Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Transdermal microneedles for the programmable burst release of multiple vaccine payloads

Nature Biomedical Engineering volume 5, pages 998–1007 (2021)Cite this article

Subjects

Abstract

Repeated bolus injections are associated with higher costs and poor compliance and can hinder the implementation of global immunization campaigns. Here, we report the development and preclinical testing of patches of transdermal core–shell microneedles—which were fabricated by the micromoulding and alignment of vaccine cores and shells made from poly(lactic-co-glycolic acid) with varying degradability kinetics—for the preprogrammed burst release of vaccine payloads over a period of a few days to more than a month from a single administration. In rats, microneedles loaded with a clinically available vaccine (Prevnar-13) against the bacterium Streptococcus pneumoniae induced immune responses that were similar to immune responses observed after multiple subcutaneous bolus injections, and led to immune protection against a lethal bacterial dose. Microneedle patches delivering preprogrammed doses may offer an alternative strategy to prophylactic and therapeutic protocols that require multiple injections.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Fully embedded dermal core–shell microneedles for single-administration vaccines with delayed burst release that simulate multiple bolus injections over a long period of time.
Fig. 2: In vitro delayed burst release, loading capacity and mechanical properties of core–shell microneedles.
Fig. 3: In vivo delayed burst release from the core–shell microneedles and OVA vaccination.
Fig. 4: Prevnar-13-loaded core–shell microneedle vaccination and in vivo infectious pneumococcal challenge.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. All data generated in this study, including source data and the data used to generate the figures, are available at Figshare under the identifier https://doi.org/10.6084/m9.figshare.12951794.

References

  1. Ochoa, T. J. et al. Vaccine schedule compliance among very low birth weight infants in Lima, Peru. Vaccine 33, 354–358 (2015).

    Article  PubMed  Google Scholar 

  2. Majumder, M. S., Cohn, E. L., Mekaru, S. R., Huston, J. E. & Brownstein, J. S. Substandard vaccination compliance and the 2015 measles outbreak. JAMA Pediatr. 169, 494–495 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pierce, C. et al. The impact of the standards for pediatric immunization practices on vaccination coverage levels. JAMA 276, 626–630 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Simonsen, L., Kane, A., Lloyd, J., Zaffran, M. & Kane, M. In focus—unsafe injections in the developing world and transmission of bloodborne pathogens: a review. Bull. World Health Organ. 77, 789–800 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Dicko, M. et al. Safety of immunization injections in Africa: not simply a problem of logistics. Bull. World Health Organ. 78, 163–169 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Bloom, B. R. Vaccines for the third world. Nature 342, 115–120 (1989).

    Article  CAS  PubMed  Google Scholar 

  7. McHugh, K. J., Guarecuco, R., Langer, R. & Jaklenec, A. Single-injection vaccines: progress, challenges, and opportunities. J. Control. Release 219, 596–609 (2015).

    Article  CAS  PubMed  Google Scholar 

  8. Hutin, Y. & Chen, R. T. Injection safety: a global challenge. Bull. World Health Organ. 77, 787–788 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Kermode, M. Unsafe injections in low-income country health settings: need for injection safety promotion to prevent the spread of blood-borne viruses. Health Promot. Int. 19, 95–103 (2004).

    Article  PubMed  Google Scholar 

  10. Tzeng, S. Y. et al. Stabilized single-injection inactivated polio vaccine elicits a strong neutralizing immune response. Proc. Natl Acad. Sci. USA 115, E5269–E5278 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Li, W. et al. Rapidly separable microneedle patch for the sustained release of a contraceptive. Nat. Biomed. Eng. 3, 220–229 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Joyce, J. C. et al. A microneedle patch for measles and rubella vaccination is immunogenic and protective in infant rhesus macaques. J. Infect. Dis. 218, 124–132 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang, C., Ye, Y., Hochu, G. M., Sadeghifar, H. & Gu, Z. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PD1 antibody. Nano Lett. 16, 2334–2340 (2016).

    Article  CAS  PubMed  Google Scholar 

  14. Yu, J. et al. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery. Proc. Natl Acad. Sci. USA 112, 8260–8265 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. van der Maaden, K., Jiskoot, W. & Bouwstra, J. Microneedle technologies for (trans) dermal drug and vaccine delivery. J. Control. Release 161, 645–655 (2012).

    Article  PubMed  CAS  Google Scholar 

  16. Moga, K. A. et al. Rapidly-dissolvable microneedle patches via a highly scalable and reproducible soft lithography approach. Adv. Mater. 25, 5060–5066 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sullivan, S. P. et al. Dissolving polymer microneedle patches for influenza vaccination. Nat. Med. 16, 915–920 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen, M.-C., Huang, S.-F., Lai, K.-Y. & Ling, M.-H. Fully embeddable chitosan microneedles as a sustained release depot for intradermal vaccination. Biomaterials 34, 3077–3086 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. DeMuth, P. C., Min, Y., Irvine, D. J. & Hammond, P. T. Implantable silk composite microneedles for programmable vaccine release kinetics and enhanced immunogenicity in transcutaneous immunization. Adv. Healthc. Mat. 3, 47–58 (2014).

    Article  CAS  Google Scholar 

  20. Hong, X. et al. Dissolving and biodegradable microneedle technologies for transdermal sustained delivery of drug and vaccine. Drug Des. Devel. Ther. 7, 945–952 (2013).

    PubMed  PubMed Central  Google Scholar 

  21. Grayson, A. C. R. et al. Multi-pulse drug delivery from a resorbable polymeric microchip device. Nat. Mater. 2, 767–772 (2003).

    Article  CAS  Google Scholar 

  22. Stevenson, C. L., Santini, J. T. Jr & Langer, R. Reservoir-based drug delivery systems utilizing microtechnology. Adv. Drug Deliv. Rev. 64, 1590–1602 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Goole, J. & Amighi, K. 3D printing in pharmaceutics: a new tool for designing customized drug delivery systems. Int. J. Pharm. 499, 376–394 (2016).

    Article  PubMed  CAS  Google Scholar 

  24. Zhang, J. et al. 3D-printed magnetic Fe3O4/MBG/PCL composite scaffolds with multifunctionality of bone regeneration, local anticancer drug delivery and hyperthermia. J. Mater. Chem. B 2, 7583–7595 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Curry, E. J., Henoun, A. D., Miller, A. N. & Nguyen, T. D. 3D nano- and micro-patterning of biomaterials for controlled drug delivery. Ther. Deliv. 8, 15–28 (2016).

    Article  PubMed  CAS  Google Scholar 

  26. Tran, K. T. & Nguyen, T. D. Lithography-based methods to manufacture biomaterials at small scales. J. Sci. Adv. Mater. Devices 2, 1–14 (2017).

    Article  Google Scholar 

  27. McHugh, K. J. et al. Fabrication of fillable microparticles and other complex 3D microstructures. Science 357, 1138–1142 (2017).

    Article  CAS  PubMed  Google Scholar 

  28. Deegan, R. D. et al. Capillary flow as the cause of ring stains from dried liquid drops. Nature 389, 827–829 (1997).

    Article  CAS  Google Scholar 

  29. Park, J.-H., Allen, M. G. & Prausnitz, M. R. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J. Control. Release 104, 51–66 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Davis, S. P., Landis, B. J., Adams, Z. H., Allen, M. G. & Prausnitz, M. R. Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force. J. Biomech. 37, 1155–1163 (2004).

    Article  PubMed  Google Scholar 

  31. Chen, M.-C., Chan, H.-A., Ling, M.-H. & Su, L.-C. Implantable polymeric microneedles with phototriggerable properties as a patient-controlled transdermal analgesia system. J. Mater. Chem. B 5, 496–503 (2017).

    Article  CAS  PubMed  Google Scholar 

  32. Bronaugh, R. L., Stewart, R. F. & Congdon, E. R. Differences in permeability of rat skin related to sex and body site. J. Soc. Cosmet. Chem. 34, 127–135 (1983).

    CAS  Google Scholar 

  33. O’hagan, D. et al. Biodegradable microparticles as controlled release antigen delivery systems. Immunology 73, 239–242 (1991).

    PubMed  PubMed Central  Google Scholar 

  34. Draize, J. H., Woodard, G. & Calvery, H. O. Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. J. Pharmacol. Exp. Ther. 82, 377–390 (1944).

    CAS  Google Scholar 

  35. ACIP Preventing Pneumococcal Disease Among Infants and Young Children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). Recommendations and Reports: Morbidity and Mortality Weekly Report 49, 1–38 (MMWR, 2000).

  36. Darkes, M. J. & Plosker, G. L. Pneumococcal conjugate vaccine (Prevnar™1; PNCRM7). Pediatr. Drugs 4, 609–630 (2002).

    Article  Google Scholar 

  37. Elert, G. Temperature of a Healthy Human (Skin Temperature) (The Physics Factbook, 2007); http://hypertextbook.com/facts/2001/AbantyFarzana.shtml

  38. Ripolin, A. et al. Successful application of large microneedle patches by human volunteers. Int. J. Pharm. 521, 92–101 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li, W. et al. Long-acting reversible contraception by effervescent microneedle patch. Sci. Adv. 5, eaaw8145 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Levine, M. M. Can needle-free administration of vaccines become the norm in global immunization? Nat. Med. 9, 99–103 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Nossal, G. J. The Global Alliance for Vaccines and Immunization—a millennial challenge. Nat. Immunol. 1, 5–8 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Boopathy, A. V. et al. Enhancing humoral immunity via sustained-release implantable microneedle patch vaccination. Proc. Natl Acad. Sci. USA 116, 16473–16478 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. ThIel, M. & Hermatschweiler, M. Three-dimensional laser lithography: a new degree of freedom for science and industry. Opt. Photon. 6, 36–39 (2011).

    Article  Google Scholar 

  44. Rolland, J. P. et al. Direct fabrication and harvesting of monodisperse, shape-specific nanobiomaterials. J. Am. Chem. Soc. 127, 10096–10100 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Romero-Steiner, S. et al. Standardization of an opsonophagocytic assay for the measurement of functional antibody activity against Streptococcus pneumoniae using differentiated HL-60 cells. Clin. Diagn. Lab. Immunol. 4, 415–422 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank staff at the UConn Clean room and IVIS SpectrumCT facilities for equipment support on the microfabrication and in vivo imaging, respectively; C. Schondelmeyer and staff at the University of Connecticut Animal Facility for training and support for our animal research; staff at the UConn/Thermo Fisher Scientific Center for Advanced Microscopy and Materials Analysis for SEM imaging; staff at the UConn Machine shop, K. S. Wrobel, N. Romano and A. N. Miller for making the custom-built alignment device; F. Almonte for his assistance with mechanical testing; the undergraduate students A. Johnson, K. Berkery, E. Grandell, N. Pasnoori and H. Patel for help with the fabrication process, biological experiments and measuring release time points. The initial funding of this project was provided by Bio pipeline CT and Start-up funding from University of Connecticut (USA). This work was performed in part at the Advanced Science Research Center NanoFabrication Facility of the Graduate Center at the City University of New York, USA.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, University of Connecticut, Storrs, CT, USA

    Khanh T. M. Tran, Nicholas J. Farrell, Eli J. Curry & Thanh D. Nguyen

  2. Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT, USA

    Tyler D. Gavitt, Arlind B. Mara, Lindsey Brown, Neha Mishra & Steven M. Szczepanek

  3. Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT, USA

    Avi Patel

  4. Advanced Science Research Center, Graduate Center, City University of New York, New York, NY, USA

    Shawn Kilpatrick & Roxana Piotrowska

  5. Department of Chemistry, Graduate Center, City University of New York, New York, NY, USA

    Roxana Piotrowska

  6. Department of Chemistry, Hunter College, City University of New York, New York, NY, USA

    Roxana Piotrowska

  7. Connecticut Veterinary Medical Diagnostic Laboratory, Storrs, CT, USA

    Neha Mishra

  8. Department of Mechanical Engineering, University of Connecticut, Storrs, CT, USA

    Thanh D. Nguyen

Authors
  1. Khanh T. M. Tran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tyler D. Gavitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicholas J. Farrell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eli J. Curry
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arlind B. Mara
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Avi Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lindsey Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shawn Kilpatrick
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Roxana Piotrowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Neha Mishra
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Steven M. Szczepanek
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Thanh D. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

K.T.M.T. and T.D.N. designed the concepts and research studies. K.T.M.T., S.M.S. and T.D.N. conceived the experiments. K.T.M.T., T.D.G., N.J.F., E.J.C., A.B.M., A.P., L.B., S.K., N.M. and R.P. performed the research and experiments. T.D.G., S.M.S. and T.D.N. provided reagents, advice and materials. K.T.M.T., T.D.G., S.M.S. and T.D.N. wrote the paper.

Corresponding author

Correspondence to Thanh D. Nguyen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary Information

Supplementary Figs. 1–19, Tables 1–3 and references.

Reporting Summary

Supplementary Video 1

Fabrication process for the core–shell microneedles.

Supplementary Video 2

Administration of the microneedles into rat skin using a commercial applicator.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tran, K.T.M., Gavitt, T.D., Farrell, N.J. et al. Transdermal microneedles for the programmable burst release of multiple vaccine payloads. Nat Biomed Eng 5, 998–1007 (2021). https://doi.org/10.1038/s41551-020-00650-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-020-00650-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing