Polymer-modified regenerated cellulose membranes: following the atom transfer radical polymerization concepts consistent with the principles of green chemistry

Synthetic routes for functionalization of cellulose membranes by polymer chains characterized by controlled structures are constantly developed to precisely adjust the properties of the prepared material while minimizing the impact on the membrane performance. The review presents a critical and integrative evaluation of prior research on atom transfer radical polymerization (ATRP) techniques, emphasizing methods carried out with diminished catalyst concentration that were used for grafting polymers from cellulose membranes. The paper introduces cellulose as a naturally-derived and efficient material for filtration membrane production focusing on the fundamentals of the cellulose structure, and the reasons, and advantages of using cellulose as a membrane-built substrate. It also covers fundamental mechanistic aspects of ATRP and introduces the basic principles of low ppm ATRP methods focusing on the latest reports. The works up to date concerning the functionalization of cellulose membranes by the “classic” ATRP concept, paying attention to the concentration of the complex used and synthetic methodology, as well as the final properties of the obtained materials are shown. Subsequent, low ppm ATRP techniques are discussed against the background of the “classic” approach in synthesizing bioactive surfaces and functional biomaterials based on the structure of cellulose membranes, with emphasis on the advantages of methods with diminished catalyst level as a more cost-effective and thus more compatible to use in a commercial application. The present work is a concise and perspective review, which shows both the achievements to date and broad prospects for the development of this issue in the coming years.

of low ppm ATRP methods focusing on the latest reports. The works up to date concerning the functionalization of cellulose membranes by the "classic" ATRP concept, paying attention to the concentration of the complex used and synthetic methodology, as well as the final properties of the obtained materials are shown. Subsequent, low ppm ATRP techniques are discussed against the background of the "classic" approach in synthesizing bioactive surfaces and functional biomaterials based on the structure of cellulose membranes, with emphasis on the advantages of methods with diminished catalyst level as a more cost-effective and thus more compatible to use in a commercial application. The present work is a concise and perspective review, which shows both the achievements to date and broad prospects for the development of this issue in the coming years.
Abstract Synthetic routes for functionalization of cellulose membranes by polymer chains characterized by controlled structures are constantly developed to precisely adjust the properties of the prepared material while minimizing the impact on the membrane performance. The review presents a critical and integrative evaluation of prior research on atom transfer radical polymerization (ATRP) techniques, emphasizing methods carried out with diminished catalyst concentration that were used for grafting polymers from cellulose membranes. The paper introduces cellulose as a naturally-derived and efficient material for filtration membrane production focusing on the fundamentals of the cellulose structure, and the reasons, and advantages of using cellulose as a membrane-built substrate. It also covers fundamental mechanistic aspects of ATRP and introduces the basic principles

Introduction
Membrane technology has emerged as a new promising and pervasive concept, e.g., for water purification due to its undoubted advantages over traditional technologies such as adsorption, distillation, and extraction. Considering substrates for membrane preparation, cellulose is an excellent candidate. It is the most abundant polymer material in nature. It possesses some promising properties as a material for membrane preparation, such as mechanical robustness, hydrophilicity, biocompatibility, and biodegradability (Kang et al. 2015;Tu et al. 2021). Cellulose is a major component of plant cell walls. It is an organic polysaccharide compound consisting of a linear chain of several hundred to many thousand β-1,4 glycosidic linkages D-glucose units (Kang et al. 2015). The membranes made of cellulose fibers are both chemically and mechanically stable with many applications in various industry and medicine branches (Liu et al. 2022b). However, due to its difficult dissolution, there are limited physiologically relevant or pharmaceutically clinical applications for this polymer. Moreover, considering the purpose of the membranes for purification, native cellulose membranes efficiently separate the components of the mixture against the molecular weight of the individual components (Kang et al. 2015).
Thus, the modification of cellulose membranes to improve their properties and extend their application is extensively studied. In this context, modification with polymers allows giving quite new properties for the membrane to separate components about their characteristics other than their molecular weight, e.g. charge and sensitivity to changes in pH (Bayramoglu and Arica 2021;Bhut and Husson 2009;Bhut et al. 2008;Chenette et al. 2012;Liu et al. 2009;Menkhaus et al. 2010;Pan et al. 2011;Porter et al. 2020;Qian et al. 2013;Singh et al. 2008b;Wang et al. 2015Wang et al. , 2014Wei et al. 2011;Zeng et al. 2021;Zhang et al. 2011) or temperature (Pan et al. 2010a, b), as well as hydrophobic (Ye et al. 2020) or hydrophilic (Qiu et al. 2013) characteristics, etc. This allows for a precise separation with a wide range of applications in many industries. Polymers can also endow the characteristics of the membrane for use in tissue engineering or as an efficient wound dressing ).
There is a critical need for controlled grafting of polymers from cellulose membranes to precisely adjust the properties of the prepared material. The properties of the modified cellulose membranes strongly depend on the grafting density , topology (Porter et al. 2022), structure, and molecular weight ) of the attached polymer chains. It is also important to selectively modify only the outer or inner surface of the membrane (Carter et al. 2018;Sengupta and Wickramasinghe 2020), depending on the end-use of the product. It is also important to precisely control the polymerization while minimizing the effect on membrane performance.
Reversible deactivation radical polymerization (RDRP) techniques are currently one of the most influential solutions in the preparation of preciselydefined polymers with a predetermined structure and specialist purposes with a wide range of potential industrial applications (Matyjaszewski 2018;O'Brien and Ignaszak 2022;Truong et al. 2021;Zhou et al. 2022). It is compatible with the modification of a wide range of substrates, ranging from naturally-derived structures (Chmielarz 2018; going to flat surfaces (Chmielarz et al. 2017c;Flejszar et al. 2022;Kang et al. 2014Kang et al. , 2015 and nanoparticles (Alheety et al. 2022;Balis et al. 2020;Chmielarz et al. 2017d;Flejszar and Chmielarz 2019;Pu and Xu 2022), receiving functional hybrid nanomaterials, according to the "grafting from" approach. In this consideration, the atom transfer radical polymerization (ATRP) technique is especially privileged in the preparation of polymers with various architectures. The phenomenon of this method is associated with excellent control over molecular weight (MW), narrow molecular weight distribution (MWD) of received polymers (Chmielarz 2016;Qiao et al. 2022;Yin et al. 2021;Zaborniak et al. 2021b), ability to incorporate functionality in specific macromolecule places (Chmielarz 2017;Grześ et al. 2022;Matyjaszewski 2018), and possibilities for the optimization of a catalyst system (Fung and Coote 2021;Qiao et al. 2022;Zhou et al. 2022). The above-mentioned features of ATRP make that technique an adequate tool for the modification of cellulose membranes. Up to now, the classical ATRP with high catalyst concertation (up to several hundred thousand ppm calculated with respect to the monomer concentration (Jiang et al. 2013)) has most often been used to modify cellulose membranes. The use of a high concentration of catalyst for polymerization from the surface requires long-term purification from the transition metal contamination, and the usability of such membranes is problematic for the separation of biomolecules. Moreover, modern polymer chemistry is heading towards the development of processes consistent with the "principles of green chemistry" to make syntheses more sustainable, therefore, the use of a high concentration of a metal catalyst is thriftless and generates a lot of waste for disposal (Anastas and Eghbali 2010;Dworakowska et al. 2022;Flejszar et al. 2021). The breakthrough in ATRP was the development of the techniques with the regeneration of catalyst complex in the form of an activator, significantly reducing the catalyst concentration to low ppm (Chmielarz and Sobkowiak 2017). Low catalyst loading methods offer more environmentally benign and industrially scalable reaction conditions compared to "classical" ATRP but also provide an option to prepare polymers with designed dispersity, defined by the catalyst content (Discekici et al. 2016(Discekici et al. , 2017(Discekici et al. , 2018Lu et al. 2019;Matyjaszewski 2012a;Parkatzidis et al. 2020;Treat et al. 2014). Up to date, cellulose membranes were modified only a few times by low ppm ATRP techniques utilizing copper-based catalyst concentrations of 50-10,000 ppm and ascorbic acid to reduce the deactivated form of copper (II) halide catalytic complex to its active form (Bhut et al. 2012;Qiu et al. 2013;Worthley et al. 2011). Therefore, the main direction of research for cellulose membranes modification by controlled polymerization is the use of ATRP techniques with a reduced catalyst concentration. Development should focus mainly on concepts controlled by external factors, such as electric current (Chmielarz et al. 2017a;Luo et al. 2021;Zaborniak et al. 2020a;Zhao et al. 2021), ultrasound (Liu et al. 2022a;Mohapatra et al. 2017;Zaborniak and Chmielarz 2019a, b) and light (Corbin and Miyake 2022;Liu et al. 2020;Wei et al. 2022;Xu et al. 2022;Yan et al. 2020;Zaborniak et al. 2020b). Among externally controlled methods, light-triggered ATRP besides simple experimental setup, mild conditions with limited side reactions, easily accessible and tunable external stimuli source, and temporal control is the only externally controlled approach providing a metal-free catalyst system (Bian et al. 2019;Corbin and Miyake 2022;Discekici et al. 2016;Treat et al. 2014;Xu et al. 2021;Zhou et al. 2022Zhou et al. , 2020. A full transition metal-free reaction setup is ensured by an organic photoredox catalytic cycle achieved by a single electron transfer from photoinitiator in the excited state (Theriot et al. 2016;Xu et al. 2022Xu et al. , 2021Zhou et al. 2020). The use of the light-mediated concept is the main goal to provide efficient membrane functionalization.
This concise review achieves an organization and statement of past work that significantly advances the membrane field in the context of functionalization by controlled radical polymerization techniques. The motivation for the proposed review paper is the high potential of the latest ATRP solutions for the modification of cellulose membranes, which are widely used in many industries. Therefore, it is necessary to prepare a literature review on the achievements to date in this field to precisely define the most promising prospects.

Cellulose-naturally-derived material for production of filtration membranes
Cellulose is a major component of plant cell walls. It is an organic polysaccharide compound consisting of a non-branched linear chain of several hundred to many thousand β-1,4 glycosidic linkages D-glucose units (Kang et al. 2015). Cellulose is the most abundant polymer material in nature and possesses some promising properties, such as mechanical robustness, hydrophilicity, biocompatibility, and biodegradability, therefore it has many applications for use e.g. in tissue engineering. It is one of the most promising substitutes for petroleum-derived synthetic polymers.
Pure cellulose can be found in nature in several allomorphs-cellulose I to IV, depending on the location of hydrogen bonds between and within strands of units. Native cellulose I exists in two distinct allomorphs-one chain triclinic structure Iα produced mainly by bacteria and algae, and two chains monoclinic unit cell Iβ, which is the main component of higher plants, and both allomorphs are packed in parallel chain arrangement. Cellulose I can be irreversibly transitioned to the form arranged antiparallel in a two-chain unit cell-cellulose II, a more stable crystalline form. This type of cellulose can be found in mercerized cotton and regenerated cellulose (RC). The treatment of native cellulose with anhydrous ethylamine or liquid ammonia leads to cellulose III structure, while cellulose IV is produced by heat treatment (Zugenmaier 2001).
The most common method for the preparation of cellulose membranes is the phase inversion technique (Khan et al. 2020)-the polymer is precipitated from a polymer solution film by a solvent which totally miscible with the solvent appropriate for the cellulose but does not dissolve the cellulose. Another one also includes the thermally induced phase separation (TIPS) method, namely, the homogenous solution of the cellulose is formed by dissolution in a diluent with a high boiling point, and then the temperature is reduced to induce a phase separation (Yu et al. 2017). Vapor-assisted nonsolvent induced phase separation (VNIPS) technique is also known, as being based on the dry-wet casting process, i.e. cellulose solution is exposed to a nonsolvent vapor (usual water), and then immersed in a coagulation bath (Wang et al. 2022a).
Cellulose membranes can be categorized as regenerated cellulose, cellulose membranes with hydroxyl groups blocked by acetate groups, or tertiary amine and benzyl groups. RC membranes are composed of cellobiose and have a high density of hydroxyl groups. Cellulosic acetate membranes have only 20-30% of unsubstituted hydroxyl groups (Vatanpour et al. 2022), while bulky chemical groups (tertiary amine (Zhang et al. 2019a) and benzyl moieties (Shokri et al. 2021)) substitute a relatively small fraction (< 5%) of the hydroxyl groups. Considering the usefulness of the cellulose membranes the substitution of the hydroxyl groups improved its properties in medical application because it prevents the interaction between hydroxyl groups present within the membrane structure and complement cascade products via steric hindrance (Eduok et al. 2021). Another strategy for the development of a more useful cellulose membranes is the modification of the hydroxyl groups by polymers using various concepts, making the final product hydrophobic and/or giving them different and quite new properties (Thakur and Voicu 2016).

Fundamentals of flat surfaces modification: atom transfer radical polymerization as a promising tool for membrane functionalization
Reversible deactivation radical polymerization (RDRP) techniques are currently one of the most influential solutions in the preparation of preciselydefined polymers with a predetermined structure and specialist purposes with a wide range of potential industrial applications (Cao et al. 2022;Matyjaszewski 2018). It is compatible with the modification of a wide range of substrates, ranging from naturallyderived structures (Chmielarz 2018; going to flat surfaces (Chmielarz et al. 2017c;Kang et al. 2014Kang et al. , 2015 and nanoparticles (Balis et al. 2020;Chmielarz et al. 2017d;Flejszar and Chmielarz 2019), receiving functional hybrid nanomaterials, according to the "grafting from" approach. In this consideration, the atom transfer radical polymerization (ATRP) technique is especially privileged in the preparation of polymers with various architectures. The phenomenon of this method is associated with excellent control over molecular weight (MW), narrow dispersity (MWD) of received polymers (Chmielarz et al. 2017c;Williams et al. 2015), ability to incorporate functionality in specific macromolecule places (Chmielarz et al. 2017a), and possibilities for the optimization of a catalyst system. The abovementioned features of ATRP make that technique an excellent tool for the modification of cellulose membranes (Scheme 1a).
The mechanism of ATRP is based on the use of a transition metal complex as a catalyst, which participates in redox reactions, thus controlling polymerization (Krys and Matyjaszewski 2017;Matyjaszewski 2012b) (Scheme 1b). Usually, alkyl halide or polymer chain terminated with a halogen (P n X) reacts with reduced catalytic complex (activator, Cu I L). As a result, propagating radicals (P˙) and oxidized catalytic complex (deactivator, XCu II L) are formed. Initially developed classic ATRP concept suffers from several major disadvantages. It is necessary to use a large amount of a catalyst, up to several hundred thousand ppm, thus it generates additional costs, due to the necessity to use additional stages for purification of the polymerization products. Moreover, the catalyst is introduced to the reaction mixture in its reduced form, which is sensitive to the action of oxygen from the air. Therefore, the preparation for the catalytic complex is demanding and time-consuming because it must take place under an inert gas atmosphere, and consequently, it is also necessary to use the freeze-pumpthrew cycle to remove the oxygen completely from the reaction setup. One disadvantage was solved by Scheme 1 a Synthetic route for the functionalization of cellulose membranes with polymers by ATRP; b Mechanism of ATRP with diminished catalyst concentration the use of a reducing agent to generate the active form of the catalytic complex in activators generated by electron transfer (AGET) ATRP approach. Therefore, the catalyst (reduced form) susceptible to the action of oxygen from the air is introduced to the reaction mixture in the form of a deactivator, thus every step of preparing the catalytic complex and introducing it to the flask may take place in the air atmosphere (Szczepaniak et al. 2021).
Modern polymer chemistry is heading towards the development of processes consistent with the "principles of green chemistry" to make syntheses more sustainable, therefore the use of a high concentration of a metal catalyst is thriftless and generates a lot of waste for disposal. The breakthrough in ATRP was the development of the techniques with the regeneration of catalyst complex in the form of an activator, significantly reducing the catalyst concentration to low ppm (up to 1 ppm (Chmielarz and Sobkowiak 2017)). Low catalyst loading methods offer more environmentally benign and industrially scalable reaction conditions compared to "classical" ATRP but also provide an option to prepare polymers with designed dispersity, defined by the catalyst content (Discekici et al. 2018(Discekici et al. , 2016(Discekici et al. , 2017Lu et al. 2019;Matyjaszewski 2012a;Parkatzidis et al. 2020;Treat et al. 2014). The new low ppm ATRP methods regenerate the activator by the use of a chemical reducing agent as a radical initiator in initiators for continuous activator regeneration (ICAR) ATRP (Konkolewicz et al. 2012;Luan et al. 2022), chemical compounds Matyjaszewski et al. 2007;Min et al. 2007) and silver (Williams et al. 2015) in activators regenerated by electron transfer (ARGET) ATRP-used a few times for membrane modification (Bhut et al. 2012;Worthley et al. 2011), zerovalent metals in supplemental activator and reducing agent (SARA) ATRP (Chmielarz et al. 2015a;Konkolewicz et al. 2014Konkolewicz et al. , 2013, external stimuli as an electrical current in electrochemically mediated ATRP (eATRP) (Chmielarz 2017;Chmielarz et al. 2015b;De Bon et al. 2022;Han et al. 2022;Park et al. 2015;Zhao et al. 2022), light in metal-free (Soly et al. 2022;Su et al. 2022;Treat et al. 2014) or photochemically mediated ATRP (photo-ATRP) Huang et al. 2017;Tasdelen et al. 2011), mechanical forces in mechanically induced ATRP (mechano-ATRP) (Liu et al. 2022a;Mohapatra et al. 2018;Wang et al. 2019), ultrasound in ultrasonication-induced atom transfer radical polymerization (sono-ATRP) (Wang et al. 2018; or ultrasonicationlight mediated ATRP . Low catalyst loading methods enable a significant reduction of the catalyst concentration, and the use of naturallyderived chemical compounds, or external stimuli as reducing agents, which allows the design of an economic reaction setup, simultaneously providing welldefined polymer structures with various architecture (Matyjaszewski 2012a;Pan et al. 2018).
Currently, the most intensively developing ATRP technique is light-controlled controlled polymerization in which the catalytic complex has been eliminated from the reaction system (Liu and Yi 2018;Razeghi et al. 2021;Soly et al. 2022;Xu et al. 2021). In this consideration light-triggered ATRP besides simple experimental setup, mild conditions with limited side reactions, easily accessible and tunable external stimuli source, and temporal control is the only externally controlled approach providing a metal-free catalyst system (Discekici et al. 2016;Treat et al. 2014). A full transition metal-free reaction setup is ensured by an organic photoredox catalytic cycle achieved by a single electron transfer from photoinitiator in the excited state. This approach usually uses organic photocatalysts such as pyrene and anthracene (Allushi et al. 2016), perylene and phenazines (Theriot et al. 2016), phenoxazines (Park et al. 2019), and phenothiazines (Discekici et al. 2016;Treat et al. 2014) derivatives for direct reduction of the alkyl halide initiator. It is achieved due to appropriate characteristics in the excited state e.g. stable triplet state and sufficient negative reduction potential, or reductive quenching pathway with an additional electron donor (Bian et al. 2018) to enable efficient reduction of the initiator. The recent achievements include the complete elimination of synthetic photocatalyst structures by their environmentally friendly counterparts, e.g. riboflavin (Zaborniak et al. 2020b(Zaborniak et al. , 2021a or curcumin . Externally controlled ATRP methods have never been used to modify membranes and are therefore of particular importance in future perspectives. From the ATRP point of view, among various types of cellulose membranes the most interesting are regenerated cellulose membranes due to the high density of hydroxyl groups in their structures because when using the ATRP technique for precise grafting of polymers from this type of substrates, the "grafting  Ascorbic acid from" concept should be applied (Balis et al. 2020;Chmielarz et al. 2017b;Macior et al. 2022;Zaborniak et al. , 2021bZhang et al. 2021). In this concept, polymerization is initiated directly from the initiator (alkyl halide) attached to the substrates by an esterification reaction. It provides the formation of well-ordered and dense layers composed of surfaceattached macromolecules with extended conformation. These thin organic layers covalently grafted to various flat/porous surfaces enable the formation of a wide range of materials with specific use.

Cellulose membrane modification by high catalyst concentration ATRP concept
The classical ATRP has most often been used to modify cellulose membranes compared to the low ppm concepts. The ATRP of different vinyl monomers was initiated by cellulose modified with halogen initiators and catalyzed with copper salts in the presence of various amine-type ligands. The details for the modification of cellulose membranes via high catalyst surfaceinitiated classical ATRP are summarized in Table 1. Cellulose membranes were grafted with polymers with various characteristics using the high catalyst ATRP technique to improve or give membranes novel properties, e.g. formation of cation- (Bayramoglu and Arica 2021;Chenette et al. 2012;Liu et al. 2009;Porter et al. 2020;Qian et al. 2013;Wang et al. 2015Wang et al. , 2014Zhang et al. 2011), anion-exchange (Bhut and Husson 2009;Bhut et al. 2008;Menkhaus et al. 2010;Pan et al. 2011;Qian et al. 2013;Singh et al. 2008b;Wei et al. 2011;Zeng et al. 2021) or multifunctional (Feng et al. 2014;Liu et al. 2014;Porter et al. 2022;Yang et al. 2016;Ye et al. 2020;Zhao et al. 2010) adsorption membrane for proteins (Bhut et al. 2008;Chenette et al. 2012;Himstedt et al. 2013;Liu et al. 2010;Qian et al. 2013;Singh et al. 2008b;Wang et al. 2015Wang et al. , 2014Zhao et al. 2010) or enzymes (Feng et al. 2014;Zeng et al. 2021) absorption. Cation, anion or zwitterion surfaces are created by polymerization of monomers with functional group, e.g.-polyelectrolytes (Chen and Lee 2021), from the flat surface.
Cation exchange cellulose-based surfaces were prepared by polymerization of acrylic acid (AA) from the membrane (Menkhaus et al. 2010;Pan et al. 2010bPan et al. , 2011Singh et al. 2008b). Poly(acrylic acid) (PAA) contains many carboxyl groups, which under pKa (~ 4.5) are protonated, while in alkaline conditions are deprotonated (Hu et al. 2015;Wang et al. 2009). Hence, PAA forms a negatively charged anion capable of adsorbing cations in high pH aqueous solutions, while under low pH conditions positively charged molecules desorb. Regenerated cellulose membrane was firstly grafted with PAA using up to ca. 626,616 ppm (catalyst to monomer ratio) of copper(I) chloride (Cu I Cl) catalyst. The modification decreased the permeability of the membrane, however, in comparison to commercially available ion-exchange membranes, higher static and dynamic binding capacity for lysozyme as a model protein was obtained (Singh et al. 2008b). Due to the ability of negatively charged acrylic acid residues to intermolecular cyclization in aqueous ATRP, in effect leading to loss of chain-end functionalities and ultimately a cessation of the polymerization , the syntheses were carried out in an alkaline environment with the addition of a salt-sodium chloride, forming an ion pair with acid residues (Menkhaus et al. 2010;Pan et al. 2010bPan et al. , 2011Singh et al. 2008b). Among commercially available regenerated cellulose membranes, electrospun cellulose acetate membrane was modified by PAA (Menkhaus et al. 2010) with the same catalyst complex-Cu I Cl/1,4,8,11-tetraazacyclotetradecane (Me 4 Cyclam), nevertheless a much lower catalyst concentration was used-ca. 7000 ppm. The polymer grafting imparted the membrane with 50-fold higher adsorption capacities of lysozyme compared to commercial membrane adsorption systems and over 12-fold higher than packed bed resins. Moreover, PAA-based membranes demonstrated tenfold faster adsorption kinetics than packed bed resins and the permeance was over 15-fold higher.
Another concept for incorporation of acrylic acid moieties on cellulose membrane is the surface-initiated polymerization of (meth)acrylates with tert-butyl side chains (Porter et al. 2022(Porter et al. , 2020. Elimelech et al. (Porter et al. 2020) grafted poly(tert-butyl acrylate) (PtBA) chains from films and membranes, controlling the location of brush growth using a sealing wafer (Fig. 1b,c). Tert-butyl moieties were then hydrolyzed to PAA brushes to elaborate a novel concept for direct measurements of brush density, namely by binding silver ions to PAA brush layers grafted from dense cellulose films by carboxyl group deprotonation, followed by anions elution (Fig. 1a). As a controlled character of ATRP allows the incorporation of other polymer blocks to an existing chain due to the presence of halides at the chain ends, the surface of the membranes grafted with PtBA was further modified with poly(2 hydroxyethyl acrylate) (PHEA) to create a membrane with selective capabilities of brush layer (Fig. 1d-f).
Another monomer with easily hydrolyzed tertbutyl groups is tert-butyl methacrylate (tBMA). The monomer was used for the preparation of polyelectrolyte multilayer membranes (PEMs) by the sequential, layer-by-layer deposition of polyelectrolytes-poly(tert-butyl methacrylate) hydrolyzed to a negatively charged poly(methacrylic acid) (PMAA) block and poly(2-dimethyl)aminoethyl methacrylate (PDMAEMA) quaternized to a positively charged block, on porous supports (Fig. 2a) (Porter et al. 2022). The prepared PEMs exhibited favorable ionion selectivity and significant salt rejection at relatively high water flux (Fig. 2b, c). PDMAEMA is another type of polyelectrolyte-a weak polybase that contains tertiary amine groups.
The functional groups are positively charged at low pH, becoming a typical cationic polyelectrolyte, while at high pH the amino groups are deprotonated (Han et al. 2013). Husson et al. used relatively low catalyst loading in classical ATRP (ca. 550 ppm) for polymerization of 2-(dimethylamino)ethyl methacrylate (DMAEMA) from RC membranes creating Fig. 1 a Hydrolysis of tert-butyl moieties from tBA attached to cellulose membrane to acrylic acid side chains, followed by determination of grafting density by silver-binding method; b Components of a sealing wafer to control brush growth location; c Photographs of the sealing wafer; d Characteristics of solutes involved in transport experiments for diblock copolymer brush-layered cellulose membranes, where LogP is an octanol/water partition coefficients; e Fluxes of solutes with varying LogP coefficients through bare and modified membranes i.e. membrane modified with bromide, homopolymer chains, and block copolymers; f Rejections of sodium chloride and lysozyme, and pure water permeability measured for unmodified cellulose membrane and a membrane grafted with PtBA. Reproduced from Ref. (Porter et al. 2020) with permission. Copyright 2019 Elsevier B.V high-capacity anion-exchange membranes for chromatographic bioseparation (Bhut and Husson 2009;Bhut et al. 2008). The prepared materials exhibited high static and dynamic binding capacity measured for bovine serum albumin (BSA) up to 140 mg/mL and 130 mg/mL, respectively (Bhut and Husson 2009). The measurements were performed at pH 7.4 when PDMAEMA is charged positively, and BSA carried a net negative charge. Then the ion exchange interaction is possible because it is most efficient between the isoelectric point (pI) of protein (pI of BSA is ca. 4.7-4.9) and acid dissociation constant (pK a ) of the polymer-the pK a value for the tertiary amine group in DMAEMA side chains is up to 7.9 (Brilmayer et al. 2020). A significantly higher catalyst concentration (26,848 ppm) was used for the preparation of PDMAEMA-based cellulose membranes for laccase immobilization. The modified membrane was characterized by approximately 3.3 times higher immobilization amount compared to the initial RC membrane ). This type of material can be effectively used for recycling enzymes. Over a dozen of million ppm of catalyst was utilized for grafting of PDMAEMA from RC membrane to obtain a material capable of removing Cu 2+ ions due to the high reactivity of the amino groups in the formation of strong complexes with metallic ions (Jiang et al. 2013).
The polymer successfully used for cellulose membrane modification by classical ATRP (2500-46,090 ppm of catalyst loading) is poly(glycidyl methacrylate) (PGMA). The polymer contains three-membered epoxide side chains in its structure, therefore it is susceptible to the nucleophilic ring-opening reactions of the pendent epoxide groups. Post-polymerization modification of PGMA allows for the incorporation of a variety of functionalities onto the reactive scaffold, thus membrane with a wide range of new properties can be obtained (Muzammil Ezzah et al. 2017). It is possible to receive anion-exchange membrane by derivatization of PGMA with diethylamine , and also materials with cation-exchange properties (Bayramoglu and Arica 2021; Wang et al. 2015Wang et al. , 2014 by ring-opening reaction with 4-mercaptobenzoic acid  or orthophosphoric acid and sulfuric acid (Fig. 3a) (Bayramoglu and Arica 2021). Both types of membranes were characterized by high pH-dependent static capacity evaluated for BSA ) and immunoglobulin G (IgG)  protein. While cationexchange films with phosphate and sulfate groups were successfully used for the removal and recovery of Chlorazole Black E (CBE) dye from aqueous solutions depending on adsorbent dosage, pH, ionic strength, initial concentration of dye, and contact time of the adsorbate and the adsorbent receiving the maximum adsorption capacities up to 165.7 and 268.6 mg/g for the phosphate-and sulfate-based membrane, respectively (Fig. 3b, c) (Bayramoglu and Arica 2021). Cellulose membrane with polyhydroxyl functional groups for efficient boron complexation was received by reaction of N-methylglucamine with epoxide rings (Wei et al. 2011).
Strong cation-exchange membranes with sulfonate as the exchange groups were examined in terms of application for protein (lysozyme) capture (Chenette et al. 2012;Qian et al. 2013). The static and dynamic binding capacities measurements indicate the PNASS-based layers as more efficient for lysozyme binding, reaching a maximum capacity of 138.3 mg/ mL and 92.9 mg/mL  vs. 79.0 mg/ mL and 70.0 mg/mL-PSMP grafted CM (Chenette et al. 2012) for static and dynamic adsorption, respectively. Beside, PNASS modified membrane effectively adsorbed an optical indicator ligand for cadmium ions-5,10,15,20-tetrakis(1-methyl-4-pyridinio) porphyrin tetra(p-toluenesulfonate) (TMPyP) . Therefore, it was found the polymer-modified cellulose-based material possessed performance for selective removal of cadmium ions, even in the presence of other cationic species such as K + , Na + , Ca 2+ , and Mg 2+ ions existing together in the aqueous solutions. The multifunctional membrane enabled also rapid detection of cadmium ions with the naked eye without using other sophisticated instruments due to the quick color change (within 2 min) from yellow to green when it was exposed to cadmium ions even at relatively low ion concentrations.
Sulfobetaines-a special class of zwitterionic polyelectrolytes with ammonium cation and sulfonic anion located on the same monomer residue, were grafted from cellulose membranes (Fig. 4a) to receive stimuli-responsive porous membranes with varying permeation/separation properties (Liu et al. 2009(Liu et al. , 2014Zhao et al. 2010). The membrane modified with SBMA separated BSA from model impurities (polystyrene nanoparticles of different sizes) depending on the change of NaCl concentration in the solutions. The membrane allowed BSA to permeate regardless of the presence of NaCl, whereas the rejection rates of nanoparticles changed remarkably with the concentration of NaCl in the solutions (Zhao et al. 2010). Both sulfobetaines (Liu et al. 2009 and phosphobetaine ) grafted from CM significantly improved the blood compatibility of the modified materials, namely, zwitterionic brushes endowed the functionalized CMs with improved resistance to nonspecific protein adsorption and platelet adhesion examined on fresh human platelet-poor plasma (PPP) made of fresh blood. Another essential parameter of blood-contacting biomaterials for biomedical applications is cytocompatibility. CM substrates modified with zwitterionic polymers exhibited improvement in cytocompatibility evaluated by 2D and 3D cell culture, namely, a direct culture of the cells (rat bone marrow stem cells) on CM-modified materials and in situ encapsulation of cells in crosslinked polymethacrylate hydrogels bearing the respective zwitterionic motifs, respectively (Liu et al. 2014). The results of cytocompatibility of zwitterion-based cellulose membranes were comparable to poly(ethylene glycol) (PEG)-based coatings (Fig. 4b-e).
Another material with potential application as an effective hemostasis dressing based on electrostatic interactions was developed by functionalization of a biocompatible cellulose membrane with choline phosphate, namely, the membrane was grafted with N- (11-azido-3,6,9-trioxaundecanyl) methacrylamide monomer in water/methanol environment, followed by functionalization with substrates bearing multiple choline phosphate groups via click chemistry . The mechanism of bioadhesion of human red blood cells is based on a universal adhesion reaction between phosphatidylcholine (PC)-a major component of biological membranes, and CM grafted with polymer brushes carrying a choline phosphate (CP) group per monomer. The adhesion of human blood cells was strongly dependent on CP density, thus the molecular weight of the tethered polymer chains, while grafting density affected the properties much less. The authors also evaluated a novel method for determining the brush density for these rough surfaces by atomic force microscopy (AFM) technique. The brush densities were estimated on the hydrated materials through calibration and interpretation of force-distance curves simultaneously applying the Alexander theory of brush structure to relate to each other the three essential parameters of the polymer brushes, namely the measured brush height with the chain density and the estimated polymer molecular weight.
An approach different from the preparation of cellulose membranes with ion-exchange coatings is grafting the CM surface with thermosensitive (Pan et al. 2010a, b) and simultaneously anti-fouling polymers (Liu et al. 2014;Singh et al. 2008a;Wandera et al. 2012Wandera et al. , 2011. Molecules of this type are soluble in water, therefore the polymerizations were conducted in an aqueous or aqueous/alcoholic environment usually with content from about 12,000 ppm to Fig. 2 a Synthesis of polyelectrolyte multilayer membranes (PEMs) by initial modification by ATRP initiator and crosslinker, followed by functionalization with poly(tert-butyl methacrylate) (PtBMA) and PDMAEMA, and conversion to charged blocks by hydrolysis of tert-butyl moieties of PtBMA to receive negatively charged poly(methacrylic acid) (PAA) and quaternization of amines in PDMAEMA receiving a positively charged poly(2-(methacryloyloxy)ethyl trimethylammonium iodide) (PMOTA) block; b Various salt rejection by bare and modified membranes; c The proposed hypothesis for diminished salt rejection with an increasing number of blocks. Reproduced from Ref. (Porter et al. 2022) with permission. Copyright 2021 Elsevier B.V ◂ over several hundred thousand ppm of a copper-based catalyst (Pan et al. 2010a;Singh et al. 2008a;Wandera et al. 2012Wandera et al. , 2011. The best-known thermosensitive polymer is poly(N-isopropylacrylamide) (PNIPAM). The polymer aqueous solution undergoes transitions between the water-soluble state and the insoluble state above the lower critical solution temperature (LCST) of approximately 31 °C to 33 °C (Jain et al. 2015). The CM modified by PNIPAM exhibited thermally modulated permeability properties, namely, flux values increased as the temperature increased (Pan et al. 2010a). Another concept includes polymerization of biocompatible, non-toxic, and miscible with many solvents PEG-based macromolecules from  (Singh et al. 2008a). The controlled characteristics of the ATRP process enable the synthesis of block copolymers due to the presence of initiation sites at the end of the polymer chains, thus PNIPAM-b-PEGMA block copolymers were successfully grafted from cellulose membranes (Fig. 5a-c) (Wandera et al. 2012(Wandera et al. , 2011. The motivation for grafting this type of polymer blocks from a material with a cellulose structure was the nature of PEGMA to suppress attachment of foulants, while PNIPAM was selected for its thermoresponsive feature. As a result, materials with controlled fouling during filtration of oily water were obtained to provide a chemical-free strategy to reverse foulant accumulation (Fig. 5d, e). Other stimuli-responsive membranes based on thermo-sensibility were prepared by grafting poly N-vinylcaprolactam (PVCL) from microfiltration cellulose films (Himstedt et al. 2013). PVCL exhibits LCST around 32 ºC, which can be altered by changing the ionic strength of the buffer solution. Below LCST the chains swell while above this temperature separation occurs and the polymer adopts a collapsed and dehydrated conformation (Maeda et al. 2002). The prepared material was used for efficient absorption and recovery of BSA based on hydrophobic interaction chromatography (HIC) behavior.
Classic ATRP concept suffers from several major disadvantages. One disadvantage was solved by the use of a reducing agent to generate the active form of the catalytic complex in AGET ATRP approach. Therefore, the catalyst susceptible to the action of oxygen from the air is introduced in the form of a deactivator to the reaction mixture, thus the very step of preparing the catalytic complex and introducing it to the flask may take place in the air atmosphere. AGET ATRP was successfully used for the polymerization of SBMA (Xu et al. 2020), [2-(acryloyloxy) ethyl]trimethylammonium chloride (DAC) (Xu et al. 2020), 2-hydroxyethyl methacrylate (HEMA) (Carter et al. 2018), GMA (Sengupta and Wickramasinghe 2020) and DMAEMA ) monomers from cellulose membrane surfaces (Table 2). The polymerizations were conducted in water/methanol environment, in the presence of ascorbic acid (AsAc) as a reducing agent in an equimolar amount or in molar insufficiency with respect to the catalyst, using a copper concentration from about 2000 to 90,000 ppm.
Grafting copolymer brushes consisting of a zwitterion-poly([2-(methacryloyloxy)-ethyl]-dimethyl-(3-sulfopropyl)ammonium hydroxide) (PSBMA), and quaternary ammonium units-poly ([2-(acryloyloxy) ethyl]trimethylammonium chloride) (PDAC) of different proportions from a transparent cellulose  *DMAEMA serves as an internal reducing agent in aqueous environment (Dong and Matyjaszewski 2008;Flejszar et al. 2021;)  . 6 a Structural composition of antifouling, antibacterial, and non-cytotoxic cellulose membrane grafted with zwitterion and quaternary ammonium copolymers; b Adsorption of proteins (BSA and Lyz) on CMs, CM-1-PDAC modified CM, CM-2 to CM-4-CMs modified with PDAC-b-PSBMA copolymers, CM-5-PSBMA modified CM; c Synthetic route for the preparation of zwitterion and quaternary ammonium copolymers grafted from CM; d Demonstration of high transparency of the modified cellulose membranes; e Illustration of high flexibility, affinity, and adaptability to human body parts of the modified CM. Reproduced from Ref. (Xu et al. 2020) with permission. Copyright 2020 Elsevier Ltd membrane led to an improvement in the antifouling and antibacterial effect of the modified material ( Fig. 6) (Xu et al. 2020). As the grafting ratios of PSBMA increased, a significant reduction of water contact angle from 55 to 13º was observed. More hydrophilic surfaces reduced nonspecific protein adsorption evaluated for negatively charged BSA and positively charged lysozyme (Lyz) at pH 7.4 (Fig. 6b). The inhibition of absorption was stronger for Lyz due to its net positive charge, therefore electrostatic repulsive forces between the positively charged cellulose membrane grafted with cationic PDAC and zwitterionic PSBMA, and Lyz lead to inhibition of its adsorption. While negatively charged BSA protein can be more promoted in these conditions. Additionally, modified CM exhibited antimicrobial properties against both Gram-positive and Gram-negative bacteria, up to 95.1% and 90.5% of S. aureus and E. coli reduction rates, respectively. It is worth mentioning that CM grafted with a polyelectrolyte layer demonstrated no in vitro toxicity to using a range of different target cells or cell lines.

RC
Another concept for grafting of zwitterion polymer from CM includes a direct polymerization of DMAEMA from the membrane surface followed by ring-opening reacted with beta-propiolactone to yield carboxybetaine brush ). Carboxybetaine-based membrane exhibited improved resistance to nonspecific protein adsorption and platelet adhesion evaluated by plasma protein adsorption and platelet adhesion test, and also reduced hemolysis rate compared to unmodified CM.
Wickramasinghe et al. controlled grafting of PHEMA (Carter et al. 2018) and PGMA (Sengupta and Wickramasinghe 2020) through the AGET ATRP concept on the external cellulose membrane surface and the internal pores of the membrane utilizing various pore filling solvents (i.e. acetonitrile, ethanol, PEG 400, Pluronic L 64 and glycerol). The used solvents have a wide range of viscosity and different reactivity during the acylation of RC membrane to incorporate ATRP initiator. The immobilization of the initiator within the membrane pores was mostly suppressed using glycerol as a filling solvent. The presented concept of cellulose membrane modification demonstrates the method for controlling the location of the grafted polymer in the stage of ATRP initiator immobilization. Therefore it is possible to modify only the outer surface of the membrane, thus the properties of the material can be enhanced while minimizing the effect on membrane performance.
Summarizing the work to date, the use of a high concentration of catalyst for polymerization from the surface is not overly problematic in the context of purifying the final product in the form of a cellulose membrane grafted with various polymers. It is enough to rinse the membrane with a suitable solvent or use ultrasounds to remove unreacted substrates and a catalyst from the flat surfaces (Balis et al. 2020;Flejszar et al. 2022). On the other hand, modern polymer chemistry is heading towards the development of processes consistent with the "principles of green chemistry" to make syntheses more sustainable, therefore the use of a high concentration of a metal catalyst is thriftless and generates a lot of waste for disposal. For this reason, a number of new concepts in ATRP have been developed, which made it possible to significantly reduce the concentration of the catalyst in the reaction systems, even down to 1 ppm (Chmielarz and Sobkowiak 2017), or allowed for its elimination from the reaction mixture Zaborniak et al. 2020b).

Low ppm ATRP methods in cellulose membrane functionalization
Low ppm ATRP techniques were only used a few times to modify cellulose membranes utilizing copper-based catalyst concentrations of 50-10,000 ppm and ascorbic acid to reduce the deactivated form of copper (II) halide catalytic complex to its active form (Table 3) (Bhut et al. 2012;Qiu et al. 2013;Worthley et al. 2011). Analogous to AGET ATRP, an ATRP concept with activator regeneration was applied for DMAEMA (Bhut et al. 2012) and HEA (Worthley et al. 2011) polymerization from CM. The essential difference between the AGET and ARGET ATRP techniques is the amount of reducing agent used in relation to the catalyst. AGET ATRP typically uses an equimolar amount or molar insufficiency with respect to the catalyst to generate an activator (Carter et al. 2018;Sengupta and Wickramasinghe 2020;Wang et al. 2013;Xu et al. 2020), while ARGET ATRP introduces a significant excess of reductant to the catalyst into the reaction system, ensuring continuous regeneration of the activators (Bhut et al. 2012;Worthley et al. 2011). Husson et al. greatly simplified Temperature-and pH-responsive membrane Qiu et al. (2013) the modification of cellulose membranes to produce adsorptive material for protein binding, polymerizing DMAEMA in the reaction mixture containing only 50-200 ppm of catalyst (Bhut et al. 2012). In addition to overcoming the need for specialized catalyst handling, the proposed concept also avoided the solution deoxidation steps required for standard ATRP approaches. A significant excess of ascorbic acid in relation to the catalyst (up to 31:1) is sufficient to consume headspace oxygen in the reaction chamber, therefore, the proposed concept does not require deoxygenation of the reaction mixture or specialized preparatory equipment. Additionally, DMAEMA containing tertiary amine group serves as an internal reducing agent, therefore also consuming the oxygen in the headspace of the reaction vial (Dong and Matyjaszewski 2008;Flejszar et al. 2021). For HEMA polymerization from initiators attached to cellulose acetate membranes, tris(2-pyridylmethyl) amine (TPMA) was used as copper complexes with TPMA are more active catalysts compared to the previously mentioned and used in the classic ATRP concept (Worthley et al. 2011). The received materials were tested in the context of biofouling resistance compared to pristine CA membrane by immersion in a natural seawater aquarium with a salinity of 20,000 ppm. HEMA-modified membranes with low graft density exhibited up to 28% improvement in resistance to seawater microbial biofouling in comparison to an unmodified material, and the salt rejection and water flux decreased just by 6%, therefore the attachment of the polymer did not significantly affect the functions of the membranes. A membrane with different characteristics on both sides was developed by simultaneously grafting NIPAM and 2-(diethylamino)ethyl methacrylate (DEAEMA) from different sides of an initiatorfunctionalized CM conducted in a diffusion device (Fig. 7a-e) (Qiu et al. 2013).
The polymerization was conducted in the presence of copper powder as a reducing agent and the membrane was sandwiched between two chambers, where the reaction mixtures with different monomers were introduced. The produced membrane showed individual features depending on the side. The surface grafted with PNIPAM exhibited LCST temperature-the layer became hydrophobic above LCST (Fig. 7f, h). While the PDEAEMA-based side demonstrated pH responsiveness and depending on the reaction of the environment, it was either hydrophilic or hydrophobic in acidic aqueous solution and under basic conditions, respectively (Fig. 7g, h).

Summary and outlook
Cellulose is a biobased and widely available compound, therefore the production of the membrane made of this substrate is an economic and efficient approach. Despite the high chemical and mechanical stability of the cellulose membrane, there are limited physiologically relevant or pharmaceutically clinical applications for this polymer due to its dissolution difficulty. Moreover, native cellulose membranes efficiently separate the components of the mixture only against the molecular weight of the individual components. With the rapid development of industry e.g. pharmaceutical purification, water treatment, and following synthetic routes in accordance with the principles of green chemistry, higher requirements are put forward for precision separation. Thus, the modification of cellulose membranes with polymers to improve their properties and extend their application is extensively studied, simultaneously looking for controlled grafting methods while minimizing the effect on membrane performance after modification. In this context, ATRP techniques are widely used due to excellent control over molecular weight (MW), narrow dispersity (MWD) of received polymers, and the possibility of polymerization of various types of monomers i.e. acrylates, methacrylates, and acrylamides. Cellulose membranes have been modified by classical ATRP technique in most cases. This concept uses high catalyst concentration and the catalysts must be prepared in a de-oxygenated solvent under an oxygen-free environment, and stored in an inert atmosphere. Moreover, a strictly oxygen-free environment must be maintained throughout the process. The application of high catalyst concentration is not economic, and the process of catalyst handling can be challenging, therefore classical ATRP approach may become impractical at the industrial scale. Some of these obstacles have been overcome by using the methods with catalyst regeneration, thus the metal transition catalyst was incorporated into the reaction mixture in its oxidized form in much lower concentration and then reduced in situ by an appropriate chemical reducing agent. Looking at the dynamic development of economic and effective ATRP techniques in recent years, the main direction of research on the modification of cellulose membranes should be focused mainly on concepts controlled by external factors, such as electric current, ultrasound, and especially light. Light-triggered ATRP besides simple experimental setup, mild conditions with limited side reactions, easily accessible and tunable external stimuli source, and temporal control is the only externally controlled approach providing a metal-free catalyst system. Moreover, it is possible to use naturallyderived photocatalysts eliminating harmful organic chemicals from the reaction setup. The use of the light-mediated concept is the main goal to provide efficient membrane functionalization. Furthermore, the newest achievement in RDRP techniques controlled by light enables also controlling a penetration gradient and omits limited diffusion of photocatalysts using ultrasonication waves , which is crucial for uniform modification of the external cellulose membrane surface and its internal pores.
Oxygen tolerance is another direction for efficient membrane modification in microscale or large membrane surfaces for potential industrial application by ATRP. Here, several potential development directions can be cited in the context of membrane surface modification (Szczepaniak et al. 2021). There are examples of the modification of flat surfaces (silicon Fig. 7 a Transdermal diffusion device consisted of two detachable glass chambers with two sampling ports, a stirrer, and an interlayer; XPS spectra of unmodified b CM, c brominated CM, d CM side grafted with PNIPAM, and e CM side grafted with PDEAEMA. Water contact angles for surface grafted with f PNIPAM at varying temperatures, and g PDE-AEMA at different pH values. h Water contact angles determined periodically for surface grafted with PNIPAM at different temperatures: cycles from 20 to 50 °C, and for surface grafted with PDEAEMA at different pH values cycles from pH 1.0 to pH 7.0. Reproduced from Ref. (Qiu et al. 2013) with permission. Copyright 2012 Elsevier Ltd wafers) using a copper (Zhang et al. 2019b) or iron (Layadi et al. 2020) plate as both a catalyst source and a reducing agent. In the proposed reaction setup, polymerization was conducted between an initiatorbearing silicon wafer and a copper plate, because the microliter volumes of the reaction mixture were injected between the substrate and the plate. The limited oxygen diffusion into the system was received due to the small distance between the plates, therefore oxygen exclusion was unnecessary. Oxygen tolerance in ATRP can be achieved by using an excess of a ligand  or reducing agent , which continuously regenerates the oxidized catalyst, and the monomers with tertiary amine groups can also play a role of a reducing agent e.g., DAMEMA (Dong and Matyjaszewski 2008;. The abovementioned concepts are based on activator regeneration and can only tolerate a limited amount of oxygen and do not allow open vessel polymerization. It is also possible to use cheap, nontoxic, highly active enzymes with good thermal stability for reaction mixture deoxygenation (Sun et al. 2019). The enzymeassisted techniques consume oxygen without interacting with the polymerization process and offer oxygen tolerance high enough to allow open vessel polymerization. The proposed concepts of oxygen tolerant reaction setups, especially photoinduced techniques, have tremendous potential for cellulose membrane modification, especially in µL-volumes, and also for modification of large surfaces. Funding This study has no financial interest.

Competing interests
The authors declare no competing interests.
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