Engineering Antifouling Conducting Polymers for Modern Biomedical

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Engineering Antifouling Conducting Polymers for Modern Biomedical Applications Jhih-Guang Wu, Jie-Hao Chen, Kuan-Ting Liu, and Shyh-Chyang Luo ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.9b04924 • Publication Date (Web): 23 May 2019 Downloaded from http://pubs.acs.org on May 27, 2019

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ACS Applied Materials & Interfaces

Engineering Antifouling Conducting Polymers for Modern Biomedical Applications Jhih-Guang Wu, † Jie-Hao Chen, † Kuan-Ting Liu, † and Shyh-Chyang Luo*,†,‡ Department of Materials Science and Engineering, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei 10617, Taiwan ‡Advanced

Research Center for Green Materials Science and Technology, National Taiwan

University, Taipei 10617, Taiwan

KEYWORDS: conducting polymer, antifouling and antibacterial, controlled capture and release, zwitterionic polymer, smart surface

ABSTRACT

Conducting polymers are considered as favorable electrode materials for implanted biosensors and bioelectronics because their mechanical properties are similar to biological tissues, such as nerve and brain tissues. However, one of the primary challenges for implanted devices is to prevent the unwanted protein adhesion or cell binding within biological fluids. The nonspecific adsorption generally causes the malfunction of implanted devices, which is problematic for long-term applications. When responding to the requirements of solving the problems caused by nonspecific

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adsorption, an increasing number of studies on antifouling conducting polymers have been recently published. In this review, synthetic strategies for preparing antifouling conducting polymers, including direct synthesis of functional monomers and post-functionalization, are introduced. The applications of antifouling conducting polymers in modern biomedical applications are particularly highlighted. This paper presents focuses on the features of antifouling conducting polymers and the challenges of modern biomedical applications.

Introduction

The surface properties of conducting polymers are crucial for controlling their interactions with proteins, cells or tissues in biological environments. Being conductive biointerfaces or bioelectrodes to bridge conventional electronics with cells and tissues, conducting polymers can be used to detect biological activity by examining their electrochemical signals through devices, such as electrochemical biosensors and neural probes. Moreover, they can be used to provide electrical signals for electrotherapy, such as deep brain stimulation and neuropathic pain treatment. The applications of organic bioelectronics using conducting polymers have attracted considerable attention over the last decade, primarily because of their intrinsic mechanical properties compared with those of conventional conducting inorganic materials. This subject has been addressed in several excellent review articles.1-6 In general, the softness of conducting polymers is beneficial for manufacturing flexible and stretchable bioelectronics.7-9 Although conducting polymer-based organic bioelectronics have demonstrated considerable success in various biomedical applications, several challenges are encountered, particularly for implanted devices and long-term applications. One of the primary concerns is the nonspecific adsorption of biomolecules and cells, which


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generates an inflammatory response and causes electrode malfunction.10-12 The development of antifouling coating or antifouling biomaterials is important to reduce the damages caused by the nonspecific adsorption.13-16 The aforementioned concept has been applied to various organic and inorganic biomaterials for biomedical applications. Kuliasha et al.17 developed an ultravioletinitiated photografting process, which utilizes benzophenone coupled with a reversible addition fragmentation chain transfer (RAFT) living polymerization technique to modify the antifouling surface properties of poly(dimethylsiloxane) (PDMS). Moreover, Pranantyo et al.18 demonstrated the grafting of an antifouling polymer brush on polyurethane surfaces through the photoinduced anchoring of initiators and surface-initiated atom transfer radical polymerization (SI-ATRP). The antifouling coating on polyurethane effectively reduces the adsorption of bovine serum albumin (BSA) and bacteria, and barnacle cyprid settlement. Wang et al.19 demonstrated a different strategy to graft zwitterionic betaine-based polymer chains on cellulose membranes for promoting the antifouling property and hemocompatibility of cellulose membranes. Fang et al.20 grafted antifouling poly(ethylene glycol) on polyvinyl chloride/poly(methyl methacrylate) polymer blends to prevent coagulation. Furthermore, Huang et al.21 demonstrated that through an adhesive dopamine layer, the surface of TiO2 can be modified and immobilized using a zwitterionic sulfobetaine moiety, which can effectively prevent bacterial adsorption.

On the basis of these successful demonstrations of various biomaterials, conducting polymers with antifouling properties are anticipated to be favorable for promoting and stimulating new biomedical applications of conducting polymers. Various types of antifouling conducting polymers have been reported.22-28 Figure 1 shows the classification of antifouling conducting polymers.


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Figure 1. Design and classification of conducting polymers with an antifouling property.

In general, antifouling polymers are classified into three groups, namely polymers with poly(ethylene glycol) (PEG) or oligo(ethylene glycol) (OEG)-based, with zwitterions, and with other hydrophilic units, such as glycan or hydrophilic peptides. To immobilize these antifouling groups on conducting polymer surfaces, some groups started with a molecular design for synthesizing monomers with antifouling moieties. Antifouling conducting polymers can be directly formed using electropolymerization or oxidation polymerization. Antifouling moieties form a monolayer-like structure on conducting polymer surfaces. The density of the surface functional group is generally 1015 cm-2 for a smooth surface.29 With the increasing surface roughness increases or nanostructure formation, the density per unit are of antifouling moieties increases. Other researchers have used surface modification to create antifouling layers on conducting polymer surfaces. The antifouling layer can be introduced through direct covalent bonding or surface-initiated polymerization methods, such as ATRP and RAFT polymerization. Because of the increasing number of studies on antifouling conducting polymers, a comprehensive review article examining this emergent research field is essential. In this review article, the classification of antifouling conducting polymers based on synthetic strategies as depicted in


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Figure 1. Three essential applications that use antifouling conducting polymers are introduced, including a sustainable biosensor, antibacterial coating, and controlled cell capture and release, are presented. The selected features of antifouling conducting polymers are discussed, and the prospects of this topic are provided in this review article. This contribution can further promote the development of new antifouling conducting polymers for modern biomedical applications.

Molecular Design and Synthetic Strategies

Figure 2. Synthetic strategy for monomers with antifouling moieties.


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Synthesis of Functional Monomers. An antifouling moiety can be directly bonded with monomers having a functional group, such as chlorine, thiol, carboxylic acid, hydroxyl groups, for polymerization by using a synthetic method (Figure 2).

Cao et al.30 first used thiophene with a

carboxylic acid group, thiophene-3-acetic acid, to react with N,N’-dimethylethylenediamine. Followed by an oxidation polymerization with FeCl3 and a reaction with ethyl bromoacetate, a polythiophene with protected group was received. After the hydrolysis of ethyl ester with an ion exchange resin (Amberlite), a zwitterionic poly-(carboxybetaine thiophene) (PCBTh) was synthesized. Moreover, they demonstrated PCBTh-based copolymers and hydrogels, which exhibit appropriate ionic conductivity and electrochemical stability. PCBTh effectively prevented nonspecific BSA and fibrinogen adsorption, and provided a low percentage of the bovine aortic endothelial cell attachment. Moreover, the same group also used a 3,4-thylenedioxythiophene with a chloromethyl group (EDOT-Cl) as a starting molecule to react with dimethylamine and then used 1,3-propanesultone to synthesize zwitterionic sulfobetaine-functionalized EDOT (SBEDOT).31 The

conducting

polymer

films

can

then

be

synthesized

on

electrodes

through

electropolymerization in an aqueous solution containing SBEDOT monomers. The authors demonstrated suitable antifouling and antimicrobial properties of this platform. The antimicrobial property of a zwitterionic conducting polymer is elaborated in the Application section of this article. Goda et al.32 also used EDOT-Cl as a starting material. The chloromethyl group was first reacted with potassium thioacetate to form methanethioester. An EDOT-methanethiol monomer was obtained after performing deprotection by using MeONa. The thiol group can be directly conjugated

with

a

zwitterionic

methacrylate

monomer

[i.e.,

2-methacryloyloxyethyl

phosphorylcholine (MPC)]33-35 through a thiol-ene reaction to form a PC- functionalized EDOT (EDOTPC). More recently, Goda and Miyahara36 synthesized CB- and SB- functionalized EDOTs


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(EDOTCB and EDOTSB) by applying similar thiol-ene reactions. In a series of zwitterionic PEDOTs coating, a poly(EDOT-co-EDOTPC) could provide the lowest impedance and the best resistances to protein adsorption and cell adhesion. The differences of the resistances to protein adsorption between PC and SB group might be due to the antipolyelectrolyte effect. The previous studies demonstrated that poly(MPC) showed completely no charge when increased the concentration of electrolyte. However, poly(SBMA) expanded during increasing the concentration of electrolyte only at low concentration due to the breakup of intermolecular pairing.37-38 Yu group studied the feasibility of synthesizing various functionalized EDOTs starting with hydroxymethyl EDOT (EDOT-OH).39-41 On the basis on this synthesis method, three types of antifouling EDOTs have been proposed. After activating the hydroxyl group by using a strong base, such as NaH, EDOT-OH becomes a strong nucleophile, which can react with an electrophile group. Therefore, by activating tri(ethylene glycol) with a methanesulfonyl chloride to form a sulfonate ester, EDOT-OH can react with tri(ethylene glycol) to form EDOT-EG3.42 By activating protected mannose with trichloroacetonitrile to form trichloroacetimidate group, the hydroxyl group on EDOT-EG3 can react with activated mannose to form EDOT-Man after mannose deprotection.43 Both EDOT-EG3 and EDOT-Man showed low nonspecific binding to BSA, indicating appropriate antifouling properties. The copolymer of EDOT-EG3 and EDOT-Man can be used to particularly recognize the Concanavalin A. It is worth mentioning here that, Zhao et al. fabricated methyl- or benzyl-capped OEG-functionalized polythiophene through Grignard metathesis and reductive coupling polymerization. However, these polymers did not show suitable antifouling properties, thus indicating that the end-cap groups on OEG are crucial for antifouling properties. Zhu et al25 demonstrated the synthesis of zwitterionic PC-functionalized EDOT (EDOT-PC) by directly incorporating EDOT-OH with 2-chloro-2-oxo-1,3,2-dioxaphospholane.


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The phosphorylcholine group subsequently formed after the ring was opened by adding trimethylamine. Poly(EDOT-PC) was formed through electropolymerization in a reverse microemulsion solution and was highly resistant to the nonspecific binding of proteins and cells. Compared to poly(EDOT-EG3), zwitterionic poly(EDOT-PC) has much lower impedance mainly because of the contribution of ionic conductivity from zwitterionic groups.

Surface-Initiated Polymerization and Direct Grafting. To apply a surface-initiated polymerization method or direct grafting is another recognized approach for coating an antifouling layer on the conducting polymer surface.44-45 Several groups have successfully studied the antifouling conducting polymer platform by using this approach as shown in Figure 3. Pei et al.27 used SI-ATRP to graft zwitterionic polymer brushes containing sulfobetaine units on conducting polypyrroles as shown in Figure 3(a). Bromoisobutyryl bromide was the initiator for ATRP and was immobilized on polypyrroles through two steps: (1) Converting carboxylic acid groups of 4(3-pyrrolyl)

butyric

acid

into

a

reactive

hydroxyl

group

by

using

1-ethyl-3-(3-

dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysuccinimide (NHS) coupling with ethanolamine and (2) attaching bromoisobutyryl bromide through a nucleophilic substitution reaction in the presence of triethylamine and 4-(dimethylamino)pyridine. Travas-Sejdic group46 demonstrated a new grafting route by incorporating (3,4-ethylenedioxythiophene)-methyl 2bromopropanoate (BrEDOT), which comprises an initiator for ATRP. The BrEDOT can be simply electropolymerized on the electrodes to form a conducting polymer, P(BrEDOT).

Hackett et al.

grafted P(PEGMMA-co-DEGMMA) brushes directly on P(BrEDOT) through SI-ATRP as shown in Figure 3(b). Zhao et al.26 used the same method to graft both OEG-based poly((oligo(ethylene glycol)

methacrylate)

and

zwitterion-based

poly([2-(methacryloyloxy)ethyl]dimethyl-(3-

sulfopropyl)ammonium on conductive PEDOT substrates as shown in Figure 3(c). In general,


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these platforms acted as an antifouling coating for protein adsorption and cell adhesion. Because these substrates are made of conducting polymers, the surface properties of polymer brushes can be manipulated by applying different surface potentials on substrates. The application of this dynamic switching property for advanced cell engineering is elaborated in the Application section of this article.

Apart from ATRP, Wang and Hui47 presented a photopolymerization method to coat a zwitterionic poly(carboxybetaine methacrylate) (polyCBMA) layer on the surface of polyaniline (PANI) nanowires as shown in Figure 3(d). CBMA monomers were conjugated onto PANI nanowires by using EDC and NHS as coupling agents; thus, reactive double bonds on methacrylate could be used for the photopolymerization of polyCBMA. Moreover, this platform shows appropriate antifouling properties to resist the nonspecific binding of proteins. Akbulut et al.48 first grafted PEG on thiophene-3-carboxylic acid monomers through Steglich esterification followed by Suzuki condensation polymerization to obtain PEG-grafted polythiophenes as shown in Figure 3(e). Furthermore, Wang et al.49 proposed a method to functionalize PEDOT with carboxylic groups by adding sodium citrate during electropolymerization. Nickel cations (Ni2+) were used to bridge carboxylic acid groups between citrate molecules in PEDOT and anchor the antifouling peptides on PEDOT through the formation of Ni−O coordination bonds. An ultrasensitive electrochemical DNA biosensor was examined based on this platform.


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Figure 3. Applications of surface-initiated polymerization or grafting to immobilize antifouling polymers on conducting polymers. (a) Using SI-ATRP to graft zwitterionic betaine polymers on polypyrrole. Reprinted with permission from ref 27. Copyright 2012 American Chemical Society. (b) Application electropolymerization of P(BrEDOT) for grafting P(PEGMMA-co-DEGMMA) brushes through SI-ATRP. Reproduced with permission from ref 46. Copyright 2015 with permission from The Royal Society of Chemistry. (c) Application of SI-ATRP to graft poly(SBMA) and poly(OEGMA) brushes from poly(EDOT-Br-co-EDOT) electropolymerization of P(BrEDOT) for grafting of P(PEGMMA-co-DEGMMA) brushes. Reprinted with permission from ref 26. Copyright 2013 American Chemical Society. (d) Poly(carboxybetaine methacrylate), polyCBMA, was photopolymerized on a PANI nanowire. Reproduced with permission from ref 47. Copyright 2019 Elsevier. (e) A PEG-grafted polythiophene conducting polymer was synthesized through Suzuki condensation polymerization. Reprinted with permission from ref 48. Copyright 2015 American Chemical Society. (f) Immobilization of antifouling peptide on PEDOT. Reprinted with permission from ref 49. Copyright 2017 Elsevier.


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Biomedical Applications for Antifouling Conducting Polymers

In Vivo Electrochemical Biosensing with High Sensitivity. With an excellent antifouling ability and a conductive substrate, researchers have studied the potential applications of in vivo biosensing and demonstrated superior performance from their platform in terms of sensitivity and reliability. Figure 4(a) shows that Hui et al.23 grafted PEG onto PANI to form a PEGylated PANI nanofibers, and these nanofibers provided appropriate antifouling properties in human serum samples. After immobilizing capture probes on their PEGylated PANI nanofibers through NHS/EDC coupling, a sensitive DNA electrochemical biosensors was fabricated for the breast cancer susceptibility gene (BRCA1). This platform showed ultrahigh sensitivity with a broad linear range (0.01 pM to 1 nM). Furthermore, BRCA1 was able to be quantified in complex human serum. As shown in Figure 4(b), Wu et al. developed a sensitive and stable glucose electrochemical sensor based on a zwitterionic poly(sulfobetaine-3,4-ethylenedioxythiophene) (PSBEDOT) platform.50 Glucose oxidase (GOx) was directly trapped and immobilized on the substrate through the electropolymerization of PSBEDOT in an aqueous solution containing GOx. Here, zwitterionic PSBEDOT was used as a hydrated 3-D matrix for GOx encapsulation, which can improve the stability and lifetime of GOx. Moreover, the conducting polymer acted as a transducer to transmit signals produced during the glucose oxidation. Compared to an unfunctionalized PEDOT-GOx electrode, the zwitterionic PSBEDOT-GOx electrode provided considerably higher stability in human blood plasma. The remaining current signal was more over 90% after the electrode was stored in human blood plasma for 14 days. This study emphasized the necessity of antifouling surfaces for the continuous electrochemical monitoring of glucose in blood.51 In Figure 4(c), Liu et al.52 used a carbon fiber microelectrode (CFE) coated with zwitterionic phosphorylcholinefunctionalized PEDOT-PC for in vivo dopamine monitoring. Compared to CEF coated with


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PEDOT or hydroxyl-functionalized PEDOT-OH, CEF coated with PEDOT-PC could resist protein adsorption and maintain the sensitivity and time response for the in vivo monitoring of dopamine.

The use of antifouling PEG or zwitterionic groups to improve electrochemical sensing performance in a complex biological medium or to monitor in vivo electrochemical reaction was also demonstrated on other platforms.53-54 The antifouling characteristics of conducting polymers are crucial for improving the performance of in vivo electrochemical sensing in terms of sensitivity and lifetime. However, other factors may considerably affect the sensing performance, such as the electrostatic interaction with analytes55 or the active surface area of electrodes.56 To effectively integrate these essential features is crucial for developing an advanced electrode for in vivo electrochemical sensing or continuous monitoring of human blood.

Figure 4. Electrochemical biosensing applications from antifouling conducting polymer platforms. (a) PEGylated PANI nanofibers for sensitive electrochemical DNA sensing in human serum. Reprinted with permission from ref 23. Copyright 2017 American Chemical Society. (b)


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Zwitterionic PSBEDOT-GOx electrode for glucose monitoring in blood. Reproduced with permission from ref 50. Copyright 2018 with permission from The Royal Society of Chemistry. (c) CFE coated with zwitterionic phosphorylcholine-functionalized PEDOT-PC for in vivo dopamine monitoring. Reproduced with permission from ref 52. Copyright 2017 John Wiley & Sons, Inc.

Dual-functional Antibacterial Surface. Although some improvement has been made recently, the infection caused by polymeric implants and biomedical devices is still a critical concern, particularly in clinical settings, such as hospitals.57-58 In general, two types of surfaces, namely antifouling and antimicrobial surfaces, are used to prevent such infection. The antifouling surface passively prevents the adhesion of microbes using PEG or zwitterionic materials as a coating.14, 59 The antimicrobial surfaces can actively kill approaching microorganisms through the release antibacterial agents60 or the immobilization of contact-killing moieties.61 Recently, the dualfunctional or so-called smart antibacterial surfaces have attracted considerable attention.62-65 These surfaces combine killing and releasing functions as shown in Figure 5(a).66 PEDOT and its composites are favorable as antibacterial polymers because of their intrinsic positively charged features

and

the

ability

of

carrying

ions.67-68

A

nanocomposite

combined

with

poly(vinylpyrrolidone) sulfobetaines-coated iron oxide nanoparticles became a near-infrared (NIR)-irradiated photothermal agent, which can effectively kill bacterial because of the efficient absorption of NIR light from PEDOT.69 Cao et al. demonstrated a dual-function antibacterial surface from sulfobetaine-functionalized PEDOT (PSBEDOT) by applying different surface potentials on it as shown in Figure 5(b).31 PSBEDOT can be switched between the cationic antimicrobial state (PSBEDOT-Ox) and zwitterionic antifouling state (PSBEDOT-Red). Figure 5(c) shows that the reduced PSBEDOT (Red) surfaces had antifouling properties and showed


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excellent resistance to the attachment of E. coli K12. After a potential of 0.6 V vs. Ag/AgCl was applied to oxide PSBEDOT, the positively charged PSBEDOT (Ox) surfaces damage E. coli by up to 89% in 1 h as shown in Figure 5(d). The surface potential was then decreased to 0 V for the reduction of PSBEDOT. Within in 1 h, 96.7% of E. coli K12 bacteria that was killed were released from PSBEDOT (Red) as shown in Figure 5(e).

Although these results were favorable for dual-function antibacterial applications from zwitterionic conducting polymers, some studies must be performed before implementation. The long-term stability and the maintenance of antibacterial effectiveness are particular crucial for clinical useage.60, 70-71 Moreover, because the function switch requires the manipulation of surface potential, this platform may be more useful for bioelectronics devices.

Figure 5.

(a) Schematic of dual-function antibacterial surface and (b) redox switching of

PSBEDOT. Reprinted with permission from ref 66. Copyright 2017 American Chemical Society. Quantitative bacterial adhesion, antimicrobial and release studies on PSBEDOT and control surfaces. (c) Attachment of E. coli K12 on PSBEDOT (Ox), PSBEDOT (Red) and control surfaces.


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(d) Bactericidal activity of PSBEDOT and the control surface against E. coli K12. (e) Detachment of E. coli K12 from PSBEDOT (Ox) and gold after subjection to 0 V for 1 hr. Reproduced with permission from ref 31. Copyright 2018 with permission from The Royal Society of Chemistry.

Controlled Cell Capture and Release. The applications of conducting polymers have been demonstrated for the controlled release of ions72-73 and drugs,74-78 which are primarily attributed to the tunable charged state of the polymer backbones. The redox states of conducting polymers were manipulated by applying different surface potentials, and ions can move in and out of the conducting polymers to maintain their electrostatic neutrality.79

　

Recently, Lin et al.80

demonstrated the antifouling zwitterionic PEDOT-based platform for controlled cell capture and release as shown in Figure 6(a). A redox-responsive hydroquinone-functionalized EDOT (EDOTHQ) was synthesized as shown in Figure 6(b). The hydroquinone group was used for oxime ligation to immobilize aminooxy-terminated molecules onto it, which can be obtained by oxidizing hydroquinone to form benzoquinone.81 The linkage of oxime ligation is stable under physiological conditions. Oxime ligation can then be cleaved by applying a reduction potential.82 EDOT-HQ and zwitterionic EDOT-PC were first coelectropolymerized to form poly(EDOT-PC-co-EDOT-HQ) films. The controlled attachment and release of NIH3T3 cells on this copolymer film was presented. Before the conjugation of a RGD peptide on poly(EDOT-HQ-co-EDOT-PC), the polymer film showed suitable antifouling properties and resisted NIH3T3 attachment. After applying the oxidation potential on the polymer film to convert hydroquinone into benzoquinone, RGD peptide with an amino-oxy terminal can be conjugated on the polymer film, thus creating a strong binding of NIH3T3 cells on the polymer. After applying a reduction potential, NIH3T3 cells were released from poly(EDOT-HQ-co-EDOT-PC) films because of the cleavage of RGD peptide linkages. Previously researchers have demonstrated applications of the nanostructured PEDOT


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platform for the enhanced capture efficiency of circulating tumor cells (CTCs).83-85 Shen et al. combined antifouling EDOT-EG3 with phenylboronic acid-functionalized EDOT (EDOT-PBA) to develop a glycan-stimulated PEDOT-based nanomaterial platform for the purification of CTCs from blood samples.86

Figure 6(c) shows that a poly(EDOT-PBA-co-EDOT-EG3) layer was first

electropolymerized on a NanoVelcro chip.87-88

In a mechanism for capturing CTC, the antibody

probe can be immobilized through their affinity with surface-grafted PBA, which then enables capturing CTCs as shown in Figure 6(d). After introducing sorbitol with stronger affinity to PBA, CTCs were released from the chip because of competitive binding. The 3D PEDOT NanoVelcro chip provides high capture efficiency and allows the gentle release of CTC cells, which enables CTC purification for further analysis from purified CTCs.

The results of these studies indicate that the presence of antifouling moieties on surfaces and their density are crucial for the smooth release of cells without causing damage. This is primarily because of the strong binding of cells with culture substrates. Antifouling elements may not be necessary for releasing small molecules from conducting polymers.89


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Figure 6. (a) Schematic of controlled release of cells and (b) molecular design of dynamic PEDOT platform, which allows the controlled attach and release of NIH3T3 cells by manipulating the redox state of hydroquinone on polymers. Reproduced with permission from ref 80. Copyright 2018 John Wiley & Sons, Inc. (c) Schematic of fabricating PBA-grafted NanoVelcro chip and (d) the mechanism and results of controlled CTC capture and release from this platform. Reproduced with permission from ref 86. Copyright 2018 John Wiley & Sons, Inc.


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Properties of Antifouling Conducting Polymers

The Ionic Effect on Antifouling Properties. Researchers have examined the ionic effect90-92 on the antifouling property, particularly for zwitterionic surfaces,37, 93-95 for many years. The ions are generally categorized as chaotropes and kosmotropes based on their tendency to salt-in or saltout proteins, which is summarized as the Hofmeister series.96-97 Previous studies have revealed that weakly hydrated chaotropes can efficiently form ion pairs with zwitterionic groups and enhance the hydration of zwitterionic polymers, whereas strongly hydrated kosmotropes can dehydrate zwitterionic polymers, thus degrading the antifouling property.90-91 Some recent studies have focused on the ionic effect on antifouling conducting polymers. Chen and Luo.98 studied the ionic effect on two antifouling PEDOT derivatives, namely poly(EDOT-PC) and poly(EDOTEG3) as shown in Figure 7. The adsorption of negatively charged BSA and positively charged lysozyme (LYZ) was evaluated as a function of ionic concentration in the presence of three anions, namely ClO4- ions (as chaotropes), Cl- ions, and SO42- ions (as kosmotropes). In contrast to other antifouling polymers, the backbone of PEDOT is generally positively charged because the low oxidation potential. Compared with bare Au surface, poly(EDOT-PC) and poly(EDOT-EG3) can reduce most of nonspecific binding from BSA and LYZ. Because of the electrostatic interaction with positively charged PEDOT, more BSA binding was observed than LYZ binding in DI water as shown in Figure 7(a) and 7(b). For BSA, the nonspecific binding decreased with the increasing ionic concentrations. In this study, two mechanisms were proposed to explain these results. First, the electrostatic interaction between the negatively charged BSA and poly(EDOT-PC) was weakened after the binding of anions on PEDOT. Moreover, the anions could weaken the inter/intrachain associations within zwitterionic units,99-100 thus resulting in the formation of a more compact hydration layer on poly(EDOT-PC). The more compact hydration layer has superior


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resistance against BSA binding. In contrast to BSA, LYZ showed minimum binding in DI water primarily because of the electrostatic repulsion between positively charged LYZ and poly(EDOTPC). The increasing ionic strength initially promoted nonspecific binding because the adsorbed anions on poly(EDOT-PC) shielded the electrostatic repulsion between LYZ and polymers. Similar to BSA binding, when the ionic strength increased, the resistance against nonspecific LYZ binding was improved primarily because of the formation of a superior hydration layer on poly(EDOT-PC). For both BSA and LYZ, the nonspecific binding increased with the increasing concentration of SO42- ions from 100 mM to 500 mM. This observation may be attributed to high affinity to water molecules from SO42- ions, which leads to the dehydration of the PC group on polymer films and the reduction of the antifouling property.91 The mechanism can be schematically illustrated in Figure 7(c).

The ionic effect on the binding of BSA and LYZ on poly(EDOT-EG3) showed similar a trend as that on poly(EDOT-PC) as shown in Figure 7(d) and 7(e). The antifouling property of poly(EDOT-EG3) was also affected by the ion concentration and its species. In contrast to the zwitterionic PC group, uncharged ethylene glycol moiety did not form ion pairs and the electrostatic interaction among protein, ions and PEDOT backbones dominates the antifouling property of poly(EDOT-EG3). Highly concentrated SO42- ions lead to the dehydration of ethylene glycol group on polymer films and reduced the antifouling property as shown in Figure 7(f).


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Figure 7. (a) BSA adsorption and (b) LYZ adsorption on poly(EDOT-PC) based on QCM study. (c) Schematic of the anion effect on conformational behavior of poly(EDOT-PC) film. (d) BSA adsorption and (e) LYZ adsorption on poly(EDOT-EG3) based on QCM study. (f) Schematic of the anion effect on conformational behavior of poly(EDOT-EG3) film. Reproduced with permission from ref 98. Copyright 2019 American Chemical Society. Although the antifouling property is related to ionic strength, the surface immobilized with antifouling moieties generally present low nonspecific binding with proteins. For conducting polymers, the electrostatic interaction between the backbone and proteins are particularly essential. A few studies have demonstrated the ability to switch the antifouling property simply by manipulating the ionic strength of solutions,46,

101-102

which is the potential application of

antifouling surfaces. The Specific Interaction with Zwitterionic Phosphorylcholine (PC). The zwitterionic PC groups have been used to prevent the nonspecific binding of proteins and cells. In the presence of calcium ion, PC can specifically bind C-reactive protein (CRP) and trigger a series of immune


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response.103-104 Nowadays, CRP is a biomarker for inflammation, tissue damage, and cardiovascular diseases.104-107 Several studies have proposed PC-based polymers as sensing platforms for CRP detection.108-111 Goda et al. demonstrated the use of PC-functionalized PEDOT as an electrochemical biosensor platform for detection of CRP as shown in Figure 8(a).32 Poly(EDOT-co-EDOT-PC) thin film was first deposited on a glassy carbon electrode through electropolymerization. The performance of several copolymer thin films of different compositions was examined, a copolymer film with 25% EDOTPC feed ratio was selected for the detecting CRP. The detection of CRP was demonstrated through an electrochemical differential pulse voltammetry (DPV) method as shown in Figure 8(b). This electrochemical CRP biosensor was developed using poly(EDOT-co-EDOT-PC) and exhibited slight interference from BSA binding and a suitable detection limit of approximately 4.3 µg/ml (37 nM) as shown in Figure 8(c). Wu et al.112 studied the interfacial phenomenon of the specific binding between CRP and PC groups on poly(EDOT-PC) by using a quartz crystal microbalance with dissipation (QCM-D) as shown in Figure 8(d). During CRP recognition, the presence of calcium ion is necessary because each protomer has a calcium pocket in the PC binding domain.113 Therefore, authors revealed the presence of calcium ion as a switch to initiate binding of CRP binding on poly(EDOT-PC). After shifting the mobile phase to the buffer without calcium ion, CRP was released from the poly(EDOT-PC) film CRP, and the initial frequency before CRP binding was obtained, which indicates the regeneration of the poly(EDOT-PC) film as shown in Figure 8(e). Figure 8(f) shows that the dissipation decreased with the adsorption of CRP on the poly(EDOT-PC) films. This observation is different from most protein binding studies by QCM-D. The most reasonable explanation for this is the release of bound water molecules in the vicinity of the PC groups when CRP adsorbed on poly(EDOT-PC).


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Figure 8. (a) Schematic of applying poly(EDOT-co-EDOTPC) as a CRP biosensor. (b) CRP detection through DPV method at different concentrations. (c) The comparison between CRP and BSA adsorption. Reproduced with permission from ref 32. Copyright 2015 American Chemical Society. (d) Schematic of applying QCM-D to study the CRP adsorption on poly(EDOT-PC). (e) The frequency and (f) dissipation change when the binding and releasing CRP from poly(EDOTPC) by adding and removing calcium ions from the buffer solutions. Reproduced with permission from ref 112. Copyright 2018 American Chemical Society. In this study, the dissipation changed rapidly when CRP binding to and releasing from poly(EDOT-PC), thus showing dynamics of the bound water around PC groups. The structure and mobility of the bound water are crucial for the antifouling properties.114-116 The bound water near PC groups can be rapidly and simultaneously released when CRP binds to PC group. So far, it is unknown if the CRP binding to PC groups is the only case for the specific affinity with antifouling moieties. Since the specific interaction greatly reduce their antifouling properties, it is crucial to understand the nature of this interaction and identify the molecules which could bind to antifouling moieties.


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The Influence of Surface Potential. Another crucial feature is to allow electric transmission, which ensures the antifouling conducting polymers are different from other polymeric materials. On the basis of the application of a surface potential to the surface, ions and biomolecules approach or leave from the conducting polymers because of the electrostatic force as shown in Figure 9(a). The antifouling properties are then affected by the variation in ionic concentration near the surface. Few studies have focused on this fundamental phenomenon. On the other hand, the surface potential can also change the orientation of surfactant-type dopants, which leads to an alternation of surface properties as shown in Figure 9(b). When conducting polymers was positively charged, the anionic sulfate head groups move toward conducting polymers and hydrophobic tails face outward. Zhang et al.117 used an electrochemical force spectroscopy to quantify the de-adhesion force of a single cell from conducting polymers containing surfactants. By applying the electrical stimulation to the conducting polymer, they could change the orientation of surfactants to control the hydrophilic and hydrophobic surface properties. Marzocchi et al118 studied how redox states affected cell behavior by comparing the growth behavior of two cells, namely human glioblastoma multiforme cells and primary human dermal fibroblasts, on PEDOT:PSS films at different oxidation states. Chen and Luo98 demonstrated that for zwitterionic poly(EDOT-PC) surfaces, the surface potential dominates the nonspecific finding of proteins in DI water. The proteins can be adsorbed on antifouling poly(EDOT-PC) when a surface potential is applied to induce an electrostatic interaction. Figure 9(c) and (d) show that applying a positive potential induced the adsorption of negatively charged BSA and repulsion of positively charged LYZ, whereas applying a negative potential induced the adsorption of positively charged LYZ and repulsion of negatively charged BSA. The application of surface potentials in the presence of concentrated ions can


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promote the complete release of adsorbed proteins from the surfaces of antifouling conducting polymers as shown in Figure 9(e).

Figure 9. (a) Schematic of the effect of surface potential on protein adsorption and ion concentrations near the surface on antifouling PEDOT. (b) Schematic showing the interface between a cell and PEDOT trapping surfactants as dopants. (c) BSA and (d) LYZ adsorptions on poly(EDOT-PC) films under an electrochemically oxidized or reduced potential. (e) Approximately 100% LYZ desorption from poly(EDOT-PC) induced by both high ionic concentration and potential. Reproduced with permission from ref 98. Copyright 2015 American Chemical Society.


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Recent studies have been focused on developing conducting polymer-based polymeric microelectrode arrays for cellular or in vivo electrophysiological recording.119-123 To apply electrical stimuli through conducting polymers for promoting cell growth is receiving attention because of its potential for regeneration medicine.25, 124-127 Studies have demonstrated that the biomaterials with an antifouling property heals the wounds.128-129 Therefore, for these implanted biomedical applications, integrating antifouling conducting polymers into current platforms is beneficial. Therefore, the fundamental studies on the surface potential and antifouling properties are crucial and must be further explored. Conclusion and Prospective

With the increasing attention on the applying conducting polymers for various biomedical applications, antifouling conducting polymers is one of the most favorable fields of modern biomedical applications because of their distinct properties. The strategies for engineering antifouling conducting polymers have been recently explored and developed. Numerous studies appropriately demonstrated and elaborate on the application of antifouling conducting polymers in modern biomedical applications, including the implanted bioelectronics, dual-function antibacterial coating, and controlled cell capture/release platforms. However, several challenges are still encountered when converting these platforms into commercialized products. For applications, similar to various polymeric materials, the durability and stability are one of the primary challenges that must be overcome. For long-term applications, such as devices for continues monitoring, the conducting polymers must be durable and stable. For biomedical applications related to tissue regeneration, the development of biodegradable conducting polymers is still a big challenging although several examples have been demonstrated.130 Therefore, the


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combination of these two features is favorable for conducting scaffolds in tissue engineering applications. New types of antifouling conducting polymers must be studied continuously.131 The development should not be limited to the current molecular design. New antifouling conducting polymers may provide unexpected results, such as the combination of antifouling moieties with fouling release segments.132-134 In terms of fundamental studies, the synergistic effects of surface potentials on the modulation of ionic strength and bound water structure near zwitterionic groups, which leads to the alternation of antifouling properties, are still lacking in comprehensive understanding. More efforts are required to appropriately interpret the complicated relationship between these factors. Another important issue is that, although it has been observed that the prevention of non-specific adsorption is beneficial to life-time and sensitivity of bioelectronics, not many studies have been conducted to quantitatively correlate the performance penalty with the protein adsorption level as well as the protein adsorption level that is tolerable for specific applications. These fundamental studies and data will provide important guideline for the design of antifouling conducting polymers. For characterizing the antifouling surface, the techniques demonstrated for identifying the water structure near antifouling moieties on biomaterials,135-136 must be available and should be used for characterizing antifouling conducting polymers. Moreover, the application of surface analysis techniques137-140 is highly beneficial to understand the mechanism of antifouling properties. The integration of these characterization techniques for overcoming fundamental concerns provides more insight in this field.

AUTHOR INFORMATION

Corresponding Author


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*Email: [email protected]

ORCID Shyh-Chyang Luo: 0000-0003-3972-1086

Funding Sources

National Taiwan University

Ministry of Science and Technology (MOST) of Taiwan

Ministry of Education of Taiwan

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT

We gratefully acknowledge the financial support provided by National Taiwan University under grant 108L7824, the “Advanced Research Center for Green Materials Science and Technology” from The Featured Area Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (108L9006) and Ministry of Science and Technology of Taiwan under grant MOST 106-2113-M-002-017-MY2 and 107-3017-F-002-002.

ABBREVIATIONS


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RAFT, reversible addition fragmentation chain transfer; SI-ATRP, surface-initiated atom transfer radical polymerization; PDMS, poly(dimethylsiloxane); EDOT, 3,4-ethylenedioxythiophene; PPy, polypyrrole; PANI, polyaniline; PEG, poly(ethylene glycol); OEG, oligo(ethylene glycol); PC, phosphorylcholine;

EDC,

ethyl-3-(3-dimethylaminopropyl)carbodiimide;

NHS,

N-

hydroxysuccinimide; CTC, circulating tumor cell; QCM-D, quartz crystal microbalance with dissipation; CRP, C-reactive protein; BSA, bovine serum albumin; LYZ, lysozyme; FNG, fibrinogen; GOX, glucose oxidase; CRP, C-reactive protein; SEM, scanning electron microscope; AFM, atomic force microscope.

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Engineering Antifouling Conducting Polymers for Modern Biomedical

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