A Bayesian Implementation of Quality-by-Design for the Development of Cationic Nano-Lipid for siRNA Transfection.

Unlike Quality by Testing approach, where products were tested only after drug manufacturing, Quality by Design (QbD) is a proactive control quality paradigm, which handles risks from the early development steps. In QbD, regression models built from experimental data are used to predict a risk mapping called Design Space in which the developers can identify values of critical input factors leading to acceptable probabilities to meet the efficacy and safety specifications for the expected product. These empirical models are often limited to quantitative responses. Moreover, in practice the smallness and incompleteness of datasets degrade the quality of predictions. In this study, a Bayesian approach including variable selection, parameter estimation and model quality assessment is proposed and assessed using a real case study devoted to the development of a Cationic Nano-Lipid Structures for siRNA Transfection. Two original model structures are also included to describe both binary and percentage response variables. The results confirm the practical relevance and applicability of the Bayesian implementation of the QbD analysis.

Macrophage autophagy protects mice from cerium oxide nanoparticle-induced lung fibrosis.

BACKGROUND: Cerium (Ce) is a rare earth element, rapidly oxidizing to form CeO2, and currently used in numerous commercial applications, especially as nanoparticles (NP). The potential health effects of Ce remain uncertain, but literature indicates the development of rare earth pneumoconiosis accompanied with granuloma formation, interstitial fibrosis and inflammation. The exact underlying mechanisms are not yet completely understood, and we propose that autophagy could be an interesting target to study, particularly in macrophages. Therefore, the objective of our study was to investigate the role of macrophagic autophagy after pulmonary exposure to CeO2 NP in mice. Mice lacking the early autophagy gene Atg5 in their myeloid lineage and their wildtype counterparts were exposed to CeO2 NP by single oropharyngeal administration and sacrificed up to 1 month after. At that time, lung remodeling was thoroughly characterized (inflammatory cells infiltration, expression of fibrotic markers such as αSMA, TGFß1, total and type I and III collagen deposition), as well as macrophage infiltration (quantification and M1/M2 phenotype). RESULTS: Such pulmonary exposure to CeO2 NP induces a progressive and dose-dependent lung fibrosis in the bronchiolar and alveolar walls, together with the activation of autophagy. Blockage of macrophagic autophagy protects from alveolar but not bronchiolar fibrosis, via the modulation of macrophage polarization towards M2 phenotype. CONCLUSION: In conclusion, our findings bring novel insight on the role of macrophagic autophagy in lung fibrogenesis, and add to the current awareness of pulmonary macrophages as important players in the disease.

Enrichment of nanoparticles and bacteria using electroless and manual actuation modes of a bypass nanofluidic device.

Current efforts in nanofluidics aimed at detecting scarce molecules or particles are focused mainly on the development of electrokinetic-based devices. However, these techniques require either integrated or external electrodes, and a potential drop applied across a carrier fluid. One challenge is to develop a new generation of electroless passive devices involving a simple technological process and packaging without embedded electrodes for micro- and nanoparticles enrichment with a view to applications in biology such as the detection of viral agents or cancers biomarkers. This paper presents an innovative technique for particles handling and enrichment based exclusively on a pressure-driven silicon bypass nanofluidic device. The device is fabricated by standard silicon micro-nanofabrication technology. The concentration operation was demonstrated and quantified according to two different actuation modes, which can also be combined to enhance the concentration factor further. The first, "symmetrical" mode involves a symmetric cross-flow effect that concentrates nanoparticles in a very small volume in a very local point of the device. The second mode, "asymmetrical" mode advantageously generates a streaming potential, giving rise to an Electroless Electropreconcentration (EL-EP). The concentration process can be maintained for several hours and concentration factors as high as ~200 have been obtained when both symmetrical and asymmetrical modes are coupled. Proof of concept for concentrating E. coli bacteria by the manual actuation of the EL-EP device is also demonstrated in this paper. Experiments demonstrate more than a 50-fold increase in the concentration of E. coli bacteria in only ~40 s.