WO2020087288A1 - Biomedical material with synergistic effect, manufacturing method therefor and system comprising same - Google Patents

Abstract

Disclosed are a biomedical material (1) with a synergistic effect, a manufacturing method therefor and a system comprising the biomedical material (1) with a synergistic effect. The biomedical material (1) with a synergistic effect comprises a biomedical ceramic carrier (11) with a multistage pore structure (111), wherein the biomedical ceramic carrier (11) with a synergistic effect at least contains silicon and oxygen ingredients; one nano-scaled silver particle (12) confined in the multistage pore structure (111), wherein the multistage pore structure (111) comprises one pore wall with multiple mesopores (114) and multiple large pores (112), and the pore wall separates the multiple large pores (112); and a bioactivator (13), wherein the bioactivator (13) is confined in a part of the multiple mesopores (114) or is attached to one surface of the pore wall. The biomedical material (1) is located in a system comprising microorganisms and a hydrophilic medium, and after a certain time, generates a synergistic effect and has a fractional inhibitory concentration index (FIC index) less than or equal to 0.5.

Description

Synergistic biomedical material, its manufacturing method and system including this biomedical material Technical field

The invention relates to a biomedical material, a method for manufacturing the same and a system including the biomedical material, in particular to a biomedical material having a synergistic effect in a system including microorganisms and hydrophilic media and a method for manufacturing the same.

Background technique

Due to its biological toxicity considerations, it is necessary to limit the amount of addition and control of biological active agents, so that the existing effective biological active agents become safer.

Multi-level porous silica-based materials are very promising carrier materials that have only been proposed in the past 10 years. Through mesoporous (referred to as a pore size of about 2-50 nm) material preparation technology, silicon oxide-based materials can be made to have a high specific surface area. The mesoporous structure makes it possible to carry drugs. Compared with polymer drug carrier; its special rigid pore wall and surface hydrophilicity and hydrophobicity can be adjusted to make it have higher structural strength, temperature and pH resistance, anti-oxidation and other characteristics. (FDA) certified safe biomedical materials.

Summary of the invention

technical problem

In view of the above, the applicant has proposed the biomedical material with synergy according to the present invention in view of the shortcomings of the prior art, a manufacturing method thereof, and a system including the biomedical material to improve the above shortcomings.

Solution to the problem

Technical solution

In order to solve the above problems, the object of the present invention is to provide a biomedical material with a synergistic effect and a manufacturing method thereof. The carrier material coating technology can reduce the amount of bioactive agent used to reduce the bioactive agent's poor stability The resulting biological toxicity.

An object of the present invention is to propose a biomedical material that has synergistic effects in a system including microorganisms and hydrophilic media, including: a biomedical ceramic carrier whose composition contains at least silicon and oxygen, and The biomedical ceramic carrier has a multi-level pore structure, wherein the multi-level pore structure includes a pore wall and a plurality of giant pores, the pore wall separates the plurality of giant pores, and the pore wall has a plurality of mesopores; one nanometer Grade silver particles, limited to the multi-level pore structure; and a bioactive agent, limited to part of the multiple mesopores, or attached to a surface of the pore wall; and the biomedical material is located in the system Medium, and has a fractional bacteriostatic concentration index (FIC index) less than or equal to 0.5.

Wherein, the biologically active agent is located in the system alone to produce an antimicrobial effect after a specific time t1 and has a minimum bacteriostatic concentration (MIC) of A. The nano-scale silver particles are restricted to the organism of the multi-level pore structure The medical ceramic carrier is located in the system alone, and has an antimicrobial effect after a specific time t2 and has a minimum bacteriostatic concentration of B; the biomedical material is located in the system and has an antimicrobial effect after a specific time t3, Wherein the bioactive agent has a minimum bacteriostatic concentration of C, the nano-scale silver particles are limited to the biomedical ceramic carrier of the multi-level pore structure, and has a minimum bacteriostatic concentration of D; where t1 and t2 , T3 is greater than 0.5 hours, C is less than A, D is less than B.

Wherein, the number of moles of silicon is greater than or equal to 70% of the total number of moles of components of the biomedical ceramic carrier, and the number of moles of the nano-scale silver particles is less than or equal to 10% of the moles of components of the biomedical ceramic carrier The sum of the numbers.

Wherein, the nano-scale silver particles are also limited to part of the plurality of mesopores, or attached to a surface of the pore wall; and the particle size of the nano-scale silver particles is less than or equal to 10 nm.

Wherein, the bioactive agent is selected from one or more combinations of antimicrobial agent, antiviral agent, antitumor agent, anti-inflammatory agent, anti-dandruff agent, analgesic agent, anesthetic agent and tissue regeneration agent.

Wherein, the pore diameter of the plurality of giant pores is 200-700 μm, and the pore diameter of the plurality of mesopores is 2-20 nm.

Wherein, the components of the biomedical ceramic carrier further include phosphorus, calcium or a combination thereof.

Wherein, the number of moles of the nano-scale silver particles is equal to the sum of the number of moles of the components of the biomedical ceramic carrier.

An object of the present invention is to propose a method for manufacturing biomedical materials with synergy in a system including microorganisms and hydrophilic media, including: providing and mixing raw materials of biomedical ceramic carriers or precursors thereof, silver raw materials or Its precursor and mesoporous template forming agent to form a mixture, wherein the raw material or precursor of the biomedical ceramic carrier contains at least silicon and oxygen components; from this mixture to form the biomedical ceramic carrier, wherein the biomedical ceramic carrier has A multi-level pore structure, and one nano-scale silver particle is limited to this multi-level pore structure; provide a bioactive agent; and use the coating or adsorption mode to load the bioactive agent onto the biomedical ceramic carrier; The graded hole structure includes a hole wall and a plurality of giant holes, the hole wall separates the plurality of giant holes, and the hole wall has a plurality of mesopores; and the biomedical material manufactured by the manufacturing method of the biomedical material is located at In this system, it has a fractional bacteriostatic concentration index less than or equal to 0.5.

Wherein, using the mixture to form the biomedical ceramic carrier, further includes:

Using the sol-gel method, the mixture is formed into a starting gel;

Provide a three-dimensional bracket template, wherein the three-dimensional bracket template has a giant hole structure;

Soaking the three-dimensional scaffold template in the starting gel at least once; and

The three-dimensional scaffold template soaked with the starting gel is heat-treated at a temperature above 400 ° C to remove the three-dimensional scaffold template and the mesoporous template forming agent.

Where the total number of moles of the raw materials or precursors constituting the biomedical ceramic carrier is M ₁ , and the moles of the silicon component-containing biomedical ceramic carrier raw materials or their precursors are M _Si and the silver raw material or its precursor When the mole number is M _metal , M _{Si is} at least 70% of M ₁ , and M _metal is 10% or less of M ₁ .

Wherein, the bioactive agent is loaded on the biomedical ceramic carrier using the coating or adsorption mode, further including:

Disperse the bioactive agent in a solvent to form a solution;

Add the biomedical ceramic carrier to the solution and mix it uniformly; and

The solvent is removed so that the bioactive agent is coated or adsorbed on the multi-level pore structure.

Wherein, the pore wall is formed by the raw material or its precursor constituting the biomedical ceramic carrier, the nano-scale silver particles are formed by the silver raw material or its precursor, and the nano-scale silver particles are limited to the mesopores At least one, the particle size of the nano-scale silver particles is less than or equal to 10 nm.

Wherein, the pore diameter of the plurality of giant pores is 200-700 μm, and the pore diameter of the plurality of mesopores is 2-20 nm.

Wherein, the three-dimensional stent template is a porous organism or a synthetic porous body, the porous organism is a natural sponge, and the synthetic porous body is a polyurethane foam or a polylactic acid macroporous structure.

Among them, the mixture also includes a stabilizer to reduce the probability of aggregation or oxidation of the silver raw material or its precursor.

Wherein, the components of the raw material of the biomedical ceramic carrier or the precursor thereof further include phosphorus, calcium or a combination thereof. Among them, M _metal is 1% of M ₁ .

Wherein, the bioactive agent is selected from one or more combinations of antimicrobial agent, antiviral agent, antitumor agent, anti-inflammatory agent, anti-dandruff agent, analgesic agent, anesthetic agent and tissue regeneration agent.

An object of the present invention is to propose a system including a microorganism and a hydrophilic medium, the microorganism has a first quantity of A1 colony forming unit (CFU), biomedical materials are added to the system, and after a certain time, the microorganism has A second quantity A2 CFU, wherein the biomedical material includes: a biomedical ceramic carrier, the composition of the biomedical ceramic carrier includes at least silicon and oxygen, and the biomedical ceramic carrier has a multi-level pore structure, wherein the multi-level pore structure The pore structure includes a pore wall and a plurality of macropores, the pore wall separates the plurality of macropores, and the pore wall has a plurality of mesopores; a nano-scale silver particle is limited to the multi-level pore structure; and a The bioactive agent is localized in a part of the plurality of mesopores or attached to a surface of the pore wall; and (A1-A2) / A1 is greater than or equal to 0.5.

Wherein, the hydrophilic medium is biological body fluid, aqueous solution, alcohol, human blood, deionized water, microorganism culture medium or simulated body fluid.

Among them, the system is biological cells, biological tissues, biological organs, cosmetics, medicines, medical appliances or biomedical materials.

Wherein, the microorganism is bacteria, virus, fungus or protozoa.

Among them, the specific time is greater than 0.5 hours.

Beneficial effects of invention

Brief description of the drawings

BRIEF DESCRIPTION

FIG. 1a is a schematic structural diagram of a biomedical material with synergy according to Embodiment 1 of the present invention.

FIG. 1b is an enlarged view of a partial structure of a biomedical material with a synergistic effect according to Embodiment 1 of the present invention.

FIG. 2 is a flow chart of an isothermal coating mode of biomedical materials according to Embodiment 1 of the present invention.

FIG. 3 is an electron microscope image of biomedical materials according to Embodiment 1 of the present invention.

4 is a time bacteriostatic curve for evaluating the bacteriostatic effect of Staphylococcus aureus ATCC 6538 in a liquid medium with a bioactive agent at different concentrations according to Example 1 of the present invention.

FIG. 5 is a time bacteriostatic curve for evaluating the bacteriostatic effect of Staphylococcus aureus ATCC 6538 in a liquid medium with different concentrations of biomedical materials according to Example 1 of the present invention.

FIG. 6 is a time bacteriostatic curve for evaluating the bacteriostatic effect of E. coli ATCC 8739 with different concentrations of biomedical materials in a liquid medium according to Example 1 of the present invention.

7 is a time bacteriostatic curve for evaluating the bacteriostatic effect of Pseudomonas aeruginosa ATCC 9027 in a liquid medium with different concentrations of biomedical materials in Example 1 of the present invention.

DESCRIPTION OF REFERENCE NUMERALS

1 Biomedical materials

11 Biomedical ceramic carrier 111 multi-level pore structure

112 giant hole 113 hole wall

114 Mesoporous 12 nanometer silver particles

13 Biologically active agent.

The best embodiment of the invention

Best Mode of the Invention

The embodiments of the present invention are described in detail below, however, in addition to this detailed description, the present invention can be widely implemented in other embodiments. That is, the scope of the present invention is not limited by the embodiments that have been proposed, but should be based on the claims of the present invention. The scope of the entire application of this application can be understood as "in".

Example one

1a and 1b are schematic structural diagrams of biomedical materials with synergistic effect according to Embodiment 1 of the present invention. This embodiment discloses a biomedical material with a synergistic effect; wherein the biomedical material includes a biomedical ceramic carrier with a multi-level pore structure (hierarchically meso-macroporous structure). In order to make the description of this embodiment more detailed and complete, reference may be made to FIGS. 1 a, 1 b, and 2 to 7 to describe the biomedical material structure and manufacturing method thereof. The present invention provides a biomedical material 1, which includes a biomedical ceramic carrier 11 having a multi-level pore structure 111. The biomedical ceramic carrier 11 contains at least silicon and oxygen components; the multi-level pore structure 111 is composed of A pore wall 113 and a plurality of macropores 112 with a pore diameter of 200-700 μm, and the pore wall 113 has a plurality of mesopores 114 with a pore diameter of 2-20 nm, the pore wall 113 separates the plurality of macropores 112; one nano-scale silver particle 12 Confined to (confine din) (can be understood to be in) this mesopore 114; and a biologically active agent 13 confined to a portion of a plurality of mesopores 114 or attached to a surface of the pore wall 113, Reference can be made to FIG. 1 a; FIG. 1 b is an enlarged view of the hole wall 113. The particle size of the nano-sized silver particles 12 is less than or equal to 10 nm; it is a metal with the characteristics of inhibiting the growth of microorganisms or killing microorganisms. The bioactive agent 13 may be selected from one or more combinations of antimicrobial agents, antiviral agents, antitumor agents, antiinflammatory agents, analgesics, anesthetics, and tissue regeneration agents. The synergistic effect refers to nano-scale silver The particles are confined to the biomedical ceramic carrier with the multi-level pore structure and the bioactive agent has a synergistic effect.

At room temperature, the biomedical material of this embodiment uses a biomedical ceramic carrier 11 with a Si: Ag molar ratio of 99: 1, nano-sized silver particles 12 and bioactive agent 13 as isopropyl methylphenol (IPMP for short) ) As an example, it is synergistic in an environment or system containing microorganisms and hydrophilic media. The nano-scale silver particles contained therein have an active slow-release effect; that is, they actively release the concentration of their silver ions at least 2ppm within 1 hour and continue to release for at least 24 hours; therefore, the nano-scale silver particles have microbial inhibition in this biomedical material The effect of growing or killing microorganisms. The isopropyl methylphenol contained in it is used as an antibacterial agent, preservative or preservative. It is an odorless phenolic synthetic substance with partial astringency, good sterilization ability, and can inhibit product oxidation. At present, isopropylmethylphenol is listed as a positive antibacterial agent listed in the cosmetics regulations. Most of them are used to replace Paraben benzene preservatives, which have antibacterial and anti-acne effects; the regulatory limit is 0.1mg / mL. If the content of isopropyl methylphenol in commercial products is too high, it may be irritating to the skin, mucous membranes and other tissues or cause skin microvessels to undergo spasm, and even cause poisoning through skin absorption, which is carcinogenic. If the isothermal coating mode is used to confine isopropylmethylphenol in a part of the plurality of mesopores 114 or adhere to one surface of the pore wall 113, the bacteriostatic effect can be exerted and the user's discomfort can be reduced. Synergy is a phenomenon in which when two or more substances are mixed with each other, the overall effect is greater than the advantages of using each substance alone or less than the disadvantages of using each substance alone. Therefore, the biomedical materials of this embodiment can be added to cosmetics and other products; users of these products can not only achieve the antibacterial effect of the USP-51 antiseptic efficacy test standard, but also reduce their discomfort, that is, have a synergistic effect. Therefore, the biomedical material of this embodiment can be directly added to commercially available personal care products such as cleansing hair or skin.

This embodiment proposes a method for manufacturing a biomedical material with a synergistic effect, including forming a silver-carrying biomedical ceramic carrier with a hierarchically meso-macroporous structure and isothermally coating a bioactive agent The pattern is wrapped in this silver-carrying biomedical ceramic carrier. The step of forming a silver-carrying biomedical ceramic carrier with a multi-level pore structure includes providing and mixing the silicon and oxygen component raw materials or their precursors, silver raw materials or their precursors and mesoporous template forming agent that constitute the multi-level pore structure, to Forming a mixture; preparing this mixture by a sol-gel technique to form a starting gel; providing a three-dimensional scaffold template with a macroporous structure; soaking the three-dimensional scaffold template in this starting gel At least once in the glue; and heat treatment at a temperature ≥400 ° C to remove the three-dimensional stent template and mesoporous template forming agent. Wherein, the silicon precursor may be tetraethyl orthosilicate; the silver precursor may be silver nitrate; the mesoporous template forming agent may be pluronic F- 127; The three-dimensional scaffold template with a macroporous structure can be a natural sponge or synthetic porous body of porous organisms, such as polyurethane foam or polylactic acid that forms a macroporous structure using 3-D printing technology (polylactic acid). When the total number of moles of raw materials or precursors constituting the biomedical ceramic carrier component is M ₁ and the moles of silver raw materials or precursors thereof is M _metal , M _metal is 0 to 10% of M1. Preferably, M _metal is 1% of M ₁ .

The bioactive agent isopropyl methylphenol is coated in this silver-carrying biomedical ceramic carrier using an isothermal coating mode, which includes the following steps: using a solvent to dissolve the isopropylmethylphenol with maximum solubility and forming a solution; wherein the solvent type is selected It can dissolve isopropylmethylphenol and silver-carrying biomedical ceramic carriers that can disperse the multi-level pore structure well, and it is preferable to have a certain degree of volatility; in this embodiment, organic solvents such as methanol or acetone can be used. The silver-carrying biomedical ceramic carrier with a multi-stage pore structure is added to this solution, and the mixture is stirred at room temperature for at least 24 hours until the isopropylmethylphenol fully penetrates into the mesopores of the silver-carrying biomedical ceramic carrier. Then, the solvent is removed by filtration, suction drying, reduced pressure concentration, etc., so that isopropylmethylphenol is adsorbed on the pore wall of the silver-carrying biomedical ceramic carrier and nucleated and grown in the mesopores; for example, this embodiment is at a temperature of 25 ~ At 50 ℃, pressure 130 ～ 160hpa, the solvent is concentrated under reduced pressure to remove the solvent; it takes about 30 minutes for isopropyl methylphenol to adsorb on the pore wall and grow into the mesopores, which is the coated biomedical material. Refer to Figure 2 for the flow chart of isothermal coating mode.

The bioactive agent isopropyl methyl phenol can also be coated in this silver-carrying biomedical ceramic carrier using the adsorption mode, including the following steps: mixing isopropyl methyl phenol with propylene glycol to form a solution; multi-level The pore-loaded silver-carrying biomedical ceramic carrier powder is added into a protein-containing solvent to form a solution, wherein the concentration of the silver-carrying biomedical ceramic carrier powder is 2.5-20 mg / mL, and the nano-silver in the silver-carrying biomedical ceramic carrier powder is here A slow-release effect is produced in the solution, and this protein-containing solvent can be used as a stabilizer to control the size of silver particles, to avoid silver aggregation and affect the antibacterial efficacy. The two solutions are mixed and coated in an adsorption mode; propylene glycol is removed so that isopropyl methylphenol is adsorbed on the pore walls and mesopores of the silver-carrying biomedical ceramic carrier; that is the coated biomedical material. The bioactive agent isopropylmethylphenol of this embodiment is a fat-soluble substance; in another embodiment, the bioactive agent may be a water-soluble substance. In another embodiment, the bioactive agent may be coated in the silver-carrying biomedical ceramic carrier by changing the temperature or changing other coating modes.

The electron microscope image of the biomedical material of this embodiment is shown in Fig. 3: where area A is mesopores without bioactive agent coating, and the hole diameter is about 6-10 nm; area B is mesopores coated with bioactive agent hole.

In this example, a time-kill curve was used to evaluate the bacteriostatic effect of this biomedical material with synergistic effects. Staphylococcus aureus ATCC 6538 (abbreviated as S. aureus) and E. coli ATCC 8739 (abbreviated as E. coli), Pseudomonas aeruginosa ATCC 9027 (P. aeruginosa for short) as experimental strains; these three pathogenic bacteria are not detectable strains according to the test specifications EU EP 5.1.3 and USP 51. First, the biologically active agent isopropyl methylphenol was serially diluted and cultured in a microorganism culture medium (Mueller-Hinton broth, MHB for short), and 200 mL was taken into a 96-well microplate. The preparation step of the tested bacterial solution is to disperse the experimental strain in MHB, and use the turbidity of 0.5 McFarland as the quantitative standard; the actual bacterial amount is equal to 10 ⁹ CFU / mL. Then, each microwell is injected with 20 mL of the bacterial solution to be tested, and finally the actual bacterial concentration in the microplate is 5 × ^{10 5} CFU / mL. The 96-well microplate was placed in a spectrophotometer (Infinite F50, TECAN), and the absorbance value (OD ₆₀₀ ) was measured once every hour for a total of 24 times, and the temperature was fixed at 36 ° C. Record the change of absorbance value to form a curve of time and bacterial concentration kinetics, called time inhibition curve, and find the minimum inhibition concentration (MIC) based on it. The bacteriostatic effect of Staphylococcus aureus ATCC 6538 was evaluated by adding 0.02-0.35 mg / mL of different concentrations of the bioactive agent isopropylmethylphenol in Example 1 of the present invention in a liquid medium. Shown in Figure 4; where control (-) is isopropyl methylphenol without added bioactive agent, used as a control group. It can be known from Figure 4 that the absorbance value (OD ₆₀₀ ) decreases (0.4 to 0.1) as the concentration of the bioactive agent isopropylmethylphenol increases (0.02 to 0.35 mg / mL), that is, it inhibits Staphylococcus aureus ATCC 6538 (S. aureus for short) The effect is enhanced accordingly. When the biologically active agent concentration of isopropyl methylphenol 0.02 ~ 0.08mg / mL when the absorbance value (OD ₆₀₀₎ and the control (-) absorbance value (OD ₆₀₀₎ of the control or less; when the biologically active agent iso When the concentration of propylmethylphenol ≥0.17mg / mL, the absorbance value (OD ₆₀₀ ) has a significant decrease. Due to existing regulations, the concentration limit of isopropyl methylphenol is 0.1 mg / mL. In order to achieve its predetermined antibacterial effect and reduce user discomfort, the biomedical material of the present invention is a feasible solution.

In another embodiment, a synergistic biomedical material is proposed, which includes forming a silver-carrying biomedical ceramic carrier with a multi-stage pore structure (concentrations of 2.5, 5, 10, and 20 mg / mL, respectively) Meso SiO _2- Ag and 0.02mg / mL bioactive agent isopropyl methylphenol were coated in this silver-carrying biomedical ceramic carrier by adsorption mode; respectively, Staphylococcus aureus ATCC 6538, E. coli ATCC 8739, Evaluation of the antibacterial effect of Pseudomonas aeruginosa ATCC 9027. The time bacteriostasis curves obtained from the experiment are shown in Figures 5 to 7; where control (-) is the biomedical material of this example without addition, used as a control group. It can be known from FIG. 5: the absorbance value (OD ₆₀₀ ) (0.3 to 0) of each group of biomedical materials in this example and the absorbance value (OD ₆₀₀ ) (0.4 ₆₀₀ ) of isopropyl methylphenol added with 0.02 mg / mL bioactive agent alone (0.4 ) Many reductions, showing that the biomedical materials of this example have a synergistic effect; and the absorbance value (OD ₆₀₀ ) decreases with the concentration of silver-containing biomedical ceramic carrier Meso SiO ₂ -Ag (2.5 to 20 mg / mL) (0.3 to 0 ), That is, the effect of inhibiting Staphylococcus aureus ATCC 6538 (S. aureus for short) is enhanced accordingly. When the concentration of silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag is 5 mg / mL, its absorbance (OD ₆₀₀ ) rises rapidly in 18 hours; when the silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag concentration ≥10 mg / mL , The absorbance value (OD ₆₀₀ ) is still close to 0 in 24 hours. Therefore, the biomedical material with synergistic effect in this embodiment includes forming a silver-carrying biomedical ceramic carrier with a multi-stage pore structure (concentration ≥10 mg / mL) Meso SiO ₂ -Ag and the bioactive agent isopropyl methylphenol ( (Concentration ≥0.02mg / mL) coated in this silver-containing biomedical ceramic carrier by adsorption mode, which can effectively inhibit Staphylococcus aureus ATCC 6538. It can be seen from FIG. 6: the absorbance value (OD ₆₀₀ ) (0.2 to 0) of each group of biomedical materials in this embodiment and the absorbance value (OD ₆₀₀ ) (OD ₆₀₀ ) (0.3 ) A lot of reduction, showing that the biomedical material of this example has a synergistic effect; and the absorbance value (OD ₆₀₀ ) decreases with the concentration of silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag (2.5-20 mg / mL) (0.2-0 ), That is, the effect of inhibiting E. coli ATCC 8739 (referred to as E. coli) is enhanced. When the concentration of silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag is 2.5 mg / mL, its absorbance value (OD ₆₀₀ ) rises rapidly in 11 hours; when the silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag concentration ≥5 mg / mL At that time, its absorbance value (OD ₆₀₀ ) still approached 0 at 24 hours. Therefore, the biomedical material with synergistic effect in this embodiment includes forming a silver-carrying biomedical ceramic carrier with a multi-stage pore structure (concentration ≥ 5 mg / mL) Meso SiO ₂ -Ag and the bioactive agent isopropyl methylphenol ( (Concentration ≥0.02mg / mL) coated in this silver-carrying biomedical ceramic carrier by adsorption mode, which can effectively inhibit E. coli ATCC8739. It can be known from FIG. 7: the absorbance value (OD ₆₀₀ ) of each group of biomedical materials in this embodiment (≈0) and the absorbance value (OD ₆₀₀ ) of isopropyl methylphenol added with 0.02 mg / mL bioactive agent alone (0.1) Low, indicating that the biomedical materials of this example have a synergistic effect; and the absorbance value (OD ₆₀₀ ) decreases slightly (≈0) as the concentration of silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag increases (2.5-20 mg / mL), That is, the effect of inhibiting Pseudomonas aeruginosa ATCC 9027 (abbreviated as P. aeruginosa) is enhanced accordingly. When the concentration of silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag is ≥2.5 mg / mL, its absorbance value (OD ₆₀₀ ) still approaches zero at 24 hours. Therefore, the biomedical material with synergistic effect in this embodiment includes forming a silver-carrying biomedical ceramic carrier with a multi-level pore structure (concentration ≥2.5mg / mL) Meso SiO ₂ -Ag and the bioactive agent isopropyl methylphenol (Concentration ≥0.02mg / mL) Wrapped in this silver-carrying biomedical ceramic carrier by adsorption mode, it can effectively inhibit Pseudomonas aeruginosa ATCC 9027.

In addition, the fractional inhibitory concentration index (fractional inhibition concentration index, FIC index for short) is used as the reference index of whether the biomedical material of this embodiment has a synergistic effect. According to the Clinical and Laboratory Standards Association (CLSI) standard: when the two substances A and B are used in combination, their FIC index value is less than or equal to 0.5, indicating that they have a synergistic effect (synergisy); FIC index value between 0.5 and 2 indicates that it is Invalid effect (indifference); FIC index value greater than 2 indicates that it is antagonistic (antagonism). The FIC index formula is as follows:

FIC index = FIC _A + FIC _B ;

FIC _A = MIC concentration of A when used in combination / MIC concentration of A when used alone;

FIC _B = MIC concentration of B when used in combination / MIC concentration of B when used alone;

The minimum inhibitory concentration (MIC) refers to the minimum concentration that can inhibit the growth of microorganisms after 24 hours of cultivation.

According to the absorbance value (OD ₆₀₀ ), it is used as the experimental basis for the inhibition of the biomedical materials of this example against Staphylococcus aureus ATCC 6538; the MIC of isopropylmethylphenol alone is 0.17 mg / mL; the multi-pore structure is used alone The MIC of the silver-loaded biomedical ceramic carrier Meso SiO ₂ -Ag powder extract was 30 mg / mL. When used in combination (that is, the biomedical material in this example), the MIC concentration of isopropyl methylphenol is 0.02 mg / mL; the MIC of the silver-loaded biomedical ceramic carrier Meso SiO ₂ -Ag powder extract with multi-stage pore structure The concentration is 10 mg / mL. The FIC index formula is used to calculate 0.451; the FIC index value is less than 0.5, indicating that the biomedical material of this embodiment has a synergistic effect against S. aureus ATCC 6538.

The absorbance value (OD ₆₀₀ ) is used as the experimental basis for the inhibition of the biomedical materials of this example against E. coli ATCC 8739; the MIC of isopropylmethylphenol alone is 0.17 mg / mL; the multi-level pore structure of silver is used alone The MIC of the biomedical ceramic carrier Meso SiO ₂ -Ag powder extract is 20 mg / mL. When used in combination (that is, the biomedical material in this example), the MIC concentration of isopropyl methylphenol is 0.02 mg / mL; the MIC of the silver-loaded biomedical ceramic carrier Meso SiO ₂ -Ag powder extract with multi-stage pore structure The concentration is 5 mg / mL. The FIC index formula calculated 0.368; the FIC index value is less than 0.5, indicating that the biomedical material of this embodiment has a synergistic effect against E. coli ATCC 8739.

The absorbance value (OD ₆₀₀ ) is used as the experimental basis for the inhibition of the biomedical material of this example against Pseudomonas aeruginosa ATCC 9027; the MIC of isopropylmethylphenol alone is 0.17 mg / mL; the multi-stage pore structure is used alone. The MIC of the silver biomedical ceramic carrier Meso SiO ₂ -Ag powder extract is 20 mg / mL. When used in combination (that is, the biomedical material in this example), the MIC concentration of isopropyl methylphenol is 0.02 mg / mL; the MIC of the silver-loaded biomedical ceramic carrier Meso SiO ₂ -Ag powder extract with multi-stage pore structure The concentration is 2.5 mg / ml. The FIC index formula is used to calculate 0.243; the FIC index value is less than 0.5, indicating that the biomedical material of this embodiment has a synergistic effect against Pseudomonas aeruginosa ATCC 9027.

Conclusion: The biomedical material of Example 1 of the present invention is a biomedical ceramic carrier (concentration ≥2.5mg / mL) coated with bioactive agent isopropylmethylphenol (multi-pore structure ceramic carrier containing silicon, oxygen and nano-scale silver particles) (Concentration ≥0.02mg / mL) has a synergistic effect, which can greatly reduce the use concentration of the bioactive agent isopropyl methylphenol to achieve its intended bacteriostatic effect and reduce the user's discomfort. Among them, the biomedical material of the first embodiment has the best inhibitory effect on Pseudomonas aeruginosa ATCC 9027, followed by E. coli ATCC 8739, and Staphylococcus aureus ATCC 6538 again.

Example 2

The structure diagram of the biomedical material with synergy in Embodiment 2 of the present invention is similar to FIG. 1a. This embodiment provides a biomedical material with a synergistic effect; wherein the biomedical material includes a biomedical ceramic carrier with a multi-level pore structure (hierarchically meso-macroporous structure), the biomedical material structure and its Manufacturing method. At room temperature, the biomedical material of this embodiment uses the biomedical ceramic carrier 11 with a Si: Ag molar ratio of 99: 1, the nano-sized silver particles 12 and the bioactive agent 13 are zinc pyrithione (ZP) or Ketoconazole (ketoconazole) as an example, located in an environment or system that includes microorganisms and hydrophilic media has a synergistic effect. The nano-sized silver particles contained therein have an active slow-release effect; that is, they actively release a concentration of at least 2 ppm of their silver ions within 1 hour and continue to release for at least 24 hours; therefore, the nano-sized silver particles have inhibition in this biomedical material The effect of microorganism growth or killing microorganisms. The zinc pyrithione or ketoconazole contained therein is an anti-dandruff agent.

The scalp is prone to dandruff, itchy scalp, or seborrheic folliculitis when the seasons change or the body's immunity deteriorates; it is caused by infection of acne bacillus, dandruff, or mold in the scalp. At present, most of the products on the market that fight dandruff or treat seborrheic folliculitis are added zinc pyrithione or ketoconazole. Although the content of zinc pyrithione in shampoos is limited to not more than 1.5%, in recent years Several studies have pointed out that zinc pyrithione may cause heat shock in human keratinocytes and melanocytes and cause DNA damage. Ketoconazole is also one of the main ingredients of commercially available anti-dandruff shampoo, which has antibacterial and bactericidal activity; but ketoconazole has strong liver toxicity and other side effects, and is sensitive to some users who are sensitive or have poor metabolism Words are not applicable. If the coating mode is used to confine zinc pyrithione or ketoconazole in a part of the plurality of mesopores 114 or adhere to one surface of the pore wall 113, the bacteriostatic effect can be exerted and the user's discomfort can be reduced. Synergy is a phenomenon in which when two or more substances are mixed with each other, the overall effect is greater than the advantages of using each substance alone or less than the disadvantages of using each substance alone. Therefore, the biomedical materials of this embodiment can be added to products for anti-dandruff or treatment of lipid leakage folliculitis; users can not only achieve the effect of inhibiting bacteria and mold by using these products; the MIC concentration needs to be reduced, when the concentration is reduced Its cytotoxicity is also reduced, which can reduce the user's discomfort, that is, has a synergistic effect. Therefore, the biomedical material of this embodiment can be directly added to products for cleaning hair and skin or care products for patients.

This embodiment proposes a method for manufacturing a biomedical material with a synergistic effect, which includes forming a silver-carrying biomedical ceramic carrier with a multi-stage pore structure and coating a medium bioactive agent on the silver-containing biomedical using an adsorption mode In the ceramic carrier; wherein, the step of forming a silver-carrying biomedical ceramic carrier with a multi-level pore structure is the same as that in the first embodiment. The bioactive agent zinc pyrithione or ketoconazole is coated in this silver-carrying biomedical ceramic carrier by an adsorption mode, which includes the following steps: at least one anti-dandruff agent (zinc pyrithione or ketoconazole) and propylene glycol (propylene glycol) Mix to form a solution; add the silver-loaded biomedical ceramic carrier powder with a multi-stage pore structure to the protein-containing solvent to form a solution, wherein the concentration of the silver-loaded biomedical ceramic carrier powder is 2.5-20 mg / mL, and the silver The nano-silver in the biomedical ceramic carrier powder produces a slow-release effect in this solution, and this protein-containing solvent can be used as a stabilizer to control the size of the silver particles, avoiding silver aggregation and affecting the antibacterial efficacy. The two solutions are mixed and coated in an adsorption mode; propylene glycol is removed, and zinc pyrithione or ketoconazole is adsorbed on the pore walls and mesopores of the silver-carrying biomedical ceramic carrier; that is, the coated biomedical material . The bioactive agent in this embodiment may be a fat-soluble substance or a water-soluble substance. In another embodiment, other coating modes may be used to coat the bioactive agent in the silver-carrying biomedical ceramic carrier.

In another embodiment, a synergistic biomedical material is proposed, which includes forming a silver-carrying biomedical ceramic carrier with a multi-stage pore structure (concentrations of 2.5, 5, 10, and 20 mg / mL, respectively) Meso SiO _2- Ag and the 0.06mg / mL bioactive agent zinc pyrithione or ketoconazole were coated on this silver-carrying biomedical ceramic carrier by adsorption mode; Evaluation of antibacterial effect. It is known from the experimental results that the absorbance value (OD ₆₀₀ ) of each group of biomedical materials in this example and the absorbance value of 0.06 mg / mL bioactive agent zinc pyrithione or ketoconazole alone are much lower, showing the biomedical materials of this example It has a synergistic effect; and the absorbance value (OD ₆₀₀ ) decreases with the increase of the concentration of silver-carrying biomedical ceramic carrier Meso SiO ₂ -Ag (2.5-20 mg / mL), that is, the bacteriostatic effect increases.

Conclusion: The biomedical material of the second embodiment of the present invention is a biomedical ceramic carrier (concentration ≥10mg / mL) coated with bioactive agent zinc pyrithione or ketoconazole, which contains silicon, oxygen and nano-scale silver particles. (Concentration ≥0.06mg / mL) has a synergistic effect, which can greatly reduce the use concentration of the biologically active agent zinc pyrithione or ketoconazole to achieve its intended bacteriostatic effect and reduce the user's discomfort. The biomedical material of the embodiment of the present invention has a MIC concentration of ≤0.5 times the MIC concentration of the bioactive agent zinc pyrithione or ketoconazole.

Example Three

The third embodiment of the present invention has a structural schematic diagram of a biomedical material with a synergistic effect similar to FIG. 1a. This embodiment provides a biomedical material with a synergistic effect; wherein the biomedical material includes a biomedical ceramic carrier with a multi-level pore structure (hierarchically meso-macroporous structure), the biomedical material structure and its Manufacturing method. At room temperature, the biomedical material of this embodiment uses the biomedical ceramic carrier 11 with a Si: Ag molar ratio of 99: 1, the nano-sized silver particles 12 and the bioactive agent 13 are gentamicin sulfate (abbreviated as GS) For example, it has a synergistic effect in an environment or system that includes microorganisms and hydrophilic media. The nano-scale silver particles contained therein have an active slow-release effect; that is, they actively release a concentration of at least 2 ppm of their silver ions within 1 hour and continue to release for at least 24 hours; therefore, the nano-scale silver particles have microbial inhibition in this biomedical material The effect of growing or killing microorganisms. The gentamicin sulfate contained in it is an aminoglycoside broad-spectrum antibiotic, which has bacteriostatic and bactericidal effects on a variety of gram-negative and positive bacteria; especially against Pseudomonas aeruginosa, aerogenes, pneumoniae, Gram-negative bacteria such as Salmonella, Escherichia coli, and Proteus are stronger. Gentamicin sulfate is slightly toxic to the vestibule of the inner ear and auditory nerves. After long-term or high-dose use, dizziness, dizziness, ears, and hearing loss are easy to occur. Another research report pointed out: Long-term excessive use of gentamicin sulfate, due to the increase in blood nitrogen, non-protein nitrogen and serum sarcosin, or the occurrence of oliguria, cylindrical urine and proteinuria, shows significant changes in renal function ; Patients with reduced renal function should avoid long-term overdose. If the adsorption coating mode is used to confine gentamicin sulfate to a part of the plurality of mesopores 114 or attach to a surface of the pore wall 113, the pathogenic bacteria can be suppressed, which has a therapeutic effect and can reduce its side effects. Synergy is a phenomenon in which when two or more substances are mixed with each other, the overall effect is greater than the advantages of using each substance alone or less than the disadvantages of using each substance alone. Therefore, the biomedical materials of this embodiment can be added to medicines; when users use these medicines, they can achieve the effect of inhibiting pathogenic bacteria and reduce the side effects of using antibiotics, that is, have a synergistic effect. Therefore, the biomedical material of this embodiment can be directly added to the medicine containing antibiotics.

This embodiment proposes a method for manufacturing a biomedical material with a synergistic effect, which includes forming a silver-carrying biomedical ceramic carrier with a multi-stage pore structure and coating a bioactive agent on the silver-carrying biomedical using an adsorption mode In the ceramic carrier; wherein, the step of forming a silver-carrying biomedical ceramic carrier with a multi-level pore structure is the same as that in the first embodiment. The bioactive agent gentamicin sulfate is coated in this silver-carrying biomedical ceramic carrier using an adsorption mode, which includes the following steps: adding gentamicin sulfate to water and configuring it into aqueous solutions of different concentrations; The silver-carrying biomedical ceramic carrier powder was added to these aqueous solutions, and stirred at room temperature for 24 hours, so that gentamicin sulfate was adsorbed on the pore wall surface and mesopores of the silver-carrying biomedical ceramic carrier, and the solution was removed by filtration. Moisture; then put the coated biomedical material in an oven to dry, that is, the biomedical material of this embodiment can be obtained. The bioactive agent gentamicin sulfate in this embodiment is a water-soluble substance; in another embodiment, the bioactive agent may be a fat-soluble substance. In another embodiment, other coating modes can be used to coat the bioactive agent in the silver-carrying biomedical ceramic carrier.

In another embodiment, a biomedical material with synergistic effect is proposed, which includes forming a silver-carrying biomedical ceramic carrier with a multi-stage pore structure (concentration range 0.31 ～ 10 mg / mL) Meso SiO ₂ -Ag and bioactive The agent gentamicin sulfate (concentration range 1.25-40 μg / mL) is coated in this silver-carrying biomedical ceramic carrier by adsorption mode. Evaluation of the synergistic bacteriostasis test of the biomedical materials of this example through the checkerboard test with K. pneumoniae 700623 as the experimental strain. First, each gentamicin sulfate was diluted to 160 μg / ml, and 50 μL of gentamicin sulfate was added laterally to a 96-well microplate in a two-fold serial dilution using microbial culture medium (MHB). The two-fold sequence was diluted six times, and the antibiotic concentration used for K. pneumoniae 700623 ranged from 1.25 to 40 μg / mL. Using silver-loaded biomedical ceramic carrier powder extracted with MHB, repeat the above steps to dilute the concentration to 10 mg / mL, and use MHB to serially dilute 50 μL of extraction solution into a 96-well microplate in a two-fold serial dilution mode, and then double The sequence was diluted six times and the concentration range was 0.31 ～ 10mg / mL. The bacteria as a 0.5 McFarland turbidity standard quantitative ^{(0.5Mcfarland = 10 8 CFU / mL} ), then diluted to a bacterial concentration 5x10 ⁵ CFU / mL, 100μL of diluted bacteria was added to 96-well microtiter plate. Finally, place the 96-well microplate in a 37 ° C incubator for 18 to 24 hours, and determine the growth of bacteria based on the absorbance value (OD ₆₀₀ ); interpret K.pneumoniae 700623 in gentamicin sulfate and silver-carrying biomedical ceramic carrier The bacteriostatic effect of the powder extract in different concentrations used alone or in combination.

The fractional inhibitory concentration index (fractional inhibitory concentration index, FIC index for short) is used as the reference index of whether the biomedical material of this embodiment has a synergistic effect. Based on the absorbance value (OD ₆₀₀ ), it is used as the experimental basis for the inhibition of biomedical materials against K. pneumoniae 700623 in this example; the MIC of gentamicin sulfate alone is 40 μg / mL; the biomedical ceramic carrier powder extract of silver The MIC is 2.5 mg / mL. When used in combination (ie, the biomedical material of this example), the MIC concentration of gentamicin sulfate is 5 μg / mL; the MIC concentration of the silver-loaded biomedical ceramic carrier powder extract is 0.63 mg / mL. Calculated by the same FIC index formula as provided in Example 1, 0.377 is obtained; its FIC index value is less than 0.5, indicating that the biomedical material of this example has a synergistic effect against K. pneumoniae 700623. Clinically, MIC can not only confirm the effective dosage of antibiotics to patients; it can also be used to evaluate the type of antibiotics to reduce the risk of antibiotic resistance in patients. Therefore, the use of MIC to determine the concentration of drugs that inhibit 50% (MIC ₅₀ ) and 90% (MIC ₉₀ ) of the same bacterial strain is another method to estimate the sensitivity of bacterial strains to antibiotics.

Conclusion: The biomedical material of Example 3 of the present invention is a multi-stage porous biomedical ceramic carrier (concentration range 0.31 ～ 10mg / mL) coated with gentamicin sulfate (concentration range 1.25) containing silicon, oxygen and nano-scale silver particles ~ 40μg / mL) has a synergistic effect, which can greatly reduce the use concentration of the bioactive agent gentamicin sulfate to achieve its intended effect of inhibiting pathogenic bacteria and reducing side effects during use.

Invention Example

Examples

1. A biomedical material with synergistic effects in a system including microorganisms and hydrophilic media, including: a biomedical ceramic carrier, the composition of the biomedical ceramic carrier contains at least silicon and oxygen, and the biomedical ceramic carrier It has a multi-level pore structure, wherein the multi-level pore structure includes a pore wall and a plurality of giant pores, the pore wall separates the plurality of giant pores, and the pore wall has a plurality of mesopores; one nano-scale silver particle, limited Localized in this multi-level pore structure; and a bioactive agent restricted to part of the plurality of mesopores, or attached to a surface of the pore wall; and the biomedical material is located in this system and has less than Or a fractional bacteriostatic concentration index equal to 0.5.

2. The biomedical material as described in embodiment 1, wherein the bioactive agent is located in the system alone, has an antimicrobial effect after a specific time t1, and has a minimum inhibitory concentration (MIC) of A, this nanoscale The biomedical ceramic carrier with silver particles confined to the multi-level pore structure is located in this system alone, has an antimicrobial effect after a certain time t2 and has a MIC of a quantity B; this biomedical material is located in this system, after a certain An antimicrobial effect occurs after time t3, where the bioactive agent has a MIC of C, and the nano-scale silver particles are limited to the multi-level pore structure. The biomedical ceramic carrier has a MIC of D; where t1 and t2 , T3 is greater than 0.5 hours, C is less than A, D is less than B.

3. The biomedical material according to embodiments 1 to 2, wherein the mole number of silicon is greater than or equal to 70% of the total mole number of components of the biomedical ceramic carrier, and the mole number of the nano-scale silver particles is less than Or equal to 10% of the total number of moles of the components of the biomedical ceramic carrier.

4. The biomedical material as described in Embodiments 1 to 3, wherein the nano-scale silver particles are more confined to part of the plurality of mesopores or attached to a surface of the pore wall; and the nano-scale silver particles The particle size is less than or equal to 10 nm.

5. The biomedical material according to embodiments 1 to 4, wherein the bioactive agent is selected from antimicrobial agents, antiviral agents, antitumor agents, antiinflammatory agents, antidandruff agents, analgesics, anesthetics, and tissue regeneration One or more combinations of agents.

6. The biomedical material as described in Examples 1 to 5, wherein the pore diameter of the plurality of macropores is 200-700 μm, and the pore diameter of the plurality of mesopores is 2-20 nm.

7. The biomedical material according to embodiments 1 to 6, wherein the biomedical ceramic carrier further contains phosphorus, calcium or a combination thereof.

8. The biomedical material as described in Examples 1-7, wherein the number of moles of the nano-sized silver particles is equal to the sum of the number of moles of the components of the biomedical ceramic carrier equal to 1%.

9. The biomedical material according to embodiments 1 to 8, wherein the hydrophilic medium is biological fluid, aqueous solution, alcohol, human blood, deionized water, microbial culture medium or simulated fluid; this system is biological cells , Biological tissues, biological organs, cosmetics, medicines, medical appliances or biomedical materials; where the microorganisms are bacteria, viruses, fungi or protozoa.

10. A method for manufacturing biomedical materials with synergy in a system including microorganisms and hydrophilic media, comprising: providing and mixing raw materials of biomedical ceramic carriers or their precursors, silver raw materials or their precursors, and A mesoporous template forming agent to form a mixture, wherein the raw material or precursor of the biomedical ceramic carrier contains at least silicon and oxygen; this mixture forms the biomedical ceramic carrier, wherein the biomedical ceramic carrier has a multi-level pore Structure, and a nano-scale silver particle is limited to this multi-level pore structure; providing a bioactive agent; and loading the bioactive agent into the biomedical ceramic carrier using a coating or adsorption mode; wherein the multi-level pore structure includes A hole wall and a plurality of giant holes, the hole wall separates the plurality of giant holes, and the hole wall has a plurality of mesopores; and the biomedical material manufactured by the manufacturing method of the biomedical material is located in the system, And it has a fractional bacteriostatic concentration index less than or equal to 0.5.

11. The method for manufacturing a biomedical material according to embodiment 10, wherein the biomedical ceramic carrier is formed from the mixture, further comprising: forming the starting gel by the sol-gel method; providing a three-dimensional support Template, wherein the three-dimensional scaffold template has a macroporous structure; soak the three-dimensional scaffold template in the starting gel at least once; and heat-treat the three-dimensional scaffold template soaked in the starting gel at a temperature above 400 ° C To remove the three-dimensional stent template and the mesoporous template forming agent.

12. The method for manufacturing a biomedical material according to embodiments 10 to 11, wherein the total number of moles of the raw materials or precursors constituting the biomedical ceramic carrier is M ₁ , and the raw material of the silicon-containing biomedical ceramic carrier Or when the mole number of the precursor is M _Si and the mole number of this silver raw material or its precursor is M _metal , M _{Si is} at least 70% of M ₁ , and M _metal is 10% or less of M ₁ .

13. The method for manufacturing a biomedical material according to embodiments 10 to 12, wherein the bioactive agent is loaded onto the biomedical ceramic carrier using a coating or adsorption mode, further comprising: dispersing the bioactive agent in a solvent, Form a solution; add this biomedical ceramic carrier to this solution and mix it uniformly; and remove this solvent, so that this bioactive agent is coated or adsorbed on this multilevel pore structure.

14. The method for manufacturing a biomedical material as described in Embodiments 10 to 13, wherein the pore wall is formed from the raw material or precursor of the biomedical ceramic carrier, and the nano-sized silver particles are formed from the silver raw material or the precursor thereof Forming, and the nano-scale silver particles are limited to at least one of the plurality of mesopores, and the particle size of the nano-silver particles is less than or equal to 10 nm.

15. The method for manufacturing a biomedical material as described in Examples 10-14, wherein the pore diameter of the plurality of macropores is 200-700 μm, and the pore diameter of the plurality of mesopores is 2-20 nm.

16. The method for manufacturing biomedical materials according to embodiments 10 to 15, wherein the three-dimensional stent template is a porous organism or a synthetic porous body, the porous organism is a natural sponge, and the synthetic porous body is a polyurethane foam Body or polylactic acid macroporous structure.

17. The method for manufacturing biomedical materials as described in Examples 10-16, wherein the mixture further includes a stabilizer to reduce the probability of aggregation or oxidation of the silver raw material or its precursor.

18. The method for manufacturing a biomedical material according to embodiments 10 to 17, wherein the raw material of the biomedical ceramic carrier or the components of its precursors further include phosphorus, calcium, or a combination thereof.

19. The method for manufacturing a biomedical material as described in Examples 10 to 18, wherein M _metal is 1% of M ₁ .

20. The method for manufacturing a biomedical material according to embodiments 10-19, wherein the bioactive agent can be selected from antimicrobial agents, antiviral agents, antitumor agents, antiinflammatory agents, antidandruff agents, analgesics, One or more combinations of anesthetics and tissue regeneration agents.

21. The method for manufacturing biomedical materials according to embodiments 10 to 20, wherein the hydrophilic medium is biological fluid, aqueous solution, alcohol, human blood, deionized water, microbial culture medium or simulated body fluid; this system It is a biological cell, biological tissue, biological organ, cosmetics, medicine, medical appliance or biomedical material; wherein the microorganism is bacteria, virus, fungus or protozoa.

22. A system including a microorganism and a hydrophilic medium, the microorganism has a first quantity A1 colony forming unit (CFU), biomedical materials are added to the system, and after a certain period of time the microorganism has a second quantity A2 CFU, wherein the biomedical material includes: a biomedical ceramic carrier, the composition of the biomedical ceramic carrier includes at least silicon and oxygen, and the biomedical ceramic carrier has a multi-stage pore structure, wherein the multi-stage pore structure includes a hole Wall and a plurality of macropores, the pore wall separates the plurality of macropores, and the pore wall has a plurality of mesopores; a nano-scale silver particle, limited to the multi-level pore structure; and a bioactive agent, limited It is located in part of the plurality of mesopores, or is attached to a surface of the pore wall; and (A1-A2) / A1 is greater than or equal to 0.5.

23. The system of embodiment 22, wherein the hydrophilic medium is biological fluid, aqueous solution, alcohol, human blood, deionized water, microbial culture medium, or simulated fluid.

24. The system according to embodiments 22 to 23, wherein the system is a biological cell, biological tissue, biological organ, cosmetics, medicine, medical appliance, or biomedical material.

25. The system according to embodiments 22-24, wherein the microorganism is bacteria, virus, fungus or protozoa.

26. The system of embodiments 22-25, wherein the specific time is greater than 0.5 hour.

Claims (24)

1. A biomedical material with synergistic effect in a system including microorganisms and hydrophilic media, characterized in that it includes:

   A biomedical ceramic carrier, the composition of the biomedical ceramic carrier includes at least silicon and oxygen, and the biomedical ceramic carrier has a multi-stage pore structure, wherein the multi-stage pore structure includes a hole wall and a plurality of giant holes, the hole The wall separates the plurality of giant holes, and the hole wall has a plurality of mesopores;

   A nano-scale silver particle, limited to the multi-level pore structure; and

   A bioactive agent, limited to part of the plurality of mesopores, or attached to a surface of the pore wall; and the biomedical material is located in the system and has a fractional bacteriostatic rate of less than or equal to 0.5 Concentration index.
2. The biomedical material according to claim 1, wherein the bioactive agent is located alone in the system to produce an antimicrobial effect after a specific time t1 and has a minimum bacteriostatic concentration of A, the nano-scale silver particles are limited The biomedical ceramic carrier based on the multi-stage pore structure is located in the system alone, and after a specific time t2 produces an antimicrobial effect and has a minimum bacteriostatic concentration of B; the biomedical material is located in the system, and An antimicrobial effect occurs after a specific time t3, where the bioactive agent has a minimum bacteriostatic concentration of a number C, the nano-scale silver particles are limited to the biomedical ceramic carrier of the multi-level pore structure, and have a number D The minimum bacteriostatic concentration; where t1, t2, and t3 are greater than 0.5 hours, C is less than A, and D is less than B.
3. The biomedical material according to claim 1, wherein the number of moles of silicon is greater than or equal to 70% of the total number of moles of components of the biomedical ceramic carrier, and the number of moles of nano-scale silver particles is less than or equal to It is equal to 10% of the total number of moles of the components of the biomedical ceramic carrier.
4. The biomedical material according to claim 1, wherein the nano-scale silver particles are further confined in part of the plurality of mesopores or attached to a surface of the pore wall; and

   The particle size of the nano-sized silver particles is less than or equal to 10 nm.
5. The biomedical material according to claim 1, wherein the bioactive agent is selected from antimicrobial agents, antiviral agents, antitumor agents, antiinflammatory agents, antidandruff agents, analgesics, anesthetics, and tissue regeneration agents One or more combinations.
6. The biomedical material according to claim 1, wherein the pore diameter of the plurality of macropores is 200-700 μm, and the pore diameter of the plurality of mesopores is 2-20 nm.
7. The biomedical material according to claim 1, wherein the component of the biomedical ceramic carrier further contains phosphorus, calcium or a combination thereof.
8. The biomedical material according to claim 3, wherein the number of moles of the nano-sized silver particles is equal to the sum of the number of moles of components of the biomedical ceramic carrier equal to 1%.
9. A method for manufacturing biomedical materials with synergy in a system including microorganisms and hydrophilic media is characterized by including:

   Providing and mixing raw materials or precursors of biomedical ceramic carriers, silver raw materials or precursors thereof, and mesoporous template forming agents to form a mixture, wherein the raw materials or precursors of biomedical ceramic carriers contain at least silicon and oxygen components;

   Forming the biomedical ceramic carrier with the mixture, wherein the biomedical ceramic carrier has a multi-level pore structure, and one nano-scale silver particle is limited to the multi-level pore structure;

   Provide a biologically active agent; and

   Loading the bioactive agent into the biomedical ceramic carrier using a coating or adsorption mode;

   The multi-level hole structure includes a hole wall and a plurality of giant holes, the hole wall separates the plurality of giant holes, and the hole wall has a plurality of mesopores; and

   The biomedical material manufactured by the manufacturing method of the biomedical material is located in the system and has a fractional bacteriostatic concentration index less than or equal to 0.5.
10. The method for manufacturing a biomedical material according to claim 9, wherein forming the biomedical ceramic carrier with the mixture further comprises:

    Using the sol-gel method, the mixture is formed into a starting gel;

    Provide a three-dimensional bracket template, wherein the three-dimensional bracket template has a giant hole structure;

    Soaking the three-dimensional scaffold template in the starting gel at least once; and

    The three-dimensional scaffold template soaked with the starting gel is heat-treated at a temperature above 400 ° C to remove the three-dimensional scaffold template and the mesoporous template forming agent.
11. The method for manufacturing a biomedical material according to claim 9, wherein when the total number of moles of the raw materials or precursors constituting the biomedical ceramic carrier is M ₁ , the biomedical ceramic carrier raw material containing silicon component or When the mole number of the precursor is M _Si and the mole number of the silver raw material or its precursor is M _metal , M _{Si is} at least 70% of M ₁ , and M _metal is 10% or less of M ₁ .
12. The method for manufacturing a biomedical material according to claim 9, wherein the bioactive agent is loaded onto the biomedical ceramic carrier using a coating or adsorption mode, further comprising:

    Disperse the bioactive agent in a solvent to form a solution;

    Add the biomedical ceramic carrier to the solution and mix it uniformly; and

    The solvent is removed so that the bioactive agent is coated or adsorbed on the multi-level pore structure.
13. The method for manufacturing a biomedical material according to claim 9, wherein the pore wall is formed by the raw material or its precursor constituting the biomedical ceramic carrier, and the nano-sized silver particles are formed by the silver raw material or its precursor The nano-scale silver particles are limited to at least one of the plurality of mesopores, and the particle size of the nano-scale silver particles is less than or equal to 10 nm.
14. The method for manufacturing a biomedical material according to claim 9, wherein the pore diameter of the plurality of macropores is 200-700 μm, and the pore diameter of the plurality of mesopores is 2-20 nm.
15. The method for manufacturing a biomedical material according to claim 10, wherein the three-dimensional stent template is a porous organism or a synthetic porous body, the porous organism is a natural sponge, and the synthetic porous body is a polyurethane foam Or polylactic acid macroporous structure.
16. The method for manufacturing a biomedical material according to claim 9, wherein the mixture further includes a stabilizer to reduce the probability of aggregation or oxidation of the silver raw material or its precursor.
17. The method for producing a biomedical material according to claim 9, wherein the raw material of the biomedical ceramic carrier or its precursor component further contains phosphorus, calcium or a combination thereof.
18. The method for manufacturing a biomedical material according to claim 11, wherein M _metal is 1% of M ₁ .
19. The method for manufacturing a biomedical material according to claim 9, wherein the bioactive agent is selected from the group consisting of antimicrobial agents, antiviral agents, antitumor agents, antiinflammatory agents, antidandruff agents, analgesics, anesthetics and One or more combinations of tissue regeneration agents.
20. A system including microorganisms and a hydrophilic medium, characterized in that the microorganism has a first quantity A1 colony forming unit, a biomedical material is added to the system, and after a certain time the microorganism has a second quantity A2 Colony forming unit, where the biomedical materials include:

    A biomedical ceramic carrier, the composition of the biomedical ceramic carrier includes at least silicon and oxygen, and the biomedical ceramic carrier has a multi-stage pore structure, wherein the multi-stage pore structure includes a hole wall and a plurality of giant holes, the hole The wall separates the plurality of giant holes, and the hole wall has a plurality of mesopores;

    A nano-scale silver particle, limited to the multi-level pore structure; and

    A bioactive agent limited to a part of the plurality of mesopores or attached to a surface of the pore wall; and (A1-A2) / A1 is greater than or equal to 0.5.
21. The system of claim 20, wherein the hydrophilic medium is biological fluid, aqueous solution, alcohol, human blood, deionized water, microbial culture medium, or simulated fluid.
22. The system of claim 20, wherein the system is biological cells, biological tissues, biological organs, cosmetics, medicines, medical appliances, or biomedical materials.
23. The system of claim 20, wherein the microorganism is a bacterium, virus, fungus, or protozoan.
24. The system of claim 20, wherein the specific time is greater than 0.5 hour.

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