Space- and time-resolved investigation on diffusion kinetics of human skin following macromolecule delivery by microneedle arrays

Abstract

Microscale medical devices are being developed for targeted skin delivery of vaccines and the extraction of biomarkers, with the potential to revolutionise healthcare in both developing and developed countries. The effective clinical development of these devices is dependent on understanding the macro-molecular diffusion properties of skin. We hypothesised that diffusion varied according to specific skin layers. Using three different molecular weights of rhodamine dextran (RD) (MW of 70, 500 and 2000 kDa) relevant to the vaccine and therapeutic scales, we deposited molecules to a range of depths (0–300 µm) in ex vivo human skin using the Nanopatch device. We observed significant dissipation of RD as diffusion with 70 and 500 kDa within the 30 min timeframe, which varied with MW and skin layer. Using multiphoton microscopy, image analysis and a Fick’s law analysis with 2D cartesian and axisymmetric cylindrical coordinates, we reported experimental trends of epidermal and dermal diffusivity values ranging from 1–8 µm2 s−1 to 1–20 µm2 s−1 respectively, with a significant decrease in the dermal-epidermal junction of 0.7–3 µm2 s−1. In breaching the stratum corneum (SC) and dermal-epidermal junction barriers, we have demonstrated practical application, delivery and targeting of macromolecules to both epidermal and dermal antigen presenting cells, providing a sound knowledge base for future development of skin-targeting clinical technologies in humans.

Cellular metabolism and pore lifetime of human skin following microprojection array mediation

“…Projection penetration depth through the full imaging stack of at least 100 µm was confirmed using the same application procedure, conditions, and skin specimens, reported in a previous study 47 . In brief, patches were coated as per 35 with FluoSpheres fluorescent labelling dye.…”

A low inflammatory, Langerhans cell-targeted microprojection patch to deliver ovalbumin to the epidermis of mouse skin

“…Targeting and activating LCs in the thin epidermis using the common mouse model is notoriously difficult for several reasons. First, the target site is much thinner than its human counterpart (mouse and human viable epidermal thicknesses, are respectively ~ 20 µm and ~50-100 µm) [17]. Second, small therapeutics do not specifically target the viable epidermis and instead often enter systemic circulation, increasing the chance of an inflammatory…”

Topical and Transdermal Drug Delivery: From Simple Potions to Smart Technologies

“…Alternative minimally invasive vaccination methods have been developed with most focus being on the use of microneedles for the delivery of influenza antigens and DNA vaccines [151, 172-174]. A microneedle patch for the delivery of inactivated influenza vaccine has reached the clinical trial stage (Phase I) in humans (NCT02438423), led by Mark Prausnitz’s research team (Georgia Institute of Technology, GA, USA).…”