FEA-guided co-design of bubble microneedles: controlled tip separation for rapid transdermal and sublingual delivery

Separable bubble microneedles (BMNs) incorporate an internal cavity that enables tip-confined loading and controlled tip-baseplate separation, yet their design has largely relied on empirical iteration. Here, we present a finite element analysis (FEA)-guided co-design framework that co-optimizes BMN geometry, cavity parameters, and matrix properties to enable controlled tip-baseplate separation while preserving insertion robustness. Simulations predicted stress localization at the engineered cavity, thereby reducing the transverse separation force without compromising axial failure load. Using minoxidil sulfate-loaded BMNs (MXS-BMNs) and insulin-loaded BMNs (INS-BMNs) as transdermal and sublingual models, respectively, the measured transverse separation forces were 5.23 N and 4.17 N, compared with FEA predictions of 6.16 N and 4.79 N. The corresponding axial failure loads were 0.13 N and 0.28 N, exceeding reported penetration thresholds for skin and sublingual mucosa. Release studies showed that more than 80% of the payload was liberated within 10 min. In ex vivo Franz diffusion tests, MXS-BMNs achieved approximately sevenfold greater cumulative minoxidil permeation over 24 h than an equivalent-dose topical gel. In vivo, MXS-BMNs accelerated hair regrowth in C57BL/6 mice, and INS-BMNs produced rapid and sustained glucose lowering in diabetic rats comparable to subcutaneous injection via an injection-free mucosal route. Collectively, this work establishes a semi-quantitative screening approach that reduces empirical iteration and expedites the development of separable microneedle systems for rapid transdermal and sublingual delivery.