PLGA-PEG-PLGA溫度敏感水凝膠的制備及在骨科應(yīng)用基礎(chǔ)研究
發(fā)布時(shí)間：2018-09-05 20:01
【摘要】：骨髓炎以及跟腱術(shù)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(dá)到良好的預(yù)防以及治療效果，因此尋找一種能夠在局部長(zhǎng)時(shí)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(xué)者研究的目標(biāo)。近年來，，高分子水凝膠在生物醫(yī)用領(lǐng)域已獲得了越來越多的應(yīng)用。溫度敏感水凝膠由于可以在接近人體溫度時(shí)由液態(tài)轉(zhuǎn)變?yōu)槟z狀態(tài)而引起了廣大學(xué)者的高度關(guān)注，其具有可以注射操作、不引入交聯(lián)劑、可以包埋擔(dān)載多肽、蛋白、細(xì)胞以及小分子藥物等諸多特點(diǎn)。隨著美國(guó)FDA批準(zhǔn)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(yàn), 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(xué)領(lǐng)域，尤其是體內(nèi)原位藥物釋放領(lǐng)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(duì)其進(jìn)行了相關(guān)表征，同時(shí)我們研究了該聚合物對(duì)萬古霉素以及5-氟尿嘧啶的緩釋行為并進(jìn)行了相關(guān)的動(dòng)物實(shí)驗(yàn)，具體內(nèi)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(zhuǎn)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(zhuǎn)變特性，流變學(xué)檢測(cè)顯示共聚物在體溫時(shí)可以達(dá)到最大的儲(chǔ)能模量。體外藥物釋放以及抗菌結(jié)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(xì)胞實(shí)驗(yàn)及體內(nèi)外降解表明這些三嵌段共聚物具有良好的細(xì)胞相容性、生物相容性以及可降解性。體內(nèi)抗菌實(shí)驗(yàn)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(guān)的藥物副損傷。 2)針對(duì)單純使用聚合物緩釋抗生素骨修復(fù)不佳的問題，我們進(jìn)一步設(shè)計(jì)了一種PLGA-PEG-PLGA/HA復(fù)合凝膠。流變學(xué)、sol-gel相轉(zhuǎn)變以及CMC證明PLGA-PEG-PLGA/HA復(fù)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(zhuǎn)變特性，羥基磷灰石的復(fù)合還使得體系的儲(chǔ)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(xì)胞相容性。最后體內(nèi)的抗菌實(shí)驗(yàn)表明載萬古霉素的PLGA-PEG-PLGA/HA凝膠在治療骨髓炎的同時(shí)還能夠促進(jìn)骨組織的修復(fù)。 3)最后我們還設(shè)計(jì)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(nèi)被機(jī)體降解掉，并表現(xiàn)出了良好的生物相容性。體內(nèi)的防粘連實(shí)驗(yàn)通過肉眼評(píng)分以及病理學(xué)評(píng)價(jià)后認(rèn)為載5-氟尿嘧啶凝膠相對(duì)于單純應(yīng)用凝膠以及對(duì)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(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R318.08
本文編號(hào)：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(xué)位授予單位】：吉林大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R318.08
【參考文獻(xiàn)】
相關(guān)期刊論文 前2條
1 賀超良;湯朝暉;田華雨;陳學(xué)思;;3D打印技術(shù)制備生物醫(yī)用高分子材料的研究進(jìn)展[J];高分子學(xué)報(bào);2013年06期
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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