CN113198044A - HHC 36-loaded polydopamine-functionalized hydroxyapatite composite material and preparation method and application thereof - Google Patents
HHC 36-loaded polydopamine-functionalized hydroxyapatite composite material and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a polydopamine functionalized hydroxyapatite composite material loaded with HHC36, and a preparation method and application thereof. The method comprises the following steps: preparing a hydroxyapatite composite material; ultrasonically dispersing the compound in Tris & HCl, adding dopamine to fully dissolve, stirring in the dark, centrifuging, washing and drying to obtain a poly-dopamine functionalized hydroxyapatite composite material; and adding the mixture and antibacterial peptide HHC36 into water, stirring, incubating, centrifuging, and freeze-drying to obtain the polydopamine functionalized hydroxyapatite composite material loaded with HHC 36. The composite material can efficiently load HHC36 and has good biocompatibility; meanwhile, the composite material can realize long-acting slow release of the antibacterial agent HHC36, and the photo-thermal coating on the functionalized surface can be quickly sterilized under the irradiation of 808nm laser; the micro-nano multilevel structure and the polydopamine coating of the composite material can synergistically and efficiently promote the regeneration and repair of bone tissues.
Description
Technical Field
The invention belongs to the technical field of biomedical materials, and particularly relates to a polydopamine-functionalized hydroxyapatite composite material loaded with HHC36, and a preparation method and application thereof.
Background
Bone tissue defects are a common clinical problem in trauma orthopedics, and large-area bone defects can cause non-healing and even necrosis of bones after being treated improperly. At present, autologous bone transplantation and allogeneic bone transplantation are used as bone defects, but the shortage of bone sources and rejection reaction limit the application to some extent. The development of novel multifunctional bone substitute materials has become a research hotspot in the field. The success of bone defect repair depends not only on the effective integration of the bone substitute with the bone tissue, but also on whether a sterile environment is surrounding the bone substitute material. Bacterial infections are one of the most serious complications that can occur after surgery. It is estimated that despite the use of rigorous disinfection procedures, the infection rate of one surgery is between 0.5% and 5%, and the re-infection rate of a second surgery can be as high as 10%. Therefore, the development of multifunctional biological materials which can efficiently promote bone regeneration and repair and can continuously resist bacteria through local sustained release has important significance for solving the clinical treatment problem of infectious bone defects.
With the increasing adaptation of bacteria, the effectiveness of traditional antibiotics is continuously threatened. Cationic antimicrobial peptides (AMPs) are widely present in organisms, are important components of the immune system, and have the advantages of low toxicity, low immunogenicity, rapid bactericidal activity, no drug resistance of bacteria and the like. However, AMPs are susceptible to degradation or inactivation in vivo due to proteolysis or high ionic strength, etc., and clinical application of AMPs is limited. For surgery, local delivery of AMPs is an ideal solution for peri-implant infection treatment because of its higher antibacterial efficiency, lower bacterial resistance and better control of antibacterial agent distribution to avoid systemic toxicity.
The natural bone tissue has a multi-level complex structure from nano-scale to macroscopic level, so that the natural bone tissue has strong mechanical properties and biological functions. Therefore, the multifunctional biomaterial with the micro/nano multilevel structure is developed, the composition, the structure and the performance of natural bone tissues are simulated, and the multifunctional biomaterial has an important clinical application prospect. Hydroxyapatite has good biocompatibility, low immunogenicity, excellent osteogenic activity and pH-dependent degradation, and is widely used as a carrier for drugs and growth factors. In addition, the three-dimensional hollow structure material has outstanding performance in drug delivery due to unique structure and ultrahigh specific surface area. However, pure hydroxyapatite has large brittleness and poor mechanical stability. Therefore, the hollow HA particles with a multistage micro/nano structure, high specific surface area and excellent biocompatibility can be obtained by a biomimetic synthesis technology, and can be subjected to surface modification by polydopamine, and the HA micro-nano particles can simultaneously provide good bone repair performance and realize efficient loading of antibacterial agents, so that the HA micro-nano particles can be used for developing multifunctional infectious bone defect treatment materials.
In the literature (Wang, N., et al, Nisin-loaded polypamine/hydroxyurea composites: biomedical synthesis, and in vitro biological activity and activity evaluation. colloids and Surfaces A: physical and Engineering applications, 2020.602: p.125101.) although in-situ mineralization of hydroxyapatite is achieved by using polydopamine as a template, the formed composite microspheres have no mesoporous structure, rapid drug release rate and no photothermal synergistic antibacterial effect.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a polydopamine functionalized hydroxyapatite composite material loaded with HHC36, and a preparation method and application thereof.
Aiming at the defects and shortcomings of the existing infectious bone defect treatment material in design performance, the invention provides a polydopamine functionalized hydroxyapatite composite material loaded with HHC36 and a preparation method thereof.
The composite micro-nano particles are prepared by uniformly dispersing HA particles with a bionic structure and dopamine in Tris-HCl (pH 8.5), centrifuging and washing for multiple times, and freeze-drying to obtain the dopamine-functionalized hydroxyapatite composite material. And then uniformly dispersing the obtained composite material and antibacterial peptide HHC36 in deionized water, centrifuging to remove supernatant, and freeze-drying to finally obtain the polydopamine functionalized hydroxyapatite composite material loaded with HHC 36. The poly-dopamine functionalized hydroxyapatite composite material has a high specific surface, and the hierarchical micro-nano structure of the poly-dopamine functionalized hydroxyapatite composite material has high osteogenic activity and osteoinductivity; the composite micro-nano particles have high drug loading capacity and a local delivery function, can generate a photothermal effect to quickly sterilize, and have good biocompatibility; when the drug loading is high, the composite particles can effectively kill the bacteria growth in the surrounding environment of the bone defect tissue, when the drug loading is micro-scale, the composite particles can effectively inhibit the bacteria breeding in the surrounding environment, and the micro-nano structure of the composite particles can promote the regeneration and repair of the bone tissue.
The purpose of the invention is realized by at least one of the following technical solutions.
A preparation method of a polydopamine functionalized hydroxyapatite composite material loaded with HHC36 comprises the following steps:
(1) adding solid diammonium hydrogen phosphate into water, dissolving, and adjusting the pH value of the solution to 5.8-6.2 to obtain solution 1; adding calcium nitrate solid into the solution 1 for dissolving, and adjusting the pH value to 4.6-5.2 to obtain a solution 2; adding sodium citrate into the solution 2 for dissolving, reacting, centrifuging to remove supernatant, and freeze-drying to obtain a hydroxyapatite composite material;
(2) ultrasonically dispersing the hydroxyapatite composite material in the step (1) in a Tris-HCl buffer solution, adding dopamine to dissolve to obtain a mixed solution, stirring in a dark place, centrifuging, washing, and drying to obtain a poly-dopamine functionalized hydroxyapatite composite material;
(3) and (3) adding the polydopamine-functionalized hydroxyapatite composite material obtained in the step (2) and antibacterial peptide HHC36 into water, stirring to obtain a mixed solution, incubating, centrifuging, and freeze-drying to obtain the polydopamine-functionalized hydroxyapatite composite material loaded with HHC 36.
Preferably, the concentration of diammonium hydrogen phosphate in the solution 1 in the step (1) is 1-30 mM;
further preferably, the concentration of the diammonium phosphate solution in the step (1) is 1-24 mM.
Preferably, the molar volume ratio of the calcium nitrate to the solution 1 is 1-90:1 mmol/L;
further preferably, the molar volume ratio of the calcium nitrate to the solution 1 is 1-60:1 mmol/L.
Preferably, the molar ratio of the calcium nitrate to the sodium citrate is 5-8: 1.
Further preferably, the molar ratio of calcium nitrate to sodium citrate is 6-7: 1.
Preferably, the temperature of the reaction in the step (1) is 150-200 ℃, and the reaction time is 1-12 h.
Further preferably, the temperature of the reaction in the step (1) is 160-200 ℃, and the reaction time is 2-6 h.
Preferably, the concentration of Tris-HCl in the mixed solution in the step (2) is 1-50 mM; the pH value of the Tris-HCl buffer solution is 7.2-9.0.
Further preferably, the concentration of Tris-HCl in the mixture of step (2) is 0.1-20 mM; more preferably, the concentration of Tris-HCl in the step (2) is 10 mM.
Preferably, the stirring time in the step (2) is 0.1-24h in a dark place.
Further preferably, the stirring time in the step (2) is 3-8h in a dark place; more preferably, the stirring time in the dark is 4-6 h.
Preferably, in the mixed solution in the step (2), the concentration of the hydroxyapatite composite material is 0.1-20 mg/mL;
more preferably, in the mixed solution in the step (2), the concentration of the hydroxyapatite composite material is 0.5-5 mg/mL.
Preferably, the mass ratio of the dopamine to the hydroxyapatite powder composite material is 0.1-1.5: 1;
further preferably, the mass ratio of the added dopamine to the hydroxyapatite composite material is 0.1-1: 1.
Preferably, the concentration of the poly-dopamine functionalized hydroxyapatite composite material in the mixed solution in the step (3) is 0.1-40 mg/mL.
Further preferably, the concentration of the poly-dopamine functionalized hydroxyapatite composite material in the step (3) is 0.5-5 mg/mL.
Preferably, the mass ratio of the poly-dopamine functionalized hydroxyapatite composite material in the step (3) to the antibacterial peptide HHC36 is 1: 0.1-5;
further preferably, the mass ratio of the poly-dopamine functionalized hydroxyapatite composite material in the step (3) to the antibacterial peptide HHC36 is 1: 0.1-2.
Preferably, the incubation time is 1-24 h;
further preferably, the incubation adsorption time is 10-24 h.
Preferably, the water is deionized water.
The polydopamine functionalized hydroxyapatite composite material loaded with HHC36 prepared by the preparation method.
The application of the polydopamine functionalized hydroxyapatite composite material loaded with HHC36 in preparing infectious bone defect medicines.
The polydopamine functionalized hydroxyapatite composite material loaded with HHC36 has a more excellent bone-promoting effect, so that the composite material loaded with antibacterial peptide HHC36 has bone repair-promoting and antibacterial properties.
Compared with the prior art, the invention has the following advantages and effects:
the micro-nano particles prepared by the method have a unique hierarchical structure and a high drug loading rate;
the composite micro-nano particles prepared by the method have good biocompatibility and photo-thermal effect, and can be efficiently sterilized in a short period;
the composite micro-nano particles loaded with a certain amount of antibacterial peptide HHC36 are filled in the infectious bone defect part, and the regeneration and repair of the infectious bone defect can be effectively promoted by utilizing the high-efficiency antibacterial activity and high bone promotion activity of the composite material.
Drawings
Fig. 1 is a scanning electron microscope image of the poly-dopamine functionalized hydroxyapatite composite material prepared in examples 1-2 and 4. Wherein A is the appearance of the composite microsphere of example 1 when the feeding ratio of the hydroxyapatite to the dopamine is 1: 0; b is the appearance of the composite microsphere of example 2 when the feeding ratio of the hydroxyapatite to the dopamine is 1: 0.6; and C is the appearance of the composite microsphere of example 4 when the feeding ratio of the hydroxyapatite to the dopamine is 1: 1.0.
FIG. 2 is a graph showing the N of HA particles (curve a) and functionalized HA composite microspheres (curve b) obtained in examples 1 and 32Adsorption-desorption curve.
Fig. 3 is a graph showing the pore size distribution of the HA particles (curve a) and functionalized HA composite microspheres (curve b) prepared in examples 1 and 3.
FIG. 4 shows the photothermal effect evaluation curves of 0.5mg/mL and 1mg/mL for the polydopamine-functionalized hydroxyapatite composite material prepared in example 2.
Fig. 5 is an evaluation chart of antibacterial performance of the composite micro-nano particles prepared in example 5 on staphylococcus aureus, wherein the left part is a control group, and the right part is a composite micro-nano particle treatment group.
Detailed Description
The following examples are presented to further illustrate the practice of the invention, but the practice and protection of the invention is not limited thereto. It is noted that the processes described below, if not specifically described in detail, are all realizable or understandable by those skilled in the art with reference to the prior art. The reagents or apparatus used are not indicated to the manufacturer, and are considered to be conventional products available by commercial purchase.
Example 1
The preparation method of the bionic hydroxyapatite micro-nano particles with high specific surface area comprises the following steps:
preparing hydroxyapatite powder with a hierarchical structure: diammonium phosphate solution with a concentration of 24mM was prepared, and the pH thereof was adjusted to 6.0 with nitric acid to obtain solution 1. Calcium nitrate was added to the above solution 1 so that the molar volume ratio of calcium nitrate to solution 1 was 40:1mmol/L, and stirred to mix thoroughly, and the pH thereof was adjusted to 5.0, to obtain solution 2. Then, sodium citrate is added into the solution 2, the molar volume ratio of the sodium citrate to the solution 1 is 6:1mmol/L, and after the mixture is fully stirred, the mixture is transferred into a polytetrafluoroethylene-lined high-pressure reaction kettle and reacts for 3 hours at 180 ℃. And centrifuging the obtained precipitate, and freeze-drying to prepare the micro-nano HA particles with the hierarchical structure.
Example 2
The preparation method of the poly-dopamine functionalized hydroxyapatite composite material comprises the following steps:
50mg of the HA particles prepared in example 1 were dispersed in 49.5mL of 10mM Tris/HCl buffer (pH 8.5), and 30mg of dopamine was added thereto, respectively, and the mixture was placed on a roller mixer in the dark for reaction for 6 hours. And then, centrifugally washing the obtained reaction solution for multiple times, and freeze-drying to obtain the micro-nano hydroxyapatite composite microsphere with the poly-dopamine surface functionalized hierarchical structure.
Example 3
The preparation method of the poly-dopamine functionalized hydroxyapatite composite material comprises the following steps:
50mg of the HA particles prepared in example 1 were dispersed in 49.5mL of 10mM Tris/HCl buffer (pH 8.5), and 40mg of dopamine was added thereto, respectively, and the mixture was placed on a roller mixer in the dark for reaction for 6 hours. And then, centrifugally washing the obtained reaction solution for multiple times, and freeze-drying to obtain the micro-nano hydroxyapatite composite microsphere with the poly-dopamine surface functionalized hierarchical structure.
Example 4
The preparation method of the poly-dopamine functionalized hydroxyapatite composite material comprises the following steps:
50mg of the HA particles prepared in example 1 were dispersed in 49.5mL of 10mM Tris/HCl buffer (pH 8.5), and 50mg of dopamine was added thereto, respectively, and the mixture was placed on a roller mixer in the dark for reaction for 6 hours. And then, centrifugally washing the obtained reaction solution for multiple times, and freeze-drying to obtain the micro-nano hydroxyapatite composite microsphere with the poly-dopamine surface functionalized hierarchical structure.
Example 5
The preparation method of the polydopamine functionalized hydroxyapatite composite material loaded with HHC36 comprises the following steps:
weighing 5mg of the polydopamine-functionalized HA particles prepared in example 3, adding 5mL of 1mM antibacterial peptide HHC36 solution, placing the mixture in a shaker at 37 ℃ for overnight incubation, centrifuging to remove supernatant, and freeze-drying to obtain the HHC 36-loaded composite micro-nano particles.
Example 6
The appearance characteristics of the composite micro-nano particles in the embodiments 1-2 and 4 are observed by using a field emission scanning electron microscope and are shown in figure 1.
Wherein A is the appearance of the composite microsphere of example 1 when the feeding ratio of the hydroxyapatite to the dopamine is 1: 0; b is the appearance of the composite microsphere of example 2 when the feeding ratio of the hydroxyapatite to the dopamine is 1: 0.6; and C is the appearance of the composite microsphere of example 4 when the feeding ratio of the hydroxyapatite to the dopamine is 1: 1.0.
The result shows that the prepared hydroxyapatite micro-nano particles have a large number of mesoporous structures (figure 1A); when the mass ratio of the HA particles to dopamine is 1:0.6, the assembly of dopamine molecules on the surface of the HA particles mainly takes the form of a two-dimensional coating (fig. 1B); as the proportion of dopamine increased, it self-assembled on the surface of the HA particles in a coating and nanoparticle dual form (fig. 1C).
Example 7
By using N2The specific surface area and the pore size distribution of the composite micro-nano particles in the examples 1 and 3 were analyzed by an adsorption-desorption method.
As a result, as shown in FIG. 2, the HA powder had a specific surface area of 120.2m2The specific surface area of the polydopamine surface functionalized HA composite microspheres is 88.2m2(ii) in terms of/g. In-depth analysis, the larger specific surface area of the HA particles is mainly attributed to the mesoporous structure in the range of 3-5nm, while the majority of mesopores in the polydopamine surface functionalized HA composite microspheres are distributed in the range of 3-10nm (FIG. 3).
Example 8
The thermal effect of the polydopamine surface-functionalized composite in example 2 was evaluated using a photo-thermal imager.
FIG. 4 shows the photothermal effect evaluation curves of 0.5mg/mL and 1mg/mL for the polydopamine-functionalized hydroxyapatite composite material prepared in example 2.
The result shows that when the concentration of the particles is 0.5mg/mL, the temperature of the composite microspheres with different functionalized coatings can reach 50 ℃ under the action of 808nm infrared light, which provides effective thermal effect for the composite material.
Example 9
The antibacterial performance of the composite micro-nano particles in the embodiment 5 on staphylococcus aureus is evaluated by a plate counting method.
Fig. 5 is an evaluation chart of antibacterial performance of the composite micro-nano particles prepared in example 5 on staphylococcus aureus, wherein the left part is a control group, and the right part is a composite micro-nano particle treatment group.
The result shows that almost no bacterial colony is formed on the agar plate after the composite micro-nano particles act for 2 hours, and the composite microspheres have quick and efficient antibacterial activity.
The above examples are only preferred embodiments of the present invention, which are intended to be illustrative and not limiting, and those skilled in the art should understand that they can make various changes, substitutions and alterations without departing from the spirit and scope of the invention.
Claims (10)
1. A preparation method of a polydopamine functionalized hydroxyapatite composite material loaded with HHC36 is characterized by comprising the following steps:
(1) adding solid diammonium hydrogen phosphate into water, dissolving, and adjusting the pH value of the solution to 5.8-6.2 to obtain solution 1; adding calcium nitrate solid into the solution 1 for dissolving, and adjusting the pH value to 4.6-5.2 to obtain a solution 2; adding sodium citrate into the solution 2 for dissolving, reacting, centrifuging to remove supernatant, and freeze-drying to obtain a hydroxyapatite composite material;
(2) ultrasonically dispersing the hydroxyapatite composite material in the step (1) in a Tris-HCl buffer solution, adding dopamine to dissolve to obtain a mixed solution, stirring in a dark place, centrifuging, washing, and drying to obtain a poly-dopamine functionalized hydroxyapatite composite material;
(3) and (3) adding the polydopamine-functionalized hydroxyapatite composite material obtained in the step (2) and antibacterial peptide HHC36 into water, stirring to obtain a mixed solution, incubating, centrifuging, and freeze-drying to obtain the polydopamine-functionalized hydroxyapatite composite material loaded with HHC 36.
2. The preparation method according to claim 1, wherein the concentration of diammonium hydrogen phosphate in the solution 1 in the step (1) is 1-30mM, and the molar volume ratio of the calcium nitrate to the solution 1 is 1-90:1 mmol/L; the molar ratio of the calcium nitrate to the sodium citrate is 5-8: 1.
3. The method as claimed in claim 1, wherein the reaction temperature in step (1) is 150 ℃ to 200 ℃ and the reaction time is 1-12 h.
4. The method according to claim 1, wherein the concentration of Tris-HCl in the mixture of step (2) is 1 to 50 mM; the pH value of the Tris-HCl buffer solution is 7.2-9.0.
5. The preparation method according to claim 1, wherein the stirring in step (2) is carried out for 0.1 to 24 hours without light.
6. The preparation method according to claim 1, wherein the mixed solution in the step (2) has a concentration of the hydroxyapatite composite material of 0.1-20 mg/mL; the mass ratio of the dopamine to the hydroxyapatite powder composite material is 0.1-1.5: 1.
7. The preparation method according to claim 1, wherein the concentration of the poly-dopamine-functionalized hydroxyapatite composite in the mixed solution in the step (3) is 0.1-40 mg/mL.
8. The preparation method according to claim 1, wherein the mass ratio of the poly-dopamine functionalized hydroxyapatite composite material in the step (3) to the antibacterial peptide HHC36 is 1: 0.1-5; the incubation time is 1-24 h.
9. A polydopamine-functionalized hydroxyapatite composite material loaded with HHC36, prepared by the preparation method according to any one of claims 1 to 8.
10. Use of the polydopamine-functionalized hydroxyapatite composite material loaded with HHC36 according to claim 9 in the preparation of drugs for infectious bone defects.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114432490A (en) * | 2021-11-10 | 2022-05-06 | 北京大学口腔医学院 | 3D printing material and preparation method and application thereof |
| CN115804866A (en) * | 2022-12-08 | 2023-03-17 | 广东省科学院生物与医学工程研究所 | Polyester-based microsphere containing drug-loaded calcium inorganic matter and preparation method and application thereof |
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