La mucoviscidose est une maladie génétique mortelle qui limite ou empêche la production de composés antimicrobiens tels que l’hypothiocyanite (OSCN-) et la lactoferrine. L’objectif de cette étude est de produire un médicament contenant ces deux composés antimicrobiens (10 mL). Cependant l’hypothiocyanite est instable et nécessite une production juste avant administration. Pour cela, une unité de production de médicament portable, destinée à une utilisation par le patient à domicile, est développée avec un appareil réutilisable comprenant le système de pilotage du procédé et une cassette jetable composée par le circuit fluidique et le module membranaire. Le développement du circuit fluidique associé à un module membranaire nécessaire à la purification de l’hypothiocyanite, présent dans le milieu réactionnel, en prenant en compte les contraintes pharmaceutiques, constitue le verrou scientifique et technologique de cette thèse. Au travers de deux géométries membranaires testées, l’étude des paramètres opératoires pour la réalisation de la réaction enzymatique (mécanique des fluides, ultrafiltration, réaction) a permis de mieux appréhender et d’optimiser la production d’hypothiocyanite mais aussi de mettre en évidence les paramètres clés de l’élimination de la glycérine, présente initialement dans les membranes. En parallèle des essais cliniques modifiant les contraintes imposées, l’unité de production et la cassette jetable développées ont permis d’obtenir des résultats proches de ces nouvelles contraintes. / Cystic fibrosis is a fatal genetic disease that limits or prevents antimicrobial compounds such as hypothiocyanite (OSCN-) or lactoferrin. The aim of this study is to produce a drug with those two antimicrobial compounds (10 mL). However hypothiocyanite is unstable and requires production just prior to administration. In order to do so, a portable drug production unit, to be used by the patient at home, is developed. It is made with a reusable device including a control process system and a disposable cassette composed by a fluidic circuit and a membrane module. The scientific and technological challenge of this work is the development of a fluidic circuit incorporating the membrane module for the purification of hypothiocyanite present in a reaction medium while taking into account pharmaceutical constraints. Through two membrane geometries tested, the study of operating parameters to achieve enzymatic reaction (fluid mechanics, ultrafiltration and reaction) allowed to better understand and to optimize the hypothiocyanite production. Furthermore it highlighted the important parameters of the removal of glycerin, initially contained in the membranes. Finally the production unit and the disposable cassette allowed to obtain results close to the specifications. Even though these specifications were redefined and more stringent for clinical trials.

In this thesis, conventional and unconventional technologies have been studied and combined in order to make heterogeneous microfluidics with potential advantages, especially in biological applications. Many conventional materials, like silicon, glass, thermoplastic polymers, polyimide and polydimethylsiloxane (PDMS) have been combined in building heterogeneous microfluidic devices or demonstrators. Aside from these materials, unconventional materials for microfluidics such as stainless steel and the fluoroelastomer Viton have been explored. The advantages of the heterogeneous technologies presented were demonstrated in several examples: (1) For instance, in cell biology, surface properties play an important role. Different functions were achieved by combining microengineering and surface modification. Two examples were made by depositing a Teflon-like film: a) a non-textured surface was made hydrophobic to allow higher pressures for cell migration studies and b) a surface textured by ion track technology was even made super-hydrophobic. (2) In microfluidics, microactuators used for fluid handling are important, e.g. in valves and pumps. Here, microactuators that can handle high-pressures were presented, which may allow miniaturization of high performance bioanalyses that until now have been restricted to larger instruments. (3) In some applications the elastomer PDMS cannot be used due to its high permeability and poor solvent resistivity. Viton can be a good replacement when elasticity is needed, like in the demonstrated paraffin actuated membrane.(4) Sensing of bio-molecules in aquatic solutions has potential in diagnostics on-site. A proof-of-principle demonstration of a potentially highly sensitive biosensor was made by integrating a robust solidly mounted resonator in a PDMS based microfluidic system. It is concluded that heterogeneous technologies are important for microfluidic systems like micro total analysis systems (µTAS) and lab-on-chip (LOC) devices.