Designs of Zwitterionic Interfaces and Membranes - Langmuir (ACS

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Biological and Environmental Phenomena at the Interface

Designs of Zwitterionic Interfaces and Membranes Antoine Venault, and Yung Chang Langmuir, Just Accepted Manuscript • DOI: 10.1021/acs.langmuir.8b00562 • Publication Date (Web): 13 Jul 2018 Downloaded from http://pubs.acs.org on July 15, 2018

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- Invited Feature Article -

Designs of Zwitterionic Interfaces and Membranes Antoine Venault, Yung Chang* Department of Chemical Engineering and R&D Center for Membrane Technology, Chung Yuan Christian University, Chungli District, Taoyuan 320, Taiwan, R.O.C.

ABSTRACT Zwitterionic materials are the latest generation of materials for nonfouling interfaces and membranes. They outperform poly(ethylene glycol)-derivatives because they form tighter bonds with water molecules and can trap more water molecules. This feature article summarizes our laboratory’s fundamental developments related to the functionalization of interfaces and membranes using zwitterionic materials. Our molecular designs of zwitterionic polymers and copolymers, sulfobetaine-based, carboxybetaine-based or phosphobetainebased are first reviewed. Then, the strategies to functionalize surfaces/membranes by coating, grafting onto, grafting from or in-situ modification are examined and discussed, while the third part of this article lays the focuss on key applications of zwitterionized materials. Last, some potential future directions on molecular designs, functionalization processes and applications are presented. KEYWORDS Zwitterionic copolymer; antifouling interfaces; antifouling membranes; molecular designs INTRODUCTION Since nonfouling became an important research focus in materials-related engineering fields, three generations of antifouling materials have been successively developed and evolved. The first one is constituted of 2-hydroxyethyl methacrylate (HEMA) and of its derivatives. The abundance of hydroxyl functional groups facilitates hydrogen bonding with water, hence the formation of a protective hydration layer repelling biofoulants.1 However, 1 ACS Paragon Plus Environment

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studies tended to show that HEMA materials did not provide an optimal protection against biofouling materials in complex media and that polyHEMA cast film actually exibited rather poor biocompatibility.2,3 Therefore, HEMA-materials have been slowly replaced and further efforts were put in the development of other materials that could exhibit better nonfouling performance regardless of the composition of the medium. These efforts led to the design of poly(ethylene glycol) (PEG) and polymeric derivatives, which became very successful from the early 90’s, and continue to attract siginificant attraction, for both the surface-modification and in-situ modification of materials.4-25 The downside of PEG-derivatives, however, is that the ethylene glycol groups tend to decompose in contact with transition metals and oxygen, questioning the stability of the modification.25,26 Zwitterionic materials and pseudozwitterionic materials, which do not face this issue, have then been developed and introduced as the third generation of antifouling materials. They have been extensively studied worldwide over the past 20 years and are probably today the preferred choice for providing a surface with nonfouling property.27-54 Zwitterionic materials fit in the requirements earlier defined by Whitesides for nonfouling applications.55 But unlike with PEG, the protective hydration layer formed at an interface modified with zwitterions arises from ionic interactions, making it tight and stable. In addition, low-field nuclear magnetic resonance tests proved that much more water molecules surrounded zwitterionic units than PEG units.56 This improved hydration property combined to a better stability explain why zwitterionic modifications tend to be preferred. Some groups such as those of Professor Jiang or Professor Ishihara mostly focuss on the moelcular designs for the zwitterionization of dense interfaces or for the preparation of zwitterionic hydrogels,27-29, 32, 33, 36, 37, 48, 49 while others spend most of their efforts on the modification of membranes like those of Professor Matsuyama, Profesor Gao and Professor Jiang.22, 38, 43, 46, 50, 52 On our side, we have extensively worked on molecular designs to modify versatile interfaces including model dense surfaces, gels (soft membranes) and membranes for diverses applications among with the design of (i) general biofouling resistant interfaces for water treatment, (ii) wound-dressings, (iii) membranes for blood filtration and blood cell selection, (iv) coatings for dental protection and (iv) coatings for biomedical devices. The present feature article aims at summarizing these works by first laying the focuss on the different zwitterionic molecular designs that we have worked on to contribute to the exploration of the oustanding antifouling properties of zwitterionic molecules. In a second part, we will scrutinize the nature and type of material architecture that we modified using zwitterionic polymers, as well as we will examine the functionalization processes 2 ACS Paragon Plus Environment

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permiting to fix the zwitterionic polymers at the surface or within the bulk of these materials. In particular, we highlight that if surface zwitterionization of membranes is well-established, some recent studies explore their bulk functionalization while others address the solubility issues of zwitterionic copolymers by simultaneously synthesizing and self-assembling the copolymer on membranes. Thirdly, we will review the spectrum of applications that we have exlusively targeted over these past 12 years. Finally, we will end this article with personal throughts and opinions on current challenges to take on in the field of zwitterionic materials, and on where more efforts should be put in to take full advantage of poly(zwitterionic) materials and further extend their range of uses. ZWITTERIONIC MOLECULAR DESIGNS Derivatives of Sulfobetaine. The major classes of zwitterionic materials for nonfouling have been presented and reviewed elsewhere.57 In our laboratory, we have mainly investigated derivatives of sulfobetaine because the polymers and copolymers of sulfoebtaine are relatively easy to synthesize and provide high yields, compared to other zwitterionic materials. However, we also put efforts in the design and application of carboxybetaine and phosphobetaine copolymers. The different structures that we synthesized, possessing sulfobetaine units or derivatives, are gathered in Figure 1 while magnified images of the related chemical structures are also displayed in the supporting information section (Figures S1, S2 and S3). In addition to contributing to studies on the grafting of poly(sulfobetaine) (or poly(N-(3-sulfopropyl)-N-(methacryloxyethyl)-N,N-dimethylammonium betaine, PSBMA) or crosslinked PBSMA on surfaces and membranes,58-61 or to investigations on the biocompatibility of PSBMA in solution,62 we worked on a number of copolymers for which the nature of the second or third kind of repeat unit was chosen based on either the type of surface modification process that we would use or on the property that we wanted to control. More precisely, numerous designs involved the use of anchoring units which are necessary to the binding of the copolymer to a surface in processes such as coating or grafting onto. Typical anchoring units are butyl methacrylate,63 styrene64 or propylene oxide,65 which can establish hydrophobic interactions with hydrophobic surface, or glycid methacrylate, which base-catalyzed ring opening can covalently bond the copolymer.66,67 In other cases, we incorporated functional groups other than anchoring units, such as N-isopropylacrylamide (NIPAAm)68-70 or 2-dimethylaminoethyl methacrylate (DMAEMA).71 The rationale for the use of stimuli-responsive poly(NIPAAm) and poly(DMAEMA) in the molecular design 3 ACS Paragon Plus Environment

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rested on the possibility of controlling the swelling of the copolymer network by adjusting the temperature and the ionic strength, or the pH and the ionic strength, respectively. Besides, it is also worth mentioning the synthesis of copolymers of acrylic acid and PSBMA, used in polyplexes with PDMAEMA in gene delivery application.72 While PAA interacted with PDMAEMA, forming a core surrounding DNA, PSBMA formed the outter shell of the polyplexe and permitted to decrease its cytotoxicity. Indeed, if cationic vectors are ideal for gene delivery, they also display a significant level of cytotoxicity, which can be reduced by adding a zwitterionic protective shell.

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PSBMA Grafted from versatile surfaces

PSA-co-PSBMA Coated by ion-pair self-assembling

PPO-co-PSBMA Grafted onto dense surfaces

PGMA-co-PSBMA Grafted onto versatile surfaces

Interfaces

PS-co-PEGMA-co-PSBMA In-situ modification of membranes

PVP-co-PSBMA Hydrogel/network coated on metal

Hydrogels

Membranes

PS-co-PSBMA Combined synthesis and selfassembling on membranes

PDMAEMA-co-PSBMA Hydrogel network

PNIPAAm-co-PSBMA Hydrogel network

PBMA-co-PSBAA Coated on membranes

PSBMA and derivatives of PSBMA for surface/membrane modification and hydrogel networks Figure 1. Molecular structure of the major sulfobetaine-based copolymers synthesized in Professor Chang’s group.

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Derivatives of Carboxybetaine. Zwitterionic polymers derived from carboxybetaine are also widely employed antifouling materials. However, their synthesis is somewhat trickier than that of sulfobetaine derivatives which are overall easier to produce. In our group, we mainly exploited the antifouling ability of carboxybetaine-derivatives in the design of porous membranes, for nanofiltration73 and microfiltration74-77. Most of these membranes were prepared by a coating procedure, which justified the use of hydrophobic anchoring segments in the copolymer. One segment that was shown to be readily polymerizable and that interacted fairly well through its long akyl chain with hydrophobic polymers such as polypropylene (PP) or poly(vinylidene fluoride) (PVDF) was octadecyl acrylate.75-78 Besides, we studied the effect of the carbon space length (CSL) between the positively charge moieties and the negatively charge moieties of carboxybetaine-derivatives on the antifouling properties of PVDF membranes.74 Our experimental results showed that a subtle increase of this structural factor could deteriorate the nonfouling properties of the coated membranes. It supported molecular simulation studies carried out a few years before by Mi et al. who showed that the CSL influenced the charge distribution, eventually resulting in different levels of hydration, that is, in different antifouling abilities.79 Besides, we worked in collaboration with Professor Jiang’s group on the design of carboxybetaine-based hydrogels, spin-coated on model smooth surfaces including gold and silicon dioxide, that not only exhibited ultra-lowfouling but also were capable in the same time of antibody functionalization which did not alter their nonfouling property.78 Derivatives of Phosphobetaine. As for phosphobetaine-derivatives, they mimic the biological cell membranes and are, in this respect, choice materials for making biocompatible and hemocomaptible surfaces. Their preparation, however, remains expensive, which limits their synthesis at large scales. Professor Ishihara proposed a synthesis for

2-

methacryloyloxyethyl phosphorylcholine (MPC) polymer almost 30 years ago,80, 81 which then opened extraordinary perpsectives in the field of in-vivo biomedical implants. In our group and in collaboration with Professor Ishihara, we investigated the coating of PP membranes using a copolymer of n-butyl methacrylate and MPC,63 as well as we in-situ modified PVDF membranes with

a copolymer of MPC and methacryloyloxyethyl

butylurethane.82 In all case, excellent resistance of the functionalized membranes to plasma protein and blood cells adhesion were obtained, consistent with the hemocompatible nature of phosphobetaine-derivatives.

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Pseudo-zwittterionic Molecular Designs. Introduced for the first time by Professor Jiang’s group,83-85 the mixed-charge copolymers are formed from at least two different units, one positively charged and the other negatively charged, which eventually mimic zwitterionic copolymers as the resulting net charge of the copolymer is zero. Professor Jiang’s group demonstrated the excellent resistance to nonspecific protein adsorption of these mixed-charge units. Then we extended the research to the hemocompatibility of these systems in solutions,86 or on model interfaces by grafting on gold surfaces

copolymers made of

positively charge [2-(methacryloyloxy)ethyl] trimethylammonium

(TMA) units and

negatively charge 3-sulfopropyl methacrylate (SA) units.87 In particular, the nonthrombogenicity of poly(TMA-co-SA) copolymer brushes was demonstrated provided an homogeneous charge distribution, that is, no positive nor negative charge bias. Likewise, the excellent general antifouling properties and hemocompatibility of mixed-charge copolymers grafted on highly porous membranes, which included poly(tetrafluoroethylene) (PTFE)88 or PVDF89 membranes, was also proven. It is also worth mentioning the design of softmembranes (or gels) made of mixed-charge pairs of TMA and SA, and copolymerized with stimuli-responsive NIPAAm90 that were shown to exhibit low fouling, selective fouling or no fouling by blood components, depending on their composition (molar ratio between stimuliresponsive and mixed-charge units). Similarly, SA was copolymerized with an excess of DMAEMA to obtain neutral hydrogels that also showed improved biocompatibility.91 Besides, an attempt to quaternize DMAEMA was also presented, in order to form positively charged

moieties

which

would

balance

the

negative

charges

brought

by

3-

sulfopropylmethacrylate (SPMA) units.92 This design can also be classified in the pseudozwitterionic materials as the polymer was formed of distinctive negatively charged and positively charged moieties. MATERIAL DESIGNS AND FUNCTIONALIZATION PROCESSES Zwitterionic Materials Designs. Given the boundless spectrum of applications of zwitterionic materials, we have studied the surface modification of interfaces such as gold,58, 78

titanium,66, 67, 93 steel,66, 67, 93 silicon,66 or tissue culture polystyrene plate,66 rather smooth

and dense as well as we used these materials to provide antifouling property to porous and rough polymeric membranes,75-77, 82 and ceramic such as hydroxyapatite.94 We are mostly targeting biomedical and wastewater-treatment related applications, which justifies the choice of these materials. For example, titanium or steel metals are common metals in hospitals for 7 ACS Paragon Plus Environment

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surgical tools or implants, hydroxyapatite ceramic simulates teeth, and PP or PVDF polymers are common materials for designing blood filtration or wastewater treatment membranes. In addition to the typical metal-polymer-ceramic classification, Figure 2 intends to group these attempts by gathering model interfaces (dense) and porous/rough materials.

DENSE MATERIALS

Au Ag Ti Fe-C alloy (steel)

METAL

POLYMER

POROUS MATERIALS

PDMS

PS

PP

PTFE

PP

PTFE

PHB

PU

CERAMIC

PVDF

Ca5(PO4)3(OH) (Hydroxyapatite) Al2O3

Glass

Figure 2. Summary of the different classes of dense and porous materials that we modified with zwitterionic polymers and copolymers.

There are 3 majors classes of modification processes, 2 of them are exclusively surface modifications: grafting (from or onto) and coating, while the third one is a bulk modification, that we will refer to as in-situ modification process (Figure 3). Owing to solubility/compatibility issues, we have mostly investigated surface functionalization, i.e. grafting and coating. However, we have also proposed some effective designs for in-situ zwitterionic modifications of membranes. The next sections provide further details on these zwitterionic functionalization processes.

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+ +

+-

+

Zwitterionic units

+

+

+

++

Zwitterionic units

+

Anchoring segment

Anchoring segment

Hydrophobic interaction

Covalent bonding In-situ modification

+ +

+

++ +

+ +

++

+ + - ++ + +

+

+

++

++ + +

+ +

+

+

Functionalization processes

+

+

Coating

+

+- +

+-

+ + + + -+ + - + + - + + ++ + + + + ++ + + + + + + + + +

+-

+-

+

+

Grafting

Figure 3. Summary of the three major classes of functionalization processes. In grafting, covalent bonding is at play while in coating and in-situ modification, stability is ensured by hydrophobic interactions. An anchoring polymer unit is also represented on the grafting pictogram, essential to grafting “onto” (use of copolymers) but that can be absent in grafting “from” (use of polymers).

Surface Functionalization by Grafting Processes. Grafting processes involve the formation of covalent bonds between the surface to modify and the zwitterionic copolymer. These strong interactions are expected to lead to high stability by preventing leaching of the copolymer during operation. In addition, the copolymer can either be synthesized before the grafting process and then anchored to the surface, or it can be formed while the grafting process is occurring. This is how grafting onto and grafting from are distinguished. Additionnally and regardless of the type of grafting process, the quality of the grafting and so, the ability of the molecular design to perform nonfouling, will not only depend on the materials chemistry, but also on the grafting coverage. Starting with grafting from, we have widely used surface initiated-atom transfer radical polymerization (SI-ATRP),58, 60, 95, 96 for controlling the composition and architecture of the polymer formed at the surface of interest, as well as their homogeneous growth from the surface. An advantage of this process is it applicability to a large variety of monomers, which is particularly useful when different types of functional groups need to be incorporated in a control fashion in the polymer design. We have successfully tested this process to the surface-

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modification of uniform SPR sensor chips,95 titanium surfaces,96 or to porous PVDF membranes.60 Other than using SI-ATRP, we have modified materials by grafting from using plasmainduced polymerization. The major advantage of this technique is that surface-modification times are importantly reduced, and a fair control of the thickness and homogeneity of the grafted layers can be achieved by playing with plasma parameters (exposure time, plamsa power, ect.). We have mainly used this technique to modify highly porous hydrophobic membranes including PP membranes,97 PVDF membranes,61 and PTFE membranes.86 In the case of PP membranes from which were grown a PSBMA layer, we compared low-pressure and atmospheric pressure plasma treatment, and concluded that if the grafting densities achievable were in the same range regardless of the pressure parameter, PP membranes treated by atmospheric pressure plasma treatment were more hydrophilic and more biofouling resistant than if a low pressure plasma treatment was used to generate the zwitterionic layer. This was explained by different arrangements of the PSBMA layer: while a brush type structure was generated using atmospheric pressure plasma treatment, a network with higher crosslinking was obtained by low-pressure plasma treatment, preventing form the formation of an optimum protective hydration layer.97 Finally, a third grafting from technique that we used for surface zwitterionization is thermalinduced polymerization.93 Among the advantages of this common technique, biomaterial surfaces can be functionalized without using catalyst nor toxic solvents. We applied this method to silicon wafers that were first grafted with organosilane molecules. Then, the silane-coupled surfaces were coated with a solution of SBMA monomer, and thermalpolymerization conducted, leading to the formation of PSBMA brushes covalently bonded to the wafers, and permitting to drastically improve the hemocompatibility of the materials. If both types of method lead to covalent attachement of the zwitterionic layer on the surface at play, the grafting onto method differs from the grafting from method in the sense that the copolymer is formed first before initiating the modification of the surface. Therefore, a better control of the copolymer chain length as well as a better knowledge of its structure are achievable by the grafting onto technique, as the copolymer can be fully characterized before the grafting step. This technique requires the use of anchoring block that can react with functional groups of the surface to modify. As one knows, zwitterionization of a surface is done to improve its antifouling properties, through the formation of a hydration layer. Hence, most bare surfaces to modify are hydrophobic materials which do not contain common functional groups such as hydroxyl or amine groups, used to react with the anchoring 10 ACS Paragon Plus Environment

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segments of the copolymer. Therefore, an activation of the material is necessary to generate these groups. It is then followed by the coating of the activated material with the copolymer, and covalent bonding is formed under specific conditions of pH or temperature. In our group, we grafted a random poly(glycidyl methacrylate-co-sulfobetaine methacrylate) copolymer, poly(GMA-co-SBMA), onto a variety of surfaces including silicon, glass, titanium, silver, steel or polystyrene.66, 67, 98 These surfaces were first activated by UV/ozone treatment. Then a ring-opening reaction, catalyzed by trimethylamine, arose in the grafting of the poly(GMAco-SBMA) copolymer to the surface. We used a similar approach to graft onto various metals a triblock copolymer containing two repeat units of SBMA per GMA unit.67 Surface Functionalization by Coating Processes. Coating processes involve low-energy interactions between the surface to modify and the surface modifier, as opposed to covalent bonding, characteristic from grafting processes. Often, hydrophobic interactions are at play. The major advantages of coating processes is their ease of applicability and their low-cost, compared to grafting processes, as there is no need for surface activation of the material to modify. Surface modifications by coating have been developed in numerous variations, but perhaps, dip-coating and thermal-evaporation coating are the most employed because they do not require the use of any sophisticated instrument. Indeed, in dip-coating, the material is immersed in a coating bath containing the diluted copolymer, while in thermal-evaporation coating, a given volume of copolymer solution is dropped on the surface to modify and the solvent allowed to evaporate, which can be done at ambient temperature. The coating density is a key parameter that serves at monitoring the effectiveness of the modification. It is greatly affected by the concentration of the copolymer in the coating solution.75-77 The obtaining of a plateau for the coating density likely indicates saturation of the interface with the copolymer. If the value of the coating density reachable varies from one copolymer to another and one surface to another, we observed that excellent bioinert control of highly porous materials could be obtained for coating densities ranging between 0.5 and 1 mg/cm2,75-77 which suggests that lower values can be expected as effective on dense materials. Alike for the evaluation of the grafting density, an accurate estimate of the coating density is extremely difficult to reach for porous surfaces, as it depends on the actual surface that has been modified: if the coating solution partially penetrates within the pores, then the pore walls surface should be taken into account. Moreover, multilayer coating is likely to occur in the case of random copolymers, which complicates the calculation. The stability of the coating mainly relies on the strength of the hydrophobic interactions established between the surface 11 ACS Paragon Plus Environment

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to modify and the hydrophobic units forming the zwitterionic copolymer. It is undoubtedly one major weakness of coating processes considering that it is also affected by the polar interactions existing between the zwitterionic units and the surrounding medium, which tend to destabilize the coating. In our group or with our collaborators, we have designed a variety of copolymers containing hydrophobic groups such as poly(propylene oxide) (PPO),55, 99, 100 polyvinylpyrrolidone,101 poly(octadecyl acrylate),75,

polystyrene,92 77

poly(maleicanhydride-alt-1-octadecene),74

or poly(n-butyl methacrylate)63 to modify surfaces by dip-

coating or thermal-evaporation coating. In another work, we functionalized by grafting from SPR glass chips and silicone wafers with poly(11-mercapto- N , N , N -trimethylammonium chloride), positively charged. Then we proceeded to the charge-driven self-assembling of copolymers containing negatively charged moieities, and zwitterionic SBMA, namely poly(11-mercaptoundecyl sulfonic acid-co-)block-poly- (sulfobetaine methacrylate) (PSA-b-PSBMA).102 The self-assembling is a coating procedure, which stability was ensured by the ionic interactions between TMA and SA units. Finally, we also used a charge-driven coating procedure to functionalize hydroxyapatite, mimicking teeth material.94 In that particular study, we formed copolymers of polyethyleneimine and PSBMA. Coating of the copolymer on the surface was driven by electrostatic interactions occurring between polyethyleneimine blocks and hydroxyapatite. Finally, it is worth mentioning in this section a surface-modification process that we recently presented, that consists in polymerizing a copolymer and modifying surfaces in the same time.103 As we were facing difficulties in trying to solubilize a copolymer of styrene and sufobetaine methacrylate, it was decided to try to self-assemble a PVDF membrane along the course of the polymerization procedure. It was shown that in particular conditions of molar composition of the reaction bath, temperature, and reaction/deposition time, an homogeneous and stable coating was obtained. While the styrene groups effectively interacted with PVDF, the zwitterionic groups permitted to mitigate biofouling by plasma proteins, blood cells or bacteria. Bulk Functionalization by In-situ Modification Processes. In the case of membranes prepared by phase-inversion of a polymeric solution, it can be interesting to blend the main polymer, the antifouling copolymer and the solvent, and then form the membrane by exposing the casting solution to a non-solvent. This approach enables to form and modify the membrane in one step, and to modify not only the surface but also the bulk of the membranes, even though surface segregation is very likely to occur.104 It has successfully 12 ACS Paragon Plus Environment

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been tested with many PEGylated systems, using either the liquid-induced phase separation (LIPS) process (or wet-immersion process) or the vapor-induced phase separation (VIPS) process. However, it is much harder to modify membranes with a zwitterionic copolymer using this approach, for solubility reasons. To tackle this challenge, we very recently presented two molecular designs. In the first one, we polymerized styrene, sulfobetaine methacrylate and poly(ethylene glycol methacrylate), the latter units serving as a solubility/compatibility enhancer. By varying the SBMA/PEGMA molar ratio in the feed, we found a composition range that permitted to solubilize the PS-r-PEGMA-r-PSBMA copolymer

together

with

PVDF

in

a

mixture

of

N-methyl-2-pyrrolidone

and

dimethylformamide, two common solvents used in membrane formation. As a result, zwitterionic membranes were formed in one step by in-situ modification.64 In a second work, we collaborated with Prof. Ishihara and used a derivative of MPC copolymer containing urethane

groups,

namely

poly(2-methacryloyloxyethyl

phosphorylcholine-co-

methacryloyloxyethyl butylurethane) PMBU, earlier presented.105 These groups provide flexibility to the copolymer, which was believed to contribute to its miscibility with PVDF in NMP. Porous membranes were formed by VIPS process, and were shown to be biofouling resistant after incubation with whole blood, bacteria for 24h, platelet-poor-plasma or humic acids, all considered to be harsh environments.82 APPLICATIONS OF ZWITTERIONIC INTERFACES AND MEMBRANES In our laboratory, we mainly focuss on the design of zwitterionic copolymers to provide interfaces with general bio-inert control, to functionalize membranes to make them suitable for (i) blood filtration and selection (ii) wound healing and (iii) wastewater treatment. In addition, we put efforts on the coating of dental materials, to improve their bacterial resistance and biocompatibility, as well as in the coating of general biomedical tools. These major applications are presented in Figure 4, and detailed after.

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Figure 4. Summary of the major applications of Prof. Chang’s zwitterionic designs. (a) design of general antifouling interfaces; (b) design of wound-dressing materials; (c) design of hemocomatpible membranes for selective depletion; (d) design of wastewater treatment membranes; (e) design of antifouling coating for teeth protection; (f) design of antifouling coating for biomedical tools.

Zwitterionic Interfaces for General Bio-inert Control. Although biofouling can have numerous distinctive origins depending on the nature of the medium in which the interface is immersed in, the mechanisms for biofouling resistance are very similar whether one designs a material for water treatment or blood filtration related applications. Therefore, the development of interfaces with a general bio-inert control is a critical step for the application of zwitterionic materials. In addition, it is considered that resistance to proteins is very important in the assessment of the general antifouling properties of interfaces, because (i) 14 ACS Paragon Plus Environment

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they are responsible for biofouling at the nanoscale, and (ii) they are able to mediate biofouling by larger biofoulants such as bacteria or cells. So, in numerous past works in which we presented the surface-modification of model interfaces by zwitterionic materials, we investigated biofouling by proteins, using surface plasmon resonance58, 65, 106 or enzymelinked immunosorbent assay (ELISA) tests in the case of fibrinogen or other blood plasma proteins,59, 66, 67, 69, 95, 101, 107 or by UV-detection in the case of bovine serum albumin or lysozyme.77 Bacteria are a second major class of biofoulant, which adhesion must be avoided particularly in medical-related applications of materials. In this respect, we studied how the molecular design of diblock copolymers, containing PPO anchoring segments and PSBMA antifouling moieties, combined to the interface topography could play a key role on the attachment of Escherichia coli, Staphylococcus epidermidis, Streptococcus mutans and Escherichia coli modified with a green fluorescent protein.100 We reported resistances to bacteria on convex and indented surfaces as good or even better in some cases than the resistance to bacteria measured on flat surfaces. The rationale for this result is that the brushes coated on convex and indented surfaces were not necessarily oriented perpendicularly to the surface but in all directions of the space which implies that the surface coverage was dense enough to mitigate fouling by large biofoulants. Finally, when our zwitterionic materials are used for the functionalization of metals as in the work of Sin et al.,107 or more generally for versatile surfaces, polymer, ceramic and metal, as in the work of Chou et al.,66,

101

an in-depth investigation of the general antifouling

properties of the modified surfaces is carried out not only with proteins or bacteria, but also with human tissue cells such as fibroblasts HT1080 or osteoblasts or blood cells. These extensive biofouling studies are carried out as we are constantly looking for zwitterionic copolymers for the surface modification of biomedical devices (eg.: surgical blade, dental mouth mirror, root implants, etc…) that must be bio-inert. Zwitterionic Membranes for Skin Wound Dressing. To promote healing and reduce recovery times, a wound dressing should combine a set or properties that include (i) high porosity, to promote gas exchanges essential to healing, breathability and exudates drainage, (ii) antifouling, to prevent bacterial infection or secondary injury as a result of skin-tissuedressing interactions, (iii) moisture retainment as it was shown decades ago that a humid environment accelerates the entire healing process,108 and (iv) sufficient mechanical properties. Zwitterionic porous membranes (dry membranes or gels) should be able to fulfill these roles because gas can readily permeate through the membrane pores while the 15 ACS Paragon Plus Environment

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formation of a hydration protective layer due to the presence of antifouling copolymer maintains humidity above the wound and prevents biofouling by bacteria or skin-tissue cells. Based on the obserbation that essential properties of general antifouling membranes and wound-dressings overlap, we have investigated the applicability of zwitterionic materials for wound-healing. We presented in 2013 the surface-modification of PTFE membranes by PSBMA, and demonstrated that the obtained membranes accelerated healing, compared to commercial dressing or PEGylated membranes, with a newly formed skin-tissue presenting very similar histological characteristics (thickness of the granulation layer, vascularization, fibroblasts and hair follicles density) to those of unharmed skin tissue.109 One year later, we found that mixed-charged copolymers of TMA and SA could also fulfill this role.88 Interestingly, we also observed that if a slightly positive charge bias could still lead to a fair re-epithelialization, it could enhance clotting, which could be of major interest in the particular case of severe bleeding of the wounds: applying a mixed-charge dressing with an excess of positively charged moieties in a first step would serve at stopping bleeding, and it would then be replaced by a pseudo-zwitterionic membranes (no net charge) in the second stage of healing. Hemocompatible Membranes and Blood Cell Selection Membranes. Blood cells and plasma proteins are biofoulants that can readily adhere to non-biocompatible interfaces and membranes, which has two major consequences: blood cells disruption and biofouling of membranes. The design of surfaces with general bio-inert control permits to address this issue, because not only proteins and bacteria are repelled, but also blood components. We spent efforts on the development of PP membranes,75,

97

PVDF membranes,61, 99 or even

PTFE membranes intended to be used as wound-dressings,87, 109 that presented numerous characteristic of hemocompatible materials (reduced plasma protein adsorption, low to no blood cell adhesion, prolonged plasma clotting time, low hemolysis activity). In particular, we presented a carboxybetaine-based copolymer coated on PP membranes. The copolymer was shown to almost totally inhibit the interactions of the membrane material with the cells and more importantly, a 2.5-fold decrease of platelet activation was measured in the permeate using these membranes, compared to unmodified PP membranes.75 Then we started to develop materials that enabled blood cell selection.91 In particular, the presence of leukocytes in whole blood for transfusion can raise serious concerns because leukocytes can be, for example, responsible for the transmission of viruses. The separation of blood components using membranes cannot be based on moelcular sieving, but instead, should rely on smart 16 ACS Paragon Plus Environment

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mechanisms. We are currently developing zwitterionic materials that enable blood cells selection and in particular leukodepletion, inspired from our recent PEGylated designs,110 that highlighted that the combination of antifouling brushes and the control of the charge bias through the introduction of an excess of positively charged moieties could fulfill this role without inducing blood coagulation. Zwitterionic Membranes for Wastewater Treatment. Wastewater treatment is among the very classic applications of porous NF, UF and MF membranes. Wastewater contains numerous inorganic and organic foulants, which can quickly foul the membranes, and so, generate supplementary costs associated to membrane cleaning, membrane replacements, and production delays. PVDF or polysulfone are common materials for water treatment membrane, chosen for their excellent bulk properties. However, their hydrophobicity make them prone to biofouling. Therefore, these membranes have to be hydrophilize. In our laboratory, we have studied biofouling of NF,73 UF,60 and MF89 PVDF membranes in static conditions (incubation with Escherichia coli, commonly found in water) or during BSA/water or humic acids/water filtration cycles, and the results highlighted that the grafting with zwitterionic moieties prevented bacterial adhesion and importantly decreased the irreversible flux decline ratio while increasing the flux recovey ratio of the membrane at play. Performances (flux recovery ratio, irreversible flux decline ratio, etc.) were compared with those of commercially available hydrophilic PVDF membranes, and the results indicated that membranes modified with zwitterionic copolymers, either sulfobetaine-based (selfassembling coating),103 or phosphobetaine-based (in-situ modification),82 outperformed the commercial membranes. Zwitterionic Coatings for Teeth Protection and Dental Implants. As above-mentioned, bacteria are major biofoulants that we systematically use to evaluate the biofouling resistance of zwitterionic interfaces and membranes. One potential key application of effective bacteria resistant zwitterionic materials is the coating of teeth materials because dental cavities are often due to bacterial invasion and biofilm formation on the teeth. In 2014, we proposed an effective zwitterionic copolymer composed of polyethyleneimine and poly(sulfobetaine methacrylate), PEI-g-PSBMA, that was coated on both hydroxyapatite and teeth, via chargedriven self-assembling process.94 The adhesion of Streptococcus mutans was reduced by 70% on the resulting modified surfaces. More recently, we presented a triblock copolymer made of one block of GMA and two blocks of SBMA units, that was grafted onto titanium teeth root 17 ACS Paragon Plus Environment

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implants, and that was shown to resist to the adhesion of HT1080 fibroblasts cells.67 This result is of particular interest because teeth root implants are directly in contact with the mandible bone. Therefore, infections due to unwanted cell-metal interactions are likely to happen if the material is not bio-inert. Zwitterionic Coatings for General Biomedical Tools. Another key application of our zwitterionic materials is their use as coating agent for general biomedical tools such as dental mirrors, surgical blades or blood-typing microplates.66, 67 Despite all care and attention put in the sterilization of medical tools, nosocomial infections remain widely spread in hosptials, nursing-homes or dental clinics, which suggests the need for biomedical coatings that would further inhibit the attachment of bacteria. We recently reported that after incubation with Streptococcus mutans, a 85% reduction of bacterial attachment was obtained on a dental mirror coated with a random copolymer of glycid methacrylate and SBMA.12 Similarly, we managed to decrease the attachement of Escherichia coli on surgical blades by 90% with the same coating. PROSPECTIVE DIRECTIONS Although a lot of objectives related to the bio-inert control of interfaces and membranes have been achieved by the major groups worldwide focusing on zwitterionic materials, including ours, investigations are still needed to improve the applicability of zwitterionic materials. Firstly, the zwitterionic polymers synthesis and their production at an industrial scale remain tricky. In order to maximize the chances for scale-up, a possibility is to focuss on random copolymers rather than on diblock or triblock polymeric systems. Despite their recognized higher efficiency for biofouling mitigation, the block systems are not only harder to synthesize, but also offer less possibility for self-assembling on an interface than random copolymers, with wich much higher coating densities are achievable. As examples of efficient antifouling zwitterionic random copolymers are available,66,

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scale-up should be

organized around the synthesis of random copolymers rather than diblock or triblock copolymers. Secondly and although we tackled this challenge, some surfaces such as PDMS or PTFE remain very difficult to modify in a controllable and inexpensive fashion. Because grafting processes are difficult to conduct on these materials at low-energy demands, and because the coating approaches presented so far remain relatively unstable in the long-term, there is a 18 ACS Paragon Plus Environment

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need for re-thinking or re-orientating the polymer designs. Stickier anchoring units that could provide better stability should be developed for a readily-achieved surface modification of PDMS or PTFE materials. In particular, the combination of ultralow fouling zwitterionic copolymers containing dopamine-derivatives mimicking the adhesive proteins in mussels, as tested by Professor Jiang’s group,111 is a path to further explore, given the ability of polydopamine-based polymers to adhere to versatile substrates.112-115 Thridly, concerning in particular the zwitterionization of membranes, it is clear that surface modification processes dominate among the functionalization approaches and few attemps have been made to modify the membranes while forming them. Yet, forming and modifying the membrane in one single step opens great perspectives for industrial production of zwitterionic membranes. The problem to solve here is related to a better understanding and control of the zwitterionic polymer/matrix polymer/solvent interactions. The solubility of zwitterionic polymers have to be tuned to make them soluble with major membrane polymer. In general, once a novel copolymer is formed for membrane modification, more efforts should be put in the assessment of its thermodynamic properties, controlled partly by the anchoring segment/zwitterionic segment molar ratio and by the molecular weight. Two copolymers having a similar chemical composition but different molar distribution of each type of repeat units are likely to behave very differently once blended with a polymer matrix for membrane formation, and it is regrettable to notice that little is said on these aspects in literature. Instead, researchers tend to focuss on the chemistry (nature of hydrophobic and hydrophilic segment), and do not report much on solubility aspects. As we believe that in-situ modification is the most patentable functionalization process among the three major classes, research efforts have to be made in this direction to match with the numerous prospective developments of zwitterionic membranes. Fourthly, another direction worth investigating is the stability of the modification in coating processes. These approaches are interesting because they are readily carried out and require small amount of antifouling materials. However, stability concerns often arise. The coating stability is ensured by hydrophobic interactions established between the hydrophobic units and the hydrophobic interface. But once contacted with hydrophilic media, they are challenged by hydrophilic interactions established between the zwitterionic units and the surrounding liquid environment. These hydrophilic interactions tend to destabilize the system. Therefore, for coating processes, designing longer zwitterionic chains in the copolymer does not imply that fouling reisstance will be better. Instead, researchers should probably focus first on the molecular design of the hydrophobic segments of the copolymers. 19 ACS Paragon Plus Environment

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More efforts should also be made on the development of smart surfaces and membranes, with both killing and self-cleaning properties. Developing nonfouling materials is good but not enough when bacterial concentration is high, because some cells always manage to elude the antifouling trap and penetrate within the brushes. Then killing upon contact followed by release offers another alternative to antifouling coatings.116, 117 However, further efforts have to be carried out to gain control over the switcahbility, the stability and the reuse of these smart materials. While bactericidal activity is brought by polycation brushes, clicking kosmotropic counterions can arise in controlled self-cleaning. Last but not least, a major membrane field of interest that has gained momentum over the past 5 years is the separation of oil and water by gravity-driven or low-pressure membrane separation. As oil/water separation is mostly based on interfacial phenomema, a fine tuning of the wetting properties of a membrane, and so, of its structure and of its surface chemistry, can greatly decrease separation times withouth generating high operating costs. Zwitterionization of membranes can be of interest in the case of O/W emulsions, to increase water transfer and decrease oil fouling. In other words, zwitterionization of membranes could lead to the formation of unique matrices combining the advantages of gravity separation (low cost) and centrifugation (fast separation). ASSOCIATED CONTENT Supporting information Magnification of the molecular designs presented in Figure 1. This material is available free of charge via the internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *Yung Chang: E-mail: [email protected]. Phone: 886-3-265-4122. Fax: 886-3-265-4199 Author Contributions This manuscript was written through contributions of all authors. Notes

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The authors declare no competing financial interest.

ACKNOWLEDGEMENT The authors would like to thank the Chung Yuan Christian University, and the Ministry of Science and Technology of Taiwan for funding this project through the following grants: MOST 106-2628-E-033-001-MY3, MOST 106-2632-E-033-001, and MOST 107-2923-E033-001.

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Dual-Thermoresponsive Phase Behavior of Blood Compatible Zwitterionic Copolymers Containing Nonionic Poly(N-isopropyl acrylamide). Biomacromolecules 2009, 10, 2092-2100. (69) Chang, Y.; Yandi, W.; Chen, W.-Y.; Shih, Y.-J.; Yang, C.-C.; Chang, Y.; Ling, Q.-D.; Higuchi, A. Tunable Bioadhesive Copolymer Hydrogels of Thermoresponsive Poly(N-isopropyl acrylamide) Containing Zwitterionic Polysulfobetaine. Biomacromolecules 2010, 11, 1101-1110. (70) Shih, Y.J.; Chang, Y.; Deratani, A.; Quemener, D. “Schizophrenic” Hemocompatible Copolymers via Switchable Thermoresponsive Transition of Nonionic/Zwitterionic Block Self- Assembly in Human Blood. Biomacromolecules 2012, 13, 2849-2858. (71) Venault, A.; Huang, C.-W.; Zheng, J.; Chinnathambi, A.; Alharbi, S.A.; Chang, Y.; Chang, Y. Hemocompatible Biomaterials of Zwitterionic Sulfobetaine Hydrogels Regulated With pH-Responsive DMAEMA Random Sequences. Int. J. Polym. Mater. Polym. Biomater. 2016, 65, 65-74. (72) Shih, Y.; Venault, A.; Tayo, L.L.; Chen, S.-H.; Higuchi, A.; Deratani, A.; Chinnathambi, A.; Alharbi, S.A.; Quemener, D.; Chang, Y. A Zwitterionic-Shielded Carrier with pH-Modulated Reversible Self- Assembly for Gene Transfection. Langmuir 2017, 33, 1914-1928. (73) Chiang, Y.-C.; Chang, Y.; Chuang, C.-J.; Ruaan, R.C. A Facile Zwitterionization in the Interfacial Modification of Low Bio-fouling Nanofiltration Membranes. J. Membr. Sci. 2012, 389, 76-82. (74) Venault, A.; Huang, W.-Y.; Hsiao, S.-W.; Chinnathambi, A.; Alharbi, S.A.; Chen, H.; Zheng, J.; Chang, Y. Zwitterionic Modifications for Enhancing the Antifouling Properties of Poly(vinylidene fluoride) Membranes. Langmuir 2016, 32, 4113-4124. (75) Venault, A.; Ye, C.-C.; Lin, Y.-C.; Tsai, C.-W.; Jhong, J.-F.; Ruaan, R.-C.; Higuchi, R.-C.; Chinnathambi, A.; Ho, H.T.; Chang, Y. Zwitterionic fibrous polypropylene assembled with amphiphatic carboxybetaine copolymers for hemocompatible blood filtration. Acta Biomater. 2016, 40, 130-141. (76) Venault, A.; Trinh, K.M.; Chang, Y. A Zwitterionic zP(4VP-r-ODA) Copolymer for Providing Polypropylene Membranes With Improved Hemocompatibility. J. Membr. Sci. 2016, 501, 68-78. (77) Venault, A.; Subarja, A.; Chang, Y. Zwitterionic Polyhydroxybutyrate Electrospun Fibrous Membranes With a Compromise of Bioinert Control and Tissue-Cell Growth. Langmuir 2017, 33, 2460-2471. (78) Chou, Y.-N.; Sun, F.; Hung, H.-C.; Jain, P.; Sinclair, A.; Zhang, P.; Bai, T.; Chang, Y.; Wen, T.-C.; Yu, Q.; Jiang, S. Ultra-low Fouling and High Antibody Loading Zwitterionic Hydrogel Coatings for Sensing and Detection in Complex Media. Acta Biomater. 2016, 40, 31-37. (79) Mi, L.; Giarmarco, M. M.; Shao, Q.; Jiang, S. Divalent Cation-mediated Polysaccharide Interactions with Zwitterionic Surfaces. Biomaterials 2012, 33, 2001-2006. (80) Ishihara, K.; Ueda, T.; Nakabayashi, N. Preparation of Phospholipid Polylners and Their Properties as Polymer Hydrogel Membranes. Polymer J. 1990, 22, 355-360. (81) Ishihara, K.; Ishikawa, E.; Iwasaki, Y.; Nakabayashi, N. Inhibition of Cell Adhesion on the Substrate by Coating with 2-Methacryloyloxyethyl Phosphorylcholine Polymers. J. Biomater. Sci., Polym. Ed. 1999, 10, 1047-1061. (82) Venault, A.; Hsu, C.-H.; Ishihara, K.; Chang, Y. Zwitterionic Bi-continuous Membranes from a Phosphobetaine Copolymer/poly(vinylidene fluoride) Blend via VIPS for Biofouling Mitigation. J. Membr. Sci. 2018, 550, 377-388. (83) Chen, S.; Yu, F.; Yu, Q.; He, Y.; Jiang, S. Strong Resistance of a Thin Crystalline Layer of Balanced Charged Groups to Protein Adsorption. Langmuir 2006, 22, 8186-8191. (84) Chen, S.; Jiang, S. A New Avenue to Nonfouling Materials. Adv. Mater. 2008, 20, 335-338. (85) Mi, L.; Bernards, M.T.; Cheng, G.; Yu, Q.; Jiang, S. pH Responsive Properties of Non-fouling Mixedcharge Polymer Brushes Based on Quaternary Amine and Carboxylic Acid Monomers. Biomaterials 2010, 31, 2919-2925. 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Chang, Y.; Shu, S.-H.; Shih, Y.J.; Chu, C.-W.; Ruaan, R.-C.; Chen, W.-Y. Hemocompatible Mixed-Charge Copolymer Brushes of Pseudozwitterionic Surfaces Resistant to Nonspecific Plasma Protein Fouling. Langmuir 2010, 26, 3522-3530. Jhong, J.F.; Venault, A.; Liu, L.; Zheng, J.; Chen, S.-H.; Higuchi, A.; Huang, J.; Chang, Y. Introducing Mixed-Charge Copolymers As Wound Dressing Biomaterials. ACS Appl. Mater. Interfaces 2014, 6, 9858-9870. Venault, A.; Wei, T.-C.; Shih, H.-L.; Yeh, C.-C.; Chinnathambi, A.; Alharbi, S.A.; Carretier, S.; Aimar, P.; Lai, J.-Y.; Chang, Y. Antifouling Pseudo-Zwitterionic Poly(Vinylidene Fluoride) Membranes with Efficient Mixed-charge Surface Grafting Via Glow Dielectric Barrier Discharge Plasma-induced Copolymerization. J. Membr. Sci. 2016, 516, 13-25. Venault, A.; Zheng, Y.-S.; Chinnathambi, A.; Alharbi, S.A.; Ho, H.-T.; Chang, Y.; Chang, Y. StimuliResponsive and Hemocompatible Pseudozwitterionic Interfaces. Langmuir 2015, 31, 2861-2869. Venault, A.; Hsu, K.-J.; Yeh, L.-C.; Chinnathambi, A.; Ho, H.-T.; Chang, Y. Surface Charge-bias Impact of Amine-contained Pseudozwitterionic Biointerfaces on the Human Blood Compatibility. Colloids Surf., B. 2017, 151, 372-383. Nehache, S.; Yeh, C.-C.; Semsarilar, M.; Deratani, A.; Chang, Y.; Quemener, D. Anti-Bioadhesive Coating Based on Easy to Make Pseudozwitterionic RAFT Block Copolymers for Blood-Contacting Applications. Macromol. Biosci. 2016, 16, 57-62. Sin, M.-C.; Lou, P.-T.; Cho, C.-H.; Chinnathambi, A.; Alharbi, S.A.; Chang, Y. An Intuitive ThermalInduced Surface Zwitterionization for Versatile, Well-controlled Haemocompatible Organic and Inorganic Materials. Colloids Surf., B. 2017, 127, 54-64. Venault, A.; Yang, H.-S.; Chiang, Y.-C.; Lee, B.-S,; Ruaan, R.-C.; Chang, Y. Bacterial Resistance Control on Mineral Surfaces of Hydroxyapatite and Human Teeth via Surface Charge-Driven Antifouling Coatings. ACS Appl. Mater. Interfaces 2014, 6, 3201-3210. Chang, Y.; Liao, S.-C.; Higuchi, A.; Ruaan, R.-C.; Chu, C.-W.; Chen, W.-Y. A Highly Stable Nonbiofouling Surface with Well-Packed Grafted Zwitterionic Polysulfobetaine for Plasma Protein Repulsion. Langmuir 2008, 21, 5453-5458. Yu, B.-Y.; Zheng, J.; Chang, Y.; Sin, M.-C.; Chang, C.-H.; Higuchi, A.; Sun, Y.-M. Surface Zwitterionization of Titanium for a General Bio-Inert Control of Plasma Proteins, Blood Cells, Tissue Cells, and Bacteria. Langmuir 2014, 30, 7502-7512. Chen, S.-H.; Chang, Y.; Lee, K.R.; Wei, T.C.; Higuchi, A.; Ho, F.-M.; Tsou, C.-C.; Ho, H.-T.; Lai, J.Y. Hemocompatible Control of Sulfobetaine-Grafted Polypropylene Fibrous Membranes in Human Whole Blood via Plasma-Induced Surface Zwitterionization. Langmuir 2012, 28, 17733-17742. Sivashanmugan, K.; Liu, P.-C.; Tsai, K.-W.; Chou, Y.-N.; Lin, C.-H.; Chang, Y.; Wen, T.-C. An Antifouling Nanoplasmonic SERS Substrate For Trapping And Releasing A Cationic Fluorescent Tag From Human Blood Solution. Nanoscale 2017, 9, 2865-2874. 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the Young Domestic Pig. Nature 1962, 193, 293-294. (109) Jhong, J.-F.; Venault, A.; Hou, C.-C.; Chen, S.-H.; Wei, T.-C.; Zheng, J.; Huang, J.; Chang, Y. Surface

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Figure Captions

Figure 1. Molecular structure of the major sulfobetaine-based copolymers synthesized in Professor Chang’s group................................................................................................ 5 Figure 2. Summary of the different classes of dense and porous materials that we modified with zwitterionic polymers and copolymers. .................................................................. 8 Figure 3. Summary of the three major classes of functionalization processes. In grafting, covalent bonding is at play while in coating and in-situ modification, stability is ensured by hydrophobic interactions. An anchoring polymer unit is also represented on the grafting pictogram, essential to grafting “onto” (use of copolymers) but that can be absent in grafting “from” (use of polymers). ................................................................. 9 Figure 4. Summary of the major applications of Prof. Chang’s zwitterionic designs. (a) design of general antifouling interfaces; (b) design of wound-dressing materials; (c) design of hemocomatpible membranes for selective depletion; (d) design of wastewater treatment membranes; (e) design of antifouling coating for teeth protection; (f) design of antifouling coating for biomedical tools....................................................................... 14

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AUTOBIOGRAPHY OF THE AUTHORS

Antoine Venault is an associate professor of chemical engineering at Chung Yuan Christian University (Taiwan). He obtained his PhD in process engineering at the University of Montpellier (France) in 2010 under the lead direction of Prof. Catherine Faur. He then moved to Taiwan where he accomplished his postdoctoral research work under the guidance of Prof. Yung Chang and Prof. Da-Ming Wang, before taking an assistant professor position. His research interests include the design of membranes for wastewater treatment and biomedical applications, and the functionalization of interfaces and membranes to gain control over biofouling.

Yung Chang is a distinguished professor of chemical engineering at Chung Yuan Christian University (Taiwan) and the current director of the research and development center for membrane technology (RDCMT). He received his PhD in chemical engineering from the National Taiwan University in 2004. He was then a postdoctoral scholar at the University of Washington where he studied molecular simulation and macromolaular synthesis in bio-inert material works before moving back to Taiwan where he became assistant professor in 2006 and promoted to full professor in 2013. His current professional specialty and interests 28 ACS Paragon Plus Environment

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include the research of bio-inspired macromolecules/interfaces/membranes, and the development of zwitterionic membranes in blood separation technology, with a focuss on the the molecular design of biocompatible smart materials for blood cells selection. He was awarded numerous national and international awards, including the 2012 MOST Wu Da-Yu Award for Outstanding Young Professors (The ministry of science and technology, Taiwan), and the 2018 SCEJ Award for Outstanding Young Asia Researchers and Engineers (The Society of Chemical Engineers, Japan).

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