Springer Nature is making Coronavirus research free. View research | View latest news | Sign up for updates

Microneedle Array Patch (MAP) Consisting of Crosslinked Hyaluronic Acid Nanoparticles for Processability and Sustained Release

  • 54 Accesses



Crosslinked hyaluronic acid (X-linked HA) is not suitable for making microneedles because of the low fluidity of X-linked HA hydrogel. Microneedles were fabricated using X-linked HA nanoparticles (X-linked HA-NPs) to utilize the sustained drug delivery capability of X-linked HA-NPs and to obtain the processability advantages of X-linked HA.


The puncture performance of a microneedle array patch (MAP) made of crosslinked hyaluronic acid nanoparticles (X-linked HA-NP-MAP) was evaluated by insertion in vitro into porcine skin. After a predetermined attachment time, the remaining height of the X-linked HA-NP-MAP was measured to determine the dissolution rate. X-linked HA-NP-MAP and free HA-MAP containing Rhodamine B isothiocyanate-dextran were administered into the back skin of mice, and the relative fluorescent intensity in the back skin was measured over time.


The puncture performance of the X-linked HA-NP-MAP was over 90%. The diameter of redispersed X-linked HA-NPs was same as that of the premolded X-linked HA-NPs. The dissolution rate was not different from that of free HA-MAP. In an in vivo experiment, X-linked HA-NP-MAP was administered into the mouse’s back skin successfully and the relative fluorescent intensity of X-linked HA-NP-MAP lasted longer than that of HA-MAP.


X-linked HA-NPs provide the biocompatibility, the processability of micromolding, sustained drug release, successful penetration into the skin, and relatively short insertion time for full disintegration of NPs in the skin. X-linked HA-NP-MAP can be used for various applications that require several days of sustained drug release.

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


Free HA:

Non-crosslinked HA


Hyaluronic acid


Microneedle array patch made of free hyaluronic acid



X-linked HA-NP-MAP:

Microneedle array patch made of crosslinked hyaluronic acid nanoparticles

X-linked HA-NP:

Crosslinked hyaluronic acid nanoparticle


  1. 1.

    Jeong H-R, Lee H-S, Choi I-J, Park J-H. Considerations in the use of microneedles: pain, convenience, anxiety and safety. J Drug Target. 2017;25:29–40.

  2. 2.

    Marshall S, Sahm LJ, Moore AC. The success of microneedle-mediated vaccine delivery into skin. Hum Vacc Immunother. 2016;12:2975–83.

  3. 3.

    Hao Y, Li W, Zhou X, Yang F, Qian Z. Microneedles-based transdermal drug delivery systems: a review. J Biomed Nano Technol. 2017;13:1581–97.

  4. 4.

    Prausnitz MR. Engineering microneedle patches for vaccination and drug delivery to skin. Annu Rev Chem Biomol. 2017;8:177–200.

  5. 5.

    Arya J, Henry S, Kalluri H, McAllister DV, Pewin WP, Prausnitz MR. Tolerability, usability and acceptability of dissolving microneedle patch administration in human subjects. Biomaterials. 2017;128:1–7.

  6. 6.

    Ita K. Dissolving microneedles for transdermal drug delivery: advances and challenges. Biomed Pharmacother. 2017;93:1116–27.

  7. 7.

    Bhatnagar S, Dave K, Venuganti VVK. Microneedles in the clinic. J Cotrol Res. 2017;260:164–82.

  8. 8.

    Kennedy J, Larrañeta E, McCrudden MT, McCrudden CM, Brady AJ, Fallows SJ, et al. In vivo studies investigating biodistribution of nanoparticle-encapsulated rhodamine B delivered via dissolving microneedles. J Cotrol Res. 2017;265:57–65.

  9. 9.

    Mc Crudden MT, Larrañeta E, Clark A, Jarrahian C, Rein-Weston A, Lachau-Durand S, et al. Design, formulation and evaluation of novel dissolving microarray patches containing a long-acting rilpivirine nanosuspension. J Cotrol Res. 2018;292:119–29.

  10. 10.

    Donnellyand RF, Larrañeta E. Microarray patches: potentially useful delivery systems for long-acting nanosuspensions. Drug Discov Today. 2018;23:1026–33.

  11. 11.

    DeMuth PC, Su X, Samuel RE, Hammond PT, Irvine DJ. Nano-layered microneedles for transcutaneous delivery of polymer nanoparticles and plasmid DNA. Adv Mater. 2010;22:4851–6.

  12. 12.

    Du H, Liu P, Zhu J, Lan J, Li Y, Zhang L, et al. Hyaluronic acid dissolving microneedle patch loaded with methotrexate for improved treatment of psoriasis. ACS Appl Mater Interfaces. 2019.

  13. 13.

    Liu S, Wu D, Quan Y-s, Kamiyama F, Kusamori K, Katsumi H, et al. Improvement of transdermal delivery of exendin-4 using novel tip-loaded microneedle arrays fabricated from hyaluronic acid. Mol Pharm. 2015;13:272–9.

  14. 14.

    Highley CB, Prestwich GD, Burdick JA. Recent advances in hyaluronic acid hydrogels for biomedical applications. Curr Opin Biotechnol. 2016;40:35–40.

  15. 15.

    Moillard S, Bétemps JB, Hadjab B, Topchian D, Micheels P, Salomon D. Key rheological properties of hyaluronic acid fillers: from tissue integration to product degradation. Plast Aesthet Res. 2018;5:17–24.

  16. 16.

    Isa ILM, Abbah SA, Kilcoyne M, Sakai D, Dockery P, Finn DP, et al. Implantation of hyaluronic acid hydrogel prevents the pain phenotype in a rat model of intervertebral disc injury. Sci Adv. 2018;4:eaaq0597.

  17. 17.

    Khunmanee S, Jeong Y, Park H. Crosslinking method of hyaluronic-based hydrogel for biomedical applications. J Tissue Eng. 2017;8:2041731417726464.

  18. 18.

    Choi J-T, Park S-J, Park J-H. Microneedles containing cross-linked hyaluronic acid particulates for control of degradation and swelling behaviour after administration into skin. J Drug Target. 2018;26:884–94.

  19. 19.

    Berkó S, Maroda M, Bodnár M, Erős G, Hartmann P, Szentner K, et al. Advantages of cross-linked versus linear hyaluronic acid for semisolid skin delivery systems. Eur Polym J. 2013;49:2511–7.

  20. 20.

    Nakai T, Hirakura T, Sakurai Y, Shimoboji T, Ishigai M, Akiyoshi K. Injectable hydrogel for sustained protein release by salt-induced association of hyaluronic acid nanogel. Macromol Biosci. 2012;12:475–83.

  21. 21.

    Burdickand JA, Prestwich GD. Hyaluronic acid hydrogels for biomedical applications. Adv Mater. 2011;23:H41–56.

  22. 22.

    Falconeand SJ, Berg RA. Crosslinked hyaluronic acid dermal fillers: a comparison of rheological properties. J Biomed Mater Res. 2008;87:264–71.

  23. 23.

    Al-Ghananeem AM, Malkawi AH, Muammer YM, Balko JM, Black EP, Mourad W, et al. Intratumoral delivery of paclitaxel in solid tumor from biodegradable hyaluronan nanoparticle formulations. AAPS PharmSciTech. 2009;10:410–7.

  24. 24.

    Bodnár M, Daróczi L, Batta G, Bakó J, Hartmann JF, Borbély J. Preparation and characterization of cross-linked hyaluronan nanoparticles. Colloid Polym Sci. 2009;287:991–1000.

  25. 25.

    Maroda M, Bodnár M, Berkó S, Bakó J, Erős G, Csányi E, et al. Preparation and investigation of a cross-linked hyaluronan nanoparticles system. Carbohydr Polym. 2011;83:1322–9.

  26. 26.

    Vignesh S, Sivashanmugam A, Annapoorna M, Janarthanan R, Subramania I, Jayakumar R. Injectable deferoxamine nanoparticles loaded chitosan-hyaluronic acid coacervate hydrogel for therapeutic angiogenesis. Colloid Surface B. 2018;161:129–38.

  27. 27.

    Zhong Y, Zhang J, Cheng R, Deng C, Meng F, Xie F, et al. Reversibly crosslinked hyaluronic acid nanoparticles for active targeting and intelligent delivery of doxorubicin to drug resistant CD44+ human breast tumor xenografts. J Cotrol Res. 2015;205:144–54.

Download references


This work was supported by the Industrial Strategic Technology Development Program (10067809: Development of vaccine formulation and patient-convenient vaccine microneedle), funded by the Ministry of Trade, Industry & Energy (MOTIE, South Korea), and by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI15C2971, HI18C0590).

Author information

Correspondence to Jae Myun Lee or Jung-Hwan Park.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kim, D., Choi, J., Kim, C.B. et al. Microneedle Array Patch (MAP) Consisting of Crosslinked Hyaluronic Acid Nanoparticles for Processability and Sustained Release. Pharm Res 37, 50 (2020).

Download citation

Key Words

  • crosslinked hyaluronic acid
  • microneedles
  • nanoparticles
  • processability
  • puncture performance
  • sustained release