Programmable and monitorable intradermal vaccine delivery using ultrasound perforation array.

Skin disruptions of micrometer- or submillimeter-diameter generated by microneedle or laser ablation can be used for intradermal vaccination. Here, we report a new skin-disruption method that uses highly-focused ultrasound to controllably perforate murine skin. We showed that programming of ultrasound parameters varied skin perforation area from 0.078 ± 0.045 mm to 1.295 ± 0.279 mm. The skin perforation area increased with increasing ultrasound pressure and exposure time, and decreased with increasing ultrasound frequency and incidence angle. Moreover, successful perforation can be monitored using ultrasound pulse-echo imaging. We found that ultrasound perforation elevated local skin expression of heat shock protein 70 and effectively attracted MHC II-positive immune cells after intradermal delivery of Hepatitis B surface antigen (HBsAg). We demonstrated that the antigen dose delivered by ultrasound perforation can be effectively modulated via programmable perforation arrays (comprised of 1 × 2, 1 × 3, 1 × 5 or 3 × 3 areas of exposure). Using a 1 × 3 perforation array for vaccination, the measured mean optical density (OD) value of serum anti-HBsAg IgG was slightly higher than that of intradermal injection. The addition of an adjuvant of recombinant cholera toxin B further increased OD values of anti-HBsAg IgG. This ultrasound perforation method holds great promise for monitorable and programmable intradermal vaccination.