本研究開發兩款經皮輸送晶片系統以輸送金奈米粒子(gold nanoparticles)進入人體角質層(stratum corneum)與鼠的皮膚。離子導入式經皮輸送晶片系統乃利用微機電製程製作晶片，並使用雷射雕刻機製作壓克力(polymethylmethacrylate, PMMA)反應槽，透過電性原理來輸送金奈米粒子進入人體角質層。此型晶片應用的原理為輸入一低電壓之直流電源，藉著靜電力來驅動金奈米粒子以便輸送進入人體角質層。實驗結果證實，當角質層厚度為240 µm，實驗時間固定為一小時，分別通以3、6及9 V之電壓。其中3 V並無明顯效果，而6 V即可於人體角質層中觀察到金奈米粒子沿著細胞間通道或是直接穿透角質層來進行輸送。而電穿孔滲透式經皮輸送晶片系統乃利用微機電製程製作電穿孔晶片，將晶片通以脈衝電壓之後，電極間會產生一穿膜電場，此電場會在實驗鼠皮膚上形成孔洞，以使金奈米凝膠得以滲透。本型經皮輸送晶片系統有別於一般的電穿孔法，使用5與10 V及10 Hz的脈衝電壓即能得到經皮輸送的效果。藉由兩種經皮輸送晶片系統可知金奈米粒子是被動式的輸送，且以模擬與實驗結果來觀察，可得到電壓之增加也會增加金奈米粒子經皮輸送的結論。

This paper reports two transdermal delivery chip systems for delivering gold nanoparticles (AuNPs) into human stratum corneum (HSC) and rat skin. The proposed iontophoresis transdermal delivery chip system cloud provides electrostatic force to drive AuNPs. The AuNPs were via intercellular route to deliver into HSC. Various DC voltages (3, 6, 9 V) were employed to generate different intensity electric fields (32~98 V/mm) for driving AuNPs into HSC. The electroporation transdermal delivery chip system could provide appropriate electric field for the EP on the chip surface. The electric field could generate pathway on rat skin to delivery gel of gold nanoparticles. Various DC voltages (5, 10 V) and 10 Hz were employed to generate different intensity electric fields (819~1638 V/cm) for driving AuNPs into rat skin. The results of simulation show permeability of the skin and rat skin increases with the electric voltage. We use micro-electro-mechanical systems (MEMS) technology to design and fabricated the proposed chip systems. The proposed transdermal delivery chip system will provide many potential usages for biomedical applications.

[1] M. B. Brown, G. P. Martin, S. A. Jones and F. K. Akomeah, “Dermal and transdermal drug delivery systems: current and future prospects,” Drug Delivery, 13, 175, 2006.
[2] M. R. Prausnitz, S. Mitragotri and R. Langer, “Current status and future potential of transdermal drug delivery,” Nature Reviews Drug Discovery, 3, 115, 2004.
[3] R. R. Wickett and M. O. Visscher, “Structure and function of the epidermal barrier,” American Journal of Infection Control, 34, s98, 2006.
[4] www.pharmpress.com/shop/samples/T&T-ch1.pdf
[5] C. R. Harding, “The stratum corneum: structure and function in health and disease,” Dermatologic Therapy, 17, 6, 2004.
[6] P. W. Wertz and B. V. D. Bergh, “The physical, chemical and functional properties of lipids in the skin and other biological barriers,” Chemistry and Physics of Lipids, 91, 85, 1998.
[7] T. M. Suhonen, J. A. Bouwstra and A. Urtti, “Chemical enhancement of percutaneous absorption in relation to stratum corneum structural alternations,” Journal of Controlled Release, 59, 149, 1999.
[8] B. W. Barry, “Novel mechanisms and devices to enable successful transdermal drug delivery,” European Journal of Pharmaceutical Sciences, 14, 101, 2001.
[9] B. W. Barry, “Breaching the skin's barrier to drugs,” Nature Biotechnology, 22, 165, 2004.
[10] M. R. Prausnitz, “The effects of electric current applied to skin: a review for transdermal drug delivery,” Advanced Drug Delivery Reviews, 18, 395, 1996.
[11] A. Denet, R. Vanbever and V. Pre´at, “Skin electroporation for transdermal and topical delivery,” Advanced Drug Delivery Reviews, 56, 659, 2004.
[12] M. Uchida, Y. Jin, H. Natsume, D. Kobayashi, K. Sugibayashi and Y. Morimoto, “Introduction of poly-L-lactic microspheres into the skin using supersonic flow: effects of helium gas pressure, particle size and microparticle dose on the amount introduced into hairless rat skin,” Journal of Pharmacy and Pharmacology, 54, 781, 2002.
[13] P. Karande, A. Jain and S. Mitragotri, “Discovery of transdermal penetration enhancers by high-throughput screening,” Nature Biotechnology, 22, 192, 2004.
[14] A. C. Williams and B. W. Barry, “Penetration enhancers,” Advanced Drug Delivery Reviews, 56, 603, 2004.
[15] G. Merino, Y. N. Kalia and R.H. Guy, “Ultrasound-enhanced transdermal transport,” Journal of Pharmaceutical Sciences, 92, 1125, 2003.
[16] A. F. Coston and J. K. Li, “Transdermal drug delivery: a comparative analysis of skin impedance models and parameters,” Proceedings of the 25th Annual Intemational Conference of the IEEE EMBS, 17, 2003.
[17] A. F. Coston and J. K. Li, “Iontophoresis: modeling, methodology, and evaluation,” Cardiovascular Engineering, 1, 127, 2001.
[18] Y. Wang, R. Thakur, Q. Fan and B. Michniak, “Transdermal iontophoresis: combination strategies to improve transdermal iontophoretic drug delivery,” European Journal of Pharmaceutics and Biopharmaceutics, 60, 179, 2005.
[19] J. C. Weaver and Y. A. Chizmadzhev, “Theory of electroporation: A review,” Bioelectrochemistry and Bioenergetics, 41, 135, 1996.
[20] Y. N. Kalia, A. Naik, J. Garrison and R. H. Guy, “Iontophoretic drug delivery,” Advanced Drug Delivery Reviews, 56, 619, 2004.
[21] A. K. Nugroho, L. Li, D. Dijkstra, H. Wikstrfm, M. Danhof and J. A. Bouwstra, “Transdermal iontophoresis of the dopamine agonist 5-OH-DPAT in human skin in vitro,” Journal of Controlled Release, 103, 393, 2005.
[22] S. W. Hui, “Low voltage electroporation of the skin, or is it iontophoresis,” Biophysical Society, 74, 679, 1998.
[23] E. Neumann, M. Schaefer-Ridder, Y. Wang and P. H. Hofschneider, “Gene transfer into mouse lyoma cells by electroporation in high electric fields,” The EMBO Journal, 1, 841, 1982.
[24] T. Nishi, K. Yoshizato, S. Yamashiro, H. Takeshima, K. Sato, K. Hamada, I. Kitamura, T. Yoshimura, H. Saya, J. Kuratsu and Y. Ushio, “High-efficiency in vivo gene transfer using intraarterial plasmid DNA injection following in vivo electroporation,” Cancer Research, 56, 1050, 1996.
[25] J. A. Tamada, M. Lesho and M. J. Tierney, “Keeping watch on glucose,” IEEE Spectrum, 39, 52, 2002.
[26] A. Sen, M. E. Daly and S. W. Hui, “Transdermal insulin delivery using lipid enhanced electroporation,” Biochimica et Biophysica Acta, 1564, 5, 2002.
[27] A. K. Banga, S. Bose and T. K. Ghosh, “Iontophoresis and electroporation: comparisons and contrasts,” International Journal of Pharmaceutics, 179, 1, 1999.
[28] U. Pliquett, R. Langer and J. C. Weaver, “Changes in the passive electrical properties of human stratum corneum due to electroporation,” Biochimica et Biophysica Acta, 1239, 111, 1995.
[29] D. A. Edwards, M. R. Prausnitz, R. Langer and J. C. Weaver, “Analysis of enhanced transdermal transport by skin electroporation,” Journal of Controlled Release, 34, 211, 1995.
[30] L. P. Lee, S. A. Berger, D. Liepmann and L. Pruitt, “High aspect ratio polymer microstructures and cantilevers for biomems using low energy ion beam and photolithography,” Sensors and Actuators A, 71, 144, 1998.
[31] I. Moser, G. Jobst and G. A. Urban, “Biosensor arrays for simultaneous measurement of glucose, lactate, glutamate and glutamine,” Biosensors and Bioelectronics, 17, 297, 2002.
[32] L. Lauer, S. Ingebrandt, M. Scholl and A. Offenhausser, “Aligned microcontact printing of biomolecules on microelectronic device surfaces,” IEEE Transaction on Biomedical Engineering, 48, 838, 2002.
[33] A. R. Denet, R. Vanbever and V. Pre´at, “Skin electroporation for transdermal and topical delivery,” Advanced Drug Delivery Reviews, 56, 659, 2004.

[34] R. Vanbever, E. L. Boulenge and V. Pre´at, “Transdermal delivery of fentanyl by electroporation. I. influence of electrical factors,” Pharmaceutical Research, 13, 559, 1996.
[35] A. Sharma, M. Kara, F. R. Smith and T. R. Krishnan, “Transdermal drug delivery using electroporation. I. factors influencing in vitro delivery of terazosin hydrochloride in hairless rats,” Journal of Pharmaceutical Sciences, 89, 528, 2000.
[36] A. Roucoux, J. Schulz and H. Patin, “Reduced transition metal colloids: a novel family of reusable catalysts,” Chemical Reviews, 102, 3757, 2002.
[37] G. F. Paciotti, D. G. I. Kingston and L. Tamarkin, “Colloidal gold nanoparticles: a novel nanoparticles platform for developing multifunctional tumor-targeted drug delivery vectors,” Drug Development Research, 67, 47, 2006.
[38] R. K. Visaria, R. J. Griffin, B. W. Williams, E. S. Ebbini, G. F. Paciotti, C. W. Song and J. C. Bischof, “Enhancement of tumor thermal therapy using gold nanoparticle–assisted tumor necrosis factor-A delivery,” Molecular Cancer Therapeutics, 5, 1014, 2006.
[39] B. Yu, C. Y. Dong, P. T. C. So, D. Blankschtein and R. Langer, “In vitro visualization and quantifcation of oleic acid induced changes in transdermal transport using two-photon fluorescence microscopy,” The Journal of Investigative Dermatology, 117, 16, 2001.
[40] M. Heisig, R. Lieckfeldt, G. Wittum, G. Mazurkevich and G. Lee, “Non steady-state descriptions of drug permeation through stratum corneum. I. the biphasic brick-and-mortar model,” Pharmaceutical Research, 13, 421, 1996.
[41] M. E. Garcia, L. A. Baker and R. M. Crooks, “Preparation and characterisation of dendrimer gold colloid monolayers,” Analytical Chemistry, 71, 256, 1999.
[42] M. T. Reetz and W. Helbig, “Size-selective synthesis of nanostructured transition metal clusters,” Journal of the American Chemical Society, 116, 401, 1994.
[43] M. T. Reetz, W. Helbig and S. A. Quaiser, “Electrochemical preparation of nanostructured bimetallic clusters,” Chemistry of Materials, 7, 227, 1995.
[44] M. T. Reetz and S. A. Quaiser, “A new method for the preparation of nanostructured metal clusters,” Angewandte Chemie International Edition, 34, 240, 1995.
[45] S. S. Chang, C. W. Shih, C. W. Chen, W. C. Lai and C. R. C. Wang, “The shape transition of gold nanorods,” Langmuir, 15, 701, 1999.
[46] J. Belloni, M. Mastafavi, S. Remita, J. L. Marignier and M. O. Delcourt, “Radiation-induced synthesis of mono- and multi-metallic clusters and nanocolloids,” New Journal of Chemistry Articles, 22, 1257, 1998.
[47] A. Henglein, “Physicochemical properties of small metal particles in solution: “Microelectrode” reactions, chemisorption, composite metal particles, and the atom-to-metal transition,” Journal of Physical Chemistry, 97, 5457, 1993.
[48] M. Treguer, C. Cointet, H. Remita, J. Khatouri, M. Mostafavi, J. Amblard, J. Belloni and R. Keyzer, “Dose rate on radiolytic synthesis of gold-silver bimetallic clusters in solution,” Journal of Physical Chemistry, 102, 4310, 1998.
[49] H. Remita, J. Khatouri, M. Treguer, J. Amblard and J. Belloni, “Silver-palladium alloyed clusters synthesized by radiolysis,” Zeitschrift Fur Physik D - Atoms Molecules and Clusters, 40, 127, 1997.
[50] T. Yonezawa, T. Sato, S. Kurada and K. Kuge, “Photochemical formation of colloidal silver: peptizing action of acetone ketyl radical,” Journal of the Chemical Society, 87, 1905, 1991.
[51] M. Y. Han and C. H. Quek, “Photochemical synthesis in formamide and room-temperature coulomb staircase behavior of size-controlled cold nanoparticles,” Langmuir, 16, 362, 2000.
[52] K. Okitsu, H. Bandow, Y. Maeda and Y. Nagata, “Sonochemical preparation of ultrafine palladium particles,” Chemistry Materials, 8, 315, 1996.
[53] Y. Mizukoshi, K. Okitsu, Y. Maeda, T, A. Yamamoto, R. Oshima and Y. Nagata, “Sonochemical preparation of bimetallic nanoparticles gold/palladium in aqueous solution,” Journal of Physical Chemistry B, 101, 7033, 1997.
[54] S. Link, Z. L. Wang and M. A. El-Sayed, “Alloy formation of gold-silver nanoparticles and the dependence of the plasmon absorption on their composition,” Journal of Physical Chemistry B, 103, 3529, 1999.
[55] N. Toshima, K. Kushihashi, T. Yonezawa and H. Hirai, “Colloidal dispersions of palladium-platinum bimetallic clusters protected by polymers,” Chemistry Letters, 18, 1769, 1989.
[56] L. Sangregorio, M. Galeotti, U. Bardi and P. Baglioni, “Synthesis of Cu3Au nanocluster alloy in reverse micelles,” Langmuir, 12, 5800, 1996.
[57] U. Kreibig and C. V. Z. Fragstein, “The limitation of electron mean free path in small silver particles,” Physical, 224, 307, 1969.
[58] K. Selby, M. Vollmer, J. Masui, V. Kersin, W. De Heer and W. Knight, “Surface plasma resonances in free metal clusters,” Physical Review B, 40, 5417, 1989.
[59] J. Lisiecki, F. Billoudet and M. P. Pileni, “Control of the shape and the size of copper metallic particles,” Journal of Physical Chemistry, 100, 4160, 1996.