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.
Highlights
The skin has long been employed as a route for the delivery of bioactive molecules for local and systemic effects, and more recently, a route for the detection of analytes[1], with the particular advantage of avoiding hepatic first-pass metabolism
We have shown that solute diffusion is dependent on molecular weights (MWs) and differs in the individual layers of the skin, which possess distinct mechanical and structural properties for both small solutes[30]; local deep tissue penetration of compounds after dermal application: structure-tissue penetration relationships[30]; molecular size as the main determinant of solute maximum flux across skin31. and, in mice, macromolecules, where diffusion gradually increased as the depth from the skin surface increased[32]
We investigated macromolecule diffusion in all layers of ex vivo human skin through the minimally invasive application microprojection arrays to deposit rhodamine dextran (RD) of various MWs, and imaged the skin using non-invasive multiphoton microscopy (MPM)
Summary
The skin has long been employed as a route for the delivery of bioactive molecules for local and systemic effects, and more recently, a route for the detection of analytes[1], with the particular advantage of avoiding hepatic first-pass metabolism. In the past several decades, there has been considerable interest in the development of nanotechnologies for improved topical and transdermal delivery These include formulation-based nanosystems, such as colloidal nanocarrier systems (nanoemulsions, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs)), flexible nanovesicles: elastic liposomes, transfersomes, ethosomes and niosomes, and microdevices involving microneedle-based technologies[8,9,10,11]. The latter physically and mechanically overcomes the SC to deliver actives directly to the VE and dermis. We have reported significant differences between mice and human skin in small solute permeability[33] and in the stiffness of the skin[34], it is expected the diffusion kinetics of macromolecules in the VE and dermis would vary between the two species
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