研究生: |
傅誠耀 Fu, Cheng-Yao |
---|---|
論文名稱: |
以微流體雙重乳化晶片製備PLGA多孔性藥物微球 Preparation of Porous PLGA Microparticles from Microfluidic Double Emulsified Chip |
指導教授: |
葉思沂
Yeh, Szu-I |
學位類別: |
碩士 Master |
系所名稱: |
工學院 - 航空太空工程學系 Department of Aeronautics & Astronautics |
論文出版年: | 2020 |
畢業學年度: | 108 |
語文別: | 中文 |
論文頁數: | 79 |
中文關鍵詞: | 微流體晶片 、藥物釋放控制 、PLGA藥物微球 、多孔結構藥物微球 |
外文關鍵詞: | Microfluidic chip, Drug release, Porous PLGA microspheres, PLGA microsphere |
相關次數: | 點閱:77 下載:0 |
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微流體乳化晶片廣泛應用於石油、化妝品、生醫以及製藥等領域,並具有傳統乳化方式所沒有的優點,本研究將沿用本研究團隊在過去開發的雙重乳化微流體晶片,透過調整注射幫浦控制流道入口的各相流率參數,以改變液珠生成的尺寸及孔洞的疏密程度,以製備不同結構的藥物微球。固定第一階段總流率(Qt,1)改變第一階段連續相以及分散相流率比(R1)以及外部水相流率(Qo)製作多種孔隙率以及多種幾何尺寸的PLGA藥物微球,實驗結果發現R1越小其孔洞程度越密集,Qo越大藥物微球尺寸越小。非多孔結構以及R1=3所製作出來的PLGA藥物微球其藥物包覆率(E.E.)及載藥率(L.C.)值不會隨著Qo的改變而有明顯改變,但R1=5及R1=7所製作出來的PLGA藥物微球其E.E.及L.C.值會隨著Qo的升高而逐漸下降。以恆溫培養箱以及迴轉震盪器模擬生物體內環境,進行藥物釋放實驗,較大尺寸的PLGA藥物微球有更高的初始藥物釋放,而由R1=3及R1=7所製作出來的藥物微球中,無論其藥物微球尺寸大小,R1=3所製作出來的藥物微球之初始釋放速率始終大於R1=7所製作出來的藥物微球,因R1=5所製作出來的藥物微球因內外部相連通的孔洞結構以及相較R1=3所製作出來的藥物微球來的稀疏的孔洞密度,使自催化作用具有相對高的影響,因此R1=5所製作出來的藥物微球其釋放曲線具有初始釋放速率不隨著藥物微球尺寸改變而改變的特性。本研究成功製作出多種不同結構的藥物微球,並具有廣泛的藥物釋放特性,未來在藥物載體或藥物釋放的實驗中,可利用微流體裝置製作少量且精確的藥物微球以進行實驗,以大幅減少實驗成本。
In this research, the double emulsion microfluidic chip was used to make the porous PLGA microspheres. The PLGA microspheres with multiple porosities and multiple sizes was fabricated by operation parameters, which includes the 1st flow rate ratio (R1) and external water phase flow rate (Qo). The experimental results showed that the Porosity of PLGA microsphere increases as R1 decreases; the size of PGLA microsphere decreases as Qo increases. The drug entrapment efficiency (E.E.) and drug loading capacity (L.C.) of non-porous PLGA microsphere (R1=∞) and porous PLGA microspheres made by R1 = 3 do not change significantly with the change of Qo. The E.E. and L.C. of the porous PLGA microspheres made by R1 = 5 and R1 = 7 decrease with the increase of Qo. Use a constant temperature incubator and a rotary oscillator to simulate the biological environment for drug release experiments. The results verified that larger PLGA microspheres have higher initial drug release rate even with porous structure. Regardless of the size of the porous PLGA microspheres made by R1=3 and R1=7, the initial release rate of the porous PLGA microspheres made by R1=3 is always higher than that of the porous PLGA microspheres made by R1=7. The porous PLGA microspheres made by R1=5 initial release rate does not depend on the size of the PLGA microspheres. In the future, the presented microfluidic devices and the fabrication process can be used to make small quantities of precise PLGA microsphere for clinical or pharmaceutical test.
1. Hoffman, A., Pharmacodynamic aspects of sustained release preparations. Advanced drug delivery reviews, 1998. 33(3): p. 185-199.
2. Bae, S.E., et al., Fabrication of covered porous PLGA microspheres using hydrogen peroxide for controlled drug delivery and regenerative medicine. Journal of Controlled Release, 2009. 133(1): p. 37-43.
3. Klose, D., et al., How porosity and size affect the drug release mechanisms from PLGA-based microparticles. International journal of pharmaceutics, 2006. 314(2): p. 198-206.
4. Doerdelmann, G., D. Kozlova, and M. Epple, A pH-sensitive poly (methyl methacrylate) copolymer for efficient drug and gene delivery across the cell membrane. Journal of Materials Chemistry B, 2014. 2(41): p. 7123-7131.
5. 宋俊彥, 雙重乳化微流體晶片設計, in 航空太空工程學系. 2020, 國立成功大學
6. Srinivasan, V., V.K. Pamula, and R.B. Fair, Droplet-based microfluidic lab-on-a-chip for glucose detection. Analytica Chimica Acta, 2004. 507(1): p. 145-150.
7. Whitesides, G.M., The origins and the future of microfluidics. Nature, 2006. 442(7101): p. 368-373.
8. Dittrich, P.S. and A. Manz, Lab-on-a-chip: microfluidics in drug discovery. Nature reviews Drug discovery, 2006. 5(3): p. 210-218.
9. Su, F., S. Ozev, and K. Chakrabarty. Concurrent testing of droplet-based microfluidic systems for multiplexed biomedical assays. in 2004 International Conferce on Test. 2004. IEEE.
10. Kwapiszewska, K., et al., A microfluidic-based platform for tumour spheroid culture, monitoring and drug screening. Lab on a Chip, 2014. 14(12): p. 2096-2104.
11. Caplin, J.D., et al., Microfluidic organ‐on‐a‐chip technology for advancement of drug development and toxicology. Advanced healthcare materials, 2015. 4(10): p. 1426-1450.
12. Yang, Y., et al., Development of highly porous large PLGA microparticles for pulmonary drug delivery. Biomaterials, 2009. 30(10): p. 1947-1953.
13. Kataoka, E.r.M., et al., Simple, expendable, 3D-printed microfluidic systems for sample preparation of petroleum. Analytical chemistry, 2017. 89(6): p. 3460-3467.
14. Tan, Y.-C., V. Cristini, and A.P. Lee, Monodispersed microfluidic droplet generation by shear focusing microfluidic device. Sensors and Actuators B: Chemical, 2006. 114(1): p. 350-356.
15. Xu, J., et al., Preparation of highly monodisperse droplet in a T‐junction microfluidic device. AIChE journal, 2006. 52(9): p. 3005-3010.
16. Yobas, L., et al., High-performance flow-focusing geometry for spontaneous generation of monodispersed droplets. Lab on a Chip, 2006. 6(8): p. 1073-1079.
17. Gu, Y., H. Kojima, and N. Miki, Theoretical analysis of 3D emulsion droplet generation by a device using coaxial glass tubes. Sensors and Actuators A: Physical, 2011. 169(2): p. 326-332.
18. Pathak, M., Numerical simulation of membrane emulsification: Effect of flow properties in the transition from dripping to jetting. Journal of membrane science, 2011. 382(1-2): p. 166-176.
19. Nie, Z., et al., Emulsification in a microfluidic flow-focusing device: effect of the viscosities of the liquids. Microfluidics and Nanofluidics, 2008. 5(5): p. 585-594.
20. Xu, J., et al., The dynamic effects of surfactants on droplet formation in coaxial microfluidic devices. Langmuir, 2012. 28(25): p. 9250-9258.
21. Peng, L., et al., The effect of interfacial tension on droplet formation in flow-focusing microfluidic device. Biomedical microdevices, 2011. 13(3): p. 559-564.
22. Hao, L. and P. Cheng, An analytical model for micro-droplet steady movement on the hydrophobic wall of a micro-channel. International journal of heat and mass transfer, 2010. 53(5-6): p. 1243-1246.
23. Thorsen, T., et al., Dynamic pattern formation in a vesicle-generating microfluidic device. Physical review letters, 2001. 86(18): p. 4163.
24. Garstecki, P., et al., Formation of droplets and bubbles in a microfluidic T-junction—scaling and mechanism of break-up. Lab on a Chip, 2006. 6(3): p. 437-446.
25. Nunes, J., et al., Dripping and jetting in microfluidic multiphase flows applied to particle and fibre synthesis. Journal of physics D: Applied physics, 2013. 46(11): p. 114002.
26. Anna, S.L., N. Bontoux, and H.A. Stone, Formation of dispersions using “flow focusing” in microchannels. Applied physics letters, 2003. 82(3): p. 364-366.
27. Hong, Y. and F. Wang, Flow rate effect on droplet control in a co-flowing microfluidic device. Microfluidics and Nanofluidics, 2007. 3(3): p. 341-346.
28. Takeuchi, S., et al., An axisymmetric flow‐focusing microfluidic device. Advanced materials, 2005. 17(8): p. 1067-1072.
29. Chang, F.-C. and Y.-C. Su, Controlled double emulsification utilizing 3D PDMS microchannels. Journal of Micromechanics and Microengineering, 2008. 18(6): p. 065018.
30. Adamson, A.W. and A.P. Gast, Physical chemistry of surfaces. Vol. 150. 1967: Interscience publishers New York.
31. Abate, A. and D. Weitz, High‐order multiple emulsions formed in poly (dimethylsiloxane) microfluidics. Small, 2009. 5(18): p. 2030-2032.
32. Okushima, S., et al., Controlled production of monodisperse double emulsions by two-step droplet breakup in microfluidic devices. Langmuir, 2004. 20(23): p. 9905-9908.
33. Huang, X. and C.S. Brazel, On the importance and mechanisms of burst release in matrix-controlled drug delivery systems. Journal of controlled release, 2001. 73(2-3): p. 121-136.
34. Lee, J., et al., Facile control of porous structures of polymer microspheres using an osmotic agent for pulmonary delivery. Journal of controlled release, 2010. 146(1): p. 61-67.
35. Ilyas, A., et al., Salt-leaching synthesis of porous PLGA nanoparticles. IEEE transactions on nanotechnology, 2013. 12(6): p. 1082-1088.
36. Kim, T.K., et al., Gas foamed open porous biodegradable polymeric microspheres. Biomaterials, 2006. 27(2): p. 152-159.
37. Sona, J.S., et al., Preparation and Characteristics of Novel Porous PLGA Microsphere by Gas Foaming Method Using Hydrogen Peroxide.
38. Pan, Y., et al., Osmotic dehydration pretreatment in drying of fruits and vegetables. Drying Technology, 2003. 21(6): p. 1101-1114.
39. Crank, J., The mathematics of diffusion. 1979: Oxford university press.
40. Siepmann, J., et al., How autocatalysis accelerates drug release from PLGA-based microparticles: a quantitative treatment. Biomacromolecules, 2005. 6(4): p. 2312-2319.
41. Raman, C., et al., Modeling small-molecule release from PLG microspheres: effects of polymer degradation and nonuniform drug distribution. Journal of Controlled Release, 2005. 103(1): p. 149-158.
42. Vey, E., et al., Degradation kinetics of poly (lactic-co-glycolic) acid block copolymer cast films in phosphate buffer solution as revealed by infrared and Raman spectroscopies. Polymer degradation and stability, 2011. 96(10): p. 1882-1889.
43. Wang, J., B.M. Wang, and S.P. Schwendeman, Characterization of the initial burst release of a model peptide from poly (D, L-lactide-co-glycolide) microspheres. Journal of controlled release, 2002. 82(2-3): p. 289-307.
44. Fu, T., et al., Droplet formation and breakup dynamics in microfluidic flow-focusing devices: from dripping to jetting. Chemical engineering science, 2012. 84: p. 207-217.
45. Fuard, D., et al., Optimization of poly-di-methyl-siloxane (PDMS) substrates for studying cellular adhesion and motility. Microelectronic Engineering, 2008. 85(5-6): p. 1289-1293.
46. P. E. N. P. SU-8 2000 - MicroChem, PROCESSING GUIDELINES FOR: SU-8 2025, SU-8 2035, SU-8 2035 and SU-8 2075, website: www.microchem.com/.
47. Bodas, D. and C. Khan-Malek, Hydrophilization and hydrophobic recovery of PDMS by oxygen plasma and chemical treatment—An SEM investigation. Sensors and Actuators B: Chemical, 2007. 123(1): p. 368-373.
48. Li, J., M. Wang, and Y. Shen, Chemical modification on top of nanotopography to enhance surface properties of PDMS. Surface and Coatings Technology, 2012. 206(8-9): p. 2161-2167.
49. Siepmann, J., et al., Effect of the size of biodegradable microparticles on drug release: experiment and theory. Journal of Controlled Release, 2004. 96(1): p. 123-134.