Latest advances in zwitterionic structures modified dialysis membranes

Materials Today Chemistry 15 (2020) 100227

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Latest advances in zwitterionic structures modified dialysis membranes A. Mollahosseini a, A. Abdelrasoul a, b, *, A. Shoker c, d a

Department of Chemical and Biological Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, Saskatchewan, S7N 5A9, Canada Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, Saskatchewan, S7N 5A9, Canada c Nephrology Division, College of Medicine, University of Saskatchewan, 107 Wiggins Rd, Saskatoon, Saskatchewan, S7N 5E5, Canada d Saskatchewan Transplant Program, St. Paul’s Hospital, 1702 20th Street West Saskatoon Saskatchewan, S7M 0Z9, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 September 2019 Received in revised form 5 November 2019 Accepted 8 November 2019

End-stage renal diseases are affecting many patients and as a result, demand to receive dialysis service is growing annually. Morbidity and mortality rates are reported to be higher in comparison with healthy humans. The reason is reported to be the hemoincompatiblity of blood purification membranes, which hinders patients’ lives. Activation of different immune systems in the body, in case of blood-membrane interaction, results in several side effects, of which cardiovascular shocks have been mentioned to be a major one. Efforts to solve this issue have resulted in different generations of dialysis membranes. Zwitterionic immobilized membranes are the latest (third) generation, which owns a higher degree of hemocompatiblity with more stability of immobilized structures. This critical review intends to cover recent efforts conducted over the zwitterionization of polymeric membrane surfaces with the goal of improving hemocompatibility. Different aspects of third-generation membranes are discussed for a better understanding of the current gap and gathering the knowledge to further develop the field. Accordingly, this critical survey provides an in-depth understanding of blood purification membranes zwitterionization for paving the way for the optimum enhancement of hemodialysis membrane hemocompatibility. © 2019 Elsevier Ltd. All rights reserved.

Keywords: Hemodialysis Blood Hemocompatibility Zwitterionization Interactions Activations Surface modification

1. Introduction End-stage renal diseases (ESRD) patients receive blood purification dialysis services due to the low chance of kidney transplant as the main and best therapy. On an annual basis, more than one

million patients receive dialysis services all around the world [1]. Yet the mortality rate in renal replacement therapy (RRT) still remains over 20% [2]. On the other hand, the expenses for each patient is significantly high in comparison with other illnesses. As an instance, U.S. hemodialysis services are annually spending more

Abbreviations: Zwitterionic material, ZW; Sulfobetaine methacrylate, SBMA; Water contact angle, WCA; Polystyrene, pr; Polyvinlypyrolidone, PVP; Glycidyl methacrylate, GMA; Polydimethylsiloxane, PDMS; enzyme-linked immunosorbent assay, ELISA; Ethylenediamine, EDA; Sodium polystyrene sulfonate, SSNa; Ammonium persulfate, APS; 2Hydroxyethyl methacrylate, HEMA; (3-carboxypropylbetaine-propyl)-trimethoxysilane, CPPT; (3-sulfopropylbetaine-propyl)-trimethoxysilane, SPPT; (3-sulfobutylbetainepropyl)-trimethoxysilane, SBMT; N,N-Dimethyl-N-(p-vinylbenzyl)-N-(3-sulfopropyl)ammonium, DMSVA; rat bone marrow-derived stromal cells, rMSCs; platelet-poor plasma, PPP; N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl) ammonium, DMMSA; Ceric ammonium nitrate, CAN; 2-dimethylaminopryridine, DAMP; tetrahydrofuran, THF; Triethylamine, TEA; N,N dimethyl- N-(p-vinylbenzyl)-N-(3-sulfopropyl) ammonium, PDMVSA; random radical polymerization, RRP; human serum albumin, HSA; Scanning electron microscopy, SEM; (MPC)-co-n-butyl methacrylate), BMA; 2-methacryloyloxyethyl phosphorylcholine, MPC; butyl methacrylate, BMA; N,N-diethyl-Npropargyl-N-(3-sulfopropyl) ammonium, DEPAS; sodium methacrylate, MAANa; N,N’ -Methylenebisacrylamide, MBA; tri-layer polyelectrolyte, TLP; poly(acrylic acid)-gazide, PAA-g-AZ; Acrylic acid, AA; Poly (lactic acid), PLA; N,N0 -methylene bisacrylamide, MBAA; Hexamethylenediisocyanate, HDI; 4-vinylpyrrolydene-r-octadecyl acrylate, zP(4VP-r-ODA); [3-(methacryloylamino)propyl]- dimethyl(3-sulfopropyl) ammonium hydroxide, MPDSAH; [3-(methacryloylamino)propyl]dimethyl(3-sulfopropyl)ammonium hydroxide inner salt, SBAA; cellulose triacetate, CTA; Poly (methyl methacrylate), PMMA; ethylene vinyl alcohol, EVAL; hazard ratio, HR; activated partial thromboplastin time, APTT; Thrombin time, TT; Prothrombin time, PT; Thrombin-antithrombin III complex, TAT; Platelet factor 4, PF4; Polymorphonuclear elastase, PMN; Tissue factor, TF; Adenosine diphosphate, ADP; b-thromboglobulin, b-TG; Glycoprotein IIb/IIIa, GP IIb/IIIa; Membrane attack complex, MAC; Thromboxane A2, TXA2; Von Willebrand factor, vWF; Flux recovery ratio, FRR; Total resistance, Rt; Irreversible resistance, Rir; Reversible resistance, Rr; Water contact angle, WCA; partial thromboplastin time, APTT; Thrombin time, TT; Prothrombin time, PT; thrombin-antithrombin III, TAT; platelet factor 4, PF4; phosphate buffer saline solution, PBS. * Corresponding author. E-mail address: [email protected] (A. Abdelrasoul). https://doi.org/10.1016/j.mtchem.2019.100227 2468-5194/© 2019 Elsevier Ltd. All rights reserved.

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than 90,000 USD/patient of ESRD [3], while it costs the Canadian health care system $70,000e$107,000 per patient/year. Since the number of dialysis services receiving patients would be more than 4 million based on the predictions [4,5], great academic efforts have been put on reducing hemodialysis morbiditymortality,due to the many side effects or complications, such as anemia (low level of red blood cells), inflammation, vitamin D disorder, and hyperphosphatemia (in micromolecular and cell scale), and cardiovascular complications, hypertension, CKDassociated-mineral and bone disorders, ineffective energy generation, and nutritional issues morbidities (in body scale) [6e9]. Among the aforesaid complications, more than 50% of the mortality rate is attributed to cardiovascular shocks. Hemoincompatibility of dialysis membranes has been identified to be responsible for many activated cascades, inflammations, and side effects. A great amount of research has been focused on improving the hemocompatibility of the membranes. One of the most recent trends in the modification of hemodialysis membranes, is the immobilization of zwitterionic (ZW) materials, as a biomimetic structure, to control the hemoincompatibility of the membranes. This short review intends to cover various aspects of ZW immobilization on polymeric blood purification membranes. Accordingly, biological interactions between blood and polymeric structure of membranes are discussed in section 2. Section 3 briefly covers different generations of blood purification membranes and the route through which ZW-immobilized membranes were introduced as the new generation of hemodialysis membranes. Section 4 offers a short introductory part over ZW structures and their immobilization techniques. Section 5, which is the main part of this review, covers the efforts conducted over ZW-immobilized hemocompatible membranes. Section 6 critically discusses the data gathered in section 5, and section 7 gives an outlook into the future of this field. 2. Blood-membrane interactions In an incompatible surface-blood contact, several incidences will occur, including complement cascade activation, thrombogenesis (formation and attachment of blood clots on the surface), adsorption and conformation of plasma proteins, such as albumin and fibrinogen, platelet consumption (from blood side), attachment to the surface (from foreign material point of view), material calcification, and biodegradation resulting in loss of properties [10]. It is worth noting that these biological reactions are not limited to dialysis membranes. It was found that all the biomedical instruments with cardiovascular and non-cardiovascular applications suffer from the deposition of calcium-containing apatite substances, which affects the life span and efficiency of the devices [11]. In the first stage of blood-membrane touch (or in general, any biomedical deviceetissue contact), small proteins will attach to the surface. This will be followed by the replacement of initial proteins with higher molecular weight proteins (Vroman effect) [12] along with activation and conformation of proteins, which will produce mediators (mainly enzymes) for activation of other proteins and systems in the body. The autocatalytic reaction chains of enzymes and activated system of the body are all defending the body from foreign threats; however, in case of a hemodialysis membrane or implanted devices, higher activations and mediator production in the body reflects a higher degree of incompatibility of materials with the biological environment of the body. While several different approaches are proposed in different biomedical applications to which human blood interacts with foreign materials (such as vascular grafts, coronary stents, heart valves, catheters, heartelung bypass systems, etc.), hemodialysis

membranes are generally coated with a hydrophilic polymer or biomimetic layer. As blood cells interact with hemodialysis membrane surfaces without any hemocompatible top layers, the membrane will trigger the human blood, and a rapid blood protein coverage occurs over the surface. This will be followed by platelet adhesion to the protein fouled layer. Activation of platelets after attachment to the surface will result in aggregation of blood clots and formation of fibrin [10]. A more detailed illustration of blood reactions with hemodialysis surface is depicted in Fig. 1. Generally, enzymatic or similar mediator structures are secreted by activated cell components. Mediators could be specifically attributed to one activation cascade or parallel activate several cascades. The measurement of these mediators could also reflect the extent of the compatibility of membranes. A further detailed description of cascades could be found elsewhere [13]. 3. Generations in hemocompatible membranes The route to reach to hemocompatible membranes for blood purification applications was studied, and different levels of modification through time were classified by Sin and his team [15]. First-class of hemodialysis membranes are those made out of hydroxyl rich polymers, such as 2-hydroxyethyl methacrylate (HEMA). The presence of eOH functions could result in the presence of water molecules on the membrane surface, due to hydrogen bonding, which accordingly results in less protein fouling. The general perception of membrane modification was that higher hydrophilicity could result in less protein attachment, controlled displacement of proteins (Voreman effect), and consequently, less incompatibility. However, higher hydrophilicity did not result in higher hemocompatibility. In the real situation, the poor performance of first-generation membranes (protein activation, conformation, and attachment) led to top layers modification of separative membranes with ethylene glycol branched polymers (Second generation) [16,17]. These second-generation membranes performed slightly better due to their better activation profile than the previous types; however, thermal instability, chain cleavage in the presence of aqueous oxidative media were still the main barriers for a stable and sufficient performance [18e20]. Biomimetic structures were reported to be ideal coating structures for surface modification as they mimic the natural organs’ surface [21e23]. Biomimetic structures are capable of minimizing interactions between synthetic surfaces and living cells, blood, etc. [22,24,25]. ZW structures (dual positive-negative functional group contacting structures with net neutral charge) have significant antifouling performance and comparably better stability and hemocompatible functionality [26e28]. Biomimetic structures of ZW materials are introduced as the third generation of modifications incorporated with hemodialysis membranes with comparatively superior antithrombotic behavior, low hemolysis percentage, and stable structure. Fig. 2 represents three generations of the blood purification membranes. Three types of ZWs, namely, phosphobetaines, sulfobetaines, and carboxybetaines. 4. Zwitterionic structures The initial introduction of ZW materials was performed back in the 1950s [29]. However, more specific investigations in the 1990s on human blood cells resulted in the development of the ZW materials. Assessment of red blood cells, in 1997, revealed that two sides of the cells behaved differently in terms of thrombogenesis activation. The outer side of red blood cells, which showed neutral nature, was further studied to develop similar structures. Amphiphilic structures with both negative and positive moiety on the same backbone were developed based on the phospholipid

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Fig. 1. Blood biological reactions, including complement system activation, intrinsic, and extrinsic coagulation activation, fibrin network formation, platelet attachment to the surface, and leukocytes activation [14].

structures identified in red blood cells. Accordingly, ZW structures are biomimetic chemicals, as reported by Zwaal [30]. Polyzwitterionian structures (also named as polybetaines) have attracted many attentions and own several applications, such as live-cell imaging [31,32], antibacterial surfaces [33] and wound dressings [34], dental applications [35], separative membrane coatings [36], and most importantly blood purification [15]. There are few papers covering various aspects of ZW papers, from fabrication to immobilization techniques. This survey is, however, assessing the hemocompatiblity aspects of blood purification membranes bearing ZW structures. 4.1. Types of zwitterionic structures Common structures of the ZW materials are phosphobetaine, carboxybetaine, and sulfobetaines. These structures commonly own quaternary ammonium groups as the positive functional group and phosphoric, carboxylic, and sulfuric structures as the negative functional groups, respectively [37]. Based on the explanations of Chapman and his team, ZW structures that have dual positive-negative charged functional groups must acquire the following characteristics: electric charge-neutral, should not possess H-bond donor sites, and should own H-bond acceptors [38]. Pseudo-zwitterionic1 materials or mixed charged polymers are a modified class of positively dual charged structures that are

1 “Pseudo-zwitterionic membrane modification” would be discussed in a separate review from this research group.

not affected by other chemical functional groups due to higher stability. Accordingly, they have been introduced as a better candidate for improving hemodialysis membranes by surface immobilization or forming hydrogels [39e41]. While the three mentioned classes of materials share common characteristics, i.e., bearing positive and negative functional groups on the same moiety, high density of charges, overall neutral net charge, and high dipole moment, they could possess different properties [29]. Initial ZW materials used for nonfouling or super-low-fouling were phosphor-containing structures, which had the purpose of mimicking human cell structures. Common structures of these classes had phosphorylchlorine (PC) functional groups. While the choices of negative functional groups are not limited to the PC monomers, all phosphobetaine ZW structures have the disadvantage of sensitivity to moisture. Moreover, they all suffer from expensive production processes, and accordingly, industrial-scale applications of such materials are still limited [42]. Sulfobetaine structures are similar to those having phosphoric functional group. However, despite the similar antifouling behavior, synthesis routes are mentioned to be easier for sulfobetaine, while complicated production process and low production yield makes phosphobetaines commercially expensive [15]. More importantly, due to internal tethering proximity of the sulfuric and ammonium groups in sulfobetaine, hydrogen bonding network of the material would be less affected by the environment when applied on biomedical surfaces, in comparison with phospobetaines [43,44]. Sulfobetaines with ammonium and sulfonate functional groups, easily mimic the structure of 2-aminoethanesulfonic acid. Based on

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Fig. 2. Generations of Hemodialysis membranes.

lower cost, higher yield and easier handling, an acceptable level of endotoxin, noncytotoxity, and biocompatibility, sulfobetaine ZW structures (commonly polysulfobetaine with methacrylate backbone) are widely used in enhancing membrane surface [15]. Carboxybetaine structures are also significantly capable of creating antifouling surfaces. Zwitterionization of surfaces bearing carboxyl groups also allows more surface modification through the immobilization of extra ligands and functional groups [45]. Ester groups are efficient substituents for carboxyl structures in carboxybetaines since the newer structure offers better properties upon hydrolysis [46]. Table 1 summarizes points mentioned about ZW structures. Different methods of simultaneously synthesizing ZWs with only one anionic group or pair of weak and strong anionic groups could be found elsewhere [36]. Fig. 3 shows three common ZW structures most frequently used in the modifications. It was noted that, despite several other surface modifications, ZW materials are able to perform electrostatic interaction induction with water molecules [15]. This would result in a great ability to bind with water molecules and form a hydration layer on the membrane’s surface. The surface hydration layer, as explained by Ishihara et al. would create a strong repulsive force inhibiting the protein to a specified distance with negligible protein conformational variation [47]. This mechanism is commonly mentioned to be the reason for the low- or nonfouling surface of the zwitterionized membranes [48]. Hydrophobic bonds in protein structures resist the diffusion of zwitterion structures, and accordingly, ZW functionalized surfaces in the aqueous environment do not stimulate normal conformation of the protein [49]. Although electrostatic interaction with the water molecules results in hydration layer formation and consequent low fouling behavior, the neutrality of ZW-immobilized surfaces is mentioned to be crucial as it results in minimized interaction of surface-plasma proteins [50]. More importantly, ZWs, in the form of brushes, are able to create ionic

structures of water molecules in their vicinity, which results in super-hydrophilic surfaces [51]. There are several theoretical choices of ZW structures with different architectures (Fig. 4) [52]. Experimentally, the production of some architectures’ is not feasible, as it is too complicated or uneconomical. While there are several ZW modifications reported for polymeric membranes, ZWbased hemocompatible membranes are more limited (as structures reported in Ref. [52] and reviewed literature in the current paper are compared).

4.2. Common methods of surface modification using zwitterionic polymers Surface treatment methods have been used widely for membrane modifications. However, there have been only a few options applied for the ZW structure attachment over polymeric membranes. Based on classification of He et al. [53] incorporation of ZW structures could be utilized with membrane materials through surface grafting, segregation (blending modifiers in casting solution so that the hydrophilic end of the blocks would be segregated on the surface after casting and phase inversion), biomimetic adhesion (using bioinspired molecular structures for attaching modifier blocks to membranes), and surface coating. Based on the literature review over ZW immobilized hemocompatible membranes, most of the modifications are mainly centered around graft polymerization. The grafting procedure could be conducted through chemical, thermal, or irradiation-induced processes. Grafting polymerization could be divided into two classes of free radical polymerization (which is relatively easy and short in process time and steps) and controlled, i.e., living graft polymerization (which is more efficient with higher grafting yield density and more even distribution of immobilized structures). A more detailed discussion

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Table 1 Various zwitterionic structures and their characteristics. Zwitterionic material

Positive functional Negative group functional group

Mimicking structure of:

Advantages

Disadvantages

Phosphobetaine Ammonium

Phosphate

Human cell phospholipids

Highly hemocompatible structure

High production cost, low production yield, sensitivity to moisture

Sulfobetaine

Sulfate

2-aminoethanesulfonic acid, taurine betaine

Lower cost and easier production process

e

Carboxybetaine

Carboxyl

e

Can be further functionalized e or modified

Fig. 3. Chemical structure of common zwitterionic structures (a) phosphoric functional group, (b) sulfuric functional group, and (c) carboxylic functional group.

over each method could be in literature [53]. Fig. 5 offers a schema of two common zwitterionization methods. Regardless to the classification mentioned above, common methods of zwitterionization include, atom transfer radical polymerization (ATRP), free radical graft polymerization (FRGP), redox graft polymerization (RGP), physisorbed free radical graft polymerization, photo-induced graft polymerization (POIGP), plasmainduced graft polymerization (PLIGP), surface-initiated reversible addition-fragmentation chain atom transfer radical (RAFT) polymerization, etc. [54e57]. There have been reports over metal contamination, rigid deoxygenation, and high expenses attributed to some of the immobilization techniques [58]. Methods, such as plasma or UV induced polymerizations have been mentioned to degrade the graft structure due to high energy [59,60]. Other nondestructive and nonstructure changing methods, such as thermal-induced polymerization, were reported to result in better ZW modified membranes as they result in surfaces with less toxic

solvents or catalysts [61]. An advantageous method should have high grafting yield, monomer versatility, moderate reaction parameter, tolerance to impurities, tailorable length, and controllable products [62,63]. The aforesaid methods could generally be applied through “graft onto” (using polymers in surface modifications, i.e., synthesizing modifier ZW separately and grafting it on the membrane in one step) or “graft from” (using copolymers in surface modification, i.e., using monomers, initiators and catalysts to form the ZW step by step on the membrane) strategy. A detailed description of each method besides the pros and cons could be found elsewhere [37]. The “graft from” strategy could offer more control over the polymerization process resulting in the adjustment of immobilized chain length, chemical structure, and concentration. Since the strategy requires multistep procedures, it could result in deficient superficial uniformity. The “graft onto” strategy, on the other hand, consists of only two steps: covalent binding site preparation and ZW polymer growth [64]. Since the ZW material is completely synthesized prior to the surface immobilization in a separate process, there exists the possibility of using several monomers and synthesizing processes without affecting the membrane’s structure [65]. Accordingly, this strategy has a higher chance of being commercialized. One should note that while there are pros and cons over each strategy, the steric hindrance of bulky ZW in one step immobilization would result in less grafting density, where higher grafting density would be achieved through step by step immobilization of ZW. This has been mentioned to be a probable barrier over the commercialization of ZW immobilized membranes [53]. 5. Recent efforts in modification of dialysis membranes Recent efforts over hemocompatibility improvement of polymeric membranes are reviewed here. The major share of research articles reported zwitterionization of cellulose and polysulfone membranes (including polyethersulfone as one of the higher interest subjects). While several other types of polymeric membranes are also subjected to ZW surface modification, there are still polymeric substances that are not being considered for such an application. From the ZW point of view, SBMA and sulfone-sulfonic

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containing structure are more commonly applied in comparison with other classes. Here, literature reviews are classified based on the membrane materials, and further discussion is postponed to section 6. The papers were selected to be reviewed even if only one of the parameters related to blood components fouling or adhesion, biocompatibility, cytocompatibility, or hemocompatibility was reported. 5.1. Poly (dimethyl siloxane) (PDMS) To overcome the harsh plasma or UV treatments side effects over polydimethylsiloxane (PDMS) membranes in zwitterionization process, Dizon and his team reported the application of poly (glycidyl methacrylate-sulfobetaine methacrylate) (PGMA-SBMA) immobilization on PDMS through creating binding sites with tannic acid (TA) and Fe(III) complex [66]. Pretreatment approach using the aforesaid polyphenyl-metal complex results in the formation of a thin film on superficial interfaces that bears hydroxyl groups. The functional groups will ultimately create reaction cites for the covalent binding of ZW substances. The application of ethylenediamine (EDA) was also assessed as a precursor, which resulted in higher hydrophilic membranes; both did not affect antibacterial behaviors of the membrane. This was further explained to be a result of EDA-PDMS or EDA-TA interaction, which resulted in nonbiocompatible amine producing procedure. 5.2. Cellulose and cellulose acetate (CA) One of the first efforts over 2-methacryloyloxyethyl phosphorylcholine (MPC) zwitterionization for higher hemocompatibilitiy purposes is conducted over cellulose membranes by Ishihara et al. [67] using cerium ammonium nitrate as the initiator of ATRP. Biomembrane-like structure of phosphobetaine immobilized on the membrane, which mimicked phospholipids, mentioned to be responsible for non-thrombogenicity of MPC grafted cellulose membranes. Despite common protein deposition on hemodialysis membranes (which was reported to be thicker than 70 nm in general), human serum albumin (HSA) protein adsorption assessment with scanning electron microscopy (SEM) revealed no protein adsorption at all. Other aspects of the research were reported in other published papers from the same group. Interestingly, it was noted that while MPC immobilization increment with increasing polymerization time results in loss of permeability, initiator (cerium substance) concentration control would result in grafting improvement without any performance loss [68]. Ye et al. (under the supervision of the same team) reported a blending technique to improve cellulose hemodialysis membranes further [69]. 2methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate was blended into cellulose acetate using N,N-dimethylformamide (DMF) as the solvent. Wang et al. reported the application of three different silane coupling agents to synthesize ZW structures on cellulose membranes [70]. Alkoxysilane polycondensation of three silane coupling agents ((3-carboxypropylbetaine-propyl)-trimethoxysilane (CPPT), (3-sulfopropylbetaine-propyl)-trimethoxysilane (SPPT), and (3sulfobutylbetaine-propyl)-trimethoxysilane (SBMT)) were conducted through “graft from” strategy. Polycondensation was simply performed by dipping the hydroxyl-containing cellulose membrane in immersion baths containing each previously synthesized

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ZW silane coupling agent. A higher rate of silanol supplementation and increment of hydrolysis time (to 2 h extent) was reported to increase the grafting density. Three ZW-silane structures that had almost the same structure resulted in different final grafting where SBMT had higher grafting density (around 2.6 mg/cm2). This was attributed to the higher affinity, i.e., wettability between cellulose and SBPT. Hepatocyte (liver cell) growth on the membranes was assessed through MTT assay, and SBMT was reported to be the most biocompatible membrane structure after 6 days. Zhang and his coworkers reported covalent immobilization of N,N-dimethyl-N-methacryloxyethyl-N-(3-sulfopropyl) ammonium (DMMSA) on cellulose acetate membranes using ceric ammonium nitrate (CAN) as the initiator of the one-step “grafting from” polymerization [71]. The only assessed and reported controlling factor over the extent of polymerization in the literature was DMMSA concentration in polymerization bath (proportional increment of polymer grafting with the growth of the concentration). Zero platelet adhesion of the modified membranes with even lowest concentration of DMMSA in polymerization bath (2 wt %) and complete superficial antithrombogenicity was reported; however, more analysis over biocompatibility and stability of the ZW grafted structures were not offered. Cellulose carboxybetaine “graft onto” modification was also performed using surface-initiated activator regenerated by electron transfer ATRP using 2-bromoisobutyryl bromide (BIBB) and CuBr2 were used to create Br functional, active sites over the membranes surface [64]. 2-(dimethylamino) ethyl methacrylate (DMAEMA) and pentamethyldiethylenetriamine (PMDETA, 99%) were used as initial monomers to create amine functional groups and followed by that, beta-propiolactone (PL) was used to add carboxyl groups to the functional moieties. As mentioned by Wang et al. [64] and also observed in other “graft onto” strategies, middle structures of functional initiators are commonly hydrophobic (even more than the neat unfunctionalized membranes), and accordingly, they possess more bioincompatible and protein adsorbing nature. This would ultimately affect the final result of polyzwitterionization, in case not all the active sites are turned into ZW containing structures. Best antifouling behavior and lowest contact angle were designated to tertiary amine-PL ring-opening reaction time equal to 480 min. The same membrane material and the same chemical initiator were used by Liu and his team approach was used in “graft from” strategy to immobilize N,N dimethyl- N-(p-vinylbenzyl)-N-(3sulfopropyl) ammonium (PDMVSA) [72]. ZWs were synthesized separately using random radical polymerization (RRP) using ammonium persulfate and sodium sulfite as redox initiator monomers. This research is one of a few kinds that reported thermal stability, and interestingly, the grafted membranes own higher pyrolysis temperature (Ti or initial temperature of structure decomposition). ZW grafted cellulose membrane (with polymerization time of 460 min) had higher Ti. This high thermal stability was attributed to the higher amount of doubled bond carboncarbon structures in grafted structure in comparison with weaker single bond carbon-oxygen-carbon structures in bare cellulose (with Ti around 160  C). Different polymerization times all resulted in non-platelet adhesion fouling. Liu et al. reported two other more detailed research over zwitterionization of membranes. Covalent immobilization of N,Ndimethyl-N-(p-vinylbenyl)-N-(3-sulfopropyl) ammonium)

Fig. 4. Possible zwitterionc architecture (AeK) along with zwitterionc structure, which have been used for polymer modifications ammoniophosphates (phosphobetaines or lecithin analogues) I and XIV, ammoniophosphonates (phosphonobetaines) II, IV and XV, ammoniophosphonates (phosphinobetaines) III, ammoniosulfonates (sulfobetaines) V and XVI, ammoniosulfates VI and XVII, ammoniocarboxylates (carbo- or carboxybetaines) VII, X, XI, XVIII and XXI, ammoniosulfonamides VIII, ammonisulfonamides IX, guanidiniocarboxylates (asparagine analogues) X, pyridiniocarboxylates XI, ammonio(alkoxy)dicyanoethenolates XII, ammonioboronates XIII, sulfoniocarboxylates XIX, phosphoniosulfonates XX, phosphoniocarboxylates XXI, squaraine dyes XXII, oxypyridine betaines XXIII and XXIV) [52].

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Fig. 5. Schema of “grafting to” (using complete polymer chains) and “grafting from” (using monomer blocks) for zwitterionic modification of surfaces.

(DMVSA), 2-(methacryloyloxyethyl) ethyl-dimethyl-(3sulfopropyl)-ammonium (DMMSA) and 2-methacryloyloxyethyl phosphorylcholine (MPC) [73]. Two ZWs out of the three are also included in their next research, for comparison purposes (with additional cytocompatibility studies) [73,74]. The immobilization technique was a “graft from” surface-initiated ATRP. The thermal stability of the ZW grafted membranes was tested and it was shown that cellulose covalently attached to DMVSA is more stable in comparison with the two others. Interestingly, sulfobetaine grafted surfaces had Ti near to each other (near 200  C), while phosphobetaine did not own initial decomposition temperature significantly less than the two others. Protein adsorption (general protein adsorption experiment from platelet-poor plasma (PPP) was lowest for MPC immobilized surface as it owned higher hydration layer formation capability and ionic interaction with water. All the surfaces showed zero platelet adhesion. Liu et al. compared two sulfobetaine ([2-(Methacryloyloxy)ethyl]-dimethyl-(3-sulfopropyl) ammonium (SBMA) and dimethylN-(p-vinylbenzyl)-N-(3-sulfopropyl) ammonium (DMVSA)), one phosphobetaine (2-Methacryloyloxyethyl-phosphorylcholine (MPC)) ZW and a PEG structure (all in the form of methacrylate monomers) on cellulose membranes using surface-initiated ATRP with the help of CuBr (immobilizing Br on cellulose as ATRP initiator) [74]. The comparison would have served the academic society in case a carboxybetaine was also considered in the experiments. Each experimented ZW structure and the results attributed to the modified membrane are classified in Table 2. While ZW-modified structures owned non-specific protein fouling (general protein picked from platelet-poor plasma (PPP) (less than 1 mg/cm2), zero platelet adhesion was reported for all the surfaces. Cytocompatibility of the modified surfaces was also reported to be greatly enhanced where PSBMA modified surface had a slightly better cell proliferation profile. 3D cytocompatibility test (proliferation within the hydrogel, not on membrane surface) did not’ reveal any dead cell on ZW substances, while PEG failed to perform so. 5.3. Poly (vinylidene fluoride) (PVDF) Venault et al. describe the need for a middle molecule structure in conventional ZW immobilization on the polymeric membrane in “grafting from” strategy [75]. While both coating procedures and in situ covalent binding of the ZW structures would both result in binding between the modifier structures and the base membrane (with stronger covalent bonds in in situ surface treatment due to higher entanglement of the chains). However, the economical aspects of the process reject the chance of common immobilization

techniques, such as plasma polymerization an irradiation-induced grafting, as an industrial scale candidate. Apparently, a middle structure, such as styrene, is proposed as a binder to offer hydrophobic end for covalent binding with the membrane structure and hydrophilic end for fouling control. This approach was reported to be efficient in “grafting from” strategy, which resulted in successful immobilization of SMBA-r-styrene on Poly (vinylidene fluoride) (PVDF) membrane. Chung et al. reported the application of PVDF membranes functionalized with SBMA using interfacial atmospheric plasmainduced surface copolymerization [76]. The method was proposed as a better immobilization method (with more ZW grafting control) in comparison with the same group’s previous research. Tailoring the surface modification process to optimize the grafting coverage is mentioned to significantly affect the membrane’s surface biocompatibility [77,78]. The functionalization steps were simply reported as plasma treatment, SBMA immobilization through immersion of membranes in SBMA-ethanol bath and unattached monomer removal. Surprisingly, plasma treatment time till 90 s results in the growth of grafting yield while higher treatment time, decreases the amount of SBMA attached to the surface. Grafting yield of 0.8 mgSBMA/cm2 was reported to be the saturation extent of the PVDF membrane as higher treatments resulted in no further change in contact angle (18 ). Zhang et al. have reported the application of natural occurring zwitterion structures of cysteine over PVDF membranes [79]. This could have been introduced as the application of biomimetic membranes in hemodialysis. Alkaline treatment of PVDF membranes resulted in a superficial layer of carbonyl groups, which consequently created the opportunity of PEG hydrogel immobilization on the membrane through interfacial polymerization. PEG hydrogel would ultimately create a better binding bridge for cysteine monomers to attach to the membrane. The specific area of the final treated membrane was reported to be 30% less than the original PVDF membrane; however, this did not result in less scarification of the membrane’s general performance. One of the most interesting aspects of the report was the super hydrophilic structure of the PVDF-PEGhydrogel and PVDF-Cysteine structures, which showed zero contact angle in time dependence water contact angle measurement after 1 s (initial water contact angles for the membranes were reported to be 63 and 58 respectively). Protein adsorption was tested with both bovine albumin and bovine fibrinogen. As expected, adsorption decreased by increasing the hydrogel amount and cysteine grafting. The reported amount for the modified membrane is significantly lower in comparison with other researches.

Table 2 Zwitterionic-immobilized hemocompatible polymeric membranes*1 Membrane-ZW

Immobilization method

PDMS- GMA-SBMA

and 8

* .

ZW Density (mg/ cm2)

Clotting time (sec)

Hemolysis Protein (%)*5 adhesion

N/A

N/A

N/A N/A N/A

Platelet adhesion Antibacteriality

Cytocompatibility

APTT*2 TT*3 PT*4

Antifouling properties (%)

WCA Ref. (degree)

FRR*7 RT RR RIR 90% reduction

N/A

N/A

N/ N/ N/ 79 A A A

[66]

N/A

N/A

N/A

N/A

85 hepatocyte cytocompatibility test: Enhancement reported with no clear rank order N/A 84

N/ N/ N/ N/A A A A

[70]

N/ N/ N/ N/A A A A

[70]

N/A

N/A

N/A

78

N/ N/ N/ N/A A A A

[70]

Zero adhesion

N/A

N/A

N/ N/ N/ 20.3 A A A

[74]

N/A

N/ N/ N/ 34 A A A

[74]

N/A

N/ N/ N/ 20.3 A A A

[74]

N/A

N/ A N/ A

N/ A N/ A

N/ N/A A N/ 20 A

[71]

N/ A N/ A N/ A N/ A N/ A N/ A

N/ A N/ A N/ A N/ A N/ A N/ A

N/ A N/ A N/ A N/ A N/ A N/ A

Cellulose- SBPT

Alkoxysilane polycondensation.

2.65

N/A

N/A N/A N/A

Cellulose- SPPT

Alkoxysilane polycondensation.

1.54

N/A

N/A N/A N/A

Cellulose- CPPT

Alkoxysilane polycondensation.

0.77

N/A

N/A N/A N/A

Cellulose- SBMA

Surface initiated atom transfer radical N/A polymerization

N/A

N/A N/A N/A

Cellulose- DMSVA

Surface initiated atom transfer radical N/A polymerization

N/A

N/A N/A N/A

N/A

Zero adhesion

N/A

Cellulose- MPA

Surface initiated atom transfer radical N/A polymerization “graft onto”

N/A

N/A N/A N/A

N/A

Zero adhesion

N/A

N/A

N/A

N/A N/A N/A

N/A

Zero adhesion

N/A

rat bone marrowderived stromal cell proliferation: enhanced rat bone marrowderived stromal cell proliferation: enhanced rat bone marrowderived stromal cell proliferation: enhanced N/A

Surface initiated activator regenerated N/A by electron transfer atom transfer radical polymerization Cellulose- PDMVSA atom transfer radical polymerization N/A

N/A

N/A N/A 0.3

0.3 mg cm2

Qualitative reduction

N/A

N/A

N/A

N/A

N/A N/A N/A

0.8 mg/cm2

Zero adhesion

N/A

N/A

N/A

N/A

N/A N/A N/A

0.85 mg/cm

Zero adhesion

N/A

N/A

N/A

N/A

N/A N/A N/A

0.8 mg/cm2

Zero adhesion

N/A

N/A

N/A

N/A

N/A N/A N/A

0.7 mg/cm2

Zero adhesion

N/A

N/A

N/A

N/A

N/A N/A N/A

0

Zero adhesion

N/A

N/A

N/A

N/A N/A 0.3

88% Fibrinogen adhesion reduction 90% Fibrinogen adhesion reduction

Zero adhesion

N/A

N/A

N/A

500 cells per mm2

1000 cell/mm2

N/A

92

18 15 3

N/A

N/A

99.1

N/ N/ N/ N/A A A A

[79]

N/A

N/A

N/A

[81]

N/A

N/A

N/A

N/ N/ N/ 12.3 A A A 17.2

Cellulose- DMMSA Cellulose- CBMA

Cellulose- DMVSA Cellulose- DMMSA Cellulose- MPC Cellulose- MPC

Surface initiated atom transfer radical N/A polymerization Surface initiated atom transfer radical N/A polymerization Surface initiated atom transfer radical N/A polymerization ATRP N/A

PVDF- SBMA

interfacial atmospheric plasma induced surface copolymerization

0.7

N/A

PVDF- SBMA

In situ immobilization

5

Plasma clotting 2 time was reported to be 15 min 60 21 N/A N/A

PVDF- Cysteine

PSF- SBMA-r-SSNa PSF- SBMA-b-SSNa

0.125

Surface initiated atom transfer radical 0.95 polymerization 0.88

78

18

N/A N/A

85

23

N/A N/A

ibrinogen/

2

0.017 mgBSA/cm2 Zero adhesion and 0.103 mgBFG/ cm2 4 mgBSA/cm2 and Zero adhesion 2 mgBFG/cm2

[64]

36

[72]

34

[73]

21.7

[73]

20.3

[73]

N/A

[67]

18

[76]

10

[75]

A. Mollahosseini et al. / Materials Today Chemistry 15 (2020) 100227

60% reduction

90% Fibrinogen adhesion reduction Fibrinogen qualitative reduction reported Fibrinogen qualitative reduction reported Fibrinogen qualitative reduction reported N/A

[81]

(continued on next page) 9

Membrane-ZW

10

Table 2 (continued ) Immobilization method

ZW Density (mg/ cm2)

Clotting time (sec)

Hemolysis Protein (%)*5 adhesion

16 mgBSA/cm2 87  105 cells/ cm2 and 13 mgBFG/ cm2 2.5 mg BSA or BFG/ Zero adhesion cm2

N/A 0.9

74

20

N/A N/A

76

21

N/A N/A

surface initiated atom transfer radical N/A polymerization surface initiated atom transfer radical 0.162 polymerization

N/A

N/A N/A N/A

32.5 mgBSA/cm2

59

22

11

N/A

PSF-SBMA

surface initiated atom transfer radical 0.171 polymerization

52.5

22

11

N/A

PSF- SSNa

surface initiated atom transfer radical 0.110 polymerization

73.1

22

11

N/A

PES-SBMA

In situ polymerization

N/A

75

19

N/A N/A

PES-SBMA

In situ polymerization

N/A

65

18

N/A N/A

PES- SSNa

In situ polymerization

N/A

115

18

N/A N/A

PES- SBMA-SSNa

In situ polymerization

N/A

85

18

N/A N/A

PES-SSNa-SBMA

Radical graft polymerization

0.2

55

30

10

N/A

PES- SBMA

Radical graft polymerization-

0.22

51

30

10

N/A

PES- SSNa

Radical graft polymerization

0.14

90.10

30

10

N/A

PSF- Caboxylterminated SBMA PDMS- Caboxylterminated SBMA PDMS- SBMA-co-AA

carbodiimide free radical polymerization carbodiimide free radical polymerization carbodiimide free radical polymerization

N/A

N/A

N/A N/A N/A

N/A

N/A

N/A N/A N/A

N/A

N/A

N/A N/A N/A

11.26mgBSA/cm and 5.82 mgBFG/ cm2 2.70mgBSA/cm2 and 2.51mgBFG/ cm2 13.02mgBSA/cm2 and 10.07mgBFG/ cm2 8 mgBSA/cm2 and 10 mgBFG/cm2 3 mgBSA/cm2 and 2.5 mgBFG/cm2 12.5 mgBSA/cm2 and 12 mgBFG/ cm2 8 mgBSA/cm2 and 7 mgBFG/cm2 6.5 mgBSA/cm2 and 4.2 mgBFG/ cm2 5 mgBSA/cm2 and 4 mgBFG/cm2 10 mgBSA/cm2 and 7 mgBFG/cm2 Zero fibrinogen adsorption Zero fibrinogen adsorption N/A

PU- SBMA-co-AA

carbodiimide free radical polymerization

N/A

N/A

N/A N/A N/A

N/A

PLA- SBMA*6

Atom transfer radical polymerization

1.3

N/A

N/A N/A N/A

N/A

PU- MBAA

Atom transfer polymerization

N/A

50

35.6 17.4 N/A

N/A

PSF- MAANa

WCA Ref. (degree)

98.01 N/ N/ N/ 30 A A A

[80]

N/A

human liver cells LO-2 proliferation, higher cytocompatibility N/A

N/A

[54]

N/A

N/A

N/A

Qualitative N/A reduction 5 0.12  10 cells/ N/A cm2

N/A

N/A

3.5 mgBSA/cm2 Zero adhesion and 2 mgBFG/cm2 3.5 mgBSA/cm2 50  105 and 2 mgBFG/cm2

2

N/ N/ N/ A A A N/A

N/A

N/ A N/ A

N/ A N/ A

N/ 38 A N/ 37 A

N/ A 78.41 N/ A

N/ A N/ A

N/ 38 A N/ 16.95 A

[54]

[83] [84]

0.34  105 cells/ N/A cm2

N/A

87.76 N/ N/ N/ 31.35 A A A

[84]

6.94  105 cells/ N/A cm2

N/A

72.46 N/ N/ N/ 20.80 A A A

[84]

10  105 cells/ cm2 100  105 cells/ cm2 40  105 cells/ cm2

N/A

N/A N/A

N/A

N/A

N/ A N/ A N/ A

N/ 11.1 A N/ 30 A N/ 57 A

[85]

N/A

99.11 N/ A 99.11 N/ A 62.74 N/ A 71.86 N/ A N/A N/ A

N/ A N/ A

N/ 45 A N/ 55 A

[86]

N/ A N/ A N/ A N/ A N/ A

N/ A N/ A N/ A N/ A N/ A

60  105 cells/ N/A cm2 3  105 cells/cm2 10  105 cells/cm2

N/A

3  105 cells/cm2 1  105 cells/cm2

N/A

N/A

37  105 cells/ cm2 Zero adhesion

36  105 cells/cm2

N/A

N/A

N/A

N/A

N/A

Zero adhesion

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A

N/A N/A

5

0.1  10 cells/ cm290% adhesion reduction 0.2  105 cells/ cm280% adhesion reduction 3.2  105 cells/ cm2 N/A

N/A

N/ A N/ A N/ A N/ A N/ A

[86] [86]

[87]

54

[87]

53

[87]

32.8

[92]

10

[92]

N/A

[93]

N/A

N/ N/ N/ N/A A A A

[93]

N/A

85

35 20 15 9

[88]

N/A

N/A

N/ N/ N/ 33 A A A

[91]

A. Mollahosseini et al. / Materials Today Chemistry 15 (2020) 100227

19

N/A

Antifouling properties (%) FRR*7 RT RR RIR

58

PSF- Alkylyl-ABMA and azide-SBMA PSF- Alkylyl-ABMA and azide-SBMA and citric acid PSF- DEPAS

surface initiated atom transfer radical N/A polymerization

Cytocompatibility

APTT*2 TT*3 PT*4

Surface initiated atom transfer radical polymerization PSF- SBMA

Platelet adhesion Antibacteriality

N/A N/A 0.01  105 cells/ 0 cm2 N/A N/A N/A N/A N/A Evaporation coating PP- ODA-rDMAEMA

N/A

Dip-coating PP- HEMA-b-BMA

*1: None of the papers reported values for C3a, C5a, TAT or PF4, *2: activated partial thromboplastin time; *3: Thrombin time; *4: Prothrombin time; *5: Hemolysis ranges: 0e2% of hemolysis: nonhemolytic; 2e5% of hemolysis: slightly hemolytic, more than 5% of hemolysis: hemolytic; *6: toxin clearance was reported as 66% urea and 60% creatinine; *7: in case there were flux recovery ratio measurement more than one cycle, the first cycle was reported; *8: all tests are briefly defined in hemodialysis membrane assessment methods table.

[99] 80

[98] N/A N/A 2  105 cells/cm2 N/A

Dip-coating

N/A

N/A

N/A N/A N/A

0.7mgBFG/cm2

N/A N/A 8  10 cells/cm N/A

3.4 mgBFG/cm

N/A

PP- SBAA-b-BMA

N/A

N/A

N/A N/A N/A

5

Dip-coating PP- MPC-b-BMA

N/A

N/A

N/A N/A N/A

10  105 cells/ cm2 0 3 mgBFG/cm2 N/A N/A N/A N/A Dip-coating PP- HEMA-r-BMA

N/A

2.5 mgBFG/cm2 N/A N/A N/A N/A Dip-coating PP- SBAA-r-BMA

N/A

0.5 mgBFG/cm N/A N/A N/A N/A PP- MPC-r-BMA

N/A

0

2

N/A

N/A

2

0.2 mgBFG/cm

N/A N/A N/A

2

N/A N/A N/A

N/A N/A N/A 0

Zero adhesion 2 mgBSA/cm2

O2 plasma-UV induced graft polymerization Dip-coating PP- MPDSAH

0.349

N/A

N/A N/A N/A

2

Zero adhesion 5 mgBSA/cm2 N/A N/A 0.5 N/A Self-assembly thermal evaporation PP- zP(4VP-r-ODA)

1.5

60.2

[98] 85.3

[98] 10.6

[98] 80.6

[98] 16.8

[98] 20

[97] 17

N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A N/ A 80 N/A

100% reduction for grafting density higher than 0.03 mg/cm2 N/A

N/A

85

N/ N/ N/ N/A A A A

[96]

A. Mollahosseini et al. / Materials Today Chemistry 15 (2020) 100227

11

5.4. Poly (sulfone) (PSF) Yue et al. reported chloromethylation of polysulfone membrane to create active sites for the surface-initiated atom transfer radical polymerization [80]. As reported by the research group, chloromethylation is a common method to form initiators structures eCH2Cl on polymeric structures. The “graft onto” strategy was then incorporated for the immobilization of the SBMA structure. Cl functionalized Poly (sulfone) (PSF) polymers were created before fabricating membranes through the immersion-induced phase separation technique. While general modification measures were reported through WCA, FRR, and protein adsorption measurements, liver cell proliferation on the membrane showed higher cytocompatibility on the membranes. Cytocompatibility studies revealed that human liver cells LO-2 could easily grow over the modified membranes without any proliferation of morphological change. Surface initiated ATRP of polysulfone chloromethylation (PSFeCl) was also suggested by Xiang et al. via covalent grafting of SSNa and SBMA monomers to form random (P(SBMA-co-NaSS)) and block (P(SBMA-b-NaSS)) zwitterionic copolymers on the surface [81]. Different reaction conditions were considered for the grafting of the block and random copolymerization on the surface. In the synthesis of the block copolymer, the PSBMA grafted was used as the substrate, the NaSS monomer concentration kept constant while the reaction time was increased to obtain higher grafting yield. In contrast, the PSF-Cl was used as a substrate and the reaction time kept constant, whereas the SBMA concentration decreased, and the NaSS content increased to attain higher grafting yield in the case of the random copolymer. By increasing the grafting yields, the water contact angle decreased for both the random (12.3 ) and block (17.2 ) copolymers, indicating higher surface hydrophilicity. Although this higher hydrophilicity results in considerably lower protein deposition of the P(SBMA-co-NaSS) membrane surface, the P(SBMA-b-NaSS) one demonstrated remarkably higher protein adsorption rate (both BSA and BFG) with grafting yields increment (from 4.6 to 16.1 mg/cm2). The authors attributed this higher BSA adsorption to the increased concentration of NaSS, while the NaSS content kept constant in block copolymer reaction condition, and its amount increased in case of random copolymerization. It seems that this enhanced BSA should have ascribed to the specific steric arrangement of the SBMA and NaSS in the chain structure of P(SBMA-b-NaSS) modified membrane. In other words, the longer chain structure of SBMA imparts steric hindrance to the NaSS monomers. Although both the BSA and BFG adsorption decreased considerably by decreasing the SBMA concentration and increasing the NaSS content in the case of P(SBMA-co-NaSS) membrane, an optimum concentration could have considered for these monomers to attain the lowest protein adsorption. Accordingly, there must be other explanations, and those might be the steric hindrance of SBMA monomers, the charge balance disturbance after copolymerization, the different surface roughness of P(SBMA-b-NaSS) membrane with that of P(SBMA-coNaSS) one. The charge balance could have been better assessed if the researchers had measured the surface zeta-potential accompanied by addressing more discussions over the surface charge of P(SBMA-co-NaSS) and P(SBMA-b-NaSS) of the modified membranes. The FRR parameter was reported only for two random and block copolymer grafted membranes, which represented the lowest protein adsorption rate. Although the PBS flux was decreased considerably after the zwitterionic copolymers grafting most likely due to the membrane pore blocking [80,82], both the block and random copolymer modified membranes showed improved antifouling property than the PSFeCl membrane. Simultaneously, the P(SBMA-co-NaSS) modified membrane

12

A. Mollahosseini et al. / Materials Today Chemistry 15 (2020) 100227

presented higher FRR compared to that of the P(SBMA-b-NaSS) one. Besides, the influence of the chemical structures of the block and random copolymers was also investigated on the blood compatibility of the modified membranes, and the results of hemocompatibility tests are listed Table 2 in terms of the best clotting time (APTT and TT). Even though the clotting time of the P(SBMA-bNaSS) modified membrane was slightly better than that of the P(SBMA-co-NaSS) one, the hemocompatibility results of the random copolymer modified membrane were reported to be more acceptable due to improved resistance against protein adsorption and platelet deposition. Layer by Layer (LBL) assembly of the ZW structures on PSF was reported Xiang et al. to covalently attach alkynylpoly(sulfobetainemethacrylate) (alkylyl-PSBMA) and azidepoly(sulfobetaine methacrylate) (azide-PSBMA) [54]. The “graft onto” strategy was applied for the fabrication of membranes, which were previously functionalized with azide groups using chloromethylation and oxidation reactions. Different numbers of covalently immobilized ZW layers were attached to the surface so that the final structure could have both alkylyl-PSBMA and azidePSBMA. This structure was compared with the same structure bearing immobilized citric acid on the top layer. Citric acid could bind to Ca2þ in blood cells and consequently suppress the coagulation cascade. Water contact angle, protein adsorption (BSA or BFG), and blood clotting improvement behaviors did not change significantly for ZW-citric acid-containing membranes and ZW immobilized membranes (slightly better conditions for samples with citric acid). The number of immobilized ZW layers growth also had a negligible effect on the hydrophilicity and protein resistance of the surfaces. Platelet adhesion, however, was affected by the citric acid immobilization and a higher amount of attachments in stretched forms of pseudopodia. Samples without citric acid, had all zero adhesion regardless of the number of layers. Similar efforts related to combination of ATRP and click chemistry were reported by Gu et al. [83] who immobilize N,N-diethyl-N-propargyl-N-(3sulfopropyl) ammonium (DEPAS) on PSF membranes and by Xiang et al. [84] who used the same technique to compare SMBA, SSNa, and sodium methacrylate (MAANa) as reported in Table 2. 5.5. Poly (ether sulfone) (PES) Poly (ether sulfone) (PES) hemodialysis ZW modification was also reported by a few authors [85e87]. Zhao’s research team suggested polymer modification before blending in different studies [85,86]. In-situ membrane modification was offered by blending PES with SBMA as ZW modifier, AIBN as initiator, and N,N’ eMethylenebisacrylamide (MBA) as cross-linker [85]. He reported the general biocompatibility aspects along with more focus on ionic strength sensitivity of the zwitterionized structure. The same synthesizing approach was suggested by the group in another paper, with a detailed comparison of SBMA and SSNa [86]. While the authors mentioned the membrane with both SBMA and SSNa had the best performance, based on the published data, SBMA in situ treatment of PES membrane resulted in higher hydrophilicity along with better protein resistance. The platelet adhesion resistance and APTT clotting time were reported to be significantly improved for the samples with SSNa only. Accordingly, no clear best candidate could be introduced out of the modified membranes. Along with initial polymer modification, the same team reported surface zwitterionization of PES for biocompatible applications [87] (discussed in another section). Xie and his team proposed the application of sodium polystyrene sulfonate (more specifically sodium 4- vinylbenzenesulfonate) (SSNa) beside SBMA to create both advantages of zwitterionization and biomimetic surfaces on PES membranes

[87]. Styrene (as mentioned by Vanualt [75]) enhances the attachment of ZW substances due to owning hydrophilic and hydrophobic moieties. Furthermore, as reported by Xie et al. SSNa possesses sulfonic groups, which mimic the structure of heparin anticoagulant. To pursue this, initially, membrane surface was functionalized with hydroxyl functional groups through in situ cross-linking polymerization (by blending 2-Hydroxyethyl methacrylate (HEMA), azobisisobutyronitrile (AIBN) and polyethylene glycol (PEG)) with PES before casting). Amine containing functional groups were created as active sites over the membrane by treating the surface with ammonium persulfate (APS). SSNa-co-SBMA was grafted on membranes through covalent binding (free radical polymerization) of vinyl functional group (present in styrene structure) of the ZW containing copolymer and active sites created on membrane. Rather than the clotting time experiments, which were slightly better for the samples with SSNa only, contact angle, fibrinogen adsorption and antibacterial behavior of the modified samples with both SSNa and SBMA (1:3 wt ratio) were reported to be better. 5.6. Poly (lactic acid) (PLA) Zhu et al. reported the application of ATRP to immobilize SBMA on Poly (lactic acid) (PLA) membranes. Dopamine inspired bromoalkyl initiator was used to pretreating membranes for “grafting from” procedure [88]. Dopamine was mentioned to own neurotransmitter behavior, and within the alkaline environment and in the presence of oxidants, it could self-polymerize [89,90]. Accordingly, dopamine and similar structures could be used as individual modifiers of membrane surfaces or as an initiator for further modification. The paper is one of the few ones, which reported the clearance performance of the membrane, 66% for urea, and 60% for creatinine. The effect of ATRP duration was studied, and the best values were reported to be for the highest reaction time (10 h). 5.7. Polyurethane (PU) Huang et al. reported three-step immobilization of N,N0 -methylene bisacrylamide (MBAA) on Poly (urethane) (PU) membranes with initially PEG immobilized layer [91]. Ce (IV)-induced atom transfer polymerization was used to immobilize MBAA over pretreated membranes. Clotting time tests of APTT, TT, and PT were reported as measures of biocompatibility of membranes without any further measurements. While step by step modification (Hexamethylenediisocyanate (HDI) functionalization, PEG immobilization, and zwitterionization) resulted in biocompatibility characteristics growth; PT test result was slightly shorter clotting time for ZW-immobilized membranes. LBL assembly of ZW structures (poly(ethylene imine) (PEI), poly(acrylic acid)-g-azide (PAA-g-AZ), and PEI) on two membranes structures (PSF and PDMS) followed by UV irradiation was proposed to enhance the biocompatibility of the hemodialysis membranes [92]. This was performed to create a tri-layer polyelectrolyte (TLP) coated sublayer, which was then used for carboxylterminated-SMBA immobilization (using carbodiimide free radical polymerization). The study focused more on different pHs and behavior of ZWs. Water contact angle, fibrinogen adsorption, and platelet adhesion were three measures that were reported (as seen in Table 2). The same group used the same TLP structure and immobilization method for SBMA-co-acrylic acid (SBMA-co-AA) on non-polymeric substrates [93]. PU and PDMS substrates were immobilized with SBMA-co-AA structures, and platelet adhesion was reported to be more effectively eliminated for PDMS. The aforesaid research targeted again various pH range of 3e10 for hemocompatibility assessment, which seems illogical as

A. Mollahosseini et al. / Materials Today Chemistry 15 (2020) 100227

hemodialysis membranes are meant to operate within blood pH range with specific and narrow pH range. More research over nonpolymeric membrane substrates with polyelectrolyte layers, including SBMA copolymers, could be found elsewhere [93e95]. 5.8. Polypropylene (PP) Random copolymers octadecyl acrylate (ODA) and 4vinylpyrrolydene (4VP) (zP(4VP-r-ODA)) [96], [3-(methacryloylamino)propyl]- dimethyl(3-sulfopropyl) ammonium hydroxide (MPDSAH) [97], random and block copolymers of MPC, [3(methacryloylamino)propyl] dimethyl(3-sulfopropyl)ammonium hydroxide inner salt (SBAA), and HEMA [98], and random copolymers of ODA and 2-(dimethylamino)ethyl methacrylate (DMAEMA) (ODA-r-DMAEMA) [99] were reported as ZW structures, which were immobilized on ply (propylene) (PP) membranes for improving hemocompatibility. Chen et al. reported a comparatively complete study over the immobilization of different ZW materials on PP, which was initially coated with MBA hydrophobic structures. MBA coating on PP allowed attachment of the nonionic structures [98]. MBA has a hydrophobic nature, and it could completely affect the biocompatible behavior of the surfaces. However, as it could assist higher self-attachment of the ZW materials, in case of complete surface coverage, there could be a better hemocompatible profile achieved. While the ZW structures were synthesized separately using reversible additioneRAFT technique, immobilization of the random and block copolymers was performed simply by dip-coating techniques. Interestingly, block copolymers resulted in better fibrinogen attachment elimination on the membranes’ surface in comparison with random copolymers of the same kind. The trend, however, was not the same for other assessment aspects as platelet adhesion was completely eliminated for MPC-r-BMA, SBAA-r-BMA, and also MPC-b-BMA, however other membranes, despite lower platelet adhesion in comparison with the PP membrane, still showed attached and activated form of platelets. 6. Differences between final immobilized zwitterionic structures This section will cover different characteristics of a surfaceimmobilized zwitterionic structure on its general behavior and nonspecific protein resistance. Charges: One of the most important factors in designing zwitterionic structures for hemocompatibility is the right selection of positive and negative charges as the two ionic groups will define, to a great extent, the overall behavior of zwitterionic structure. There are several types of charges, which one could use to design a zwitterionic structure. Hydration layer formation is identified as one of the main mechanisms of nonspecific protein repulsion by zwitterionized surface. The hydration energy of a zwitterionized surface must be minimized to achieve a denser hydration layer. A general understanding of charged structures suggests that the more electronegative a structure gets, the more water molecule it attracts. This idea is correct in the field of water treatment when general higher hydrophilicity is desirable. However, the case is different for blood proteins. Zwitterionic structures’ charged moieties decrease each other’s charge density [100]. Accordingly, the strongest charge may result in the most intense diminishment in charge density [101]. Molecular dynamics simulation performed by Shao et al. reveals that a perfect zwitterionic structure for nonspecific protein resistance must own a low positively charged moiety (to prevent interaction with carboxylic groups on proteins’ surface) with minimum attached hydrogens (to prevent self-

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association between zwitterionic structures) and high-charged anionic group [101]. Connector branch: Another important factor, which is also missed in many articles, is the organic branch, which connects the two charges. Functional groups present on the branch, as well as the length of the branch, will affect the behavior of the zwitterionic structure immobilized on the surface [102]. In a zwitterionic structure with a short connector (one carboxylic group), wider dipole orientation was observed along with shorter hydration shell residence time. While it is commonly believed that longer hydration residence time would result in a higher hemocompatibility degree, a wide range of dipole distribution would reflect a surface, which provokes blood proteins to a smaller extent. It is worth mentioning that most of the variations in electrostatic behavior are designated to negatively charged ion, and the positive charges structure hydration does not change by changing the connector’s length. Yet the authors of this paper believe that choosing a proper positive ion is crucial for designing an optimum zwitterionic structure, as it plays a significant role in adjusting the dipole’s final distribution. Dipoles: Rather than the chemical route, monomers and reagents could have a substantial influence on the final structure of the hemocompatible membrane. The charge stoichiometry of polyions could be equal, which results in a final electroneutral structure (desirable for hemocompatibility). Despite the fact that higher immobilization surface density results in higher surface modification characteristics, based on the computational efforts [44], a minimized net dipole moment is desirable to achieve hemocompatible surface as large dipole accumulation of zwitterionic materials would result in higher protein stimulation. Antiparallel distribution of each ZW branch’s positive-negative dipoles would also result in the minimization of electrostatic energy [44]. Coating surface density is identified among the key factors for optimized modification [103], yet there are cases in which lower surface densities have resulted in better hemocompatibility. An initial conclusion based on the literature reviews would be equality of “graft to” and “graft from” techniques as both methodologies would result in ultralow fouling [104]. This was reported in the royal society of chemistry (RSC), a highly prestigious journal; however, the authors of the present work believe the key to higher hemocompatible membranes is a random distribution of zwitterionic structures (dipoles) and electroneutrality of the final structure. Despite the general belief that gradual growth of ZW structures through “graft from” could result in a gradual growth and higher final surface density, “graft to” strategy takes advantage of a random distribution of zwitterionic structures and owns a higher chance for commercialization. Hydration energy: Another important comparison offered by Shao et al. [105], who compared zwitterionic structures with PEG, revealed that the hydration energy of ZWs is lower than the nonionic structure of the PEG. Since one explanation for protein resistant surfaces is the hydration layer on the surface-modified membrane, the minimization of hydration energy to reach the highest hydration is crucial. In spite of the fact that molecular simulations are available for ZWs, no one has offered a comparison between different newly proposed ZW architectures and their related hydration energy comparison. Based on the previously mentioned parameters, the authors of this research believe any high-yield “graft from” technique (as it results in more randomly located and wide distribution of dipoles), with a weekly charged cationic group which owns zero or minimum number of attached hydrogens (to eliminate interaction with carboxyl groups on blood proteins) and moderately charges anionic group with final neutral structures on the surface, would enhance the hemocompatibility of a hemodialysis membrane to the best

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extent. An example of such a suggestion would be a zwitterionic structure with quaternary ammonium (with no hydrogen attached) as the positive moiety and a carboxylic group as the negative moiety. 7. Zwitterionization techniques Atom transfer radical polymerization (ATRP), a living polymerization method, has been so far used as the most common technique for surface zwitterionization of the hemodialysis membranes. Most of the articles that are reviewed here, also include ATRP as the zwitterionization method. The technique owns several advantages, i.e., control over the growth of ZW polymeric chain, low disparities (Mw/Mn˂1.1), control over the sequence of the blocks (to have a block, graft, or altering gradient copolymers) [106]. The reaction (Fig. 6) is an equilibrium between propagating radicals and dormant species in the form of alkyl halidesmacromolecules (Pn-X). Transition metal complexes’ reaction with dormant species. The produced radicals could propagate with a vinyl monomer or terminate by disproportionation or be reversibly deactivated [107,108]. The process is a catalytic reaction, and metal oxides are frequently used as mediators. The redox equilibrium mediated process of ATRP commonly involves metal catalysts, such as Cu(I), Ru(II) or Fe(II). However, metal contamination is considered a huge issue in the field of biomaterial production [110e112]. Accordingly, a key limiting factor in zwitterionized hemodialysis membranes is the right incorporation of the catalyst. For resolving this issue, several approaches were taken, such as reduction of the catalyst amount (which might affect the surface density), removal of the metal residues (which will create further production step) or utilization of new non-metal catalysts [58]. In spite of the signs of progress in metal-free ATRP, new catalysts and reagents result in structures that could contribute to self-association of immobilized structures, or reaction of newly formed hydrogen bonds with negatively charged functional groups on proteins’ surface. Although most of the articles present ATRP as the zwitterionization technique, different reagents and catalysts are used. Based on introduced affecting parameters in the previous section, a comparison of these structures would not be possible without computational tools. Accordingly, the effect of different reagents and structures on model proteins and in the aqueous environment will be offered by the same authorship soon. 8. Discussion 8.1. Critical assessments of hemodialysis membrane hemocompatibility There are numerous efforts over modifying polymeric membranes and in general materials that are supposed to be in direct contact with tissues and blood. However, it’ is unfortunate incompletely reported in most of the cases as assessment methods of newly modified products are limited to a few tests. In the case of ZW immobilized membranes, as reported in the previous section, most of the researchers have relied on the limited, modified aspects of membranes, such as higher hydrophilicity or less platelet adhesion. There is a defined framework for hemocompatibility assessment of materials. International standardization organization (ISO) has issued guidelines over hemocompatibility measures in medical device evaluations [14]. Accordingly, modified biohemocompatible hemodialysis membrane should pass thrombosis, coagulation, platelet adhesion resistance, immunology (complement systems and leukocytes), and hematology tests [14]. The complement system involves more than 30 proteins, from which C3a and C5a are commonly used to assess cascade activation

[113]. While it is common to involve complement activation assessment through the aforesaid proteins in hemocompatibility improvement studies, none of the literature reviewed the reported measurement of C3a and C5a. Similarly, platelet factor 4 (PF4) and thrombin-antithrombin III complex (TAT) measurements were not presented. To offer a better understanding of what the modifications could result in studying the hemocompatibility to a complete extent is inevitable. One of the main gaps of the hemocompatible hemodialysis membrane field is accordingly lack of accurate and complementary assessments.

8.2. Debates over ZW immobilization techniques and surface grafting density As mentioned previously, there have been many methods through which ZWs could be covalently immobilized on membrane surfaces. There are several aspects to consider, such as ease of procedures, number of steps, environmentally friendly processes, efficiency, and grafting density. While final grafting density is mentioned to be an important index, no one, by the extent of the authors’ knowledge, has ever gone through the discussion, which offers information about the proper amount of grafting, which could perform all the desired targets of a hemocompatible membrane. Step by step ZW using monomers would result in higher densities in comparison with grafting a macromolecule at once. Moreover, for high energy-induced methods, such as UV or plasmainitiated graft polymerization, there is a level of energy exposure from which the polymeric structures would be affected. So far, every researcher has mentioned the grafting density of a utilized method, but questions still remaining to be answered are as to what extent grafting should be increased? Is there any low grafting density, enough and acceptable, to be used in blood purification processes? Researches focusing on antifouling aspects of polymeric membrane zwitterionization have tried to answer these questions. It was reported that surface grafting densities between 0.5 and 1 mg/cm2 would efficiently eliminate fouling on membranes. Higher grafting densities (as a result of higher reaction times) will not further improve the outcome significantly [80,97,114]. This was, however, mentioned to be a function of stability, flexibility, composition and length of the ZW grafted material [96]. The gap still to be addressed, is the same, for each polymeric membrane and each ZW material with the purpose of hemocompatibility. Simpler methods, such as UV-assisted immobilization would be applicable for those base membrane materials, which are highly photosensitive. Simple methods could have a better potential for industrialization of production processes. Instances of industrial membrane production using UV or IR treatment have been mentioned in the water treatment area (crosslinking of polyamide structures). Irradiation on photosensitive polymer would result in the generation of free radicals, which consequently would let the surface be further modified through grafting of polymerization initiators or the modifier moiety directly. Accordingly, the initial difference between irradiation-assisted immobilization of ZW

Fig. 6. Metal-catalyzed ATRP mechanism; Mt:transition metal, L:complexing ligand, Pn:polymer chain, Pn*:growing radicals, X:halies, m:oxidation state, kact and kdeact:reaction constants (reproduced with permission from Elzevier and ACS [106,109]).

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materials and conventional chemical routes, such as ATRP, would be using UV for superficial free radical production. Instances of photosensitive polymers for such an application are PSF and PES [53]. While irradiation assisted immobilization of ZW materials over membranes has the advantage of an easier and faster fabrication process, degradation chances exist due to high energy exposure (as previously mentioned in section 4.2. This, however, will only happen if the ZW structure would be exposed to high energy irradiation itself (when irradiation is used for covalent attachment of membrane surface, not creating initial grafting sites [115]). More importantly, there has been reported a level from which higher irradiation will appear to be destructive for zwitterions. Accordingly, there is always an optimum level of UV exposure, which depends on the membrane and zwitterion’s chemical structure. Finding this optimum condition might help the field to have a more efficient and economical immobilization procedure. Fig. 7 depicts different ZW grafting densities on polymeric membrane surfaces. Based on the reviewed literature, SBMA had the highest rate of immobilization of 5 mg/cm2 (with in situ immobilization technique) [75]. The highest grafting density did not result in non-protein fouling and no-platelet adhesion. Interestingly other membranes with lower grafting density of same ZW structure did reach to such desired condition (This includes PPzP(4VP-r-ODA) with grafting densities higher than 0.03 mg/cm2 [96], PP-MPDASH with 0.349 mg/cm2 [97], PVDF-cysteine with 0.125 mg/cm2 [79], and PSF-SBMA-r-SSNa with 0.95 mg/cm2 [81], all of which showed zero platelet adhesion and low protein fouling). Accordingly, the polymeric membrane affects the final behavior of the modified blood purification system, although it is intensively covered by the hemocompatible ZW structure. It is worth mentioning that PVDF-SBMA with lower grafting density (0.7 mg/cm2) with interfacial atmospheric plasma-induced surface copolymerization as an immobilization method [76] also resulted in zero platelet adhesion. This means that in case the base polymer and the ZW are similar, there are still other affecting parameters, such as immobilization technique, which could affect the final performance of the membranes. The authors of this paper suggest a grafting density between 0.3 and 1 mg/cm2 depending on the type of ZW.

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8.3. Clotting time assessment of ZW- immobilized membranes Activated partial thromboplastin time (APTT) and thrombin time (TT) are common tests to antithrombogenicity evaluation of the prepared hemodialysis membranes [116]. APTT assay conducts an assessment of clotting time by reflecting the formation of stable fibrin clots as a result of Factor XII activation [14]. Fig. 8 illustrates the bar chart representing APTT values based on Table 2. This is, however, not a holistic assessment, as many of the researches did not consider the test. The highest value (115 s) is reported for SSNa immobilization over PES membranes, and the lowest (51 s) is attributed to the PU-MBAA membrane. Most of the reported values are between 55 and 90 s. SBMA immobilized membranes as one of the most frequent modified structures had APTT values ranging from 51 to 75 s (both immobilized over PES). In comparison with SSNa immobilized membranes, SBMA containing membranes owned lower APTT clotting time. The experiments with combined copolymers of SBMA-SSNa showed slightly better APTT clotting time. Accordingly, despite the general believes that SBMA is the best ZW option, setting APTT as a comparison index reveals that SSNa significantly better. Fig. 9 shows clotting time assessment based on TT measurement. Values range from 18 to 35.6 s. Just like APTT, the highest TT value is attributed to the SSNa immobilized over PES membranes, and combined ZW structures of SBMA-SSNa showed higher TT in comparison with individual SBMA membranes. 8.4. Influence of ZW- immobilized membranes on clearance performance Dialysis modes could own different fluxes in a defined range, based on the modality and medical prescription considered. The performance of blood purification systems must be reported based on these fluxes and uremic toxin clearance. Unfortunately, few reports included such data over the clearance of creatinine and uremia. A commonly reported aspect of the papers, however, was the flux recovery ratio (FRR). This was along with reporting fouling resistances of different kinds (reversible, irreversible, and total). FRR improvement reveals the ability of the modified membrane to

Fig. 7. Grafting density of ZW materials on hemodialysis polymeric membranes.

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Fig. 8. APTT values for zwitterionic immobilized polymeric membranes.

Fig. 9. TT values for zwitterionic immobilized polymeric membranes.

be less prone to fouling. While this could be important for hemodialysis membranes to some extent, high resistance to fouling is not concerning the field as the main barrier at this moment. Fig. 10 depicts available FRR values in the reviewed literature. PVDF, PSF, and PES modified membranes owned FRR higher than 98%. SBMA immobilized PES and PSF membranes showed superior FRR values (99.11 and 98.01, respectively). Similar values for PVDF membranes was achieved when cysteine was used on the surface. The combination of PVDF and SBMA, however, did not result in FRR

percentages higher than 92. The SSNa ZW structures also did not result in significant FRR values, despite acceptable performances in clotting time assessments. The water contact angle of the membranes was also reported as an index of surface hydrophilicity. Hydrophilicity could be hugely affected by the change in surface chemistry, available functional groups, and surface charge. As it is conventionally believed that more hydrophilic surfaces own a higher degree of hemocompatibility, many researchers have an attempt to modify blood

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Fig. 10. Flux recovery ratio for zwitterion-immobilized membranes.

purification membranes by improving hydrophilicity. Fig. 11 reports contact angle values for ZW modified membranes. There were only three membranes with WCA values equal to or lower than 10 (PLA-SBMA, PDMS-carboxyl terminated SBMA, and PVDFSBMA). Surprisingly, the immobilization of SBMA alone on the membranes resulted in WCA less than 30, with the exception of PES-SBMA, which had WCA value around 54. Hydrophilicity, along with surface topological, chemical, and electrochemical characteristics, could all together result in a better understanding of the fouling behavior of membranes [117e119]. 8.5. Key findings of fibrinogen and proteins adsorption There are debates over the good and bad aspects of protein fouling on hemodialysis membranes. The initial key player, which was suspected to be a key role player, was fibrinogen. Fibrinogen was thought to be chemically inducing interactions between exterior materials (herein, hemodialysis membranes) and platelet [120,121]. Fibrinogen is a protein with two disulfide parts bridged together. The fibrin polymerization production process is initiated through fibrinopeptide A (FPA) [122]. Interactive sites present on fibrinogen surface, turn the protein, simultaneous (sometimes overlapping) role player in several biological reactions in blood [122]. Based on the published literature, fibrinogen adsorption in the smallest amounts (about 10 ng/cm2), could trigger a complete thrombosis and embolism [123]. On the other hand, protein adsorption experiments using bloodstreams have proven that ZW immobilized membranes with zero platelet adhesion characteristics, still adsorb proteins [72]. Accordingly, the functionality of the protein interaction to fibrinogen has to be more specific studies. Another more mature hypothesis is the conformational variations in fibrinogen structure as a result of “receptor-induced binding site” exposure. Exposed binding sites would trigger the “ligand-induced binding site” on the platelet outer membrane. Accordingly, the

conformation of adsorbed fibrinogen could induce the platelet adsorption and following cascade activations [72,120,121,124]. However, this is still a hypothesis and more importantly, it has to be proven that these incidences occur just for fibrinogen and not others. Otherwise, the general conformation of all adsorbed proteins should be assessed in detail as fibrinogen is only one of the hundreds of proteins available in the blood. 8.6. Influence of ZW-Immobilized membrane on fibrinogen and albumin adsorption Fibrinogen adsorption on the membrane surface is one of the aspects that had been attracting much attention in dialysis membrane modification studies. Due to fibrinogen’s ability to bind to Gb IIb/IIIa receptors of platelet, adsorption studies of this protein is believed to be advantageous in biocompatibility studies [54]. There are available reports over higher importance of fibrinogen conformation after being adsorbed on the hemodialysis membrane in comparison with the adsorption amount itself [120,121]. Accordingly, controlling the conformational behavior of the adsorbed proteins seems to own a higher level of importance. Zwitterionization of surfaces is mentioned to reduce the conformation of adsorbed proteins, and as a result, activation cascades are controlled for platelets [49,125]. Fig. 12 shows the fibrinogen adsorption amount (in mg/cm2) on the surface-modified membranes. The target value would be zero amount of attachment, which was achieved with PSF and PDMS membranes, which were both modified using carboxyl terminated SBMA zwitterionic structures. The common reported value lay between 0.2 and 3 mg/cm2. The highest reported amount, however, is 32.5, 13, and 10.5, all related to PSF, immobilized with DEPAS, SBMA-b-SSNa, and SSNa, respectively. The main reason in all literature for protein adsorption is mentioned to be hydrophilicity. Since higher wettability and hydrophilicity profiles result in thicker hydration layer, accordingly, fewer chances would

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Fig. 11. water contact angle for modified zwitterionic immobilized membranes.

exist for proteins to be attached to membrane surfaces. Higher PSF-DEPAS protein adsorption in comparison with other ZW immobilized surfaces could be due to the higher hydrophobicity, charge disturbance of ZWs after immobilization, or grafting density differences. Sadly, no assessment method has yet been reported for further study of the conformation of adsorbed fibrinogen. Fig. 13 depicts the values related to adsorbed bovine serum albumin (BSA) values on the modified membranes. While BSA is frequently being used in membrane performance tests, human serum albumin (HSA) would have served better than BSA in hemocompatibility studies. Fig. 14 compares the results available for both fibrinogen and BSA. Fibrinogen is slightly adsorbed less than to the membranes’ surfaces (with PES-SMBA as an exception). Highest albumin-fibrinogen adsorption difference is attributed to PVDF-cysteine (83%) and PSF-SBMA-r-SSNa (50%). The lowest difference is observed for PES-SSNa (4%). Higher adsorption, a protein, in a similar experimental condition is normally attributed to the higher molecular weight of the protein and surface chemistry. However, a deeper understanding of conformation behaviors and the role of specific protein residues could significantly affect future blood purification technologies.

8.7. Influence of ZW-Immobilized membrane on hemolysis An important aspect of hemocompatibility assessment, which was not commonly reported in the papers, is hemolysis percentage. This index reflects the percentage of cell destruction (especially for red blood cells, i.e., erythrocytes, which are the most fragile cell types in the bloodstream), which is followed by hemoglobin release. Red blood cell damage could result in platelet activation and further cascade system activations. The desired values of hemolysis factor should be less than 2% so that the membrane could be identified as non-hemolytic material [126]. All the reported hemolysis percentages in the papers are less than 2. Fig. 15 depicts the hemolysis percentage available in the reviewed literature. PVDF membrane modified with SBMA owned the highest hemolysis percentage (2%); however, it still remained in the nonhemolytic range. Since there are other PVDF membranes with SBMA, which reflected better behavior, there must be other factors rather than the ZW immobilized structure and base membrane. These factors could be listed as charge neutrality of ZW after immobilization, surface topological pattern (roughness), test condition, etc. Better characteristics regarding the hemolysis factor are attributed to cellulose-CBMA (0.3%).

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Fig. 12. Fibrinogen adsorption on zwitterionic-immobilized membranes (mg/cm2).

8.8. Influence of ZW immobilization technique on electro-neutrality As it is understood, one of the main ZW’s characteristics is neutrality in charge. While this is being mentioned by almost every researcher, the fact that the immobilization technique affects the charges and composition of the ZW structure on the membrane is ignored commonly. Although several types of research reported the hemocompatibility of ZW immobilized structures, in case the neutrality of the structure is jeopardized, the final result would not be what the ZW could have shown as hemocompatible behavior individually. This was reported by

Chang et al. [76], who proved that high plasma treatment time might affect the ratio of opposite functional charges atoms. Accordingly, one might bear in mind the importance of the immobilization method as it could affect the final neutrality of the immobilized modifiers. 8.9. Effect of polymer substrate of ZW structure on hazard ratio Several substrates were used in hemocompatible blood purification membranes, including PSF, PES, PU, PP, PDMS, PVDF, and cellulose acetate. Each membrane material has a specific chemical

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Fig. 13. Albumin adsorption on zwitterionic-immobilized membranes (mg/cm2).

Fig. 14. Comparison between albumin and fibrinogen adsorption on zwitterionic-immobilized membranes (mg/cm2).

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Fig. 15. Hemolysis percentage reported for zwitterion-immobilized hemocompatible membranes.

characteristic which offers an opportunity to further functionalize the surface. While there are debates over the priority of some of the materials over the others, researches revealed that the same immobilization method and the same ZW immobilized structure would result in different hemocompatible behaviors for different polymeric substrates [93]. A major share (more than 93%) of blood purification membranes (no matter what modalities, hemodialysis, hemodiafiltration, and hemofiltration) are made from poly (arylsulfones) (with the distribution of 22% PES and 77% PSF) [127]. A reason for this share distribution is the capability of aryl ether sulfone family to be controlled and to deliver a desirable range of pore size and molecular weight cut off. On the other hand, PSF membranes have the capacity to remove a broad range of uremic toxins, effectively retain endotoxins due to its controlled MWCO. In addition to its higher sieving capability, PSF has an increased hydraulic permeability promotes efficient transport through solvent drag (convection). A major percent of modifications reviewed in this article are done over the mentioned membranes. There are debates over the probability of the relationship between using PSF membranes and the rate of mortality of the patients. Research observing more than 139,000 patients revealed that most mortality rate is attributed to PSF membranes (comparison was made between cellulose triacetate (CTA), polyester polymer alloy, poly(methyl methacrylate) (PMMA), PSF, PES, ethylene vinyl alcohol (EVAL) and PAN [128]. The research announced PMMA membranes to have the lowest hazard ratio (HR) (the factor that they defined for comparing membranes). Interestingly, one of the biggest questions of the field would be as to why the biggest share of blood purification membranes is devoted to a membrane with higher HR. 9. Conclusion and outlook Several approaches are so far introduced for hemodialysis membrane modification. For comparing different advantages and disadvantages of these modification strategies, there should exist a framework of comparison, which brings aspects of the process together. There are several important factors from a technical point of view, such as easier methods for material synthesis, room condition immobilization techniques (instead of a high-tech device-

based immobilizations), lower final cost. As the technology is related to human health, a more important side of modification strategies would be the final performance and hemocompatibility. High hemocompatible membranes are commonly reported as the result of ZW immobilization over polymeric membranes. Regarding clotting time assessments, SBMA and SSNa immobilized on PVDF and PES membranes, resulted in more elongated clotting times. The highest flux recovery ratio was also attributed to the PES-SBMA membranes. Interestingly, cysteine immobilized PVDF membranes had lowed protein adsorption profiles, which implies that there are great chances to be natural hemocompatible structures. PLA, PVDF, and PES, all three with SBMA, had the best hydrophilicity profiles. While ZW-immobilized membranes are introduced as a new generation of hemocompatible dialysis membranes, there are still many steps for the appropriate incorporation of such products in extracorporeal therapies. Since there are different modification techniques (immobilization methods), base polymeric membranes, various ZW structures and modalities, a holistic investigation must be performed to reach to best combination for each purpose. Low mechanical strength and thermal stability high cost and complicated production process are also three main concerns in using membranes with ZW structures. Several aspects of the field are still not clear; the effect of zwitterionization on clearance, charge neutrality after immobilization and modification influences on complement cascade activations. The scalability of the modified membranes also is an important aspect of the field. Although there are higher hopes for more hemocompatible membranes through zwitterionization, without addressing the aforesaid concerns, there could not be fast and efficient progress toward a complete hemocompatible membrane. The authors believe the key to finding the best structure for enhancing hemocompatibility of hemodialysis membranes is hidden in understanding the molecular behavior of the immobilized structures through molecular dynamics simulations and density functional theory studies. While several previous efforts have been reported regarding these studies, experimentally proposed structures must be further analyzed by computational simulations to further understand their hydration profiles, self-associations, hydrogen bonding, dipole distribution, mechanical stability, etc.

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Accordingly, based on the advantages of the widely distributed dipole, “graft from” was suggested as the better modification technique.

Hemodialysis membranes Hemocompatibility assessments techniques’ description. No. Test name

Description

1

Clotting time

2

Hemolysis

3

Cytocompatibility

4

Protein adhesion

5

Complement activation

6

Platelet adhesion and activation

Clotting time assessments measure the time duration from blood contact initiation to the point when clots are created. The most common factor to assess regarding this would be activated partial thromboplastin time (APTT). While it is frequently used for biocompatibility screening, APTT could also assist the measurement of functional deficiencies in fibrinogen, Factors II, III, VIII, and X [129,130]. Thrombin time (TT) test is a clinical laboratory core test, which reflects the abnormalities in fibrinogen to fibrin conversion. This factor could be affected by the presence of inhibitors (anticoagulation substances), hypofibrinogenemia and dysfibrinogenemia [130]. Prothrombin time (PT) test is a method for simply measuring the time it takes for the blood to clot [131]. PT and TT are commonly used for antithrombogenity evaluation of the prepared hemodialysis membranes [116]. This could be conducted either with the conventional manual methods using special kits or with the assistance of automated blood coagulation analyzer devices. Hemolysis assessment could be presented as an authentic method for the hemocompatibility of the membranes. This method is incorporated to assess enhancement in modified membrane samples in comparison with the neat ones. The calculation is based on ISO 10993e4 (2009) standard and measures the supernatant absorbance from membrane and control samples incubation media with diluted blood in normal saline solution (formulations could be found elsewhere [132]). Accordingly, the final number reported is a comparisonbased percentage. Based on the introduced standard, classification of hemolytic materials would be as: (i) 0e2% of hemolysis: non-hemolytic, (ii) 2e5% of hemolysis: slightly hemolytic, (iii) > 5% of hemolysis: hemolytic When an object is brought to contact with blood or body organs, cytocompatibility is defined as staying inert, i.e., unchanged, both from the living body parts and the foreign material. Cytological compatibility is one of the factors assessed in hemodialysis membranes. The method was commonly performed by comparing the ability of culturing cells on reference and modified hemodialysis surfaces. Common cells used for this assessment are hepatocyte, L 929 fibroblast cells, human vein endothelial cells, and human embryonic kidney-293. Cell proliferation extent is assessed by measuring the amount of specific chemicals extracted from the cells. Common model proteins, such as albumin and fibrinogen, are selected for studying the antiadhesion behavior of hemodialysis surfaces [79,81]. This is commonly performed by immersing the measured area of a membrane into a solution containing known amount of the model protein. Initially, membrane samples are immersed and incubated in phosphate buffer saline solution (PBS), including the specific concentration of target proteins for one day at 37  C. Samples are washed using deionized water to remove non-firmly attached proteins. PBS solution containing 2 wt% sodium dodecyl sulfate is then used to remove all the adhered proteins in a shaker for 2 h protein measurement assay kits are used for measuring the concentration of the removed proteins. Once incompatible substances activate the immune system of the body, complement activation results in the production and release of biochemicals and enzymes (C3a, C4a, and C5a, as previously described in section 3.1.2) [113]. Accordingly, measuring the released amount of these substances and comparing it in different activated complement systems could result in biocompatibility assessment of modified hemodialysis membranes [133]. Platelet activation results in the initiation of the coagulation cascade. This will consequently result in thrombin generation. Followed by that, antithrombin III will be generated and attached to thrombin forming thrombin-antithrombin III (TAT) complex. Measuring the concentration of TAT would be a method for expressing the extent of thrombogenesis. The less the concentration, the higher the hemocompatibility. Another amino acid, platelet factor 4 (PF4), is released into the local body environment as a result of platelet activation [134]. Just identical to TAT, PF4 measurement could reflect the extent of platelet activation. Platelet adhesion on membrane surfaces is a mean of reflecting how biocompatible the surfaces are. The shape of the attached platelet also conveys the message of activation, in case it is wide spreard, flattened, and with the formation of pseudopodium. The resistant surface would adsorb fewer platelets with round forms. For assessing the adhesion, the membrane is dipped into the fresh blood, generally received from a healthy volunteer. After a constant period of time, the sample is removed, and counting is conducted using SEM scans. The dipping method is similarly used for assessment of other proteins adsorption to the membrane surface following by removing and measuring the adsorbed proteins. Red blood cell and whole blood cell adhesion are also measured similarly and used as biocompatibility identification.

Declaration of competing interest No conflict of interest to declare.

Acknowledgment The authors would like to acknowledge and express their gratitude to Saskatchewan Health Research Foundation (SHRF) for funding the project. The authors are also thankful for the Department of Chemical and Biological Engineering at the University of Saskatchewan and Saskatchewan Transplant Program at St. Paul’s Hospital for the support provided.

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