Antoine Venault

Bacterial Resistance Control on Mineral Surfaces of Hydroxyapatite and Human Teeth via Surface Charge-Driven Antifouling Coatings

This works reports a set of new functionalized polyethyleneimine (PEI) polymers, including a neutral PEGylated polymer PEI-g-PEGMA, a negatively charged polymer PEI-g-SA, and a zwitterionic polymer PEI-g-SBMA, and their use as antibiofouling coating agent for human teeth protection. Polymers were synthesized by Michael addition, XPS analysis revealed that each polymer could be efficiently coated onto hydroxyapatite, ceramic material used as a model tooth. Polymers carrying a negative net charge were more efficiently adsorbed, because of the establishment of electrostatic interactions with calcium ions. Protein adsorption tests revealed that two factors were important in the reduction of protein adsorption. Both the surface charge and the surface ability to bind and entrap water molecules had to be considered. PEI-g-SBMA, which zeta potential in PBS solution was negative, was efficient to inhibit the adsorption of BSA, a negative protein. On the other hand, it also resisted the adsorption of lysozyme, a positive protein, because zwitterionic molecules can easily entrap water and provide a very hydrophilic environment. Streptococcus mutans attachment tests performed unveiled that all modified polymers were efficient to resist this type of bacteria responsible for dental carries. Best results were also obtained with PEI-g-SBMA coating. This polymer was also shown to efficiently resist the adsorption of positively charged bacteria (Stenotrophomonas maltophilia). Tests performed on real human tooth showed that PEI-g-SBMA could inhibit up to 70% of bacteria adhesion, which constitutes a major result considering that surface of teeth is very rough, therefore physically promoting the attachment of proteins and bacteria.

Introducing Mixed-Charge Copolymers As Wound Dressing Biomaterials

Herein, a pseudozwitterionic structure bearing moieties with mixed positive and negative charges is introduced to develop a potential biomaterial for wound dressing applications. New mixed-charge matrices were prepared by copolymerization of the negatively charged 3-sulfopropyl methacrylate (SA) and positively charged [2-(methacryloyloxy)ethyl] trimethylammonium (TMA) onto expanded polytetrafluoroethylene (ePTFE) membranes. The charge balance was effectively regulated through the control of the initial SA/TMA ratio. The focus was then laid on the assessment of a variety of essential properties of efficient wound dressings including, hydration property, resistance to fibrinogen adsorption, hemocompatibility, as well as resistance to fibroblast attachment and bacteria colonization. It was found that the pseudozwitterionic membranes, compared to those with charge bias in the poly(SA-co-TMA) structure, exhibited the best combination of major properties. Therefore, they were further tested for wound healing. Histological examination of mouse wound treated with the pseudozwitterionic membranes exhibited complete re-epithelialization and total formation of new connective tissues after 14 days, even leading to faster healing than using commercial dressing. Results presented in this work suggest that the mixed-charge copolymers with a perfect balance of positive and negative moieties represent the newest generation of biomaterials for wound dressings.

Bacterial resistance of self-assembled surfaces using PPOm-b-PSBMAn zwitterionic copolymer - concomitant effects of surface topography and surface chemistry on attachment of live bacteria.

Three well-defined diblock copolymers made of poly(sulfobetaine methacrylate) (poly(SBMA)) and poly(propylene oxide) (PPO) groups were synthesized by atom transfer radical polymerization (ATRP) method. They were physically adsorbed onto three types of surfaces having different topography, including smooth flat surface, convex surface, and indented surface. Chemical state of surfaces was characterized by XPS while the various topographies were examined by SEM and AFM. Hydrophilicity of surfaces was dependent on both the surface chemistry and the surface topography, suggesting that orientation of copolymer brushes can be tuned in the design of surfaces aimed at resisting bacterial attachment. Escherichia coli, Staphylococcus epidermidis, Streptococcus mutans and Escherichia coli with green fluorescent protein (E. coli GFP) were used in bacterial tests to assess the resistance to bacterial attachment of poly(SBMA)-covered surfaces. Results highlighted a drastic improvement of resistance to bacterial adhesion with the increasing of poly(SBMA) to PPO ratio, as well as an important effect of surface topography. The chemical effect was directly related to the length of the hydrophilic moieties. When longer, more water could be entrapped, leading to improved anti-bacterial properties. The physical effect impacted on the orientation of the copolymer brushes, as well as on the surface contact area available. Convex surfaces as well as indented surfaces wafer presented the best resistance to bacterial adhesion. Indeed, bacterial attachment was more importantly reduced on these surfaces compared with smooth surfaces. It was explained by the non-orthogonal orientation of copolymer brushes, resulting in a more efficient surface coverage of zwitterionic molecules. This work suggests that not only the control of surface chemistry is essential in the preparation of surfaces resisting bacterial attachment, but also the control of surface topography and orientation of antifouling moieties.

A Review on Polymeric Membranes and Hydrogels Prepared by Vapor-Induced Phase Separation Process

In 1918, Zsigmondy and Bachmann presented a new method to induce phase separation of a homogeneous polymeric solution from a vapor phase. The so-called vapor-induced phase separation (VIPS) was born. In a century, the body of knowledge on polymer membranes and hydrogels prepared by VIPS has grown importantly, which suggests the need for a critical review. Slowness of mass transfers involved in VIPS, attributed to the resistance at the gaseous phase/liquid phase interface, permits reaching better control of polymer membrane formation than with the popular wet-immersion process. As a result, a broad variety of morphologies can be obtained and well controlled. The control of testing conditions and formulation parameters also permits tuning and tailoring morphologies, which arises in various membranes properties, and led scientists to investigate the possibility of forecasting mass transfers in VIPS. Therefore, at the end of the twentieth century, first models were developed to describe this process, and validated by comparing simulated data to experimental results. Afterwards, studies demonstrated the possibility of predicting membrane morphologies from the knowledge of operating conditions. This article aims at reviewing the work done so far reporting this process to prepare polymer membranes and hydrogels. The experimental set-ups will be introduced as well as the different polymer/solvent/nonsolvent and polymer/additive(s)/solvent/nonsolvent systems used and the morphologies obtained. The effect of testing conditions and formulation parameters on the structure of the matrices will be subsequently discussed. Close attention will be given to the fundamental theory of VIPS before moving onto the potential applications of such polymer matrices.

Zwitterionic Modifications for Enhancing the Antifouling Properties of Poly(vinylidene fluoride) Membranes

The development of effective antibiofouling membranes is critical for many scientific interests and industrial applications. However, the existing available membranes often suffer from the lack of efficient, stable, and scalable antifouling modification strategy. Herein, we designed, synthesized, and characterized alternate copolymers of p(MAO-DMEA) (obtained by reaction between poly(maleic anhydride-alt-1-octadecene) and N,N-dimethylenediamine) and p(MAO-DMPA) (obtained by reaction between poly(maleic anhydride-alt-1-octadecene) and 3-(dimethylamino)-1-propylamine) of different carbon space length (CSL) using a ring-opening zwitterionization. We coated these copolymers on poly(vinylidene fluoride) (PVDF) membranes using a self-assembled anchoring method. Two important design parameters-the CSL of polymers and the coating density of polymers on membrane-were extensively examined for their effects on the antifouling performance of the modified membranes using a series of protein, cell, and bacterial assays. Both zwitterionic-modified membranes with different coating densities showed improved membrane hydrophilicity, increased resistance to protein, bacteria, blood cells, and platelet adsorption. However, while p(MAO-DMEA) with two CSLs and p(MAO-DMPA) with three CSLs only differ by one single carbon between the amino and ammonium groups, such subtle structural difference between the two polymers led to the fact that the membranes self-assembled with MAO-DMEA outperformed those modified with MAO-DMPA in all aspects of surface hydration, protein and bacteria resistance, and blood biocompatibility. This work provides an important structural-based design principle: a subtle change in the CSL of polymers affects the surface and antifouling properties of the membranes. It can help to achieve the design of more effective antifouling membranes for blood contacting applications.

Stimuli-responsive and hemocompatible pseudozwitterionic interfaces.

We report a novel biomacromolecular formula for the design of hemocompatible gel interfaces of N-isopropylacrylamide (NIPAAm) and mixed-charge pairs of [2-(methacryloyloxy)ethyl]trimethylammonium (TMA) and 3-sulfopropyl methacrylate (SA) with overall electrical neutrality. The study stresses on how well-defined compositions of nonionic NIPAAm and pseudozwitterionic TMA/SA in the poly(NIPAAm-co-TMA/SA) hydrogels along with environmental conditions (temperature, ionic strength, and solution pH) affect swelling and adhesion of biofoulants on their surfaces. When challenged with plasma proteins, bacteria, recalcified platelets, or whole blood, stimuli-responsive hydrogels better resisted their adhesion as the content of mixed charges in the copolymer increased, to reach nonbiofouling for the gels made of 100% TMA/SA. The low hemolytic activity (0.5%) associated with a long plasma clotting time (10 min) suggests excellent hemocompatibility excellent hemocompatibility. Finally, hydrogels containing both NIPAAm and TMA/SA tend to exhibit preferential adhesion of leukocytes.

A Zwitterionic-Shielded Carrier with pH-Modulated Reversible Self-Assembly for Gene Transfection

Cationic vectors are ideal candidates for gene delivery thanks to their capability to carry large gene inserts and their scalable production. However, their cationic density gives rise to high cytotoxicity. We present the proper designed core-shell polyplexes made of either poly(ethylene imine) (PEI) or poly(2-dimethylamino ethyl methacrylate) (PDMAEMA) as the core and zwitterionic poly(acrylic acid)-block-poly(sulfobetaine methacrylate) (PAA-b-PSBMA) diblock copolymer as the shell. Gel retardation and ethidium bromide displacement assays were used to determine the PEI/DNA or PDMAEMA/DNA complexation. At neutral pH, the copolymer serves as a protective shell of the complex. As PSBMA is a nonfouling block, the shell reduced the cytotoxicity and enhanced the hemocompatibility (lower hemolysis activity, longer plasma clotting time) of the gene carriers. PAA segments in the copolymer impart pH sensitivity by allowing deshielding of the core in acidic solution. Therefore, the transfection efficiency of polyplexes at pH 6.5 was better than at pH 7.0, from β-galactosidase assay, and for all PAA-b-PSBMA tested. These results were supported by more favorable physicochemical properties in acidic solution (zeta potential, particle size, and interactions between the polymer and DNA). Thus, the results of this study offer a potential route to the development of efficient and nontoxic pH-sensitive gene carriers.

Hemocompatible biomaterials of zwitterionic sulfobetaine hydrogels regulated with pH-responsive DMAEMA random sequences

ABSTRACT Polyzwitterionic biomaterial with pH-responsive and hemocompatible dual functions is formulated by the copolymerization of 2-(N, N-dimethyl amino) ethyl methacrylate (DMAEMA) sequences and sulfobetaine methacrylate (SBMA) moieties. Hydrogels are salt responsive, due to the interplay between hydrogen bonds formation, ions solvation, and antipolyelectrolyte effect, while DMAEMA sequences provide pH-responsiveness. Their low-fouling nature is demonstrated using plasma proteins and bacteria. Improved hemocompatibility with SBMA content is unveiled by the resistance to platelet and erythrocyte attachment, as well as from delayed plasma clotting time. Overall, this study suggests that dual-functional zwitterionic hydrogels are promising pH-responsive and hemocompatible polymeric biomaterials. GRAPHICAL ABSTRACT

Surface charge-bias impact of amine-contained pseudozwitterionic biointerfaces on the human blood compatibility

This work discusses the impact of the charge bias and the hydrophilicity on the human blood compatibility of pseudozwitterionic biomaterial gels. Four series of hydrogels were prepared, all containing negatively-charged 3-sulfopropyl methacrylate (SA), and either acrylamide, N-isopropylacrylamide, 2-dimethylaminoethyl methacrylate (DMAEMA) or [2-(methacryloyloxy)ethyl]trimethylammonium (TMA), to form SnAm, SnNm, SnDm or SnTm hydrogels, respectively. An XPS analysis proved that the polymerization was well controlled from the initial monomer ratios. All gels present high surface hydrophilicity, but varying bulk hydration, depending on the nature/content of the comonomer, and on the immersion medium. The most negative interfaces (pure SA, S7A3, S5A5) showed significant fibrinogen adsorption, ascribed to the interactions of the αC domains of the protein with the gels, then correlated to considerable platelet adhesion; but low leukocyte/erythrocyte attachments were measured. Positive gels (excess of DMAEMA or TMA) are not hemocompatible. They mediate protein adsorption and the adhesion of human blood cells, through electrostatic attractive interactions. The neutral interfaces (zeta potential between -10mV and +10mV) are blood-inert only if they present a high surface and bulk hydrophilicity. Overall, this study presents a map of the hemocompatible behavior of hydrogels as a function of their surface charge-bias, essential to the design of blood-contacting devices.

Zwitterionic fibrous polypropylene assembled with amphiphatic carboxybetaine copolymers for hemocompatible blood filtration.

UNLABELLED The present study serves three main functions. First, it presents a novel random copolymer, made of octadecyl acrylate hydrophobic blocks and 2-(dimethylamino)ethyl methacrylate hydrophilic groups, and it zwitterionic form. Second, random copolymer and zwitterionic random copolymer, OmDn and Z-OmDn, are used to modify polypropylene membranes by evaporation coating. Our investigations unveil that this method leads to sufficiently stable self-assembling provided a minimum number of hydrophobic repeat units of 77, which also corresponds to a hydrophobic degree of 74%. Third, antifouling and hemocompatible properties of membranes are thoroughly investigated using all types of blood cells separately, as well as challenging membranes against whole blood in static and dynamic conditions. Membranes modified with zwitterionic copolymer containing 26% of zwitterionic groups are shown to be highly antifouling and hemocompatible, for a coating density as low as 0.2mg/cm(2). Their application in a specially designed blood filtration module enabled to almost totally inhibit blood cells interactions with membrane material, as well as to importantly reduce platelet activation in the permeate (2.5-fold reduction). STATEMENT OF SIGNIFICANCE The design of new zwitterionic copolymer material is proposed and demonstrated in this study. It was showed that hydrophobicoctadecyl acrylate segments can be introduced in the zwitterioniccarboxybetaine polymer chain with a well-controlled random sequence. Stable, efficient, and effective surface zwitterionization of hydrophobic polypropylene are obtained via grafting onto approach by evaporation-induced self-assembling coating. In the perspective of potential application, hemocompatible blood filtration was demonstrated with the excellent results of non-activated platelets obtained. SUMMARY OF IMPACTS DESIGN New zwitterionicmaterial, amphiphatic carboxybetaine copolymers. DEVELOPMENT Evaporation-induced self-assembling grafting. APPLICATION Hemocompatible blood filtration.