Pharmaceutical Research

, Volume 31, Issue 1, pp 117–135 | Cite as

Dissolvable Microneedle Arrays for Intradermal Delivery of Biologics: Fabrication and Application

  • Bekir Bediz
  • Emrullah Korkmaz
  • Rakesh Khilwani
  • Cara Donahue
  • Geza Erdos
  • Louis D. FaloJr
  • O. Burak OzdoganlarEmail author
Research Paper



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.


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.


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.


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.


cutaneous drug delivery dissolvable microneedle arrays immunization micro-fabrication micromilling 



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.


  1. 1.
    Donnelly RF, Singh TRR, Woolfson AD. Microneedle-based drug delivery systems: microfabrication, drug delivery, and safety. Drug Deliv. 2010;17(4):187–207.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 3.
    Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364(2):227–36.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2012;26(11):1261–8.CrossRefGoogle Scholar
  5. 5.
    Bouwstra JA. The skin barrier, a well-organized membrane. Colloids Surf. 1997;123:403–13.CrossRefGoogle Scholar
  6. 6.
    Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2012;64(14):1547–68.PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Walker RB, Smith EW. The role of percutaneous penetration enhancers. Adv Drug Deliv Rev. 1996;18:295–301.CrossRefGoogle Scholar
  8. 8.
    Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog Polym Sci. 2007;32:762–98.CrossRefGoogle Scholar
  9. 9.
    Karande P, Mitragotri S. Enhancement of transdermal drug delivery via synergistic action of chemicals. Biochim Biophys Acta. 2009;1788(11):2362–673.PubMedCrossRefGoogle Scholar
  10. 10.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37.CrossRefGoogle Scholar
  11. 11.
    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.Google Scholar
  12. 12.
    Wissink JM, Berenschot JW, Tas NR. Atom sharp microneedles, the missing link in microneedle drug delivery? Proceedings of Medical Devices Conference; 2008.Google Scholar
  13. 13.
    Gill H, Denson D, Burris B. Effect of microneedle design on pain in human subjects. Clin J Pain. 2008;24(7):585–94.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Jain RA. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials. 2000;21:2475–90.PubMedCrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    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.PubMedCrossRefGoogle Scholar
  17. 17.
    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.CrossRefGoogle Scholar
  18. 18.
    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.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    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.CrossRefGoogle Scholar
  24. 24.
    Park JH, Allen MG, Prausnitz MR. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J Control Release. 2005;104(1):51–66.PubMedCrossRefGoogle Scholar
  25. 25.
    Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharm Res. 2006;23(5):1008–19.PubMedCrossRefGoogle Scholar
  26. 26.
    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.PubMedCrossRefGoogle Scholar
  27. 27.
    Sammoura F, Kang J, Heo YM, Jung T, Lin L. Polymeric microneedle fabrication using a microinjection molding technique. Microsyst Technol. 2006;13:517–22.CrossRefGoogle Scholar
  28. 28.
    Lippmann JM, Geiger EJ, Pisano AP. Polymer investment molding: method for fabricating hollow, microscale parts. Sensors Actuators A Phys. 2007;134:2–10.CrossRefGoogle Scholar
  29. 29.
    Sullivan SP, Murthy N, Prausnitz MR. Minimally invasive protein delivery with rapidly dissolving polymer microneedles. Adv Mater. 2008;20(5):933–8.PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Lee JW, Park J, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008;29(13):2113–24.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    Kolli CS, Banga AK. Characterization of solid maltose microneedles and their use for transdermal delivery. Pharm Res. 2008;25(1):104–13.PubMedCrossRefGoogle Scholar
  36. 36.
    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.CrossRefGoogle Scholar
  37. 37.
    Falo LD Jr, Erdos G, Ozdoganlar OB. Dissolvable microneedle arrays for transdermal delivery to human skin. US Patent No. 0098651; 2011.Google Scholar
  38. 38.
    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.CrossRefGoogle Scholar
  39. 39.
    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.Google Scholar
  40. 40.
    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.PubMedCrossRefGoogle Scholar
  41. 41.
    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.PubMedGoogle Scholar
  42. 42.
    Larregina AT, Falo LD. Changing paradigms in cutaneous immunology: adapting with dendritic cells. J Investig Dermatol. 2005;124(1):1–12.PubMedCrossRefGoogle Scholar
  43. 43.
    Condon C, Watkins S, Celluzzi C. DNA–based immunization by in vivo transfection of dendritic cells. Nat Med. 1996;2(10):1122–8.PubMedCrossRefGoogle Scholar
  44. 44.
    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.PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    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.PubMedCrossRefGoogle Scholar
  46. 46.
    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.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Bekir Bediz
    • 1
  • Emrullah Korkmaz
    • 1
  • Rakesh Khilwani
    • 1
  • Cara Donahue
    • 2
  • Geza Erdos
    • 2
  • Louis D. FaloJr
    • 3
  • O. Burak Ozdoganlar
    • 4
    Email author
  1. 1.Department of Mechanical EngineeringCarnegie Mellon UniversityPittsburghUSA
  2. 2.Department of DermatologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  3. 3.Department of Dermatology; Department of Bioengineering Pittsburgh Clinical and Translational Science InstituteThe McGowan Institute for Regenerative Medicine and the University of Pittsburgh Cancer Institute University of Pittsburgh School of MedicinePittsburghUSA
  4. 4.Departments of Mechanical Engineering, Biomedical Engineering, and Materials Science and EngineeringCarnegie Mellon UniversityPittsburghUSA

Personalised recommendations