生物可分解之溫感性水膠及其生醫應用之研究

The Study of Biodegradable Thermo-Sensitive Hydrogels and their Biomedical Applications

陳進富(Chin-Fu Chen)

指導教授 ： 朱一民

國立清華大學/工學院/化學工程學系/博士(2010年)

https://doi.org/10.6843/NTHU.2010.00010

摘要

在過去十年中，有關溫度敏感性水膠於不同生醫領域之應用已被文獻廣泛地報導出來，其中包括藥物遞送、細胞包覆及組織修復。此種溫度敏感性水膠為一種可注射性之液體，可利用微小化之侵入方式進入體內於需求之組織、器官內固化或膠化。此外，溫度敏感性水膠具有下列優點，不需要有機溶劑、可以在特定部位形成膠體。因為具有簡單的溶液混合藥劑型態、與生理系統之生物相容性、方便的投藥方式，所以此種水性之溶液膠體系統於藥物治療及生醫之應用，可作為藥物遞送與控制系統、生物活性物質之遞送及組織工程之應用。當此成形水膠可提供生物相容性及生物降解性及無毒性之降解產物時，其在活體內之應用將可有很大之利基。在本研究中，一系列的生物降解型溫度敏感性水膠藉由甲基化聚乙二醇與不同之聚酯類單體如D,L-乳酸酐(D,L-lactide), 甘醇酸酐(Glycolide), b-丙內酯(b-propiolactone), d-戊內酯(d-valerolactone) 及 e-己內酯(e-caprolactone)進行開環共聚合反應。所製得之產物利用1H質譜儀(1H NMR)分析其結構皆如預期之物質，並利用可見光紫外光光度計分析臨界微胞濃度且使用粒徑分析儀量測微胞之粒徑大小，同時可用可見光紫外光光度計分析此類共聚物水膠之溫度敏感性，而水膠之黏彈性則可用流變儀加以量測，此種溶膠行為是一種奈米微胞隨溫度上升自動聚集為物理性膠體之現象。此類水膠之生物相容性利用瓊脂擴散法(agar diffusion)加以分析判斷。在生醫應用之測試則針對環孢靈及替考普寧作藥物遞送之測試，並作活體外對皮膚之生物黏膠測試，在活體內之測試則對骨組織缺損作修補及骨髓炎之治療測試，並完成複合組織之異體移植耐受性實驗。環孢靈及替考普寧可分別在31及13天持續釋放到約70 %左右。包含替考普寧的mPEG-PLGA水凝膠對骨髓炎治療是一種有效的方法，其結果可由組織切片染色及免疫分析加已證實。對於骨肌皮瓣的複合組織異體移植與抑制免抑反應的環孢靈藥物，mPEG-PVLA水膠系統是一種良好的同種異體移植的藥物遞送系統。

關鍵字

水膠 ； 溫感性 ； 生物可分解性 ； 生醫應用 ； 藥物遞送

並列摘要

In the past ten years, an increasing number of thermo-sensitive hydrogels have been widely reported in the literature for various biomedical applications, including drug delivery, cell encapsulation, and tissue repair. These thermo-sensitive hydrogels are injectable fluids that can be introduced into the body in a minimally invasive manner prior to solidifying or gelling with the desired tissue or organ. Additionally, the thermo-sensitive hydrogels own many advantages, such as it does not require organic solvents and can be an in-situ forming gel. Because of the simplicity of pharmaceutical and biomedical uses of the water-based sol–gel transition that can be used as drug delivery-control systems, bioactive compounds delivery, and tissue engineering. When the formed gel is proven to be biocompatible and biodegradable, producing non-toxic degradation products, it will provide further benefits for in vivo applications where degradation is desired. In this study, a series of the biodegradable thermo-sensitive hydrogels were synthesised by the ring open polymerization of the methoxy polyethylene glycol with various kinds of the ester monomers, such as the D,L-lactide, glycolide, b-propiolactone, d-valerolactone and e-caprolactone. Results of those products defined by 1H n.m.r. spectras indicated that these materials were indeed the compounds expected. The critical micelle concentrations of those copolymers were measured by the UV-VIS Spectrophotometer and the particle sizes of those polymeric micelles were measured by the dynamic light scattering (DLS). The thermo-sensitive properties of those copolymeric hydrogels were measured by the UV-VIS Spectrophotometer. The viscoelastic properties of those copolymers were measured by Rheostress(Haake rheostress 600). The sol-gel transition behavior of diblock copolymers was confirmed by the nano micelle spontaneous aggregating to physical gel with increasing temperature. The biocompatability of those novel thermo-sensitive hydrogels were tested by the agar diffusion. The biomedical applications were tested by the drug delivery of cyclosporine A and teicoplanin, the bioglue for skin in vitro and the bone tissue repair in vivo, the therapy of osteomyelitis in vivo, and the induced tolerance of the composite tissue allotransplanation (CTA). The sustained release of cyclosporine A and teicoplanin was about 70% for 31 and 13 days, respectively. The mPEG-PLGA hydrogel containing teicoplanin was effective for treating osteomyelitis in rabbits as detected by the histological staining and immunoblotting analyses. The results of the osteomyocutaneous flap transfer indicated that the CTA with the immunosuppression drug, CsA, was an excellent allograft with the mPEG-PVLA sol-gel delivery system.

並列關鍵字

hydrogel ； thermosensitive ； biodegradable ； bioapplication ； drug delivery

參考文獻

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