Review Switchable Materials Containing Polyzwitterion Moieties

Markéta Ilˇcíková 1, Ján Tkáˇc 2 and Peter Kasák 1,*

Received: 8 September 2015 ; Accepted: 12 November 2015 ; Published: 20 November 2015 Academic Editor: Carsten Werner

1 Center for Advanced Materials, Qatar University, 2713 Doha, Qatar; [email protected] 2 Chemistry Institute, Slovak Academy of Sciences, Dúbravská cesta 9, 845 38 Bratislava, Slovakia; [email protected] * Correspondence: [email protected]; Tel.: +974-4403-5674

Abstract: In recent decades, the design and construction of smart materials capable of switching into a polyzwitterionic state by an external trigger have been intensively pursued. Polyzwitterionic states have unique antifouling and surface properties and external triggers, such as pH, light, ions, electric field and CO2, cause significant changes in materials with regard to overall charge, ionic strength and wettability. This survey highlights current progress in the irreversible as well as the reversible switching process involving polyzwitterionic moieties, which can, in turn, be applied to studying the interaction of various interfaces with biological species as protein, DNA, bacteria or platelets and also for advanced use.

Keywords: responsive materials; polycarboxybetaines; carboxybetaine ester; smart polymers; polyzwitterion

1. Introduction Smart materials are attracting increased attention due to the possibility of effectively switching their properties in response to external stimuli such as temperature, light, electrical potential, pH and ionic strength. Materials with the capacity to switch their properties can find a variety of applications, i.e., in biosensing, nanomedicine, tissue engineering and intelligent nanoelectronics and optics [1–5]. The switching capacity of a material upon external stimulus plays an important role in biological systems. As an example, the surface properties and characteristics of polypeptides may vary markedly due to changes in the secondary/tertiary structures as a response to an external trigger [6] or an adhesion–repellent switch in a muscle is triggered by changes in pH or by the presence of cooperative ions [7]. Stimuli-responsive polymer surfaces have been described in many review articles [8–10]. Control of the surface properties has been achieved by various stimuli including temperature [11,12], light potential [13], pH and ionic strength [14,15]. Surface properties such as wettability, biocompatibility, roughness, and adhesiveness can be controlled. Such materials can be further used as self-cleaning materials [16], in drug delivery systems [17–21], for designing controlled permeation membranes [22], in separation [23], etc. Currently, progress in the use of smart materials, where one of the states during the switching process involves polyzwitterions, is attracting considerable interest due to their unique properties. Structurally, zwitterions contain both a positive and a negative charge at different non-neighboring atoms and, simultaneously, the overall charge of the substance is neutral with highly ionic properties [24]. Moreover, they are considered to be biomimetic, since the basic zwitterionic structures appear in nature. For example, a phosphoryl choline head-group can be found in the outer layer of

Polymers 2015, 7, 2344–2370; doi:10.3390/polym7111518 www.mdpi.com/journal/polymers Polymers 2015, 7, 2344–2370 cell membranes creating a hydrophilic polar part of the membrane, in free amino acid as a building block for proteins or as taurine in choline conjugate. A special group of zwitterions is represented by betaines with a cationic group such as quaternary ammonium bearing no hydrogen atoms; these are denoted according to the anionic groups as phosphobetaines, sulfobetaines or carboxybetaines. The surfaces containing polyzwitterions are mainly formed from zwitterionic monomers based on (meth)acrylates with a quaternary ammonium group due to a simple synthetic protocol [25]. Polyzwitterionic materials consist of highly ionic monomers and form a strong hydration layer based on electrostatic interaction with water molecules [26]. This effect is most remarkable in the formation of polyzwitterionic brushes, which were applied to the formation of surfaces highly resistant to protein adsorption [27], non-specific protein adsorption from serum and plasma [28,29] and bacterial adhesion [30–32]. Intensive research has revealed that the best surfaces inhibiting protein adsorption exhibited several common features such as the presence of hydrophilic groups, electrical neutrality and hydrogen-bond donors [33,34]. These features are also common for zwitterionic polymers [35], which nowadays are replacing the widely used polyethyleneglycol (PEG)-based polymers, which can lose their function in biological media due to degradation [36–38]. This review provides a survey of recent progress in attempts to develop smart polymeric materials involving the polyzwitterionic state with the main attention paid to describing a switchable process and the interaction of such switchable polymers with biological species and their use in further applications [27]. As an example, protein adsorption represents one of the major challenges in biomaterials research since the process may lead to the dysfunction of long-term (e.g., implants and biosensors) or short-term devices (e.g., catheters). The process of protein adsorption is highly complex and the main contribution results from a change in forces between the surface of materials and protein [39]. The forces involved are van der Waals, hydrophobic and electrostatic forces, all of which initiate protein conformation change and allow the hydrophobic amino acid side-chains to be oriented to the environment [40]. A common approach to reducing protein adsorption is to attach highly hydrophilic synthetic polymers such as polyzwitterionic or PEG onto the surfaces [41]. The highly hydrophilic character and electrical neutrality of polyzwitterions lead to a decrease in the hydrophobic and electrostatic interactions with the protein [42,43] and, conversely, the polycationic character promotes the adsorption of the protein linked directly to the followed cell adhesion, causing a biofouling film formation in the organism. The methodology for the synthesis and preparation of polymeric systems based on polyzwitterions has recently been summarized in excellent reviews [44–46] and is outside the scope of this review. In the first and second parts of this review, the irreversible and reversible switching processes of such polymeric materials are described. Reversible switches can be divided into two categories based on physical and chemical principles. The physical principle employs a switch between distinguished states with different properties. A schematic presentation of particular switches is depicted in Scheme1. In this review, interactions with water and biological species such as proteins, bacteria, DNA, gene drugs, blood samples and miscellaneous applications are also summarized. This survey also includes some experimental details of the switching process to indicate the capacity to perform transformations in certain sensitive applications such as bioengineering, biomedicine, biotechnology, etc.

2. Irreversible Switch to Form Polyzwitterionic Moiety An irreversible switch is effected predominantly by the transformation of polymers containing an ester group into a betaine moiety in the polymeric backbone. This was observed as an irreversible switch from a polycationic into a polyzwitterionic state as well as from a polyzwitterionic into a polyanionic state. This process is related to hydrolysis and its rate varies with the structural composition.

2345 Polymers 2015, 7, 2344–2370 Polymers 2015, 7, page–page

Polymers 2015, 7Polymers, page–page 2015 , 7, page–pagePolymers 2015 , 7, page–page

Scheme 1. Schematic presentation of irreversible and reversible switches.switches.

2.1. Switch from Polycationic to Polyzwitterionic State Conversion from the polycationic to the polyzwitterionicpolyzwitterionic state exhibits dramatic changes in the interaction withwith water,water, proteins,proteins, drugs,drugs, DNA,DNA, andand bacteria.bacteria. This conversion is represented solely by transformation ofof thethe esterester oror amideamide groupsgroups intointo thethe carboxylatecarboxylate groupgroup inin thethe monomermonomer unit.unit. The transformation occursoccurs asas a response toto an external stimulus (pH, buffering capacity or light) and the polyzwitterionic stateScheme is 1. preserved.SchematicScheme presentation 1. Schematic The Scheme of progresspresentation irreversible1. Schematic of and of presentationirreversible thereversible transformation and ofswitches. irreversible reversible switches.and reversible is influencedinfluenced switches. by several factors such as length of the spacer between the quaternary amine and the carboxyl group, the nature of the 2.1. Switch from2.1. Polycationic Switch from2.1. to Polycationic PolyzwitterionicSwitch from to PolycationicPolyzwitterionic State to Polyzwitterionic State State hydrolysable group, pHpH andand temperature;temperature; thesethese willwill alsoalso bebe discusseddiscussed below.below. Conversion fromConversion the polycationic fromConversion the polycationicto the from polyzwi the to polycationic tterionicthe polyzwi state totterionic exhibitsthe polyzwi state dramatic tterionicexhibits changes dramaticstate exhibitsin the changes dramatic in the changes in the interaction withinteraction water, proteins,withinteraction water, drugs, proteins, with DNA, water, drugs, and proteins, ba DNA,cteria. anddrugs, This ba conversion cteria.DNA, Thisand is baconversion representedcteria. This is conversionrepresentedsolely by is solely represented by solely by 2.1.1. transformation(Meth)acrylic transformation of the Type estertransformation or PolymersofPolymers amidethe ester groups or of amide the into ester groupsthe orcarboxylate amide into the groups groupcarboxylate into in thethe group monomercarboxylate in the unit. monomergroup The in theunit. monomer The unit. The transformationtransformation occurs as atransformation response occurs as to a anresponse occursexternal asto stimulus ana response external (pH, tostimulus bufferingan external (pH, capacity stimulus buffering or (pH,light) capacity buffering and or the light) capacity and the or light) and the Thepolyzwitterionic mostpolyzwitterionic common state is preserved.polyzwitterionic polymer state is The preserved. progress backbone state The isof preserved. the progress transformation motifs ofThe the progress usedtransformation is influenced of in the these transformation is by influenced several switches factors by is influencedseveral are factors (meth)acrylic-based by several factors polymerssuch as due duelength suchto toof their theas their length spacer simplesuch of simplebetween the as spacer lengthsynthetic the synthetic betweenquaternaryof the spacer modification the amine quaternary modification,between and thethe amine, quaternary carboxylready and ready the group,availability amine carboxyl theavailability and nature group, the carboxyland of the the naturethe andgroup, possibility of the the nature possibility ofto the prepare to hydrolysablehydrolysable group, pH and group,hydrolysable temperature; pH and group, temperature; these pH will and also thesetemperature; be discussedwill also these be below. discussed will also below.be discussed below. preparepolymer polymerbrushes brushesusing surface-initiated using surface-initiated (SI) atom-transfer (SI) atom-transfer radical radicalpolymerization polymerization (ATRP) (ATRP) or SI orphotointerpherter SI2.1.1. photointerpherter (Meth)acrylic2.1.1. (Meth)acrylic mediated Type Polymers2.1.1. mediated (Meth)acrylicType polymerization Polymers polymerization Type Polymers (PMP), mainly (PMP), through mainly a thiolated through initiator a thiolated immobilized initiator immobilizedonto the goldThe most ontosurface, commonThe the most or polymer gold polymerscommonThe surface,backbone most polymer commonwith motifs orbackbone controlled polymerspolymerused motifsin backbonethese lengths.used withswitches inmotifs these controlled areThe used switches (meth)acrylic-based simple in these are lengths. (meth)acrylic-basedsyntheticswitches are The (meth)acrylic-basedprotocol simple permits synthetic the polymers duepolymers to their simpleduepolymers to theirsynthetic simple due modification to synthetic their simple modification, ready synthetic availability, modificationready and availability the, possibilityready and availability the to possibility prepare and the to preparepossibility to prepare protocolapplicationpolymer permits ofbrushes polymera modern theusing brushes application surface-initiatedpolymer method using brushes surface-initiated such of (SI) ausing modernasatom-transfer surfacesurface-initiated (SI) methodatom-transfer radicalplasmon (SI)polymerization such atom-transferradical resonance as polymerization surface (ATRP) radical (SPR) plasmon orpolymerization SI (ATRP)to evaluate or resonance SI (ATRP) modifications or (SPR)SI to evaluateor adsorptionphotointerpherter modificationsphotointerpherter change mediated or photointerpherter evenpolymerization adsorption mediated down polymerization (PMP),mediated changeto mainly0.1 polymerization even(PMP), ng·cmthrough downmainly a−2 thiolated. (PMP), through toTypical 0.1 mainly initiator a ngthiolated ¨ through(meth)acrylic-basedcm immobilized´ initiator2 a. thiolated Typical immobilized initiator (meth)acrylic-based immobilized pH-triggered onto the gold surface, or polymersonto the withgold controlledsurface, or lengths.polymers The with simple controlled synthetic lengths. protocol The permits simple syntheticthe protocol permits the pH-triggered irreversibleonto the gold surface, switches, or polymers their with triggers controlled and lengths. applied The simple forms synthetic are protocol summarized permits the in Table1. irreversibleapplication switches, ofapplication a modern their ofmethodapplication a modern triggers such method ofas asurface modernand such plasmonapplied asmethod surface resonance such formsplasmon as surface (SPR) areresonance toplasmonsummarized evaluate (SPR) resonance modifications to evaluate in (SPR) Table modifications to evaluate 1. modifications or adsorptionor adsorptionchange evenor change adsorptiondown evento 0.1changedown ng·cm evento− 2.0.1 Typicaldown ng·cm to−(meth)acrylic-based2. 0.1Typical ng·cm (meth)acrylic-based−2. Typical pH-triggered (meth)acrylic-based pH-triggered pH-triggered irreversibleTable 1. switches,Irreversibleirreversible their switches,irreversible triggers pH-triggered their and switches, triggersapplied (meth)acrylic-based(met andformstheirh)acrylic-based applied triggers are summarized forms and applied are summarized in switches Tableforms 1. are containing incontainingsummarized Table 1. in polyzwitterionicpolyzwitterionic Table 1. state.state. Table 1. IrreversibleTable 1.pH-triggered IrreversibleTable (metpH-triggered 1. Irreversibleh)acrylic-based (met pH-triggeredh)acrylic-based switches (metcontaining h)acrylic-basedswitches polyzwitterionic containing switches polyzwitterionic state. containing polyzwitterionic state. state. InitialInitial state state Trigger Trigger( (appliedapplied form) form reference) reference Polyzwitterionic Polyzwitterionic state state Initial state Initial state Trigger Initial(applied state Trigger form()applied reference Trigger form)( referenceapplied Polyzwitterionic form) reference Polyzwitterionic state Polyzwitterionic state state NaOH (polymerNaOHNaOH brush) (polymer (polymer NaOH brush) brush) (polymer brush) NaOH (polymer brush)

Poly(1): m = 1Poly(1): m = 1 Poly(1): m = 1 Poly(2) m = 1Poly(2) m = 1 Poly(2) m = 1 Poly(1): m = 1[47] Poly(2) m = 1 Poly(3): m = 3 Poly(3): m =[47] 3 [47] Poly(4) m = 3 Poly(4) m = 3 Poly(1):Poly(3): m ==Poly(3): 31 m = 3 [47] Poly(4) m = 3Poly(4)Poly(2) m m= 3= 1 Poly(5): m = 5 Poly(5): m = 5 Poly(6) m = 5 Poly(6) m = 5 Poly(3):Poly(5): m ==Poly(5): 53 m = 5 [47] Poly(6) m = 5Poly(6)Poly(4) m m= 5= 3

Poly(5): m = 5 Poly(6) m = 5

3 3 3

2346 3 Polymers 2015, 7, page–page

Scheme 1. Schematic presentation of irreversible and reversible switches.

2.1. Switch from Polycationic to Polyzwitterionic State Conversion from the polycationic to the polyzwitterionic state exhibits dramatic changes in the interaction with water, proteins, drugs, DNA, and bacteria. This conversion is represented solely by transformation of the ester or amide groups into the carboxylate group in the monomer unit. The transformation occurs as a response to an external stimulus (pH, buffering capacity or light) and the polyzwitterionic state is preserved. The progress of the transformation is influenced by several factors such as length of the spacer between the quaternary amine and the carboxyl group, the nature of the hydrolysable group, pH and temperature; these will also be discussed below.

2.1.1. (Meth)acrylic Type Polymers The most common polymer backbone motifs used in these switches are (meth)acrylic-based polymers due to their simple synthetic modification, ready availability and the possibility to prepare polymer brushes using surface-initiated (SI) atom-transfer radical polymerization (ATRP) or SI photointerpherter mediated polymerization (PMP), mainly through a thiolated initiator immobilized onto the gold surface, or polymers with controlled lengths. The simple synthetic protocol permits the Polymers 2015, 7, 2344–2370 application of a modern method such as surface plasmon resonance (SPR) to evaluate modifications or adsorption change even down to 0.1 ng·cm−2. Typical (meth)acrylic-based pH-triggered irreversible switches, their triggers and applied forms are summarized in Table 1. Polymers 2015, 7, page–page Polymers 2015, 7, page–page Table 1. Cont. Polymers 2015, 7, page–pageTable 1. PolymersIrreversible 2015 ,pH-triggered 7, page–page (meth)acrylic-based switches containing polyzwitterionic state. Table 1. Cont. Table 1. Cont. Polymers 2015, 7, page–page Polymers 2015, 7, page–page Initial stateInitial state TriggerTable Trigger 1. (appliedCont.(applied for form)m) referenceTable reference 1. Cont. Polyzwitterionic Polyzwitterionic state state Initial state Trigger (applied form) reference Polyzwitterionic state Initial state Trigger (applied NaOHform) reference (polymer brush)Table Polyzwitterionic 1. Cont. state Table 1. Cont.˝ Initial state TriggerInitialpHpH (applied state10, 10, 37 37 °Cfor 8m Cdays) reference 8 days Trigger (polymerpH (applied 10, Polyzwitterionic 37 brush) °Cfor 8m days) reference state Polyzwitterionic state InitialpH(polymer state10, 37 °C brush) 8 days TriggerpH ((polymerapplied 10, 37 °C for brush) 8m days) reference Polyzwitterionic state Initial state Trigger (applied form) reference Polyzwitterionic state (polymer brush) pH(polymer 10, 37 °C brush) 8 days Poly(1): m = 1 pH 10, 37 °C 8 days [48] Poly(2) m = 1 Poly(7) Poly(7) [48] (polymer[48] brush) Poly(8) Poly(8) Poly(7) Poly(3): m = 3 (polymer brush) [47] Poly(4) m = 3 Poly(8) Poly(7) pH 10.2,Poly(7) 37 °C, [48] CAPS buffer, pH8 h 10.2, 37 °C,[48] CAPS Poly(8) buffer, 8 h Poly(8) Poly(5): m = 5 ˝ Poly(6) m = 5 pH 10.2, 37 C, CAPS buffer, 8 h (polymerpH 10.2,Poly(7) on37 PP°C, non-wovenCAPS buffer, fabric)(polymer pH8 h 10.2, on37 PP°C,[48] non-wovenCAPS buffer, fabric) 8 h Poly(8) Poly(7) (polymer [48] on PP non-woven fabric) Poly(8) (polymer on PP non-woven fabric) (polymer on PP non-woven fabric)pH 10.2, 37 °C, CAPS buffer, 8 h pH 10.2, 37 °C, CAPS buffer, 8 h Poly(9) Poly(9) [49] (polymer on PP[49] non-woven Poly(8) fabric) Poly(8) (polymer on PP non-woven fabric) Poly(9) Poly(9)pH [49] 13, 1 h [49] pH[49] 13, 1 h Poly(8) Poly(8)

Poly(9) Poly(8) (copolymerPoly(9)pH with 13, poly(EGMA)1 h (copolymer pH with[49] 13, poly(EGMA)1 h Poly(8) Poly(9) [49] Poly(8) (copolymer pHwith13, poly(EGMA) 1 h (copolymer(copolymer pH withwith 13, poly(EGMA)1 h pH 13, 1 h poly(EGMA)(copolymer with poly(EGMA) (copolymer with poly(EGMA) 3 Poly(10) Poly(10)[50,51] [50,51] Poly(11) Poly(11)

Poly(10) Poly(10)[50,51] [50,51] Poly(11) Poly(11)

2.1.1.1. pH Trigger 2.1.1.1. pH Trigger Poly(10) [50,51] [50,51] Poly(11) Poly(10)Poly(10) [50,51] Poly(11) Poly(11) 2.1.1.1.Structural pH EffectTrigger on Hydrolysis2.1.1.1.Structural pH EffectTrigger on Hydrolysis 2.1.1.1. pH Trigger 2.1.1.1.StructuralOne pH parameter EffectTrigger on Hydrolysis investigatedStructuralOne is parameter theEffect effect on Hydrolysis ofinvestigated the spacer islength the effect between of th quaternarye spacer length ammonium between quaternary ammonium Structural Effect on Hydrolysis 2.1.1.1.Structuraland pH esterOne Trigger parameter groups.Effect on This Hydrolysis investigated wasand studied ester One is parameter thegroups.on effectpolyacrylamides This ofinvestigated th wase spacer studied having islength theon three effectpolyacrylamides between different of th quaternarye spacer spacers: having length ammonium methylene three between different quaternary spacers: ammonium methylene and(poly(1)), ester groups.propylene This (poly(3))wasand(poly(1)), studied esterOne and parameter groups.onpropylene pentenepolyacrylamides This investigated (poly(3))wasgrou studiedp having(poly(5)), isand theon three pentenepolyacrylamideseffect respectively different of thgroue spacer spacers:p (Tablehaving(poly(5)), length methylene three1) between respectively[47]. different quaternary spacers: (Table ammonium methylene 1) [47]. One parameter investigated is the effect of the spacer length between quaternary ammonium (poly(1)),The hydrolysis propylene was studied (poly(3))(poly(1)),andThe on hydrolysisester polymers and groups.propylene pentene wasin solutionThis studied (poly(3))wasgrou as studiedpon well polymers(poly(5)), and as on on pentenepolyacrylamides polymer inrespectively solution groubrushes asp well (Tablehaving(poly(5)), prepared as on three1) polymer byrespectively[47]. differentSI brushes spacers: (Table prepared methylene 1) by[47]. SI Structuraland ester Effect groups. on This Hydrolysis was studied on polyacrylamides having three different spacers: methylene TheATRP hydrolysis on gold-coated was studied siliconeThe(poly(1)),ATRP on SPRhydrolysis polymers on chips. gold-coatedpropylene The wasin solution complete studied silicone(poly(3)) as don SPRwellhydrolyses polymers and chips.as on pentene Thepolymer forin solution poly(1)complete groubrushes inasdp the wellhydrolyses (poly(5)), preparedsolution as on polymerandfor byrespectively poly(1) SIat brushes in the (Table preparedsolution 1) and by[47]. SIat (poly(1)), propylene (poly(3)) and pentene group (poly(5)), respectively (Table 1) [47]. ATRPthe surface on gold-coated occurred undersiliconeATRPThethe rather SPRsurfacehydrolysis on chips. gold-coatedharsh occurred The wasconditions complete studied undersilicone after donrather SPRhydrolyses polymers treatment chips. harsh The forinconditions with solutionpoly(1)complete 1 M in asafterNaOHd the wellhydrolyses solutiontreatment assolution on polymerandfor with forpoly(1) at 1 brushes M in NaOH the preparedsolution solution and by for SIat OneThe hydrolysis parameter was studied investigated on polymers is in thesolution effect as well of as the on polymer spacer brushes length prepared between by SI quaternary ammonium the1 h surfacein solution occurred and withundertheATRP1 0.1 hrather surface inM on solutionNaOH gold-coatedharsh occurred appliedconditionsand withundersilicone fo r 0.1 after uprather SPR M totreatment NaOHchips. 2harsh h to The appliedconditions thewith complete surface-confined 1 foMr afterNaOHdup hydrolyses totreatment 2solution h polymer, to for thewith forpoly(1) surface-confined 1 M in NaOH the solution solution polymer, and for at ATRP on gold-coated silicone SPR chips. The completed hydrolyses for poly(1) in the solution and at and ester1respectively. h in groups.solution An andeven This with slower1therespectively. was 0.1h hydrolysis surfaceinM studiedsolutionNaOH occurred An is applied andexpeeven on ctedwith underslower polyacrylamidesfo forr0.1 uprather hydrolysispoly(3) M to NaOH 2harsh hand to is appliedpoly(5)conditions theexpe surface-confinedcted having duefo forr aftertoup poly(3) the totreatment three higher2 h andpolymer, to pdifferent poly(5) theKwitha of surface-confined 1due M toNaOH spacers: the higher solution polymer, p methyleneK afor of the surface occurred undercarboxylate rather harsh compared conditions with after poly(1). treatment With with regard 1 M to NaOH the approach, solution foran increase in the protein (poly(1)),respectively.carboxylate propylene comparedAn even (poly(3)) slower withrespectively.1 h hydrolysis poly(1).in solution and WithAn penteneis andexpeeven regard cted withslower for groupto0.1 hydrolysispoly(3) theM NaOHapproach, (poly(5)), and is poly(5)applied expe ancted increase due respectivelyfo forr toup poly(3) the toin higher 2the hand toprotein p (Tablepoly(5)theKa of surface-confined due1)[ to47 the]. higher The polymer, hydrolysispKa of 1adsorption h in solution was observedand with adsorptionwith0.1 Mthe NaOH increasing was appliedobserved polymer fo withr up hydrophobicity theto 2increasing h to the in polymersurface-confined zwitterionic hydrophobicity polymers. polymer, inIn zwitterionic polymers. In carboxylate compared withcarboxylaterespectively. poly(1). comparedWithAn even regard slower with to hydrolysispoly(1).the approach, With is expe regardancted increase forto poly(3)the in approach, the and protein poly(5) an increasedue to the in higher the protein pKa of respectively. An even slower hydrolysis is expected for poly(3) and poly(5) due to the higher pKa of was studiedadsorptionpoly(1), poly(3) was on andobserved polymers poly(5), adsorptioncarboxylatepoly(1),with the the inhydrophobicity poly(3) increasing solution wascompared andobserved polymerpoly(5), increased aswith withwell thehydrophobicitypoly(1). the hydrophobicitywith increasing as spacerWith on lengths regardpolymer inpolymer zwitterionicincreased ofto one,hydrophobicitythe with brushes three approach,polymers. spacer and five lengths preparedinInan zwitterionic increase of one, in bythree polymers.the SI andprotein ATRPfive In on carboxylate compared with poly(1). With regard to the approach, an increase in the protein poly(1),carbons, poly(3) respectively and poly(5), [47],poly(1),adsorptioncarbons, as the was hydrophobicity poly(3) respectivelyconfirmed was andobserved poly(5), by increased[47], fibrinogen with as the wasthe hydrophobicitywith increasing confirmedadsorption spacer lengths polymer by increasedon fibrinogen theof one, hydrophobicitypolymer with three adsorption spacer andbrushes five lengths in zwitterionicon theof one, polymer three polymers. andbrushes five In gold-coatedadsorptionsilicone was observed SPR with chips. the increasing The polymer completed hydrophobicity hydrolyses in zwitterionic for poly(1) polymers. inIn the solution and at the carbons,investigated respectively on the SPR [47], sensors.carbons,poly(1),investigated as was Similarly,poly(3) respectivelyconfirmed on andthe after poly(5),SPR by[47], hydrolysis fibrinogensensors. as the was hydrophobicity Similarly, to confirmedadsorption poly(2) after and by onincreased hydrolysispoly(4), fibrinogenthe polymer withthe to adsorptionfibrinogen spacerpoly(2) brushes lengths and on poly(4), theof one, polymer thethree fibrinogen andbrushes five surfacepoly(1), occurred poly(3) and under poly(5), rather the hydrophobicity harsh conditions increased with after2 spacer treatment lengths of one, with three2 1and M five NaOH solution for 1 h in investigatedadsorption was on belowthe SPR the sensors.investigated carbons,adsorptionSPR limit Similarly, respectively of was ondetection belowthe after SPR [47],theof hydrolysis sensors.0.3 SPR as ng/cm waslimit Similarly, toconfirmed ofafter poly(2) detection hydrolysis, after and by of hydrolysispoly(4),fibrinogen 0.3 while, ng/cm the in to adsorptionafterthefibrinogen poly(2) case hydrolysis, ofand on poly(4), the while, polymer the in thefibrinogen brushes case of carbons, respectively [47], as was confirmed by fibrinogen2 adsorption on the polymer2 brushes solutionadsorptionpoly(6), and the withwasfibrinogen below 0.1 wasthe M adsorptionpoly(6),investigatedSPR adsorbed NaOH limit the of at wasfibrinogen applied ondetectiona density belowthe SPR wastheoffor sensors.1.50.3 SPR adsorbed ng/cmng/cm up limit Similarly, to2. ofafterTheat 2 detectiona hdensitypolycationic hydrolysis,to after the of hydrolysis 1.50.3surface-confined while,character ng/cmng/cm in to2. afterThe the ofpoly(2) poly(1), casepolycationic hydrolysis, ofand poly(4), polymer, while,character the in thefibrinogenof respectively. poly(1), case of investigated on the SPR sensors. Similarly, after hydrolysis to poly(2) and poly(4), the fibrinogen poly(6),poly(3) andthe fibrinogen poly(5) made waspoly(6),poly(3)adsorption adsorbedit possible andthe at wasfibrinogen poly(5)toa density condensebelow made wasofthe 1.5 DNA SPRadsorbedit ng/cm possible limit and2. ofTheatthe todetectiona densitypolycationic particlescondense of thus1.5 0.3DNA character ng/cmng/cm formed and22. Theafter ofthe (106 poly(1), polycationic particleshydrolysis, nm, thus while,character formed in theof (106 poly(1), case nm, of An evenadsorption slower was hydrolysisbelow the SPR limit is expected of detection forof 0.3 poly(3) ng/cm2 after and hydrolysis, poly(5) while, due in tothe thecase of higher pKa of carboxylate poly(3)136 nm andand 150 poly(5) nm, respectively) madepoly(3)136poly(6), it nmpossible were and andthe 150fibrinogen smallerpoly(5)to nm,condense respectively)than made was 150 DNA adsorbedit nm possible [47], andwere athencethe smaller toa densityparticlescondense able than to of internalize 150 thus 1.5DNA nmng/cm formed [47],and 2the. Thehencethe (106cells polycationicparticles able[52].nm, to internalizethus character formed the of (106cells poly(1), [52].nm, poly(6), the fibrinogen was adsorbed at a density of 1.5 ng/cm2. The polycationic character of poly(1), compared136 nmMoreover, and with 150 nm, poly(1).the antibacterialrespectively)136poly(3) WithnmMoreover, properties were andand regard 150smallerpoly(5) nm,the of antibacterialpolycarbrespectively)than made to 150 the it oxybetainenm possibleapproach, [47],properties were hence smallerto esters condense ofable polycarbthanpoly(1), anto internalize 150 increaseDNA poly(3)oxybetainenm [47],and the and hencethe cells in esters poly(5) particles the able[52]. poly(1), to protein internalizethus poly(3) formed adsorption the and cells(106 poly(5) [52].nm, was poly(3) and poly(5) made it possible to condense DNA and the particles thus formed (106 nm, wereMoreover, investigated the usingantibacterial Escherichiawere136 nmMoreover, investigatedproperties and coli150 nm,the(E. of usingantibacterial colipolycarbrespectively)) cells Escherichiaoxybetaine in properties weresolution. coli smaller esters (E. Theof colipolycarbthanpoly(1), most) cells150 hydrophilic poly(3)oxybetainenm in [47],solution. and hence esters poly(5)poly(1) Theable poly(1), mostto internalize hydrophilic poly(3) the and cells poly(5)poly(1) [52]. observed136 nm with and 150 the nm, increasingrespectively) were polymer smaller than hydrophobicity 150 nm [47], hence able in to zwitterionic internalize the cells polymers. [52]. In poly(1), poly(3) wereexhibited investigated 95% of theusing bacteria Escherichiawereexhibited Moreover, toinvestigated be 95% colialive of(the E.after the usingantibacterialcoli bacteria)30 cells Escherichiamin in while,to propertiessolution. be colialivein the ( E.Theofafter case colipolycarb most )30 ofcells min poly(3)hydrophilicoxybetaine in while, solution. and in esterspoly(5), poly(1)the The case poly(1), most of poly(3)hydrophilic poly(3) and and poly(5), poly(1)poly(5) Moreover, the antibacterial properties of polycarboxybetaine esters poly(1), poly(3) and poly(5) and poly(5),exhibited87% and 46%,95% the respectively,of hydrophobicitythe bacteriaexhibitedwere87% were and toinvestigated foundbe 46%,95% alive alive.respectively,of increased after theusing The bacteria30 mostminEscherichia were withwhile,hydrophobicto foundbe alivecoliin spacer alive.the( E.after poly(5)casecoli The )30 lengthsofcells most min exhibitedpoly(3) in while,hydrophobic solution. and ofthe in poly(5), one,highestthe The poly(5)case most three of exhibited poly(3)hydrophilic and and the five poly(5),highestpoly(1) carbons, were investigated using Escherichia coli (E. coli) cells in solution. The most hydrophilic poly(1) 87%antimicrobial and 46%, activity,respectively, which87%exhibitedantimicrobial were andindicated found 46%,95% activity,alive.respectively,ofsufficient the The bacteria which mostbinding were hydrophobicindicatedto found beto alivethe alive. sufficient acidicafter poly(5) The 30 polymers most minbindingexhibited hydrophobicwhile, atto the theinthe highestthe outeracidic poly(5)case polymersof exhibitedpoly(3) atand the the poly(5),highest outer respectivelyexhibited 95% [47 ],of asthe wasbacteria confirmed to be alive after by 30 fibrinogen min while, in adsorption the case of poly(3) on theand poly(5), polymer brushes investigated antimicrobialmembrane of activity,the bacteria whichantimicrobial87%membrane and andindicated the 46%, abilityof activity, therespectively,sufficient tobacteria re adilywhich binding and werepermeate indicated the found to ability thethe alive. sufficient acidic bacterialto There adilypolymers most bindingmembranes permeate hydrophobic atto the the thecausing outer acidicbacterial poly(5) polymers exhibitedmembranes at the the causinghighest outer on the87% SPR and sensors.46%, respectively, Similarly, were found after alive. hydrolysis The most hydrophobic to poly(2) poly(5) and exhibited poly(4), the thehighest fibrinogen adsorption was membranedeath [53]. of the bacteriamembraneantimicrobialdeath and [53].the abilityof activity,the tobacteria re adilywhich and permeate indicated the ability the sufficient bacterialto readily bindingmembranes permeate to the thecausing acidicbacterial polymers membranes at the causing outer antimicrobial activity, which indicated sufficient binding2 to the acidic polymers at the outer belowdeath theJiang [53]. SPR et al.limit reported of thatdeathmembrane detection polymerJiang [53]. et of brushesal. the ofreported 0.3bacteria of poly(7) ng/cmthat and polymer wi theth anafterability brushes ethyl hydrolysis,toester ofre adilypoly(7) pendant permeate wi preparedthwhile, an ethylthe by bacterial ester inSI the pendant membranes case prepared of poly(6),causing by SI the membrane of the bacteria and the ability to readily permeate the bacterial membranes causing ATRPJiang were et transformedal. reported thattodeathATRP poly(8) polymerJiang [53].were in et abrushestransformedal. N reported-cyclohexyl-3-aminopropanesu of poly(7) thatto poly(8) polymer with inan abrushes ethyl 2N-cyclohexyl-3-aminopropanesu ester oflphonic poly(7) pendant acid wi prepared th(CAPS) an ethyl buffer by ester SIlphonic pendant acid prepared (CAPS) buffer by SI fibrinogendeath [53]. was adsorbed at a density of 1.5 ng/cm . The polycationic character of poly(1), poly(3) ATRPat 37 °Cwere within transformed 24 h. The toATRPat poly(8)transformation 37Jiang °Cwere inwithin et a transformedal. N reported-cyclohexyl-3-aminopropanesu 24also h. proceededThe thatto poly(8)transformation polymer by in the abrushes N -cyclohexyl-3-aminopropanesudead also lphonic ofbacterial proceededpoly(7) acid wicells th(CAPS)by anor the ethylproteins bufferdead esterlphonic bacterial pendant acid cells prepared(CAPS) or proteins buffer by SI Jiang et al. reported that polymer brushes of poly(7) with an ethyl ester pendant prepared by SI and poly(5)atadhered, 37 °C within madehowever, 24 it h.the possible The timeatATRPadhered, transformation 37 could °C wereto withinhowever, be condensetransformed prolonged 24also h.the proceededThe timeto DNA[48]. poly(8)transformation could Application by andin be thea N prolonged thedead-cyclohexyl-3-aminopropanesu also of particles bacterial thisproceeded [48].switch cellsApplication thusbyis or theshown proteins formeddead ofin lphonic bacterial this (106switch acid cells nm,(CAPS) is or shown proteins 136 buffer nmin and ATRP were transformed to poly(8) in a N-cyclohexyl-3-aminopropanesulphonic acid (CAPS) buffer adhered,Figure 1. Poly(7)however, in thethe polycationic timeadhered,atFigure 37 could °C 1. Poly(7)withinstatehowever, be destroyedprolonged 24in theh.the Thepolycationic timealmost [48]. transformation could Application99.9% state be of E.destroyedprolonged colialso of and thisproceeded deadalmost [48].switch bacteria Application99.9% byis the shownofremained E.dead coli ofin and bacterial this dead switch bacteriacells is or shown remainedproteins in 150 nm,at 37 respectively) °C within 24 h. The were transformation smaller than also proceeded 150 nm by [47 the], hencedead bacterial able cells to internalize or proteins the cells [52]. Figureon the surface 1. Poly(7) (Figure in the 1a), polycationic and,Figureadhered,on the after surface 1. hydrolysis Poly(7)statehowever, (Figure destroyed in thetothe 1a), poly(8) polycationic timealmostand, after(Figurecould 99.9% hydrolysis state be 1b),of E.destroyedprolonged almost coli toand poly(8) 98% deadalmost [48]. of (Figurebacteriathe 99.9%Application dead 1b),ofremained bacteria E. almost coli of and this 98% dead switch of bacteriathe deadis shown remained bacteria in adhered, however, the time could be prolonged [48]. Application of this switch is shown in Moreover,onwere the releasedsurface (Figure the(Figure antibacterial 1a), 1c). and,onFigurewere Additionally, the after releasedsurface 1. hydrolysisPoly(7) properties (Figure (Figurepoly(8) in theto 1a), poly(8) polycationic1c).showed and, ofAdditionally, after(Figure polycarboxybetaine non hydrolysis state fouling1b), destroyed almostpoly(8) propertiesto poly(8) 98%showed almost of (Figurethefor 99.9%non estersdeadproteins fouling1b),of bacteria E. almost coli poly(1),and properties and 98% dead of poly(3) bacteriathefor deadproteins remained bacteria and and poly(5) Figure 1. Poly(7) in the polycationic state destroyed almost 99.9% of E. coli and dead bacteria remained were released (Figure 1c).wereon Additionally, the releasedsurface (Figure (Figurepoly(8) 1a), 1c).showed and, Additionally, after non hydrolysis fouling poly(8) propertiesto poly(8) showed (Figurefor non proteins fouling1b), almost and properties 98% of thefor deadproteins bacteria and wereon investigated the surface (Figure using 1a), and,Escherichia after hydrolysis colito poly(8)4 (E. (Figure coli) cells1b), almost in 98%4 solution. of the dead Thebacteria most hydrophilic poly(1) were released (Figure 1c). Additionally, poly(8) showed non fouling properties for proteins and exhibitedwere released 95% of(Figure the 1c). bacteria Additionally, to bepoly(8) alive 4showed after non 30 fouling min properties while,4 for in proteins the case and of poly(3) and poly(5), 4 87% and 46%, respectively, were found4 alive. The most hydrophobic poly(5) exhibited the highest antimicrobial activity, which indicated sufficient binding to the acidic polymers at the outer membrane of the bacteria and the ability to readily permeate the bacterial membranes causing death [53]. Jiang et al. reported that polymer brushes of poly(7) with an ethyl ester pendant prepared by SI ATRP were transformed to poly(8) in a N-cyclohexyl-3-aminopropanesulphonic acid (CAPS) buffer at 37 ˝C within 24 h. The transformation also proceeded by the dead bacterial cells or proteins adhered, however, the time could be prolonged [48]. Application of this switch is shown in Figure1. Poly(7) in the polycationic state destroyed almost 99.9% of E. coli and dead bacteria remained on the surface (Figure1a), and, after hydrolysis to poly(8) (Figure1b), almost 98% of the dead bacteria were released (Figure1c). Additionally, poly(8) showed non fouling properties for proteins and bacteria

2347 Polymers 2015, 7, 2344–2370 Polymers 2015, 7, page–page bacteria(Figure1 d).(Figure This 1d). switchable This switchable polymer coating,polymer enabling coating, transformation enabling transformation from initial antibacterialfrom initial antibacterialcharacter through character self-cleaning through self-cleaning process to non-foulingprocess to non-fouling properties, properties, opens opportunity opens opportunity for capable for capablecoating forcoating implantable for implantable devices. devices.

Figure 1. 1. AA schematic schematic application application of ofpoly(7) poly(7) as a as switch a switch where where (a) a( asurface) a surface with withpolycationic polycationic state poly(7)state poly(7) possessing possessing antibacterial antibacterial properties properties that, that, (b) (bthrough) through alkaline alkaline hydrolysis, hydrolysis, (c (c) )the the surface switches toto polyzwitterionicpolyzwitterionic state state poly(8) poly(8) and and dead dead bacteria bacteria cells cells are released are released from surfacefrom surface and, finally, and, finally,(d) the ( poly(8)d) the poly(8) surface surface becomes becomes resistant resistant to bacterial to bacterial adhesion. adhesion. Reprinted Reprinted with permissionwith permission from fromReference Reference [48], Copyright[48], Copyright 2008, 2008, Wiley-VCH. Wiley-VCH.

Structurally similar, a methacrylate analogue to poly(1), carboxybetaine methylester poly(9), Structurally similar, a methacrylate analogue to poly(1), carboxybetaine methylester poly(9), was was used for modification of the non-woven polypropylene (PP) membranes [49]. The polymerization used for modification of the non-woven polypropylene (PP) membranes [49]. The polymerization was performed via UV-induced radical polymerization from the plasma pre-treated PP membrane was performed via UV-induced radical polymerization from the plasma pre-treated PP membrane surface. The switch from poly(7) to poly(9) was scrutinized to find milder hydrolysis conditions. surface. The switch from poly(7) to poly(9) was scrutinized to find milder hydrolysis conditions. Complete hydrolysis was observed in the N-cyclohexyl-3-aminopropanesulphonic acid (CAPS) Complete hydrolysis was observed in the N-cyclohexyl-3-aminopropanesulphonic acid (CAPS) buffer (pH 10) within 8 h and the methacrylate backbone ester group remained intact. The PP buffer (pH 10) within 8 h and the methacrylate backbone ester group remained intact. The PP membrane with poly(7) exhibited antibacterial activities with no bacterial colonies detected. After the membrane with poly(7) exhibited antibacterial activities with no bacterial colonies detected. After transformation of poly(7) to poly(8), strong resistance to platelets adhesion was exhibited and the the transformation of poly(7) to poly(8), strong resistance to platelets adhesion was exhibited and thromboresistance properties were enhanced. The hemocompatibility and platelet adhesion is a the thromboresistance properties were enhanced. The hemocompatibility and platelet adhesion crucial parameter for the preparation of polymers designed for biomedical applications such as is a crucial parameter for the preparation of polymers designed for biomedical applications such catheters, implants, blood bags, etc. When blood comes into contact with a surface, first the adsorption as catheters, implants, blood bags, etc. When blood comes into contact with a surface, first of plasma proteins occurs, followed by platelet adhesion, coagulation and finally thrombus formation the adsorption of plasma proteins occurs, followed by platelet adhesion, coagulation and finally [54,55]. Accordingly, a material possessing antibacterial properties capable of switching upon mild thrombus formation [54,55]. Accordingly, a material possessing antibacterial properties capable of transformation to antifouling and hemocompatible properties is of extreme interest to switching upon mild transformation to antifouling and hemocompatible properties is of extreme abovementioned biomedical applications. interest to abovementioned biomedical applications. The rate of hydrolysis of the carboxybetaine ester to the zwitterionic state was systematically The rate of hydrolysis of the carboxybetaine ester to the zwitterionic state was systematically studied with regard to the different ester leaving groups such as ethyl (Et) or tert-butyl (tBu), and a studied with regard to the different ester leaving groups such as ethyl (Et) or tert-butyl (tBu), and spacer between the ester and the tertiary amine group. Polymers poly(10) were prepared via a spacer between the ester and the tertiary amine group. Polymers poly(10) were prepared via reversible addition fragmentation (RAFT) polymerization. The effect of the spacer between charged reversible addition fragmentation (RAFT) polymerization. The effect of the spacer between charged groups in poly(11) was found to affect the buffering capacity of the tertiary amine, which has an groups in poly(11) was found to affect the buffering capacity of the tertiary amine, which has an important impact on the clinical applications of such polymers as potential DNA vectors that are important impact on the clinical applications of such polymers as potential DNA vectors that are prone to acidic degradation to form poly(11). It was revealed that poly(10) with a methylene spacer prone to acidic degradation to form poly(11). It was revealed that poly(10) with a methylene spacer exhibited a buffering range of the amino group in the endosomal environment, the highest buffering exhibited a buffering range of the amino group in the endosomal environment, the highest buffering capacity and was the most stable in physiological and endosomal pH for ethyl ester group [51]. capacity and was the most stable in physiological and endosomal pH for ethyl ester group [51]. As the As the materials enter into endosomes, the pH is decreased from the physiological pH 7.4 to 5 by materials enter into endosomes, the pH is decreased from the physiological pH 7.4 to 5 by protons protons pumped through the endosomal membrane. The tertiary amines with a pKa value close to pumped through the endosomal membrane. The tertiary amines with a pK value close to the pH the pH values inside the endosomes can adsorb the protons and create ana osmotic pressure that values inside the endosomes can adsorb the protons and create an osmotic pressure that results in results in membrane rupture and the endosomal escape of polymers via a “proton sponge” membrane rupture and the endosomal escape of polymers via a “proton sponge” mechanism [56,57]. mechanism [56,57]. Moreover, the same nontoxic poly(10) mediated transfection of DNA is an order of magnitude better than branched polyethylene imide due to slow hydrolysis rate to poly(11). 2348 5 Polymers 2015, 7, page–page

Scheme 1. Schematic presentation of irreversible and reversible switches. Polymers 2015, 7, 2344–2370 2.1. Switch from Polycationic to Polyzwitterionic State Polymers 2015, 7, page–page Moreover,Conversion the same from nontoxic the polycationic poly(10) mediated to the polyzwi transfectiontterionic of DNAstate exhibits is an order dramatic of magnitude changes better in the interaction with water, proteins, drugs, DNA, and bacteria. This conversion is represented solely by than branchedAdditionally, polyethylene the poly(10) imide structure due to slowwith methyl hydrolysis ester rate group to poly(11). and ethylene spacer was used for transformationPolymers 2015 of, 7the, page–page ester or amide groups into the carboxylate group in the monomer unit. The thePolymers modificationAdditionally, 2015, 7, page–page of the medical poly(10) gauze structure in the with form methyl of a estercopolymer group andwith ethylene poly(ethylene spacer glycol) was used (PEG) for thetransformationPolymers modification 2015Polymers, 7, page–page 2015 occurs of, 7, medicalpage–page as a response gauze in to thean external form of stimulus a copolymer (pH, withbuffering poly(ethylene capacity or glycol) light) and (PEG) the methacrylatePolymers 2015, 7Additionally,, page–pageand cross-linked the poly(10) with structure hexamethylene with methyl diisocyanate ester group and[50]. ethylene A small spacer amount was used of forPEG methacrylatepolyzwitterionicAdditionally, and state the cross-linked poly(10) is preserved. structure with The hexamethylene with progress methyl of ester the diisocyanate transformationgroup and ethylene [50 ].is influenced spacer A small was amount byused several for of factors PEG methacrylateAdditionally,the modification was usedthe poly(10) for of improvementmedical structure gauze with ofin themethylthe mechanform ester of icalgroupa copolymer properties and ethylene with such poly(ethylene spacer as flexibility was used glycol) and for strength. (PEG) suchthe modification as lengthAdditionally, of ofthe medical spacer the gauzepoly(10)between in structurethe the form quaternary withof a methylcopolymer amine ester and with group the poly(ethylene carboxyland ethylene group, glycol) spacer the (PEG)was nature used of for the methacrylateFurther,Additionally, methacrylateto inhibit was used the bacterialand poly(10) for cross-linked improvement structuregrowth with afterwith of hexamethylene the methylthe mechanical switch, ester group adiisocyanate propertiessmall and ethylenehydrop such[50]. hobicspacer asA flexibilitysmall drug—aspirin—waswas amount used and for strength.of PEG methacrylatethe modificationthe modification and of cross-linked medical of medical gauze with ingauze hexamethylene the formin the of form a copolymerdiisocyanate of a copolymer with [50]. poly(ethylene withA small poly(ethylene amount glycol) of glycol)(PEG) PEG (PEG) Further,hydrolysablethe modificationmethacrylate to inhibit group, of bacterialmedicalwas pH used and gauze for growthtemperature; improvement in the after form these the of of the switch, awill mechancopolymer also aical be small propertieswithdiscussed hydrophobicpoly(ethylene such below. as flexibility glycol) drug—aspirin—was (PEG)and strength. introducedmethacrylatemethacrylate into wasand the used cross-linked andcopolymer. for improvementcross-linked with The hexamethylene with ofreleased the hexamethylene mechan aspirin icaldiisocyanate properties inhibited diisocyanate [50]. such E. Aascoli [50]. flexibilitysmall growth A amountsmall and within amountstrength. of PEG 12 of h. PEGAfter introducedmethacrylateFurther, into and theto cross-linkedinhibit copolymer. bacterial with The growthhexamethylene released after aspirinth ediisocyanate switch, inhibited a small [50].E. hydrop coliA smallgrowthhobic amount drug—aspirin—was within of PEG 12 h. After hydrolysisFurther,methacrylatemethacrylate to (pH inhibit was 13, used bacterial was1 h),for used improvementthe growth for material improvement after of exhibited thethe mechan ofswitch, the re mechanicalsistance a propertiessmallical to hydropproperties non-specific suchhobic as suchflexibility drug—aspirin—was as protein flexibility and strength.adsorption and strength. and hydrolysis2.1.1.methacrylate (Meth)acrylicintroduced (pH was 13, used into 1Type h),for the improvement thePolymers copolymer. material ofThe exhibited the released mechan resistance icalaspirin properties inhibited to non-specific such E. as coli flexibility growth protein and within strength. adsorption 12 h. After and HUVECintroducedFurther,Further, cellto intoinhibit attachment. tothe inhibit bacterialcopolymer. bacterialThe growth normalThe growthreleasedafter cell th after e growth aspirinswitch, the inhibited switch,arounda small a E.hydropthesmall coli modified growthhydrophobic drug—aspirin—was hobicwithingauze drug—aspirin—was 12indicated h. After the low Further,hydrolysis to inhibit (pHbacterial 13, 1 h),growth the materialafter th eexhibited switch, are sistancesmall hydrop to non-specifichobic drug—aspirin—was protein adsorption and HUVECcytotoxicityhydrolysisintroducedTheintroduced cell most (pHofinto attachment. the common13,the material. into 1copolymer. h), the thepolymer Thecopolymer. material normalThe backbone releasedexhibited The cell released growthaspirin motifsresistance aspirininhibited aroundused to inhibitednon-specificin theE.these coli modified growthE.switches coliprotein growthwithin gauze areadsorption (meth)acrylic-basedwithin12 indicated h. After 12and h. the After low introducedHUVEC into cellthe copolymer.attachment. TheThe releasednormal cellaspirin growth inhibited around E. thecoli modifiedgrowth within gauze 12indicated h. After the low cytotoxicityHUVEChydrolysishydrolysis cell of(pH attachment. the 13, material.(pH 1 h), 13, theThe 1 h),material normal the material exhibitedcell growth exhibited re sistancearound resistance tothe non-specific modified to non-specific gauze protein indicated proteinadsorption adsorptionthe andlow and polymershydrolysiscytotoxicity due (pH to 13, their of1 h),the simple thematerial. material synthetic exhibited modification resistance, ready to non-specific availability protein and the adsorption possibility and to prepare HUVECHUVEC cell attachment. cell attachment. The normal The normalcell growth cell growtharound aroundthe modified the modified gauze indicatedgauze indicated the low the low StructuralpolymerHUVECcytotoxicity cell brushesEffect of attachment. the on material.using Hydrolysis Thesurface-initiated normal with Releasedcell growth (SI) Active atom-transferaround Molecules the modified radical gauze polymerization indicated the (ATRP) low or SI Structuralcytotoxicitycytotoxicity Effect of the on material. of Hydrolysis the material. with Released Active Molecules photointerphertercytotoxicityStructural of the Effectmaterial. mediated on Hydrolysis polymerization with Released (PMP), Active mainly Molecules through a thiolated initiator immobilized StructuralIn addition Effect onto theHydrolysis intrinsic with antibacterial Released Active character Molecules of polycationic state, mild antibacterial agent ontoIn the addition gold surface, to the or intrinsic polymers antibacterial with controlled character lengths. of polycationic The simple state, synthetic mild protocol antibacterial permits agent the suchStructural as salicylateStructural EffectIn addition on Effection Hydrolysis (SA toon −the )Hydrolysis as intrinsic counterwith Released withantibacterial ions Released orActive as ancharacter MoleculesActive esteric Molecules of part polycationic were reported state, mild and antibacterial these switches agent are Structural Effect on Hydrolysis´ with Released Active Molecules suchapplication asIn salicylate addition of a tomodern ion the (SA intrinsic method) as counterantibacterial− such ionsas surfacecharacter or as an plasmon of esteric polycationic partresonance were state, reported (SPR) mild antibacterialto andevaluate these agentmodifications switches are summarizedIn suchaddition asin salicylateTable to the 2.intrinsic ion (SA antibacterial) as counter characterions or as of an polycationic esteric part werestate, reportedmild antibacterial and these agent switches are such as salicylateIn addition ion (SA to−) the as counterintrinsic ions antibacterial or as an esteric character −part2 of were polycationic reported andstate, these mild switches antibacterial are agent summarizedor adsorptionIn summarizedaddition in Table tochange the in2. intrinsicTable − even 2. antibacterial down to character0.1 ng·cm of polycationic. Typical state,(meth)acrylic-based mild antibacterial agentpH-triggered such as suchsalicylate as salicylate ion (SA ion) as (SA counter−) as counter ions or ionsas an or esteric as an partesteric were part reported were reported and these and switches these switches are are irreversiblesuchsummarizedTable as salicylate 2. Irreversibleswitches, in Table ion (SA2. their pH-triggered−) as triggers counter (meth)acrylic-basedionsand orapplied as an esteric forms partswitches are were summarized containing reported and inpolyzwitterionic Table these 1.switches state are and summarizedTablesummarized 2. IrreversibleTable in Table 2. Irreversible in 2. Table pH-triggered 2. pH-triggered (meth)acrylic-based (meth)acrylic-based switches switches containing containing polyzwitterionic polyzwitterionic state and and summarizedreleasedTable 2. Irreversible activein Table molecule. 2. pH-triggered (meth)acrylic-based switches containing polyzwitterionic state and releasedTable activereleased1. Irreversible molecule. active molecule. pH-triggered (meth)acrylic-based switches containing polyzwitterionic state. releasedTable 2. Table Irreversibleactive 2. molecule. Irreversible pH-triggered pH-triggered (meth)acrylic-based (meth)acrylic-based switches switches containing containing polyzwitterionic polyzwitterionic state and state and Table 2. Irreversible pH-triggered (meth)acrylic-based switches containing polyzwitterionic state and releasedreleased active molecule. active molecule. Trigger (applied form) Polyzwitterion state and released releasedInitialInitial active state molecule.state TriggerTrigger(Triggerapplied (applied (applied form form)) reference form) Polyzwitterion Polyzwitterionic state and releasedstate Initial stateInitial state Trigger (appliedreference form) Polyzwitterion activestate and molecule released Initial state referencereference active molecule TriggerreferenceTrigger (applied (applied form) form)PolyzwitterionPolyzwitterionactive moleculestate and state released and released Initial stateInitial state TriggerNaOH (applied (polymer form) brush)Polyzwitterion state and released Initial state pH 10,reference 37pH˝C 10,pH 8reference days 3710, °C37 (hydrogel) °C active moleculeactive molecule pHreference 10, 37 °C active molecule 8 days8 days (hydrogel) (hydrogel) pH 10, 37pH °C 10, 37 °C 8 dayspH 10, (hydrogel) 37 °C 8 days (hydrogel)8 days (hydrogel) 8 days (hydrogel) Poly(1): m = 1 Poly(2) m = 1 [58] − Poly(12) [58] Poly(2) and SA − Poly(12) [58] Poly(2) −and SA´ Poly(3):Poly(12) m = 3 [58] [47] Poly(2)Poly(2) and Poly(4) SA and m SA = 3 Poly(12) − Poly(12) [58] Poly(2) and SA − Poly(5): mPoly(12) = 5 pH 10 (hydrogel) [58] Poly(2) Poly(6) −and m SA = 5 Poly(12) pHpH 10pH [58](hydrogel)10 10 (hydrogel) (hydrogel) Poly(2) and SA pH 10 (hydrogel)pH 10 (hydrogel) pH 10 (hydrogel)

Poly(13) [59] Poly(8) and SA− [59] − Poly(13) [59] Poly(8) and SA − Poly(13) [59] Poly(8) −and SA´ Poly(13) [59] Poly(8)Poly(8) and SA and SA − Poly(13)Poly(13) pH 7.4, 20 [59]°C (hydrogel) Poly(8) −and SA Poly(13) pH 7.4, 20 [59]°C (hydrogel) Poly(8) and SA pH 7.4, 20 °C˝ (hydrogel) pH 7.4,pH pH20 7.4, °C7.4, 20 (hydrogel) 20C (hydrogel)°C (hydrogel) pH 7.4, 20 °C (hydrogel)

Poly(14) [60] Poly(8) and SA− − Poly(14) [60] Poly(8) and SA 3 − Poly(14)Poly(14) [60] [60][60] [60] Poly(8) Poly(8) Poly(8)and SA and SA SA− − AnPoly(14) interesting application of a block [60] copolymer containing Poly(8)poly(12)Poly(8) and prepared SA and− SAby´ reversible An interesting application of a block copolymer containing poly(12) prepared by reversible addition fragmentation chain-transfer (RAFT) polymerization was shown. Polycationic poly(12), additionAn interestingfragmentationAn interesting application chain-transfer application of a block (RAFT)of a copolymer block polymerization copolymer containing containing was poly(12) shown. poly(12) prepared Polycationic prepared by reversiblepoly(12), by reversible AnAn with interestinginteresting the ethyl applicationapplication ester terminal of of agroup blocka block and copolymer salicylatecopolymer containing (SA −containing) as a counter-ion,poly(12) poly(12) prepared was preparedused by as reversible an innerby reversible B block withadditionAn theaddition interesting ethylfragmentation ester fragmentation terminal application chain-transfer group chain-transfer of and a salicylate(RAFT) block copolymer(RAFT) polymerization (SA−) aspolymerization a counter-ion, containing was shown. waswas poly(12) used shown.Polycationic as prepared an Polycationic inner poly(12), B byblock reversiblepoly(12), additionadditionin fragmentation fragmentationan ABA triblock chain-transfer chain-transfer copolymer (RAFT)in (RAFT)combination polymerization polymerization− with an was A blockshown.was consistingshown. Polycationic Polycationic of poly poly(12), N-isopropyl poly(12), within an the ABAwith ethyl thetriblock ester ethyl terminal copolymerester terminal group in and groupcombination salicylate and salicylate (SAwith) asan (SA a Acounter-ion,− )block as a counter-ion, consisting was used wasof aspoly used an innerN as-isopropyl an B innerblock B block additionwithwith the theacrylamide ethyl fragmentationethyl ester poly(NIPAM).terminal terminal chain-transfer group group The and and hydrolysis salicylate (RAFT)salicylate (SAof polymerization poly(12) −(SA) as −a) counter-ion,as and a counter-ion, transformation was was shown. used was from as used an Polycationic the inner aspolycationic an B blockinner poly(12), Bto block the acrylamidein an ABAin an poly(NIPAM).triblock ABA triblock copolymer The copolymer hydrolysis in combination in of combination poly(12) with and an withtransformation A´ blockan A consistingblock from consisting the of polycationicpoly of N -isopropylpoly toN the-isopropyl withinin an an the ABAABApolyzwitterionic ethyl triblock ester terminalcopolymercopolymer state was group in ininvestigatedcombination combination and salicylate indirectlywith with (SAan Athroughan )block asA ablock counter-ion,consistingthe release consisting of of poly was an of anionic usedN -isopropylpoly as counterN an-isopropyl inner ion B polyzwitterionicacrylamideacrylamide poly(NIPAM). state poly(NIPAM). was The investigated hydrolysis The hydrolysis indirectlyof poly(12) of poly(12)through and transformation andthe transformationrelease fromof an the anionicfrom polycationic the counter polycationic to ionthe to the blockacrylamide insalicylate an ABA poly(NIPAM). triblock(SA−) from copolymerThe a hydrogelhydrolysis in disc combinationof poly(12) in a phosphate and with transformation saline an A buffer block from (PBS, consisting the pH polycationic 7.4) of at poly 37 °C.toN the -isopropylAfter 1 h, acrylamidepolyzwitterionic poly(NIPAM).− state was Theinvestigated hydrolysis indirectly of poly(12) through and the transformation release of an fromanionic the counter polycationic ion to the salicylatepolyzwitterionic (SA ) from− a hydrogel state was disc investigated in a phosphate indirectly saline throughbuffer (PBS, the releasepH 7.4) ofat 37an °C.anionic After counter 1 h, ion acrylamidepolyzwitterionic50% poly(NIPAM). of− SA state was wasreleased Theinvestigated and hydrolysis the complete indirectly of poly(12) hydrolysis through and thewas transformation releasedetected of after an anionic10 from h [58]. thecounter polycationic ion to polyzwitterionicsalicylate (SA− ) from state −a hydrogelwas investigated disc in a phosphate indirectly saline through buffer the(PBS, release pH 7.4) of at an37 °C.anionic After 1counter h, ion 50% of SAsalicylate was− released (SA ) from and athe hydrogel complete disc hydrolysis in a phosphate was detected saline bufferafter 10 (PBS, h [58]. pH 7.4) at 37 °C. After 1 h, thesalicylate polyzwitterionic (SA− The−) from initial statea hydrogelpolycation was investigateddisc state in ofa phosphatepoly(12) indirectly ensures saline through bufferattachment (PBS, the of releasepH the 7.4) material ofat 37 an °C. anionicto Aftermammalian counter1 h, cells ion salicylate50% ofThe SA50% initial(SA was of )SA polycationfromreleased− was a released hydrogel and state the and ofcomplete discpoly(12) the completein hydrolysisa ensures phosphate hydrolysis attachment was salinedetected was ofbuffer detected theafter material 10(PBS, after h [58]. pH 10to h mammalian7.4) [58]. at 37 °C. cells After 1 h, 50% of SAand− wasantibacterial´ released andproperties. the complete Moreover, hydrolysis during was mild detected hydrolysis after condition 10 h [58]. the slow release˝ of SA− as salicylate50%and of antibacterialThe SA (SAinitial− wasThe) polycation released frominitial properties. apolycation hydrogel and state Moreover, the of statecomplete discpoly(12) ofduring in poly(12) a ensures phosphatehydrolysis mild ensures attachmenthydrolysis salinewas attachment detected conditionof buffer the material of (PBS, after thethe slow material pH10 to h mammalian 7.4)release [58]. to at mammalian 37of SA C.cells− as After cells 1 h, Thea ´mildinitial antibacterial polycation stateagent of occurred poly(12) andensures after attachment transformation of the to materialpolyzwitterionic to mammalian poly(2) cells −material is 50%anda mild ofThe antibacterial SA antibacterialand initial wasantibacterial polycation released properties. agent properties. andoccurred stateMoreover, the of complete andMoreover, poly(12) duringafter transfor hydrolysis duringmildensures hydrolysismation mild attachment was hydrolysis to detected conditionpolyzwitterionic of condition the after the material slow 10 poly(2)the h release [ 58slow to]. material mammalianreleaseof SA asofis SA − cellsas and antibacterialbiocompatible properties. and preventsMoreover, furt duringher mildadhesion. hydrolysis Additionally, condition the slowouter release blocks of SAconsisting− as of biocompatiblea mildThe antibacteriala initialmild antibacterialand polycation agentprevents occurred agent state furt occurredher ofand poly(12) adhesion.after and transfor after ensuresAdditionally, transformation attachment mationto polyzwitterionic the to outerpolyzwitterionic of theblocks poly(2) material consisting poly(2)material to mammalian material ofis −is anda mild antibacterial antibacterialthermo-responsive properties. agent occurredpoly(NIPAM) Moreover, and after haveduring transfor LCST mild mationenabling hydrolysis to polyzwitterionicthe transition condition from thepoly(2) slowliquid material release to solid is of above SA as thermo-responsivebiocompatiblebiocompatible and poly(NIPAM)prevents and prevents furt haveher furt adhesion.LCSTher enablingadhesion. Additionally, the Additionally, transition the outerfrom the liquidblocksouter toblocksconsisting solid consistingabove of of cellsa biocompatiblemild and antibacterial37 antibacterial °C, permittingand agentprevents properties. application occurred further Moreover, inand adhesion. a sprayafter duringtransforsolution Additionally, mild mationand gelation hydrolysis theto polyzwitterionicouter occurs condition blocks at body consisting the temperature,poly(2) slow materialof release as is of is 37thermo-responsive´ °C, permittingthermo-responsive application poly(NIPAM) poly(NIPAM) in ahave spray LCST havesolution enablingLCST and enabling gelationthe transition theoccurs transition fromat body liquid from temperature, toliquid solid to above assolid is above SAbiocompatiblethermo-responsiveasschematically a mild and antibacterial poly(NIPAM) presentedprevents agent infurt Figurehaveher occurred LCST 2.adhesion. The enabling combinatio and afterAdditionally, then transformation transitionof the above fromthe properties outerliquid to polyzwitterionic toblocksmakes solid this aboveconsisting interesting poly(2) of schematically37 °C, permitting37 °C, presentedpermitting application in application Figure in a2. spray The in combinatioa solutionspray solution andn of gelationthe and above gelation occurs properties occursat body makes at temperature, body this temperature,interesting as is as is materialthermo-responsive37 °C, permittingmaterials is biocompatible highly application poly(NIPAM) promising and in prevents a forspray have use solution asfurtherLCST an antimicrobial enabling adhesion.and gelation thewound Additionally, occurs transition dressing at body from the[58]. temperature, outer liquid blocks to assolid consistingis above materialsschematicallyschematically highly presented promising presented in Figurefor use in 2. Figureas The an antimicrobialcombinatio 2. The combination ofwound then above of dressing the properties above [58]. properties makes thismakes interesting this interesting of37schematically thermo-responsive°C, permitting presented application poly(NIPAM) in Figure in 2. aThe spray have combinatio LCSTsolutionn enabling of and the abovegelation the properties transition occurs makes fromat body this liquid temperature,interesting to solid above as is materialsmaterials highly promisinghighly promising for use foras an use antimicrobial as an antimicrobial wound wounddressing dressing [58]. [58]. schematicallymaterials highly presented promising in for Figure use as 2. an The antimicrobial combinatio woundn6 of the dressing above [58]. properties makes this interesting 6 materials highly promising for use as an antimicrobial wound dressing [58]. 62349 6 6

6 Polymers 2015, 7, 2344–2370

37 ˝C, permitting application in a spray solution and gelation occurs at body temperature, as is schematically presented in Figure2. The combination of the above properties makes this interesting materialsPolymers 2015 highly, 7, page–page promising for use as an antimicrobial wound dressing [58].

Figure 2. Schematic presentation of spray application of poly(12) as an antibacterial wound dressing hydrogel. Reprinted with permissionpermission from Reference [[58],58], CopyrightCopyright 2011,2011, Wiley-VCH.Wiley-VCH.

Similarly, the methacrylic poly(13) analogue to acrylic poly(12), was investigated in hydrogel Similarly, the methacrylic poly(13) analogue to acrylic poly(12), was investigated in hydrogel form prepared by redox polymerization [59]. The hydrogel based on poly(13) inhibited the growth form prepared by redox polymerization [59]. The hydrogel based on poly(13) inhibited the growth of planktonic bacteria, both Gram-negative E. coli K12 and Gram-positive Staphylococcus epidermidis of planktonic bacteria, both Gram-negative E. coli K12 and Gram-positive Staphylococcus epidermidis (S. epidermidis), by 99.9% due to the polycationic character as well as by the controlled releasing of (S. epidermidis), by 99.9% due to the polycationic character as well as by the controlled releasing of SA− as a mild antibacterial agent. After hydrolysis, the hydrogel prevented protein adsorption or SA´ as a mild antibacterial agent. After hydrolysis, the hydrogel prevented protein adsorption or bacterial accumulation. bacterial accumulation. Alternatively, covalent attachment of the salicylate molecule as an ester via the phenolic group Alternatively, covalent attachment of the salicylate molecule as an ester via the phenolic group in a monomer unit poly(14) was developed for enhancing the controlled SA− release over the system in a monomer unit poly(14) was developed for enhancing the controlled SA´ release over the system with an ionic-forces stabilized SA− in poly(13) [60]. Fabricated hydrogel from poly(14) was prepared redox with an ionic-forces stabilized SA´ in poly(13) [60]. Fabricated hydrogel from poly(14) was prepared polymerization. Hydrolysis of the salicylate ester poly(14) was completed in 16 h, while the complete redox polymerization. Hydrolysis of the salicylate ester poly(14) was completed in 16 h, while the release of the drug SA− from poly(13) was completed in 3 h under the same condition. complete release of the drug SA´ from poly(13) was completed in 3 h under the same condition. The hydrogel after the transformation to poly(5) still retained the non-fouling properties for protein The hydrogel after the transformation to poly(5) still retained the non-fouling properties for protein and bacteria. and bacteria. 2.1.1.2. Light Trigger 2.1.1.2. Light Trigger Since photolysis is a non-invasive trigger and initiation is timely and spatially localizable, this Since photolysis is a non-invasive trigger and initiation is timely and spatially localizable, this approach has attracted the greatest interest in bio-related applications. Recently, a photolysis of a approach has attracted the greatest interest in bio-related applications. Recently, a photolysis of photolabile unit for the preparation of switchable polymers poly(15) and poly(16) [51,61] was a photolabile unit for the preparation of switchable polymers poly(15) and poly(16) [51,61] was reported. Their structures are shown in Table 3. reported. Their structures are shown in Table3. In the poly(15) [61] switch to the polyzwitterionic state, poly(16) was enabled via the abstraction In the poly(15) [61] switch to the polyzwitterionic state, poly(16) was enabled via the abstraction of a photolabile o-nitrobenzyl-carboxymethyl pendant during irradiation at 365 nm in PBS solution. of a photolabile o-nitrobenzyl-carboxymethyl pendant during irradiation at 365 nm in PBS solution. In the polycationic state, poly(15) was able to bind double-strand DNA (dsDNS), showing the size of In the polycationic state, poly(15) was able to bind double-strand DNA (dsDNS), showing the size the DNA complex of 170 nm in solution and on a dextrane-modified surface. Upon irradiation at of the DNA complex of 170 nm in solution and on a dextrane-modified surface. Upon irradiation 365 nm, the polyzwitterionic state poly(16) was formed and the dsDNA was released in solution as at 365 nm, the polyzwitterionic state poly(16) was formed and the dsDNA was released in solution well as from the surface [61]. In addition, dramatic differences in polycationic poly(15) and the as well as from the surface [61]. In addition, dramatic differences in polycationic poly(15) and the polyzwitterionic form was observed where the antibacterial activity of poly(15) was tested against polyzwitterionic form was observed where the antibacterial activity of poly(15) was tested against E. coli cells in solution and on the surface, where 91% was killed compared with the inactive E. coli cells in solution and on the surface, where 91% was killed compared with the inactive poly(16) [61]. poly(16) [61]. Similarly, poly(17) formed a polycomplex with DNA and, after photolysis at 365 nm, 72.5% of Similarly, poly(17) formed a polycomplex with DNA and, after photolysis at 365 nm, 72.5% of free DNA was released from the polyplex, as confirmed by a quantitative PicoGreen DNA binding free DNA was released from the polyplex, as confirmed by a quantitative PicoGreen DNA binding assay [51]. assay [51]. Table 3. Irreversible light-triggered (meth)acrylic-based switches containing polyzwitterionic state.

Trigger (applied form) Initial state Polyzwitterion state reference

UV light 365 nm (polymer)

Poly(15) [61] Poly(16) 2350 UV light 365 nm (polymer)

Poly(17) [51] Poly(8)

7 Polymers 2015, 7, page–page Polymers 2015Polymers, 7, page–page 2015, 7 , page–page Polymers 2015Polymers, 7, page–page 2015, 7 , page–page

Figure 2. SchematicFigure 2. presentation Schematic presentation of spray application of spray applicationof poly(12) asof poly(12)an antibacterial as an antibacterial wound dressing wound dressing hydrogel.Figure 2. Schematic ReprintedFigurehydrogel. 2. presentation withSchematic Reprinted perm ission presentationwith of spray permfrom application issionReference of spray from [58],applicationof Reference poly(12) Copyright [58],asof poly(12)an 2011, Copyright antibacterial Wiley-VCH. as an 2011, antibacterial wound Wiley-VCH. dressing wound dressing hydrogel. Reprintedhydrogel. with Reprinted permission with permfrom issionReference from [58], Reference Copyright [58], 2011, Copyright Wiley-VCH. 2011, Wiley-VCH. Similarly, Similarly,the methacrylic the methacrylic poly(13) analogue poly(13) toanalogue acrylic poly(12),to acrylic waspoly(12), investigated was investigated in hydrogel in hydrogel formSimilarly, preparedform Similarly, thebyprepared redoxmethacrylic polymerization theby redoxmethacrylic poly(13) polymerization analogue[59]. poly(13) The hydrogelto analogue[59]. acrylic The basedpoly(12),hydrogelto acrylic on poly( wasbasedpoly(12), investigated13) on inhibited poly(was investigated13) in theinhibited hydrogel growth inthe hydrogel growth ofform planktonic preparedformof planktonic bacteria, byprepared redox both bacteria, polymerizationby Gram-negativeredox both polymerization Gram-negative [59]. E. Thecoli K12hydrogel [59]. E. and Thecoli Gram-positive basedK12hydrogel and on Gram-positive poly(based Staphylococcus13) on inhibited poly( Staphylococcus13) theepidermidisinhibited growth theepidermidis growth (ofS. planktonicepidermidisof(S. planktonic epidermidis),bacteria, by 99.9% both ),bacteria, dueby Gram-negative 99.9% to theboth duepolycationic Gram-negative to the E. colipolycationic character K12 E. and coli asGram-positivecharacter K12 well and as asGram-positiveby wellthe Staphylococcus controlledas by the Staphylococcus controlledreleasing epidermidis ofreleasing epidermidis of SA(S. −epidermidis as a mildSA(S. −epidermidis), asantibacterial by a 99.9%mild), antibacterial dueby agent. 99.9% to the After due polycationic agent. tohydrolysis the After polycationic character hydrolysis, the hydrogel ascharacter ,well the preventedhydrogelas asby wellthe preventedcontrolledasprotein by the adsorption controlledreleasingprotein adsorption or ofreleasing orof − bacterialSA− as a accumulation.mildSAbacterial asantibacterial a accumulation.mild antibacterial agent. After agent. hydrolysis After hydrolysis, the hydrogel, the preventedhydrogel preventedprotein adsorption protein adsorption or or bacterialAlternatively, accumulation.bacterialAlternatively, covalentaccumulation. attachment covalent attachment of the salicyla of thete moleculesalicylate as molecule an ester as via an the ester phenolic via the group phenolic group in a monomerAlternatively,in a unitmonomerAlternatively, poly(14)covalent unit wasattachment poly(14)covalent developed wasattachment of thedeveloped for salicyla enhancing of the tefor moleculesalicyla enhancing the controlledte as molecule thean ester controlledSA− as releasevia an the ester SA overphenolic− releasevia the the system group overphenolic the system group − within a monomer an ionic-forcesinwith a monomerunit an ionic-forces stabilizedpoly(14)Scheme unit was SA 1.stabilizedpoly(14) −Schematic indeveloped poly(13) was SA −presentation indeveloped [60].for poly(13) enhancing Fabricated [60].for of enhancing irreversibletheFabricatedhydrogel controlled from thehydrogel and controlledpoly(14)SA reversible− release from was SApoly(14) overswitches. prepared release the was system redoxover prepared the system redox − polymerization.with an ionic-forceswithpolymerization. an Hydrolysis ionic-forces stabilized Hydrolysis of SA stabilized the− in salicylate poly(13) of SA the in[60]. ester salicylate poly(13) Fabricated poly(14) [60]. ester wasFabricatedhydrogel poly(14) completed from washydrogel poly(14)completed in 16 from h, waswhile poly(14) in prepared 16 the h, complete waswhile redox prepared the complete redox releasepolymerization.2.1. Switch ofpolymerization.release the from Hydrolysisdrug ofPolycationic theSA − Hydrolysisdrug offrom the to SA salicylate poly(13)Polyzwitterionic− offrom the ester wassalicylatepoly(13) poly(14)completed State esterwas was poly(14)completed in completed 3 hwas under incompleted in 316 htheh, whileunder same in 16 the theh,condition. complete while same the condition. complete − release ofrelease the drug of theSA − drugfrom SApoly(13) from waspoly(13) completed was completed in 3 h underin 3 hthe under same thecondition. same condition. The hydrogelConversionThe after hydrogel the from transformation after the the polycationic transformation to poly(5) to the stillto poly(5)polyzwi retained stilltterionic the retained non-foul state theing non-foul exhibits propertiesing dramatic propertiesfor protein changes for protein in the andThe bacteria.hydrogelTheand after bacteria.hydrogel the transformation after the transformation to poly(5) stillto poly(5) retained still the retained non-foul theing non-foul propertiesing propertiesfor protein for protein interaction with water, proteins, drugs, DNA, and bacteria. This conversion is represented solely by and bacteria.and bacteria. 2.1.1.2.transformation Light2.1.1.2. Trigger Light of the Trigger ester or amide groups into the carboxylate group in the monomer unit. The 2.1.1.2.transformation Light2.1.1.2. Trigger Light occurs Trigger as a response to an external stimulus (pH, buffering capacity or light) and the Since photolysisSince photolysis is a non-invasive is a non-invasive trigger and trigger initiation and isinitiation timely and is timely spatially and localizable, spatially localizable, this this polyzwitterionic state is preserved. The progress of the transformation is influenced by several factors approachSince hasapproachphotolysis attractedSince hasphotolysis is theaattracted non-invasive greatest is thea non-invasiveinterest greatest trigger in interestandbi o-relatedtrigger initiation in andbi applications.o-related isinitiation timely applications. and is Recently, timely spatially and aRecently, localizable,photolysis spatially a localizable, photolysis ofthis a ofthis a such as length of the spacer between the quaternary amine and the carboxyl group, the nature of the photolabileapproach hasapproachphotolabile unit attracted for has theunit theattracted preparation greatestfor the the preparationinterest greatestof switchable in interestbi ofo-related switchable polymers in bi applications.o-related polymerspoly(15) applications. Recently, andpoly(15) poly(16) a Recently, andphotolysis [51,61]poly(16) a photolysis wasof [51,61]a wasof a reported.photolabilehydrolysable Theirphotolabilereported. unit structures group,for Their theunit pH preparationstructuresare for and shown the temperature; preparationare in of Tableshown switchable 3. in theseof Table switchable polymers will 3. also polymerspoly(15) be discussed andpoly(15) poly(16) below. and [51,61]poly(16) was [51,61] was reported.In the Theirreported. poly(15)In structures the [61]Their poly(15) switch structuresare shown[61] to the switch are inpolyzwitterion Tableshown to the 3. inpolyzwitterion Tableic state, 3. poly(16)ic state, was poly(16) enabled was via enabled the abstraction via the abstraction of2.1.1. a photolabileIn the(Meth)acrylicof poly(15) a photolabileIn o -nitrobenzyl-carboxymethylthe [61] poly(15) Type switch o-nitrobenzyl-carboxymethyl Polymers[61] to the switch polyzwitterion to the pendant polyzwitterionic state,during pendant poly(16) irradiationic state,during was poly(16) irradiation enabledat 365 was nm via enabledatin the 365PBS abstraction nm solution. via in the PBS abstraction solution. Inof thea photolabile polycationicof a photolabile o-nitrobenzyl-carboxymethyl state, poly(15) o-nitrobenzyl-carboxymethyl was able to bind pendant double-strand during pendant irradiation DNAduring (dsDNS), irradiation at 365 nm showing atin 365PBS thenm solution. size in PBS of solution. TheIn most the polycationic common state,polymer poly(15) backbone was able motifs to bind used double-strand in these DNAswitches (dsDNS), are (meth)acrylic-basedshowing the size of theIn the DNA polycationic complexInthe the DNA polycationic state,of complex 170 poly(15) nm state, ofin 170 solutionwas poly(15) nm able in and to solutionwas bind on able adouble-strand dextrane-modifiedand to bind on adouble-strand dextrane-modified DNA (dsDNS),surface. DNA Upon showing (dsDNS),surface. irradiation theUpon showing size irradiation ofat the size ofat polymers due to their simple synthetic modification, ready availability and the possibility to prepare 365the DNAnm, the complexthe365 polyzwitterionic DNAnm, theof complex 170polyzwitterionic nm state ofin 170solution poly(16) nm state in and solutionwas poly(16) on formed a dextrane-modifiedand was and on formed athe dextrane-modified dsDNA and thesurface. was dsDNA released Upon surface. was inirradiation released solution Upon inirradiation asat solution asat well365polymer nm, as fromthe365well brushespolyzwitterionic thenm, as surface fromthe usingpolyzwitterionic the [61]. surface statesurface-initiated In addition,poly(16) [61]. state In was dramaticaddition,poly(16) formed(SI) atom-transferwas differencesdramatic and formed the dsDNAdifferences inand polycationicradical the was dsDNA inreleased polymerizationpolycationic poly(15)was in released solution and poly(15) inthe (ATRP)as solution and orthe as SI polyzwitterionicwellphotointerpherter as fromwellpolyzwitterionic the as form surfacefrom mediatedwas the [61]. observedform surface In waspolymerization addition, [61]. whereobserved In thedramaticaddition, whereantibacterial (PMP), differencesthedramatic antibacterialmainly activity differences in through ofpolycationic activitypoly(15) ain thiolated polycationicof was poly(15) tested initiator was andagainstpoly(15) testedthe immobilized and against the E.polyzwitterioniconto coli cellsthepolyzwitterionicE. gold incoli solution surface,formcells wasin and orsolution observedform polymerson wasthe and wheresurface,observed withon thethe controlledwhere wheresurface,antibacterial 91% the where lengths. antibacterialwas activity killed91% The wasof compared simpleactivitypoly(15) killed syntheticof comparedwas withpoly(15) tested the protocol wasinactive withagainst tested the permits inactiveagainst the poly(16)E.application coli cells [61].poly(16)E. in coli ofsolution cellsa [61].modern in and solution methodon the and surface,such on theas where surfacesurface, 91% plasmon where was killed91% resonance was compared killed (SPR) comparedwith to evaluatethe inactivewith modificationsthe inactive poly(16) [61]. poly(16)or Similarly,adsorption [61]. poly(17)Similarly, change formed poly(17) even a polycomplexformed down a polycomplexto with0.1 DNAng·cm with and,−2. DNA afterTypical photolysisand, (meth)acrylic-basedafter photolysisat 365 nm, at 72.5% 365 nm, ofpH-triggered 72.5% of Similarly, poly(17) formed a polycomplex with DNA and, after photolysis at 365 nm, 72.5% of freePolymersirreversible DNASimilarly,2015 freewas, 7 ,DNAswitches,releasedpoly(17) 2344–2370 was fromformed releasedtheir the triggersa polyplex, polycomplexfrom the and aspolyplex, appliedconf withirmed DNA as forms confby and, airmed arequantitative after summarized by photolysis a quantitative PicoGreen atin 365 Table PicoGreenDNA nm, 1. 72.5%binding DNA of binding assayfree DNA [51]. freeassaywas DNAreleased [51]. was from released the polyplex, from the aspolyplex, confirmed as confby airmed quantitative by a quantitative PicoGreen PicoGreen DNA binding DNA binding assay [51].Tableassay 1. [51]. Irreversible pH-triggered (meth)acrylic-based switches containing polyzwitterionic state. TableTable 3. 3.IrreversibleIrreversibleTable 3. Irreversiblelight-triggered light-triggered light-triggered (meth)acrylic-based (meth)acrylic-based (meth)acrylic-based switches switches containing switches containing polyzwitterioniccontaining polyzwitterionic polyzwitterionic state. state.state. Table 3. IrreversibleTable 3. Irreversible light-triggered light-triggered (meth)acrylic-based (meth)acrylic-based switches containing switches polyzwitterioniccontaining polyzwitterionic state. state. Initial state TriggerTrigger(applied(appliedTrigge forform)r (appliedm) reference form) Polyzwitterionic state InitialInitial state Initial state Trigger (applied form) referencePolyzwitterion PolyzwitterionPolyzwitterion state state state TriggeNaOHrreference(applied (polymerTrigge form)rreference(applied brush) form) Initial stateInitial state PolyzwitterionPolyzwitterion state state UV lightreference 365 nm reference (polymer) UV light 365UV nm light (polymer) 365 nm (polymer) UV light 365UV nm light (polymer) 365 nm (polymer)

Poly(1):Poly(15) m = Poly(15)1 [61] [61] [61] Poly(16) Poly(2)Poly(16) m = 1 Poly(15) Poly(16) Poly(3):Poly(15) m = Poly(15)3 [61] [47] [61] Poly(16) Poly(4)Poly(16) m = 3 UV light 365UV nm light (polymer) 365 nm (polymer) UV light 365 nm (polymer) Poly(5): m = 5 UV light 365UV nm light (polymer) 365 nm (polymer) Poly(6) m = 5

Poly(17) Poly(17) [51] [51] Poly(8) Poly(8) [51] Poly(17) Poly(17) [51] [51] Poly(8) Poly(8) Poly(17) 7 7 Poly(8) Polymers 2015, 7, page–page 7 7

The same monomer unit as in poly(15) was copolymerized under ATRP condition with carboxybetaine methacrylate methacrylate to toform form a block a blockcopolymer copolymer poly(18) poly(18) with switch with to switchpoly19 (Figure to poly19 3a). (FigurePoly(18)3a). formed Poly(18) by formed self-assembly by self-assembly polyionic polyionic complex complex micelles micelles with with a anegatively negatively chargedcharged 3 protein-bovine serum albuminalbumin (BSA)—and was used as a vehiclevehicle to internalize the model protein drug to tumor cells. The formation of micelles, as shown in Figure 3 3b,b, improvesimproves thethe protectionprotection ofof thethe protein against denaturation, shields the negative chargecharge of the protein with polyzwitterionic hairy structure and provides an overall positive surface charge to effect an efficientefficient cellular uptake to tumor cell enhancement; penetration to the tumor cell is also due to the EPR effect. Transformation to the fully zwitterionic state poly(19) by UV irradiation at 365 nm significantlysignificantly accelerated the release of BSA Figure3 3bb [62[62].].

Figure 3. (a(a) )Structure Structure of of copolymer copolymer poly(18) poly(18) and and irreversible irreversible switch switch to poly(19) (b) schematic application of poly(18) in the complexation with negatively charged BSA to form self-assembly polyionic complex that improve the protection of the protein against denaturation, shields the negative charge of the protein and penetration to the tumor cell due to the enhanced and permeability and retention (EPR) effect and by UV light irradiation accelerated the release of bovine serum albumin (BSA). Reprinted with permission from ReferenceReference [[62].62]. Copyright (2014) American Chemical Society.

Despite the advantages of using photolytic transformation, further studies should be directed towards the employment of a photolabile group (i.e., coumarine type ester) with a non-toxic site product of photolysis [63] and satisfy the two photon absorption properties for improved biomedical applications [64]. 2351

2.1.2. Norbornene Type Polymers Structurally unusual polyzwitterionic polymers that contain anion and cation in the same repeated unit but on a separate side-chain, poly(21), poly(23), poly(25), poly(27) and poly(29) [65,66], were reported and the structures are shown in Table 4. The application of such polymers made it possible to tune the hydrophilicity of the system at a repeating unit level. A direct comparison of various structures based on norbornene carboxy and sulfobetaines, and methacrylate sulfobetaines confirmed that the non-fouling performance was affected by the overall structure, hydrophilicity, charge, and backbone type present within the polymer.

8 Polymers 2015, 7, page–page

Scheme 1. Schematic presentation of irreversible and reversible switches.

Polymers 2015, 7, 2344–2370 2.1. Switch from Polycationic to Polyzwitterionic State Conversion from the polycationic to the polyzwitterionic state exhibits dramatic changes in the Despite the advantages of using photolytic transformation, further studies should be directed interaction with water, proteins, drugs, DNA, and bacteria. This conversion is represented solely by towards the employment of a photolabile group (i.e., coumarine type ester) with a non-toxic site transformation of the ester or amide groups into the carboxylate group in the monomer unit. The product of photolysis [63] and satisfy the two photon absorption properties for improved biomedical transformation occurs as a response to an external stimulus (pH, buffering capacity or light) and the applications [64]. polyzwitterionic state is preserved. The progress of the transformation is influenced by several factors such2.1.2. as length Norbornene of the Typespacer Polymers between the quaternary amine and the carboxyl group, the nature of the hydrolysable group, pH and temperature; these will also be discussed below. Structurally unusual polyzwitterionic polymers that contain anion and cation in the same 2.1.1.repeated (Meth)acrylic unit but Type on a separatePolymers side-chain, poly(21), poly(23), poly(25), poly(27) and poly(29) [65,66], were reported and the structures are shown in Table4. The application of such polymers made it The most common polymer backbone motifs used in these switches are (meth)acrylic-based possible to tune the hydrophilicity of the system at a repeating unit level. A direct comparison of polymers due to their simple synthetic modification, ready availability and the possibility to prepare various structures based on norbornene carboxy and sulfobetaines, and methacrylate sulfobetaines polymer brushes using surface-initiated (SI) atom-transfer radical polymerization (ATRP) or SI confirmed that the non-fouling performance was affected by the overall structure, hydrophilicity, photointerpherter mediated polymerization (PMP), mainly through a thiolated initiator immobilized charge, and backbone type present within the polymer. onto the gold surface, or polymers with controlled lengths. The simple synthetic protocol permits the Polymers 2015, 7, page–page PolymersPolymers 20152015,, 77,, page–pagepage–pagePolymers 2015, 7, page–page application ofTable a modern 4. Irreversible method switches such as of surface norbornene plasmon polymers resonance containing (SPR) polyzwitterionic to evaluate modifications state. or adsorption change even down to 0.1 ng·cm−2. Typical (meth)acrylic-based pH-triggered TableTable 4.4. IrreversibleIrreversible switchesswitchesTable 4. ofofIrreversible norbornenenorbornene switches polymerspolymers of norbornene containicontainingng polyzwitterionicpolyzwitterionicpolymers containi state.state.ng polyzwitterionic state. irreversible switches, their triggers and applied forms are summarizedPolyzwitterion in Table 1.state and released Initial state Trigger (applied form) references TriggeTriggerr(applied(applied form)form)Trigger (appliedPolyzwitterionPolyzwitterion form) statestate andandPolyzwitterion state and InitialInitial statestate Initial state active molecule Table 1. Irreversible pH-triggered (metreferencesreferencesh)acrylic-based referencesswitchesreleasedreleased containing activeactive moleculemolecule releasedpolyzwitterionic active molecule state. 0.10.1 NaOHNaOH pHpH 7.47.4 0.1 NaOH pH 7.4 buffer, 20 min buffer, 20 min Initial state Triggerbuffer,(applied 20 min formbuffer,) reference 20 min Polyzwitterionic state (attached(attached toto surface)surface) (attached to surface) 0.1NaOH NaOH pH(polymer 7.4 buffer, brush) 20 min (attached to surface)

[65] Poly(1): m = 1 Poly(2) m = 1

Poly(3): m = 3 [47] Poly(4) m = 3 [65][65] [65] Poly(5): m = 5 Poly(6) m = 5 HCl,HCl, dioxanedioxane 44 h,h, RTRT HCl, dioxane 4 h, RT

HCl, dioxane 4 h, RT

(attached to surface) [65] (attached(attached toto surface)surface) (attached to surface)

[65][65] [65]

TheThe hydrolysishydrolysis waswasThe investigatedinvestigated hydrolysis onwason a a investigatedsiliconesilicone substratesubstrate on a siliconecoatedcoated withwithsubstrate copolymerscopolymers coated withwith copolymers with 5-bicycloheptenyl5-bicycloheptenylThe hydrolysis triethoxysilanetriethoxysilane5-bicycloheptenyl was investigatedthatthat triethoxysilane providedprovided aa on stablestablethat a provided siliconelinkagelinkage throughthrougha substratestable Si–O–SiSi–O–Silinkage coated bonds.bonds.through withTheThe Si–O–Si copolymers bonds. The with zwitterionic forms poly(21), poly(23), poly(25) and poly(27) were prepared by treatment of the zwitterioniczwitterionic5-bicycloheptenyl formsforms zwitterionicpoly(21),poly(21), triethoxysilane poly(23),poly(23), forms poly(21),poly(25)poly(25) that andandpoly(23), provided poly(27)poly(27) poly(25)3 were awere stable andpreparedprepared poly(27) linkage byby weretreatmenttreatment through prepared ofof thethe Si–O–Si by treatment bonds. of the The modifiedmodifiedzwitterionic surfacesurface forms withwithmodified 0.10.1 poly(21), NaOHNaOH surface forfor poly(23),with 2020 min,min,0.1 NaOH whilewhile poly(25) theforthe 20hydrolysishydrolysis andmin, while poly(27) ofof polycarboxybetainepolycarboxybetainethe hydrolysis were prepared of polycarboxybetaine estersestersby treatment esters of the poly(28) to zwitterionicpoly(28) polymer to zwitterionic poly(29) was polymer carried poly(29) out in an was acidic carried medium out in and an acidicproceeded medium within and proceeded within poly(28)modified to zwitterionic surfacepoly(28) withpolymer to 0.1zwitterionic poly(29) NaOH was polymer for carried 20 poly(29) out min, in an whilewas acidic carried themedium out hydrolysis in and an acidicproceeded ofmedium polycarboxybetaine within and proceeded within esters 44 hh atat ambientambient temperature.temperature.4 h at ambient Norbornene-basedNorbornene-based temperature. zwitterionicNorbornene-basedzwitterionic polymerspolymers zwitterionic ofof variousvarious polymers architecturearchitecture of various werewere architecture were investigatedinvestigatedpoly(28)to andand zwitterionic comparedcomparedinvestigated inin order polymerorderand compared toto followfollow poly(29) inthethe order effecteffect was to ofof follow carriedaa backbonebackbone the outeffect structurestructure in of ana backbone onon acidic thethe proteinprotein mediumstructure on and the protein proceeded adsorptionadsorptionwithin 4 hpropertiesproperties at ambientadsorption [65].[65]. temperature.InIn comparisoncomparisonproperties [65]. withwith Norbornene-based In thethe comparison methacrylatemethacrylate with basedbased the zwitterionic methacrylate sulfobetaine,sulfobetaine, polymers based thethe analogueanalogue sulfobetaine, of various the analogue architecture norbornenenorbornenewere investigated sulfobetainesulfobetainenorbornene andand carboxcarboxcompared sulfobetaineybetaineybetaine and poly(29)inpoly(29) carbox order exhibitedexhibitedybetaine to follow lowelowe poly(29)rr proteinprotein the exhibited effect fibrinogenfibrinogen lowe ofr a adsorption, adsorption,protein backbone fibrinogen structure adsorption, on the 2 2 being 3.39, 1.03 andbeing 0.84 ng/mm3.39, 1.032 , respectively. and 0.84 ng/mm With2, therespectively. increasing With hydrophilicity the increasing of the hydrophilicity pendant on of the pendant on beingprotein 3.39, adsorption1.03 andbeing 0.84 ng/mm properties3.39, 1.03, respectively. and [0.8465]. ng/mm InWith comparison ,the respectively. increasing with Withhydrophilicity the the increasing methacrylate of the hydrophilicity pendant based on of sulfobetaine,the pendant on the thethe ammoniumammonium group,group,the ammoniumthethe fibrinogenfibrinogen group, adsorptionadsorption the fibrinogen dedecreased.creased. adsorption Poly(21)Poly(21) de exhibitedexhibitedcreased. a aPoly(21) proteinprotein exhibitedadsorptionadsorption a protein adsorption 2 2 lowerloweranalogue thanthan 0.10.1 norbornene ng/nmng/nmlower2,, i.e.i.e. than,, belowbelow sulfobetaine 0.1 thetheng/nm limitlimit2, i.e.ofof and , a abelow biofilmbiofilm carboxybetaine the formation.formation. limit of a SinceSincebiofilm poly(29) thethe formation. uniqueunique exhibited designdesign Since allows allowsthe lower unique aa protein design allows fibrinogen a 2 simplesimpleadsorption, protocolprotocol being forforsimple polycarboxybetaines 3.39,polycarboxybetaines protocol 1.03 andfor 0.84polycarboxybetaines pendpend ng/mmantant modification,modification,, respectively. pend antinfluenceinfluence modification, With thethe the lipophilicity,lipophilicity, increasinginfluence the hydrophilicity lipophilicity, of respectively,respectively,the pendant thethe onlipophobicitylipophobicityrespectively, the ammonium of ofthe pendantpendant lipophobicity group, attachattacheded theof totopendant fibrinogenaa quaternaryquaternary attach ed adsorptionammoniumammonium to a quaternary groupgroup decreased. ammoniumtoto proteinprotein Poly(21) group to exhibitedprotein a adsorption was studied.adsorption Surprisingly, was studied. the lowestSurprisingly, values theof BSA lowest and values lysozyme of BSA adsorption and lysozyme were adsorption were adsorptionprotein adsorption was studied.adsorption lowerSurprisingly, was than studied. 0.1the lowest ng/nmSurprisingly, values2, i.e. ofthe, belowBSA lowest and thevalues lysozyme limit of BSA ofadsorption aand biofilm lysozyme were formation. adsorption Sincewere the detecteddetected inin thethe casecase detected ofof thethe hydrophobichydrophobic in the case ofandand the lipophobiclipophobic hydrophobic perfluoratedperfluorated and lipophobic poly(27),poly(27), perfluorated whichwhich waswas poly(27), eveneven lowerlower which was even lower thanthanunique thethe hydrophilichydrophilic designthan allows PEG-modifiedPEG-modified the ahydrophilic simple poly(21)poly(21) protocolPEG-modified [66][66].. ThisThis for poly(21) polycarboxybetainesindicatesindicates [66] thatthat. This combinationcombination indicates pendant ofofthat lipophobiclipophobic combination modification, of lipophobic influence character,character,the lipophilicity, whichwhich preventspreventscharacter, respectively, interactioninteraction which prevents lipophiliclipophilic the lipophobicity interaction fofoulinguling species,species, lipophilic of andand pendant fo polyzwitterionicpolyzwitterioniculing species, attached and charactercharacter polyzwitterionic to a quaternary cancan character ammonium can enhanceenhancegroup tononnon protein biofoulingbiofoulingenhance adsorption properties.properties. non biofouling Moreover,Moreover, was studied.properties. thethe resultsresults Surprisingly,Moreover, showshow thatthat the thetheresults the norbornene-basednorbornene-basedlowest show that values the dual-dual-norbornene-based of BSA and lysozymedual- functional polymerfunctional in the polyzwitterion polymer in thestate polyzwitterion is comparable state with isthe comparable methacrylate-based with the methacrylate-based polymers polymers functionaladsorption polymer were functionalin the detected polyzwitterion polymer in the in statethe case polyzwitterion is comparable of the hydrophobic statewith isthe comparable methacrylate-based and with lipophobic the methacrylate-basedpolymers perfluorated polymers poly(27), withwith regardregard toto proteinproteinwith antifoulingantifouling regard to proteinproperties.properties. antifouling ThThee advantageadvantage properties. ofof these theseThe advantage dual-functionaldual-functional of these polymerspolymers dual-functional isis polymers is thatthatwhich nono hydrolysablehydrolysable was eventhat esterester lowerno hydrolysablegroupgroup than isis alsoalso the ester present,present, hydrophilic group whichwhich is also improvesimproves PEG-modified present, stabilitystability which improvesunderunder poly(21) physiologicalphysiological stability [66]. under This physiological indicates that conditions.conditions.combination InIn addition,addition, ofconditions. lipophobic eveneven thethe In perfluoratedperfluorated addition, character, even liplip ophobictheophobic which perfluorated andand prevents hydrophobichydrophobic lipophobic interaction motifmotif and cancanhydrophobic decreasedecrease lipophilic proteinprotein motif foulingcan decrease species, protein and adsorption.adsorption. adsorption.

2.2.2.2. SwitchSwitch fromfrom PolyzwittPolyzwitt2.2. Switcherionicerionic from toto PolyanionicPolyanionic Polyzwitterionic StateState to Polyanionic2352 State Recently,Recently, transformationstransformationsRecently, fromfrom transformations thethe polyzwitterionicpolyzwitterionic from the toto polyzwitterionic polyanionicpolyanionic statestate to on onpolyanionic polymerspolymers statewerewere on polymers were investigatedinvestigated andand aa summarysummaryinvestigated ofof thisthisand typetypea summary ofof switchesswitches of this isis giventypegiven of inin switches TableTable 5.5. isPolysulfobetainesPolysulfobetaines given in Table 5. poly(30),poly(30), Polysulfobetaines poly(30), poly(32),poly(32), poly(34)poly(34) andandpoly(32), poly(36)poly(36) poly(34) wewerere transformed transformedand poly(36) viavia we hydrolysishydrolysisre transformed toto polymerspolymers via hydrolysis alsoalso bearingbearing to polymers secondarysecondary also bearing secondary negativelynegatively chargedcharged negatively functionalities.functionalities. charged InIn thethefunctionalities. casecase ofof poly(30)poly(30) In the andand case poly(32),poly(32), of poly(30) acidicacidic and hydrolyseshydrolyses poly(32), ofofacidic thethe hydrolyses of the

99 9 Polymers 2015, 7, page–page

Polymers 2015, 7, 2344–2370 polyzwitterionic character can enhance non biofouling properties. Moreover, the results show that the norbornene-based dual-functional polymer in the polyzwitterion state is comparable with the Scheme 1. Schematic presentation of irreversible and reversible switches. methacrylate-based polymers with regard to protein antifouling properties. The advantage of these dual-functional2.1. Switch from polymers Polycationic is that to noPolyzwitterionic hydrolysable State ester group is also present, which improves stability under physiological conditions. In addition, even the perfluorated lipophobic and hydrophobic motif can decreaseConversion protein from adsorption. the polycationic to the polyzwitterionic state exhibits dramatic changes in the interaction with water, proteins, drugs, DNA, and bacteria. This conversion is represented solely by 2.2.transformation Switch from Polyzwitterionic of the ester or to amide Polyanionic groups State into the carboxylate group in the monomer unit. The transformation occurs as a response to an external stimulus (pH, buffering capacity or light) and the Recently, transformations from the polyzwitterionic to polyanionic state on polymers were polyzwitterionic state is preserved. The progress of the transformation is influenced by several factors investigated and a summary of this type of switches is given in Table5. Polysulfobetaines poly(30), such as length of the spacer between the quaternary amine and the carboxyl group, the nature of the poly(32),PolymersPolymers 2015 poly(34) 2015, 7, page–page, 7, andpage–page poly(36) were transformed via hydrolysis to polymers also bearing secondary hydrolysable group, pH and temperature; these will also be discussed below. negativelyPolymersPolymers 2015 charged2015, 7, page–page, 7, page–page functionalities. In the case of poly(30) and poly(32), acidic hydrolyses of the carboxybetainecarboxybetainecarboxybetaine esterester ester withwith with 66 M M 6 HCl HClM HCl were were were performed performe performed at atd 53 53at˝ C°C53 for °Cfor 48 for48 h h48 and andh neutralizationand neutralization neutralization with with with two two two Polymers2.1.1.Polymers (Meth)acrylic2015 2015, 7, page–page, 7, page–page Type Polymers equivalentsequivalentscarboxybetainecarboxybetaineequivalents of of NaOH NaOH ofester NaOH ester resulted withresulted withresulted 6 M in6 in HClM the thein HCl formation thewereformation wereformation performe performe of of polymers polymersofd polymersatd 53at poly(31)°C53 poly(31) °Cfor poly(31) for48 and andh48 and poly(33)andh poly(33) and neutralizationpoly(33) neutralization [67 [67,68].,68 [67,68].]. Similarly, Similarly,with Similarly,with two two PolymersPolymers 2015 2015, 7, page–page, 7, page–page thecarboxybetaineequivalentsthe acidic equivalentsthecarboxybetaineacidicThe acidic hydrolysis most hydrolysisof hydrolysisNaOH ofester common NaOH ester with of resultedof phosphatewith resulted phosphateofpolymer6 M phosphate6 in HClM thein HCl diesterbackbone thewereformationdiester wereformationdiester performe in in performemotifs poly(34) ofpoly(34)in polymers ofdpoly(34) usedpolymersatd and53 atand in°C53 poly(31) poly(36)and thesepoly(36)°Cfor poly(31) poly(36)for48 switches andh48 was was andandh poly(33) was performedand neutralization performedpoly(33)are neutralizationperformed (meth)acrylic-based [67,68]. [67,68]. at at 95 Similarly, with95at˝ Similarly,Cwith95°C two in °Cin two in the24polymers h the24 acidic[69,70]. h acidic[69,70]. hydrolysisdue hydrolysis to their of simple phosphateof phosphate synthetic diester modificationdiester in poly(34)in poly(34), ready and availabilityand poly(36) poly(36) wasand was theperformed performedpossibility at to95at prepare95°C °Cin in 24equivalentscarboxybetaine hcarboxybetaine [equivalents69,70]. of NaOH ofester NaOH ester withresulted with resulted 6 M 6 in HClM the inHCl thewereformation wereformation performe performe of polymers ofd atpolymersd 53at °C53 poly(31) °Cfor poly(31) for48 andh48 and andh poly(33) and neutralizationpoly(33) neutralization [67,68]. [67,68]. Similarly,with Similarly,with two two 24polymer h24 [69,70].It h should[69,70].It shouldbrushes be be notedusing noted thatsurface-initiated that the theintroduction introduction (SI) atom-transferof aof seconda second negativelyradical negatively polymerization charged charged group group(ATRP) increased increased or SI equivalentsthe equivalentstheItacidic should acidic hydrolysisof beNaOHhydrolysisof NaOH noted resultedof thatresulted phosphateof phosphate thein thein introduction theformationdiester formationdiester in of poly(34)in polymers aofpoly(34) secondpolymers and poly(31)and negativelypoly(36) poly(31) poly(36) and was and charged poly(33) was performedpoly(33) performed group[67,68]. [67,68]. at increased Similarly, 95at Similarly,°C95 °Cin in solubilityphotointerphertersolubilityIt shouldIt shouldin waterin be water benoted mediatedand noted and goodthat goodthat polymerization theanti-scaling theintroductionanti-scaling introduction properti (PMP), propertiof aof mainlyes second aeswere second were through observednegatively observednegatively a thiolated in charged ain charged saturateda initiator saturated group group immobilizedsolution increased solution increased of of solubilitythe24 h the24 acidic[69,70]. h acidic [69,70]. in hydrolysis water hydrolysis and of good phosphateof phosphate anti-scaling diester diester properties in poly(34)in poly(34) were and and observed poly(36) poly(36) inwas awas performed saturated performed solutionat 95at 95°C of °Cin in solubilityCaSOontosolubilityCaSO 4the [68,69].4 gold[68,69].in waterin surface, water and orand goodpolymers good anti-scaling anti-scaling with controlled properti properti lengths.es eswere were The observed simple observed synthetic in ain saturateda protocolsaturated solution permits solution ofthe of CaSO24 h24 4[69,70].It [h 68should [69,70].It,69 should]. be benoted noted that that the theintroduction introduction of aof seconda second negatively negatively charged charged group group increased increased CaSOapplicationCaSO4 [68,69].4 [68,69]. of a modern method such as surface plasmon resonance (SPR) to evaluate modifications solubilitysolubilityIt shouldIt shouldin waterin be water Table benoted Tableand noted 5.and Irreversiblegoodthat 5. Irreversiblethatgood theanti-scaling theintroductionanti-scaling switches introduction switches fromproperti from properti ofpolyzwitterionic a ofpolyzwitterionices second awerees second were observednegatively tonegativelyobserved polyanionic to polyanionic in charged ain charged saturatedstate.a state.saturated group group solution increased solution increased of of or adsorption Tablechange 5. Irreversible even down switches to from0.1 polyzwitterionicng·cm−2. Typical to polyanionic(meth)acrylic-based state. pH-triggered solubilityCaSOsolubilityCaSO4 [68,69].4 [68,69].in waterin waterTable Tableand 5.and Irreversiblegood 5. Irreversiblegood anti-scaling anti-scaling switches switches fromproperti fromproperti polyzwitterionic polyzwitterionices werees were observed toobserved polyanionic to polyanionic in ain saturatedstate.a state.saturated solution solution of of irreversible switches, their triggers andTrigger appliedTrigger (form) forms(form) are summarized in Table 1. CaSOCaSO4 [68,69].4Polyzwitterion [68,69].Polyzwitterion Table Table 5.state Irreversible 5. state Irreversible switches Triggerswitches from (form) from polyzwitterionic polyzwitterionic reference to polyanionic to Polyanionic polyanionicPolyanionic state. state state. state reference Table 1. Irreversible pH-triggered (metTriggerreferenceTriggerh)acrylic-based (form) (form) switches containing polyzwitterionic state. PolyzwitterionPolyzwitterionTableTable 5.state Irreversible 5.state Irreversible switches switches from from polyzwitterionic polyzwitterionic to polyanionic toPolyanionic polyanionicPolyanionic state. state state. state (1)Trigger 6(1)reference MTrigger 6 HClreference M (form) HCl (form) PolyzwitterionPolyzwitterion state state (1) 6 M HCl PolyanionicPolyanionic state state Initial state Trigger(1)(2)Trigger NaOH6(1)(2)reference MTrigger( appliedNaOH6 HClreference M (form) HCl (form) for m) reference Polyzwitterionic state PolyzwitterionPolyzwitterion state state (2) NaOH PolyanionicPolyanionic state state (1)(2)NaOH 6NaOH(2)(1)reference M NaOH6 HClreference M(polymer HCl brush)

(1)(2) NaOH6(1)(2) M 6NaOH HCl M HCl Poly(30)Poly(30) (polymer)(polymer) [67] [67] Poly(31)Poly(31)

(2) NaOH(2) NaOH Poly(30)Poly(30) (polymer)(polymer) (polymer) [67] [67] [67 ] Poly(31)Poly(31) Poly(1): m = 1 (1) 6(1) M 6 HCl M HCl Poly(2) m = 1 Poly(30)Poly(30) (2)(polymer) NaOH(2)(polymer) NaOH [67] [67] Poly(31)Poly(31) Poly(3): m = 3 (1) 6(1) M 6 HCl M HCl [47] Poly(4) m = 3 (1) 6 M HCl Poly(5):Poly(30)Poly(30) m = 5 (1)(2)(polymer) 6NaOH(2)(1) M(polymer) NaOH6 HCl M HCl [67] [67] Poly(31)Poly(31) Poly(6) m = 5 (2) NaOH

(1)(2) NaOH6(1)(2) M 6NaOH HCl M HCl Poly(32)Poly(32) (polymer)(polymer) [69] [69] Poly(33)Poly(33) (2) NaOH(2) NaOH Poly(32)Poly(32) (polymer)(polymer) [69] [69] Poly(33)Poly(33) (1) HCl(1) HCl Poly(32)Poly(32) (2)(polymer) NaOH(2)(polymer) NaOH (polymer) [69] [69] [69 ]Poly(33) Poly(33) (1) HCl(1) HCl (3) NaOH(3) NaOH Poly(32)Poly(32) (1)(2)(polymer) HClNaOH(2)(1)(polymer) NaOHHCl [69] [69] Poly(33)Poly(33) (2)(3)(1) NaOH(3)(2) HCl NaOH (1) HCl(1) HCl (3)(2) NaOH(3) NaOH NaOH Poly(34)Poly(34) (2)(polymer) NaOH(2)(polymer) NaOH [69] [69] Poly(35)Poly(35) (3) NaOH (3) NaOH(3) NaOH 3 Poly(34)Poly(34) (polymer)(polymer) [69] [69] Poly(35)Poly(35) (1) HCl(1) HCl Poly(34)Poly(34) (polymer)(polymer) [69] [69] Poly(35)Poly(35) (1)(2) HClNaOH(1)(2) HClNaOH Poly(34)Poly(34) (3)(polymer) NaOH(3)(polymer) NaOH (polymer) [69] [69] [69 ]Poly(35) Poly(35) (1)(2) HClNaOH(2)(1) NaOHHCl (2)(3) NaOH(3)(2) NaOH (1) HCl(1) HCl (3)(1) NaOH(3) HCl NaOH Poly(36)Poly(36) (2)(polymer) NaOH(2)(polymer) NaOH [70] [70] Poly(37)Poly(37) (2) NaOH (3) NaOH(3) NaOH Poly(36)Poly(36) (3)(polymer) NaOH(polymer) [70] [70] Poly(37)Poly(37)

3. Reversible3. Reversible switch switch Poly(36)Poly(36) (polymer)(polymer) [70] [70] Poly(37)Poly(37) 3. Reversible3. Reversible switch switch TwoTwo principles principlesPoly(36)Poly(36) of theof thereversible reversible switch(polymer) switch(polymer) of zwitteof [70] zwitte [70] rionic rionic polymers polymers were werePoly(37) reportedPoly(37) reported based based on eitheron either 3.physical Reversiblephysical3.Two ReversibleTwo or principles chemicalor principles switch chemical switchPoly(36) ofchanges the of changes thereversible inreversible a in polymer a polymerswitch switch structure. (polymer)of structure. zwitteof zwitte [rionic70 ]rionic polymers polymers were were Poly(37) reported reported based based on eitheron either 3.physical Reversible3.physicalTwo ReversibleTwo or principles chemicalor principles switch chemical switch of changes the ofchanges thereversible inreversible a in polymer a polymerswitch switch structure. of structure. zwitte of zwitte rionic rionic polymers polymers were were reported reported based based on eitheron either 3.1.3.1. Physically Physically Induced Induced Reversible Reversible Switch Switch in Solutions in Solutions physicalphysicalTwoTwo or principles chemical or principles chemical ofchanges the of changes thereversible inreversible a in polymer a polymerswitch switch structure. of structure. zwitte of zwitte rionic rionic polymers polymers were were reported reported based based on eitheron either 3.1.3.1. Physically Physically Induced Induced Reversible Reversible Switch Switch in Solutions in Solutions2353 physicalphysicalTheThe orphysical chemical orphysical chemical principle changesprinciple changes is inbased is a inbased polymer a on polymer theon thestructure.temperat structure.temperature-dependent ure-dependent self-assem self-assembly blyof polymer of polymer chains. chains. 3.1.TheThe3.1. Physicallythermally-dependentThe Physicallythermally-dependentThe physical physical Induced Induced principle principleReversible Reversible self-assembly is basedself-assembly is Switch based Switch on in theon ofSolutions in the temperat polyzwi ofSolutions temperatpolyzwi tterionicure-dependent tterionicure-dependent groups groups self-assem is self-assem madeis made blypossible blypossibleof polymer of bypolymer byextremely chains.extremely chains. 3.1.Thehigh3.1.Thehigh Physically thermally-dependentThedipole Physically thermally-dependentThe dipolephysical physicalmoments Induced moments Induced principle principleReversible between Reversible betweenself-assembly is basedself-assembly is Switchzwitterionic based Switch zwitterionicon in theon ofSolutions in thetemperat polyzwiofSolutions groups temperatpolyzwi groups ure-dependenttterionic [71].tterionicure-dependent [71]. The groupsThe polyzwitterionic groups polyzwitterionic self-assem is self-assem madeis made blypossible feature possibleblyof polymerfeature of bypolymer offers byextremely offers chains.extremely such chains. such highuniquehighunique dipole propertiesdipole properties moments moments as anas between anantipolyelectrolyte between antipolyelectrolyte zwitterionic zwitterionic effectgroups effectgroups and [71].and upper [71]. Theupper Thecritical polyzwitterionic critical polyzwitterionic solution solution temperature feature temperature feature offers offers(UCST). (UCST).such such TheThe thermally-dependentThe thermally-dependentThe physical physical principle principle self-assembly is basedself-assembly is based on theon of the temperat polyzwiof temperat polyzwitterionicure-dependenture-dependenttterionic groups groups self-assem is self-assemmade is made blypossible blypossibleof polymer of bypolymer extremelyby chains.extremely chains. TheuniqueuniqueThe cationic cationicproperties properties and and anionic as anionic anas anantipolyelectrolytepolymers antipolyelectrolytepolymers exhibit exhibit the effect thepolyelectrolyte effect polyelectrolyte and and upper upper criticaleffect, criticaleffect, i.e. solution ,i.e. thesolution, thesolubility temperature solubility temperature and and viscosity(UCST). viscosity(UCST). ThehighThehigh thermally-dependentdipole thermally-dependent dipole moments moments between betweenself-assembly self-assembly zwitterionic zwitterionic of polyzwiof groups polyzwi groupstterionic [71].tterionic [71]. The groupsThe polyzwitterionic groups polyzwitterionic is made is made possible featurepossible feature by offers byextremely offers extremely such such decreaseThedecreaseThe cationic cationic upon uponand addition and anionic addition anionic of polymers theof polymers theelectrolyte. electrolyte. exhibit exhibit Onthe Onthepolyelectrolytethe polyelectrolytetheother other hand, hand, effect,in effect,thein thei.e.case , i.e.casethe of, the solubility theof solubility theantipolyelectrolyte antipolyelectrolyte and and viscosity viscosity highuniquehighunique dipole propertiesdipole properties moments moments as an asbetween antipolyelectrolytean between antipolyelectrolyte zwitterionic zwitterionic effectgroups effectgroups and [71]. and upper [71]. Theupper Thecritical polyzwitterionic criticalpolyzwitterionic solution solution temperature feature temperature feature offers (UCST).offers (UCST).such such decreaseeffect,decreaseeffect, the upon theviscosity upon viscosity addition addition and and solubilityof thesolubilityof theelectrolyte. electrolyte.increase increase On[24,72]. On[24,72].the the otherThe otherThe addition hand, addition hand, in of thein electrolyteof thecase electrolyte case of theof to the antipolyelectrolytetheto antipolyelectrolyte thepolyzwitterion polyzwitterion TheuniqueuniqueThe cationic cationicproperties properties and and anionic as anionic anas anantipolyelectrolytepolymers antipolyelectrolytepolymers exhibit exhibit the effect thepolyelectrolyte effect polyelectrolyteand and upper upper criticaleffect, criticaleffect, i.e. solution, i.e.thesolution, thesolubility temperature solubility temperature and and viscosity(UCST). viscosity(UCST). effect,solutioneffect,solution the results theviscosity results viscosity in an in and expansionan and expansionsolubility solubility of theincrease of theincreasepolymer polymer [24,72]. [24,72].chai chai n,The hence n,The addition hence addition disintegration disintegration of electrolyteof electrolyte of the of to thephysical theto physical thepolyzwitterion polyzwitterion net netformed formed decreaseTheThedecrease cationic cationic upon uponand addition and anionic addition anionic of polymers the ofpolymers theelectrolyte. electrolyte. exhibit exhibit Onthe theOnpolyelectrolytethe polyelectrolytetheother other hand, hand, effect,in effect, thein i.e.thecase , i.e.thecase of, the solubility theof solubility theantipolyelectrolyte antipolyelectrolyte and and viscosity viscosity solutionby solutionbyions. ions. resultsThe resultsThe electrolyte in electrolyte an in expansionan expansionions ions shield of shield the of the thepolymer thecharged polymer charged chai polymer chain, polymer hencen, hence parts disintegration parts disintegration that that prevent prevent of the ofthe the physical theintra-group, physical intra-group, net netformed intra- formed intra- decreaseeffect,decreaseeffect, the upon theviscosity upon viscosity addition addition and and solubilityof thesolubilityof theelectrolyte. electrolyte.increase increase On[24,72]. On[24,72].the the otherThe otherThe addition hand, addition hand, in of thein electrolyteof thecase electrolyte case of theof to theantipolyelectrolyte theto antipolyelectrolyte thepolyzwitterion polyzwitterion bychain bychainions. ions.and Theand inter-chainThe electrolyte inter-chain electrolyte interactions, ions interactions, ions shield shield thewhich thewhichcharged chargedresults results polymer inpolymer anin anpartsextension partsextension that that preventof preventtheof thepolymer the polymer theintra-group, intra-group, chains chains andintra- andintra- a a effect,solutioneffect,solution the results theviscosity results viscosity in an in and expansionan and solubilityexpansion solubility of theincrease of theincreasepolymer polymer [24,72]. [24,72].chai chai n,The hence n,The addition hence addition disintegration disintegration of electrolyteof electrolyte of the of to thephysical theto physical thepolyzwitterion polyzwitterion net netformed formed chainsubsequentchainsubsequent and and inter-chainincrease inter-chainincrease in polymer interactions,in polymerinteractions, solubi solubi whichlity, whichlity, as results shownas results shown in in aninFigure in anFigureextension extension4 [72,73]. 4 [72,73]. of theof thepolymer polymer chains chains and and a a solutionby solutionions.by ions. resultsThe resultsThe electrolyte in electrolyte an in expansionan expansionions ions shield of shield the of the thepolymer thecharged polymer charged chai polymer chain, polymer hencen, hence parts disintegration parts disintegration that that prevent prevent of the ofthe the physical theintra-group, physical intra-group, net netformed intra- formed intra- subsequentsubsequent increase increase in polymer in polymer solubi solubility,lity, as shownas shown in Figure in Figure 4 [72,73]. 4 [72,73]. bychain byions.chain andions. Theand inter-chainThe electrolyte inter-chain electrolyte interactions, ions interactions, ions shield shield thewhich thewhichcharged chargedresults results polymer inpolymer anin anpartsextension partsextension that that preventof preventtheof thepolymer the polymer theintra-group, intra-group, chains chains andintra- and intra-a a chainsubsequentchainsubsequent and and inter-chainincrease inter-chainincrease in polymer interactions,in polymerinteractions, solubi solubi whichlity, whichlity, as results shown as results shown10 in 10in anFigurein in anFigureextension extension4 [72,73]. 4 [72,73]. of theof thepolymer polymer chains chains and and a a subsequentsubsequent increase increase in polymer in polymer solubi solubility,lity, as shown as shown10 10in Figure in Figure 4 [72,73]. 4 [72,73]. 10 10 10 10 Polymers 2015, 7, 2344–2370

3. Reversible Switch Two principles of the reversible switch of zwitterionic polymers were reported based on either physical or chemical changes in a polymer structure.

3.1. Physically Induced Reversible Switch in Solutions The physical principle is based on the temperature-dependent self-assembly of polymer chains. The thermally-dependent self-assembly of polyzwitterionic groups is made possible by extremely high dipole moments between zwitterionic groups [71]. The polyzwitterionic feature offers such unique properties as an antipolyelectrolyte effect and upper critical solution temperature (UCST). The cationic and anionic polymers exhibit the polyelectrolyte effect, i.e., the solubility and viscosity decrease upon addition of the electrolyte. On the other hand, in the case of the antipolyelectrolyte effect, the viscosity and solubility increase [24,72]. The addition of electrolyte to the polyzwitterion solution results in an expansion of the polymer chain, hence disintegration of the physical net formed by ions. The electrolyte ions shield the charged polymer parts that prevent the intra-group, intra-chain and inter-chain interactions, which results in an extension of the polymer chains and a Polymerssubsequent 2015, 7, page–page increase in polymer solubility, as shown in Figure4[72,73].

FigureFigure 4. Proposed 4. Proposed mechanism mechanism for for antipolyelectrolyte antipolyelectrolyte effecteffect onon polyzwitterionpolyzwitterion structure structure by by simplesimple electrolyte. electrolyte.

SomeSome zwitterionic zwitterionic polymers polymers (mainly (mainly polysulfobetaines) polysulfobetaines) exhibit UCSTUCST (Figure(Figure5b) 5b) as as a resulta result of strongof stronginter- inter-and intramolecular and intramolecular interactions interactions leading leading to to a reversiblereversible self-association self-association of polymerof polymer chainschains [74] [and74] and might might signify signify as as a reversible a reversible switch switch in physicalphysical properties properties in in a solution a solution or on or a on surface. a surface. AboveAbove UCST, UCST, the thedipolar dipolar interactions interactions are are broken broken andand thethe isolatedisolated polymer polymer chains chains are are completely completely solvated.solvated. In other In other words, words, the high-viscosity the high-viscosity gel gelis transformed is transformed into into a transparent a transparent low-viscosity low-viscosity sol sol above above UCST [75]. UCST [75].

2354 (a) (b)

Figure 5. (a) Structure of poly(38) and (b) schematic illustration of upper critical solution temperature (UCST) of a polymer in solution.

The most studied and applied polymer possessing UCST in an aqueous solution is polysulfobetaine poly(38) depicted in Figure 5a and its UCST is highly dependent on pressure, type of polymer and its molecular mass characteristics as well as on the single electrolyte presence. Schulz et al. [76] studied the phase behavior of polysulfobetaine poly(38) in terms of dependence on concentration and salt type. The 0.1% aqueous solution of poly(38) with Mn 4.35 × 105 g/mol exhibited the UCST of 32 °C while, in 0.3% NaCl solution, the UCST declined to 15 °C. At low concentrations of aqueous polymer solutions (0.01%–0.1%), an increase in UCST was observed, with the maximal USCT achieved at 0.1%. With increasing the concentration of polymer poly(38) in the aqueous solution, the UCST declined from 32 °C at 0.1% to 18 °C for the 5% solution [76]. The type of salt added significantly affects the UCST of the polymer solution. The anionic dissolving strength accords with the Hofmeister lyotropic series (HLS) [77] and with the Pearson theory of acids and bases [78]. The relatively soft ammonium cation in the polymer prefers soft anions such as SCN−; in their presence the USCT decreases to 0 °C in a poly(38) solution in concentrations ranging from 0.01% to 10%, even at a low concentration of 0.05 mol/L NaSCN. The sulfate group of poly(38) is soft and prefers interactions with soft cations such as Ag+ in the presence of which the USCT declines even below 0 °C in a concentration range of poly(38) from 0.01% to 10% [79]. Chen et al. [80]

11 Polymers 2015, 7, page–page

Figure 4. Proposed mechanism for antipolyelectrolyte effect on polyzwitterion structure by simple electrolyte.

Some zwitterionic polymers (mainly polysulfobetaines) exhibit UCST (Figure 5b) as a result of strong inter- and intramolecular interactions leading to a reversible self-association of polymer chains [74] and might signify as a reversible switch in physical properties in a solution or on a surface. Above UCST, the dipolar interactions are broken and the isolated polymer chains are completely solvated.Polymers 2015 In, 7other, 2344–2370 words, the high-viscosity gel is transformed into a transparent low-viscosity sol above UCST [75].

(a) (b)

Figure 5. ((aa)) Structure Structure of of poly(38) poly(38) and and ( (bb)) schematic schematic illustration illustration of of upper upper critical critical solution solution temperature temperature (UCST)(UCST) of of a a polymer in solution.

The most studied and applied polymer possessing UCST in an aqueous solution is The most studied and applied polymer possessing UCST in an aqueous solution is polysulfobetaine poly(38) depicted in Figure 5a and its UCST is highly dependent on pressure, type polysulfobetaine poly(38) depicted in Figure5a and its UCST is highly dependent on pressure, of polymer and its molecular mass characteristics as well as on the single electrolyte presence. type of polymer and its molecular mass characteristics as well as on the single electrolyte presence. Schulz et al. [76] studied the phase behavior of polysulfobetaine poly(38) in terms of dependence on Schulz et al. [76] studied the phase behavior of polysulfobetaine poly(38) in terms of dependence 5 concentration and salt type. The 0.1% aqueous solution of poly(38) with Mn 4.35 × 10 g/mol exhibited5 on concentration and salt type. The 0.1% aqueous solution of poly(38) with Mn 4.35 ˆ 10 g/mol the UCST of 32 °C while, in 0.3% NaCl solution, the UCST declined to 15 °C. At low concentrations exhibited the UCST of 32 ˝C while, in 0.3% NaCl solution, the UCST declined to 15 ˝C. At low of aqueous polymer solutions (0.01%–0.1%), an increase in UCST was observed, with the maximal concentrations of aqueous polymer solutions (0.01%–0.1%), an increase in UCST was observed, with USCT achieved at 0.1%. With increasing the concentration of polymer poly(38) in the aqueous the maximal USCT achieved at 0.1%. With increasing the concentration of polymer poly(38) in solution, the UCST declined from 32 °C at 0.1% to 18 °C for the 5% solution [76]. The type of salt the aqueous solution, the UCST declined from 32 ˝C at 0.1% to 18 ˝C for the 5% solution [76]. added significantly affects the UCST of the polymer solution. The anionic dissolving strength accords The type of salt added significantly affects the UCST of the polymer solution. The anionic with the Hofmeister lyotropic series (HLS) [77] and with the Pearson theory of acids and bases [78]. dissolving strength accords with the Hofmeister lyotropic series (HLS) [77] and with the Pearson The relatively soft ammonium cation in the polymer prefers soft anions such as SCN−; theory of acids and bases [78]. The relatively soft ammonium cation in the polymer prefers soft in their presence the USCT decreases to 0 °C in a poly(38) solution in concentrations ranging from anions such as SCN´; in their presence the USCT decreases to 0 ˝C in a poly(38) solution in 0.01% to 10%, even at a low concentration of 0.05 mol/L NaSCN. The sulfate group of poly(38) is soft concentrations ranging from 0.01% to 10%, even at a low concentration of 0.05 mol/L NaSCN. and prefers interactions with soft cations such as Ag+ in the presence of which the USCT declines ThePolymers sulfate 2015, 7 group, page–page of poly(38) is soft and prefers interactions with soft cations such as Ag+ in the even below 0 °C in a concentration range of poly(38) from 0.01% to 10% [79]. Chen et al. [80] presence of which the USCT declines even below 0 ˝C in a concentration range of poly(38) from 0.01%studied to the 10% dependence [79]. Chen ofet UCST al. [80 ]on studied poly(38) the in11 dependence the presence of UCSTof polymers on poly(38) complexing in the poly(38). presence ofThe polymers polyanion complexing poly(2-acrylamido-2-metylpropan poly(38). The polyanion poly(2-acrylamido-2-metylpropan sulfonic acid) and polycation sulfonic poly(3- acid) andacryloylaminopropyl polycation poly(3-acryloylaminopropyl trimethylamonium chloride) trimethylamonium were used as complexing chloride) were agents. used It was as complexing found that agents.complexation It was with found poly(2-acrylamido-2-methylpropane that complexation with poly(2-acrylamido-2-methylpropane sulfonic acid) resulted in a decrease sulfonic in UCST acid) resulteddue to inthe a decrease presence in UCSTof free due tosulfonic the presence groups of free at sulfonic the end groups of atthe endpolymer of the polymerchains. chains.On the Onother the hand, other hand,the complexation the complexation with with a low a low amount amount of of poly(3 poly(3-acryloylaminopropyl-acryloylaminopropyl trimethylamonium chloride)chloride) results in an increase in UCST, whilewhile withwith an increasing ratio of polycation/poly(38) th thee UCST UCST decreased. decreased. UCST can be further modulated by the copolymerisationcopolymerisation of monomer(38) with other monomers containing hydrophobic pentyl-(PAA),pentyl-(PAA), benzyl-(BAA) and dodecylacrylamide (DAA) functionalities [[81],81], N-vinyl caprolactame (VCL) [[82]82] or blocks of 2-(2-methoxyethoxy)ethyl methacrylate (PEG MA)MA) [[83],83], NN-isopropyl-isopropyl acrylamideacrylamide (NIPAM)(NIPAM) [84[84,85],85] (Figure(Figure6 ).6). HydrophobicHydrophobic monomers in copolymers typically provide an increase in UCST and the presence of a simple electrolyte decreasesdecreases UCST,UCST, whichwhich cancan easilyeasily modulatemodulate thethe solubilitysolubility propertiesproperties ofof polymerspolymers [81[81].].

Figure 6. Structures of monomer (38) and monome monomersrs used in copolymers to vary UCST.

Additionally, UCST response for different sulfobetaine polymers was investigated and representants are summarized in Figure 7. 2355 Vasanta et al. [86] prepared a dual hydrophilic block copolymer containing polyethyleneglycole segment PEG and poly(40). The block copolymer was able to form micelles and undergo core-shell transition depending on the nature of the dispersing medium. In the distilled water (DW), the poly(40) formed the core part, while in an electrolyte solution the PEG was present in the micelle core. The antifouling properties were investigated in seawater. The block copolymers exhibited improved antifouling properties over neat homopolymers. The lower critical solution temperature (LCST) is a solution characteristic of some polymers where a reversible transition such as UCST occurs. Typical polymers possessing LCST in water contain NIPAM or VCL as monomer units [87]. Thermoresponsive copolymers containing a combination of the sulfobetaine monomer and monomers such as NIPAM [88,89] or VCL [82] can vary their UCST as well as LCST. The effect of a specific ion on LCST was investigated on a copolymer of poly(NIPAM) and poly(41) by using rheology [90]. The LCST was varied from 28 °C to 33 °C. The change in viscosity reflected the effectiveness of the ions in weakening the interactions of the sulfobetaine groups that provided the electrostatic cross-linking. The anions were observed to follow the HLS, while the cations followed the reverse HLS. In the case of the cations, the viscosity decreased in the order: Fe3+ > Al3+ > Ca2+ > K+ > Ni2+, while, in the case of the anions, the decrease was in the order: Cl− < Br− < I−. Arotcarena et al. [91] prepared block copolymers containing poly(NIPAM) and polysulfobetaine methacrylamide poly(42) which exhibited both the LCST of the poly(NIPAM) blocks and the UCST of the poly(42). The LCST of the neat poly(42) was 12.5 °C and the UCST of the neat poly(NIPAM) was 29.8 °C. The copolymers were soluble in this temperature range; beyond this range they formed micelles with different polarities, polar at low temperatures and unipolar at high temperatures. The authors showed that the transition temperatures could be adjusted by the length of the polymer chains. The copolymer containing 74 mol % poly(NIPAM) (10,800 g/mol) and 26 mol % of poly(22) (9700 g/mol) exhibited LSCT of 8.6 °C and USCT of 31.5 °C. The copolymer composed of 35 mol % 12 Polymers 2015, 7, 2344–2370

Additionally, UCST response for different sulfobetaine polymers was investigated and representants are summarized in Figure7. Vasanta et al. [86] prepared a dual hydrophilic block copolymer containing polyethyleneglycole segment PEG and poly(40). The block copolymer was able to form micelles and undergo core-shell transition depending on the nature of the dispersing medium. In the distilled water (DW), the poly(40) formed the core part, while in an electrolyte solution the PEG was present in the micelle core. The antifouling properties were investigated in seawater. The block copolymers exhibited improved antifouling properties over neat homopolymers. The lower critical solution temperature (LCST) is a solution characteristic of some polymers where a reversible transition such as UCST occurs. Typical polymers possessing LCST in water contain NIPAM or VCL as monomer units [87]. Thermoresponsive copolymers containing a combination of the sulfobetaine monomer and monomers such as NIPAM [88,89] or VCL [82] can vary their UCST as well as LCST. The effect of a specific ion on LCST was investigated on a copolymer of poly(NIPAM) and poly(41) by using rheology [90]. The LCST was varied from 28 ˝C to 33 ˝C. The change in viscosity reflected the effectiveness of the ions in weakening the interactions of the sulfobetaine groups that provided the electrostatic cross-linking. The anions were observed to follow the HLS, while the cations followed the reverse HLS. In the case of the cations, the viscosity decreased in the order: Fe3+ > Al3+ > Ca2+ > K+ > Ni2+, while, in the case of the anions, the decrease was in the order: Cl´ < Br´ < I´. Arotcarena et al. [91] prepared block copolymers containing poly(NIPAM) and polysulfobetaine methacrylamide poly(42) which exhibited both the LCST of the poly(NIPAM) blocks and the UCST of the poly(42). The LCST of the neat poly(42) was 12.5 ˝C and the UCST of the neat poly(NIPAM) was 29.8 ˝C. The copolymers were soluble in this temperature range; beyond this range they formed micelles with different polarities, polar at low temperatures and unipolar at high temperatures. The authors showed that the transition temperatures could be adjusted by the length of the polymer chains. The copolymer containing 74 mol % poly(NIPAM) (10,800 g/mol) and 26 mol % of poly(22) (9700 g/mol) exhibited LSCT of 8.6 ˝C and USCT of 31.5 ˝C. The copolymer composed of 35 mol % poly(NIPAM) (10,800 g/mol) and 65% poly (42) (52,800 g/mol) exhibited LCST of 18.4 ˝C and USCT of 31.4 ˝C. Maeda et al. [92] prepared a double-responsive diblock copolymer consisting of poly(38) as a USCT block and poly(N,N-diethylacrylamide) as an LCST block. By using FTIR and DSC techniques, the mechanism of micelles formation below USCT and above LCST based on selective hydration of the blocks at different temperatures was explained. The LCST and UCST were controlled by different ratios of the sulfobetaine monomer(38) and N-vinylcaprolactam (PVCL) in a random copolymer [82]. While the neat PVCL exhibited the LCST of 34 ˝C, in the copolymers the LCST increased to 36 ˝C, 38 ˝C and 43 ˝C when 23.6%, 44.1% and 56.8%, respectively, of monomer(39) was incorporated. The USCT appeared for a copolymer with a higher ratio of poly(38) segments and shifted from 9 ˝C to 27 ˝C when the ratio of poly(38) increased from 44.1% to 56.8%. The neat poly(38) exhibited the UCST of 46 ˝C. The copolymers were soluble between LCST and UCST, and were insoluble beyond these temperatures. The copolymers were used for the preparation of hydrogels with N,N1-methylenebisacrylamide as a cross-linker. The water contact angle decreased from 59.88˝ to 45.44˝ with the monomer(38) content in the feed increasing from 0% to 100%. The adjustment of the ratio between poly(38) and PVCL made it possible to tune protein resistance and cell adhesion. The fouling and proliferation of cells on the hydrogel surface was suppressed by increasing the poly(38) content. The hydrogels containing a higher ratio of PVCL readily detached the cells from the surface at decreased temperatures. Moreover, changing the monomer character by the introduction of a backbone moiety such as styrene poly(40) [93], or imidazole-based poly(44) [75,94] or changing the distance of the charged

2356 Polymers 2015, 7, page–page poly(NIPAM) (10,800 g/mol) and 65% poly (42) (52,800 g/mol) exhibited LCST of 18.4 °C and USCT of 31.4 °C. Maeda et al. [92] prepared a double-responsive diblock copolymer consisting of poly(38) as a USCT block and poly(N,N-diethylacrylamide) as an LCST block. By using FTIR and DSC techniques, the mechanism of micelles formation below USCT and above LCST based on selective hydration of the blocks at different temperatures was explained. The LCST and UCST were controlled by different ratios of the sulfobetaine monomer(38) and N- vinylcaprolactam (PVCL) in a random copolymer [82]. While the neat PVCL exhibited the LCST of 34 °C, in the copolymers the LCST increased to 36 °C, 38 °C and 43 °C when 23.6%, 44.1% and 56.8%, respectively, of monomer(39) was incorporated. The USCT appeared for a copolymer with a higher ratio of poly(38) segments and shifted from 9 °C to 27 °C when the ratio of poly(38) increased from 44.1% to 56.8%. The neat poly(38) exhibited the UCST of 46 °C. The copolymers were soluble between LCST and UCST, and were insoluble beyond these temperatures. The copolymers were used for the preparation of hydrogels with N,N′-methylenebisacrylamide as a cross-linker. The water contact angle decreased from 59.88° to 45.44° with the monomer(38) content in the feed increasing from 0% to 100%. The adjustment of the ratio between poly(38) and PVCL made it possible to tune protein resistance and cell adhesion. The fouling and proliferation of cells on the hydrogel surface was suppressed by increasing the poly(38) content. The hydrogels

Polymerscontaining2015 a, 7 higher, 2344–2370 ratio of PVCL readily detached the cells from the surface at decreased temperatures. Moreover, changing the monomer character by the introduction of a backbone moiety such as styrene poly(40) [93], or imidazole-based poly(44) [75,94] or changing the distance of the charged moieties within within the the polymer polymer backbone backbone can can result result in polymeric in polymeric materials materials with a with variability a variability of UCST. of UCST.It should It shouldbe noted be that noted the thatpolymers the polymers with styren withe moieties styrene in moieties the backbone in the prevent backbone any prevent hydrolytic any hydrolyticcleavage of cleavage the ester of theor esteramide or amidegroups groups in the in backbone, the backbone, which which can can occur occur in in methacrylic-type polymers [[95].95]. Poly(41) [90] Poly(41) [90] Poly(42) [81] Poly(43) [67] Poly(40) [86] Poly(44) [75]

m = 2, 3

Figure 7. Structures of sulfobetaine zwitteri zwitterioniconic polymers with UCST response.

3.2. Physical Switch on Surface 3.2. Physical Switch on Surface It was observed that the polymeric brushes of poly(38) prepared by SI ATRP on a gold surface It was observed that the polymeric brushes of poly(38) prepared by SI ATRP on a gold surface varied the wetting characteristics depending on the layer thickness and the temperature varied the wetting characteristics depending on the layer thickness and the temperature applied [96]. applied [96]. A non-associated structure was formed and the water contact angle attained 12° when A non-associated structure was formed and the water contact angle attained 12˝ when the polymer the polymer brushes were formed from poly(38) with a thickness up to 50 nm. While the increased brushes were formed from poly(38) with a thickness up to 50 nm. While the increased hydrophobicity hydrophobicity with a contact angle up to 75°, due to the formation of self-associated structures, was with a contact angle up to 75˝, due to the formation of self-associated structures, was observed with observed with polymers 110 nm in thickness. Moreover, the UCST of polymeric brushes with an polymers 110 nm in thickness. Moreover, the UCST of polymeric brushes with an approximate approximate thickness of 180 nm was observed and the contact angle changed from 78° at 22 °C to thickness of 180 nm was observed and the contact angle changed from 78˝ at 22 ˝C to 53˝ at 53° at 52 °C. A detailed investigation of the surface wetting properties on the polymer layer thickness 52 ˝C. A detailed investigation of the surface wetting properties on the polymer layer thickness up up to >500 nm showed that the critical thickness, where the transition from hydrophobic to to >500 nm showed that the critical thickness, where the transition from hydrophobic to hydrophilic hydrophilic occurred, varied depending on the grafting density and polymerization rate [97]. occurred, varied depending on the grafting density and polymerization rate [97]. Another smart switchable surface with a salt-responsive character were developed by polymer Another smart switchable surface with a salt-responsive character were developed by polymer brushes of poly(44) prepared by SI ATRP on a glass substrate [14]. Poly(44) in the presence of a simple brushes of poly(44) prepared by SI ATRP on a glass substrate [14]. Poly(44) in the presence of a electrolyte such as NaCl exhibited super low protein adsorption <0.3 ng/cm2, lower contact angle simple electrolyte such as NaCl exhibited super low protein adsorption <0.3 ng/cm2, lower contact and higher surface hydration compared to a surface in the presence of water with adsorption up angle and higher surface hydration compared to a surface in the presence of water with adsorption up to 145 ng/cm2. This behavior is related to the anti-polyelectrolyte effect and is reversible. In addition, 13 the surface friction can be tuned by metal ions and counter ions from ultrahigh friction (µ in range 0 2´ ´3 ´ 10 ) for water or SO4 to superior lubrication (µ in range 10 ) in the presence of Br ions, which is comparable to that of natural synovial joints.

3.3. Reversible Switch from Polycationic to Polyzwitterionic State The reversible switches based on chemical change observed in zwitterions that transform into ring-forming cationic structures are summarized in Table6. The structure of the cationic ring was observed to be formed at the quaternary amine carboxybetaines having hydroxyl and carboxylate groups at different distances. Under acidic conditions, the lactone rings were formed, while the rings opened under neutral or basic conditions. An increasing number of bonds in the lactone made the ring formation difficult, hence stronger conditions were necessary to form the ring. The switching performance of the polymer was also dependent on the type of backbone. The methacrylamide backbone imparted a marked hydrophilic performance to the carboxybetaine polymer compared with the methacrylate-based carboxybetaine polymer, which resulted in an improvement in the elasticity and tensile strength of the polymers due to the formation of hydrogen-bonding. However, the mechanical properties of carboxybetaine structures with a methacrylate backbone were improved with the introduction of hydroxyl groups to lactone rings that resulted in the formation of intermolecular hydrogen-bonding.

2357 Polymers 2015, 7, page–page PolymersPolymers 2015, 72015, page–page, 7, page–page PolymersPolymers 2015, 7 2015, page–page, 7, page–page Polymersto Polymers145 2015 ng/cm, 72015, page–page, 72., page–pageThis behavior is related to the anti-polyelectrolyte effect and is reversible. 2 Polymersto 145toPolymers 2015ng/cm145, 7 2015, ng/cmpage–page., 7This, page–page2. Thisbehavior behavior is related is related to theto anti-polthe anti-polyelectrolyteyelectrolyte effect effect and andis reversible. is reversible. toPolymers In145 Polymersaddition,to 2015ng/cm145, 7 2015, ng/cmpage–page the2., , 7This, , surfacepage–pagepage–page2. Thisbehavior friction behavior iscan related beis tunedrelated to bythe to me anti-polthetal ionsanti-polyelectrolyte and yelectrolytecounter effections effectfrom and ultrahighandis reversible. is reversible.friction In addition,In addition, the2 0surface the2 surface friction friction can2- be can tuned be tuned by me bytal me ionstal andions counterand counter ions−3 fromions fromultrahigh ultrahigh friction- friction to (μ145 toin rangeng/cm145 ng/cm102. )This for2. water Thisbehavior orbehavior SO is4 torelated issuperior related to lubrication theto anti-polthe anti-pol (μyelectrolyte in rangeyelectrolyte 10 effect) in theeffect and presence andis reversible. isof Brreversible. ions, Into addition,145toIn addition,ng/cm145 theng/cm02. surface theThis. surface Thisbehavior friction behavior friction can 2- is be relatedcan istuned berelated tuned toby theme tobytal anti-poltheme ions talanti-pol andionsyelectrolyte counterandyelectrolyte counter−3 ions effect fromions effect and fromultrahigh andis ultrahigh reversible. is friction -reversible. friction to(μ in145 (rangeμ inng/cm range 10 2). for 10This 0water2)2 for behavior water or SO or4 SOisto superior4related2- to superior tolubrication the lubrication anti-pol (μ inyelectrolyte (rangeμ in range 10 ) 10ineffect −the3) in presence andthe presenceis ofreversible. Br of ions, Br- ions, (Intoμ which addition,in145 toIntorange addition,145ng/cm 145is comparable10 theng/cmng/cm0). forsurface theThis 0water.. surface ThisThis behavior tofriction orthat behaviorbehavior SOfriction of 4can 2- natural isto be superiorrelatedcan 2- isistuned synovialberelatedrelated tuned tobylubrication the me joints.totoby tal anti-polthetheme ions tal (μanti-polanti-pol andinionsyelectrolyte range counterandyelectrolyte 10counter−3 )ions ineffect −the 3 fromions effect presenceand fromultrahigh andis ultrahigh ofreversible. is Br friction -reversible. ions, friction- Inwhich addition,In(μ is addition,in comparable range the surface10 the) forsurfaceto that frictionwater of friction ornatural can SO be 4can synovialtotuned besuperior tuned by joints. me bylubricationtal me ionstal andions (μ counter andin range counter ions 10 from)ions in the fromultrahigh presence ultrahigh friction of Br friction ions, which is 0comparable0 to that42- of natural2- synovial joints. −3 −3 - - In(μ addition,in In(rangeμ addition,in range 10 the0) for surface 10the 0water) forsurface frictionwater or SOfriction or can2- SOto be superior4can2- totuned besuperior tuned bylubrication me bylubricationtal me ions taltal(μ andionsinions (rangeμ counterandandin range 10countercounter−3 )ions 10in −the 3 from)ionsions in presence the fromfromultrahigh presence ultrahighultrahigh of Br friction -of ions, Br frictionfriction- ions, which(μ in (whichrangeμ is in comparable range 10is 0comparable) for 10 water) forto that water orto ofSOthat ornatural42- of SOto natural superior4 synovialto superior synovial lubrication joints. lubrication joints. (μ in (rangeμ in range 10−3) 10in the) in presence the presence of Br -of ions, Br ions, (μ in range 10 ) for 0water or SO4 to superior2- lubrication (μ in range 10 ) in −the3 presence of Br ions,- (whichμ3.3. in (whichrange μReversible is inin comparable rangerange 10is comparable0) forSwitch 10100 water) forto from thatwater orto Polyca ofSOthat ornatural42- of SOtionicto natural 4superior42- synovialtoto to superior superiorPolyzwitterionic synovial lubrication joints. lubricationlubrication joints. ( Stateμ in (( rangeμ inin rangerange 10−3) 10in10 −the3) in presence the presence of Br -of ions, Br- ions,ions, 3.3.which Reversiblewhich is comparable is Switchcomparable fromto that Polyca to ofthat naturaltionic of natural to synovial Polyzwitterionic synovial joints. joints. State which3.3.which is comparableReversible is comparable Switch to that fromto ofthat Polycanatural of naturaltionic synovial to synovial Polyzwitterionic joints. joints. State 3.3.which Reversiblewhich3.3. isThe comparableReversible reversibleis comparableSwitch Switch fromto switches that Polycafromto ofthat Polyca naturalbasedtionic of naturaltionic toon synovial Polyzwitterionic chemical to synovial Polyzwitterionic joints. change joints. State observed State in zwitterions that transform into 3.3. ReversibleThe3.3. Reversiblereversible Switch Switch switches from Polycafrom based Polycationic ontionic to chemical Polyzwitterionic to Polyzwitterionic change State observed State in zwitterions that transform into 3.3.ring-forming ReversibleThe3.3. ReversiblereversibleThe Switchreversible cationic Switch switches from structuresswitches Polycafrom based Polycationic based areontionic to chemicalsummarized Polyzwitterionic on to chemical Polyzwitterionic change in change TableState observed State observed6. The in structurezwitterions in zwitterions of thatthe cationic transformthat transform ring into was into 3.3.ring-forming Reversible3.3. ReversibleThe cationicSwitchreversible Switch from structures switches Polycafrom Polycationic are based tionic summarizedto Polyzwitterionic on to chemical Polyzwitterionic in Tablechange State 6. State observedThe structure in zwitterions of the cationic that transformring was into ring-formingobservedThering-forming reversibleThe to cationic reversiblebe formed cationic switches structures switches at structures thebased quaternaryare based on summarized are chemical on summarized chemicalamine change in carboxybetaines Tablechange in observed Table 6. observedThe 6. instructureThe havingzwitterions instructure zwitterions ofhydroxyl the thatof cationic the transformthatand cationic transformcarboxylatering wasintoring intowas observedThering-forming reversibleTheto be reversible formed cationic switches at switches thestructures based quaternary based on are chemical on summarizedamine chemical change carboxybetaines change in observed Table observed 6. inhavingThe zwitterions instructure zwitterionshydroxyl thatof theand transformthat cationic carboxylate transform intoring wasinto observedring-forminggroupsThering-formingobserved reversibleTheatto differentbe cationicreversible to formed be cationic switches formed distances. structures at switches thestructures atbased quaternary theUnder are based quaternaryon summarized are acidicchemical on summarizedamine chemical condit amine changecarboxybetaines inions, Tablechange carboxybetaines in observedthe Table 6. lactone observedThe 6. inhavingstructureThe rings zwitterions instructurehaving werezwitterionshydroxyl of theformed,hydroxyl thatof cationic theand transformthat whilecationic carboxylateand transform ring thecarboxylate wasintoring rings intowas ring-forminggroupsring-formingobserved at different cationic to be cationicdistances. formed structures structures at Under the are quaternary acidicsummarized are summarized condit amineions, in Table carboxybetainesthe in Tablelactone 6. The 6. rings structureThe havingstructurewere of formed, thehydroxyl of cationic the while cationic and ringthe carboxylate rings wasring was groupsobservedring-formingopenedring-formingobservedgroups at todifferentunder atbe cationic todifferent formed neutralbe cationic distances. formed structures atdistances. or thestructures basic at Under quaternary the areconditions. Under quaternary acidicsummarized are acidic summarized aminecondit An amine condit ions,increasingcarboxybetaines in Table ions,carboxybetainesthe in Tablelactone 6.the number The lactone 6. rings havingstructureThe of rings structurehavingwerebonds hydroxyl of wereformed, inthehydroxyl ofthe formed, cationic theand lactonewhile cationic carboxylateand while ringthe madecarboxylate rings wasringthe the rings was observedopenedobservedgroups under to atbe toneutraldifferent formed be formed or atdistances. basic the at quaternary conditions.the Under quaternary acidic amine An increasing aminecondit carboxybetaines ions,carboxybetaines number the lactone havingof bonds ringshaving hydroxyl inwere thehydroxyl formed, lactone and carboxylateand whilemade carboxylate thethe rings observedgroupsopenedringobservedgroupsopened formation atunder todifferent atbeunder toneutraldifferent formed bedifficult, distances. neutralformed or atdistances. basic thehence or at Under quaternary basicconditions.the st Under quaternaryronger acidicconditions. acidic amineconditionsconditAn increasingamine conditAn ions,carboxybetaines increasing wereions,carboxybetainesthe numberlactone thenecessary lactonenumber rings havingof bonds to rings havingwereof form hydroxylbonds in wereformed, thehydroxylthe in formed, ring.lactone andthe while lactoneThe carboxylateand whilemade the switching carboxylate ringsmade thethe rings the groupsring formationgroupsopened at different atunder differentdifficult, distances. neutral distances.hence or Under basic stronger Under acidicconditions. conditions acidic condit conditAnions, wereincreasing ions,the necessarylactone the numberlactone rings to ringsform wereof bonds weretheformed, ring. in formed, the whileThe lactone whileswitching the ringsmade the rings the groupsringopenedperformance groupsformationopenedring atunder formationdifferent atunder differentneutraldifficult,of thedistances. neutraldifficult, orpolymer distances. hence basic or Underhence basic conditions.st wasronger Under conditions.acidic stalsoronger conditions acidic dependentconditAn conditions increasing conditAnions, wereincreasing ions,onions,the were necessarythenumberlactone thethe type necessarylactonenumberlactone rings ofof to bonds backbone. ringsformrings wereof to bonds form inwere weretheformed, the ring. inThe theformed,formed, lactone the whilering.Themethacrylamide lactone whilewhileswitchingmadeThe the ringsswitchingmade the thethe ringsrings the openedperformanceopenedring under formation underof neutral the neutraldifficult,polymer or basic or hence was basicconditions. also conditions.stronger dependent An conditions increasing An onincreasing the were number type necessarynumber of of backbone. bonds of to bonds formin theThe inthe lactone methacrylamidethe ring. lactone madeThe switchingmade the the openedringperformancebackbone openedformationringperformance under formation imparted underof neutraldifficult, the of neutraldifficult, polymerthe aor marked hencebasicpolymer or hencewasbasic conditions.st rongerhydrophilic alsowas conditions.stronger dependentalsoconditions An dependent conditionsperfor increasing An wereincreasingonmance the wereon necessarynumber typetothe necessarythenumber typeof ofcarboxybetaine backbone.to bonds ofform of backbone.to bonds forminthe theThe ring. inthe lactone polymer methacrylamidetheThe ring.The lactone methacrylamide switchingmadeThe compared switchingmade the the ringbackbone formationringperformance formationimparted difficult, of difficult,a the marked hencepolymer hence hydrophilicstronger was stronger alsoconditions perfor dependentconditionsmance were wereonnecessaryto the necessary carboxybetainetype to ofform backbone.to formthe ring. polymerthe The ring.The methacrylamide comparedswitchingThe switching ringperformancebackbonewith ringformationperformancebackbone the formationimparted methacrylate-based of imparteddifficult, the of difficult,a polymerthe marked henceapolymer marked hencewas hydrophilicst carboxybetaineronger alsowas hydrophilicstronger dependentalsoconditions perfor dependentconditions polyperformance wereonmer, mancethe wereonnecessaryto which typethe necessaryto carboxybetainetype of theresulted backbone.to carboxybetaineof form tobackbone.to inform formthe anThe ring. polymer thetheimprovement methacrylamideThe ring.ring.polymerThe methacrylamide comparedswitchingTheThe comparedswitching switchingin the performancewith performancebackbonethe methacrylate-based of imparted the of polymerthe apolymer marked wascarboxybetaine alsowas hydrophilic dependentalso dependent poly perfor mer,on mancethe whichon typethe to resulted type ofthe backbone. carboxybetaineof backbone.in an Theimprovement methacrylamideThe polymer methacrylamide in compared the performancewithbackboneelasticity performancebackbonewiththe methacrylate-basedimpartedthe and of methacrylate-basedimparted tensilethe of a polymerthe marked strength apolymer marked wascarboxybetaine hydrophilic of thewasalso carboxybetainehydrophilic polymers alsodependent perfor dependent poly duperformance mer,epolyon to mancethe mer,which onto formation typethe which to resulted typecarboxybetaine ofthe backbone. resulted carboxybetaineofof hydrogen-bonding.backbone.in an in Theimprovement polymeran methacrylamideTheimprovement polymer methacrylamide compared However, in compared the in the backboneelasticitybackbonewith and impartedthe tensile methacrylate-basedimparted astrength marked a marked of hydrophilic the carboxybetaine polymershydrophilic perfor du perfore mance topoly themancemer, formationto the which to carboxybetaine the of resultedcarboxybetaine hydrogen-bonding. in polymeran improvement polymer comparedHowever, compared in the elasticitybackbonewiththe backbonewithelasticity themechanical and methacrylate-basedimpartedthe tensile andmethacrylate-basedimparted properties tensile astrength marked astrength marked of of carboxybetainecarboxybetainehydrophilic the of carboxybetaine hydrophilicpolymers the polymers perfor dustructpoly perfore mance tomer,dupolyures theemance tomer, which withformationto the the which aformationto methacrylate resulted carboxybetainethe of resultedcarboxybetaine hydrogen-bonding. ofin hydrogen-bonding.an backbonein improvement polymeran improvement polymer were comparedHowever, improved in comparedHowever, the in the withthe mechanical withelasticitythe methacrylate-basedthe andmethacrylate-based properties tensile strengthof carboxybetaine carboxybetaine ofcarboxybetaine the polymers struct polyures mer,dupolye with tomer,which the a methacrylate whichformation resulted resulted ofin backbone hydrogen-bonding.an in improvement an improvement were improved in However, the in the theelasticitywithwith mechanical withelasticitythethe the mechanical andmethacrylate-basedthe introduction tensileandmethacrylate-based properties tensile properties strength strengthofof carboxybetaine hydroxylofcarboxybetaine of the carboxybetaine ofcarboxybetaine polymers the groups polymers struct dupoly to estructures tomer,dupolyla thectonee withures tomer, whichformation the witharings methacrylate whichformation resulted a methacrylatethat of resulted hydrogen-bonding. resulted ofin backbone hydrogen-bonding.an in improvement backbone anin improvement thewere formation wereHowever,improved in However,improved the in of the elasticitywithPolymers elasticitythethe mechanical and2015introduction ,tensile and7, 2344–2370 tensile properties strength of strength hydroxyl of of the carboxybetaine of polymers thegroups polymers duto estructla to ductone theeures to formation ringsthe with formation thata methacrylate of resultedhydrogen-bonding. of hydrogen-bonding. in backbone the formation wereHowever, However,improved of withelasticitytheintermolecular mechanical elasticitythewiththe mechanical and introductionthe tensile and propertiesintroduction hydrogen-bonding. tensile properties strength of strengthof hydroxyl carboxybetaineof of of thehydroxyl carboxybetaine of polymers thegroups polymers groups struct duto estructlaures todutoctone the e lawithures to ctone formation ringsthe witha methacrylate formationrings thata methacrylate of that resultedhydrogen-bonding. of resultedbackbonehydrogen-bonding. in backbone the in were formationthe wereHowever,improved formation However,improved of of theintermolecular mechanicalthewith mechanical the hydrogen-bonding.propertiesintroduction properties of carboxybetaineof of hydroxyl carboxybetaine groups struct structures to lawithuresctone witha methacrylate rings a methacrylate that resultedbackbone backbone in were the wereimproved formation improved of intermolecularthewith mechanical thewithintermolecularthethe mechanicalmechanical introductionthe hydrogen-bonding.introductionproperties propertieshydrogen-bonding.properties of of hydroxyl carboxybetaineof ofof hydroxyl carboxybetainecarboxybetaine groups groups struct to structstructlaures toctone lawithuresctone rings witha methacrylate rings thata methacrylate thatresulted resultedbackbone in backbone the in were formationthe were improved formation improved of of with withintermolecularthe introductionthe introduction hydrogen-bonding. Tableof hydroxyl of 6. Reversiblehydroxyl groups switchesgroups to la containingtoctone lactone rings polyzwitterionic rings that thatresulted resulted state. in the in formationthe formation of of withintermolecular withintermolecularthe introductionthe introductionhydrogen-bonding. hydrogen-bonding.Table ofTable Table hydroxyl 6.of Reversible 6. hydroxylReversible6. Reversible groups switches switchesgroups switches to containing la containingtoctone containing lactone ringspolyzwitterionic polyzwitterionic ringspolyzwitterionic that thatresulted state.resulted state. state.in the in formationthe formation of of intermolecularintermolecular hydrogen-bonding. hydrogen-bonding.Table 6. Reversible switches containing polyzwitterionic state. intermolecularintermolecularintermolecular hydrogen-bonding. hydrogen-bonding.hydrogen-bonding.Table 6. Reversible switches containing polyzwitterionic state. Polycationic stateTableTable 6. Reversible 6. Reversible Triggerswitches switches (form) containing containing(reference) polyzwitterionic polyzwitterionic state. Polyzwitterionic state. state Table 6. Reversible switches containing polyzwitterionic state. PolycationicPolycationic stateTable state 6. Reversible Trigger Triggerswitches Trigger (form) (form) containing (form) (reference) (reference) (reference) polyzwitterionic state. Polyzwitterionic Polyzwitterionic state state PolycationicPolycationic stateTable stateTable 6. Reversible 6. ReversibleReversible Trigger switchesOH Trigger (form)switchesswitches− (pH containing (form) 7(reference) or containingcontaining pH (reference) 10)polyzwitterionic polyzwitterionicpolyzwitterionic state. Polyzwitterionic state.state. Polyzwitterionic state state − PolycationicPolycationic state state TriggerOH Trigger (pH(form)´ −7 (form)or (reference) pH 10)(reference) Polyzwitterionic Polyzwitterionic state state OH− OH(pH (pH 7 or 7 or pH pH 10) 10) PolycationicPolycationic state state TriggerOH Trigger (pH(form)OH −7 (pH (form)or (reference) pH 7 or 10)(reference) pH 10) Polyzwitterionic Polyzwitterionic state state PolycationicPolycationic state state Trigger Trigger− (form)− (form) (reference) (reference) Polyzwitterionic Polyzwitterionic state state OH− (pHOH −7 (pH or pH 7 or 10) pH 10) OH− (pHOH 7 (pH or pH 7 or 10) pH 10) OH− (pHOH −−7 (pH(pH or pH 77 oror 10) pHpH 10)10) H+ (TFA, HAc) (polymer brushes) Poly(45) H+ (TFA, HAc) (polymer brushes) [98] Poly(46) + [98] Poly(45) H (TFA,+ HAc) (polymer brushes) [98] Poly(46) Poly(45) + H (TFA, HAc) (polymer brushes) [98] Poly(46) Poly(45)Poly(45) H (TFA,H+ (TFA, HAc) HAc)(polymerOH (polymer− brushes) brushes) [98] [98] Poly(46) Poly(46) − + + OH − Poly(45)Poly(45) H+ (TFA,H+ (TFA, HAc) HAc)(polymer (polymerOH brushes) brushes) [98] [98] Poly(46) Poly(46) Poly(45)Poly(45) H+ (TFA,H (TFA, HAc) HAc)(polymerOH −(polymer brushes)− brushes) [98] [98] Poly(46) Poly(46) Poly(45) H+ (TFA,++ HAc) (polymerOH brushes) [98] Poly(46) Poly(45)Poly(45) H (TFA,H (TFA,(TFA, HAc) HAc)HAc)(polymer −(polymer(polymer brushes)− brushes)brushes) [98] [98][98] Poly(46) Poly(46) Poly(46) ´ OH− OH− OH OH− OH Poly(47) H+ (polymer+ brushes,OH− OH hydrogel)−− [99] Poly(48) + H (polymer brushes, hydrogel) Poly(47)Poly(47) H (polymerH+ (polymer brushes, brushes, hydrogel) hydrogel) [99] [99] Poly(48) Poly(48) Poly(47)Poly(47) H+ (polymerH+ (polymer brushes, OHbrushes,[99 ]hydrogel)− hydrogel) [99] [99] Poly(48) Poly(48) Poly(47) − Poly(48) + + OH − Poly(47)Poly(47) H+ (polymerH+ (polymer brushes, brushes, OHhydrogel) hydrogel) [99] [99] Poly(48) Poly(48) Poly(47)Poly(47) H+ (polymerH (polymer brushes,OH brushes,− hydrogel)− hydrogel) [99] [99] Poly(48) Poly(48) Poly(47) H+ (polymer++ brushes, OHhydrogel) [99] Poly(48) Poly(47)Poly(47) H (polymerH (polymer(polymer brushes, brushes,brushes,− hydrogel)− hydrogel)hydrogel) [99] [99][99] Poly(48) Poly(48) Poly(48) OH− OH− OH− OH ´ OH− −− Poly(49) H+ (polymerOH brushes,OH OH hydrogel) [99] Poly(50) + + Poly(49)Poly(49) H (polymerHH+(polymer (polymer brushes,brushes, brushes, −hydrogel) hydrogel) hydrogel) [99] [99] Poly(50) Poly(50) + + OH Poly(49)Poly(49) H (polymerH (polymer brushes, brushes,− hydrogel) hydrogel) [99] [99] Poly(50) Poly(50) OH[99 ] − + + − OH Poly(49)Poly(49) H+ (polymerH+ (polymer brushes,OH brushes, hydrogel)− hydrogel) [99] [99] Poly(50) Poly(50) Poly(49)Poly(49) H+ (polymerH (polymer brushes, brushes, OHhydrogel) hydrogel) [99] [99] Poly(50) Poly(50) Poly(49) H (polymer brushes,− hydrogel) [99] Poly(50) + ++ OH OH´ − Poly(49)Poly(49) H (polymerH (polymer(polymer brushes, OH brushes,brushes,− hydrogel)− hydrogel)hydrogel) [99] [99][99] Poly(50) Poly(50) Poly(50) OH− OH Poly(51) H+ (polymer brushes,OH− OH hydrogel)−− [100] Poly(52) + Poly(51)Poly(51) H (polymerH+ (polymer brushes, brushes, hydrogel) hydrogel) [100] [100] Poly(52) Poly(52) Poly(51)Poly(51) H+ (polymerH+ (polymer brushes, brushes,OH hydrogel)− hydrogel) [100] [100] Poly(52) Poly(52) + − + H + (polymerOH brushes, − hydrogel) Poly(51)Poly(51) H+ (polymerH+ (polymer brushes, brushes, hydrogel)OH hydrogel) [100] [100] Poly(52) Poly(52) Poly(51)Poly(51) H+ (polymerH (polymer brushes,OH brushes,− hydrogel)− hydrogel) [100] [100] Poly(52) Poly(52) Poly(51)Poly(51) H+ (polymer++ brushes,[100 hydrogel)OH] [100] Poly(52) Poly(51)Poly(51) H (polymerH (polymer(polymer brushes, brushes,brushes,− hydrogel)− hydrogel)hydrogel) [100] [100][100] Poly(52) Poly(52) Poly(52) OH− OH− OHOH− OH´ OH− OH−−

Poly(53) H+ (polymer brushes, hydrogel) [100] Poly(54) + Poly(53) H (polymer+ brushes, hydrogel) [100] Poly(54) Poly(53) + H (polymer brushes,− hydrogel) [100] Poly(54) Poly(53)Poly(53) H (polymerH++ (polymer brushes, brushes,OH hydrogel) hydrogel) [100] [100] Poly(54) Poly(54) − + H + (polymerOH brushes, − hydrogel) Poly(53)Poly(53) H+ (polymerH+ (polymer brushes, brushes,− hydrogel)OH hydrogel) [100] [100] Poly(54) Poly(54) Poly(53)Poly(53) H+ (polymerH (polymer brushes,OH brushes,[100 hydrogel)OH] − hydrogel) [100] [100] Poly(54) Poly(54) Poly(53)Poly(53) H+ (polymer+ brushes, hydrogel) [100] Poly(54) Poly(53)Poly(53) H (polymerH+ (polymer(polymer brushes, brushes,brushes,− hydrogel)− hydrogel)hydrogel) [100] [100][100] Poly(54) Poly(54) Poly(54) OH− OH− OH− OH´ OHOH− −− poly(55) H+ (modifiedOH dextran)OH [101] poly(56) + poly(55)poly(55) H (modifiedH+ (modified dextran) dextran) [101] [101] poly(56) poly(56) Thepoly(55) reversible switch was reportedH+ (modified+ on dextran)the surf [101]ace of poly(45) with a poly(56) structure based on poly(55) H (modified dextran) [101] poly(56) The reversibleThe reversible switch switch was wasreported +reported +on the on surfthe acesurf oface poly(45) of poly(45) with witha structure a structure based based on on 2-morpholinonepoly(55)poly(55) [98,102] preparedH by+ (modified SIH ATRP.+ (modified dextran) The dextran) structure [101] [101] contained a quaternary poly(56) poly(56) amine lactone The reversibleThepoly(55) reversiblepoly(55) switch switch was wasreportedH +reported (modified+ H on (modified the ondextran) surfthe dextran) acesurf [101] oface [101]poly(45) of poly(45) with witha structure poly(56) a structure poly(56) based based on on 2-morpholinone2-morpholinonepoly(55) [98,102] [98,102] prepared prepared byH SI+H (modified by ATRP.(modified +SI+ ATRP. The dextran) dextran) structureThe [101]structure [101 contained] contained a qu aternarya qu poly(56)aternary amine amine lactone lactone 2-morpholinoneThe reversibleThepoly(55) reversiblepoly(55) [98,102] switch preparedswitch was wasreported byH SIreported (modified ATRP.H on (modified(modified the The ondextran) surf thestructure dextran)dextran) acesurf [101] oface [101][101]containedpoly(45) of poly(45) witha qu aternarywitha structure poly(56) a structure poly(56) poly(56)amine based lactone based on on The2-morpholinone reversibleThe reversible switch [98,102] switch was prepared wasreported reported by SIon ATRP. the on surfthe The acesurf structure oface poly(45) of containedpoly(45) with withaa qustructure aternarya structure basedamine based onlactone on 2-morpholinoneThe2-morpholinone Thereversible reversible [98,102] switch [98,102] preparedswitch was prepared wasreported by SIreported by ATRP. SIon ATRP. the Theon 14surf the structureThe acesurf structure oface containedpoly(45) of containedpoly(45) witha qu aternarywithaa qustructure aternarya structure amine basedamine lactone based onlactone on 2-morpholinone2-morpholinone [98,102] [98,102] prepared prepared by SI by ATRP. SI ATRP. The14 structureThe structure contained contained a quaternary a quaternary amine amine lactone lactone 2-morpholinone2-morpholinone [98,102] [98,102] prepared prepared by SI by ATRP. SI ATRP. The structureThe14 structure contained contained a qu aternarya quaternary amine amine lactone lactone The reversible switch was reported on14 the 14 surface of poly(45) with a structure based on 14 14 2-morpholinone [98,102] prepared by SI ATRP.14 The 14 structure contained a quaternary amine lactone 14 14 ring that reversible transforms into a zwitterionic carboxybetaine structure as is schematically depicted in Figure8. The switch was investigated in both acetic acid (HAc) [98] or trifluoroacetic acid (TFA) [102]. The rate of the reverse switch accelerated with increasing pH [102]. The transformation of the polymer in TFA was faster and more effective; however, the use of acetic acid is advantageous since it does not corrode the gold substrate and does not damage the polymer coating. The slow transformation in acetic acid was assigned to the catalytic process caused by the protonation of the carboxylate group that led to an intramolecular Fisher esterification involving the neighboring hydroxyl group. Application of switchable character of this material is in Figure8. Polycationic state poly(46) can be formed in acidic condition and such dried surface is able to kill 99.9% of bacterial cells from directly spraying bacterial aerosols onto the material. Exposure of surface to water permit fast hydrolysis to polyzwitterionic form poly(45) release 90% of the killed bacteria and moreover prevent fouling for fibrinogen and lysozyme below the limit of detection of 0.3 ng/cm2 and, in the case of undiluted plasma, the adsorption attained 3 ng/cm2. Reversibility of this switchable process was capable to restore initial state through dehydration of surface under acidic conditions (Figure8)[98].

2358 Polymers 2015, 7, page–page ring that reversible transforms into a zwitterionic carboxybetaine structure as is schematically depicted in Figure 8. The switch was investigated in both acetic acid (HAc) [98] or trifluoroacetic acid (TFA) [102]. The rate of the reverse switch accelerated with increasing pH [102]. The transformation of the polymer in TFA was faster and more effective; however, the use of acetic acid is advantageous since it does not corrode the gold substrate and does not damage the polymer coating. The slow transformation in acetic acid was assigned to the catalytic process caused by the protonation of the carboxylate group that led to an intramolecular Fisher esterification involving the neighboring hydroxyl group. Application of switchable character of this material is in Figure 8. Polycationic state poly(46) can be formed in acidic condition and such dried surface is able to kill 99.9% of bacterial cells from directly spraying bacterial aerosols onto the material. Exposure of surface to water permit fast hydrolysis to polyzwitterionic form poly(45) release 90% of the killed bacteria and moreover prevent 2 Polymersfouling2015 for, 7fibrinogen, 2344–2370 and lysozyme below the limit of detection of 0.3 ng/cm and, in the case of undiluted plasma, the adsorption attained 3 ng/cm2. Reversibility of this switchable process was capable to restore initial state through dehydration of surface under acidic conditions (Figure 8) [98]. ReversibleReversible switchswitch allowingallowing switchswitch betweenbetween polycationicpolycationic coatingcoating withwith antibacterialantibacterial charactercharacter andand subsequentlysubsequently afterafter switchswitch releaserelease ofof deaddead bacteriabacteria andand formingforming nonfoulingnonfouling surfacesurface havehave particularparticular interestinterest inin coatingcoating forfor surgicalsurgical oror medicalmedical toolstools andand application.application.

FigureFigure 8. A Areversible reversible switch switch between between antibacterial antibacterial surfac surfacee of poly(45) of poly(45) enable enable to kill to bacteria kill bacteria in the inpolycationic the polycationic state and state hydrolysed and hydrolysed polyzwitterionic polyzwitterionic state poly(46) state poly(46) permitting permitting to release to dead release bacterial dead bacterialcells along cells with along resistance with resistanceagainst bacteria against cells bacteria adhesion. cells Regeneration adhesion. Regenerationto poly(45) is tothrough poly(45) an isacidic through dehydration an acidic process. dehydration Reprinted with process. permission Reprinted from Reference with permission [98], Copyright from 2012, Reference Wiley-VCH. [98], Copyright 2012, Wiley-VCH. Moreover, poly(45) in a pH 10 buffer transferred onto an amine-reactive surface made it possible to immobilize two antibodies (anti-hGC and anti-Salm) through reactive carboxylate. This treatment Moreover, poly(45) in a pH 10 buffer transferred onto an amine-reactive surface made it possible and reversible transformation of remaining group to poly(45) resulted in the significant specific to immobilize two antibodies (anti-hGC and anti-Salm) through reactive carboxylate. This treatment detection of hCG or Salm proteins [102]. and reversible transformation of remaining group to poly(45) resulted in the significant specific Investigation of the structure–property relationship of reversibly carboxybetaine zwitterionic detection of hCG or Salm proteins [102]. polymers revealed that even one carbon in spacer can significantly influence the switchability, Investigation of the structure–property relationship of reversibly carboxybetaine zwitterionic meachanical properties and stability of the carboxybetaine polymers [99]. Four different switchable polymers revealed that even one carbon in spacer can significantly influence the switchability, polymers poly(47), poly(49) poly(51) and poly(53) were synthetized and studied in this regard. meachanical properties and stability of the carboxybetaine polymers [99]. Four different switchable Poly(47) and poly(49) contain a methacrylamine backbone in the monomer unit and form six- polymers poly(47), poly(49) poly(51) and poly(53) were synthetized and studied in this regard. membered and seven-membered lactone rings, respectively. Poly(51) and poly(53) contain Poly(47) and poly(49) contain a methacrylamine backbone in the monomer unit and form methacrylate backbone forming six-membered lactone rings and bear methyl and hydroxyethyl six-membered and seven-membered lactone rings, respectively. Poly(51) and poly(53) contain group on ammonium group, respectively. The protein adsorption of polymer brushes prepared by methacrylate backbone forming six-membered lactone rings and bear methyl and hydroxyethyl surface-initiated photoiniferter-mediated polymerization (sensors on gold-coated chips of poly(48), group on ammonium group, respectively. The protein adsorption of polymer brushes prepared by poly(50) and poly(52) were tested by SPR [99]). All three materials in polyzwitterionic state exhibited surface-initiated photoiniferter-mediated polymerization (sensors on gold-coated chips of poly(48), ultra-low fouling properties against human fibrinogen, 100% human plasma and 100% human blood poly(50) and poly(52) were tested by SPR [99]). All three materials in polyzwitterionic state exhibited serum. The ring formation and transformation from polyzwitterionic state to polycationic states were ultra-low fouling properties against human fibrinogen, 100% human plasma and 100% human blood investigated in both HAc and TFA. Poly(49) with seven membered ring was switched with the lowest serum. The ring formation and transformation from polyzwitterionic state to polycationic states were rate was due to the high strain upon the ring closure. In acetic acid the ring was not formed; instead, investigated in both HAc and TFA. Poly(49) with seven membered ring was switched with the lowest elimination of acrylic acid was observed. Interestingly, the incorporation of hydroxyl groups in the rate was due to the high strain upon the ring closure. In acetic acid the ring was not formed; instead, monomer of poly(53) accelerated the ring formation. In TFA, the monomer of poly(53) switched up elimination of acrylic acid was observed. Interestingly, the incorporation of hydroxyl groups in the monomer of poly(53) accelerated the ring formation.15 In TFA, the monomer of poly(53) switched up to 99% in 15 minutes and in 0.2 M HAc, the monomer of poly(53) was able to reach an 84% conversion within 20 h [100]. These results indicate that the monomer of poly(53) is more favorable for ring formation than the monomer of poly(51) due to the symmetrical substitution giving rise to opportunities to cyclize on both sides, resulting in faster ring formation. The ring-opening kinetics was investigated in alkaline condition [100]. Only the poly(47) hydrogel exhibited good switchability and ring stability and thus was able to kill and subsequently release almost 99.5% of the dead E. coli cells from the surface [99]. From the perspective of the hydrogels mechanical properties, the methacrylamide backbone imparted more hydrophilic properties affording more pronounced hydrogen bonding, which resulted in improved tensile strength and elasticity. The best results were obtained with poly(47) followed by

2359 Polymers 2015, 7, page–page

to 99% in 15 minutes and in 0.2 M HAc, the monomer of poly(53) was able to reach an 84% conversion within 20 h [100]. These results indicate that the monomer of poly(53) is more favorable for ring formation than the monomer of poly(51) due to the symmetrical substitution giving rise to opportunities to cyclize on both sides, resulting in faster ring formation. The ring-opening kinetics was investigated in alkaline condition [100]. Only the poly(47) hydrogel exhibited good switchability and ring stability and thus was able to kill and subsequently release almost 99.5% of the dead E. coli cells from the surface [99]. Polymers 2015, 7, 2344–2370 From the perspective of the hydrogels mechanical properties, the methacrylamide backbone imparted more hydrophilic properties affording more pronounced hydrogen bonding, which poly(49).resulted in Since improved the carboxybetaine tensile strength zwitterionic and elasticity. hydrogel The withbest resu 6-memberedlts were obtained lactone rings, with poly(51),poly(47) suffersfollowed from by poly(49). insufficient Since mechanical the carboxybetaine properties, zwi thetterionic hydroxyl hydrogel groups with were 6-membered incorporated lactone into rings, the monomerpoly(51), suffers unit of from poly(53) insufficient [100]. mechanical The introduction properties, of hydroxylthe hydroxyl groups groups resulted were incorporated in the formation into ofthehydrogen monomer bondsunit of betweenpoly(53) the[100]. polymer The introduction chains.When of hydroxyl compared groups with resulted the hydrogel in the formation base on poly(carboxybetaineof hydrogen bonds methacrylate),between the polymer both poly(51) chains. andWhen poly(53) compared exhibited with enhancedthe hydrogel break base strain. on Poly(51)poly(carboxybetaine exhibited two methacrylate), times higher both break poly(51) stress and 30%poly(53) higher exhibited break strain,enhanced and break 73% higherstrain. modulusPoly(51) exhibited compared two with times the poly(8) higher hydrogel.break stre Thess and higher 30% number higher ofbreak hydroxyl strain, groups and 73% present higher in poly(53)modulus resultedcompared in with hydrogel the poly(8) softening, hydrogel. hence noThe enhancement higher number of theof hydroxyl modulus groups was observed. present in It shouldpoly(53) be resulted noted that in thehydrogel hydroxyl softening, groups improvedhence no theenhancement solubility of of polymers the modulus in DMSO, was DMF,observed. CHCl It3 andshould acetonitrile. be noted Antifoulingthat the hydroxyl properties groups of poly(51) improved and poly(53)the solubility were evaluatedof polymers on in polymer DMSO, brushes DMF, preparedCHCl3 and on acetonitrile. gold-coated Antifouling SPR chips withproperties a bovine of poly(51) fibrinogen and solution poly(53) (1 were mg/mL) evaluated and 100% on polymer human bloodbrushes plasma. prepared Both on polymers gold-coated exhibited SPR chips ultra-low with fouling a bovine properties fibrinogen in thesolution bovine (1 fibrinogen mg/mL) and solution. 100% Poly(53)human blood adsorbed plasma. proteins Both atpolymers a density exhibited of 0.8 ng/cm ultra-low2 and fouling poly(51) proper at a densityties in the lower bovine than fibrinogen the limit ofsolution. detection Poly(53) of 0.3 ng/cmadsorbed2; in proteins the 100% at humana density blood of 0.8 plasma ng/cm poly(51)2 and poly(51) modified at thea density surface-adsorbed lower than proteinsthe limit atof adetection density of of 0.3 0.2 ng/cm ng/cm2; 2inand the poly(30)100% human at a densityblood plasma of 2.4 poly(51) ng/cm2 .modified Since all the the surface- values ofadsorbed fibrinogen proteins adsorption at a density were belowof 0.2 ng/cm 5 ng/cm2 and2, thepoly(30) material at a can density be expected of 2.4 ng/cm to delay2. Since the all blood the coagulationvalues of fibrinogen caused by adso plateletsrption activationwere below [100 5 ng/cm]. 2, the material can be expected to delay the blood coagulationThe cell caused viability by test platelets confirmed activation that both [100]. poly(51) and poly(53) in a cationic ring form can cause cell damageThe cell toviability more than test confirmed 99% of the that attached both bacteria.poly(51) and After poly(53) overnight in a hydrolysis,cationic ring 99.6% form and can 99.4%cause ofcell dead damage cells to were more released than 99% from of the the surface attached of ba poly(51)cteria. andAfter poly(53), overnight respectively hydrolysis, [100 99.6%]. and 99.4% of deadIt can cells be were stated released that careful from and the rationalsurface engineeringof poly(51) and of the poly(53), monomer respectively unit can result[100]. in improved mechanicalIt can be properties stated that without careful and sacrificing rational theengineering switchable of the character monomer and unit retaining can result the in combinedimproved antibacterialmechanical properties and antifouling without properties. sacrificing the switchable character and retaining the combined antibacterialSimilarly, and the antifouling methacrylate-type properties. six-membered lactone ring structure was also used for modificationSimilarly, of the the methacrylate-type dextran surface six-membered to poly(55). lactone The use ring of structure structure was poly(55) also used enhance for opticalmodification properties, of the imparteddextran surf anti-biofoulingace to poly(55). properties The use to of the stru otherwisecture poly(55) natural enhance polysaccharide optical materialproperties, [101 imparted]. anti-biofouling properties to the otherwise natural polysaccharide material [101]. ´− Another type ofof reversiblereversible switchswitch waswas inducedinduced byby thethe additionaddition ofof bisulfitebisulfite ionsions HSOHSO3 3 to polymers with a a quaternary quaternary ammonium ammonium group group on on th thee pendant pendant aldehyde aldehyde functi functionalityonality in inpoly(57) poly(57) as − ´ asshown shown in inFigure Figure 9 9[103,104].[103,104]. The The addition addition of of HSO HSO3 3ionsions to toaldehyde aldehyde created created a sulfate a sulfate group, group, and and a apolyzwitterionic polyzwitterionic state state was was formed. formed. This This transition transition was was used used to to deactivate deactivate for for thin layer-by-layer structures onon the the surface. surface. Reversibility Reversibility of thisof this process process in this in system this system has not has yet beennot yet studied been instudied detail. in detail.

16 ´ Figure 9. Reversible switch of poly(57) by addition of HSO3 ions [103].

The redox switch on polymers bearing viologen with a sulfate moiety should also be considered as a switch involving the polyzwitterionic state as shown in Figure 10. The reduction and oxidation currents in the cyclic voltammetry measurements of the viologen to form the cation radical and dication were observed to be of the same intensity, which indicated the reversibility of this switch.

2360 Polymers 2015, 7, page–page Polymers 2015, 7, page–page

Figure 9. Reversible switch of poly(57) by addition of HSO3− ions [103]. Figure 9. Reversible switch of poly(57) by addition of HSO3− ions [103].

TheThe redox redox switch switch on on polymers polymers bearing bearing viologen viologen with with a a sulfate sulfate moiety moiety should should also also be be considered considered as a switch involving the polyzwitterionic state as shown in Figure 10. The reduction and oxidation Polymersas a switch2015, 7involving, 2344–2370 the polyzwitterionic state as shown in Figure 10. The reduction and oxidation currentscurrents inin thethe cycliccyclic voltammetryvoltammetry measurementsmeasurements ofof thethe viologenviologen toto formform thethe cationcation radicalradical andand dicationdication werewere observedobserved toto bebe ofof thethe samesame intensity,intensity, whichwhich indicatedindicated thethe reversibilityreversibility ofof thisthis switch.switch. Moreover,Moreover, thethe hydrophilicityhydrophilicity waswas controlledcontrolled withwith thisthis process process andand the the hydrophilicity hydrophilicity of of polymer polymer decreaseddecreased afterafter reductionreduction waswas carriedcarried outout [[105] 105[105]]...

Figure 10. Redox switch on monomer(59) bearing viologen [105]. FigureFigure 10.10. RedoxRedox switchswitch onon monomer(59)monomer(59) bearingbearing viologenviologen [[105].105].

3.4.3.4. Switch Switch in in Polymer Polymer from from Poly PolyneutralPolyneutralneutral toto PolyzwitterionicPolyzwPolyzwitterionicitterionic StateState

The fixation of CO2 by the addition of CO2 to a polymer having carbine in the imidazole ring can TheThe fixationfixation of of CO CO2 2byby the the addition addition of CO of2 CO to a2 polymerto a polymer having having carbine carbine in the imidazole in the imidazole ring can beringbe assumedassumed can be assumed toto formform to thethe form polyzwitterionpolyzwitterion the polyzwitterion state,state, state, andand andthethe therelatedrelated related polymerspolymers polymers areare are summarizedsummarized in in FigureFigure 11 11[ [106]. 106[106].]. FixationFixation Fixation viavia via carbinecarbine carbine onon on thethe the polymerpolymer polymer inin in thethe the structurestructure structure ofof of poly(70)poly(70) poly(70) waswas was performedperformed performed withinwithin within 60 min at 40 ˝°C in a CO2 environment and the release was performed at an elevated temperature of 6060 minmin atat 4040 °CC inin aa COCO22 environment andand thethe releaserelease waswas performedperformed atat anan elevatedelevated temperaturetemperature ofof 140140 °C˝°CC in in a a nitrogen nitrogen atmosphereatmosphere [[107].[107].107]. It ItIt should shouldshould be bebe noted notednoted that thatthat thisthis typetype ofof switchswitch is is probably probably only only possible in a non-aqueous environment. Amidine is a promising functionality for the addition of CO2 possiblepossible inin aa non-aqueousnon-aqueous environment.environment. AmidineAmidine isis aa promisingpromising functionalityfunctionality for for the the addition addition of of CO CO22 toto form form a a polyzwitterionic polyzwitterionic structure structure ofof poly(72).poly(72). Several Several types types based based on on a a polystyrenepolystyrene backbone backbone were were synthesized [108,109]. Nowadays, the fixation or capture of CO2 is of particular interest due to its synthesizedsynthesized [[108,109].108,109]. Nowadays,Nowadays, thethe fixationfixation oror capturecapture ofof COCO22 isis ofof particularparticular interestinterest duedue toto itsits environmental and economic aspects. CO2 is not only a cheap and valuable source of “green” C1 environmentalenvironmental andand economiceconomic aspects.aspects. COCO22 is not only aa cheapcheap andand valuablevaluable sourcesource ofof “green”“green” C1C1 synthon in technology and research but, more importantly, the increased CO2 concentration in the synthonsynthon inin technologytechnology andand researchresearch but,but, moremore importantly,importantly, thethe increasedincreased COCO22 concentrationconcentration inin thethe atmosphereatmosphere promotingpromoting globalglobal changeschanges andand serious serious environmental environmental problems problems drivesdrives the the investigation investigation ofof the the useuse ofof suchsuch carboncarbon sourcessources inin numerousnumerous applications.applications. applications.

Figure 11. Switch in polymer from polyneutral to polyzwitterionic state triggered by CO2. Figure 11. Switch in polymer from polyneutral to polyzwitterionic state triggered by CO2. Figure 11. Switch in polymer from polyneutral to polyzwitterionic state triggered by CO2.

The literature contains frequent references to the switch in polymers from the polyneutral to 1717 polyzwitterionic state in polymers containing spiropyrane monomers [110]. These derivatives might switch between two states: open merocyanine-ring and closed spiropyrane-ring isomers as shown in Figure 12[111]. This switch between states can mainly be triggered by a certain light wavelength

2361 Polymers 2015, 7, page–page Polymers 2015, 7, page–page The literature contains frequent references to the switch in polymers from the polyneutral to The literature contains frequent references to the switch in polymers from the polyneutral to polyzwitterionic state in polymers containing spiropyrane monomers [110]. These derivatives might polyzwitterionic state in polymers containing spiropyrane monomers [110]. These derivatives might switchPolymers between2015, 7, 2344–2370 two states: open merocyanine-ring and closed spiropyrane-ring isomers as shown in switch between two states: open merocyanine-ring and closed spiropyrane-ring isomers as shown in Figure 12 [111]. This switch between states can mainly be triggered by a certain light wavelength as Figure 12 [111]. This switch between states can mainly be triggered by a certain light wavelength as a light-responsive switch, but the process can also be triggered by different solvents, metal ions, aas light-responsive a light-responsive switch, switch, but but the the process process can can also also be be triggered triggered by by different different solvents, solvents, metal metal ions, acids/bases, redox potential and mechanical forces. Merocyanines are not correctly postulated as an acids/bases, redox redox potential potential and and mechanical mechanical forces. forces. Merocyanines Merocyanines are are not not correctly correctly postulated postulated as an ionic-zwitterionic state; however, the merocyanine isomer occurs naturally in a quinoidic mesomeric ionic-zwitterionicionic-zwitterionic state; state; however, however, the merocyanine isomer occurs naturally in a a quinoidic quinoidic mesomeric mesomeric form with a large conjugated system possessing a strong dipole only as shown in Figure 8. Due to formform with a large conjugated system possessing a strong dipole only as shown inin FigureFigure8 8.. DueDue toto this fact, the term polyzwitterion state in such systems is not appropriate. thisthis fact, fact, the term polyzwitterion state in such systems is not appropriate.

Figure 12. Spiropyran–merocyanine transformation with mesomeric structure. FigureFigure 12. 12. Spiropyran–merocyanineSpiropyran–merocyanine transformation transformation with mesomeric structure. 3.5. Switch in Polymer from Polyanionic to Polyzwitterionic State 3.5. Switch Switch in in Polymer Polymer from from Poly Polyanionicanionic to Polyzwitterionic State This case is limited solely to the redox-responsive switch of the organometallic polymer with a This case case is is limited limited solely solely to to the the redox-responsive redox-responsive switch switch of of the the organometallic organometallic polymer polymer with with a ferrocenylsilane backbone bearing the sulfonate pendant group poly(74), which can transform the ferrocenylsilanea ferrocenylsilane backbone backbone bearing bearing the the sulfonate sulfonate pendant pendant group group poly(74), poly(74), which which can cantransform transform the ferrocene fragment to ferrocenium at a certain potential, as depicted in Figure 13 [112]. This process ferrocenethe ferrocene fragment fragment to ferrocenium to ferrocenium at a certain at a certain potent potential,ial, as depicted as depicted in Figure in Figure13 [112]. 13 This[112 ].process This was investigated using a 5-layered layer-by-layer (LBL) system of polyanionic ferrocene poly(74) wasprocess investigated was investigated using a 5-layere using ad 5-layered layer-by-layer layer-by-layer (LBL) system (LBL) of system polyanionic of polyanionic ferrocene ferrocenepoly(74) with the poly(ferrocenylsilanes) poly(75) having a quaternary ammonium counterpart, and withpoly(74) the with poly(ferrocenylsilanes) the poly(ferrocenylsilanes) poly(75) poly(75) having having a quaternary a quaternary ammonium ammonium counterpart, counterpart, and disassembly based on the repulsive forces due to formation of the polyzwitterionic structure was disassembly based on the repulsive repulsive forces due to formation of the the polyzwitterionic polyzwitterionic structure structure was observed. At a potential of 0.4 V, the oxidation of ferrocene in poly(74) to ferrocenium succeeded and observed. At At a a potential potential of of 0.4 0.4 V, V, the the oxidation oxidation of of ferrocene ferrocene in in poly(74) poly(74) to to ferrocenium ferrocenium succeeded and the LBL disassembled within 5 has observed by UV and CV measurements [113]. thethe LBL LBL disassembled within 5 has observ observeded by UV and CV measurements [[113].113].

Figure 13. Switch from polyanionic ferrocene to polyzwitterionic ferrocenium state in poly(74) and Figure 13. Switch from polyanionic ferrocene to polyzwitterionic ferrocenium state in poly(74) and chemicalFigure 13. structureSwitch fromof positively polyanionic charged ferrocene polyferrocenylsilane to polyzwitterionic poly(75). ferrocenium state in poly(74) and chemicalchemical structure of positively charged polyferrocenylsilane poly(75). 4. Reversible Double Switch 4. Reversible Double Switch 4. Reversible Double Switch Recently, a structure performing a reversible double switch between the cationic, zwitterionic Recently, a structure performing a reversible double switch between the cationic, zwitterionic and anionicRecently, states a structure was reported; performing examples a reversible are summarized double switch in Table between 7. the cationic, zwitterionic and anionic states was reported; examples are summarized in Table 7. and anionicIn one report, states was the reported;structure examplespoly(76) with are summarized tertiary amine in Tableand carboxylic7. acid separated by one In one report, the structure poly(76) with tertiary amine and carboxylic acid separated by one methyleneIn one spacer report, were the structuredeveloped poly(76) and polymer with tertiary brushes amine were and prepared carboxylic by SI acid PMP separated [114]. Since by onethe methylene spacer were developed and polymer brushes were prepared by SI PMP [114]. Since the tertiarymethylene amine spacer can wereexist in developed positive and and neutral polymer states, brushes and werecarboxylic prepared acid bycan SI exist PMP in [the114 ].neutral Since and the tertiary amine can exist in positive and neutral states, and carboxylic acid can exist in the neutral and negativetertiary amine states, can the existtwo fully in positive reversible and neutralcharged states, states andcould carboxylic be achieved. acid When can exist the indistance the neutral between and negative states, the two fully reversible charged states could be achieved. When the distance between thenegative tertiary states, amine the and two fullythe carboxylic reversible chargedgroup isstates sufficiently could besmall achieved. (one carbon When thebond), distance the opposite between the tertiary amine and the carboxylic group is sufficiently small (one carbon bond), the opposite chargedthe tertiary states amine stimulate and theone carboxylicanother and group thus synergistically is sufficiently smallaffect and (one stabilize carbon the bond), polyzwitterionic the opposite charged states stimulate one another and thus synergistically affect and stabilize the polyzwitterionic state.charged In statesthis case, stimulate from one pH another 1 and and2 the thus tertia synergisticallyry amine was affect protonated and stabilize which the polyzwitterionicresulted in the state. In this case, from pH 1 and 2 the tertiary amine was protonated which resulted in the polycationicstate. In this state. case, The from polyzwitterionic pH 1 and 2 state the tertiarypoly(77) amine was obtained was protonated at pH between which 2 resultedand 9 so, inin the polycationic state. The polyzwitterionic state poly(77) was obtained at pH between 2 and 9 so, in the pHpolycationic range of state.6–8, which The polyzwitterionic is regarded as the state physio poly(77)logical was condition obtained and at pH suitable between for2 bioapplications, and 9 so, in the pH range of 6–8, which is regarded as the physiological condition and suitable for bioapplications, pH range of 6–8, which is regarded as the physiological condition and suitable for bioapplications, this transition can be performed. Beyond pH 9, the structure was deprotonated resulting in the 18 formation of an anionic charged form poly(78). 18

2362 Polymers 2015, 7, 2344–2370 PolymersPolymersPolymers 2015 2015, 7, 2015page–page, 7, page–page, 7, page–page PolymersPolymersPolymers 2015 2015, 7, page–page2015, 7, page–page, 7, page–page PolymersPolymersPolymers 2015 2015, 7, 2015page–page, 7, page–page, 7, page–page TableTable 7. 7.ReversibleReversible double double switch. switch. TableTable 7.Table Reversible 7. Reversible 7. Reversible double double doubleswitch. switch. switch. TableTable 7.Table Reversible 7. Reversible 7. Reversible double double doubleswitch. switch. switch. Initial form Polyzwitterion Polyzwitterion References References Second Second form form InitialInitial formInitial form form Polyzwitterion Polyzwitterion Polyzwitterion References References References Second Second Second form form form InitialInitial Initialform form form Polyzwitterion Polyzwitterion Polyzwitterion References References References Second Second Second form form form

[114] [114] [114][114] [114] [114][114] [114]

pH 1–2 Poly(76) pH pH2–9 2–9 Poly(77) Poly(77) pH > 9 pHPoly(78) > 9 Poly(78) pHpH 1–2 1–2pH Poly(76) Poly(76)1–2 Poly(76) pH pH2–9 2–9 pHPoly(77) Poly(77)2–9 Poly(77) pH pH> 9 > pHPoly(78) 9 Poly(78) > 9 Poly(78) pHpH 1–2 1–2pH Poly(76) 1–2Poly(76) Poly(76) pH pH2–9 2–9 pHPoly(77) 2–9Poly(77) Poly(77) pH pH> 9 > pHPoly(78) 9 Poly(78)> 9 Poly(78)

[115,116] [115,116][115,116][115[115,116] ,116 ] [115,116][115,116][115,116]

pH 2–4 Poly(79) pH ≈ 5 Poly(80) pH > 5 Poly(81) pHpH 2–4 2–4pH Poly(79) Poly(79)2–4 Poly(79) pH pH≈ 5 « ≈ pHPoly(80) 5 Poly(80) ≈ 5 Poly(80) pH pH > 5 > pHPoly(81) 5 Poly(81) > 5 Poly(81) pHpH 2–4 2–4pH Poly(79) 2–4Poly(79) Poly(79) pH pH pH≈ 5 ≈ pHPoly(80) 55 Poly(80) Poly(80)≈ 5 Poly(80) pH pH > 5 >pH Poly(81) 5 Poly(81) > 5 Poly(81)

[117] [117][117] [117] [117][117] [117[117] ]

pH < 2 Poly(82) pH 2–9.5 Poly(83) pH > 9.5 Poly(84) pHpH < 2 9.5 > pH 9.5Poly(84) > Poly(84) 9.5 Poly(84) pHpH < 2 9.5 > pH 9.5Poly(84) > Poly(84)9.5 Poly(84)

TheThe protein-foulingThe protein-fouling protein-fouling properties properties properties of ofdouble-switc double-switcof double-switch-performingh-performingh-performing polymers polymers polymers were were investigatedwere investigated investigated at at at TheThe protein-foulingThe protein-fouling protein-fouling properties properties properties of ofdouble-switc double-switcof double-switch-performingh-performingh-performing polymers polymers polymers were were investigatedwere investigated investigated at at at variousvariousvariousThe pH pH values. protein-fouling pHvalues. values. The The resistance The resistance properties resistance of poly(76)of poly(76) of of double-switch-performingpoly(76) was was te wassted tested tewithsted with a withset a setof a oppositelyofset polymers oppositely of oppositely charged were charged investigatedcharged proteins proteins proteins at atat at variousvariousvarious pH pH values. pHvalues. values. The The resistance The resistance resistance of poly(76)of poly(76) of poly(76) was was te wassted tested tewithsted with a with set a set of a oppositelyofset oppositely of oppositely charged charged charged proteins proteins proteins at at at anyvariousany givenany given pHgivenpH, pH, values. i.e. pH, ,i.e. lysozyme, i.e.lysozyme The, lysozyme resistance (positively (positively (positively ofpoly(76) charged, charged, charged, was pI pI≈ tested 11) ≈pI 11) and≈ with 11)and pepsin and apepsin set pepsin (negatively of oppositely(negatively (negatively charged, chargedcharged, charged, pI proteins pI≈ 1). ≈pI 1). ≈ 1). anyany givenany given givenpH, pH, i.e. pH, ,i.e. lysozyme, i.e.lysozyme, lysozyme (positively (positively (positively charged, charged, charged, pI pI≈ 11) ≈pI 11) and≈ 11)and pepsin and pepsin pepsin (negatively (negatively 2(negatively2 2charged, charged, charged, pI pI≈ 1). ≈pI 1). ≈ 1). Atat AtpH any pHAt 3 given pHthe3 the negatively3 pH, thenegatively i.e.negatively, lysozyme charged charged charged (positivelypepsin pepsin pepsin was charged,was strongly was strongly strongly pI «adsorbed 11)adsorbed andadsorbed pepsin(24 (24 ng/cm (24ng/cm (negatively 2ng/cm) while2) while2) charged,whilethe the positively thepositively pI positively« 1). At AtpH pHAt 3 thepH3 the negatively3 thenegatively negatively charged charged charged pepsin pepsin pepsin was was strongly was strongly strongly adsorbed adsorbed adsorbed (24 (24 ng/cm (24ng/cm ng/cm2) while2) while2) whilethe the positively thepositively positively At AtpH pHAt 3 pHthe3 the negatively3 thenegatively negatively charged charged charged pepsin pepsin pepsin was was strongly was strongly strongly adsorbed adsorbed adsorbed (24 (24 ng/cm (24ng/cm ng/cm) 2while) while) whilethe the positively thepositively positively chargedAtcharged pHcharged lysozyme 3the lysozyme negativelylysozyme was was negligibly was negligibly charged negligibly bound, pepsin bound, bound, thereby was thereby thereby strongly confirming confirming confirming adsorbed the the surface thesurface (24 surface ng/cmto beto bepositively to) positively be while positively charged. the charged. positively charged. On On On chargedchargedcharged lysozyme lysozyme lysozyme was was negligibly was negligibly negligibly bound, bound, bound, thereby thereby thereby confirming confirming confirming the the surface thesurface surface to beto2 bepositively2 to positively be2 positively charged. charged. charged. On On On thechargedthe other theother hand,other lysozyme hand, hand,at atpH was pH at9, pH negligiblythe9, the 9,lysozy thelysozy lysozyme bound,me was mewas therebystrongly was strongly strongly confirming adsorbed adsorbed adsorbed (26 the (26 ng/cm surface (26ng/cm 2ng/cm) torevealing2) berevealing2) positivelyrevealing the the negative charged.thenegative negative thethe other theother hand,other hand, hand,at pHat pH at9, pHthe9, the 9,lysozy thelysozy lysozymeme was mewas strongly was strongly strongly adsorbed adsorbed adsorbed (26 (26 ng/cm (26ng/cm ng/cm2) revealing2) revealing2) revealing the the negative thenegative negative thethe other theother hand,other hand, hand,at atpH pH at9, pHthe9, the 9,lysozy thelysozy lysozymeme was mewas strongly was strongly strongly adsorbed adsorbed adsorbed (26 (26 ng/cm (26ng/cm ng/cm) revealing2) revealing) revealing the the negative thenegative negative chargeOncharge thecharge on other onthe the onsurface hand, thesurface surface at[114]. pH[114]. The 9,[114]. theThe ultra-low lysozymeThe ultra-low ultra-low foulin was foulin gfoulin strongly propertiesg propertiesg properties adsorbed were were confir were (26 confir ng/cm medconfirmed withmed) with revealing undiluted with undiluted undiluted the human negative human human chargechargecharge on onthe the onsurface thesurface surface [114]. [114]. The[114]. The ultra-low The ultra-low ultra-low foulin foulin gfoulin propertiesg propertiesg properties were were confir were confir medconfirmed withmed with undiluted with undiluted undiluted human human human plasmachargeplasmaplasma and on and theserum and serum surface serumunder under [114 underphysiological]. physiological The physiological ultra-low conditions conditions fouling conditions at properties pHat pH at= 7.4. pH= were7.4. In= 7.4.Inthe confirmed the Incase thecase of case withofserum, serum,of undiluted serum, an anadsorbed adsorbedan human adsorbed plasmaplasmaplasma and and serum and serum serum under under underphysiological physiological physiological2 2 conditions2 conditions conditions at pHat pH at= 7.4.pH= 7.4. In= 7.4.Inthe the Incase thecase of case ofserum, serum,of serum, an anadsorbed adsorbedan adsorbed proteinplasmaproteinprotein surface andsurface surface serum density density underdensity of of5 physiological ng/cm 5of ng/cm 5 2ng/cm was2 was 2 conditionsdetected was detected detected while,at while, pH while,in = inthe 7.4. the incase In thecase the of case caseofplasma, plasma,of of plasma, serum, an anundetectable anundetectablean adsorbedundetectable proteinproteinprotein surface surface surface density density density of of5 ng/cm 5of ng/cm 5 ng/cm2 was2 was 2detected was detected detected while, while, while,in inthe the incase thecase of case ofplasma, plasma,of plasma, an anundetectable undetectablean undetectable proteinproteinprotein surface surface surface density density density of of5 ng/cm 5of ng/cm 5 ng/cm was2 was detected was detected detected while, while, while,in inthe the incase thecase of case ofplasma, plasma,of plasma, an anundetectable undetectablean undetectable adsorptionproteinadsorptionadsorption surface was was observed was densityobserved observed [114]. of [114]. 5 ng/cm[114]. was detected while, in the case of plasma, an undetectable adsorptionadsorptionPoly(methacryoyl-adsorption was was observed was observed observedL-lysine), [114].L [114].L [114]. structure (79), was reported to perform a double switch from the adsorptionPoly(methacryoyl-Poly(methacryoyl-Poly(methacryoyl- was observedL-lysine),L-lysine), [114L-lysine),]. structure structure structure (79), (79), wa (79), was reported swa reporteds reported to performto perform to perform a double a double a double switch switch switch from from thefrom the the Poly(methacryoyl-Poly(methacryoyl-Poly(methacryoyl-L-lysine),L-lysine),L-lysine), structure structure structure (79), (79), wa (79), was reported swa reporteds reported to toperform perform to perform a double a double a double switch switch switch from from thefrom the the polycationicpolycationicpolycationicPoly(methacryoyl- state state at state pHat pH belowatL -lysine),pHbelow below4.5 4.5 through structure through4.5 through the (79), the polyzwitterionic thepolyzwitterionic was polyzwitterionic reported state to state perform at state pHat pH =at a 4.7 doublepH= 4.7 to = theto4.7 switchthe anionicto theanionic fromanionic state state the state polycationicpolycationicpolycationic state state at state pHat pH atbelow pHbelow below4.5 4.5 through through4.5 through the the polyzwitterionic thepolyzwitterionic polyzwitterionic state state at state pHat pH at= 4.7 pH= 4.7 to = theto4.7 the toanionic theanionic anionic state state state at polycationicpHat pH >at 5 pH> [115,116]. 5 [115,116].> 5 state [115,116]. Polymeric at Polymeric pH Polymeric below brushes brushes 4.5 brushes through poly(79) poly(79) poly(79) the prepar polyzwitterionic prepar prepared edby bySIed free SIby free state SIradical free radical at radical pHpolymerization polymerization = 4.7 polymerization to the anionic in conicalin conical in state conical at pHat pH >at 5 pH> [115,116]. 5 [115,116].> 5 [115,116]. Polymeric Polymeric Polymeric brushes brushes brushes poly(79) poly(79) poly(79) prepar prepar prepared edby bySIed free SIby free SI radical free radical radical polymerization polymerization polymerization in conicalin conical in conical nanoporesatnanopores pHnanopores > 5 in [115 polyimidein ,polyimide116 in polyimide]. Polymeric membrane membrane membrane brushes were were poly(79)able were able pH able pH tunable prepared pHtunable tunable and by and controllable SI and controllable free controllable radical ionic polymerizationionic transport. ionic transport. transport. in conical nanoporesnanoporesnanopores in polyimidein polyimide in polyimide membrane membrane membrane were were able were able pH able pH tunable pHtunable tunable and and controllable and controllable controllable ionic ionic transport. ionic transport. transport. nanoporesPoly(cysteinePoly(cysteinePoly(cysteine in polyimide methacrylate), methacrylate), methacrylate), membrane poly(82) poly(82) were poly(82) ablecontaining containing pH containing tunable a primarya andprimary a controllableprimary amine amine amineand ionicand carboxylic and transport.carboxylic carboxylic acid acid was acid was was Poly(cysteinePoly(cysteinePoly(cysteine methacrylate), methacrylate), methacrylate), poly(82) poly(82) poly(82) containing containing containing a primarya primary a primary amine amine amineand and carboxylic and carboxylic carboxylic acid acid wasacid was was formedformedformedPoly(cysteine by bySI ATPR. SIby ATPR. SI ATPR. The methacrylate), The polymer The polymer polymer brushes brushes poly(82) brushes were were containing observ were observ observed edto a primarybetoed behighly to highly be aminehighlyextended extended extended and at carboxylic pHat pH =at 2 pH= and 2 and= acid above2 and above was above formedformedformed by bySI ATPR. SIby ATPR. SI ATPR. The The polymer The polymer polymer brushes brushes brushes were were observ were observ observed edto betoed behighly to highly be highly extended extended extended at pHat pH =at 2 pH= and 2 and= above2 and above above pH=formedpH= 9,pH= when9, when by 9, thewhen SI the ATPR.structure thestructure structure The became polymer became became positively positively brushes positively and were and ne and observedgativelynegatively negatively charged, to charged, be charged, highly respectively respectively extendedrespectively [117]. [117]. at pHIn[117]. Inthe = the 2InpH and thepH pH pH=pH= 9,pH= when9, when 9, whenthe the structure thestructure structure became became became positively positively positively and and ne and gativelynegatively negatively charged, charged, charged, respectively respectively respectively [117]. [117]. In[117]. Inthe the InpH thepH pH rangeaboverange rangeof pH=2–9.5,of 2–9.5, of 9,2–9.5,the whenthe polymer thepolymer the polymer structurebrushes brushes brushes were became were inwere ain positivelypolyzwitterionic a in polyzwitterionic a polyzwitterionic and negatively state state as state aspoly(83). charged, poly(83).as poly(83). Polymer respectively Polymer Polymer brushes brushes [117 brushes ]. rangerange rangeof of2–9.5, 2–9.5, of 2–9.5,the the polymer thepolymer polymer brushes brushes brushes were were inwere ina polyzwitterionic a in polyzwitterionic a polyzwitterionic state state as state aspoly(83). poly(83).as poly(83). Polymer Polymer Polymer brushes brushes brushes Poly(83)InPoly(83) thePoly(83) pHshowed showed range showed antifouling of antifouling 2–9.5, antifouling the properties polymer properties properties brushesand and low and low were cy low totoxicitycy intotoxicity cy a polyzwitterionictotoxicity to tohuman humanto human dermal statedermal dermal asfibroblast poly(83).fibroblast fibroblast cells Polymercells for cells for for Poly(83)Poly(83)Poly(83) showed showed showed antifouling antifouling antifouling properties properties properties and and low and low cy low totoxicitycytotoxicity cytotoxicity to tohuman humanto human dermal dermal dermal fibroblast fibroblast fibroblast cells cells for cells for for brushesbrushesbrushesbrushes having Poly(83)having having a thickness showeda thicknessa thickness antifouling of of24–28 24–28of 24–28 propertiesnm. nm. Poly(8nm. Poly(8 andPoly(83) 3)exhibited low exhibited3) cytotoxicityexhibited good good goodlong-term to long-term human long-term stability dermal stability stability fibroblastunder under under brushesbrushesbrushes having having having a thicknessa thicknessa thickness of of24–28 24–28of 24–28nm. nm. Poly(8nm. Poly(8 Poly(83) 3)exhibited exhibited3) exhibited good good goodlong-term long-term long-term stability stability stability under under under physiologicalphysiologicalphysiological condition, condition, condition, while while thewhile the hydrolysis thehydrolysis hydrolysis at pHat pH

5. Conclusions and Outcome In this review, the characteristics of switches in materials involving polyzwitterionic moieties were presented by way of irreversible and reversible examples. Exceptional triggers for switches, which included pH, temperature, electrical field, ions and CO2 molecules, make this type of material particularly attractive mainly due to the significant changes in the overall charges and ionic states. The materials possessing functional switches were summarized as an excellent platform for controlling the release of antimicrobial drugs and solution properties, markedly varying the interaction with biological species such as DNA, bacteria and human plasma/blood samples and smart vehicles for drug and gene deliveries. Switches to polyzwitterionic state materials triggered with CO2 have also been proposed and, due to environmental and economic concerns, research in this direction is highly motivated. Other unique characteristics for future research into switchable polyzwitterionic materials are worthy of remark. The unique combination of functional antibacterial and biofouling features addresses the huge demand for the coating of biomedical devices and leads to commercialization. Despite the promising results, the bio-distribution and clearance routes for materials are not yet available and can vary with size, form and the coated materials. Progress in the synthetic chemistry of phosphobetaine derivatives makes it particularly attractive to employ switchable processes in various biological and biomedical applications [118]. In biomedical-related research, interaction with viruses should be considered and a switchable process introducing a trigger with a specific enzyme [119] or metal complexes as mimics [120] would be beneficial as a sophisticated nanosystem for delivery. Similarly, a carboxybetaine derivative with phosphonium could be used in the preparation of valuable new synthetic products [121]. Thermo-responsive poly(38) polymers have recently been successfully used as ion-permeable membranes in energy storage devices; differences in the specific storage capacity of the electrode for Li ion when heated from 20 to 80 ˝C showed a reversibly decrease by >50%, compared to a 30% increase without polymer modification [122]. The orthogonal solubility of some polyzwitterions to solvents could typically be used in the processing of organic semiconductors [123,124] and possibly of UCST, representing an open avenue for thermo-responsive and tunable platforms in organic electronic devices [122]. The external trigger as a mechanical force via ultrasonic stimuli as a component of a spatial and time-controlled switchable process represents a highly feasible approach, which was not previously reported [125,126].

Acknowledgments: This publication was made possible by NPRP grant #NPRP-6-381-1-078 from the Qatar National Research Fund (a member of Qatar Foundation). The statements made herein are solely the responsibility of the authors. Author Contributions: Markéta Ilˇcíkováwas involved in data collection and evaluation and publication writing. Ján Tkáˇcwas involved data collection and evaluation and publication writing. Peter Kasák was involved in conceiving ideas and overall management, data collection and evaluation, publication and writing. Conflicts of Interest: The authors declare no conflict of interest.

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