Breaking the 500-Dalton Rule of Transdermal Drug Delivery by Locally Stretching Skin with Porous Micropost Array
Authors: Tottori Soichiro , Ichinose Sae , Sakai Fumika , Ishikawa Kotaro , Moriyama Natsuho , Wang Gaobo , Nishizawa Matsuhiko 
Published: December 2024

Transdermal drug administration has been attracting attention for its variety of advantages, such as elimination of pain and its minimal invasiveness. However, the efficacy of transdermal drug delivery is limited by the stratum corneum, the outermost layer of the skin. The permeable molecular size through the stratum corneum is known to be roughly below 500 Da, which is known as the 500-Da rule in the area of transdermal drug delivery (1). Various techniques have been explored to enhance transdermal permeation, including, microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound (2). Among them, microneedles, in particular, have been extensively studied and tested for clinical use.
In this work, we discovered that the blunt frustoconical-shaped microneedles or microposts can increase the permeability of skin by locally stretching the stratum corneum without penetration (Figure 1a). Through testing with various molecular sizes, we successfully demonstrated that molecules with a size of approximately up to 10 kDa can be injected. Due to its minimally invasive nature, we propose this as an alternative noninvasive approach to conventional microneedle transdermal drug delivery.
Porous frustoconical microneedle arrays (PMN) were fabricated using methacrylic-based materials with microscopic porous network structures (Figure 1b), based on our group’s protocol (3). Ions and molecules can pass through the network by applying weak electric field to introduce electrophoresis and electroosmosis. Using the developed micropost arrays, we conducted the following experiments. Firstly, we measured the transdermal electrical resistance of a pig skin with the PMN array pressed onto the skin. A non-penetrating frustoconical PMN array was found to reduce the transdermal resistance to a similar level as the sharp PMN array that physically penetrates stratum corneum, indicating that local stretching of the stratum corneum can enhance ion and molecular permeability of the skin even without penetration. Secondly, we applied a weak electric field to the PMN array to induce electroosmotic flow (EOF) inside the porous network and measured the drug permeabilities through pig skin using fluorescent-labeled drug molecules with different molecular sizes (Figure 1c). The amount of the permeated drug was evaluated by enzymatically degrading the skin samples and measuring its fluorescent intensity. We found that drug molecules could permeate only when the skin was stretched with the PMN array and EOF was present simultaneously. The synergy between the extension of the stratum corneum and EOF promotion enables the minimally invasive transdermal drug delivery that is even less invasive than the conventional sharp microneedles. We quantitatively confirmed that at least 10-kDa molecules can permeate through the stratum corneum with our developed frustoconical PMN array.
In summary, we developed a porous micropost array that can locally stretch stratum corneum to enhance chemical and drug transdermal permeability. By measuring the electric resistance and using fluorescent imaging, we confirmed that drug molecules with a size of approximately 10 kDa can be delivered using a porous micropost array without penetrating the stratum corneum. Our approach of using micropost array significantly widens the window of possible drug molecular sizes for transdermal applications.
Figure (a) Frustoconical microposts locally stretch the stratum corneum and increase drug permeability through the skin. Electroosmotic flow pumps out the drug molecules loaded in the porous structure. (b) Fabricated porous micropost array. (c) Fluorescent image of 10-kDa FITC-Dextran molecules permeating through the stratum corneum.
References

Bos JD & Meinardi MMHM (2000) The 500 Dalton rule for the skin penetration of chemical compounds and drugs. Exp Dermatol 9(3):165-169.

Prausnitz MR & Langer R (2008) Transdermal drug delivery. Nat Biotechnol 26(11):1261-1268.

Terutsuki D, Segawa R, Kusama S, Abe H, & Nishizawa M (2023) Frustoconical porous microneedle for electroosmotic transdermal drug delivery. J Control Release 354:694-700.

Figure 1