可降解聚胺酯微球之製備

Abstract

本研究藉由改變水性聚胺酯彈性體之軟鏈段種類，合成出兩種具有生物可降解性之水性聚胺酯 (waterborne biodegradable polyurethane, WBDPU)乳液，並利用噴霧冷凍乾燥法將其奈米顆粒自組裝形成微球，以雷射光散射方式量測微球之粒徑，其尺寸大小約在50 ~ 60 um，以高固含量情形下加工可獲得具有緻密皮層之微球，而以乳液低固含量情形下依聚胺酯軟鏈段的改變而可獲得不同的表面型態，說明藉由簡單調控聚胺酯軟鏈段種類及乳液固含量可製備出具有不同表面型態之微球。由體外測試結果得知，以PEB diol (Mn=2000 g/mol) 搭配 PCL diol (Mn=2000 g/mol) 作為軟鏈段 (PEB diol:PCL diol=60 wt%：40 wt%) 所合成出的水性聚胺酯 (PU02)與以純PCL diol (Mn=2000 g/mol) 作為軟鏈段所合成出的水性聚胺酯 (PU01) 相比，降解速率較快。以亞甲基藍做為親水性模擬藥物，添加於水性聚胺酯乳液加工製備出載藥微球，測試其藥物釋放，以PU02乳液固含量為10 wt%所製備出的載藥微球，在6 小時內的藥物突釋量最高，而以PU01乳液固含量為30 wt%所製備出的載藥微球在相同測試時間內之藥物突釋量最低。以L929纖維母細胞測試水性聚胺酯微球體之生物相容性，發現共培養24 h 後纖維母細胞可貼附於微球表面並增生，隨其表面型態的不同，而有不同的貼附程度。此外，我們發現水性生物可降解聚胺酯微球體具有自組裝能力，可進一步自組裝成薄膜及三維支架，自組裝薄膜的機械性質與乳液塗佈所獲得之薄膜相似，以低分子量正電荷的幾丁聚醣進行微球表面改質，可改變聚胺酯微球之自組裝行為。自組裝三維支架可藉調控微球分散液的濃度來控制支架之孔洞，同時可成功將纖維母細胞植入自組裝三維支架之中。因此本研究之水性聚胺酯微球具有作為藥物釋放及細胞載體之潛力，同時可進一步應用於組織工程支架。

Two types of waterborne biodegradable polyurethane (WBDPU) in the form of homogeneous nanoparticles (NPs) were synthesized using biodegradable polyesters as soft segment. The first WBDPU (PU01) was based on polycaprolactone diol (PCL diol, Mw 2000) and the second WBDPU (PU02) was based on 40% PCL diol and 60% polyethylene butylene adipate diol (PEB diol, Mw 2000). The dispersion of WBDPU NPs were prepared in different solid contents, sprayed into liquid nitrogen, and resuspended in water. During the process, the NPs were self-assembled into microspheres, with an average size of 50-60 um. By adjusting the contents of NPs, microspheres could be obtained with different porosity. In vitro degradation results revealed that microspheres from PU02 (i.e. PU02 MS) has faster degradation rate than those from PU01 (PU01 MS). The release of methylene blue encapsulated during MS formation was investigated. PU02 MS made from 10% dispersion (i.e. PU02 MS_10) showed a greater burst release at 6 hours, whereas PU01 MS_30 had significantly lower burst release. Biocompatibility evaluation using L929 fibroblasts demonstrated that cells could attach on the microspheres after 24 hours. On the other hand, the microspheres may self-assemble further into films and scaffolds. The mechanical properties of self-assembled solid films from microspheres were similar to those from NP dispersion. Surface modification of microspheres by low molecular weight positively charged chitosan may modify the self-assembly behavior of microspheres. Scaffolds made of microspheres may have different porous structure by controlling the amount of microspheres that built up the scaffolds. Fibroblasts were successfully seeded and grown in the scaffolds. We concluded that the biodegradable and elastic microspheres with potential applications in drug release and cell carriers may be facilely produced from a green and sustainable process.