摘要
微針藥物傳遞系統為新型態的經皮藥物給藥方式，具有無痛、藥物使用率高、無傷口感染風險、可傳遞大分子藥物等諸多優點，因此相關的研究正蓬勃發展中。截至目前，市面上微針大多用於美容領域，尚未出現應用於藥物載體的產品。本研究欲以互穿型聚合物網絡製備可分離式高分子微針貼片於水膠藥物載體之開發，藉由天然多醣聚合物海藻酸鈉與兩性離子高分子SBMA組成互穿聚合物網絡水膠，透過兩種網絡的互相纏繞、穿透，提升高分子微針的機械強度、韌性與調控微針的降解性，並評估其生物相容性、藥物釋放行為及穿透皮膚之可行性。
互穿型水膠以光起始自由基聚合反應交聯SBMA產生共價鍵網絡，再以鈣離子交聯海藻酸鈉產生離子鍵網絡，並透過拉曼與FTIR鑑定水膠鍵結。水膠內部結構與微針表面形貌由SEM觀察，確認微針陣列具有高度一致性；水膠的機械性質則由拉伸試驗測試，確立雙網絡較單一網絡可提升楊氏模數2.4倍，而延展性則提升4倍；水膠微針之應力值藉由壓縮試驗測試，顯示每根針可承受0.633 N的力，已超越文獻之微針應力值並以小鼠皮膚穿透實驗證明微針具有皮膚穿透性。接著，合成帶有雙硫鍵的交聯劑添加於微針之背板水膠，此結構可透過二硫蘇糖醇(DTT)與乙二胺四乙酸(EDTA)混合溶液瓦解，並在30分鐘內瓦解90 %之水膠，具有成為可分離式微針之潛能。水膠生物相容性測試則由細胞存活試驗探討，結果顯示在小鼠正常細胞與小鼠癌細胞皆不具有毒性，細胞存活率最低可高於85 %；微針體外藥物釋放速率可藉由不同製備手法調控，24小時內可分別釋放72 %與76 %的總藥物負載量，微針最長可以釋放超過14天，釋放量達87 %，最少可以釋放7天，釋放量達96 %；藥物半抑制濃度實驗確認微針之藥物負載量足以毒殺細胞，具有療效。本研究透過互穿聚合物網絡水膠成功製備高分子微針，並證實於經皮藥物載體之應用展現極大的潛力。

Abstract
Microneedle drug delivery system is a newly type of transdermal drug delivery method, which has many advantages such as painless, less drug losing, no wound infection risk, and can deliver macromolecular drugs. Therefore, microneedle technology has received intensive interests and developed dramatically. As of now, microneedle has only been developed for cosmetic products. There is no mature microneedle as drug carrier product on the market. Here, in this study we designed an interpenetrating polymer network hydrogel to fabricate a separable polymer microneedle patch for transdermal drug delivery by combining the polysaccharide calcium alginate with zwitterionic polymer sulfobetaine methacrylate (poly SBMA) to form the hydrogel. Through the mutual entanglement and penetration of the two networks, the mechanical strength can be improved and the degradation property of the polymer microneedles can be modulated. Here we further evaluated its biocompatibility, drug releasing behavior and the skin penetration efficiency.
The free radical polymerization was initiated by high energy light source to crosslink the SBMA monomer and to produce the covalent bonding network. The second network was formed in the presence of calcium ions to crosslink the sodium alginate. The inner hydrogel bonding was characterized by Raman and FTIR spectroscopy. The internal structure of the hydrogel and the surface morphology of the microneedles were observed by SEM and confirmed the microneedle array production quality is highly consistent. The mechanical properties of the hydrogel were characterized by tensile tests and discovered the double network significantly increase the Young's modulus by 2.4 times compared to the single network. The ductility can be increased by 4 times. The stress resistance of the hydrogel microneedles was evaluated by compression tests. The results showed that each needle can withstand a maximum force of 0.633 N, suggesting adequate skin penetration potential. Furthermore, we synthesized a crosslinking agent that contained disulfide bond and added into the hydrogel to form the backplane of the microneedle. The hydrogel structure can be disintegrated up to 90% in 30 minutes by a mixed solution of DTT and EDTA. The results indicated that the microneedles formed by the hydrogel have great potential to be separable under control.
Finally, the biocompatibility of the hydrogel was explored by MTT assay, which showed no detectable toxicity to the normal cells and the cancer cells. In vitro drug release test showed that the microneedle array can release up to 76% of the total loaded drug in 24 hours, and can consistently release for 14 days. The IC50 test results indicated that the drug loaded on the microneedles is sufficient to kill cancer cells. This study successfully fabricated interpenetrating polymer network hydrogel based microneedles, which has great potential as drug carrier for transdermal drug delivery.

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