Significance Needleless delivery into the skin would overcome a major barrier to efficient clinical utilization of advanced therapies such as nanomaterials and macromolecules. This study demonstrates that controlled skin stretching (in porcine, rat, and mouse models) using a patch comprising a hypobaric chamber, to open the skin appendages, can increase the permeability of the tissue and provide a means to enable direct delivery of advanced therapies directly into the skin without the use of a needle or injection system. This technology can facilitate the self-administration of therapeutics including vaccines, RNA, and antigens, thus improving the translation of these products into effective clinical use.

Suction cups with hypobaric pressure are widely adopted in various devices to interact with skin for various medical/therapeutic/ cosmetic purposes, such as Cutometer ® for skin elasticity analysis, drug delivery devices, and suction cups in acupuncture treatment or spa treatment. 1,2 Suction domes with various extent of skin deformation are formed upon application of hypobaric pressure. Amongst all studies, the relationship between the pressure and skin deformation is crucial for safely designing these devices without causing

Objectives To develop a simulation model to explore the interplay between mechanical stretch and diffusion of large molecules into the skin under locally applied hypobaric pressure, a novel penetration enhancement method. Methods Finite element method was used to model the skin mechanical deformation and molecular diffusion processes, with validation against in-vitro transdermal permeation experiments. Simulations and experimental data were used together to investigate the transdermal permeation of large molecules under local hypobaric pressure. Results Mechanical simulations resulted in skin stretching and thinning (20%–26% hair follicle diameter increase, and 21%–27% skin thickness reduction). Concentration of dextrans in the stratum corneum was below detection limit with and without hypobaric pressure. Concentrations in viable epidermis and dermis were not affected by hypobaric pressure (approximately 2 μg $$\bullet$$ ∙ cm−2). Permeation into the receptor fluid was substantially enhanced from below the detection limit at atmospheric pressure to up to 6 μg $$\bullet$$ ∙ cm−2 under hypobaric pressure. The in-silico simulations compared satisfactorily with the experimental results at atmospheric conditions. Under hypobaric pressure, satisfactory comparison was attained when the diffusion coefficients of dextrans in the skin layers were increased from $$\sim$$ ∼ 10 μm2$$\bullet$$ ∙ s−1 to between 200–500 μm2$$\bullet$$ ∙ s−1. Conclusions Application of hypobaric pressure induces skin mechanical stretching and enlarges the hair follicle. This enlargement alone cannot satisfactorily explain the increased transdermal permeation into the receptor fluid under hypobaric pressure. The results from the in-silico simulations suggest that the application of hypobaric pressure increases diffusion in the skin, which leads to improved overall transdermal permeation.