Insulation of thin-film parylene-C/platinum probes in saline solution through encapsulation in multilayer ALD ceramic films.

The long-term electrical leakage performance of parylene-C/platinum/parylene-C (Px/Pt/Px) interconnect in saline is evaluated using electrochemical impedance spectroscopy (EIS). Three kinds of additional ceramic encapsulation layers between the metal and Px are characterized: 50 nm-thick alumina (Al2O3), 50 nm-thick titania (TiO2), and 80 nm-thick Al2O3-TiO2 nanolaminate (NL). The Al2O3 and TiO2 encapsulation layers worsen the overall insulation properties. The NL encapsulation layer improves the insulation when combined with a TiO2 outer layer to promote adhesion to the Px. Experiments are performed with various insulation promotion treatments: A-174 silane (A174) treatment before Px deposition (to promote adhesion); SF6 plasma treatment (F) after Px deposition (to increase hydrophobicity); and ion-milling descum (IM) after Px deposition (to prevent parylene oxidation). A174 and F treatments do not have a significant impact, while IM leads to worse insulation performance. A circuit model elucidates the insulation characteristics of Px-ceramic-Pt-ceramic-Px interconnect. These studies provide a foundation for processing ultra-compliant neural probes with long-term chronic utility.

Therapeutic intradermal delivery of tumor necrosis factor-alpha antibodies using tip-loaded dissolvable microneedle arrays.

Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here, we evaluated the use of tip-loaded dissolvable microneedle arrays (MNAs) for localized intradermal delivery of anti-TNF-α Ab. MNAs with obelisk shape microneedles that incorporate the antibody cargo in the needle tips were created from carboxymethylcellulose (CMC) using a micromilling/spin-casting fabrication method. We found that anti-TNF-α Ab integrated into MNAs using this room temperature fabrication process maintained conformationally dependent TNF-α binding activity. Further, these MNAs efficiently delivered anti-TNF-α antibodies to the dermis of human skin with clinically applicable release profiles. To evaluate MNA delivered anti-TNF-α Ab function, we applied anti-TNF-α Ab containing MNAs to established psoriasiform lesions on the skin of mice. MNA anti-TNF-α Ab treatment reduced key biomarkers of psoriasiform inflammation including epidermal thickness and IL-1ß expression. Taken together, these results demonstrate efficient and biologically effective MNA delivery of anti-TNF-α Ab to the intradermal microenvironment of the skin in mice and humans, and support the development of MNA mediated antibody delivery for clinical applications. STATEMENT OF SIGNIFICANCE: Tumor necrosis factor-alpha (TNF-α) specific antibodies (anti-TNF-α Ab) have been shown to be potent TNF inhibitors and effective therapeutics for a range of inflammatory diseases. Typically, these drugs are administered systemically, but systemic dosing sufficient to achieve locally effective concentrations in peripheral tissues has been associated with systemic immunosuppression and related adverse events. Here we demonstrate efficient and biologically effective MNA delivery of anti-TNF-α Ab to the intradermal microenvironment of the skin in mice and humans. These results support the development of MNA mediated antibody delivery of therapeutic antibodies for clinical applications.