Dynamic application of microprojection arrays to skin induces circulating protein extravasation for enhanced biomarker capture and detection

Abstract

Surface modified microprojection arrays are a needle-free alternative to capture circulating biomarkers from the skin in vivo for diagnosis. The concentration and turnover of biomarkers in the interstitial fluid, however, may limit the amount of biomarker that can be accessed by microprojection arrays and ultimately their capture efficiency. Here we report that microprojection array insertion induces protein extravasation from blood vessels and increases the concentration of biomarkers in skin, which can synergistically improve biomarker capture. Regions of blood vessels in skin were identified in the upper dermis and subcutaneous tissue by multi-photon microscopy. Insertion of microprojection array designs with varying projection length (40-190 μm), density (5000-20,408 proj.cm(-2)) and array size (4-36 mm(2)) did not affect the degree of extravasation. Furthermore, the location of extravasated protein did not correlate with projection penetration to these highly vascularised regions, suggesting extravasation was not caused by direct puncture of blood vessels. Biomarker extravasation was also induced by dynamic application of flat control surfaces, and varied with the impact velocity, further supporting this conclusion. The extravasated protein distribution correlated well with regions of high mechanical stress generated during insertion, quantified by finite element models. Using this approach to induce extravasation prior to microprojection array-based biomarker capture, anti-influenza IgG was captured within a 2 min application time, demonstrating that extravasation can lead to rapid biomarker sampling and significantly improved microprojection array capture efficiency. These results have broad implications for the development of transdermal devices that deliver to and sample from the skin.

High-density microprojection array delivery to rat skin of low doses of trivalent inactivated poliovirus vaccine elicits potent neutralising antibody responses

“…1e ). This is consistent with previous work 26 , 32 , both reporting greater rates of cell death at the edges of Nanopatch application sites generated by higher stresses 33 . During the course of one week, all observable local skin reactions following Nanopatch application were resolved (Fig.…”

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

“…°C. Consistent coating was confirmed with BS-SEM (Hitachi, SU3500) (SUPP 2).Application of microprojection arrays to skinTo prepare the skin for application, a fold of flank skin was extended and fixed as described in Coffey et al[43]. The skin was not over stretched and was applied to in its natural tension (Figure 1E insert).…”

Microneedle Arrays for Sampling and Sensing Dermal Interstitial Fluid

“…Solid MNs were generally functionalised to serve as bio-electrodes and sometimes to punch the skin [91]. The fabrication techniques that were reported for producing solid MNs are 1) casting [82,[92][93][94][95][96][97][98][99][100][101]; 2) injection moulding [83,[102][103][104][105][106][107], Figure 3A; 3) DRIE [84,[108][109][110], Figure 3B, and 4) wet chemical etchant [85,111], Figure 3C. Solid MNs for ISF sampling were also fabricated using infrared laser [112] and lithographically defined chemical etching [113].…”

“…Researchers created MNs using deep reactive-ion etching (DRIE) technique [84,[108][109][110]. In DRIE, structures with high aspect ratios are produced by applying a highly anisotropic etching process.…”