Abstract
Micro-device use for vaccination has grown in the past decade, with the promise of ease-of-use, painless application, stable solid formulations and greater immune response generation. However, the designs of the highly immunogenic devices (e.g. the gene gun, Nanopatch or laser adjuvantation) require significant energy to enter the skin (30–90 mJ). Within this study, we explore a way to more effectively use energy for skin penetration and vaccination. These modifications change the Nanopatch projections from cylindrical/conical shapes with a density of 20,000 per cm2 to flat-shaped protrusions at 8,000 per cm2, whilst maintaining the surface area and volume that is placed within the skin. We show that this design results in more efficient surface crack initiations, allowing the energy to be more efficiently be deployed through the projections into the skin, with a significant overall increase in penetration depth (50%). Furthermore, we measured a significant increase in localized skin cell death (>2 fold), and resultant infiltrate of cells (monocytes and neutrophils). Using a commercial seasonal trivalent human influenza vaccine (Fluvax 2014), our new patch design resulted in an immune response equivalent to intramuscular injection with approximately 1000 fold less dose, while also being a practical device conceptually suited to widespread vaccination.
Highlights
To date, the differences in energy transfer extend to the cell death profiles that have been shown to correlate with immune responses in the skin[11]
We explore a way to overcome this, with a distinct geometry of micro-device conceived to more effectively transfer energy into skin penetration while concurrently opening up further increases in immunogenicity
We commenced this study with our existing reference point: the Nanopatch, an array of microprojections 110 μm long, made from silicon with a density of 20,000 per cm−2 17
Summary
To manufacture patches we used our previously published dry etching method[17]. Delivered dose was measured using a radio-assay described previously[6]. This was performed as described by Crichton et al, at a velocity of 2.3 m/s, to avoid variations from hand application[8]. Solid Edge (Siemens PLM Software, Texas, USA) was used to create models from which surface area and volume could be measured, for given penetration into skin. Nanopatches coated in Fluospheres (Molecular Probes, OR, USA) were applied to either live skin for histology or excised skin for CryoSEM and imaged as described previously[8]. Two unpatched mice were measured during these times to observe any environmental baseline changes in the animals. Viability staining of tissue and quantification of live/dead cells was performed as previously described[11]. The reaction was stopped by the addition of 50 μl of 1 M phosphoric acid and the plates were read spectrophotometrically at 450 nm
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