No abstract

This paper reports for the first time the use of a crosslinked poly(Nisopropylacrylamide) ionogel encapsulating the ionic liquid 1-Ethyl-3-methylimidazolium ethyl sulphate as a thermoresponsive and modular microfluidic valve. The ionogel presents superior actuation behaviour over its equivalent hydrogel.The ionogel swelling and shrinking mechanisms and kinetics are investigated as well as the performance of the ionogel when integrated as a valve in a microfluidic device.The modular microfluidic valve demonstrates fully reversible on-off behaviour without failure for up to eight actuation cycles and a pressure resistance of 1100 mbar.

Direct nose-to-brain (N-to-B) delivery enables the rapid transport of drugs to the brain, while minimizing systemic exposure. The objective of this work was to engineer a nanocarrier intended to enhance N-to-B delivery of RNA and to explore its potential utility for the treatment of neurological disorders. Our approach involved the formation of electrostatically driven nanocomplexes between a hydrophobic derivative of octaarginine (r8), chemically conjugated with lauric acid (C12), and the RNA of interest. Subsequently, these cationic nanocomplexes were enveloped (enveloped nanocomplexes, ENCPs) with different protective polymers, i.e. polyethyleneglycol -polyglutamic acid (PEG-PGA) or hyaluronic acid (HA), intended to enhance their stability and mucodiffusion across the olfactory nasal mucosa. These rationally designed ENCPs were produced in bulk format and also using a microfluidics-based technique. This technique enabled the production of a scalable nanoformulation, exhibiting; (i) a unimodal size distribution with a tunable mean size, (ii) the capacity to highly associate (100%) and protect RNA from degradation, (iii) the ability to preserve its physicochemical properties in biorelevant media and prevent the premature RNA release. Moreover, in vitro cell culture studies showed the capacity of ENCPs to interact and be efficiently taken-up by CHO cells. Finally, in vivo experiments in a mouse model of Alzheimer's disease provided evidence of a statistically significant increase of a potentially therapeutic miRNA mimic in the hippocampus area and its further effect on two mRNA targets, following its intranasal administration. Overall, these findings stress the value of the rational design of nanocarriers towards overcoming the biological barriers associated to N-to-B RNA delivery and reveal their potential value as therapeutic strategies in Alzheimer's disease.

Fluorogenic assays have many potential advantages over traditional clot-based and chromogenic assays such as the absence of interference from a range of factor deficiencies as well as offering the possibility of assays in platelet rich plasma or whole blood. A fluorogenic anti-factor Xa (anti-FXa) assay has been developed for the determination of heparin-like anticoagulants including unfractionated heparin (UFH), low-molecular weight heparins (LMWHs), namely enoxaparin and tinzaparin, and the synthetic heparinoid danaparoid, in commercial human pooled plasma. The assay was based on the complexation of heparinspiked plasmas with exogenous FXa at a concentration of 4 nM in the presence of 0.9 µM of the fluorogenic substrate methylsulfonyl-D-cyclohexylalanyl-glycyl-arginine-7-amino-4-methylcoumarin acetate (Pefafluor FXa). Pooled plasma samples were spiked with concentrations of anticoagulants in the range 0 to 1.6 U/ml. The assay was capable of the measurement of UFH and danaparoid in the range 0-1 U/ml, and enoxaparin and tinzaparin in the range 0-0.8 U/ml and 0-0.6 U/ml, respectively. Assay percentage coefficients of variation were typically below 7 %.3