Biomedical Microdevices

, 21:104 | Cite as

Fabrication and characterization of hyaluronic acid microneedles to enhance delivery of magnesium ascorbyl phosphate into skin

  • Yujin Kim
  • Sonalika A. Bhattaccharjee
  • Moritz Beck-Broichsitter
  • Ajay K. BangaEmail author


This study investigated the in vitro transdermal delivery of magnesium ascorbyl phosphate (MAP) through porcine ear skin treated with hyaluronic acid (HA) microneedles (MNs). In this study, the micro-molding method was used to fabricate HA MNs. HA solution (10% w/v) containing 3% of MAP was placed onto a poly(dimethyl siloxane) mold to fill the microchannels under vacuum followed by drying in a desiccator. Scanning electron microscopy was performed to record the dimensions of the MNs. Skin microporation was demonstrated by dye binding. Histological skin sections revealed the shape of microchannels under hematoxylin-eosin staining. The actual depth of the microchannels and drug distribution pathways were studied by confocal microscopy. In vitro permeation on Franz diffusion cells were performed to determine the rate and extent of drug delivery into and across the skin. SEM captured individual MNs from the array, and the length of each MN was found to be ~400 μm. The 10 × 10 MN array prepared, resulted in the formation of 95 to 100 microchannels after 2 mins of treatment. In addition, the histological evaluations showed the formation of microchannels in the skin, complementary in shape to the MNs. The depths of the formed microchannels amounted to ~125 μm as determined by confocal microscopy. The application of the current MN technology enhanced the delivery of MAP into skin (96.8 ± 3.9 μg/cm2) compared to the passive delivery strategy of MAP (44.9 ± 16.3 μg/cm2). HA MNs markedly enhanced the in vitro transdermal delivery of MAP into and across skin.


Microfabrication Transdermal drug delivery Dissolving microneedle Hydrophilic drug Hyaluronic acid 


Funding information

This project was funded by Merck KGaA (Darmstadt, Germany). The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada. Product designations of Merck KGaA, Darmstadt, Germany and third parties may appear in this material. For details on the ownership of mentioned trademarks, please refer to publicly available resources like

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. S.M. Bal, A.C. Kruithof, R. Zwier, E. Dietz, J.A. Bouwstra, J. Lademann, M.C. Meinke, Influence of microneedle shape on the transport of a fluorescent dye into human skin in vivo. J. Control. Release 147, 218–224 (2010)CrossRefGoogle Scholar
  2. M. Campos, Histopathological, morphometric and stereological studies of ascorbic acid and magnesium ascorbyl phosphate in a skin care formulation. Int. J. Cosmet. Sci. 22, 169–179 (2000)CrossRefGoogle Scholar
  3. M. Chen, V. Gupta, A.C. Anselmo, J.A. Muraski, S. Mitragotri, Topical delivery of hyaluronic acid into skin using SPACE-peptide carriers. J. Control. Release 173, 67–74 (2014)CrossRefGoogle Scholar
  4. M. Dangol, S. Kim, C.G. Li, S.F. Lahiji, M. Jang, Y. Ma, I. Huh, H. Jung, Anti-obesity effect of a novel caffeine-loaded dissolving microneedle patch in high-fat diet-induced obese C57BL/6J mice. J. Control. Release 265, 41–47 (2017)CrossRefGoogle Scholar
  5. P.C. DeMuth, A.V. Li, P. Abbink, J. Liu, H. Li, K.A. Stanley, K.M. Smith, C.L. Lavine, M.S. Seaman, J.A. Kramer, Vaccine delivery with microneedle skin patches in nonhuman primates. Nat. Biotechnol. 31, 1082 (2013)CrossRefGoogle Scholar
  6. R.F. Donnelly, R. Majithiya, T.R.R. Singh, D.I. Morrow, M.J. Garland, Y.K. Demir, K. Migalska, E. Ryan, D. Gillen, C.J. Scott, Design, optimization and characterisation of polymeric microneedle arrays prepared by a novel laser-based micromoulding technique. Pharm. Res. 28, 41–57 (2011)CrossRefGoogle Scholar
  7. R.F. Donnelly, D.I. Morrow, T.R. Singh, K. Migalska, P.A. McCarron, C. O'Mahony, A.D. Woolfson, Processing difficulties and instability of carbohydrate microneedle arrays. Drug Dev. Ind. Pharm. 35, 1242–1254 (2009)CrossRefGoogle Scholar
  8. R.F. Donnelly, T.R.R. Singh, M.J. Garland, K. Migalska, R. Majithiya, C.M. McCrudden, P.L. Kole, T.M.T. Mahmood, H.O. McCarthy, A.D. Woolfson, Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Adv. Funct. Mater. 22, 4879–4890 (2012)CrossRefGoogle Scholar
  9. J.C. Geesin, J.S. Gordon, R.A. Berg, Regulation of collagen synthesis in human dermal fibroblasts by the sodium and magnesium salts of ascorbyl-2-phosphate. Skin Pharmacol. Physiol. 6, 65–71 (1993)CrossRefGoogle Scholar
  10. H.S. Gill, M.R. Prausnitz, Coating formulations for microneedles. Pharm. Res. 24, 1369–1380 (2007)CrossRefGoogle Scholar
  11. S.D. Gittard, A. Ovsianikov, B.N. Chichkov, A. Doraiswamy, R.J. Narayan, Two-photon polymerization of microneedles for transdermal drug delivery. Expert Opin. Drug Deliv. 7, 513–533 (2010)CrossRefGoogle Scholar
  12. M. Han, D.K. Kim, S.H. Kang, H.-R. Yoon, B.-Y. Kim, S.S. Lee, K.D. Kim, H.G. Lee, Improvement in antigen-delivery using fabrication of a grooves-embedded microneedle array. Sensors Actuators B Chem. 137, 274–280 (2009)CrossRefGoogle Scholar
  13. M. Haq, E. Smith, D.N. John, M. Kalavala, C. Edwards, A. Anstey, A. Morrissey, J.C. Birchall, Clinical administration of microneedles: skin puncture, pain and sensation. Biomed. Microdevices 11, 35–47 (2009)CrossRefGoogle Scholar
  14. S. Henry, D.V. McAllister, M.G. Allen, M.R. Prausnitz, Microfabricated microneedles: a novel approach to transdermal drug delivery. J. Pharm. Sci. 87, 922–925 (1998)CrossRefGoogle Scholar
  15. S. Hirobe, H. Azukizawa, T. Hanafusa, K. Matsuo, Y.S. Quan, F. Kamiyama, I. Katayama, N. Okada, S. Nakagawa, Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. Biomaterials 57, 50–58 (2015)CrossRefGoogle Scholar
  16. W.W.-Y. Kao, J.G. Flaks, D.J. Prockop, Primary and secondary effects of ascorbate on procollagen synthesis and protein synthesis by primary cultures of tendon fibroblasts. Arch. Biochem. Biophys. 173, 638–648 (1976)CrossRefGoogle Scholar
  17. Y.C. Kim, J.H. Park, M.R. Prausnitz, Microneedles for drug and vaccine delivery. Adv. Drug Deliv. Rev. 64, 1547–1568 (2012)CrossRefGoogle Scholar
  18. S. Lau, J. Fei, H. Liu, W. Chen, R. Liu, Multilayered pyramidal dissolving microneedle patches with flexible pedestals for improving effective drug delivery. J. Control. Release 265, 113–119 (2017)CrossRefGoogle Scholar
  19. J.W. Lee, J.H. Park, M.R. Prausnitz, Dissolving microneedles for transdermal drug delivery. Biomaterials 29, 2113–2124 (2008)CrossRefGoogle Scholar
  20. W.-R. Lee, S.-C. Shen, K.-H. Wang, C.-H. Hu, J.-Y. Fang, Lasers and microdermabrasion enhance and control topical delivery of vitamin C. J. Investig. Dermatol. 121, 1118–1125 (2003)CrossRefGoogle Scholar
  21. W. Li, R.N. Terry, J. Tang, M.R. Feng, S.P. Schwendeman, M.R. Prausnitz, Rapidly separable microneedle patch for the sustained release of a contraceptive. Nat. Biomed. Eng. 3, 220–229 (2019)CrossRefGoogle Scholar
  22. S. Liu, D. Wu, Y.S. Quan, F. Kamiyama, K. Kusamori, H. Katsumi, T. Sakane, A. Yamamoto, Improvement of transdermal delivery of Exendin-4 using novel tip-loaded microneedle arrays fabricated from hyaluronic acid. Mol. Pharm. 13, 272–279 (2016)CrossRefGoogle Scholar
  23. P.M.B.G. Maia Campos, F.B. de Camargo Júnior, J.P. de Andrade, L.R. Gaspar, Efficacy of cosmetic formulations containing dispersion of liposome with magnesium ascorbyl phosphate, alpha-lipoic acid and kinetin. Photochem. Photobiol. 88, 748–752 (2012)CrossRefGoogle Scholar
  24. W. Martanto, S.P. Davis, N.R. Holiday, J. Wang, H.S. Gill, M.R. Prausnitz, Transdermal delivery of insulin using microneedles in vivo. Pharm. Res. 21, 947–952 (2004)CrossRefGoogle Scholar
  25. W. Martanto, J.S. Moore, T. Couse, M.R. Prausnitz, Mechanism of fluid infusion during microneedle insertion and retraction. J. Control. Release 112, 357–361 (2006)CrossRefGoogle Scholar
  26. D.V. McAllister, P.M. Wang, S.P. Davis, J.H. Park, P.J. Canatella, M.G. Allen, M.R. Prausnitz, Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc. Natl. Acad. Sci. U. S. A. 100, 13755–13760 (2003)CrossRefGoogle Scholar
  27. M.G. McGrath, S. Vucen, A. Vrdoljak, A. Kelly, C. O'Mahony, A.M. Crean, A. Moore, Production of dissolvable microneedles using an atomised spray process: effect of microneedle composition on skin penetration. Eur. J. Pharm. Biopharm. 86, 200–211 (2014)CrossRefGoogle Scholar
  28. H.X. Nguyen, A.K. Banga, Enhanced skin delivery of vismodegib by microneedle treatment. Drug Deliv. Transl. Res. 5, 407–423 (2015)CrossRefGoogle Scholar
  29. H.X. Nguyen, A.K. Banga, Delivery of methotrexate and characterization of skin treated by fabricated PLGA microneedles and fractional ablative laser. Pharm. Res. 35, 68 (2018)CrossRefGoogle Scholar
  30. H.X. Nguyen, B.D. Bozorg, Y. Kim, A. Wieber, G. Birk, D. Lubda, A.K. Banga, Poly (vinyl alcohol) microneedles: fabrication, characterization, and application for transdermal drug delivery of doxorubicin. Eur. J. Pharm. Biopharm. 129, 88–103 (2018)CrossRefGoogle Scholar
  31. J. Pan, W. Ruan, M. Qin, Y. Long, T. Wan, K. Yu, Y. Zhai, C. Wu, Y. Xu, Intradermal delivery of STAT3 siRNA to treat melanoma via dissolving microneedles. Sci. Rep. 8, 1117 (2018)CrossRefGoogle Scholar
  32. E. Papakonstantinou, M. Roth, G. Karakiulakis, Hyaluronic acid: a key molecule in skin aging. Dermato-endocrinology 4, 253–258 (2012)CrossRefGoogle Scholar
  33. J.H. Park, M.G. Allen, M.R. Prausnitz, Polymer microneedles for controlled-release drug delivery. Pharm. Res. 23, 1008–1019 (2006)CrossRefGoogle Scholar
  34. S.Y. Park, H.U. Lee, Y.C. Lee, G.H. Kim, E.C. Park, S.H. Han, J.G. Lee, S. Choi, N.S. Heo, D.L. Kim, Y.S. Huh, J. Lee, Wound healing potential of antibacterial microneedles loaded with green tea extracts. Materials science & engineering C. Mater. Biol. Appl. 42, 757–762 (2014)Google Scholar
  35. Y. Park, J. Park, G.S. Chu, K.S. Kim, J.H. Sung, B. Kim, Transdermal delivery of cosmetic ingredients using dissolving polymer microneedle arrays. Biotechnol. Bioprocess Eng. 20, 543–549 (2015)CrossRefGoogle Scholar
  36. F. Pérennès, B. Marmiroli, M. Matteucci, M. Tormen, L. Vaccari, E.D. Fabrizio, Sharp beveled tip hollow microneedle arrays fabricated by LIGA and 3D soft lithography with polyvinyl alcohol. J. Micromech. Microeng. 16, 473–479 (2006)CrossRefGoogle Scholar
  37. F. Sammoura, J. Kang, Y.-M. Heo, T. Jung, L. Lin, Polymeric microneedle fabrication using a microinjection molding technique. Microsyst. Technol. 13, 517–522 (2007)CrossRefGoogle Scholar
  38. H.P. Tham, K. Xu, W.Q. Lim, H. Chen, M. Zheng, T.G.S. Thng, S.S. Venkatraman, C. Xu, Y. Zhao, Microneedle-assisted topical delivery of photodynamically active mesoporous formulation for combination therapy of deep-seated melanoma. ACS Nano 12, 11936–11948 (2018)CrossRefGoogle Scholar
  39. K. van der Maaden, W. Jiskoot, J. Bouwstra, Microneedle technologies for (trans)dermal drug and vaccine delivery. J. Control. Release 161, 645–655 (2012)CrossRefGoogle Scholar
  40. M. Yang, J.D. Zahn, Microneedle insertion force reduction using vibratory actuation. Biomed. Microdevices 6, 177–182 (2004)CrossRefGoogle Scholar
  41. C. Zhang, K. Zhang, J. Zhang, H. Ou, J. Duan, S. Zhang, D. Wang, S. Mitragotri, M. Chen, Skin delivery of hyaluronic acid by the combined use of sponge spicules and flexible liposomes. Biomater. Sci. 7, 1299–1310 (2019)CrossRefGoogle Scholar
  42. Z. Zhu, H. Luo, W. Lu, H. Luan, Y. Wu, J. Luo, Y. Wang, J. Pi, C.Y. Lim, H. Wang, Rapidly dissolvable microneedle patches for transdermal delivery of exenatide. Pharm. Res. 31, 3348–3360 (2014)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, College of PharmacyMercer UniversityAtlantaUSA
  2. 2.MilliporeSigma a Business of Merck KGaADarmstadtGermany

Personalised recommendations