PLGA-PEG-PLGA溫度敏感水凝膠的制備及在骨科應用基礎研究
發(fā)布時間：2018-09-05 20:01
【摘要】：骨髓炎以及跟腱術后的組織粘連一直都是臨床醫(yī)生面臨的難題。二者都可以通過局部給藥達到良好的預防以及治療效果，因此尋找一種能夠在局部長時間有效釋放藥物并且能夠降解的藥物釋放系統(tǒng)一直是廣大學者研究的目標。近年來，，高分子水凝膠在生物醫(yī)用領域已獲得了越來越多的應用。溫度敏感水凝膠由于可以在接近人體溫度時由液態(tài)轉變?yōu)槟z狀態(tài)而引起了廣大學者的高度關注，其具有可以注射操作、不引入交聯(lián)劑、可以包埋擔載多肽、蛋白、細胞以及小分子藥物等諸多特點。隨著美國FDA批準可以將聚丙交酯（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臨床試驗, PLGA-PEG-PLGA(poly (D,L-lactide-co-glycolide)-poly(ethylene glycol)-poly (D，L-lactide-co-glycolide))溫敏水凝膠在醫(yī)學領域，尤其是體內原位藥物釋放領域越來越受到研究者們的重視。本研究中我們制備了一系列PLGA-PEG-PLGA溫敏聚合物并對其進行了相關表征，同時我們研究了該聚合物對萬古霉素以及5-氟尿嘧啶的緩釋行為并進行了相關的動物實驗，具體內容如下。 1)通過開環(huán)聚合制備了PLGA-PEG-PLGA。這種聚合物的溶液可以隨著溫度的升高發(fā)生凝膠轉變，包載萬古霉素后聚合物溶液仍然表現(xiàn)出溫敏sol-gel相轉變特性，流變學檢測顯示共聚物在體溫時可以達到最大的儲能模量。體外藥物釋放以及抗菌結果表明，萬古霉素可以持續(xù)穩(wěn)定從凝膠中釋放出來并且具有良好的抗菌效果。細胞實驗及體內外降解表明這些三嵌段共聚物具有良好的細胞相容性、生物相容性以及可降解性。體內抗菌實驗則說明包載萬古霉素的PLGA-PEG-PLGA共聚物緩釋系統(tǒng)可以有效的治療骨髓炎，并且沒有帶來相關的藥物副損傷。 2)針對單純使用聚合物緩釋抗生素骨修復不佳的問題，我們進一步設計了一種PLGA-PEG-PLGA/HA復合凝膠。流變學、sol-gel相轉變以及CMC證明PLGA-PEG-PLGA/HA復合物的溶液仍可以隨著溫度的變化表現(xiàn)出溫敏sol-gel相轉變特性，羥基磷灰石的復合還使得體系的儲能模量有了較大的增高。紅外、X射線衍射、TEM表明羥基磷灰石可以穩(wěn)定均勻的分散于PLGA-PEG-PLGA聚合物中。此外HA還中和了聚合物降解過程中的酸性從而帶來了更好的體外細胞相容性。最后體內的抗菌實驗表明載萬古霉素的PLGA-PEG-PLGA/HA凝膠在治療骨髓炎的同時還能夠促進骨組織的修復。 3)最后我們還設計了一種載5-氟尿嘧啶凝膠緩釋系統(tǒng)。體外藥物釋放表明5-氟尿嘧啶可以持續(xù)釋放7天，凝膠在4周內被機體降解掉，并表現(xiàn)出了良好的生物相容性。體內的防粘連實驗通過肉眼評分以及病理學評價后認為載5-氟尿嘧啶凝膠相對于單純應用凝膠以及對照組來說表現(xiàn)出了明顯防粘連效果。
[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.
【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R318.08
本文編號：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.
【學位授予單位】：吉林大學
【學位級別】：博士
【學位授予年份】：2015
【分類號】：R318.08
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2 虞冀哲;吳華;楊勇;劉朝旭;劉陽;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
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