Although the dPG-based nanogels turned out to be promising vehicles for dermal drug delivery of labile biomacromolecules, especially in barrier impaired skin, further studies are necessary. Starting with the acid-cleavable nanogels, we succeeded in generating nanogels that offer a quick protein release at a physiologically useful pH. Bioactivity and structural integrity of the protein payload were maintained. Skin penetration experiments need to follow, as these nanogels are not yet characterized for in-vitro or ex-vivo skin delivery. Adequate skin models need to be chosen, as for example ex vivo pig skin may no longer exhibit the physiologically occurring skin pH of 5.5 due to cleaning or freezing steps. The use of reconstructed skin may be preferred. Overall, future work needs to focus on the long-term stability of the nanogels. It is necessary to evaluate the benefits of adding stabilizers to facilitate longer shelf-lives. In aqueous solution, the probability of deterioration and nanogel clustering is high. Therefore, freeze-drying could be a valuable option. To unravel the mode of action of the dPG nanogels, FRET-FLIM as well as FT-IR measurements could be valuable tools.
Although HA hydrogels successfully delivered loaded model proteins into barrier-disrupted skin, further studies need to be performed to close the gap in understanding the mode of action of HA in the SC and the upper skin, focusing especially on the penetration retardation in barrier–impaired skin. As an addition, mixtures of 5kDa and 100 kDa could be investigated to combine all skin barrier altering effects for a potential increase in delivery efficiency.
Finally, the effectiveness of HA hydrogels as dermal protein delivery vehicles in skin disease adapted skin models with therapeutically relevant proteins should be tested.
MN arrays are very versatile devices for localized and systemically delivery of low and high molecular weight drugs. The coating formulations developed in this thesis provided promising
106 storage stability and quick release of the loaded proteins after insertion in the skin. However, the coating technique and the resulting applied protein concentration should be further improved to yield even and more reproducible delivery of higher protein payloads.
Subsequently, as proof of concept these proteins coated MN arrays need to be applied to diseased skin models to study whether the skin barrier at the insertion site or in the whole model is restored. When the distribution of the dissolved coating and thus the proteins is insufficient, a switch to dermal rollers for narrow and repeated skin piercing might be an option.
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