Transdermal drug delivery continues to provide an advantageous route of drug administration over injections. While the number of drugs delivered by passive transdermal patches has increased over the years, no macromolecule is currently delivered by the transdermal route. Substantial research efforts have been dedicated by a large number of researchers representing varied disciplines including biology, chemistry, pharmaceutics and engineering to understand, model and overcome the skin's barrier properties. This article focuses on engineering contributions to the field of transdermal drug delivery. The article pays tribute to Prof. Robert Langer, who pioneered the engineering approach towards transdermal drug delivery. Over a period spanning nearly 25 years since his first publication in the field of transdermal drug delivery, Bob Langer has deeply impacted the field by quantitative analysis and innovative engineering. At the same time, he has inspired several generations of engineers by collaborations and mentorship. His scientific insights, innovative technologies, translational efforts and dedicated mentorship have transformed the field.

Keywords:
Langer, Robert, Transdermal drug delivery, Engineering, Technology, Model, Drug delivery
1.
Prausnitz MR, Langer R: Transdermal drug delivery. Nat Biotechnol 2008;26:1261-1268.
2.
Bos JD, Meinardi MHM: The 500 dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 2000;9:165-169.
3.
Chuong CM, Nickoloff BJ, Elias PM, Goldsmith LA, Macher E, Maderson PA, Sundberg JP, Tagami H, Plonka PM, Thestrup-Pederson K, Bernard BA, Schroder JM, Dotto P, Chang CM, Williams ML, Feingold KR, King LE, Kligman AM, Rees JL, Christophers E: What is the ‘true' function of skin? Exp Dermatol 2002;11:159-187.
4.
Menon GK, Kligman AM: Barrier functions of human skin: a holistic view. Skin Pharmacol Physiol 2009;22:178-189.
5.
Elias PM: Stratum corneum defensive functions: an integrated view. J Invest Dermatol 2005;125:183-200.
6.
Elias PM: Therapeutic implications of a barrier-based pathogenesis of atopic dermatitis. Ann Dermatol 2010;22:245-254.
7.
Bouwstra JA, Ponec M: The skin barrier in healthy and diseased state. Biochim Biophys Acta 2006;1758:2080-2095.
8.
Potts RO, Francoeur ML: Physical methods for studying stratum corneum lipids. Semin Dermatol 1992;11:129-138.
9.
Potts RO, Guy RH: Predicting skin permeability. Pharm Res 1992;9:663-669.
10.
Hadgraft JW: Recent progress in the formulation of vehicles for topical applications. Br J Dermatol 1972;87:386-389.
11.
Hadgraft J: Recent developments in topical and transdermal delivery. Eur J Drug Metab Pharmacokinet 1996;21:165-173.
12.
Kalia YN, Naik A, Garrison J, Guy RH: Iontophoretic drug delivery. Adv Drug Deliv Rev 2004;56:619-658.
13.
Leboulanger B, Guy RH, Delgado-Charro MB: Non-invasive monitoring of phenytoin by reverse iontophoresis. Eur J Pharm Sci 2004;22:427-433.
14.
Prausnitz MR: A practical assessment of transdermal drug delivery by skin electroporation. Adv Drug Deliv Rev 1999;35:61-76.
15.
Denet AR, Vanbever R, Preat V: Skin electroporation for transdermal and topical delivery. Adv Drug Deliv Rev 2004;56:659-674.
16.
Prausnitz MR: Microneedles for transdermal drug delivery. Adv Drug Deliv Rev 2004;56:581-587.
17.
Arora A, Prausnitz MR, Mitragotri S: Micro-scale devices for transdermal drug delivery. Int J Pharm 2008;364:227-236.
18.
Schramm J, Mitragotri S: Transdermal drug delivery by jet injectors: energetics of jet formation and penetration. Pharm Res 2002;19:1673-1679.
19.
Mitragotri S: Current status and future prospects of needle-free liquid jet injectors. Nat Rev Drug Discov 2006;5:543-548.
20.
Kendall M, Mitchell T, Wrighton-Smith P: Intradermal ballistic delivery of micro-particles into excised human skin for pharmaceutical applications. J Biomech 2004;37:1733-1741.
21.
Mitchell TJ, Kendall MAF, Bellhouse BJ: A ballistic study of micro-particle penetration to the oral mucosa. Int J Impact Eng 2003;28:581-599.
22.
Tezel A, Dokka S, Kelly S, Hardee GE, Mitragotri S: Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis. Pharm Res 2004;21:2219-2225.
23.
Tezel A, Mitragotri S: Interactions of inertial cavitation bubbles with stratum corneum lipid bilayers during low-frequency sonophoresis. Biophys J 2003;85:3502-3512.
24.
Ng KY: Enhancing transdermal drug transport with low-frequency ultrasound. Drug Discov Today 2004;9:913-913.
25.
Smith NB: Perspectives on transdermal ultrasound mediated drug delivery. Int J Nanomed 2007;2:585-594.
26.
Mitragotri S, Kost J: Low-frequency sonophoresis - a review. Adv Drug Deliv Rev 2004;56:589-601.
27.
Ogura M, Paliwal S, Mitragotri S: Low-frequency sonophoresis: current status and future prospects. Adv Drug Deliv Rev 2008;60:1218-1223.
28.
Lee WR, Shen SC, Wang KH, Hu CH, Fang JF: Lasers and microdermabrasion enhance and control topical delivery of vitamin C. J Invest Dermatol 2003;121:1118-1125.
29.
Mikszta JA, Alarcon JB, Brittingham JM, Sutter DE, Pettis RJ, Harvey NG: Improved genetic immunization via micromechanical disruption of skin-barrier function and targeted epidermal delivery. Nat Med 2002;8:415-419.
30.
Svedman P, Lundin S, Svedman C: Administration of antidiuretic peptide (DDAVP) by way of suction deepithelialized skin. Lancet 1991;337:1506-1509.
31.
Svedman P, Lundin S, Hoglund P, Hammarlund C, Malmros C, Pantzar N: Passive drug diffusion via standardized skin mini-erosion: methodological aspects and clinical findings with new device. Pharm Res 1996;13:1354-1359.
32.
Baron ED, Harris L, Redpath WS, Shapiro H, Hetzel F, Morley G, Bar-Or D, Stevens SR: Laser-assisted penetration of topical anesthetic in adults. Arch Dermatol 2003;139:1288-1290.
33.
Veremis-Ley M, Ramirez H, Baron E, Hanneman K, Lankerani L, Scull H, Cooper KD, Nedorost ST: Laser-assisted penetration of allergens for patch testing. Dermatitis 2006;17:15-22.
34.
Lee S, McAuliffe DJ, Flotte TJ, Kollias N, Doukas AG: Photomechanical transcutaneous delivery of macromolecules. J Invest Dermatol 1998;111:925-929.
35.
Lee S, Kollias N, McAuliffe DJ, Flotte TJ, Doukas AG: Topical drug delivery in humans with a single photomechanical wave. Pharm Res 1999;16:1717-1721.
36.
Doukas AG, Kollias N: Transdermal drug delivery with a pressure wave. Adv Drug Deliv Rev 2004;56:559-579.
37.
Sintov AC, Krymberk I, Daniel D, Hannan T, Sohn Z, Levin G: Radiofrequency-driven skin microchanneling as a new way for electrically assisted transdermal delivery of hydrophilic drugs. J Control Release 2003;89:311-320.
38.
Murthy SN: Magnetophoresis: an approach to enhance transdermal drug diffusion. Pharmazie 1999;54:377-379.
39.
Murthy SN, Hiremath SRR: Magnetophoresis: a novel approach in transdermal drug permeation enhancement. J Control Release 2001;72:240-243.
40.
Blank IH, Scheuplein RJ, Macfarlane DJ: Mechanism of percutaneous absorption. 3. Effect of temperature on transport of non-electrolytes across skin. J Invest Dermatol 1967;49:582-589.
41.
Clarys P, Alewaeters K, Jadoul A, Barel A, Manadas RO, Preat V: In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers. Eur J Pharm Biopharm 1998;46:279-283.
42.
Akomeah F, Nazir T, Martin GP, Brown MB: Effect of heat on the percutaneous absorption and skin retention of three model penetrants. Eur J Pharm Sci 2004;21:337-345.
43.
Klemsdal TO, Gjesdal K, Bredesen JE: Heating and cooling of the nitroglycerin patch application area modify the plasma-level of nitroglycerin. Eur J Clin Pharmac 1992;43:625-628.
44.
Shomaker TS, Zhang J, Ashburn MA: A pilot study assessing the impact of heat on the transdermal delivery of testosterone. J Clin Pharmacol 2001;41:677-682.
45.
Fellinger K, Schmidt J: Klinik und Therapie des chronischen Gelenkrheumatismus. Vienna, Maudrich, 1954, pp 549-552.
46.
Mitragotri S, Blankschtein D, Langer R: An explanation for the variation of the sonophoretic transdermal transport enhancement from drug to drug. J Pharm Sci 1997;86:1190-1192.
47.
McElnay JC, Matthews MP, Harland R, McCafferty DF: The effect of ultrasound on the percutaneous absorption of lignocaine. Br J Clin Pharmacol 1985;20:421-424.
48.
Levy D, Kost J, Meshulam Y, Langer R: Effect of ultrasound on transdermal drug delivery to rats and guinea pigs. J Clin Invest 1989;83:2074-2078.
49.
McElnay JC, Benson HA, Harland R, Hadgraft J: Phonophoresis of methyl nicotinate: a preliminary study to elucidate the mechanism of action. Pharm Res 1993;10:1726-1731.
50.
Kassan DG, Lynch AM, Stiller MJ: Physical enhancement of dermatologic drug delivery: iontophoresis and phonophoresis. J Am Acad Dermatol 1996;34:657-666.
51.
Pottenger FJ, Karalfa BL: Utilization of hydrocortisone phonophoresis in United States Army Physical Therapy Clinics. Mil Med 1989;154:355-358.
52.
Mitragotri S, Edwards DA, Blankschtein D, Langer R: A mechanistic study of ultrasonically enhanced transdermal drug delivery. J Pharm Sci 1995;84:697-706.
53.
Mitragotri S, Blankschtein D, Langer R: Ultrasound-mediated transdermal protein delivery. Science 1995;269:850-853.
54.
Tezel A, Sens A, Tuchscherer J, Mitragotri S: Frequency dependence of sonophoresis. Pharm Res 2001;18:1694-1700.
55.
Mitragotri S, Farrell J, Tang H, Terahara T, Kost J, Langer R: Determination of threshold energy dose for ultrasound-induced transdermal drug transport. J Control Release 2000;63:41-52.
56.
Kushner JT, Blankschtein D, Langer R: Heterogeneity in skin treated with low-frequency ultrasound. J Pharm Sci 2008;97:4119-4128.
57.
Kushner J, Blankschtein D, Langer R: Experimental demonstration of the existence of highly permeable localized transport regions in low-frequency sonophoresis. J Pharm Sci 2004;93:2733-2745.
58.
Kushner JT, Blankschtein D, Langer R: Experimental demonstration of the existence of highly permeable localized transport regions in low-frequency sonophoresis. J Pharm Sci 2004;93:2733-2745.
59.
Tezel A, Sens A, Tuchscherer J, Mitragotri S: Synergistic effect of low-frequency ultrasound and surfactants on skin permeability. J Pharm Sci 2002;91:91-100.
60.
Schoellhammer CM, Polat BE, Mendenhall J, Maa R, Jones B, Hart DP, Langer R, Blankschtein D: Rapid skin permeabilization by the simultaneous application of dual-frequency, high-intensity ultrasound. J Control Release 2012;163:154-160.
61.
Tang H, Wang C, Blankschtein D, Langer R: An investigation of the role of cavitation in low-frequency ultrasound-mediated transdermal drug transport. Pharm Res 2002;19:1160-1169.
62.
Tezel A, Sens A, Mitragotri S: Investigations of the role of cavitation in low-frequency sonophoresis using acoustic spectroscopy. J Pharm Sci 2002;91:444-453.
63.
Morimoto Y, Mutoh M, Ueda H, Fang L, Hirayama K, Atobe M, Kobayashi D: Elucidation of the transport pathway in hairless rat skin enhanced by low-frequency sonophoresis based on the solute-water transport relationship and confocal microscopy. J Control Release 2005;103:587-597.
64.
Kushner JT, Kim D, So P, Blankschtein D, Langer R: Dual-channel two-photon microscopy study of transdermal transport in skin treated with low-frequency ultrasound and a chemical enhancer. J Invest Dermatol 2007;127:2832-2846.
65.
Tang H, Mitragotri S, Blankschtein D, Langer R: Theoretical description of transdermal transport of hydrophilic permeants: application to low-frequency sonophoresis. J Pharm Sci 2001;90:545-568.
66.
Xhauflaire-Uhoda E, Loussouarn G, Haubrechts C, Saint Léger D, Piérard G: Skin capacitance imaging and corneosurfametry. A comparative assessment of the impact of surfactants on stratum corneum. Contact Dermatitis 2006;54:249-253.
67.
Uhoda E, Lévêque J, Piérard G: Silicon image sensor technology for in vivo detection of surfactant-induced corneocyte swelling and drying. Dermatology 2005;210:184-188.
68.
Bouwstra J, de Graaff A, Gooris G, Nijsse J, Wiechers J, van Aelst A: Water distribution and related morphology in human stratum corneum at different hydration levels. J Invest Dermatol 2003;120:750-758.
69.
Paliwal S, Menon GK, Mitragotri S: Low-frequency sonophoresis: ultrastructural basis for stratum corneum permeability assessed using quantum dots. J Invest Dermatol 2006;126:1095-1101.
70.
Tachibana K, Tachibana S: Transdermal delivery of insulin by ultrasonic vibration. J Pharm Pharmacol 1991;43:270-271.
71.
Tachibana K: Transdermal delivery of insulin to alloxan-diabetic rabbits by ultrasound exposure. Pharm Res 1992;9:952-954.
72.
Tachibana K, Tachibana S: Use of ultrasound to enhance the local anesthetic effect of topically applied aqueous lidocaine. Anesthesiology 1993;78:1091-1096.
73.
Mitragotri S, Blankschtein D, Langer R: Transdermal drug delivery using low-frequency sonophoresis. Pharm Res 1996;13:411-420.
74.
Liu H, Li S, Pan W, Wang Y, Han F, Yao H: Investigation into the potential of low-frequency ultrasound facilitated topical delivery of cyclosporin A. Int J Pharm 2006;326:32-38.
75.
Tezel A, Dokka S, Kelly S, Hardee GE, Mitragotri S: Topical delivery of anti-sense oligonucleotides using low-frequency sonophoresis. Pharm Res 2004;21:2219-2225.
76.
Tezel A, Paliwal S, Shen Z, Mitragotri S: Low-frequency ultrasound as a transcutaneous immunization adjuvant. Vaccine 2005;23:3800-3807.
77.
Polat BE, Blankschtein D, Langer R: Low-frequency sonophoresis: application to the transdermal delivery of macromolecules and hydrophilic drugs. Expert Opin Drug Deliv 2010;7:1415-1432.
78.
Sivakumar M, Tachibana K, Pandit AB, Yasui K, Tuziuti T, Towata A, Iida Y: Transdermal drug delivery using ultrasound - theory, understanding and critical analysis. Cell Mol Biol (Noisy-le-Grand) 2005;51(suppl): OL767-OL784.
79.
Boucaud A: Trends in the use of ultrasound-mediated transdermal drug delivery. Drug Discov Today 2004;9:827-828.
80.
Katz N, Shapiro D, Herrmann T, Kost J, Custer L: Rapid onset of cutaneous anesthesia with EMLA cream after pretreatment with a new ultrasound-emitting device. Anesth Analg 2004;98:371-376.
81.
Becker B, Helfrich S, Baker E, Lovgren K, Minugh P, Machan J: Ultrasound with topical anesthetic rapidly decreases pain of intravenous cannulation. Acad Emerg Med 2005;12:289.
82.
Chuang H, Taylor E, Davison T: Clinical evaluation of a continuous minimally invasive glucose flux sensor placed over ultrasonically permeated skin. Diabetes Technol Ther 2004;6:21-30.
83.
Kost J, Mitragotri S, Gabbay RA, Pishko M, Langer R: Transdermal monitoring of glucose and other analytes using ultrasound. Nat Med 2000;6:347-350.
84.
Lee S, Newnham R, Smith N: Short ultrasound exposure times for noninvasive insulin delivery in rats using the lightweight cymbal array. IEEE Trans Ultrason Ferroelectr Freq Control 2004;51:176-180.
85.
Lee S, Snyder B, Newnham R, Barrie Smith N: Noninvasive ultrasonic transdermal insulin delivery in rabbits using the light-weight cymbal array. Diabetes Technol Ther 2004;6:808-815.
86.
Luis J, Park E, Meyer R Jr, Smith N: Rectangular cymbal arrays for improved ultrasonic transdermal insulin delivery. J Acoust Soc Am 2007;122:2022.
87.
Park E, Werner J, Smith N: Ultrasound mediated transdermal insulin delivery in pigs using a lightweight transducer. Pharm Res 2007;24:1396-1401.
88.
Smith NB, Lee S, Shung KK: Ultrasound-mediated transdermal in vivo transport of insulin with low-profile cymbal arrays. Ultrasound Med Biol 2003;29:1205-1210.
89.
Santoianni P, Nino M, Calabro G: Intradermal drug delivery by low-frequency sonophoresis (25 kHz). Dermatol Online J 2004;10:24.
90.
Mitragotri S, Ray D, Farrell J, Tang H, Yu B, Kost J, Blankschtein D, Langer R: Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. J Pharm Sci 2000;89:892-900.
91.
Le L, Kost J, Mitragotri S: Combined effect of low-frequency ultrasound and iontophoresis: applications for transdermal heparin delivery. Pharm Res 2000;17:1151-1154.
92.
Kost J, Pliquett U, Mitragotri S, Yamamoto A, Langer R, Weaver J: Synergistic effect of electric field and ultrasound on transdermal transport. Pharm Res 1996;13:633-638.
93.
Polat BE, Deen WM, Langer R, Blankschtein D: A physical mechanism to explain the delivery of chemical penetration enhancers into skin during transdermal sonophoresis - insight into the observed synergism. J Control Release 2012;158:250-260.
94.
Polat BE, Figueroa PL, Blankschtein D, Langer R: Transport pathways and enhancement mechanisms within localized and non-localized transport regions in skin treated with low-frequency sonophoresis and sodium lauryl sulfate. J Pharm Sci 2011;100:512-529.
95.
Mitragotri S, Ray D, Farrell J, Tang H, Yu B, Kost J, Blankschtein D, Langer R: Synergistic effect of low-frequency ultrasound and sodium lauryl sulfate on transdermal transport. J Pharm Sci 2000;89:892-900.
96.
Polat BE, Seto JE, Blankschtein D, Langer R: Application of the aqueous porous pathway model to quantify the effect of sodium lauryl sulfate on ultrasound-induced skin structural perturbation. J Pharm Sci, E-pub ahead of print.
97.
Prausnitz MR, Bose VG, Langer R, Weaver JC: Electroporation of mammalian skin: a mechanism to enhance transdermal drug delivery. Proc Natl Acad Sci USA 1993;90:10504-10508.
98.
Chen T, Segall EM, Langer R, Weaver JC: Skin electroporation: rapid measurements of the transdermal voltage and flux of four fluorescent molecules show a transition to large fluxes near 50 V. J Pharm Sci 1998;87:1368-1374.
99.
Prausnitz MR, Edelman ER, Gimm JA, Langer R, Weaver JC: Transdermal delivery of heparin by skin electroporation. Biotechnology (NY) 1995;13:1205-1209.
100.
Gallo SA, Oseroff AR, Johnson PG, Hui SW: Characterization of electric-pulse-induced permeabilization of porcine skin using surface electrodes. Biophys J 1997;72:2805-2811.
101.
Wong TW, Chen CH, Huang CC, Lin CD, Hui SW: Painless electroporation with a new needle-free microelectrode array to enhance transdermal drug delivery. J Control Release 2006;110:557-565.
102.
Wong TW, Zhao YL, Sen A, Hui SW: Pilot study of topical delivery of methotrexate by electroporation. Br J Dermatol 2005;152:524-530.
103.
Wallace MS, Ridgeway B, Jun E, Schulteis G, Rabussay D, Zhang L: Topical delivery of lidocaine in healthy volunteers by electroporation, electroincorporation, or iontophoresis: an evaluation of skin anesthesia. Reg Anesth Pain Med 2001;26:229-238.
104.
Sen A, Daly ME, Hui SW: Transdermal insulin delivery using lipid enhanced electroporation. Biochim Biophys Acta 2002;1564:5-8.
105.
Tokumoto S, Higo N, Sugibayashi K: Effect of electroporation and pH on the iontophoretic transdermal delivery of human insulin. Int J Pharm 2006;326:13-19.
106.
Roos AK, Eriksson F, Walters DC, Pisa P, King AD: Optimization of skin electroporation in mice to increase tolerability of DNA vaccine delivery to patients. Mol Ther 2009;17:1637-1642.
107.
Lin F, Shen X, Kichaev G, Mendoza JM, Yang M, Armendi P, Yan Y, Kobinger GP, Bello A, Khan AS, Broderick KE, Sardesai NY: Optimization of electroporation-enhanced intradermal delivery of DNA vaccine using a minimally invasive surface device. Hum Gene Ther Methods 2012;23:157-168.
108.
Dujardin N, Preat V: Delivery of DNA to skin by electroporation. Methods Mol Biol 2004;245:215-226.
109.
Roos AK, Eriksson F, Timmons JA, Gerhardt J, Nyman U, Gudmundsdotter L, Brave A, Wahren B, Pisa P: Skin electroporation: effects on transgene expression, DNA persistence and local tissue environment. PLoS One 2009;4:e7226.
110.
El-Kamary SS, Billington M, Deitz S, Colby E, Rhinehart H, Wu Y, Blackwelder W, Edelman R, Lee A, King A: Safety and tolerability of the Easy Vax clinical epidermal electroporation system in healthy adults. Mol Ther 2012;20:214-220.
111.
Vanbever R, Morre ND, Preat V: Transdermal delivery of fentanyl by electroporation. II. Mechanisms involved in drug transport. Pharm Res 1996;13:1360-1366.
112.
Vaughan TE, Weaver JC: Mechanism of transdermal drug delivery by electroporation. Methods Mol Med 2000;37:187-211.
113.
Pliquett U, Langer R, Weaver JC: Changes in the passive electrical properties of human stratum corneum due to electroporation. Biochim Biophys Acta 1995;1239:111-121.
114.
Gallo SA, Sen A, Hensen ML, Hui SW: Time-dependent ultrastructural changes to porcine stratum corneum following an electric pulse. Biophys J 1999;76:2824-2832.
115.
Jadoul A, Tanojo H, Preat V, Bouwstra JA, Spies F, Bodde HE: Electroperturbation of human stratum corneum fine structure by high voltage pulses: a freeze-fracture electron microscopy and differential thermal analysis study. J Investig Dermatol Symp Proc 1998;3:153-158.
116.
Prausnitz MR, Gimm JA, Guy RH, Langer R, Weaver JC, Cullander C: Imaging regions of transport across human stratum corneum during high-voltage and low-voltage exposures. J Pharm Sci 1996;85:1363-1370.
117.
Chen T, Langer R, Weaver JC: Skin electroporation causes molecular transport across the stratum corneum through localized transport regions. J Investig Dermatol Symp Proc 1998;3:159-165.
118.
Broderick KE, Kardos T, McCoy JR, Fons MP, Kemmerrer S, Sardesai NY: Piezoelectric permeabilization of mammalian dermal tissue for in vivo DNA delivery leads to enhanced protein expression and increased immunogenicity. Hum Vaccin 2011;7(suppl):22-28.
119.
Kost J, Pliquett U, Mitragotri S, Yamamoto A, Langer R, Weaver J: Synergistic effect of electric field and ultrasound on transdermal transport. Pharm Res 1996;13:633-638.
120.
Zewert TE, Pliquett UF, Vanbever R, Langer R, Weaver JC: Creation of transdermal pathways for macromolecule transport by skin electroporation and a low toxicity, pathway-enlarging molecule. Bioelectrochem Bioenerg 1999;49:11-20.
121.
Denet AR, Ucakar B, Preat V: Transdermal delivery of timolol and atenolol using electroporation and iontophoresis in combination: a mechanistic approach. Pharm Res 2003;20:1946-1951.
122.
Murthy SN, Sen A, Hui SW: Surfactant-enhanced transdermal delivery by electroporation. J Control Release 2004;98:307-315.
123.
Weaver JC, Vanbever R, Vaughan TE, Prausnitz MR: Heparin alters transdermal transport associated with electroporation. Biochem Biophys Res Commun 1997;234:637-640.
124.
Higuchi T: Physical chemical analysis of percutaneous absorption process from creams and ointments. J Soc Cosmet Chem 1960;11:85-97.
125.
Scheuplein R, Blank I, Brauner G, MacFarlane D: Percutaneous absorption of steroids. J Invest Dermatol 1969;52:63-70.
126.
Scheuplein R, Blank I: Permeability of the skin. Physiol Rev 1971;51:702-747.
127.
Blank IH: Cutaneous barriers. J Invest Dermatol 1965;45:249-256.
128.
Brenner H, Edwards DA: Macrotransport Processes. Boston, Butterworth-Heinemann, 1993.
129.
Chandrasekaran SK, Bayne W, Shaw JE: Pharmacokinetics of drug permeation through human skin. J Pharm Sci 1978;67:1370-1374.
130.
Johnson ME, Blankschtein D, Langer R: Evaluation of solute permeation through the stratum corneum: lateral bilayer diffusion as the primary transport mechanism. J Pharm Sci 1997;86:1162-1172.
131.
Mitragotri S, Johnson ME, Blankschtein D, Langer R: An analysis of the size selectivity of solute partitioning, diffusion, permeation across lipid bilayers. Biophys J 1999;77:1268-1283.
132.
Johnson ME, Berk DA, Blankschtein D, Golan DE, Jain RK, Langer RS: Lateral diffusion of small compounds in human stratum corneum and model lipid bilayer systems. Biophys J 1996;71:2656-2668.
133.
Yu B, Kim KH, So PT, Blankschtein D, Langer R: Topographic heterogeneity in transdermal transport revealed by high-speed two-photon microscopy: determination of representative skin sample sizes. J Invest Dermatol 2002;118:1085-1088.
134.
Yu B, Kim KH, So PT, Blankschtein D, Langer R: Evaluation of fluorescent probe surface intensities as an indicator of transdermal permeant distributions using wide-area two-photon fluorescence microscopy. J Pharm Sci 2003;92:2354-2365.
135.
Yu B, Kim KH, So PT, Blankschtein D, Langer R: Visualization of oleic acid-induced transdermal diffusion pathways using two-photon fluorescence microscopy. J Invest Dermatol 2003;120:448-455.
136.
Lee PJ, Ahmad N, Langer R, Mitragotri S, Prasad Shastri V: Evaluation of chemical enhancers in the transdermal delivery of lidocaine. Int J Pharm 2006;308:33-39.
137.
Peck KD, Ghanem AH, Higuchi WI: Hindered diffusion of polar molecules through and effective pore radii estimates of intact and ethanol treated human epidermal membrane. Pharm Res 1994;11:1306-1314.
138.
Tang H, Mitragotri S, Blankschtein D, Langer R: Theoretical description of transdermal transport of hydrophilic permeants: application to low-frequency sonophoresis. J Pharm Sci 2001;90:545-568.
139.
Yoshida NH, Roberts MS: Structure-transport relations in transdermal iontophoresis. Adv Drug Del Rev 1992;9:239-264.
140.
Yoshida N, Roberts M: Solute molecular size and transdermal iontophoresis across excised human skin. J Control Rel 1993;25:177-195.
141.
Dinh S, Luo C, Berner B: Upper and lower limits of human skin electrical resistance in iontophoresis. AIChE J 1993;39:2011-2018.
142.
Ruddy S, Hadzija B: Iontophoretic permeability of polyethylene glycols through hairless rat skin: application of hydrodynamic theory for hindered transport through liquid filled pores. Drug Des Discov 1992;8:207-224.
143.
Li S, Ghanem A-H, Peck KD, Higuchi WI: Iontophoretic transport across a synthetic membrane and human epidermal membrane: a study of the effect of permeant charge. J Pharm Sci 1997;86:680-689.
144.
Higuchi W, Li S, Ghanem SA, Zhu H, Song Y: Mechanistic aspects of iontophoresis in human epidermal membrane. J Control Release 1999;62:13-23.
145.
Manabe E, Numajiri S, Sugibayashi K, Morimoto Y: Analysis of skin permeation-enhancing mechanism of iontophoresis using hydrodynamic pore theory. J Control Release 2000;66:149-158.
146.
Tezel A, Sens A, Mitragotri S: A theoretical analysis of low-frequency sonophoresis: dependence of transdermal transport pathways on frequency and energy density. Pharm Res 2002;19:1841-1846.
147.
Tang H, Mitragotri S, Blankschtein D, Langer R: Theoretical description of transdermal transport of hydrophilic permeants: application to low-frequency sonophoresis. J Pharm Sci 2001;90:543-566.
148.
Polat BE, Seto JE, Blankschtein D, Langer R: Application of the aqueous porous pathway model to quantify the effect of sodium lauryl sulfate on ultrasound-induced skin structural perturbation. J Pharm Sci, E-pub ahead of print.
149.
Polat BE, Figueroa PL, Blankschtein D, Langer R: Transport pathways and enhancement mechanisms within localized and non-localized transport regions in skin treated with low-frequency sonophoresis and sodium lauryl sulfate. J Pharm Sci 2011;100:512-529.
150.
Kontturi K, Murtomaki L: Impedance spectroscopy in human skin. A refined model. Pharm Res 1994;11:1355-1357.
151.
Pikal MJ: Transport mechanisms in iontophoresis. I. A theoretical model for the electroosmotic flow on flux enhancement in transdermal iontophoresis. Pharm Res 1990;7:118-126.
152.
Mitragotri S: Modeling skin permeability to hydrophilic and hydrophobic solutes based on four permeation pathways. J Control Release 2003;86:69-92.
153.
Tezel A, Sens A, Mitragotri S: A theoretical analysis of low-frequency sonophoresis: dependence of transdermal transport pathways on frequency and energy density. Pharm Res 2002;19:1841-1846.
154.
Kushner JT, Blankschtein D, Langer R: Evaluation of the porosity, the tortuosity, and the hindrance factor for the transdermal delivery of hydrophilic permeants in the context of the aqueous pore pathway hypothesis using dual-radiolabeled permeability experiments. J Pharm Sci 2007;96:3263-3282.
155.
Edwards DA, Langer R: A linear theory of transdermal transport phenomena. J Pharm Sci 1994;83:1315-1334.
156.
Pino CJ, Gutterman JU, Vonwil D, Mitragotri S, Shastri VP: Glycosylation facilitates transdermal transport of macromolecules. Proc Natl Acad Sci USA 2012;109:21283-21288.
157.
Hsu T, Mitragotri S: Delivery of siRNA and other macromolecules into skin and cells using a peptide enhancer. Proc Natl Acad Sci USA 2011;108:15816-15821.
158.
Mitragotri S, Anissimov YG, Bunge AL, Frasch HF, Guy RH, Hadgraft J, Kasting GB, Lane ME, Roberts MS: Mathematical models of skin permeability: an overview. Int J Pharm 2011;418:115-129.
159.
Iwai I, Han H, den Hollander L, Svensson S, Ofverstedt LG, Anwar J, Brewer J, Bloksgaard M, Laloeuf A, Nosek D, Masich S, Bagatolli LA, Skoglund U, Norlen L: The human skin barrier is organized as stacked bilayers of fully extended ceramides with cholesterol molecules associated with the ceramide sphingoid moiety. J Invest Dermatol 2012;132:2215-2225.
160.
Frasch HF: A random walk model of skin permeation. Risk Anal 2002;22:265-276.
161.
Frasch HF, Barbero AM: Application of numerical methods for diffusion-based modeling of skin permeation. Adv Drug Deliv Rev 2013;65:208-220.
162.
Notman R, Anwar J, Briels WJ, Noro MG, den Otter WK: Simulations of skin barrier function: free energies of hydrophobic and hydrophilic transmembrane pores in ceramide bilayers. Biophys J 2008;95:4763-4771.
163.
Henry S, McAllister DV, Allen MG, Prausnitz MR: Microfabricated microneedles: a novel approach to transdermal drug delivery. J Pharm Sci 1998;87:922-925.
164.
Kim YC, Jarrahian C, Zehrung D, Mitragotri S, Prausnitz MR: Delivery systems for intradermal vaccination. Curr Top Microbiol Immunol 2012;351:77-112.
165.
Kim YC, Song JM, Lipatov AS, Choi SO, Lee JW, Donis RO, Compans RW, Kang SM, Prausnitz MR: Increased immunogenicity of avian influenza DNA vaccine delivered to the skin using a microneedle patch. Eur J Pharm Biopharm 2012;81:239-247.
166.
Prausnitz MR, Mikszta JA, Cormier M, Andrianov AK: Microneedle-based vaccines. Curr Top Microbiol Immunol 2009;333:369-393.
167.
Wu XM, Todo H, Sugibayashi K: Enhancement of skin permeation of high molecular compounds by a combination of microneedle pretreatment and iontophoresis. J Control Release 2007;118:189-195.
168.
Yan K, Todo H, Sugibayashi K: Transdermal drug delivery by in-skin electroporation using a microneedle array. Int J Pharm 2010;397:77-83.
169.
Prow TW, Chen X, Prow NA, Fernando GJ, Tan CS, Raphael AP, Chang D, Ruutu MP, Jenkins DW, Pyke A, Crichton ML, Raphaelli K, Goh LY, Frazer IH, Roberts MS, Gardner J, Khromykh AA, Suhrbier A, Hall RA, Kendall MA: Nanopatch-targeted skin vaccination against West Nile virus and Chikungunya virus in mice. Small 2010;6:1776-1784.
170.
Fernando GJ, Chen X, Primiero CA, Yukiko SR, Fairmaid EJ, Corbett HJ, Frazer IH, Brown LE, Kendall MA: Nanopatch targeted delivery of both antigen and adjuvant to skin synergistically drives enhanced antibody responses. J Control Release 2012;159:215-221.
171.
Schramm-Baxter J, Katrencik J, Mitragotri S: Jet injection into polyacrylamide gels: investigation of jet injection mechanics. J Biomech 2004;37:1181-1188.
172.
Arora A, Hakim I, Baxter J, Rathnasingham R, Srinivasan R, Fletcher DA, Mitragotri S: Needle-free delivery of macromolecules across the skin by nanoliter-volume pulsed microjets. Proc Natl Acad Sci USA 2007;104:4255-4260.
173.
Stachowiak JC, Li TH, Arora A, Mitragotri S, Fletcher DA: Dynamic control of needle-free jet injection. J Control Release 2009;135:104-112.
174.
Taberner A, Hogan NC, Hunter IW: Needle-free jet injection using real-time controlled linear Lorentz-force actuators. Med Eng Phys 2012;34:1228-1235.
175.
Kendall M, Mitchell T, Wrighton-Smith P: Intradermal ballistic delivery of micro-particles into excised human skin for pharmaceutical applications. J Biomech 2004;37:1733-1741.
176.
Chen D, Maa YF, Haynes JR: Needle-free epidermal powder immunization. Expert Rev Vaccines 2002;1:265-276.
177.
Chen D, Endres R, Maa YF, Kensil CR, Whitaker-Dowling P, Trichel A, Youngner JS, Payne LG: Epidermal powder immunization of mice and monkeys with an influenza vaccine. Vaccine 2003;21:2830-2836.
178.
Chen D, Periwal SB, Larrivee K, Zuleger C, Erickson CA, Endres RL, Payne LG: Serum and mucosal immune responses to an inactivated influenza virus vaccine induced by epidermal powder immunization. J Virol 2001;75:7956-7965.
179.
Chen D, Erickson CA, Endres RL, Periwal SB, Chu Q, Shu C, Maa YF, Payne LG: Adjuvantation of epidermal powder immunization. Vaccine 2001;19:2908-2917.
180.
Chen D, Endres RL, Erickson CA, Maa YF, Payne LG: Epidermal powder immunization using non-toxic bacterial enterotoxin adjuvants with influenza vaccine augments protective immunity. Vaccine 2002;20:2671-2679.
181.
Roy MJ, Wu MS, Barr LJ, Fuller JT, Tussey LG, Speller S, Culp J, Burkholder JK, Swain WF, Dixon RM, Widera G, Vessey R, King A, Ogg G, Gallimore A, Haynes JR, Heydenburg Fuller D: Induction of antigen-specific CD8+ T cells, T helper cells, and protective levels of antibody in humans by particle-mediated administration of a hepatitis B virus DNA vaccine. Vaccine 2000;19:764-778.
182.
Tacket CO, Roy MJ, Widera G, Swain WF, Broome S, Edelman R: Phase 1 safety and immune response studies of a DNA vaccine encoding hepatitis B surface antigen delivered by a gene delivery device. Vaccine 1999;17:2826-2829.
183.
Liu Y, Costigan G, Bellhouse BJ: Performance studies of a conical nozzle designed for the macromolecular skin delivery. J Drug Target 2008;16:206-212.
184.
Brown MB, Traynor MJ, Martin GP, Akomeah FK: Transdermal drug delivery systems: skin perturbation devices. Methods Mol Biol 2008;437:119-139.
185.
Stumpp O, Chen B, Welch AJ: Using sandpaper for noninvasive transepidermal optical skin clearing agent delivery. J Biomed Opt 2006;11:041118.
186.
Andrews SN, Zarnitsyn V, Bondy B, Prausnitz MR: Optimization of microdermabrasion for controlled removal of stratum corneum. Int J Pharm 2011;407:95-104.
187.
Apitz I, Vogel A: Material ejection in nanosecond Er:YAG laser ablation of water, liver, and skin. Appl Phys A Mater Sci Proc 2005;81:329-338.
188.
Yu J, Kalaria DR, Kalia YN: Erbium:YAG fractional laser ablation for the percutaneous delivery of intact functional therapeutic antibodies. J Control Release 2011;156:53-59.
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2013
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