阅读说明：本技术 一种基于天然多糖的骨科临时植入体的表面智能涂层的制备方法及其产品 (Preparation method of surface intelligent coating of orthopedic temporary implant based on natural polysaccharide and product thereof ) 是由 徐福建 章露娇 段顺 于 2019-11-25 设计创作，主要内容包括：本发明公开了一种基于天然多糖的骨科临时植入体的表面智能涂层的制备方法,步骤为：1)将第一种多糖和高碘酸钠反应,得到醛化度为55％～65％的醛化多糖；2)将补强多糖在热水中溶解,得到溶液a,将抗生素溶于pH＝9～10的碳酸钠溶液,得到溶液b,将溶液b加入溶液a中混合均匀,加入步骤1)所述的醛化多糖,制得成膜液；3)在反应器中放入骨科临时植入体,加入步骤2)所述的成膜液,在30～60℃缓慢挥发,将骨科临时植入体表面均匀包裹上复合膜；4)将步骤3)中制得的材料放入加入交联剂溶液中浸泡5～20min,取出用水清洗,烘干,得到修饰上复合膜的骨科临时植入体。本发明产品抗菌效果优异。(The invention discloses a preparation method of an intelligent coating on the surface of an orthopedic temporary implant based on natural polysaccharide, which comprises the following steps: 1) reacting the first polysaccharide with sodium periodate to obtain hydroformylation polysaccharide with a hydroformylation degree of 55-65%; 2) dissolving reinforced polysaccharide in hot water to obtain a solution a, dissolving antibiotics in a sodium carbonate solution with the pH value of 9-10 to obtain a solution b, adding the solution b into the solution a, uniformly mixing, and adding the hydroformylation polysaccharide obtained in the step 1) to obtain a film forming solution; 3) placing the orthopedic temporary implant into a reactor, adding the film-forming liquid obtained in the step 2), slowly volatilizing at 30-60 ℃, and uniformly wrapping the surface of the orthopedic temporary implant with a composite film; 4) and (3) soaking the material prepared in the step 3) in a crosslinking agent adding solution for 5-20 min, taking out, washing with water, and drying to obtain the orthopedic temporary implant decorated with the composite membrane. The product of the invention has excellent antibacterial effect.)

1. A preparation method of an intelligent coating on the surface of an orthopedic temporary implant based on natural polysaccharide is characterized by comprising the following steps:

1) reacting the first polysaccharide with sodium periodate to obtain hydroformylation polysaccharide with a hydroformylation degree of 55-65%;

2) dissolving reinforced polysaccharide in hot water to obtain a solution a, dissolving antibiotics in a sodium carbonate solution with the pH value of 9-10 to obtain a solution b, adding the solution b into the solution a, uniformly mixing, and adding the hydroformylation polysaccharide obtained in the step 1) to obtain a film forming solution;

3) placing the orthopedic temporary implant into a reactor, adding the film-forming liquid obtained in the step 2), slowly volatilizing at 30-60 ℃, and uniformly wrapping the surface of the orthopedic temporary implant with a composite film;

4) and (3) soaking the material prepared in the step 3) in a crosslinking agent adding solution for 5-20 min, taking out, washing with water, and drying to obtain the orthopedic temporary implant decorated with the composite membrane.

2. The method for preparing a surface smart coating of an orthopaedic temporary implant based on natural polysaccharides of claim 1, wherein the first polysaccharide of step 1) is cellulose, starch, sodium alginate, sodium hyaluronate, dextran, pullulan, agarose or laminaran, and the reinforcing polysaccharide of step 2) is gelatin, xanthan gum, pectin or acacia.

3. The method for preparing the surface intelligent coating of the orthopaedic temporary implant based on natural polysaccharides as claimed in claim 2, wherein the first polysaccharide in step 1) is sodium alginate and the reinforcing polysaccharide in step 2) is gelatin.

4. The method for preparing the surface intelligent coating of the orthopaedic temporary implant based on the natural polysaccharide is characterized in that the first polysaccharide in the step 1) is 1-15 parts by weight, the sodium periodate is 0.1-5 parts by weight, the hydroformylation polysaccharide in the step 2) is 1-10 parts by weight, the reinforcing polysaccharide is 5-50 parts by weight, the sodium carbonate is 0.5-5 parts by weight, the antibiotic is 0.1-3 parts by weight, and the cross-linking agent in the step 3) is 1-3 parts by weight, wherein the reinforcing polysaccharide is higher than the hydroformylation polysaccharide.

5. The method for preparing the surface intelligent coating of the orthopaedic temporary implant based on the natural polysaccharide according to claim 4, wherein the amount of the hydroformylation polysaccharide in the step 2) is 1-5 parts, and the amount of the reinforcing polysaccharide is 2-10 parts.

6. The method for preparing the surface intelligent coating of the orthopaedic temporary implant based on natural polysaccharides as claimed in claim, wherein the reaction temperature of the reaction of step 1) is 25-37 ℃ and the reaction time is 20-30 h.

7. The method for preparing the smart coating layer on the surface of the orthopaedic temporary implant based on natural polysaccharides as claimed in claim, wherein the temperature of the hot water of step 2) is 60-100 ℃.

8. The method for preparing the surface smart coating of the orthopaedic temporary implant based on natural polysaccharides as claimed in claim 1, wherein the volatilization time of step 3) is 7-10 h.

9. The method for preparing the surface smart coating of the orthopaedic temporary implant based on natural polysaccharides of claim 1, wherein the cross-linking agent of step 4) is genipin, glutaraldehyde or formaldehyde.

10. The material prepared by the method for preparing the surface intelligent coating of the orthopaedic temporary implant based on natural polysaccharides according to any one of claims 1 to 9.

Technical Field

The invention belongs to the field of medical materials, and relates to a preparation method of an intelligent coating on the surface of an orthopedic temporary implant based on natural polysaccharide and a product thereof.

Background

The orthopedics department often produces implant-related infection in clinic, and the two main problems are bacterial local reproduction and bacteremia. Orthopedic implant infections are characterized by high, repeated and delayed onset, often resulting in treatment failure and even endangering the health of the patient. In order to solve the infection problem of orthopedic implants, many efforts have been made in surface functionalization. For example, cationic coatings are built on the surface for contact sterilization. Among bactericidal cationic polymers reported in the literature, polycations derived from Quaternary Ammonium Compounds (QACs), polyethyleneimine derivatives, chitosan derivatives, and the like destroy the integrity of bacterial cell membranes by a membrane lysis mechanism, allow the contents of cells to be discharged, and exhibit strong antibacterial activity. In addition, a surface may be loaded with a bactericide to perform a release type sterilization. Biocides including silver nanoparticles (AgNPs), antibiotics, and nitric oxide, etc. are preloaded or embedded and then slowly released into the surrounding environment to kill bacteria. There is also a report that photo-thermal sterilization is performed by modifying a photosensitizer on the surface, and near infrared light is used to irradiate photo-thermal agent materials such as platinum and gold to generate excessive heat, so that bacteria are killed by a thermal ablation method.

Chinese patent publication No. CN106512083A discloses a method for preparing a medical titanium alloy. According to the preparation method, the PLGA drug-loaded nanoparticles are connected to the titanium-based surface by using a double emulsion method, a hydrothermal method and the like, and the prepared product has good biological activity and antibacterial performance. However, the method has complicated steps, involves strong acid and strong alkali in the experimental process, has certain danger and lacks high-efficiency practicability.

Chinese patent publication No. CN102758202B discloses a method for preparing medical titanium and titanium alloy surface antibacterial coatings. According to the patent, the preparation of the nano precoating layer, the silver-carrying treatment and the micro-arc oxidation technology are combined, so that the large-amount fixation and long-term slow release of silver on the surface of medical titanium and titanium alloy are realized, the antibacterial performance of the titanium and titanium alloy can be obviously improved, and the antibacterial effect can be maintained for a long time. However, the antimicrobial silver in the method has certain biological toxicity, so that the application of the method is limited.

Chinese patent publication No. CN106867042A discloses a method for preparing a nano-cellulose/chitosan/polyvinyl alcohol composite film by a tape casting method and an application method thereof in a biological antibacterial film. The patent uses polyvinyl alcohol as a matrix polymer, nano-cellulose as a reinforcing agent and chitosan as a natural antibacterial agent to complete the preparation process of the composite membrane product by adopting a tape casting method. The composite membrane prepared by the method is easy to operate, excellent in mechanical property and good in optical property, but the drug resistance of bacteria is easily caused due to the firm combination of chitosan.

Chinese patent publication No. CN103191467A discloses a method for preparing an antibacterial coating with a medical metal surface slowly releasing multiple cell growth factors. According to the method, an amide bond covalent bonding mode is adopted to graft antibiotics with amino groups on graphene oxide, and nanoparticles respectively wrapping multiple cell growth factors are fixed between graphene oxide layers by a layer-by-layer self-assembly method, so that a coating simultaneously carrying the multiple cell growth factors and the antibiotics is obtained on the surface of the medical metal. The coating prepared by the method can independently control the slow and ordered release of various cell growth factors, and can release antibiotics in the whole process of slow release of the cell growth factors. However, the method cannot regulate and control the self-adaptive release of antibiotics, the adopted graphene oxide has potential toxicity, and meanwhile, certain high-efficiency practicability is lacked by layer-by-layer self-assembly.

As described above, there are still some problems in surface functionalization, and the antibacterial agent induces bacterial resistance for a long time, bacteria are easily colonized on the surface to cause the antibacterial agent to lose efficacy, the compatibility of the implant surface is poor, and the selected material has some toxicity, etc. In order to solve the problems, the invention hopes to develop an intelligent coating which has simple preparation process, good biocompatibility and self-adaptive release antibacterial property. The intelligent coating is used for modifying the surface of the orthopedic temporary implant to enable the orthopedic temporary implant to have bacterial response capability, and can self-adaptively release antibacterial substances to sterilize so as to achieve the purpose of resisting infection, thereby improving the success rate of implantation surgery. The intelligent coating developed by the invention provides reaction sites by firmly fixing natural polysaccharide on the surface, so that the implant has good biocompatibility. The antibiotics and the polysaccharide sites are connected through the Schiff base bond which has response rupture property to the bacterial acid microenvironment, so that the antibiotics can be released and sterilized in a self-adaptive manner, the bacteria can be killed quickly, accurately and efficiently, and meanwhile, the generation of bacterial drug resistance is avoided to a great extent.

Disclosure of Invention

In view of the above, the present invention aims to provide an orthopedic temporary implant surface smart coating based on natural polysaccharides, which has good biocompatibility and excellent anti-infection performance.

The invention specifically provides the following technical scheme:

1. a method for preparing an intelligent coating on the surface of an orthopedic temporary implant based on natural polysaccharide comprises the following steps:

1) reacting the first polysaccharide with sodium periodate to obtain hydroformylation polysaccharide with a hydroformylation degree of 55-65%;

2) dissolving reinforced polysaccharide in hot water to obtain a solution a, dissolving antibiotics in a sodium carbonate solution with the pH value of 9-10 to obtain a solution b, adding the solution b into the solution a, uniformly mixing, and adding the hydroformylation polysaccharide obtained in the step 1) to obtain a film forming solution;

3) placing the orthopedic temporary implant into a reactor, adding the film-forming liquid obtained in the step 2), slowly volatilizing at 30-60 ℃, and uniformly wrapping the surface of the orthopedic temporary implant with a composite film;

4) and (3) soaking the material prepared in the step 3) in a crosslinking agent adding solution for 5-20 min, taking out, washing with water, and drying to obtain the orthopedic temporary implant decorated with the composite membrane.

Further, the first polysaccharide in the step 1) is cellulose, starch, sodium alginate, sodium hyaluronate, glucan, pullulan, agarose or laminaran, and the reinforcing polysaccharide in the step 2) is gelatin, xanthan gum, pectin or gum arabic.

Further, the first polysaccharide in the step 1) is sodium alginate, and the reinforcing polysaccharide in the step 2) is gelatin.

Further, by weight, 1-15 parts of the first polysaccharide in the step 1), 0.1-5 parts of sodium periodate, 1-10 parts of the hydroformylation polysaccharide in the step 2), 5-50 parts of the reinforcing polysaccharide, 0.5-5 parts of sodium carbonate, 0.1-3 parts of antibiotic and 1-3 parts of the cross-linking agent in the step 3), wherein the parts of the reinforcing polysaccharide are higher than the parts of the hydroformylation polysaccharide.

Further, the hydroformylation polysaccharide in the step 2) is 1-5 parts, and the reinforcing polysaccharide is 2-10 parts.

Further, the reaction temperature of the reaction in the step 1) is 25-37 ℃, and the reaction time is 20-30 h.

Further, the temperature of the hot water in the step 2) is 60-100 ℃.

Further, the volatilization time in the step 3) is 7-10 h.

Further, the cross-linking agent in the step 4) is genipin, glutaraldehyde or formaldehyde.

2. The material is prepared by the preparation method of the surface intelligent coating of the orthopedic temporary implant based on the natural polysaccharide.

The invention has the beneficial effects that:

(1) according to the invention, two different polysaccharides, one is a reinforcing polysaccharide and the other is a hydroformylation polysaccharide, are blended and slowly volatilized at 30-60 ℃, so that molecular chains are gradually orderly and orderly from a random state, a network system is formed on the surface of the material through hydrogen bond action and the like, macroscopic coating modification is realized on the surface through a one-step method, the preparation method is simple to operate, the experimental process is green and environment-friendly, the result is controllable, and the preparation cost is low. The ratio of the reinforcing polysaccharide to the hydroformylation polysaccharide is higher than that of the hydroformylation polysaccharide when the ratio of the polysaccharide is regulated and controlled, because the crosslinking degree between the two polysaccharides is increased when the ratio of the hydroformylation polysaccharide is too high, the molecular chains are more tightly entangled, the moving speed of the molecular chains is slow, the molecular chains cannot be rearranged in time when moisture volatilizes to cause the surface film to break, the gelatin still keeps the elastic characteristic of protein, when the ratio is high, the molecular chains have certain elasticity, the distance between the molecular chains is shortened when the moisture volatilizes, and the surface is uniformly formed into a film.

(2) The invention adopts Schiff base bond formed by aldehyde group on the hydroformylation polysaccharide and amino group of the antibiotic during blending volatilization to realize self-adaptive release of the antibiotic, can form higher concentration locally rather than entering a circulating system in a whole-body administration mode, has no toxic or side effect on important organs of a body, realizes intelligent, rapid, efficient and accurate sterilization, and effectively reduces the generation of bacterial drug resistance.

(3) The cross-linking agent is used, so that the material utilizes gelatin to reinforce the film-forming effect well, and simultaneously avoids the problem of easy structure dissolution, and the surface coating can realize the long-acting stable antibacterial effect. The gelatin is a temperature-sensitive material, the structure of the gelatin can be dissolved in the environment of 37 ℃ of a human body, an in-vitro simulation experiment shows that the surface coating can be completely dissolved after being soaked in physiological saline at 37 ℃ for 1-6 hours, the long-term stability is not met, the membrane can be enabled to have good stability through the post-treatment of the cross-linking agent in the step 4), the in-vitro simulation experiment at 37 ℃ for 7 days is carried out, the structural dissolution phenomenon does not occur on the surface coating after the in-vitro simulation experiment for 7 days, and the antibacterial effect is still good when the soaking material is subjected to an antibacterial experiment.

(4) The invention adopts natural polysaccharide with wide sources to provide reaction sites, so that the modified implant has good biocompatibility, good anti-fouling effect, safety and no toxicity, and can be directly used for medical application.

(5) The invention has excellent antibacterial performance and long-term stable antibacterial effect, and can reduce the infection in orthopedic surgery to a certain extent.

Drawings

In order to make the purpose, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings:

FIG. 1 is a graph showing the comparison between the effects before and after surface modification of the implant material according to example 1.

FIG. 2 is a comparison of before and after hydroformylation of polysaccharides and Schiff's reagent characterization according to step (1) of example 1.

Fig. 3 is a graph showing the antibacterial effect of the surface smart coating of the orthopedic temporary implant based on natural polysaccharides obtained according to examples 2, 4 and 5.

Fig. 4 is a graph showing the effect of film formation on the surface of the implants of comparative example 1 and comparative example 2.

Detailed Description

Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.