骨折支架表面构筑双层结构聚合物膜控释抗生素的研究

发布时间：2018-11-09 07:31

【摘要】：开放性骨折是创伤骨科的常见病,随着现代化交通工具的普及和人们生活节奏的加快,病例逐年递增,并且治疗困难。严重的骨折必须通过手术复位并植入内固定支架进行治疗。而由于伤口污染及引入内固定支架所导致的创口感染几乎是不可避免的,严重时可导致骨髓炎,必须通过抗生素给药进行治疗。然而,传统口服及注射抗生素药物容易对人体重要器官造成不可逆的损伤,长期不间断抗生素给药也存在产生超级细菌的风险,从而对人体健康甚至生命产生严重的威胁。在植入物表面构筑载药涂层局部递送抗生素,是解决上述问题的有效策略。鉴于此,本文利用静电喷涂技术,在骨折支架表面构筑具有高载药容量的聚合物膜,然后利用电纺丝技术将聚合物多孔纤维覆盖到载药膜表面,通过调整纤维孔径的密度及尺寸控制抗生素的释放速度。主要研究工作总结为以下两方面:1.静电喷涂聚乙烯醇微凝胶制备聚合物膜以硼砂作为交联剂,在水溶液中制备聚乙烯醇-硼砂(PVA-B)微凝胶。利用静电喷涂方法,以PVA-B为基元,制备PVA-B微凝胶膜。研究结果表明,当PVA和硼砂浓度分别为25 mg·mL-1和3.0 mM时,得到粒径为712.4 nm均匀分散的微凝胶。PVA-B膜的质量与沉积时间为线性关系,沉积速率为0.187mg·cm-2·h-1。喷涂时间为1 h时,得到厚度为1.35μm微凝胶膜。通过傅里叶红外(FTIR)、热重分析(TGA)对微凝胶膜进行表征;通过应力应变曲线研究了微凝胶膜的力学性能。以槲皮素作为药物模型,研究了PVA-B微凝胶膜的药物负载能力,结果表明PVA-B微凝胶膜具有高药物负载能力,在药物递送领域有潜在的应用价值。2.双层结构聚合物膜控释盐酸万古霉素将盐酸万古霉素(VH)与PVA-B微凝胶以1:1的质量比混合,利用静电喷涂技术制备VH@PVA-B膜,VH@PVA-B膜浸泡于生理盐水中,5 min内VH完全释放。为减慢VH的释放速度,利用电纺丝技术在VH@PVA-B膜表面覆盖聚乙烯醇缩丁醛(PVB)纤维毡,结果表明当PVB纤维毡的质量为1.036 mg·cm-2时,VH的释放可以持续4 d。为了进一步减缓VH的释放速率,利用乙醇蒸汽处理PVB纤维毡,随着处理时间的延长,PVB纤维毡的接触角降低,孔密度减少,孔尺寸缩小,逐渐转变为多孔膜。当PVB纤维毡(0.842 mg·cm-2)用乙醇蒸汽处理12 min时,VH的释放时间可以持续35 d(满足临床给药需求),利用Weibull模型拟合VH释放行为,相关系数R2高达0.982,证明VH从复合膜中的释放属于Fickian扩散。此外,经过乙醇蒸汽处理12 min的VH@PVA-B/PVB膜,其在生理盐水中释放VH 0.5、1和2 d时均可以有效杀灭金黄色葡萄球菌。这种聚合物膜和多孔纤维复合结构有望成为普适性的药物控释载体用于植入物表面。
[Abstract]:Open fracture is a common disease in orthopedic trauma. With the popularization of modern transportation and the acceleration of people's life rhythm, the number of cases increases year by year and the treatment is difficult. Severe fractures must be treated by surgical reduction and internal fixation. The wound infection caused by wound contamination and the introduction of internal fixation stent is almost inevitable, and can lead to osteomyelitis in severe cases, which must be treated with antibiotics. However, traditional oral and injecting antibiotic drugs are prone to irreversibly damage to important organs of human body, and long-term continuous antibiotic administration also has the risk of producing super bacteria, which is a serious threat to human health and even life. It is an effective strategy to solve the above problem by constructing a drug-loaded coating to deliver antibiotics locally on the implant surface. In view of this, a polymer film with high drug loading capacity was constructed on the surface of fracture scaffold by electrostatic spraying technology, and then the porous polymer fiber was covered on the surface of drug-loaded film by electrospinning technology. The release rate of antibiotics is controlled by adjusting the density and size of fiber aperture. The main research work is summarized as follows: 1. Poly (vinyl alcohol) borax (PVA-B) microgel was prepared by electrostatically sprayed polyvinyl alcohol (PVA) microgel with borax as crosslinking agent in aqueous solution. PVA-B microgel films were prepared by electrostatic spraying with PVA-B as the basic element. The results showed that when the concentration of PVA and borax were 25 mg mL-1 and 3.0 mM, the microgels with particle size of 712.4 nm were obtained. The quality of PVA-B film was linearly related to the deposition time. The deposition rate is 0.187mg cm-2 h-1. When spraying time is 1 h, the thickness of microgel film is 1.35 渭 m. The microgel films were characterized by FTIR (FTIR), thermogravimetric analysis (TGA) and the mechanical properties of microgel films were studied by stress-strain curves. Quercetin was used as a drug model to study the drug loading capacity of PVA-B microgel membrane. The results showed that PVA-B microgel membrane had high drug loading ability and had potential application value in drug delivery field. 2. Controlled release Vancomycin Hydrochloride (vancomycin Hydrochloride) was used to prepare (VH) / PVA-B microgel at 1:1 mass ratio. VH@PVA-B film was prepared by electrostatic spraying. VH@PVA-B film was immersed in normal saline. 5 VH was completely released within min. In order to slow down the release rate of VH, polyvinyl butyral (PVB) fiber felt was coated on the surface of VH@PVA-B membrane by electrospinning technique. The results showed that when the mass of PVB fiber felt was 1.036 mg cm-2, the release of VH could last 4 days. In order to further slow down the release rate of VH, PVB fiber felt was treated with ethanol vapor. With the extension of treatment time, the contact angle, pore density and pore size of PVB fiber felt decreased and gradually changed into porous membrane. When PVB fiber felt (0.842 mg cm-2) was treated with ethanol vapor for 12 min, the release time of VH could last 35 days (to meet the requirement of clinical administration). The Weibull model was used to fit the release behavior of VH. The correlation coefficient (R2) was as high as 0.982. It is proved that the release of VH from the composite membrane belongs to Fickian diffusion. In addition, when the VH@PVA-B/PVB membrane was treated with ethanol vapor for 12 min, it could effectively kill Staphylococcus aureus when VH was released in normal saline for 1 and 2 days. The composite structure of polymer membrane and porous fiber is expected to become a universal drug controlled release carrier for the surface of implants.
【学位授予单位】：西北农林科技大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R683;TQ465

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