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

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12
Fig. 13
Fig. 14
Fig. 15
Fig. 16
Fig. 17
Fig. 18
Fig. 19

REFERENCES

  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.

    CAS  PubMed Central  PubMed  Article  Google 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.

    PubMed  Article  Google Scholar 

  3. 3.

    Arora A, Prausnitz MR, Mitragotri S. Micro-scale devices for transdermal drug delivery. Int J Pharm. 2008;364(2):227–36.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  4. 4.

    Prausnitz MR, Langer R. Transdermal drug delivery. Nat Biotechnol. 2012;26(11):1261–8.

    Article  Google Scholar 

  5. 5.

    Bouwstra JA. The skin barrier, a well-organized membrane. Colloids Surf. 1997;123:403–13.

    Article  Google Scholar 

  6. 6.

    Kim YC, Park JH, Prausnitz MR. Microneedles for drug and vaccine delivery. Adv Drug Deliv Rev. 2012;64(14):1547–68.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  7. 7.

    Walker RB, Smith EW. The role of percutaneous penetration enhancers. Adv Drug Deliv Rev. 1996;18:295–301.

    CAS  Article  Google Scholar 

  8. 8.

    Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog Polym Sci. 2007;32:762–98.

    CAS  Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2012;64:128–37.

    Article  Google 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.

    CAS  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.

  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.

    PubMed Central  PubMed  Article  Google Scholar 

  14. 14.

    Jain RA. The manufacturing techniques of various drug loaded biodegradable poly(lactide-co-glycolide) (PLGA) devices. Biomaterials. 2000;21:2475–90.

    CAS  PubMed  Article  Google 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.

    Article  Google 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.

    CAS  PubMed  Article  Google 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.

    Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed Central  PubMed  Article  Google 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.

    PubMed Central  PubMed  Article  Google 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.

    CAS  Article  Google 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.

    Article  Google 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.

    Article  Google 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.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Park JH, Allen MG, Prausnitz MR. Polymer microneedles for controlled-release drug delivery. Pharm Res. 2006;23(5):1008–19.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    Article  Google 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.

    CAS  Article  Google 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.

    CAS  PubMed Central  PubMed  Article  Google 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.

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  31. 31.

    Lee JW, Park J, Prausnitz MR. Dissolving microneedles for transdermal drug delivery. Biomaterials. 2008;29(13):2113–24.

    CAS  PubMed Central  PubMed  Article  Google 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.

    CAS  Article  Google 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.

    CAS  PubMed Central  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  Article  Google Scholar 

  37. 37.

    Falo LD Jr, Erdos G, Ozdoganlar OB. Dissolvable microneedle arrays for transdermal delivery to human skin. US Patent No. 0098651; 2011.

  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.

    Article  Google 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.

  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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Google Scholar 

  42. 42.

    Larregina AT, Falo LD. Changing paradigms in cutaneous immunology: adapting with dendritic cells. J Investig Dermatol. 2005;124(1):1–12.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    CAS  PubMed Central  PubMed  Article  Google 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.

    CAS  PubMed  Article  Google 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.

    Article  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to O. Burak Ozdoganlar.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

KEY WORDS

  • cutaneous drug delivery
  • dissolvable microneedle arrays
  • immunization
  • micro-fabrication
  • micromilling