hours. The vacuum temperature of the freeze dryer is set to -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0092] Example 8 (1) 0.15 g of oleic acid was added to an anhydrous ethanol solution containing 30 g of hydroxyapatite (hydroxyapatite mass fraction was 0.5%), and the temperature was controlled at 80 °C. The mixture was stirred continuously at a stirring rate of 350 rpm for 3 h. After the reaction was completed, the precipitate was obtained as treated particles. The particles were washed three times with deionized water to remove residual solvent. After filtration, the filtered product was placed in a drying oven at 37 °C for 24 h. The product was collected to obtain modified inorganic particles (oleic acid modified hydroxyapatite). Take 0.2 g of hydrophobic polyester material (poly(L-lactic acid)-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, with a lactide to caprolactone mass ratio of 75:25), 0.1 g of hydrophilic polymer material (gelatin), and 0.1 g of modified inorganic particles (oleic acid modified hydroxyapatite) in a beaker, then add 10 mL of hexafluoroisopropanol, and stir at 500 rpm for 12 h to obtain a mixture; wherein, in the mixture, the mass-volume concentration of hydrophobic polyester material is 0.02 g / mL, the mass-volume concentration of hydrophilic polymer material is 0.01 g / mL, and the mass-volume concentration of modified inorganic particles is 0.01 g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 1 cm and a height of 10 cm, quickly place it in a -80℃ freezer for 4 hours, and then freeze-dry it in a freeze dryer for 72 hours. The vacuum temperature of the freeze dryer is set to -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0093] Comparative Example 1 (1) Take 1g of hydrophilic polymer material (gelatin) into a beaker, then add 20mL of solvent (hexafluoroisopropanol) and stir at 300rpm for 10h until clear to obtain a mixture; wherein, the mass volume concentration of hydrophilic polymer material in the mixture is 0.05g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 1 cm and a height of 10 cm, quickly place it in a -20℃ freezer for 2 hours, then transfer it to a -80℃ freezer for 2 hours, and then freeze-dry it in a freeze dryer for 72 hours. The freeze dryer is set to a vacuum temperature of -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0094] Comparative Example 2 (1) Take 1g of hydrophobic polyester material (poly-L-lactic acid-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, with a mass ratio of lactide to caprolactone of 75:25) in a beaker, then add 10mL of solvent (hexafluoroisopropanol) and stir at 400rpm for 10h until clear to obtain a mixture; wherein, the mass volume concentration of hydrophilic polymer material in the mixture is 0.1g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 1 cm and a height of 10 cm, quickly place it in a -20℃ freezer for 2 hours, then transfer it to a -80℃ freezer for 2 hours, and then freeze-dry it in a freeze dryer for 72 hours. The freeze dryer is set to a vacuum temperature of -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0095] Comparative Example 3 (1) Take 0.8g of hydrophobic polyester material (poly-L-lactic acid-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, with a mass ratio of lactide to caprolactone of 75:25) and 0.2g of inorganic particles (hydroxyapatite) into a beaker, then add 20mL of hexafluoroisopropanol, and stir and mix at 400rpm for 24h to obtain a mixture; wherein, in the mixture, the mass volume concentration of hydrophobic polyester material is 0.04g / mL, and the dispersion concentration of inorganic particles is 0.01g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 1 cm and a height of 10 cm, quickly place it in a -80℃ freezer for 4 hours, and then freeze-dry it in a freeze dryer for 72 hours. The vacuum temperature of the freeze dryer is set to -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0096] During the preparation process, it was found that the unmodified inorganic particles had poor compatibility with the hydrophobic polyester material, and the modified inorganic particles were unevenly distributed in the resulting porous biological scaffold.

[0097] Comparative Example 4 (1) 0.16 g of silane coupling agent (KH550) was added to an anhydrous ethanol solution containing 20 g of inorganic particles (β-tricalcium phosphate) (the mass fraction of β-tricalcium phosphate was 0.8%), and the temperature was controlled at 85 °C. Then the pH was adjusted to 11.0, and the reaction was stirred at 300 rpm for 6 h under nitrogen protection. After washing with deionized water three times to remove residual solvent, the product was filtered and placed in an oven at 37 °C for 24 h. The product was collected to obtain modified inorganic particles (KH550 modified β-tricalcium phosphate). Take 0.3g of hydrophobic polyester material (poly(L-lactic acid-caprolactone) copolymer with intrinsic viscosity of 2.0~3.0 dL / g, with a mass ratio of lactide to caprolactone of 50:50) and 0.7g of modified inorganic particles (KH550 modified β-tricalcium phosphate) in a beaker, then add 20mL of hexafluoroisopropanol, and stir at 500rpm for 12h to obtain a mixture; wherein, in the mixture, the mass-volume concentration of hydrophobic polyester material is 0.015g / mL, and the dispersion concentration of modified inorganic particles is 0.035g / mL; (2) Pour the mixture into a cylindrical mold with a diameter of 2cm and a height of 5cm, quickly place it in a -80℃ freezer for 4 hours, and then freeze-dry it in a freeze dryer for 72 hours. The vacuum temperature of the freeze dryer is set to -80℃. After demolding, a cylindrical porous biological scaffold is obtained.

[0098] Comparative Example 5 (1) Take 1.8g of hydrophobic polyester material (poly-L-lactic acid-caprolactone copolymer with intrinsic viscosity of 1.0~2.0 dL / g, with a mass ratio of lactide to caprolactone of 75:25), 0.2g of NaCl (particle size of 250~400μm), and 0.2g of hydrophilic polymer material (chitosan) into a beaker, then add 20mL of hexafluoroisopropanol, and stir and mix at 400rpm for 24h to obtain a mixture; wherein, in the mixture, the mass volume concentration of hydrophobic polyester material is 0.09g / mL, and the mass volume concentration of hydrophilic polymer material is 0.01g / mL; (2) Pour the mixture into a mold with a diameter of 1 cm and a height of 0.38 mm. Place the mold in a vacuum oven at 37°C and dry for 24 hours to remove the solvent. Then soak the scaffold in distilled water for 48 hours to remove NaCl. Dry the NaCl-free scaffold at room temperature for 72 hours to obtain a porous biological scaffold.

[0099] Performance testing 1. Scanning electron microscopy observation Scanning electron microscopy was performed on the cross-sections of the porous bioscaffolds in Examples 1, 5, and Comparative Example 4. The results are as follows: Figure 3-5 As shown.

[0100] Depend on Figure 3 and 4 As can be seen, the porous biological scaffold of the present invention has a porous internal structure; by Figure 5 It can be seen that the porous biological scaffold in Comparative Example 4 has a small pore size and low porosity.

[0101] Microscopic observation The porous biological scaffolds of Example 3 and Comparative Example 5 were observed under a microscope, and the results are as follows: Figure 6 and 7 As shown.

[0102] like Figure 6 As shown, the porous biological scaffold in Example 3 was intact, without any defects or breaks; while as Figure 7 As shown, the porous biological scaffold prepared using a porogen in Comparative Example 5 exhibited localized defects and fractures after cleaning due to NaCl occupancy, leading to localized stress failure and affecting the overall mechanical properties of the scaffold. Because microscopic observation revealed localized defects and fractures in the porous biological scaffold of Comparative Example 5, further performance testing was not conducted on it.

[0103] Pore ​​size and porosity testing The porous biological scaffolds prepared in Examples 1-8 and Comparative Examples 1-4 were tested for pore size and porosity. The test results are shown in Table 1.

[0104] Method for testing aperture size: First, the surface of the support is sprayed with gold. The microstructure of the sample is measured using a scanning electron microscope. Then, the size and aperture of the pores in the support are analyzed and statistically analyzed using Imaje-J software.

[0105] Porosity testing method: Refer to standard YY / T 1616-2018 "Performance and Testing Guidelines for Biomaterial Scaffolds in Tissue Engineering Medical Devices": Using Archimedes' principle and ethanol as the liquid medium, the porosity is calculated as follows: Porosity = (weight of scaffold immersed in ethanol - weight of scaffold) / (weight of scaffold immersed in ethanol - weight of scaffold suspended in ethanol). Each group needs to be measured 4 times and the average value is taken.

[0106] 3. Mechanical property testing The porous biological scaffolds prepared in Examples 1-8 and Comparative Examples 1-4 were subjected to mechanical property tests, and the test results are shown in Table 1.

[0107] Referring to the standard YY / T 1616-2018 "Performance and Testing Guidelines for Biomaterial Scaffolds in Tissue Engineering Medical Devices": Each set of samples obtained after demolding is poured into a cylindrical mold with a diameter of 1 cm and a height of 10 cm. Measurements are taken from at least two cross-sections perpendicular to the central axis of the sample. The sample is placed on the sample stage of the testing machine. The testing machine is started and the deformation versus load curve is plotted at a constant crosshead speed within the range of 0.05 mm / min to 2.0 mm / min. The machine is stopped when the sample breaks or when the compression height reaches 20% (i.e., from a height of 10 cm to a height of 2 cm). The peak load and elastic modulus of each set are obtained.

[0108] Degradation time test Accurately weigh 0.5 g of the porous biological scaffolds prepared in Examples 1-8 and Comparative Examples 1-4 into glass bottles, add 100 ml of phosphate buffer, place the glass bottles in a constant temperature incubator at 37°C, observe the state of the samples, record the time for complete degradation of the samples, and the results are shown in Table 1.

[0109] 5. Liquid absorption performance test Weigh the porous biological scaffolds prepared in Examples 1-8 and Comparative Examples 1-4 respectively (W1), immerse them in physiological saline and weigh the saturated weight (W2), calculate the water absorption rate (W2 / W1)×100%, and the results are shown in Table 1.

[0110] Table 1 As shown in Table 1, the porous biological scaffolds of Examples 1-8 have an average pore size of 10-80 μm and a porosity of 40-90%; their peak load in the dry state is 30-100 N, their elastic modulus is 1-10 MPa, their liquid absorption rate is 200-600%, and their degradation period is 1-12 months. It is evident that the porous biological scaffolds of the present invention possess high porosity, good liquid absorption, and excellent mechanical properties, and their degradation time is adjustable.

[0111] 5. Compressibility assessment In clinical use, the porous biological scaffold can be cut into the required shape before use, manually compressed, and then pushed to the patient's target site through interventional devices.

[0112] After compressing and thinning the strip-shaped porous biological scaffold from Example 2, it was inserted into a microcatheter using tweezers. Then, bismuth oxide and physiological saline were mixed at a mass ratio of 1:3 to obtain a suspension. This suspension was then injected into the microcatheter carrying the strip-shaped sample. The porous scaffold was allowed to soak in the suspension for 3-5 minutes to obtain a porous biological scaffold loaded with bismuth oxide contrast agent. Figure 8 As shown.

[0113] The porous biological scaffold of Example 8 was artificially compressed, and the results are as follows: Figure 9 As shown. By Figure 9 It can be seen that the porous biological scaffold of Example 8 is easily compressed artificially.

[0114] 6. In vitro liquid aspiration test The porous biological scaffold prepared in Example 5 was immersed in 50 ml of physiological saline for 5 minutes to absorb the saline solution. It was found that the porous biological scaffold could absorb the physiological saline solution relatively quickly. Figure 10 As shown, the volume of the porous biological scaffold changes little before and after liquid aspiration, with almost no change.

[0115] After cutting the porous biological scaffold prepared in Example 7, two drops of blood were drawn up using a dropper and added to a surface area of ​​1 cm². 2 On porous biological scaffolds, it was found that porous biological scaffolds can rapidly adsorb blood, such as... Figure 11 As shown, the volume of the porous biological scaffold remained almost unchanged before and after liquid aspiration.

[0116] After cutting the biological scaffold prepared in Comparative Example 4, two drops of blood were drawn up using a dropper and added to a surface area of ​​1 cm². 2 On porous bio-scaffolds, it was found that the rate of blood adsorption was relatively slow, such as... Figure 12 As shown.

[0117] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A porous biological scaffold, characterized in that, The porous bioscaffold is prepared by pre-freezing and freeze-drying a mixture of hydrophobic polyester material and hydrophilic polymer material; wherein, the scaffold has a three-dimensional porous structure, can be compressed to a size smaller than its original volume in the dry state, and can recover to its original volume after being released from the compressed state.

2. The porous biological scaffold according to claim 1, characterized in that, The mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~15):1; Preferably, the hydrophobic polyester material is at least one of poly(L-lactic acid-caprolactone copolymer), polytrimethylene carbonate, or polybutylene adipate-terephthalate. The hydrophilic polymer material is at least one of gelatin, chitosan, starch, sodium hyaluronate, regenerated oxidized cellulose, carboxymethyl cellulose, alginate, or starch polysaccharide; and / or The solvent for the mixture is hexafluoroisopropanol; More preferably, the intrinsic viscosity of the hydrophobic polyester material is 1.0~3.0 dL / g.

3. The porous biological scaffold according to claim 2, characterized in that, The hydrophobic polyester material is a poly(L-lactic acid-caprolactone) copolymer; Preferably, in the poly-L-lactic acid-caprolactone copolymer, the mass ratio of lactide to caprolactone is (50~80):(20~50).

4. The porous biological scaffold according to any one of claims 1 to 3, characterized in that, The porous bioscaffold has an average pore size of 10–80 μm and a porosity of 40–90%; and / or The porous biological scaffold has a peak load of 30~100N, an elastic modulus of 1~10MPa, a liquid absorption rate of 200~480%, and a degradation period of 1~12 months in the dry state.

5. The porous biological scaffold according to claim 1, characterized in that, The porous biological scaffold is configured to be compressible in a dry state and delivered to the target site via a tubular instrument. After implantation into the target site, it can return to its original volume before compression, thereby achieving closure or filling of the target site. Preferably, the porous biological scaffold is configured as a vascular embolization material to block blood vessels; or the porous biological scaffold is configured as a skull base bone repair material to fill the skull base bone area.

6. The porous biological scaffold according to claim 5, characterized in that, When the porous bioscaffold is configured as a vascular embolization material, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~9):

1.

7. The porous biological scaffold according to claim 5, characterized in that, When the porous biological scaffold is configured as a skull base bone repair material, the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~8):1; Preferably, when the porous biological scaffold is configured as a skull base bone repair material, the material used to prepare the porous biological scaffold further includes modified inorganic particles; More preferably, the mass ratio of the hydrophobic polyester material, the hydrophilic polymer material and the modified inorganic particles is (5~12):(0.2~3):(0.1~3); more preferably, it is (6~10):(0.5~2):(0.5~2).

8. The porous biological scaffold according to claim 7, characterized in that, The modified inorganic particles are obtained by modifying inorganic particles with a surface modifier; Preferably, the inorganic particles include at least one of hydroxyapatite, α-tricalcium phosphate, β-tricalcium phosphate, tetracalcium phosphate, calcium pyrophosphate, calcium dihydrogen phosphate, anhydrous calcium dihydrogen phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, octacalcium phosphate, calcium carbonate, calcium citrate, or calcium sulfate; more preferably, the particle size of the inorganic particles is less than 70 μm. Preferably, the surface modifier comprises a small molecule modifier or a polymer modifier; the small molecule modifier comprises at least one of oleic acid, dopamine, and silane coupling agent, and the polymer modifier comprises polydopamine and / or polyethyleneimine; More preferably, the mass ratio of the small molecule modifier to the inorganic particles is 1:(50~300), and the mass ratio of the polymer modifier to the inorganic particles is 1:(15~50).

9. A method for preparing a porous biological scaffold according to any one of claims 1 to 8, characterized in that, The method includes the following steps: (1) Add the hydrophobic polyester material and the hydrophilic polymer material to the solvent and stir to mix them to obtain a mixture; (2) The mixture is poured into a mold, pre-frozen and freeze-dried to obtain the porous biological scaffold; Optionally, the mixture may also include modified inorganic particles; Preferably, in the mixture, the mass-volume concentration of the hydrophobic polyester material is 0.01~0.1 g / mL, the mass-volume concentration of the hydrophilic polymer material is 0.001~0.06 g / mL, and the mass ratio of the hydrophobic polyester material to the hydrophilic polymer material is (1~15):1; and / or When the mixture includes modified inorganic particles, the mass-volume concentration of the modified inorganic particles is 0.001~0.02 g / mL, and the mass ratio of the hydrophobic polyester material, the hydrophilic polymer material and the modified inorganic particles is (5~12):(0.2~3):(0.1~3).

10. The preparation method according to claim 9, characterized in that, In step (1), the stirring speed is 200~1000 rpm and the time is 10~24h; In step (2), the pre-freezing temperature is -80~-10℃ and the time is 0.5~5h; the freeze-drying temperature is -80~-40℃ and the time is 48~72h. The method for preparing the modified inorganic particles includes the step of mixing a surface modifier with inorganic particles to modify the inorganic particles. Preferably, before pre-freezing, the mixture is further subjected to a quick-freezing step; wherein the quick-freezing temperature is -25~-20℃ and the time is 1~2h.

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