臨床結果顯示，藥物釋放型血管支架(drug-eluting stent)可有效地抑制，經皮冠狀動脈血管擴張術(percutaneous transluminal coronary angioplasty, PTCA)後血管再狹窄的發生機率。目前市售的藥物釋放型血管支架，如CYPHER(Cordis Corp.)與TAXUS(Boston Scientific Corp.)支架等，皆是利用不可分解之合成高分子，將藥物包覆並塗佈於金屬支架上。文獻指出，這些不可分解之合成高分子，可能會引起血管內的過敏性反應，造成晚期的血栓產生，甚至危害病患的生命。由於血管再狹窄一般只發生在PTCA手術後的3~6個月內，過了這段期間，血管支架的存在便不是如此必要。基於以上的考量，本研究利用幾丁聚醣作為血管支架的主要材料，以化學共價交聯的方式，製備出可完全生物分解的藥物釋放型血管支架。本研究分為三大部份，第一部份先利用改良後的幾丁聚醣混成膜，以環氧樹脂(epoxy)進行交聯塑形，製做具有形狀記憶(shape memory)的螺旋形血管支架。此螺旋型支架可經水合作用，快速地膨脹撐開(~150秒)，不僅可縮短手術置放時間，且能防止支架位移的情形發生。初步的動物實驗結果來看，將製備的高分子血管支架，以French sheath植入兔子腹主動脈中，24小時後取出，並沒有支架位移與急性的血栓生成，初步證實此血管支架之可行性。第二部份進行包覆抗血管內膜增生藥(sirolimus)，以製備出藥物釋放型的血管支架。為了提高親水性材料與殊水性藥物之間的作用力，本研究以乳化方式，將疏水的sirolimus包覆在pluronic L121奈米微胞的疏水核心區，防止疏水藥物的流失，並利用微胞之親水外殼區，將藥物均勻地分散於高分子支架中。由體外藥物釋放之結果來看，利用此奈米包藥技術，確實能有效地防止藥物burst release的現象發生，製備出能sustained release的藥物釋放血管支架。最後，我們同樣地將研發的藥物釋放型血管支架，植入兔子體內，1個月後進行病理切片評估。實驗證實，與未包藥之支架相比，本研究所製備之藥物釋放型血管支架，確實能有效地抑制血管內膜的增生，很有潛力實際應用於治療動脈粥狀硬化上。

The clinical importance of drug-eluting stents has been demonstrated by their unparalleled success in preventing restenosis after stenting procedures. However, hypersensitivity reactions caused by their nonerodable polymer coatings and bare-metal stents may result in serious clinical sequelae. In this report, a new biodegradable sirolimus-eluting stent, made from chitosan-based strips fixed by an epoxy compound, was developed. Due to the covalent crosslinks formed in the stent matrix, the fabricated stent had a shape-memory property to memorize its permanent shape. The developed polymeric stent could rapidly expand (~150 s) from its crimped (temporary) state to fully expanded (permanent) state stimulated by hydration, which is advantageous considering avoiding its migration during in vivo deployment. The preliminary animal study showed that this stent had a sufficient mechanical strength and a superior hemocompatibility in the stent-implanted vessel. To enhance the interactions between the poorly soluble anti-proliferative drug (sirolimus) and the hydrophilic stent matrix, a nanoscale drug-entrapment strategy was utilized to construct the sirolimus-eluting stent. Differing from other particle-embedded hydrogel systems, such an entrapment strategy substantially increases the loading efficiency of lipophilic drugs, prevents the drug from aggregation, and beneficially enhances the interaction between the drug and the stent matrix via amphiphilic Pluronic L121 micelles. Our experiments demonstrated that the developed stent can provide a sustained release profile without initial burst effect, thus evading undesirable side effects such as delayed endothelial healing caused by the overdose of sirolimus. When compared to the unloaded stent, neointima formation was significantly suppressed after implantation of the developed sirolimus-eluting stent in rabbit abdominal aortas. These findings suggested that the developed sirolimus-eluting polymeric stent can be a potential alternative for treatment of coronary artery disease.

References
1. Popma JJ, Topol EJ. Am J Med 1990;88:1:16N-24N.
2. Currier JW, Faxon DP. J Am Coll Cardiol 1995;25:516-520.
3. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O'Shaughnessy C, Caputo RP, et al. N Engl J Med 2003;349:1315-1323.
4. Muhlestein JB. J Am Coll Cardiol 2008;51:2139-2140.
5. Cardiovascular News International Issue 3, 2006.
6. Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, et al. J Am Coll Cardiol 2006;47:175-181.
7. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail A, Plant antitumor agents. VI. J Am Chem Soc 1971;93:2325-2327.
8. Marx SO, Jayaraman T, Go LO, Marks AR. Circ Res 1995; 76:412-417.
9. Lüscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R. Circulation 2007;115:1051-1058.
10. Rao S, Krauss NE, Heerding JM, et al. J Biol Chem 1994;269:3132-3134.
11. Yakacki CM, Shandas R, Lanning C, Rech B, Eckstein A, Gall K. Biomaterials 2007;28:2255-2263.
12. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, et al. Circulation 2004;109:701-705.
13. Tsimikas S. J Am Coll Cardiol 2006;47:2112-2115.
14. Koster R, Vieluf D, Kiehn M, et al. Lancet 2000;356:1895-1897.
15. Ormiston JA, Serruys PW, Regar E, Dudek D, Thuesen L, Webster MW, et al. Lancet 2008;371:899-907.
16. Corsi K, Chellat F, Yahia L, Fernandes JC. Biomaterials 2003;24:1255-1264.
17. Mi FL, Tan YC, Liang HF, Sung HW. Biomaterials 2002;23:181-191.
18. Di Martino A, Sittinger M, Risbud MV. Biomaterials 2005;26:5983-5990.
19. VandeVord PJ, Matthew HW, DeSilva SP, Mayton L, Wu B, Wooley PH. J Biomed Mater Res 2002;59:585-590.
20. Babapulle MN, Eisenberg MJ. Circulation 2002;106:2734-2740.
21. Ruygrok PN, Serruys P. Circulation 1996;94:882-890.
22. Kimura T, Yokoi H, Nakagawa Y, Tamura T, Kaburagi S, Sawada Y, et al. N Engl J Med 1996;334:561-566.
23. Serruys PW, Luijten HE, Beatt KJ, Geuskens R, de Feyter PJ, Brand Mvanden, et al. Circulation 1988;77:361-371.
24. Tamai H, Igaki K, Kyo E, Kosuga K, Kawashima A, Matsui S, et al. Circulation 2000;102:399-404.
25. Venkatraman SS, Tan LP, Joso JF, Boey YC, Wang X. Biomaterials 2006;27: 1573-1578.
26. Valimaa T, Laaksovirta S, Tammela TLJ, Laippala P, Talja M, Isotalo T, et al. Biomaterials 2002;23:3575-3582.
27. Mao HQ, Roy K, Troung-Le VL, Janes KA, Lin KY, Wang Y, et al. J Control Rel 2001;70:399-421.
28. Ravi Kumar MNV, Muzzarelli RAA, Muzzarelli C, Sashiwa H, Domb AJ. Chem Rev 2004;104:6017-6084.
29. Butler MF, Clark AH, Adams S. Biomacromolecules 2006;7:2961-2970.
30. Lin YH, Liang HF, Chung CK, Chen MC, Sung HW. Biomaterials 2004;26: 2105-2113.
31. Watts AG, Withers SG. Biochem J 2004;380:e9-e10.
32. Kolhe P, Kannan RM. Biomacromolecules 2003;4:173-180.
33. Lendlein A, Kelch S. Angew Chem Int. Ed. 2002;41:2034-2057.
34. Ahir SV, Tajbakhsh AR, Terentjev EM. Adv Funct Mater 2006;16:556-560.
35. Chang WH, Chang Y, Lai PH, Sung HW. J Biomater Sci Polym Ed 2003;14: 481-495.
36. Stryer L. Biochemistry; 3rd Ed; Freeman Press: New York 1998, p. 50-55.
37. Venkatraman S, Poh TL, Vinalia T, Mak KH, Boey F. Biomaterials 2003;24: 2105-2111.
38. Akyurek O, Berkalp B, Sayin T, Kumbasar D, Kervancioglu C, Oral D. Am Heart J 2003;145:66-72.
39. Matsumoto Y, Shimokawa H, Morishige K, Eto Y, Takeshita AJ. Cardiovasc Pharmacol 2002;39:513-522.
40. Hietala EM, Salminen US, Stahls A, Valimaa T, Maasilta P, et al. J Vasc Res 2001;38:361-369.
41. Park IK, Yang J, Jeong HJ, Bom HS, Harada I, Akaike T, Kim SI, Cho CS. Biomaterials 2003;24:2331-2337.
42. Muzzarelli RAA, Biagini G, DeBenedittis A, Mengucci P, Majni G, Tosi G. Carbohydr Polym 2001;45:35-41.
43. Genta I, Perugini P, Modena T, Pavanetto F, Castelli F, Muzzarelli RAA, et al. Carbohydr Polym 2003;52:11-18.
44. Schiffman JD, Schauer CL. Biomacromolecules 2007;8:594-601.
45. Dallan PR, Moreira PdaL, Petinari L, Malmonge SM, Beppu MM, Genari S C, et al. J Biomed Mater Res B Appl Biomater 2007;80:394-405.
46. Hu Y, Jiang X, Ding Y, Ge H, Yuan Y, Yang C. Biomaterials 2002;23:3193-3201.
47. Sung HW, Hsu CS, Lee YS, Lin DS. J Biomed Mater Res 1996;31:511-518.
48. Rabkin DJ, Lang EV, Brophy DPJ. Vasc Interv Radiol 2000;11:343-350.
49. Lendlein A, Langer R. Science 2002;296:1673-1676.
50. Lohre JM, Baclig L, Sagartz J, Guida S, Thyagarajan K, Tu R. Artif Organs 1992;16:630-633.
51. Pangburn SH, Trescony PV, Heller J. Biomaterials 1982;3:105-108.
52. Jollès P. Lysozymes: model enzymes in biochemistry and biology; Birkhauser, Basel: Switzerland, 1996.
53. Mi FL, Tan YC, Liang HC, Huang RN, Sung HW. J Biomater Sci Polym Ed 2003;12:835-850.
54. Azarbal B, Currier JW. J Am Coll Cardiol 2006;47:182-183.
55. Cardiovascular News International Issue 3, 2006.
56. Nebeker JR, Virmani R, Bennett CL, Hoffman JM, Samore MH, Alvarez J, et al. J Am Coll Cardiol 2006;47:175-181.
57. Lüscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R. Circulation 2007;115:1051-1058.
58. Yakacki CM, Shandas R, Lanning C, Rech B, Eckstein A, Gall K. Biomaterials 2007;28:2255-2263.
59. Virmani R, Guagliumi G, Farb A, Musumeci G, Grieco N, Motta T, et al. Circulation 2004;109:701-705.
60. Tsimikas S. J Am Coll Cardiol 2006;47:2112-2115.
61. Koster R, Vieluf D, Kiehn M, et al. Lancet 2000;356:1895-1897.
62. Tamai H, Igaki K, Kyo E, Kosuga K, Kawashima A, et al. Circulation 2000;102:399-404.
63. Vogt F, Stein A, Rettemeier G, Krott N, Hoffmann R, vom Dahl J, et al. Eur Heart J 2004;25:1330-1340.
64. Wang XT, Venkatraman SS, Boey FYC, Loo JSC, Tan LP. Biomaterials 2006;27:5588-5595.
65. Venkatraman SS, Tan LP, Joso JF, Boey YC, Wang X. Biomaterials 2006;27:1573-1578.
66. Bünger CM, Grabow N, Sternberg K, Ketner L, Kröger C, Lorenzen B, et al. J Endovasc Ther 2006;16:539-548.
67. Marx SO, Jayaraman T, Go LO, Marks AR. Circ Res 1995;76:412-417.
68. Gallo R, Padurean A, Jayaraman T. Marx S, Roque M, Adelman S, et al. Circulation 1999;99:2164-2170.
69. Chen MC, Tsai HW, Chang Y, Lai WY, Mi FL, Liu CT, Wong HS, Sung HW. Biomacromolecules 2007;8:2774-2780.
70. Stryer L. Biochemistry 3rd Ed. Freeman Press: New York, 1998. p. 50-55.
71. Kretsinger JK, Haines LA, Ozbas B, Pochan DJ, Schneider JP. Biomaterials 2005;26:5177-5186.
72. Yang TF, Chen CN, Chen MC, Lai CH, Liang HF, Sung HW. Biomaterials 2007;28:725-734.
73. Smith PK, Mallia AK, Herrmanson GT. Anal Biochem 1980;109:466-473.
74. Ko TM, Lin JC, Cooper SL, Biomaterials 1993;14:657-664.
75. Rosner D, McCarthy N, Bennett M. Cardiovasc Res 2005;66:601-610.
76. Liang HF, Chen SC, Chen MC, Lee PW, Chen CT, Sung HW. Bioconjug Chem 2006;17:291-299.
77. Blindt R, Vogt F, Astafieva I, Fach C, Hristov M, Krott N, Seitz B, Kapurniotu A, et al. J Am Coll Cardiol 2006;47:1786-1795.
78. Ormiston JA, Serruys PW, Regar E, Dudek D, Thuesen L, Webster MW, et al. Lancet 2008;371:899-907.
79. Corsi K, Chellat F, Yahia L, Fernandes JC. Biomaterials 2003;24:1255-1264.
80. Mi FL, Tan YC, Liang HF, Sung HW. Biomaterials 2002;23:181-191.
81. Di Martino A, Sittinger M, Risbud MV. Biomaterials 2005;26:5983-5990.
82. VandeVord PJ, Matthew HW, DeSilva SP, Mayton L, Wu B, Wooley PH. J Biomed Mater Res 2002;59:585-590.
83. Tsai CC, Chang Y, Sung HW, Hsu JC, Chen CN. Biomaterials 2001;22:523-533.
84. Acharya G, Park K. Adv Drug Deliv Rev 2006;58:387-401.
85. Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, et al. J Am Coll Cardiol 2006;48:193-202.
86. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, Gold HK, Virmani R. Circulation 2007;115:2435-2441.
87. Hirano S, Tsuchida H, Nagao N. Biomaterials 1989;10:574-576.
88. Suh JK, Matthew HW. Biomaterials 2000;21:2589-2598.
89. Lin CC, Metters AT. Adv Drug Deliv Rev 2006;58:1379-1408.
90. Luchini A, Geho D, Bishop B, Tran D, Jones C, Xia C, Zhou W, et al. Nano Lett 2008;8:350□361.
91. Torchilin VP. Cell Mol Life Sci 2004;61:2549–2559.
92. Chen MC, Tsai HW, Chang Y, Lai WY, Mi FL, Liu CT, Wong HS, Sung HW. Biomacromolecules 2007;8:2774–2780.
93. Kim DH, Martin DC. Biomaterials 2006;27:3031–3037.
94. DeFail AJ, Edington H, Matthews S, Lee WCC, Marra KG. J Biomed Mater Res A 2006;79:954□962.
95. Yang TF, Chen CN, Chen MC, Lai CH, Liang HF, Sung HW. Biomaterials 2007;28:725–734.
96. Nasongkla N, Bey E, Ren JM, Ai H, Khemtong C, Guthi JS, Chin SF, et al. Nano Lett 2006;6:2427–2430.
97. Kwon GS. Crit Rev Ther Drug Carrier Syst 2003;20:357–403.
98. Otsuka H, Nagasaki Y, Kataoka K. Adv Drug Delivery Rev 2003;55: 403–419.
99. Torchilin VP. J Controlled Release 2001;73:137–172.
100. Torchilin VP, Lukyanov AN, Gao Z. Papahadjopoulos-Sternberg B. PNAS 2003;100:6039□6044.
101. Liu HB, Farrell S, Uhrich K. J Control Release 2000;68:167–174.
102. Forrester J, Fishbein M, Helfant R. J Am Coll Cardiol 1991;17:77B–88B.
103. Casscells, W. Circulation 1992;86:723–729.
104. Marx S, Jayaraman T, Go L, Marks AR. Circ Res 1995;76:412–417.
105. Fukuda J, Khademhosseini A, Yeo Y, Yang X, Yeh J, Eng G, et al. Biomaterials 2006;27:5259–5267.
106. Rosner D, McCarthy N, Bennett M. Cardiovasc Res 2005;66:601–610.
107. Suzuki T, Kopia G, Hayashi S, Bailey LR, Llanos G, Wilensky RJ, et al. Circulation 2001;104:1188–1193.
108. Luscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, Virmani R. Circulation 2007;115:1051–1058.
109. Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, et al. J Am Coll Cardiol 2006;48:193–202.
110. Kretsinger JK, Haines LA, Ozbas B, Pochan DJ, Schneider JP. Biomaterials 2005;26:5177□5186.
111. Yang TF, Chen CN, Chen MC, Lai CH, Liang HF, Sung HW. Biomaterials 2007;28:725□734.
112. Saito T, Dojima T, Toriyama M, Park EY. J Biotechnol 2002;93:121□129.
113. Blindt R, Vogt F, Astafieva I, Fach C, Krott N, Seitz B, Kapurniotu A, et al. J Am Coll Cardiol 2006;47:1786□1795.