ABSTRACT
Purpose
Design and evaluate a new micro-machining based approach for fabricating dissolvable microneedle arrays (MNAs) with diverse geometries and from different materials for dry delivery to skin microenvironments. The aims are to describe the new fabrication method, to evaluate geometric and material capability as well as reproducibility of the method, and to demonstrate the effectiveness of fabricated MNAs in delivering bioactive molecules.
Methods
Precise master molds were created using micromilling. Micromolding was used to create elastomer production molds from master molds. The dissolvable MNAs were then fabricated using the spin-casting method. Fabricated MNAs with different geometries were evaluated for reproducibility. MNAs from different materials were fabricated to show material capability. MNAs with embedded bioactive components were tested for functionality on human and mice skin.
Results
MNAs with different geometries and from carboxymethyl cellulose, polyvinyl pyrrolidone and maltodextrin were created reproducibly using our method. MNAs successfully pierce the skin, precisely deliver their bioactive cargo to skin and induce specific immunity in mice.
Conclusions
We demonstrated that the new fabrication approach enables creating dissolvable MNAs with diverse geometries and from different materials reproducibly. We also demonstrated the application of MNAs for precise and specific delivery of biomolecules to skin microenvironments in vitro and in vivo.
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REFERENCES
Donnelly RF, Singh TRR, Woolfson AD. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv. 2010;17(4):187–207.
Hegde NR, Kaveri SV, Bayry J. Recent advances in the administration of vaccines for infectious diseases: microneedles as painless delivery devices for mass vaccination. Drug Discov Today. 2011;16:1061–8.
Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364(2):227–36.
Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2012;26(11):1261–8.
Bouwstra JA. The skin barrier, a well-organized membrane. Colloids Surf. 1997;123:403–13.
Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2012;64(14):1547–68.
Walker RB, Smith EW. The role of percutaneous penetration enhancers. Adv Drug Deliv Rev. 1996;18:295–301.
Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog Polym Sci. 2007;32:762–98.
Karande P, Mitragotri S. Enhancement of transdermal drug delivery via synergistic action of chemicals. Biochim Biophys Acta. 2009;1788(11):2362–673.
Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37.
Shivanand P, Binal P, Viral D, Shaliesh K, Manish G, Subhash V. Microneedle: various techniques of fabrications and evaluations. Int J ChemTech Res. 2009;1(4):1058–62.
Wissink JM, Berenschot JW, Tas NR. Atom sharp microneedles, the missing link in microneedle drug delivery? Proceedings of Medical Devices Conference; 2008.
Gill H, Denson D, Burris B. Effect of microneedle design on pain in human subjects. Clin J Pain. 2008;24(7):585–94.
Jain RA. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials. 2000;21:2475–90.
Khanna P, Luongo K, Strom JA, Bhansali S. Sharpening of hollow silicon microneedles to reduce skin penetration force. J Micromech Microeng. 2010;20(4):045011.
Nordquist L, Roxhed N, Griss P, Stemme G. Novel microneedle patches for active insulin delivery are efficient in maintaining glycaemic control: an initial comparison with subcutaneous administration. Pharm Res. 2007;24(7):1381–8.
Roxhed N, Gasser T, Griss P. Penetration-enhanced ultrasharp microneedles and prediction on skin interaction for efficient transdermal drug delivery. J Microelectromech Syst. 2007;16(6):1429–40.
Matriano JA, Cormier M, Johnson J, Young WA, Buttery M, Nyam K, et al. Macroflux microprojection array patch technology: a new and intracutaneous immunization. Pharm Res. 2002;19(1):63–70.
Donnelly RF, Singh TRR, Tunney MM, Morrow DIJ, McCarron PA, O’Mahony C, et al. Microneedle arrays allow lower microbial penetration than hypodermic needles in vitro. Pharm Res. 2009;26(11):2513–22.
Koutsonanos DG, Del Pilar Martin M, Zarnitsyn VG, Sullivan SP, Compans RW, Prausnitz MR, et al. Transdermal influenza immunization with vaccine-coated microneedle arrays. PLoS One. 2009;4(3):e4773.
Matteucci M, Casella M, Bedoni M, Donetti E, Fanetti M, De Angelis F, et al. A compact and disposable transdermal drug delivery system. Microelectron Eng. 2008;85(5–6):1066–73.
Wilke N, Hibert C, Brien JO, Morrissey A. Silicon microneedle electrode array with temperature monitoring for electroporation. Sensors Actuators A Phys. 2005;123–124:319–25.
Gardeniers HJGE, Luttge R, Berenschot EJW, De Boer MJ, Yeshurun SY, Hefetz M, et al. Silicon micromachined hollow microneedles for transdermal liquid transport. J Microelectromech Syst. 2003;12(6):855–62.
Park JH, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release. 2005;104(1):51–66.
Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharm Res. 2006;23(5):1008–19.
Park JH, Choi SO, Kamath R, Yoon YK, Allen MG, Prausnitz MR. Polymer particle-based micromolding to fabricate novel microstructures. Biomed Microdevices. 2007;9(2):223–34.
Sammoura F, Kang J, Heo YM, Jung T, Lin L. Polymeric microneedle fabrication using a microinjection molding technique. Microsyst Technol. 2006;13:517–22.
Lippmann JM, Geiger EJ, Pisano AP. Polymer investment molding: method for fabricating hollow, microscale parts. Sensors Actuators A Phys. 2007;134:2–10.
Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater. 2008;20(5):933–8.
Donnelly RF, Majithiya R, Singh TRR, Morrow DIJ, Garland MJ, Demir YK, et al. Design, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding technique. Pharm Res. 2011;28(1):41–57.
Lee JW, Park J, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008;29(13):2113–24.
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(2):330–5.
Donnelly RF, Morrow DIJ, Singh TRR, Migalska K, Mccarron A, Mahony CO, et al. Processing difficulties and instability of carbohydrate microneedle arrays. Drug Dev Ind Pharm. 2009;35(10):1242–54.
Miyano T, Tobinaga Y, Kanno T, Matsuzaki Y, Takeda H, Wakui M, et al. Sugar micro needles as transdermic drug delivery system. Biomed Microdevices. 2005;7(3):185–8.
Kolli CS, Banga AK. Characterization of solid maltose microneedles and their use for transdermal delivery. Pharm Res. 2008;25(1):104–13.
Moon SJ, Lee SS. A novel fabrication method of a microneedle array using inclined deep x-ray exposure. J Micromech Microeng. 2005;15:903–11.
Falo LD Jr, Erdos G, Ozdoganlar OB. Dissolvable microneedle arrays for transdermal delivery to human skin. US Patent No. 0098651; 2011.
Filiz S, Xie L, Weiss L, Ozdoganlar OB. Micromilling of microbarbs for medical implants. Int J Mach Tools Manuf. 2008;48(3–4):459–72.
Xie L, Brownridge SD, Ozdoganlar OB, Weiss LE. The viability of micromilling for manufacturing mechanical attachment components for medical applications. Transactions of NAMRI/SME 2006;445–52.
Wilson ME, Kota N, Kim Y, Wang Y, Stolz DB, LeDuc PR, et al. Fabrication of circular microfluidic channels by combining mechanical micromilling and soft lithography. Lab Chip. 2011;11(8):1550–5.
Morelli AE, Rubin JP, Erdos G, Tkacheva OA, Mathers AR, Zahorchak AF, et al. CD4+ T cell responses elicited by different subsets of human skin migratory dendritic cells. J Immunol. 2005;175(12):7905–15.
Larregina AT, Falo LD. Changing paradigms in cutaneous immunology: adapting with dendritic cells. J Investig Dermatol. 2005;124(1):1–12.
Condon C, Watkins S, Celluzzi C. DNA–based immunization by in vivo transfection of dendritic cells. Nat Med. 1996;2(10):1122–8.
He Y, Zhang J, Donahue C, Falo Jr LD. Skin-derived dendritic cells induce potent CD8(+) T cell immunity in recombinant lentivector-mediated genetic immunization. Immunity. 2006;24(5):643–56.
Larregina AT, Watkins SC, Erdos G, Spencer LA, Storkus WJ, Beer Stolz D, et al. Direct transfection and activation of human cutaneous dendritic cells. Gene Ther. 2001;8(8):608–17.
Aramcharoen A, Mativenga PT, Yang S, Cooke KE, Teer DG. Evaluation and selection of hard coatings for micro milling of hardened tool steel. Int J Mach Tools Manuf. 2008;48(14):1578–84.
ACKNOWLEDGMENTS AND DISCLOSURES
This study is funded in part by the National Institute of Health Grant R01EB012776. The authors would like to thank Mr. Eric Mellers, a former M.S. student at CMU, for his efforts in the initial stages of the project.
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Bediz, B., Korkmaz, E., Khilwani, R. et al. Dissolvable Microneedle Arrays for Intradermal Delivery of Biologics: Fabrication and Application. Pharm Res 31, 117–135 (2014). https://doi.org/10.1007/s11095-013-1137-x
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DOI: https://doi.org/10.1007/s11095-013-1137-x