Dissolving undercut microneedle arrays for multicomponent cutaneous vaccination

• Published in: Journal of controlled release 2020-01, Vol.317, p.336-346
• Main Authors: Balmert, Stephen C., Carey, Cara Donahue, Falo, Gabriel D., Sethi, Shiv K., Erdos, Geza, Korkmaz, Emrullah, Falo, Louis D.
• Format: Article
• Language: English
• Subjects: Administration, Cutaneous; Animals; Cutaneous immunization; Dissolving microneedle arrays; Drug Delivery Systems; Mice; Micro-additive manufacturing; Microinjections; Multicomponent vaccine; Needles; Skin; Transcutaneous delivery; Undercut microneedles; Vaccination; Vaccines
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2019.11.023

The skin is an attractive tissue target for vaccination, as it is readily accessible and contains a dense population of antigen-presenting and immune-accessory cells. Microneedle arrays (MNAs) are emerging as an effective tool for in situ engineering of the cutaneous microenvironment to enable diverse immunization strategies. Here, we present novel dissolving undercut MNAs and demonstrate their application for effective multicomponent cutaneous vaccination. The MNAs are composed of micron-scale needles featuring pyramidal heads supported by undercut stem regions with filleted bases to ensure successful skin penetration and retention during application. Prior efforts to fabricate dissolving undercut microstructures were limited and required complex and lengthy processing and assembly steps. In the current study, we strategically combine three-dimensional (3D) laser lithography, an emerging micro-additive manufacturing method with unique geometric capabilities and nanoscale resolution, and micromolding with favorable materials. This approach enables reproducible production of dissolving MNAs with undercut microneedles that can be tip-loaded with multiple biocargos, such as antigen (ovalbumin) and adjuvant (Poly(I:C)). The resulting MNAs fulfill the geometric (sharp tips and smooth edges) and mechanical-strength requirements for failure-free penetration of human and murine skin to simultaneously deliver multicomponent (antigen plus adjuvant) vaccines to the same cutaneous microenvironment. Cutaneous vaccination of mice using these MNAs induces more potent antigen-specific cellular and humoral immune responses than those elicited by traditional intramuscular injection. Together, the unique geometric features of these undercut MNAs and the associated manufacturing strategy, which is compatible with diverse drugs and biologics, could enable a broad range of non-cutaneous and cutaneous drug delivery applications, including multicomponent vaccination. [Display omitted] •Combines 3D laser lithography with nanoscale resolution and micromolding to manufacture dissolving microneedle arrays (MNAs)•Microneedles with undercut geometries can be directly removed from flexible molds, simplifying their fabrication•First demonstration of dissolving undercut MNAs incorporating antigen plus adjuvant vaccine components•MNAs simultaneously deliver antigen and adjuvant to the same cutaneous microenvironment in both human and murine skin•OVA ± Poly(I:C) MNAs elicit more potent cell