本研究利用具低熔點之生物可降解性高分子聚己內酯(polycaprolactone, PCL)，包覆止痛藥物利多卡因(lidocaine)和具光熱轉換效應之六硼化鑭奈米粒子(lanthanum hexaboride, LaB6)，製備出搖控驅動釋放型微針，評估其程式化經皮傳輸止痛藥物的可能性及臨床使用上之安全性。所製備之微針貼片(11 cm2)可包覆約1.58  0.17 mg (n = 4)的利多卡因。微針內的LaB6粒子可在吸收近紅外光後將其轉換為熱能，加熱微針使其熔化(約50 C)而釋放出藥物。經體外及活體皮膚穿刺結果證實，穿刺深度可達500~600 m。在光照強度3.5 W/cm2下，連續照射808-nm雷射5分鐘，即可明顯驅動微針熔化以釋放藥物。微針所釋放之藥量可隨照光週期(3分鐘/週期)增加而成比例上升，平均每照光週期可釋放11.3  2.3  (n = 4)之藥量，且能重覆地進行驅動釋放至少6次。藉由程式化設計施予不同照光時間(3、6與9分鐘)，釋放藥量也可呈現梯度增加，證實本微針具備可依臨床須求，準確控制經皮給藥量之能力。臨床使用安全性評估，分為對皮膚的熱傷害與LaB6粒子於體內代謝情形探討；結果顯示，雷射作用於微針9分鐘與12分鐘，老鼠皮膚皆有明顯紅腫，而照射6分鐘的皮膚則和控制組(僅穿刺但不照光)無明顯差異，且微針穿刺後皮膚的微傷口亦能在12小時內完全癒合，顯示連續照光6分鐘並不會對皮膚造成明顯的熱傷害，皮膚仍可正常進行修復。當微針中的LaB6完全釋放至皮膚中後，皮膚照射近紅外光並無明顯升溫情形，且經感應耦合電漿質譜分析儀(ICP-MS)分析證明，LaB6粒子在體內24小時後，幾乎已不存在於原穿刺部位或累積於特定器官中，可避免皮膚因曝露於近紅外光中所造成之不預期加熱情形，初步證明此搖控型微針使用上的安全性。

In this study, we used biodegradable polycaprolactone (PCL), encapsulated analgesic agent – lidocaine and lanthanum hexaboride (LaB6) nanoparticles (NPs), to make remotely triggerable microneedle (MN). We focused on the feasibility of MN transdermally delivering analgesic agents and its safety assessment of clinical application. Lidocaine content in each MN patch was 1.58  0.17 mg (n = 4). After giving treatment of NIR, LaB6 NPs encapsulated in MN could convert the energy into heat leading to the melt of PCL and release drugs. The skin insertion tests showed that the microneedles could be fully inserted into the skin with penetration depth of 500~600 m. The amount of released drugs can be controlled by adjusting the irradiation periods and exposure time and MN could be retriggered at least 6 cycles (3 min/cycle). Both skin scald observation and histological section confirmed that microneedles with 6 minutes NIR exposure performed the least heat damage to the skin tissue. The wound could recovered back to the original state after 12 hours. These result shows that there was no obvious heat damage in skin tissue after 6 minutes NIR exposure. We used inductively Coupled Plasma-Mass Spectroscopy (ICP-MS) to prove that LaB6 NPs did not exist in the MN puncher site neither in other specific tissues after 24 hours from MN been applied. These results suggest that remotely controlled microneedles can be used safely under 6 minutes NIR exposure without any obvious damage to the skin tissue and preliminarily reassure its using safety.

[1] Sy JC, Seshadri G, Yang SC, Brown M, Oh T, Dikalov S, Murthy N, Davis ME. Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nat Mater 2008;7:863-868.
[2] Choleris E, Little SR, Mong JA, Puram SV, Langer R, Pfaff DW. Microparticle-based delivery of oxytocin receptor antisense DNA in the medial amygdala blocks social recognition in female mice. Proc Natl Acad Sci USA 2007;104:4670-4675.
[3] Kohane DS, Holmes GL, Chau Y, Zurakowski D, Langer R, Cha BH. Effectiveness of Muscimol-containing Microparticles against Pilocarpine-induced Focal Seizures. Epilepsia 2002;43:1462-1468.
[4] Ciolino JB, Hoare TR, Iwata NG, Behlau I, Dohlman CH, Langer R, Kohane DS. A Drug-Eluting Contact Lens. Invest Ophthalmol Vis Sci 2009;50:3346-3352.
[5] Moses MA, Brem H, Langer R. Advancing the field of drug delivery: Taking aim at cancer. Cancer Cell 2003;4:337-341.
[6] Dhar S, Gu FX, Langer R, Farokhzad OC, Lippard SJ. Targeted delivery of cisplatin to prostate cancer cells by aptamer functionalized Pt(IV) prodrug-PLGA–PEG nanoparticles. Proc Natl Acad Sci USA 2008;105:17356-17361.
[7] Ruvinov E, Leor J, Cohen S. The effects of controlled HGF delivery from an affinity-binding alginate biomaterial on angiogenesis and blood perfusion in a hindlimb ischemia model. Biomaterials 2010 ;31:4573-4582.
[8] Edelman ER, Brown L, Langer R. Quantification of insulin release from implantable polymer-based delivery systems and augmentation of therapeutic effect with simultaneous release of somatostatin. J Pharm Sci 1996;85:1271-1275.
[9] Castillo J, Curley J, Hotz J, Uezono M, Tigner J, Chasin M, Wilder R, Langer , Berde C. Glucocorticoids prolong rat sciatic nerve blockade in vivo from bupivacaine microspheres. Anesthesiology 1996;85:1157-1166.
[10] Kohane DS, Smith SE, Louis DN, Colombo G, Ghoroghchain P, Hunfeld NGM, Berde CB, Langer RS. Prolonged duration local anesthesia from tetrodotoxin-enhanced local anesthetic microspheres. Pain 2003;104:415-421.
[11] Epstein-Barash H, Shichor I, Kwon AH, Hall S, Lawlor MW, Langer R, Kohane DS. Prolonged duration local anesthesia with minimal toxicity. Proc. Natl. Acad. Sci. USA 2009;106:7125-7130.
[12] Timko BP, Dvir T, Kohane DS. Remotely Triggerable Drug Delivery Systems. Adv Mater 2010;22:4925-4493.
[13] American National Standards Institute , American National Standard for the safe use of lasers , FL 1993.
[14] Bawa P, Pillay V, Choonara YE, Du Toit LC. Biomed. Mater;2009:4-10.
[15] Arruebo M, Fernandez-Pacheco R ,Ibarra MR, Santamaria SJ. Nano Today 2007;2-22.
[16] Lee JW, Foote RS . Micro and Nano Technologies in Bioanalysis : Methods and Protocols , Humana Press2009.
[17] Schroeder A, Kost J , Barenholz Y.Chem. Phys. Lipids 2009; 162:171.
[18] Steve I, Shen, Bhaskara R, Jasti, and Xiaoling L. Standard Handbook of Biomedical Engineering and Design, chapter 22: design of controlled-release drug delivery systems;2003
[19] Hisataka K, Mikako O, Raphael A. New strategies for fluorescent probe design in medical diagnostic imaging; Chem Rev.2010; 110:2620-2640
[20] Murkin JM, Arango M. Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J Anaesth 2009;103 Suppl 1:i3-13.
[21] Honar AL, Kang KA. Effect of the source and detector configuration on the detectability of breast cancer. Comp Biochem Physiol A Physiol 2002;132:9-15.
[22] Volodkin DV, Skirtach AG, Mohwald H. Near-IR remote release from assemblies of liposomes and nanoparticles. Angew Chem Int Ed Engl 2009;48:1807-1809.
[23] Yavuz MS, Cheng Y, Chen J, Cobley CM, Zhang Q, Rycenga M, Xie J, Kim C, Song KH, Schwartz AG, Wang LV, Xia Y. Gold nanocages covered by smart polymers for controlled release with near-infrared light. Nat Mater 2009;8:935-939.
[24] Hribar KC, Lee MH, Lee D, Burdick JA. Enhanced release of small molecules from near-infrared light responsive polymer-nanorod composites. ACS Nano 2011;5:2948-2956.
[25] Park JH, von Maltzahn G, Ong LL, Centrone A, Hatton TA, Ruoslahti E, Bhatia SN, Sailor MJ. Cooperative nanoparticles for tumor detection and photothermally triggered drug delivery. Adv Mater 2010;22:880-885.
[26] Kuo TR, Hovhannisyan VA, Chao YC, Chao SL, Chiang SJ, Lin SJ, Dong CY, Chen CC. Multiple release kinetics of targeted drug from gold nanorod embedded polyelectrolyte conjugates induced by near-infrared laser irradiation. J Am Chem Soc 2010;132:14163-14171.
[27] Huang X, Jain PK, El-Sayed IH, El-Sayed MA. Plasmonic photothermal therapy (PPTT) using gold nanoparticles. Lasers Med Sci 2008;23:217-228.
[28] Jain PK, Huang X, El-Sayed IH, El-Sayed MA. Noble metals on the nanoscale: optical and photothermal properties and some applications in imaging, sensing, biology, and medicine. Accounts Chem Res 2008;41:1578-1586.
[29] Jain PK, Huang X, El-Sayed IH, El-Sayad MA. Review of some interesting surface plasmon resonance-enhanced properties of noble metal nanoparticles and their applications to biosystems. Plasmonics 2007;2:107-118.
[30] Jain PK, El-Sayed IH, El-Sayed MA. Au nanoparticles target cancer. Nanotoday. 2007;2:18–29.
[31] 賴柏宏 2009，六硼化鑭複合奈米粒子的製備及其在生醫上的應用，國立成功大學化學工程研究所碩士論文.
[32] Kehlet H, Jensen TS, Woolf C. Persistent postsurgical pain: risk factors and prevention. Lancet 2006; 367: 1618–1625.
[33] Fortner BV, Okon TA, Portenoy RK. A survey of pain-related hospitalizations, emergency department visits, and physician office visits reported by cancer patients with and without history of breakthrough pain. J Pain 2002; 3:38–44.
[34] Xia Y, Chen E, Tibbit DL, Reilley TE, McSweeney TD. Comparison of effect of lidocaine hydrochloride, buffered lidocaine, diphenhydramine, and normal salin after intradermal injection. J.Clin Anesth 2002;14:339-343.
[35] Waller DG, Renwick AG, Gruchy BS, George CF. The first pass metabolism of nifedipine in man. Br J Clin Pharmacol 1984; 18:951–954.
[36] Davis SP, Martanto W, Allen MG, Prausnitz MR. Hollow metal microneedles for insulin delivery to diabetic rats. IEEE Trans Biomed Eng 2005;52:909-915.
[37] Chen X, Kask AS, Crichton ML, McNeilly C, Yukiko S, Dong L, Marshak JO, Jarrahian C, Fernando GJ, Chen D, Koelle DM, Kendall MA. Improved DNA vaccination by skin-targeted delivery using dry-coated densely-packed microprojection arrays. J ontrolled release 2010;148:327-333.
[38] Noh YW, Kim TH, Baek JS, Park HH, Lee SS, Han M, Shin SC, Cho CW. In vitro characterization of the invasiveness of polymer microneedle against skin. Int J Pharm 2010;397:201-205.
[39] Lee JW, Choi SO, Felner EI, Prausnitz MR. Dissolving microneedle patch for transdermal delivery of human growth hormone. Small 2011;7:531-539.
[40] Chabri F, Bouris K, Jones T, Barrow D, Hann A, Allender C, Brain K, Birchall J. Microfabricated silicon microneedles for nonviral cutaneous gene delivery. Br J Dermatol 2004;150:869-877.
[41] Qiu Y, Gao Y, Hu K, Li F. Enhancement of skin permeation of docetaxel: a novel approach combining microneedle and elastic liposomes. J Control Release 2008;129:144-150.
[42] Donnelly RF, Morrow DI, McCarron PA, Woolfson AD, Morrissey A, Juzenas P, Juzeniene A, Iani V, McCarthy HO, Moan J. Microneedle-mediated intradermal delivery of 5-aminolevulinic acid: potential for enhanced topical photodynamic therapy. J Control Release 2008;129:154-162.
[43] Kalluri H, Kolli CS, Banga AK. Characterization of microchannels created by metal microneedles: formation and closure. AAPS J 2011;13:473-481.
[44] Verbaan FJ, Bal SM, van den Berg DJ, Dijksman JA, van Hecke M, Verpoorten H, van den Berg A, Luttge R, Bouwstra JA. Improved piercing of microneedle arrays in dermatomed human skin by an impact insertion method. J Control Release 2008;128:80-88.
[45] Park JH, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release 2005;104:51-66.
[46] Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials 2008;29:2113-2124.
[47] Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater 2008;20:933-938.
[48] Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharm Res 2006;23:1008-1019.
[49] Sullivan SP, Koutsonanos DG, Del Pilar Martin M, Lee JW, Zarnitsyn V, Choi S, Murthy N, Compans RW, Skountzou I, Prausnitz MR. Dissolving polymer microneedle patches for influenza vaccination. Nat Med 2010;16:915-90.
[50] Chu LY, Prausnitz MR. Separable arrowhead microneedles. J Control Release 2011;149:242-249.
[51] Lee JW, Park JH, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials 2008;29:2113-2124.
[52] Fukushima K, Ise A, Morita H, Hasegawa R, Ito Y, Sugioka N, Takada K. Two-layered dissolving microneedles for percutaneous delivery of peptide/protein drugs in rats. Pharm Res 2011;28:7-21.
[53] González-González E, Kim YC, Speaker TJ, Hickerson RP, Spitler R, Birchall JC, Lara MF, Hu RH, Liang Y, Kirkiles-Smith N, Prausnitz MR, Milstone LM, Contag CH, Kaspar RL. Visualization of plasmid delivery to keratinocytes in mouse and human epidermis. Sci Rep 2011;1:158.
[54] Kim YC, Prausnitz MR. Enabling skin vaccination using new delivery technologies. Drug Deliv Transl Res 2011;1:7-12.
[55] Mikszta JA, Laurent PE. Cutaneous delivery of prophylactic and therapeutic vaccines: historical perspective and future outlook. Expert Rev Vaccines 2008;7:1329-1339.
[56] Pearton M, Allender C, Brain K, Anstey A, Gateley C, Wilke N, Morrissey A, Birchall J. Gene delivery to the epidermal cells of human skin explants using microfabricated microneedles and hydrogel formulations. Pharm Res 2008;25:407-416.
[57] Kim M, Jung B, Park JH. Hydrogel swelling as a trigger to release biodegradable polymer microneedles in skin. Biomaterials 2012;33:668-678.
[58] Tsioris K, Raja WK, Pritchard EM, Panilaitis B, Kaplan DL, Omenetto FG. Fabrication of silk microneedles for controlled-release drug delivery. Adv Funct Mater 2012;22:330-335.
[59] Hutmacher DW, Schantz T, Zein I, Ng KW, Teoh SH, Tan KC. Mechanical properties and cell cultural response of polycaprolactone scaffolds designed and fabricated via fused deposition modeling. J Biomed Mater Res 2001;55:203-216.
[60] Kweon H, Yoo MK, Park IK, Kim TH, Lee HC, Lee HS, Oh JS, Akaike T, Cho CS. A novel degradable polycaprolactone networks for tissue engineering. Biomaterials 2003;24:801-808.
[61] Loh XJ, Peh P, Liao S, Sng C, Li J. Controlled drug release from biodegradable thermoresponsive physical hydrogel nanofibers. J Control Release 2010;143:175-182.
[62] Bosworth LA, Downes S. Physicochemical characterisation of degrading polycaprolactone scaffolds. Polym Degrad Stabil 2010;95:2269-2276.
[63] Arote R, Kim TH, Kim YK, Hwang SK, Jiang HL, Song HH, Nah JW, Cho MH, Cho CS. A biodegradable poly(ester amine) based on polycaprolactone and polyethylenimine as a gene carrier. Biomaterials 2007;28:735-744.
[64] 王冠雯 2012，可依需求控制藥物釋放之光敏型高分子微針貼片，國立成功大學化學工程研究所碩士論文。
[65] 林致緯 2013，近紅外光驅動釋放型微針於癌症化療及光熱協同治療之應用，國立成功大學化學工程研究所碩士論文。