SURVIE DU GREFFON RENAL EN FONCTION DE L'AGE DU DONNEUR (INTERET PRATIQUE LORS DE LA SELECTION DES DONNEURS)

NANCY1-SCD Medecine (545472101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Synthesis of PDMS- b -POEGMA Diblock Copolymers and Their Application for the Thermoresponsive Stabilization of Water-Supercritical Carbon Dioxide Emulsions

International audienceIn this study, PDMS13-b-POEGMAx diblock copolymers consisting of a CO2-philic poly(dimethylsiloxane) (PDMS) block connected to a thermosensitive hydrophilic poly(oligoethylene glycol methacrylate) (POEGMA) block, were synthetized by reversible addition-fragmentation chain-transfer (RAFT) radical polymerization. Their ability to decrease the water-supercritical CO2 (scCO2) interfacial tension (g) and to stabilize water-scCO2 emulsions was investigated using an original home-made device developed in the laboratory. This device is able to control the pressure from 1 to 250 bar and the temperature from 40 to 80°C. It was implemented with 2 visualization windows, a drop tensiometer and a remote optical head for dynamic light scattering (DLS) measurements. These experiments revealed that PDMS-b-POEGMA decreased g down to 1-2 mN/m and was the most efficient at high pressure (250 bar) and low temperature (40°C) where PDMS and POEGMA blocks exhibited the highest affinity for their respective phase. The diblock copolymers were shown to stabilize water-scCO2 emulsions. Moreover, the thermosensitive behavior of the POEGMA block in water (with a lower critical solubility temperature around 65°C) resulted in the formation of temperature-responsive emulsions that could reversibly switch at 100 bar from stable at 40°C to unstable at 80°C. These results were rationalized based on the solubility of each individual block of the copolymers in water and scCO2 as a function of temperature and pressure

Fate of paclitaxel lipid nanocapsules in intestinal mucus in view of their oral delivery

International audienc

How additive manufacturing and microfabrication techniques could be complementary and applied to the development of the Galenic-on-chip concept?

International audienceFor many years, microfluidics has been considered as a technology which allows to transform the way research is performed in the biological and chemical fields1,2. Microfluidic devices have been used in several fields with applications including cell encapsulation3, DNA analysis4, drug development5, cell and droplet sorting and separation6, chemical synthesis1 and separations7, proteomics8 and diagnostictechnologies9, radiopharmaceuticals10 and nanomedicines11 production amongst others. Despite the diversity of these application areas and a growing interest during the last decade, microfluidics largely remains a high technologically advanced area, and especially manufacturing of microfluidic chips, which is expensive and not necessarily ease of access. Indeed, traditional microfluidic manufacturing methods, such as soft lithography and microetching, require skills and equipment that are not widespread in a standard research laboratory of biology, chemistry or pharmaceutics.In this work, we demonstrate the applicability of two common additive manufacturing techniques, namely fused deposition modelling (FDM) and multi-jet modelling (MJM), to prototype customized microfluidic devices such as chips (in Poly Ether Ether Ketone, PEEK) for nanomedicines formulation and holders with connectors and an integrated waterblock system for the chip thermalization (in PEEK and/or acrylic resin). Hence, the prototyping of chips allows to achieve a rational development in terms of costs and designs of Si/Glass chips manufactured by DRIE technology (Deep Reactive Ion Etching). Note that these Si/Glass chips are compatible for in situ physicochemical investigations (microscopy, X-ray and dynamic light scattering techniques). The internal structures (size and shape of channels) of PEEK and Si/Glass chips have been fully characterized by confocal and scanning electronic microscopy, respectively. Lastly, these sets of development contribute to the conception of a home-made microfluidic pilot with customized chips dedicated to (i) the formulation of nanomedicines in Good Laboratory and Manufacturing Practices compliance (possibility to operate in aseptic conditions in a laminar flow isolator) and (ii) the integration of in situ characterization techniques in order to investigate the physicochemical pathways of our formulation processes

How additive manufacturing and microfabrication techniques could be complementary and applied to the development of the Galenic-on-chip concept?

International audienceFor many years, microfluidics has been considered as a technology which allows to transform the way research is performed in the biological and chemical fields1,2. Microfluidic devices have been used in several fields with applications including cell encapsulation3, DNA analysis4, drug development5, cell and droplet sorting and separation6, chemical synthesis1 and separations7, proteomics8 and diagnostictechnologies9, radiopharmaceuticals10 and nanomedicines11 production amongst others. Despite the diversity of these application areas and a growing interest during the last decade, microfluidics largely remains a high technologically advanced area, and especially manufacturing of microfluidic chips, which is expensive and not necessarily ease of access. Indeed, traditional microfluidic manufacturing methods, such as soft lithography and microetching, require skills and equipment that are not widespread in a standard research laboratory of biology, chemistry or pharmaceutics.In this work, we demonstrate the applicability of two common additive manufacturing techniques, namely fused deposition modelling (FDM) and multi-jet modelling (MJM), to prototype customized microfluidic devices such as chips (in Poly Ether Ether Ketone, PEEK) for nanomedicines formulation and holders with connectors and an integrated waterblock system for the chip thermalization (in PEEK and/or acrylic resin). Hence, the prototyping of chips allows to achieve a rational development in terms of costs and designs of Si/Glass chips manufactured by DRIE technology (Deep Reactive Ion Etching). Note that these Si/Glass chips are compatible for in situ physicochemical investigations (microscopy, X-ray and dynamic light scattering techniques). The internal structures (size and shape of channels) of PEEK and Si/Glass chips have been fully characterized by confocal and scanning electronic microscopy, respectively. Lastly, these sets of development contribute to the conception of a home-made microfluidic pilot with customized chips dedicated to (i) the formulation of nanomedicines in Good Laboratory and Manufacturing Practices compliance (possibility to operate in aseptic conditions in a laminar flow isolator) and (ii) the integration of in situ characterization techniques in order to investigate the physicochemical pathways of our formulation processes

How additive manufacturing and microfabrication techniques could be complementary and applied to the development of the Galenic-on-chip concept?

International audienceFor many years, microfluidics has been considered as a technology which allows to transform the way research is performed in the biological and chemical fields1,2. Microfluidic devices have been used in several fields with applications including cell encapsulation3, DNA analysis4, drug development5, cell and droplet sorting and separation6, chemical synthesis1 and separations7, proteomics8 and diagnostictechnologies9, radiopharmaceuticals10 and nanomedicines11 production amongst others. Despite the diversity of these application areas and a growing interest during the last decade, microfluidics largely remains a high technologically advanced area, and especially manufacturing of microfluidic chips, which is expensive and not necessarily ease of access. Indeed, traditional microfluidic manufacturing methods, such as soft lithography and microetching, require skills and equipment that are not widespread in a standard research laboratory of biology, chemistry or pharmaceutics.In this work, we demonstrate the applicability of two common additive manufacturing techniques, namely fused deposition modelling (FDM) and multi-jet modelling (MJM), to prototype customized microfluidic devices such as chips (in Poly Ether Ether Ketone, PEEK) for nanomedicines formulation and holders with connectors and an integrated waterblock system for the chip thermalization (in PEEK and/or acrylic resin). Hence, the prototyping of chips allows to achieve a rational development in terms of costs and designs of Si/Glass chips manufactured by DRIE technology (Deep Reactive Ion Etching). Note that these Si/Glass chips are compatible for in situ physicochemical investigations (microscopy, X-ray and dynamic light scattering techniques). The internal structures (size and shape of channels) of PEEK and Si/Glass chips have been fully characterized by confocal and scanning electronic microscopy, respectively. Lastly, these sets of development contribute to the conception of a home-made microfluidic pilot with customized chips dedicated to (i) the formulation of nanomedicines in Good Laboratory and Manufacturing Practices compliance (possibility to operate in aseptic conditions in a laminar flow isolator) and (ii) the integration of in situ characterization techniques in order to investigate the physicochemical pathways of our formulation processes

Galenic-on-chip concept for development and production of Lipid NanoEmulsions encapsulated Miltefosine for Leishmaniasis treatment

International audienceIntroduction: Continuous production of drug delivery systems (DDS) assisted by microfluidics [1-5] has drawn a growing interest because of the high reproducibility, low batch-to-batch variation of formulations, narrow and controlled particle size distribution and scale-up facilities induced by this process. Besides, microfluidics offers opportunities for high throughput screening of process parameters and the implementation of Process Analytical Technologies (PAT) as close to the product. In this context, we propose to spotlight the GALECHIP concept through the development of an instrumented microfluidic pilot considered as a Galenic Lab-on-Chip to formulate nanomedicines, such as Lipid NanoEmulsions (LNE), under controlled process conditions which are essential to obtain DDS with controlled properties. Therefore, we propose (i) the technological development of microfluidic systems in order to rationally develop the formulation process of LNE, (ii) the in situ Small Angle X-ray Scattering (SAXS) investigations in order to understand the physicochemical mechanisms involved in the formation of LNE, and (iii) the application to the formulation development and sterile production of antiparasitic Miltefosine (MLF) loaded-LNE for Leishmaniasis treatment. Methods: LNE were produced by a phase inversion concentration (PIC) process with own-developed microfluidic pilot and chips. LNE were characterized in terms of structure, size, polydispersity index (PDI), zeta-potential, MLF loading and encapsulation efficiency. In situ SAXS characterizations of LNE were performed at the SOLEIL Synchrotron to study the PIC phenomenology. In vitro hemocompatibility, toxicity on macrophages and efficacy of MLF-LNE have been studied. Results: 3D printed PEEK chips (for production) and Silicon/Glass Chip (for SAXS characterizations) were designed and statistically proven to produce blank LNE from 25 to 100 nm with a polydispersity index below 0.1. Hence, it permitted to show the versatility of the GALECHIP pilot to carry out formulation and fundamental works to better understand and control the LNE characteristics. Then, MLF-LNE were produced aseptically in an isolator and tested in vitro. MLF-LNE had low complement activation properties. MLF-LNE had a four times higher half-maximal inhibitory concentration on macrophages than free MLF and an equivalent efficacy on Leishmania strains with the same dosage. Conclusion: GALECHIP is a microfluidic tool contributing to (i) the pharmaceutical development, (ii) the implementation of PAT for process understanding and (iii) the simulation of aseptic and GMP production of nanomedicines. All of this is done with the ultimate goal of "better understanding" and "better producing" in order to "better administrate" future nano-DDS candidates

Galenic-on-chip concept for development and production of Lipid NanoEmulsions encapsulated Miltefosine for Leishmaniasis treatment

International audienceIntroduction: Continuous production of drug delivery systems (DDS) assisted by microfluidics [1-5] has drawn a growing interest because of the high reproducibility, low batch-to-batch variation of formulations, narrow and controlled particle size distribution and scale-up facilities induced by this process. Besides, microfluidics offers opportunities for high throughput screening of process parameters and the implementation of Process Analytical Technologies (PAT) as close to the product. In this context, we propose to spotlight the GALECHIP concept through the development of an instrumented microfluidic pilot considered as a Galenic Lab-on-Chip to formulate nanomedicines, such as Lipid NanoEmulsions (LNE), under controlled process conditions which are essential to obtain DDS with controlled properties. Therefore, we propose (i) the technological development of microfluidic systems in order to rationally develop the formulation process of LNE, (ii) the in situ Small Angle X-ray Scattering (SAXS) investigations in order to understand the physicochemical mechanisms involved in the formation of LNE, and (iii) the application to the formulation development and sterile production of antiparasitic Miltefosine (MLF) loaded-LNE for Leishmaniasis treatment. Methods: LNE were produced by a phase inversion concentration (PIC) process with own-developed microfluidic pilot and chips. LNE were characterized in terms of structure, size, polydispersity index (PDI), zeta-potential, MLF loading and encapsulation efficiency. In situ SAXS characterizations of LNE were performed at the SOLEIL Synchrotron to study the PIC phenomenology. In vitro hemocompatibility, toxicity on macrophages and efficacy of MLF-LNE have been studied. Results: 3D printed PEEK chips (for production) and Silicon/Glass Chip (for SAXS characterizations) were designed and statistically proven to produce blank LNE from 25 to 100 nm with a polydispersity index below 0.1. Hence, it permitted to show the versatility of the GALECHIP pilot to carry out formulation and fundamental works to better understand and control the LNE characteristics. Then, MLF-LNE were produced aseptically in an isolator and tested in vitro. MLF-LNE had low complement activation properties. MLF-LNE had a four times higher half-maximal inhibitory concentration on macrophages than free MLF and an equivalent efficacy on Leishmania strains with the same dosage. Conclusion: GALECHIP is a microfluidic tool contributing to (i) the pharmaceutical development, (ii) the implementation of PAT for process understanding and (iii) the simulation of aseptic and GMP production of nanomedicines. All of this is done with the ultimate goal of "better understanding" and "better producing" in order to "better administrate" future nano-DDS candidates

Reactive precipitation of vaterite calcium carbonate microspheres in supercritical carbon dioxide-water dispersion by microfluidics

International audienceVaterite, a polymorphic form of precipitated calcium carbonate, is an interesting material for various applications such as formulation of drug delivery systems due to its nanoporous structure. One of the carbonation processes to obtain nanostructured microspheres of vaterite consists in mixing an aqueous calcium phase with a supercritical CO2 phase, resulting in a heterogeneous dispersion. In this study, a continuous microfluidic method has been evaluated to produce monodisperse porous vaterite microparticles. A high-pressure microfluidic set-up has been developed, revealing that the dimensions and the dispersity of the CaCO3 particles are not affected by pressure but can be decreased by increasing the flow rate of the scCO2 and aqueous phases or addition of polymers in the aqueous phase. These observations were shown not to be related to the degree of dispersion of each phase within the microfluidic channel but to the interaction of the polymer with the CaCO3 particles and to the depressurization step at the end of the channel