A rare earth-based anticoagulant material, a preparation method and application thereof

Abstract

The application provides a rare earth-based anticoagulant material and a preparation method and application thereof, and the rare earth-based anticoagulant material comprises a polymer matrix and a composite rare earth functional component, the composite rare earth functional component comprises lanthanum-doped bioactive glass functional particles and cerium oxide functional particles, the addition amount of the lanthanum-doped bioactive glass functional particles is 0.5%-5.0% of the mass of the polymer matrix, the addition amount of the cerium oxide functional particles is 0.1%-1.0% of the mass of the polymer matrix, the polymer matrix is a blend of poly(epsilon-caprolactone) and poly(L-lactic acid), and the mass ratio of the poly(epsilon-caprolactone) to the poly(L-lactic acid) is (6-9):(1-4). The material not only provides efficient anticoagulant function, but also has significant antioxidant and anti-inflammatory properties.

Description

Technical Field

[0001] This invention belongs to the field of medical device technology, and in particular relates to a rare earth-based anticoagulant material, its preparation method, and its application. Background Technology

[0002] Cardiovascular diseases encompass a range of conditions that damage blood vessels or the heart. Thrombotic disorders are the cause of most cardiovascular events. Under physiological conditions, the body uses various clotting factors such as fibrinogen, prothrombin, and thrombin to ensure normal blood flow in circulation and prevent life-threatening blood loss, playing a crucial role in maintaining hemostasis balance. However, under abnormal or pathological conditions, hemostasis disorders can accelerate thrombus formation, thereby triggering or worsening cardiovascular diseases. Therefore, timely and regular anticoagulation therapy is essential for the prevention and treatment of cardiovascular diseases when facing thrombotic disorders. In addition to thrombus formation, elevated levels of free radicals induced by oxidative stress also play a vital role in the deterioration of cardiovascular diseases.

[0003] Among current anticoagulants, heparin, a natural oligosaccharide, is considered the most widely used anticoagulant due to its unique properties. It can bind to antithrombin III (AT III), accelerating thrombin inhibition. Furthermore, heparin can alleviate some complications during dialysis, such as oxidative stress and inflammation, and also possesses anti-allergic properties, which are significant for its application. However, using heparin as an anticoagulant can cause adverse reactions such as bleeding, thrombocytopenia, elevated transaminases, and hyperkalemia. Thrombocytopenia is the most significant adverse reaction. On the other hand, the increasing scarcity and high price of raw materials for heparin production hinder its large-scale production. Therefore, the development of heparin-like materials to replace heparin has become a trend in recent years.

[0004] Rare earth elements (REEs), due to their unique electronic structure, possess excellent biological properties such as antibacterial activity, anti-infection properties, scavenging of reactive oxygen species (ROS), reduction of oxidative stress, and immune enhancement. Therefore, by chemically modifying rare earth elements, highly efficient rare earth-based anticoagulant materials can be obtained, combining anticoagulant effects, ROS removal, and anti-inflammatory properties. These materials hold great promise as a replacement for heparin and have significant application value and potential in medical anticoagulant therapy. Summary of the Invention

[0005] In view of this, the present invention aims to overcome the defects in the prior art and propose a rare earth-based anticoagulant material, its preparation method and application.

[0006] To achieve the above objectives, the technical solution of the present invention is implemented as follows:

[0007] In a first aspect, the present invention provides a rare earth-based anticoagulant material, comprising a polymer matrix and a composite rare earth functional component, wherein the composite rare earth functional component comprises lanthanum-doped bioactive glass functional particles and cerium oxide functional particles, wherein the amount of lanthanum-doped bioactive glass functional particles added is 0.5%-5.0% of the mass of the polymer matrix; the amount of cerium oxide functional particles added is 0.1%-1.0% of the mass of the polymer matrix; wherein the polymer matrix is ​​a blend of poly(ε-caprolactone) and poly(L-lactic acid), and the mass ratio of poly(ε-caprolactone) to poly(L-lactic acid) is (6-9):(1-4).

[0008] Preferably, the mass ratio of poly(ε-caprolactone) to poly(L-lactic acid) is 7:3.

[0009] Preferably, the average particle size of the lanthanum-doped bioactive glass functional particles ranges from 50 nm to 150 nm.

[0010] Preferably, the average particle size of the cerium oxide functional particles ranges from 5 nm to 20 nm.

[0011] Preferably, the preparation method of the lanthanum-doped bioactive glass functional particles includes the following steps:

[0012] S1: Dissolve the silicon source in anhydrous ethanol to obtain a silicon source solution;

[0013] S2: Dissolve the calcium source, phosphorus source and lanthanum source in deionized water to obtain mixed solution A;

[0014] S3: Add the mixed solution A obtained in step S2 dropwise to the silicon source obtained in step S1 to obtain mixed solution B. Under continuous stirring, control the pH value of mixed solution B between 2.0 and 3.0, and control the temperature between 25℃ and 30℃, and maintain the reaction for 2h-4h to obtain sol.

[0015] S4: The sol obtained in step S3 is aged at room temperature for 24-48 hours to form a gel;

[0016] S5: Dry the gel obtained in step S4 in a constant temperature oven at 50℃-70℃ to remove residual solvent and moisture.

[0017] S6: The dried gel was calcined at a temperature of 500℃-700℃ to obtain lanthanum-doped bioactive glass functional particles.

[0018] Preferably, the mass ratio of the silicon source, calcium source, phosphorus source and lanthanum source is (70-83):(15-30):(1-10):(1-5).

[0019] Preferably, the silicon source is selected from one or a mixture of two or more of tetraethoxysilane, tetramethoxysilane, tetran-propoxysilane, and tetraisopropoxysilane.

[0020] Preferably, the calcium source is selected from one or a mixture of two or more of calcium nitrate tetrahydrate, calcium chloride, and calcium acetate.

[0021] Preferably, the phosphorus source is selected from one or a mixture of two or more of triethyl phosphate, trimethyl phosphate, tripropyl phosphate, and tributyl phosphate.

[0022] Preferably, the lanthanum source is selected from one or a mixture of two or more of lanthanum nitrate hexahydrate, lanthanum acetate, lanthanum citrate, and lanthanum acetylacetonate.

[0023] Preferably, the gel in step S6 is calcined in an inert atmosphere or in air.

[0024] Preferably, the preparation method of the cerium oxide functional particles includes the following steps:

[0025] Step 1: Dissolve the cerium source in deionized water to prepare a cerium salt solution;

[0026] Step 2: Slowly add the alkaline solution dropwise to the cerium salt solution while continuously stirring until a suspension with a pH of 9.0-10.0 is obtained;

[0027] Step 3: Add hydrogen peroxide to the suspension to obtain a cerium oxide precursor with mixed valence states;

[0028] Step 4: Transfer the obtained cerium oxide precursor to a reaction vessel and carry out a hydrothermal reaction at a temperature of 180℃-200℃ for 12h-24h. After the reaction is completed, cool the reaction vessel to room temperature.

[0029] Step 5: Collect the particles by centrifugation, wash until the washing liquid is neutral, and then vacuum dry to obtain cerium oxide functional particles.

[0030] Preferably, the cerium source is selected from one or a mixture of two or more of cerium nitrate or its hydrate, cerium ammonium sulfate, cerium acetylacetone, and cerium chloride.

[0031] Secondly, the present invention also provides a method for preparing the above-mentioned rare earth-based anticoagulant material, the method comprising the following steps:

[0032] Lanthanum-doped bioactive glass functional particles and cerium oxide functional particles were added to a polymer solution and ultrasonically treated for 30-60 minutes. Then, the mixture was continuously stirred under magnetic stirring for 1-3 hours and vacuum dried to obtain a rare earth-based anticoagulant material.

[0033] Preferably, the method for preparing the polymer solution includes the following steps:

[0034] The poly(ε-caprolactone) and poly(L-lactic acid) are mixed to form a polymer matrix. The polymer matrix is ​​dissolved in a mixed solvent to obtain a mixed solution. The mixed solution is stirred continuously for 6-12 hours to obtain a polymer solution.

[0035] Preferably, the total mass ratio of poly(ε-caprolactone) and poly(L-lactic acid) in the polymer solution to the mass ratio of the mixed solvent is (8-12):100.

[0036] Preferably, the mixed solvent is prepared by mixing chloroform and N,N-dimethylformamide in a volume ratio of (4-6):1.

[0037] Thirdly, the present invention also provides the application of the above-mentioned rare earth-based anticoagulant material in the preparation of blood contact medical devices.

[0038] Preferably, the blood contact medical device includes, but is not limited to: endovascular stents, artificial blood vessel grafts, extracorporeal circulation circuit components, heart valves, and blood bags.

[0039] The rare earth-based anticoagulant material disclosed in this invention exerts its biological activity through the synergistic effect of the following multiple mechanisms:

[0040] First, the anticoagulant mechanism: The anticoagulant properties of the material are mainly achieved through the release of lanthanum ions and their precise regulation of the coagulation cascade reaction. Under physiological conditions, the lanthanum-doped bioactive glass functional particles (hereinafter referred to as La-BG functional particles) can continuously and controllably release trivalent lanthanum ions (La... 3+ The La 3+ The ion has the same properties as divalent calcium ions (Ca). 2+ Its highly similar charge and ionic radius properties enable it to react with the calcium required by coagulation factors. 2+ The γ-carboxyglutamate (Gla) residues involved form a competitive binding. This mechanism of action leads to the inhibition of the formation of the prothrombin activation complex and the prothrombinase complex, thereby significantly prolonging clotting time, manifested as a prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT).

[0041] Second, the antioxidant mechanism: The antioxidant properties of the material are mainly attributed to the enzyme-like activity exhibited by the cerium oxide functional particles (CeO2 functional particles, hereinafter the same). The CeO2 functional particles contain CeO2 in their crystal lattice structure. 3+ and Ce 4+The presence of cerium ions in two valence states, a mixed state that enables them to undergo reversible redox cycles. These continuous redox cycles allow CeO2 functional particles to efficiently and continuously scavenge reactive oxygen species (ROS), including superoxide and hydrogen peroxide, from the blood and tissues. This reduction in ROS levels effectively alleviates oxidative stress damage to vascular endothelial cells and blood components, thereby protecting endothelial barrier function and inhibiting oxidative stress-induced inflammation and thrombosis.

[0042] Third, the anti-inflammatory mechanism: the anti-inflammatory properties of the material are a synergistic result of antioxidant activity and direct regulation by lanthanum ions. By scavenging reactive oxygen species, the CeO2 functional particles indirectly inhibit the inflammatory cascade reaction. Simultaneously, La... 3+ Ions can interfere with the activity of calcium-dependent protein kinases and phosphatases, which play key roles in the activation, migration, and release of inflammatory mediators of immune cells. Through a dual mechanism of action, the rare-earth-based anticoagulant material can significantly reduce inflammatory responses at the implantation site and promote tissue repair and healing.

[0043] Compared with the prior art, the present invention has the following advantages:

[0044] (1) This invention reduces the systemic anticoagulant dose required to achieve effective anticoagulation by precisely controlling the coagulation cascade reaction rather than by broad-spectrum, systemic coagulation inhibition, thereby effectively reducing the incidence of bleeding complications caused by traditional anticoagulants, such as intracranial hemorrhage and gastrointestinal bleeding.

[0045] (2) The rare earth elements and synthetic polymers used in this invention have stable sources and controllable synthesis processes, which completely eliminates the dependence on animal tissue extracts, solves the problems of unstable raw material supply, high cost and biosafety risks faced by natural heparin, realizes the feasibility of large-scale production, and reduces manufacturing costs.

[0046] (3) The material of this invention not only provides highly efficient anticoagulant function, but also possesses significant antioxidant and anti-inflammatory properties. The CeO2 functional particles can effectively scavenge reactive oxygen free radicals and reduce oxidative stress damage; the La 3+ The ions and CeO2 functional particles synergistically inhibit the inflammatory response and promote tissue repair and endothelialization at the implantation site. This multifunctionality enables them to provide more comprehensive therapeutic effects in complex pathophysiological environments. Attached Figure Description

[0047] Figure 1 This is a diagram illustrating the anticoagulant effect of Example 1;

[0048] Figure 2 The anticoagulant effect diagrams are for Example 1 and Comparative Examples 1-6;

[0049] Figure 3 The diagram shows the reactive oxygen species scavenging effect of Example 1 and Comparative Examples 1-6. Detailed Implementation

[0050] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention.

[0051] In this document, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0052] In this document, when values ​​are described as ranges, it should be understood that such disclosure includes disclosure of all possible subranges within that range, as well as the specific numerical values ​​that fall within that range, regardless of whether the specific numerical value or specific subrange is explicitly specified.

[0053] In this article, the terms "multiple" or "more than" are used unless otherwise specified, referring to a quantity greater than or equal to 2. For example, "one or more" means one or more types.

[0054] In this document, the terms "preferred" and "more preferred" are used only to describe implementation methods or embodiments with better effects, and should be understood as not constituting a limitation on the scope of protection of this invention.

[0055] In this document, terms such as "further" are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of this invention.

[0056] In this article, the term "and / or" describes an association between objects, indicating that three relationships can exist. For example, A and / or B means: A or B, or A and B.

[0057] In this document, the term "about" means a specified value of + / - 10%, preferably + / - 5%, and more preferably + / - 1%.

[0058] In this article, the terms “include,” “including,” “have,” “contain,” etc., are all open-ended terms, meaning that they include but are not limited to.

[0059] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar to or equivalent to those described herein may be used in the implementation or testing of this invention.

[0060] The rare earth-based anticoagulant material (LALO) disclosed in this invention is based on a multi-component synergistic composite system, comprising: a polymer matrix, which is a blend of poly(ε-caprolactone) (PCL) and poly(L-lactic acid) (PLLA); and a composite rare earth functional component dispersed and incorporated within the polymer matrix, the composite rare earth functional component containing lanthanum (La) and cerium (Ce). The lanthanum element exists in the form of lanthanum-doped bioactive glass functional particles, and the cerium element exists in the form of cerium oxide functional particles.

[0061] The polymer matrix is ​​composed of poly(ε-caprolactone) and poly(L-lactic acid) blended in a specific mass ratio, ranging from 6:4 to 9:1, preferably 7:3.

[0062] The polymer matrix was selected based on its excellent biocompatibility, controllable degradation rate, and tunable mechanical properties to meet the application requirements of different medical devices. Through its own degradation, the matrix material enables the sustained release of rare earth ions, which are ultimately metabolized and eliminated in the body, thus avoiding complications that may arise from long-term implantation.

[0063] The average particle size of the La-BG functional particles ranges from 50 nm to 150 nm. The La-BG functional particles are prepared using the sol-gel method, with the specific steps as follows:

[0064] First, 70-83 parts of a silicon source were dissolved in anhydrous ethanol to obtain a silicon source ethanol solution. Second, 15-30 parts of a calcium source, 1-10 parts of a phosphorus source, and 1-5 parts of a lanthanum source were dissolved in deionized water. This aqueous solution was added dropwise to the silicon source ethanol solution. Under continuous stirring, the pH of the solution was precisely controlled between 2.0 and 3.0, and the reaction was maintained at a temperature of 25℃-30℃ for 2-4 hours to promote hydrolysis and condensation reactions. The resulting sol was aged at room temperature for 24-48 hours to form a gel. Subsequently, the gel was dried in a constant temperature oven at 60℃ for 48 hours to remove residual solvent and moisture. Finally, the dried gel was calcined at 600℃ for 3 hours to obtain highly crystalline La-BG functional particles.

[0065] The calcination process must be carried out in a controlled atmosphere (e.g., air or an inert gas) to ensure the purity and phase composition of the particles. The introduction of lanthanum into the La-BG functional particles aims to utilize its competitive binding properties with calcium ions to play a precise regulatory role in the coagulation cascade reaction.

[0066] The average particle size of the cerium oxide functional particles ranges from 5 nm to 20 nm. The CeO2 functional particles are prepared using a hydrothermal method, with the specific steps as follows:

[0067] First, cerium nitrate hexahydrate is dissolved in deionized water to prepare a solution with a concentration of 0.05 M to 0.2 M. Next, sodium hydroxide (NaOH) solution is slowly added dropwise to the cerium nitrate solution while continuously stirring until the pH of the solution reaches 9.0 to 10.0 to promote the precipitation of cerium hydroxide. Then, an appropriate amount of hydrogen peroxide (H₂O₂) is added to the suspension to oxidize some of the Ce. 3+ For Ce 4+ A mixed-valence cerium oxide precursor was obtained. The resulting mixture was transferred to a PTFE-lined stainless steel high-pressure reactor and subjected to a hydrothermal reaction at 180°C to 200°C for 12 to 24 hours. After the reaction, the reactor was cooled to room temperature. The obtained CeO2 functional particles were collected by centrifugation and repeatedly washed with deionized water until the washing solution was neutral to remove residual ions and impurities. Finally, the washed CeO2 functional particles were dried in a vacuum oven at 50-70°C for 24-48 hours.

[0068] The cerium element in the CeO2 functional particles exhibits reversible CeO2 properties. 3+ / Ce 4+ The redox couple allows it to mimic the activities of superoxide dismutase (SOD) and catalase (CAT) in living organisms, thereby efficiently scavenging reactive oxygen free radicals.

[0069] The preparation method of the rare earth-based high-efficiency anticoagulant material provided by this invention includes the following core steps:

[0070] The first step involves accurately weighing and mixing the poly(ε-caprolactone) and poly(L-lactic acid) according to the stated mass ratio to prepare a polymer matrix. The polymer matrix is ​​then dissolved in a mixed solvent at a mass ratio of (8-12):100 to obtain a mixed solution. The mixed solvent is composed of chloroform and N,N-dimethylformamide (DMF) at a volume ratio of 4:1 to 6:1. The mixed solution is continuously stirred for 6 to 12 hours to ensure complete dissolution of the polymer and the absence of visible agglomeration in the solution.

[0071] In the second step, the La-BG functional particles and the CeO2 functional particles are accurately weighed at 0.5% to 5.0% and 0.1% to 1.0% of the polymer matrix mass, respectively. These two types of functional particles are added to the polymer solution to obtain a mixture. To ensure uniform dispersion of the functional particles in the polymer solution, the mixture is ultrasonically treated in an ultrasonic bath for 30 to 60 minutes, followed by continuous stirring at low speed with magnetic stirring for 2 hours to prevent re-aggregation of the functional particles. The prepared rare-earth-based anticoagulant material is dried in a vacuum oven at 40°C to 50°C for 24 to 48 hours to completely remove residual organic solvents and moisture. This drying process helps stabilize the material structure and ensure its biocompatibility.

[0072] The present invention will be described in detail below with reference to the embodiments.

[0073] Example 1

[0074] Mix 5 parts chloroform with 1 part N,N-dimethylformamide (DMF) and stir continuously for 6 hours to prepare a mixed solvent for later use. Mix 7 parts poly(ε-caprolactone) and 3 parts poly(L-lactic acid) to prepare a polymer matrix and let it stand at room temperature for later use. Add 10 parts of the polymer matrix to 100 parts of the mixed solvent to obtain a mixed solution, and stir continuously for 8 hours to ensure that the polymer matrix is ​​completely dissolved and that there is no visible agglomeration in the solution to obtain a polymer solution.

[0075] Eighty parts of tetraethoxysilane (TEOS) were dissolved in anhydrous ethanol as the silicon source. Next, 20 parts of calcium nitrate tetrahydrate, 5 parts of triethyl phosphate, and 3 parts of lanthanum nitrate hexahydrate were dissolved in deionized water as the calcium, phosphorus, and lanthanum sources, respectively. The aqueous solutions were added dropwise to the silicon source ethanol solution. Under continuous stirring, the pH of the solution was precisely controlled at 3.0, and the reaction was maintained at 30°C for 2 hours to promote hydrolysis and condensation reactions. The resulting sol was aged at room temperature for 48 hours to form a gel. Subsequently, the gel was dried in a constant temperature oven at 60°C for 48 hours to remove residual solvent and moisture. Finally, the dried gel was calcined at 600°C for 3 hours to obtain highly crystalline La-BG functional particles.

[0076] Cerium nitrate hexahydrate was dissolved in deionized water to prepare a 0.1 M solution. Sodium hydroxide solution was slowly added dropwise to the cerium nitrate solution while continuously stirring until the pH of the solution reached 10.0 to promote the precipitation of cerium hydroxide. Then, an appropriate amount of hydrogen peroxide was added to the suspension to oxidize some of the Ce. 3+ For Ce 4+A mixed-valence cerium oxide precursor was obtained. The resulting mixed-valence cerium oxide precursor was transferred to a PTFE-lined stainless steel high-pressure reactor and subjected to a hydrothermal reaction at 200°C for 24 hours. After the reaction, the reactor was cooled to room temperature. The obtained CeO2 functional particles were collected by centrifugation and repeatedly washed with deionized water until the washing solution was neutral to remove residual ions and impurities. Finally, the washed CeO2 functional particles were dried in a vacuum oven at 60°C for 24 hours.

[0077] La-BG functional particles and CeO2 functional particles were precisely weighed at 2.5% and 1.0% of the polymer matrix mass, respectively. These two types of functional particles were added to the polymer solution to obtain a mixture. To ensure uniform dispersion of the functional particles in the polymer solution, the mixture was ultrasonically treated in an ultrasonic bath for 45 minutes, followed by continuous stirring at low speed with magnetic stirring for 2 hours to prevent re-aggregation of the functional particles. The prepared rare-earth-based anticoagulant material was dried in a vacuum oven at 45°C for 36 hours to completely remove residual organic solvents and moisture. The resulting rare-earth-based anticoagulant material was designated LALO1.

[0078] Example 2

[0079] Mix 4 parts chloroform with 1 part N,N-dimethylformamide (DMF) and stir continuously for 12 hours to prepare a mixed solvent for later use. Mix 6 parts poly(ε-caprolactone) and 1 part poly(L-lactic acid) to prepare a polymer matrix and let it stand at room temperature for later use. Add 8 parts of the polymer matrix to 100 parts of the mixed solvent to obtain a mixed solution, and stir continuously for 8 hours to ensure that the polymer matrix is ​​completely dissolved and there are no visible agglomerates in the solution to obtain a polymer solution.

[0080] 70 parts of tetraethoxysilane (TEOS) were dissolved in anhydrous ethanol as the silicon source. Next, 15 parts of calcium nitrate tetrahydrate, 1 part of triethyl phosphate, and 1 part of lanthanum nitrate hexahydrate were dissolved in deionized water as the calcium, phosphorus, and lanthanum sources, respectively. The aqueous solutions were added dropwise to the silicon source ethanol solution. Under continuous stirring, the pH of the solution was precisely controlled at 2.0, and the reaction was maintained at 25°C for 2 hours to promote hydrolysis and condensation reactions. The resulting sol was aged at room temperature for 24 hours to form a gel. Subsequently, the gel was dried in a constant temperature oven at 60°C for 48 hours to remove residual solvent and moisture. Finally, the dried gel was calcined at 600°C for 3 hours to obtain highly crystalline La-BG functional particles.

[0081] Cerium nitrate hexahydrate was dissolved in deionized water to prepare a 0.05 M solution. Next, sodium hydroxide solution was slowly added dropwise to the cerium nitrate solution while continuously stirring until the pH of the solution reached 10.0 to promote the precipitation of cerium hydroxide. Then, an appropriate amount of hydrogen peroxide was added to the suspension to oxidize some of the Ce. 3+ For Ce 4+ A mixed-valence cerium oxide precursor was obtained. The resulting mixed-valence cerium oxide precursor was transferred to a PTFE-lined stainless steel high-pressure reactor and subjected to a hydrothermal reaction at 180°C for 12 hours. After the reaction, the reactor was cooled to room temperature. The obtained CeO2 functional particles were collected by centrifugation and repeatedly washed with deionized water until the washing solution was neutral to remove residual ions and impurities. Finally, the washed CeO2 functional particles were dried in a vacuum oven at 60°C for 24 hours.

[0082] La-BG functional particles and CeO2 functional particles were precisely weighed at 0.5% and 0.1% of the polymer matrix mass, respectively. These two types of functional particles were added to the polymer solution to obtain a mixture. To ensure uniform dispersion of the functional particles in the polymer solution, the mixture was ultrasonically treated in an ultrasonic bath for 30 minutes, followed by continuous stirring at low speed with magnetic stirring for 2 hours to prevent re-aggregation of the functional particles. The prepared rare-earth-based anticoagulant material was dried in a vacuum oven at 40°C for 24 hours to completely remove residual organic solvents and moisture. The resulting rare-earth-based anticoagulant material was designated LALO2.

[0083] Example 3

[0084] Mix 4 parts chloroform with 1 part N,N-dimethylformamide (DMF) and stir continuously for 12 hours to prepare a mixed solvent for later use. Mix 9 parts poly(ε-caprolactone) and 4 parts poly(L-lactic acid) to prepare a polymer matrix and let it stand at room temperature for later use. Add 12 parts of the polymer matrix to 100 parts of the mixed solvent to obtain a mixed solution, and stir continuously for 8 hours to ensure that the polymer matrix is ​​completely dissolved and that there is no visible agglomeration in the solution to obtain a polymer solution.

[0085] Eighty-three parts of tetraethoxysilane (TEOS) were dissolved in anhydrous ethanol as the silicon source. Next, 30 parts of calcium nitrate tetrahydrate, 10 parts of triethyl phosphate, and 5 parts of lanthanum nitrate hexahydrate were dissolved in deionized water as the calcium, phosphorus, and lanthanum sources, respectively. The aqueous solutions were added dropwise to the silicon source ethanol solution. Under continuous stirring, the pH of the solution was precisely controlled at 3.0, and the reaction was maintained at 30°C for 2 hours to promote hydrolysis and condensation reactions. The resulting sol was aged at room temperature for 48 hours to form a gel. Subsequently, the gel was dried in a constant temperature oven at 60°C for 48 hours to remove residual solvent and moisture. Finally, the dried gel was calcined at 600°C for 3 hours to obtain highly crystalline La-BG functional particles.

[0086] Cerium nitrate hexahydrate was dissolved in deionized water to prepare a 0.2M solution. Next, sodium hydroxide solution was slowly added dropwise to the cerium nitrate solution while continuously stirring until the pH of the solution reached 9.0 to promote the precipitation of cerium hydroxide. Then, an appropriate amount of hydrogen peroxide was added to the suspension to oxidize some of the Ce. 3+ For Ce 4+ A mixed-valence cerium oxide precursor was obtained. The resulting mixed-valence cerium oxide precursor was transferred to a PTFE-lined stainless steel high-pressure reactor and subjected to a hydrothermal reaction at 200°C for 24 hours. After the reaction, the reactor was cooled to room temperature. The obtained CeO2 functional particles were collected by centrifugation and repeatedly washed with deionized water until the washing solution was neutral to remove residual ions and impurities. Finally, the washed CeO2 functional particles were dried in a vacuum oven at 60°C for 24 hours.

[0087] La-BG functional particles and CeO2 functional particles were precisely weighed at 5.0% and 1.0% of the polymer matrix mass, respectively. These two types of functional particles were added to the polymer solution to obtain a mixture. To ensure uniform dispersion of the functional particles in the polymer solution, the mixture was ultrasonically treated in an ultrasonic bath for 60 minutes, followed by continuous stirring at low speed with magnetic stirring for 2 hours to prevent re-aggregation of the functional particles. The prepared rare-earth-based anticoagulant material was dried in a vacuum oven at 50°C for 48 hours to completely remove residual organic solvents and moisture. The resulting rare-earth-based anticoagulant material was designated LALO3.

[0088] Comparative Example 1 Mixture

[0089] The difference between Comparative Example 1 and Example 1 is that no lanthanum-doped bioactive glass functional particles were added, and the resulting rare earth-based anticoagulant material is designated as LALO'1.

[0090] Comparative Example 2

[0091] The difference between Comparative Example 2 and Example 1 is that no cerium oxide functional particles were added, and the resulting rare earth-based anticoagulant material is designated as LALO'2.

[0092] Comparative Example 3

[0093] The difference between Comparative Example 3 and Example 1 is that lanthanum functional particles were used instead of lanthanum-doped bioactive glass functional particles, and the resulting rare earth-based anticoagulant material is denoted as LALO'3.

[0094] Comparative Example 4

[0095] The difference between Comparative Example 4 and Example 1 is that the amount of La-BG functional particles added is 0.1%, and the resulting rare earth-based anticoagulant material is designated as LALO'4.

[0096] Comparative Example 5

[0097] The difference between Comparative Example 5 and Example 1 is that the amount of CeO2 functional particles added is 1.5%, and the resulting rare earth-based anticoagulant material is designated as LALO'5.

[0098] Comparative Example 6

[0099] The difference between Comparative Example 6 and Example 1 is that the amount of La-BG functional particles added is 6%, the amount of CeO2 functional particles added is 0.05%, and the rare earth-based anticoagulant material obtained is denoted as LALO'6.

[0100] Test Example 1: Anticoagulation Effect Test

[0101] Blood samples from healthy adult male volunteers were added to sodium citrate, placed in test tubes, and centrifuged at 1500 g for 15 minutes to obtain platelet-poor plasma (PPP). Prothrombin time (PT) was measured using a coagulation analyzer (Coa DATA 501, LABitec, Germany) to assess the time required for blood clotting (in seconds). 800 μL of preheated platelet-poor plasma and an appropriate amount of LALO1 prepared in Example 1 were incubated at 37°C for 300 s to obtain a mixture. 100 μL of preheated prothrombin kinase was transferred to the mixture, and the volume was brought to 1000 μL with preheated platelet-poor plasma to obtain test solutions with LALO1 concentrations of 5 μg / mL, 10 μg / mL, and 20 μg / mL. The time required for thrombus formation was measured, with each experiment performed in triplicate. Experimental results are as follows: Figure 1 As shown, when the concentration of LALO1 in the test solution was 5 μg / mL, the thrombus formation time was significantly prolonged, and as the concentration of LALO1 increased, the thrombus formation became slower and slower, indicating that LALO1 has a good anticoagulant effect.

[0102] Subsequently, the anticoagulant effects of LALO1 and LALO'1-LALO'6 at concentrations of 20 μg / mL were tested. The experimental results are as follows: Figure 2 As shown, the rare earth-based anticoagulant material of the present invention has a highly efficient anticoagulant function and significantly reduces the risk of bleeding.

[0103] Test Example 2: Determination of Reactive Oxygen Activator Scavenging Effect

[0104] To test the reactive oxygen species scavenging capacity of rare earth-based anticoagulant materials, 16 mg of sodium salicylate and 10 mL of sterile water were weighed and mixed thoroughly. 50 mg of FeSO4·7H2O and 9 mL of sterile water were weighed and mixed thoroughly. 1 mL of 3% H2O2 and 1 mL of water were used to prepare an H2O2 solution. 4 mg of LALO1 and LALO'1-LALO'6 were weighed and mixed thoroughly with 10 mL of water respectively. Then, 1 mL of the prepared H2O2 solution was mixed with 9 mL of FeSO4·7H2O solution and reacted for 10 min to obtain free radicals. 4.5 mL of the rare earth-based anticoagulant material dispersion and 0.5 mL of the free radical solution were mixed thoroughly. A control group of 4.5 mL of water and 0.5 mL of the free radical solution was set up. The reaction was carried out at room temperature for 2 h. After centrifugation, 0.8 mL of the supernatant was mixed thoroughly with 0.2 mL of salicylic acid solution, and the absorbance was measured at ultraviolet wavelength. Under normal circumstances, the reaction between free radicals and salicylic acid will produce a characteristic absorption peak between 500-600 nm. The content of free radicals can be judged based on the size and area of ​​the peak.

[0105] like Figure 3 As shown in the figure, the experiment revealed that the control group exhibited a significant characteristic absorption peak between 500-600 nm, while the LALO'6 experimental group showed a lower absorption peak, indicating a certain degree of reactive oxygen species (ROS) scavenging effect. The experimental groups containing LALO1 and LALO'5 showed no absorption peak, indicating that ROS in the experimental groups were cleared. LALO1 and LALO'5 materials possess good ROS scavenging capabilities; however, LALO'5 had insufficient anticoagulant effect and was therefore excluded.

[0106] Test Example 3: Toxicity Testing of Rare Earth-Based Anticoagulant Materials

[0107] Twenty healthy mice weighing 18–22 g were randomly divided into two groups of 10 each. One group received 0.2 mL of physiological saline per mouse, while the other group received 0.2 mL of the rare-earth-based anticoagulant LALO1 (50 mg / L, 0.2 mL per mouse). Before the experiment, the mice were weighed on a FA1004 electronic analytical balance, and their initial weight was recorded. During the experiment, the control group received 0.2 mL of physiological saline daily while being fed, while the LALO1 group received 0.2 mL of LALO1 daily while being fed. This treatment continued for 7 days, followed by another 7 days of normal feeding. Finally, the mice were weighed on a FA1004 electronic analytical balance, and the toxicity of the LALO1 was determined based on the changes in mouse weight before and after the experiment. The results are shown in Table 1.

[0108] Table 1 Toxicity test results of LALO1, a rare earth-based anticoagulant material

[0109]

[0110] The experimental results showed that no mice died and their weight did not decrease significantly, indicating that the rare earth-based anticoagulant material LALO1 has no obvious toxicity and can be used in medical materials.

[0111] In summary, the rare earth-based high-efficiency anticoagulant material LALO proposed in this invention can effectively prevent thrombus formation, has the ability to scavenge reactive oxygen species, is simple to manufacture, inexpensive, safe and non-toxic, and has great potential for application in medical anticoagulation.

[0112] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A rare earth-based anticoagulant material, characterized in that: The invention comprises a polymer matrix and a composite rare earth functional component, wherein the composite rare earth functional component includes lanthanum-doped bioactive glass functional particles and cerium oxide functional particles. The amount of lanthanum-doped bioactive glass functional particles added is 0.5%-5.0% of the polymer matrix mass; the amount of cerium oxide functional particles added is 0.1%-1.0% of the polymer matrix mass; the polymer matrix is ​​a blend of poly(ε-caprolactone) and poly(L-lactic acid), wherein the mass ratio of poly(ε-caprolactone) to poly(L-lactic acid) is (6-9):(1-4). The preparation method of the lanthanum-doped bioactive glass functional particles includes the following steps: S1: Dissolve the silicon source in anhydrous ethanol to obtain a silicon source solution; S2: Dissolve the calcium source, phosphorus source and lanthanum source in deionized water to obtain mixed solution A; S3: Add the mixed solution A obtained in step S2 dropwise to the silicon source solution obtained in step S1 to obtain mixed solution B. Under continuous stirring, control the pH value of mixed solution B between 2.0 and 3.0, and control the temperature between 25℃ and 30℃. Maintain the reaction for 2h-4h to obtain sol. S4: The sol obtained in step S3 is aged at room temperature for 24-48 hours to form a gel; S5: Dry the gel obtained in step S4 in a constant temperature oven at 50℃-70℃ to remove residual solvent and moisture. S6: The dried gel was calcined at a temperature of 500℃-700℃ to obtain lanthanum-doped bioactive glass functional particles. The preparation method of the cerium oxide functional particles includes the following steps: Step 1: Dissolve the cerium source in deionized water to prepare a cerium salt solution; Step 2: Slowly add the alkaline solution dropwise to the cerium salt solution while continuously stirring until a suspension with a pH of 9.0-10.0 is obtained; Step 3: Add hydrogen peroxide to the suspension to obtain a cerium oxide precursor with mixed valence states; Step 4: Transfer the obtained cerium oxide precursor to a reaction vessel and carry out a hydrothermal reaction at a temperature of 180℃-200℃ for 12h-24h. After the reaction is completed, cool the reaction vessel to room temperature. Step 5: Collect the particles by centrifugation, wash until the washing liquid is neutral, and then vacuum dry to obtain cerium oxide functional particles.

2. The rare earth-based anticoagulant material according to claim 1, characterized in that: The mass ratio of the silicon source, calcium source, phosphorus source and lanthanum source is (70-83):(15-30):(1-10):(1-5).

3. The rare earth-based anticoagulant material according to claim 1, characterized in that: The silicon source is selected from one or a mixture of two or more of tetraethoxysilane, tetramethoxysilane, tetran-n-propoxysilane, and tetraisopropoxysilane; The calcium source is selected from one or a mixture of two or more of calcium nitrate tetrahydrate, calcium chloride, and calcium acetate. The phosphorus source is selected from one or a mixture of two or more of triethyl phosphate, trimethyl phosphate, tripropyl phosphate, and tributyl phosphate; The lanthanum source is selected from one or a mixture of two or more of lanthanum nitrate hexahydrate, lanthanum acetate, lanthanum citrate, and lanthanum acetylacetone.

4. The rare earth-based anticoagulant material according to claim 1, characterized in that: The cerium source is selected from one or more of cerium nitrate or its hydrate, cerium ammonium sulfate, cerium acetylacetone, and cerium chloride.

5. The method for preparing the rare earth-based anticoagulant material according to any one of claims 1-4, characterized in that: The preparation method includes the following steps: Lanthanum-doped bioactive glass functional particles and cerium oxide functional particles were added to a polymer solution and ultrasonically treated for 30-60 minutes. Then, the mixture was continuously stirred under magnetic stirring for 1-3 hours and vacuum dried to obtain a rare earth-based anticoagulant material.

6. The method for preparing the rare earth-based anticoagulant material according to claim 5, characterized in that: The method for preparing the polymer solution includes the following steps: Poly(ε-caprolactone) and poly(L-lactic acid) are mixed to form a polymer matrix. The polymer matrix is ​​dissolved in a mixed solvent to obtain a mixed solution. The mixed solution is stirred continuously for 6-12 hours to obtain a polymer solution.

7. The method for preparing the rare earth-based anticoagulant material according to claim 6, characterized in that: The total mass ratio of poly(ε-caprolactone) and poly(L-lactic acid) in the polymer solution to the mass ratio of the mixed solvent is (8-12):

100.

8. The application of the rare earth-based anticoagulant material according to any one of claims 1-4 in the preparation of blood contact medical devices, characterized in that: The blood-contact medical devices include endovascular stents, artificial blood vessel grafts, extracorporeal circulation circuit components, heart valves, and blood bags.

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