PLGA-PEG-PLGA温度敏感水凝胶的制备及在骨科应用基础研究
发布时间：2018-09-05 20:01
【摘要】：骨髓炎以及跟腱术后的组织粘连一直都是临床医生面临的难题。二者都可以通过局部给药达到良好的预防以及治疗效果，因此寻找一种能够在局部长时间有效释放药物并且能够降解的药物释放系统一直是广大学者研究的目标。近年来，，高分子水凝胶在生物医用领域已获得了越来越多的应用。温度敏感水凝胶由于可以在接近人体温度时由液态转变为凝胶状态而引起了广大学者的高度关注，其具有可以注射操作、不引入交联剂、可以包埋担载多肽、蛋白、细胞以及小分子药物等诸多特点。随着美国FDA批准可以将聚丙交酯（poly D,L-lacticacid,PLA)聚丙交酯乙交酯(poly lactic-co-glycolic acid，PLGA)等高分子聚合物用于临床试验, PLGA-PEG-PLGA(poly (D,L-lactide-co-glycolide)-poly(ethylene glycol)-poly (D，L-lactide-co-glycolide))温敏水凝胶在医学领域，尤其是体内原位药物释放领域越来越受到研究者们的重视。本研究中我们制备了一系列PLGA-PEG-PLGA温敏聚合物并对其进行了相关表征，同时我们研究了该聚合物对万古霉素以及5-氟尿嘧啶的缓释行为并进行了相关的动物实验，具体内容如下。 1)通过开环聚合制备了PLGA-PEG-PLGA。这种聚合物的溶液可以随着温度的升高发生凝胶转变，包载万古霉素后聚合物溶液仍然表现出温敏sol-gel相转变特性，流变学检测显示共聚物在体温时可以达到最大的储能模量。体外药物释放以及抗菌结果表明，万古霉素可以持续稳定从凝胶中释放出来并且具有良好的抗菌效果。细胞实验及体内外降解表明这些三嵌段共聚物具有良好的细胞相容性、生物相容性以及可降解性。体内抗菌实验则说明包载万古霉素的PLGA-PEG-PLGA共聚物缓释系统可以有效的治疗骨髓炎，并且没有带来相关的药物副损伤。 2)针对单纯使用聚合物缓释抗生素骨修复不佳的问题，我们进一步设计了一种PLGA-PEG-PLGA/HA复合凝胶。流变学、sol-gel相转变以及CMC证明PLGA-PEG-PLGA/HA复合物的溶液仍可以随着温度的变化表现出温敏sol-gel相转变特性，羟基磷灰石的复合还使得体系的储能模量有了较大的增高。红外、X射线衍射、TEM表明羟基磷灰石可以稳定均匀的分散于PLGA-PEG-PLGA聚合物中。此外HA还中和了聚合物降解过程中的酸性从而带来了更好的体外细胞相容性。最后体内的抗菌实验表明载万古霉素的PLGA-PEG-PLGA/HA凝胶在治疗骨髓炎的同时还能够促进骨组织的修复。 3)最后我们还设计了一种载5-氟尿嘧啶凝胶缓释系统。体外药物释放表明5-氟尿嘧啶可以持续释放7天，凝胶在4周内被机体降解掉，并表现出了良好的生物相容性。体内的防粘连实验通过肉眼评分以及病理学评价后认为载5-氟尿嘧啶凝胶相对于单纯应用凝胶以及对照组来说表现出了明显防粘连效果。
[Abstract]:Osteomyelitis and tissue adhesion after Achilles tendon operation have always been a difficult problem for clinicians. Both of them can achieve good preventive and therapeutic effects through local administration. Therefore, it has been the research goal of many scholars to find a drug release system that can release drugs effectively and degrade for a long time. In recent years, polymer hydrogels have been applied more and more in the field of biomedicine. Thermo-sensitive hydrogels are highly concerned by many scholars because they can change from liquid state to gel state when they are close to human temperature. They can be injected without cross-linking agent, and can be encapsulated with peptides and proteins. Cells and small molecular drugs and many other characteristics. With the approval of the FDA of the United States for the use of polymer polymers such as poly DL-lactide-co-glycolide (poly lactic-co-glycolic acid,PLGA) in clinical trials, PLGA-PEG-PLGA (poly (DL-lactide-co-glycolide -poly (ethylene glycol) -poly (DL-lactide-co-glycolide) thermo-sensitive hydrogels are in the medical field. In particular, the field of in situ drug release has been paid more and more attention by researchers. In this study, a series of PLGA-PEG-PLGA thermo-sensitive polymers were prepared and characterized, and the sustained release behaviors of the polymers to vancomycin and 5-fluorouracil were studied and related animal experiments were carried out. The main contents are as follows: 1) PLGA-PEG-PLGA. was prepared by ring-opening polymerization. The solution of this kind of polymer can change with the increase of temperature, and the polymer solution still shows a temperature-sensitive sol-gel phase transition after encapsulating vancomycin. Rheological examination shows that the copolymer can reach the maximum storage modulus at body temperature. In vitro drug release and antibacterial results showed that vancomycin could be released from the gel steadily and had a good antibacterial effect. Cell experiments and in vitro and in vivo degradation showed that these triblock copolymers had good cytocompatibility biocompatibility and biodegradability. In vivo antimicrobial experiments showed that the PLGA-PEG-PLGA copolymers containing vancomycin could effectively treat osteomyelitis. In order to solve the problem of poor bone repair using polymer sustained-release antibiotics alone, we further designed a PLGA-PEG-PLGA/HA composite gel. The rheological properties of sol-gel phase transition and CMC show that the solution of PLGA-PEG-PLGA/HA complex can still exhibit temperature-sensitive sol-gel phase transition with the change of temperature. The composite of hydroxyapatite also increases the storage modulus of the system. FTIR X-ray diffraction (TEM) shows that hydroxyapatite can be dispersed in PLGA-PEG-PLGA polymer stably and uniformly. In addition, HA neutralizes the acidity in the degradation of polymers, which leads to better cytocompatibility in vitro. Finally, antibacterial experiments in vivo showed that PLGA-PEG-PLGA/HA gel containing vancomycin could promote the repair of bone tissue while treating osteomyelitis. 3) finally, we designed a sustained-release system of 5-fluorouracil gel. In vitro drug release showed that 5-fluorouracil could be released continuously for 7 days and the gel was degraded by the body within 4 weeks and showed good biocompatibility. The anti-adhesion test in vivo showed that the 5-fluorouracil gel had obvious anti-adhesion effect compared with the control group and the application of the gel alone after the naked eye score and pathological evaluation.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R318.08
本文编号：2225321
[Abstract]:Osteomyelitis and tissue adhesion after Achilles tendon operation have always been a difficult problem for clinicians. Both of them can achieve good preventive and therapeutic effects through local administration. Therefore, it has been the research goal of many scholars to find a drug release system that can release drugs effectively and degrade for a long time. In recent years, polymer hydrogels have been applied more and more in the field of biomedicine. Thermo-sensitive hydrogels are highly concerned by many scholars because they can change from liquid state to gel state when they are close to human temperature. They can be injected without cross-linking agent, and can be encapsulated with peptides and proteins. Cells and small molecular drugs and many other characteristics. With the approval of the FDA of the United States for the use of polymer polymers such as poly DL-lactide-co-glycolide (poly lactic-co-glycolic acid,PLGA) in clinical trials, PLGA-PEG-PLGA (poly (DL-lactide-co-glycolide -poly (ethylene glycol) -poly (DL-lactide-co-glycolide) thermo-sensitive hydrogels are in the medical field. In particular, the field of in situ drug release has been paid more and more attention by researchers. In this study, a series of PLGA-PEG-PLGA thermo-sensitive polymers were prepared and characterized, and the sustained release behaviors of the polymers to vancomycin and 5-fluorouracil were studied and related animal experiments were carried out. The main contents are as follows: 1) PLGA-PEG-PLGA. was prepared by ring-opening polymerization. The solution of this kind of polymer can change with the increase of temperature, and the polymer solution still shows a temperature-sensitive sol-gel phase transition after encapsulating vancomycin. Rheological examination shows that the copolymer can reach the maximum storage modulus at body temperature. In vitro drug release and antibacterial results showed that vancomycin could be released from the gel steadily and had a good antibacterial effect. Cell experiments and in vitro and in vivo degradation showed that these triblock copolymers had good cytocompatibility biocompatibility and biodegradability. In vivo antimicrobial experiments showed that the PLGA-PEG-PLGA copolymers containing vancomycin could effectively treat osteomyelitis. In order to solve the problem of poor bone repair using polymer sustained-release antibiotics alone, we further designed a PLGA-PEG-PLGA/HA composite gel. The rheological properties of sol-gel phase transition and CMC show that the solution of PLGA-PEG-PLGA/HA complex can still exhibit temperature-sensitive sol-gel phase transition with the change of temperature. The composite of hydroxyapatite also increases the storage modulus of the system. FTIR X-ray diffraction (TEM) shows that hydroxyapatite can be dispersed in PLGA-PEG-PLGA polymer stably and uniformly. In addition, HA neutralizes the acidity in the degradation of polymers, which leads to better cytocompatibility in vitro. Finally, antibacterial experiments in vivo showed that PLGA-PEG-PLGA/HA gel containing vancomycin could promote the repair of bone tissue while treating osteomyelitis. 3) finally, we designed a sustained-release system of 5-fluorouracil gel. In vitro drug release showed that 5-fluorouracil could be released continuously for 7 days and the gel was degraded by the body within 4 weeks and showed good biocompatibility. The anti-adhesion test in vivo showed that the 5-fluorouracil gel had obvious anti-adhesion effect compared with the control group and the application of the gel alone after the naked eye score and pathological evaluation.
【学位授予单位】：吉林大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R318.08
【参考文献】
相关期刊论文 前2条
1 贺超良;汤朝晖;田华雨;陈学思;;3D打印技术制备生物医用高分子材料的研究进展[J];高分子学报;2013年06期
2 虞冀哲;吴华;杨勇;刘朝旭;刘阳;宋明宇;;Osteogenic Differentiation of Bone Mesenchymal Stem Cells Regulated by Osteoblasts under EMF Exposure in a Co-culture System[J];Journal of Huazhong University of Science and Technology(Medical Sciences);2014年02期
本文编号：2225321
本文链接：https://www.wllwen.com/yixuelunwen/swyx/2225321.html
