Fabrication of Supramolecular Bioactive Surfaces via Î²-cyclodextrin

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Spotlight on Applications

Fabrication of Supramolecular Bioactive Surfaces via #-cyclodextrin-based Host-Guest Interactions Wenjun Zhan, Ting Wei, Qian Yu, and Hong Chen ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b12130 • Publication Date (Web): 04 Oct 2018 Downloaded from http://pubs.acs.org on October 5, 2018

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ACS Applied Materials & Interfaces

Fabrication of Supramolecular Bioactive Surfaces via β-cyclodextrin-based Host-Guest Interactions Wenjun Zhan, Ting Wei, Qian Yu*, and Hong Chen

State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren'ai Road, Suzhou, 215123, P. R. China

KEYWORDS: β-cyclodextrin; host-guest interaction; supramolecular chemistry; bioactive surface; surface modification ABSTRACT: Supramolecular host-guest interactions provide a facile and versatile basis for the construction of sophisticated structures and functional assemblies through specific molecular recognition of host and guest molecules to form inclusion complexes. In recent years, these interactions have been exploited as a means of attaching bioactive molecules and polymers to solid substrates for the fabrication of bioactive surfaces. Using a common host molecule, β-cyclodextrin (β-CD), and various guest molecules as molecular building blocks, we have fabricated several types of bioactive surfaces with multifunctionality and/or function switchability via host-guest interactions. Other groups have also taken this approach and several intelligent designs have been developed. The results of these investigations indicate that compared to the more common covalent bonding-based methods for attachment of bioactive ligands, host-guest based methods are simple, more broadly (“universally”) 1

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applicable, and allow convenient renewal of bioactivity. In this Spotlight on Applications, we review and summarize recent developments in the fabrication of supramolecular bioactive surfaces via β-CDbased host-guest interactions. The main focus is on the work from our laboratory, but highlights on work from other groups are included. Applications of the materials are also emphasized. These surfaces can be categorized into three types based on: (i) self-assembled monolayers, (ii) polymer brushes, and (iii) multilayered films. The host-guest strategy can be extended from material surfaces to living cell surfaces, and work along these lines is also reviewed. Finally, a brief perspective on the developments of supramolecular bioactive surfaces in the future is presented.

2


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1


Introduction Bioactive surfaces are usually referred to as surfaces holding the ability to support or promote

specific biointeractions; such surfaces are not only of considerable research interest but are also of practical importance in diverse biomedical and biotechnology applications including disease diagnosis, implantable materials and devices, tissue engineering, antibacterial surfaces and biomolecule purification.1-3 In general, fabrication of such surfaces involves two main steps. First, the substrate is modified with a thin organic layer as a matrix to provide binding sites. The matrix layer is usually based on hydrophilic polymers or other components with anti-fouling properties, providing an appropriate microenvironment for maintenance of the activity of the ligands to be attached and to prevent non-specific interactions that may lead to unwanted biological responses.4, 5 Second, bioactive ligands such as biomolecules and functional compounds are attached to the matrix layer to endow the surface with desired bioactivity.6 Traditionally, the attachment process relies on the chemical conjugation of the bioactive ligand to the reactive groups (e.g. amine, carboxyl, azide) in the matrix layer via the formation of covalent bonds.7-9 Although generally effective, such covalent bondingbased methods do have drawbacks: (i) they are complex, often requiring multiple steps and organic solvents, with the risk of loss of bioactivity of the ligand; (ii) a given covalent bonding method may work only for ligands with a specific reactive group; and (iii) covalently bound bioactive ligands are difficult to remove from the matrix layer; this is a major limitation for some applications (e. g. biosensors) where the bioactive ligands with reduced activity are required to be removed and replaced by new ones. Therefore, it is of interest to develop improved methods to attach bioactive ligands, methods that are simple, “universally” applicable, and that allow convenient renewal of the bioactivity. In contrast to covalent bonding, supramolecular host-guest interactions provide a simple and 3



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versatile means to construct sophisticated structures and functional assemblies via specific molecular recognition between host and guest molecules to form inclusion complexes.10 Cyclodextrins (CDs) are widely investigated host molecules, which are a set of cyclic oligosaccharides composed of six, seven, or eight

D-glucopyranoside

units linked together by α-1,4-glycosidic bonds (α-, β-, and γ-CD,

respectively). Among these CDs, β-CD is the most accessible and the lowest-priced one. It features a toroidal truncated-cone topology with a hydrophilic exterior of seven primary hydroxyl groups and fourteen secondary hydroxyl groups on the narrow ring and wide ring, respectively, and an appropriately sized hydrophobic cavity for the (noncovalent) inclusion of guest molecules such as adamantine (Ada), azobenzene (Azo), and ferrocene (Fc) (Scheme 1).11 Moreover, β-CD has multiple hydroxyl groups that can be served as active sites for further functionalization. In particular, the primary hydroxyl groups on the narrow ring are more nucleophilic than the secondary hydroxyl groups on the wide ring, and more easily modified into other highly reactive groups.12 As shown in Scheme 2, post-functionalization of β-CD can be achieved using different electrophiles to activate the primary hydroxyl group. To realize mono- or per-functionalization, at first, the primary hydroxyl group is usually replaced by either tosyl group or halogen group (Br, I), respectively. The tosyl group or halogen group can be converted into several kinds of active groups (e. g. thiol, amine, azide) using suitable nucleophiles for further conjugation of bioactive ligands via conventional chemical reactions with high efficiency (e. g. thiol-ene reaction for thiol, amine-epoxy reaction for amine, and copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) for azide).

4


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Scheme 1. Left: chemical structural formula of β-cyclodextrin (β-CD) and guest molecules: adamantine (Ada), azobenzene (Azo), and ferrocene (Fc). Right: schematic illustration of reversible host-guest interactions between β-CD and guests.

Scheme 2. Representative synthetic routes for post-functionalization of β-CD.

5



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β-CD-based host-guest interactions in solution are well known and have been used extensively to construct complex systems like vesicles and micelles for various biological applications (e.g. drug delivery, gene delivery, bioimaging) due to the low toxicity and immunogenicity of β-CD.13, 14 Recently, this approach has been exploited to incorporate bioactive molecules or polymers into solid substrates for the fabrication of bioactive surfaces. It has a number of advantages including: (i) the host-guest recognition interactions take place in aqueous solution at room temperature, thus providing an environmentally friendly method that does not compromise the bioactivity of the ligand; (ii) it is a simple matter to synthesize various functional host/guest moieties by pre-incorporation of bioactive ligands,12, 15 and thus the final surface bioactivity can thus be designed in a modular fashion and can be easily tailored; (iii) the host-guest interaction is usually reversible so that the inclusion complex can be dissociated using appropriate external stimuli (Scheme 1);16-18 this is especially useful in applications where reversible bioactivity and surface renewal are needed. Overall, the β-CD-based host-guest method addresses comprehensively the limitations of the covalent bonding method, showing great promise for fabrication of robust bioactive surfaces in a facile and versatile way. In this Spotlight on Applications, we summarize recent developments on the fabrication of supramolecular bioactive surfaces on flat substrates (works on the functionalization on the surfaces of nanoparticles are excluded) via β-CD-based host-guest interactions. Here, functionalization on flat substrates and the functionalization on the surfaces of nanoparticles is excluded. The main focus is on the work from our laboratory, but highlights on work from other groups are included. We divide these surfaces into three categories based on the type of matrix layer: (i) self-assembled monolayers, (ii) polymer brushes, and (iii) multilayered films. Each category can be further divided into two subcategories according to the identity of the host and guest molecules in the matrix layer (Scheme 3). 6


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Some researchers have attempted to adapt this method for the modification of living cell surfaces aiming at regulating cellular behavior; representative work on this approach is also discussed. Finally, some perspectives on the developments of supramolecular bioactive surfaces in the future are presented.

Scheme 3. Three categories of supramolecular bioactive surfaces based on different matrix layers. The “red ball” refers to “guest” molecule, and “blue cone” refers to β-CD.

2

Supramolecular bioactive surfaces based on self-assembled monolayers The term self-assembled monolayer (SAM) refers to a highly ordered assembly of molecular

constituents that forms spontaneously on the surface of a solid material.19 Since the method is simple, SAMs have been widely used for surface modification.20 Using SAMs as matrix layers, various bioactive surfaces have been fabricated via host-guest interactions. These surfaces can be grouped into two types: (i) self-assembly of pre-synthesized functional molecules containing one head group with high affinity for the substrate (e.g. thiol for gold surface, silane for oxide surface) and one end group with either a guest moiety or β-CD, (ii) post-modification of the end groups of the SAM to introduce 7



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either the guest moiety or β-CD. These end groups are used as anchors for further incorporation of bioactive molecules, functional guests or β-CD (Table 1).

Table 1. Summary of supramolecular bioactive surfaces based on SAMs a Strategy

Functional molecule

Biofunctional/Bioactivity

Reversibility

Reference

CD-Mannose1, CD-Mannose7

Sensing proteins and macrophages

/

21

/

22

/

23, 24

Sensing bacteria

Ada exchange

25

Biofouling

Photo-responsive

26

CD-SB7, CDn-HP

Reducing adsorption of proteins and adhesion of Escherichia coli Model to analyze multivalent interactions

CDn-HA

between HA and CD44

Guest-SAM + β-CD-

CD-Mannose7, CD-Fucose7

functional molecule

CD-PEG, CD-PMMA, CDP(MMA-co-HFBMA)

CD-QAS7

Kill and release bacteria

Cb-cRGD

Promote cell adhesion

/

29

Ada-Protein

Protein immobilization/patterning

β-CD exchange

30

Ada-TPS, Ada-PEG

In situ endothelialization

/

31

Promote cell differentiation

/

32


/

33

Anticoagulant, anti-biofouling, antibacterial

/

34

Ada-PNIPAM, Ada-PMT

Kill and release bacteria

/

35

Ada-β-galactoside

Hydrolysis of lactose in milk serum

/

36

Azo-DNA aptamer

Capture and release of cancer cells

Photo-responsive

37

Azo-Mannose

Protein/cell immobilization/patterning

Photo-responsive

38

Azo-PSA, Azo-PMT

Anticoagulant, antibacterial

Photo-responsive

39

Fc-Protein


Redox-responsive

40

(VHH) Ada-Biotin/Sav Ada-PSA, Ada-PEG, AdaPMT

Ada exchange Photo-responsive, Ada exchange

functional molecule

a Abbreviations:

27

Capture and release of bacteria

Ada-NTA/His-antibodies

β-CD-SAM + guest-

Photo-responsive,

CD-Mannose7

28

CD-X7: hepta-bioactive ligand substituted β-CD; CD-X1: mono-bioactive ligand substituted β-CD;

CD-SB7: heptakis[6-deoxy-6-(N-3-sulfopropyl-N,N-dimethylammonium ethyl sulfonyl)]-β-CD; CDn-HP (n > 1 ): 8


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hydrophilic β-CD polymer; CDn-HA (n > 1): multiple β-CD grafted hyaluronic acid; CD-polymer: single β-CD grafted polymer; PEG: polyethylene glycol; PMMA: poly(methyl methacrylate); P(MMA-co-HFBMA): poly(methyl methacrylate-co-hexafluorobutyl methacrylate); QAS: quaternary ammonium salt; guest-X: guest labeled bioactive ligand; Cb: carborane; cRGD: cyclic peptide containing RGD sequence; TPS: TPSLEQRTVYAK peptide; SAv: Streptavidin; NTA/His: N-nitrilotriacetic acid/histidine; PSA: poly(styrenesulfonate-co-sodium acrylate); PMT: poly(methyl chloride-quaternized 2-(dimethylamino)ethyl methacrylate; PNIPAAm: poly(N-isopropylacrylamide).

2.1

Combination of guest-based SAMs and functional β-CD derivatives As mentioned above, one β-CD molecule contains seven highly reactive primary hydroxyl groups

at the narrow ring end; these can be activated using different chemistries to conjugate bioactive ligands;14 the attachment of bioactive ligands to the narrow ring does not affect the formation of the host-guest inclusion complex. It was reported that in solution, compared to β-CD with one ligand, βCD with multiple ligands exhibited enhanced binding affinity and selectivity for the same reactant, similar to the multivalent effect observed in carbohydrate-protein interactions in biological systems.41 This finding indicates that β-CD is an appropriate “multivalent” vehicle for incorporation of ligands with high local density. Therefore, it was of interest to explore whether this β-CD-based ligand exhibits a similar multivalent effect when attached to a surface. To this end, a simple model was established in which mannose-modified β-CDs of different “valence” (Figure 1) were attached to surfaces coated with Ada-SAM to compare their ability to recognize lectins. Mannose is a type of sugar that can recognize and bind lectin proteins (e. g. concanavalin A (ConA), C-type lectin receptors expressed on the surface of human THP-1 monocytic cells) with highly specific affinity via carbohydrate-protein interactions.42 It was found that surfaces incorporating hepta-mannose substituted β-CD (CD9



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Mannose7) showed a factor-of-two increase in binding affinity to ConA compared to those incorporating mono-mannose substituted β-CD (CD-Mannose1). Moreover, THP-1-differentiated macrophages on a CD-Mannose7 coated surface were highly spread, while on a CD-Mannose1 surface the cells were spherical and the cell density was lower (Figure 1).21 These results indicate that surfaces modified with a high local density of ligands do have a “multivalent effect” similar to that in solution, thus enhancing the recognition of the corresponding reactants on the surface.

Figure 1. Left: schematic describing hepta-mannose substituted-β-CD (CD-Mannose7) and monomannose substituted-β-CD (CD-Mannose1). Right: quantitative analysis of macrophage adhesion on Ada-SAM incorporated with CD-Mannose7 or CD-Mannose1 after 24-h incubation. Reproduced with permission from ref. 21. Copyright 2015, The Royal Society of Chemistry.

Compared with covalent bonding, a unique advantage of host-guest interactions is their ready reversibility.16-18 A simple way to “reverse” the interactions is through molecular exchange, in which 10


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guest molecules with a higher binding constant (Ka) displace those with a lower Ka from the host-guest complex. For example, Ada has higher binding affinity for β-CD (5.7 × 104 M-1)43 than Fc (9.9 × 103 M-1)44; thus it can displace β-CD/Fc from the inclusion complex via molecular exchange. Based on this mechanism, a bioactive surface for bacterial capture and release was designed based on the modification of CD-Mannose7 and hepta-fucose substituted β-CD (CD-Fucose7) to Fc-SAM.25 Due to the specific recognition of lectins on bacterial surfaces by oligosaccharide residues, this surface has the ability to capture the specific bacterial strains E. coli ORN 178 (mannose) and P. aeruginosa (fucose) selectively and with high sensitivity. In addition, the surfaces can be regenerated rapidly (5 min) via Ada exchange, then incubated with fresh hepta sugar-modified β-CD solution. The ability to capture the bacteria was retained well and the reproducibility of the “degeneration-regeneration” process was high as no significant change in performance was observed over five capture-release cycles, thus making these materials favorable as reusable bacterial sensors. It is noted that molecular exchange-based strategies usually involve high concentrations of exogenous guest molecules, which may have negative effects on the biological system. Alternatively, light is a “clean” relatively noninvasive stimulus with no chemical exposure, thus potentially providing a suitable stimulus for remote control of surface properties in biological systems.45 β-CD and Azo constitute a well-known light responsive host-guest pair. The cis-trans isomerization of Azo may be provoked upon exposure to ultraviolet light (UV) and visible light. Trans-Azo can form a stable complex with β-CD but cis-Azo cannot due to size mismatch.46 Using this pair as a basis, we developed a series of supramolecular photo-responsive bioactive surfaces. For example, using a combination of orthogonal host-guest interactions and mannose-lectin FimH interactions, a photo-responsive platform for bacterial capture and release was designed by the incorporation of CD-Mannose7 into a mixed11



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SAM of Azo-containing thiols and oligo(ethylene glycol) (OEG)-containing thiols (Figure 2a).27 When the Azo was in the trans-form, CD-Mannose7 could be attached to the mixed-SAM. Due to the high density of localized mannose moieties on the surface, this platform could capture of mannosespecific type 1-fimbriated bacteria with high specificity. Upon irradiation with UV light, the β-CD/Azo complex was dissociated and about 80% of the adherent bacteria was released. To increase the fractional release, a combination of UV light and Ada at low concentration (20 μM) was used as stimulus. The surface could be renewed upon visible light irradiation and treatment with fresh CDMannose7 solution. The capture and release process was repeatable over multiple cycles. More importantly, with high spatial resolution of the light, this method allowed for localized release of captured bacteria. These results indicate that such photo-responsive supramolecular platform based on β-CD/Azo may be used to modulate biointerfacial interactions in a remote manner. Bio-detection in complex devices like microchannels may be a possible application of this approach. Compared to smart bioactive surfaces with the ability to “turn on/turn off” a single function (such as attracting/repelling bacteria or mammalian cells), surfaces that can on demand switch between two different functions are considered as advanced “smart surfaces”.47-51 For example, smart antibacterial surfaces that can both kill bacteria and release dead bacteria are of particular interest for various applications. These surfaces may solve problems such as the degraded biocidal activity for long-term applications or the undesirable immune responses caused by remaining dead bacteria.52-56 To this end, we developed a photo-responsive smart antibacterial surface by incorporation of a multivalent biocide, β-CD conjugated with seven quaternary ammonium groups (CD-QAS7) on the mixed-SAM as mentioned above.28 QAS is a positively charged biocide that disrupts the negatively charged bacterial membrane;57 the high localized density of QAS on CD-QAS7 endowed the surface with high 12


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bactericidal efficacy (> 90%) to kill attached bacteria. Using UV light as the stimulus, the surface function could be switched from killing bacteria to releasing killed bacteria. Moreover, it is simple to regenerate the surfaces via irradiation of visible light followed by incorporation of fresh CD-QAS7 (Figure 2b). In principle, besides above-mentioned CD-QAS7 and CD-Mannose7, this supramolecular system can be extended by using other functional β-CD conjugated with specific ligands for the reversible switching of different biological functions.

Figure 2. (a) Schematic of a photo-responsive supramolecular surface for the capture and release of bacteria. Adapted with permission from ref. 27. Copyright 2017, American Chemical Society. (b) Schematic of a photo-responsive supramolecular antibacterial surface with switchable bacteria killing and releasing ability. Adapted with permission from ref. 28. Copyright 2017, American Chemical Society. 13



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Compared with small molecules, biofunctional polymers contain greater numbers of bioactive units per molecule and are of relatively low-cost. Therefore, biofunctional polymers labeled with βCD were employed to incorporate guest-SAM complexes for the fabrication of bioactive surfaces. This could also be seen as a “grafting to” strategy to modify surfaces with three-dimensional (3D) polymer brushes. Polymer chains are usually covalently tethered to surfaces; the polymer-surface interactions are then irreversible and the activity is nonrenewable. However, the noncovalent nature of host-guest interactions avoids these problems. In addition, the chemical properties of the grafted polymers are much easier to control compared to the “grafting from” method since they can be pre-synthesized using various living polymerization techniques.58 According to the number of β-CDs per polymer chain, the resulting surfaces can be divided into two types as shown in Figure 3. With only one β-CD per polymer chain, the method may be referred to as “single point grafting to”. For example, a series of polymers modified with one β-CD were assembled on Azo-SAM (Figure 3a).26 The wettability of the surfaces could be varied from hydrophilic β-CD-grafted poly(ethylene glycol) (CD-PEG) to hydrophobic βCD-grafted poly(methyl methacrylate-co-hexafluorobutyl methacrylate) (CD-P(MMA-co-HFBMA)). Based on the photo-responsive properties of the β-CD/Azo pair, the wettability of the PEGfunctionalized surfaces could be photo-controlled via alternating UV/vis irradiation. This approach could also be used to control protein adsorption. To increase the binding affinity between guest-SAM and polymer, multiple β-CD molecules were introduced into each polymer chain; this functional polymer could be grafted on a guest-SAM surface via “multiple point interactions”. For example, a well-defined model system with high specificity was designed by attaching hyaluronan bearing multiple β-CDs to Ada-SAM or Fc-SAM (Figure 3b).23, 24 These materials were used to investigate 14


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the multivalent interactions between polymers and surfaces. Using a combination of experiments and simulations, it is found that multivalent polymers in this system can show pronounced “superselective” bonding behavior. Moreover, such superselective bonding can be further modulated via rational design to give a desired receptor density to the probe. More importantly, using this model, the superselectivity of natural interactions between hyaluronan and CD44 (the main receptor of hyaluronan cell surface) is well described. This work thus contributed to a better and deeply understanding of superselectivity in biological systems.

Figure 3. Schematic illustration of two types of guest-SAM/β-CD-polymer surface. (a) One β-CD per polymer chain; functional polymers are grafted to a guest-SAM surface via “single point interactions”. Adapted with permission from ref. 26. Copyright 2014, American Chemical Society. (b) Multiple βCDs per polymer chain; functional polymers are attached to a guest-SAM surface via “multiple point interactions”. Adapted with permission from ref. 24. Copyright 2014, National Academy of Sciences.

2.2

Combination of β-CD-based SAMs and functional guest derivatives The most common substrates for β-CD-SAMs are gold and silicon dioxide. Gold is very useful

in biological studies due to its good biocompatibility and its suitability for various analytical techniques such as surface plasmon resonance (SPR), quartz crystal microbalance (QCM), and 15



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ellipsometry. Therefore, well-ordered β-CD-SAMs on gold have strong potential for biological applications. The general strategy is to introduce single or multiple thiol or sulfide groups into the βCD taking advantage of the high strength of Au-S interactions and the ease of preparation. Silicon dioxide is cheaper and better adapted for micropatterning compared to gold. For β-CD-SAMs on silicon dioxide, the common strategy is to introduce epoxy or cyano groups via silane-silicon dioxide interactions for further reaction with β-CD containing amino groups. As the β-CDs are well-packed on the ends of highly ordered SAM chains, the β-CD cavity can be used for inclusion of guest-labeled biofunctional molecules to construct surfaces with specific bioactivity. A typical application of β-CD-SAMs is to provide a matrix for protein/cell attachment; such matrices play an increasingly important role in biomedical engineering and biotechnology.59 A simple method is to incorporate a guest-labeled protein directly into the β-CD-SAM via host-guest interactions. For example, fluorescent fusion proteins were site-selectively labeled with bisadamantane by SNAP-tag technology, using the reaction between O6-benzylguanine-bisadamantane conjugate and the enzymatic alkylguanine transferase-fusion protein; the guest-modified protein was thus firmly attached to the Au-β-CD-SAM via host-guest interactions with a binding affinity on the order of 10 6 M-1 as determined by SPR. This is a very convenient method that can be carried out in phosphate buffered saline (PBS) solution. More importantly, it offers a distinct advantage over random protein labeling since the conjugation of the guest molecule to the protein is site-selective, thereby favoring molecular control and uniformity. Using patterned Si-β-CD-SAM surfaces prepared by UV lithography, uniformly patterned surfaces of bisadamantine (Ada2)-functionalized fusion proteins were constructed. The patterning was destroyed upon incubation with a solution of β-CD (10 mM), indicating that attachment of the protein was reversible.30 This work provides an attractive strategy for site-selective 16


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and reversible micropatterned protein attachment without the disadvantages of random orientation and irreversibility suffered by traditional methods. Direct labeling of biomacromolecules with guest molecules is generally difficult. An alternative approach combining orthogonal host-guest interactions with ligand-receptor interactions has been adopted for the surface attachment of proteins and cells. For example, the guest molecule carborane (Cb), was conjugated to a cyclic peptide containing the Arginine-Glycine-Aspartic acid sequence (cRGD) to obtain a carborane-peptide derivative (Cb-cRGD) (Figure 4a).29 Cb-cRGD was incorporated into β-CD-SAM and the binding affinity was quantified by QCM giving a dissociation constant (Kd) value of 178 ± 39 μM, thus comparing favorably to other bioactive host-guest assemblies on β-CD-SAM surfaces. More importantly, the high content of boron on the surfaces can be exploited for quantification of conjugation yields using spectral methods such as atomic emission spectrometry with inductively coupled plasma (ICP-AES). Based on the specific recognition properties of RGD for various integrin receptors such as αvβ3, C2C12, mouse myoblast cells seeded on the surface with cRGD ligands showed stronger cell adhesion strength and a more elongated morphology compared with those seeded on control surfaces without bioactive ligands. In another example, the N-nitrilotriacetic acid (NTA)-histidine (His) interaction (typical of ligand-receptor interactions) was combined with the βCD-Ada host-guest interaction to generate layers of human bone morphogenetic protein-6 (hBMP6) growth factor via either a one-pot or a stepwise procedure (Figure 4b).32 An Ada-NTA conjugate was used as linker in this work since the Ada group can bind to the β-CD-SAM and the NTA moiety can interact with the hexahistidine (His6)-tagged single-domain antibody VHH fragment (His6-VHH) upon co-complexation of Ni2+ ions. Also, Ada labeled hexa(ethylene glycol) (Ada-HEG) were coimmobilized on β-CD-SAM to reduce nonspecific adsorption. SPR data showed that the trivalent 17



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complex (VHH·(Ni(II)·NTA-Ada)3) is the main species (70%) contributing to coverage over the whole range of concentration up to surface saturation. Therefore this trivalent complex can enhance the binding

affinity

of

VHH

via

multivalent

interactions

between

NTA

and

His6.

Ethylenediaminetetraacetic acid (EDTA) has a higher binding affinity to Ni2+ than NTA and thus can dissociate the NTA/Ni2+/His complex; a high concentration of β-CD can also dissociate the surfacebound β-CD/Ada complex via molecular exchange. Therefore, the surface bound VHH can be released using a mixed solution of EDTA and β-CD, indicating that these highly stable, surface-attached assemblies are still reversible to appropriate agents. In addition, attachment of hBMP6 via antibodyantigen interactions induced early osteogenic differentiation of KS483-4C3 mouse progenitor cells. In other work the biotin-streptavidin (SAv) interaction was combined with host-guest interaction for enzyme immobilization in microchannels.33 A step-wise strategy was used in this work (Figure 4c). First, Ada-HEG (for protein resistance) and Ada labeled biotin (Ada-Biotin) were attached to the βCD-SAM microchannel surfaces. Second, SAv was assembled via biotin-streptavidin interactions. Third, biotinylated alkaline phosphatase (AlkPh) was immobilized on the SAv surface. Since the enzyme was site-specifically attached, its activity was retained. The progress of the catalytic conversion of the corresponding substrate by AlkPh assemblies in the microchannels was recorded in real time. The specificity constant Kcat /KM was on the order of 105 M-1·s-1, comparable to reported literature values in other environments in much smaller reaction volumes. In addition, these surfaces were shown to be “reversible” and re-usable; this approach may therefore offer a valid strategy for developing re-usable microfluidic devices with enzyme activity.

18


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Figure 4. Illustration methods for: (a) attachment of guest-labeled cell recognition peptide (Cb-cRGD) onto β-CD-SAM. Reproduced with permission from ref. 29. Copyright 2015, The Royal Society of Chemistry; (b) incorporation of growth factor (hBMP6) onto β-CD-SAM using a combination of orthogonal host-guest interaction and N-nitrilotriacetic acid (NTA)-histidine (His) interaction. Adapted 19



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with permission from ref. 32. Copyright 2014, American Chemical Society; (c) immobilization of calfintestine alkaline phosphatase (AlkPh) onto β-CD-SAM using a combination of host-guest interaction and biotin-streptavidin (SAv) interaction. Adapted with permission from ref. 33. Copyright 2012, John Wiley and Sons.

Co-immobilization of two or more biofunctional molecules with diverse functions on surfaces is an attractive means for preparation of multi-functional surfaces, for example blood-contacting surfaces.60 In work along these lines, polyethylene glycol (PEG) and TPSLEQRTVYAK (TPS) peptide labeled with Ada were attached simultaneously to PCL-β-CD (similar to β-CD-SAM) in a mild aqueous medium.31 The resulting surface showed good antifouling ability (PEG component), thereby reducing the possibility of thrombus formation. Enhanced attachment of endothelial progenitor cells was also observed due to the attached TPS peptide. Importantly, the two functions was not compromised by each other, indicating that this dual-functionalization approach may be useful in vascular graft development. From a general standpoint this work demonstrates that two functional molecules labeled with guest elements can be immobilized simultaneously on β-CD-SAM for the fabrication of dual-functional bioactive surfaces. With guest molecules Ada or Cb as described above, reversibility was realized through molecular exchange of the guest-labeled bioligand by treatment with β-CD at high concentration. However, release is slow due to the relatively strong binding between Ada/Cb and β-CD. This problem can be solved by employing stimuli-responsive β-CD/guest pairs such as a light-responsive β-CD/Azo pair or a redox-responsive β-CD/Fc pair. For example, an Azo-decorated aptamer was incorporated into βCD-SAM to form a smart surface for efficient capture and release of MCF-7 cancer cells.37 The 20


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aptamer forms unique 3D structures that could bind to target molecules and cells with high specificity. The resulting surfaces showed excellent selectivity for MCF-7 cells in a mixed cell suspension with non-specific HeLa cells and target MCF-7 cells. Upon UV irradiation, the Azo groups switched from trans-form to cis-form, leading to > 90% release of captured MCF-7 cells in a short time (80 s). In similar work, an Azo-Mannose conjugate was immobilized on β-CD-SAM to interact with its specific lectin proteins and bacteria.38 In this case, it was also demonstrated that the Azo-labeled bioactive ligands could be released by light stimulus and thus regulate the interactions between surface and ConA proteins or E. coli bacteria. Such light-responsive systems offer a novel strategy to prepare surfaces having switchable bioactivity, with potential application in the isolation and analysis of specific biomolecules. Similarly, the redox behavior of Fc has been exploited to construct redoxresponsive bioactive surfaces. This approach depends on the reversible Fc-to-Fc+ (Fc+: ferrocenium, oxidized form of Fc) transition. The reduced form (Fc) can form stable inclusion complexes with βCD.18 However, upon oxidation of Fc to Fc+ complexation is strongly inhibited. For example, yellow fluorescent protein site-selectively labeled with Fc (Fc-YFP) was incorporated along with β-CD-SAM into a molecular printboard surface.40 As the operation was carried under mild aqueous buffer conditions, the 3D structure and orientation of the protein were well conserved. To address the relative instability of the monovalent supramolecular β-CD/Fc complex, protein dimerization involving via disulfide linkage was employed. In addition, based on the noninvasive and quantitative nature of redox reactions, proteins could be detached using a specific electrochemical stimulus. This work demonstrates a biomimetic system that is able to control molecular orientation, valency, affinity, reversibility, and responsiveness, i.e. which is favorable for the fabrication of adaptive biomimetic interfaces. 21



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Besides guest-labeled molecules, guest-labeled functional polymers can also be incorporated into β-CD-SAMs for fabrication of bioactive surfaces. Compared with biomolecules and small molecule ligands, the synthetic methods for functional polymers are broader in scope and cheaper to implement. In addition, a broad range of functional polymers is available via well-controlled living polymerization methods.58 Zhao and co-workers fabricated a series of bioactive surfaces by incorporation of single guest-modified polymers into β-CD-SAMs via host-guest interactions (Figure 5).34, 35, 39 For example, three types of Ada-terminated polymers, i.e. Ada-poly(styrenesulfonate-co-sodium acrylate) (AdaPSA), Ada-methoxypoly(ethylene glycol) (Ada-PEG), and Ada-poly(methyl chloride-quaternized 2(dimethylamino)ethyl methacrylate) (Ada-PMT), were prepared by atom transfer radical polymerization using an Ada-containing initiator, and then separately assembled onto β-CD modified poly(ether sulfone) (PES-β-CD) (similar to β-CD-SAM) to endow the membranes with anticoagulant, antifouling, and antibacterial properties, respectively (Figure 5a).34 This work offers a versatile and environmentally friendly strategy for surface functionalization of PES membranes via surface anchored β-CD and Ada groups in functional polymers. It is also of promise in general for the preparation of biofunctional polymeric membranes for both industrial and clinical applications. Moreover, two or more complementary guest-labeled polymers can be immobilized simultaneously on β-CD-SAMs for the preparation of multifunctional surfaces. For example, a dual functional antibacterial surface with thermoreponsive bacterial killing and release properties was constructed using thermoresponsive Ada-poly(N-isopropylacrylamide) (Ada-PNIPAAm) and bactericidal Adapoly[2-(methacryloyloxy)-ethyl]trimethylammonium chloride (Ada-PMT) by simply immersing the surface in a mixed solution of Ada-PNIPAAm and Ada-PMT (Figure 5b).35 PNIPAAm is a wellknown temperature responsive polymer that undergoes reversible swelling/shrinking over a narrow 22


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temperature range, referred to as the lower critical solution temperature (LCST), occurring at about 32°C in aqueous solution. In this way, a switchable function between bacteria-killing and bacteriareleasing was achieved based on the expanded-to-collapsed phase transition of surface grafted PNIPAAm chains around the LCST. Above the LCST, PNIPAAm chains collapsed to expose PMT chains, which then killed the attached bacteria with high efficiency (∼90%). Below the LCST, the PNIPAM chains became swollen, leading to the efficient detachment of the killed bacteria (∼85%). In other work, it was demonstrated that light-triggered switching of biofunctionality could be achieved using photo-responsive β-CD/Azo as a building block.39 Different functional polymers labeled with Azo could be attached to β-CD-SAM, and the function could be switched on demand from antibacterial/hemostatic to bioadhesion/anticoagulant upon UV-vis stimulated cycling between AzoPMT and Azo-PSA on β-CD-SAM (Figure 5c).

Figure 5. Schematic depiction of (a) procedures for the preparation and post-modification of PES-CD membrane with three different types of adamantine-polymers (Ada-polymers). Adapted with permission from ref. 34. Copyright 2015, American Chemical Society; (b) co-immobilization of two different polymers labelled with Ada (Ada-PNIPAAm and Ada-PMT) on β-CD-SAMs. Adapted with permission from ref. 35. Copyright 2016, American Chemical Society; (c) light-triggered alternate and 23



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reversible assembly of different polymers labelled with Azo (Azo-polymers) on β-CD-SAMs. Adapted with permission from ref. 39. Copyright 2014, American Chemical Society.

3

Supramolecular bioactive surfaces based on Polymer brushes Although combining SAMs with CD-based host-guest interactions has proved to be a successful

strategy, the limitations of the method should be noted. First, the two-dimensional (2D) structure of SAMs imposes a limit on the density of binding sites for attachment of biofunctional agents. In addition, substrates which can be modified with SAMs are limited to metals and oxides.19 To address these limitations, researchers have combined β-CD-based host-guest interactions with other surface modification techniques. One example is modification with grafted polymer brushes. The 3D structure of polymer brushes allows a higher density of binding sites compared to 2D SAMs, and they can be applied to a wider range of substrates including polymer materials. In addition, different biofunctions can be obtained by varying the monomer type.61 The combination of polymer brushes with β-CDbased host-guest interactions has thus emerged as a useful approach for construction of bioactive surfaces. According to the particular guest and β-CD on the polymer brushes, this strategy can be divided into two categories: i) guest on polymer brush with β-CD labeled biofunctional molecule; ii) β-CD on polymer brush with guest labeled biofunctional molecule (Table 2).

Table 2. Summary of Supramolecular Bioactive Surfaces Based on Polymer Brushes a Strategy

Polymer brush layer

Functional molecule

Biofunction/Bioactivity

Reversibility

Reference

Guest on

P(HEMA-co-Ada)

CD-Lysine1, CD-Lysine7

Protein immobilization

/

62

Protein immobilization

SDS wash

63, 64

polymer brushes

P(NIPAAm-co-Ada)

CD-Mannose7, CDBiotin7 24


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P(HEMA-co-Lysineco-Ada) P(HEMA-co-Ada)

P(HEMA-co-Ada)

Fibrinolytic activity, anticoagulant

CD-(SO3Na)7

and promote endothelialization

CD-Lysine7, REDV

Fibrinolytic activity, promote

peptide

endothelialization

CD-Lysine7, ARMAPE

Fibrinolytic activity (in situ plasmin

peptide

generation and clot lysis)

/

65

/

66

/

67

β-CD exchange

68

Adaβ-CD on

POEGMA-β-CD

Molecular recognition

biotin

polymer brushes

Biotin/Sav/fluorescent

(PHEMA-bP(HEMA-co-GMA))-

Azo-REDV peptide

Control cell adhesion and migration

β-CD aAbbreviations:

Photo responsive, Ada exchange

69

P(HEMA-co-Ada): poly(2-hydroxyethyl methacrylate-co-1-adamantan-1-ylmethyl methacrylate);

P(NIPAAm-co-Ada): poly(N-isopropylacrylamide-co-1-adamantan-1-ylmethyl acrylate); P(HEMA-co-Lysine-coAda):

poly(2-hydroxyethyl

methacrylate-co-6-amino-2-(2-methacylamido)-hexanoic

acid-co-1-adamantan-1-

ylmethyl methacrylate); POEGMA-β-CD: β-CD grafted poly(oligo(ethylene glycol) methacrylate); (PHEMA-bP(HEMA-co-GMA))-β-CD:

β-CD

grafted

poly(2-hydroxyethyl

methacrylate)-block-poly(2-hydroxyethyl

methacrylate-co-glycidyl methacrylate); REDV peptide: a hexapeptide containing Arg-Glu-Asp-Val sequence; ARMAPE peptide: a hexapeptide containing Ala-Arg-Met-Ala-Pro-Glu sequence; SDS: sodium dodecyl sulfate.

3.1

Combination of guest-containing polymer brushes with functional β-CD derivatives The general strategy includes two steps: i) introduction of guest molecules on polymer brushes

via surface-initiated polymerization of guest monomers with other monomers or via post-modification of polymer brushes with guest molecules; ii) incorporation of functional β-CD derivatives by hostguest interactions. Enhanced recognition of the “receptor” can be achieved using hepta ligandmodified β-CDs having a high local density of ligands.

25



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The combination of polymer brushes with host-guest interactions provides a suitable platform for fundamental research, e. g. studies on the effect of ligand density on the affinity of “receptor” binding. For example, we prepared a bioinert copolymer brush containing guest Ada groups, poly(2hydroxyethyl methacrylate-co-1-adamantan-1-ylmethyl methacrylate) (P(HEMA-co-Ada)) on silicon surface, and further incorporated different densities of plasminogen (Plg) affinity ligands, i.e. lysine modified β-CD derivatives (CD-Lysine1, CD-Lysine7).62 The localized lysine density was varied by changing the lysine valency on β-CD, and the average lysine density was controlled by diluting β-CDLysine7 with unmodified β-CD (Figure 6a). The biorecognition of lysine residues in fibrin by plasminogen is an important step in fibrinolysis process. Plg binds to lysine-containing artificial surfaces as well as to fibrin surface. Plg adsorption on different surfaces, measured using the 125Ilabeled protein, showed that both the adsorbed quantity and the binding affinity were increased by CDLysine7 but less so by CD-Lysine1, presumably due to the higher localized density of lysine and the tighter multivalent binding of Plg by CD-Lysine7. In addition, the average lysine density can be tuned in a linear manner by varying the ratio of CD-Lysine7 to β-CD (Figure 6b and Figure 6c). This work indicates that ligand density (localized and average) can be simply controlled via the combination of polymer brushes and β-CD-based host-guest interactions for the regulation of binding to specific “receptors”.

26


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Figure 6. (a) Schematic illustration showing the modulation of the surface lysine density (local or average). (b) Binding affinity constants (Ka and Kd) and (c) adsorption of Plg on three surfaces with different lysine density. Adopted with permission from ref. 58. Copyright 2015, American Chemical Society.

It is of great interest to create surfaces with multi-biofunctionality to improve their biointeractions.60, 70 Supramolecular bioactive surfaces based on polymer brushes are highly promising in this regard. Specific biofunctions can be introduced via either co-polymerization of biofunctional monomers or incorporation of β-CDs with bioactive guest molecules into the polymer brushes. For example, we grafted thermo-responsive PNIPAAm brushes with the Ada groups, poly(Nisopropylacrylamide-co-1-adamantan-1-ylmethyl acrylate) (P(NIPAAm-co-Ada)), on silicon substrate for further incorporation of β-CD derivatives containing seven mannose (CD-Mannose7) or biotin residues (CD-Biotin7) via host-guest interactions (Figure 7).63, 27


64

At 37°C, the PNIPAAm chains


Page 28 of 65

collapsed to expose CD-Mannose7 or CD-Biotin7, leading to specific recognition of ConA or avidin, respectively. As the temperature decreased to 4°C, the PNIPAAm chains became hydrophilic, and the surface bound ConA or avidin were released. Surface regeneration was realized by simply washing with sodium dodecyl sulfate (SDS) to dissociate the host-guest complexes.

Figure 7. Preparation of bio-functional and thermo-responsive surfaces using P(NIPAAm-co-Ada) and CD-X7. Reproduced with permission from ref. 64. Copyright 2014, The Royal Society of Chemistry.

In

another

work,

the

terpolymer

poly(2-hydroxyethyl

methacrylate-co-6-amino-2-(2-

methacylamido)-hexanoic acid-co-1-adamantan-1-ylmethyl methacrylate) (PHLA) was grafted on polyurethane (PU) surfaces via the ter-polymerization of two functional monomers and a guest monomer: 2-hydroxyethyl methacrylate (HEMA) , 6-amino-2-(2-methacrylamido)-hexanoic acid (LysMA) and 1-adamantan-1-ylmethyl methacrylate (AdaMA).61 The resulted material could both

28


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resist non-specific protein adsorption and lyse incipient clots, which were due to the poly(HEMA) and poly(LysMA) components in the terpolymer brushes, respectively. In addition, the ability to prevent coagulation, to inhibit proliferation of smooth muscle cells, and to promote endothelialization were introduced via the incorporation of sulfonated β-CD (CD-(SO3Na)7) via host-guest interactions, thereby enhancing the blood compatibility of the PU. These results indicate that multifunctional surfaces can be constructed by combining polymer brushes with host-guest interactions, and the functions can be incorporated using functional monomers or β-CDs modified with functional ligands. Multifunctional surfaces may be fabricated not only via the copolymerization of functional monomers or incorporation of β-CD derivatives modified with bioligands, but also via coimmobilization of biomolecules with different and complementary functions. Co-immobilization of different biomolecules is usually carried out using a one-pot process by immersing the substrate in a mixed solution containing different biomolecules.67 With this method, however, it may be difficult to control the relative amounts of the biomolecules bound to the substrate due to competition among the biomolecules for surface sites. To overcome this difficulty, we proposed a new sequential coimmobilization strategy.66 As illustrated in Figure 8, two different biomolecules, a hexapeptide containing the REDV (Arg-Glu-Asp-Val) sequence, and a modified β-CD bearing 7 lysine ligands (CD-Lysine7), were incorporated into hydrophilic polymer brushes containing the Ada guest molecule poly(2-hydroxyethyl methacrylate-co-1-adamantan-1-ylmethyl methacrylate) (PHA), via covalent bonding and host-guest interactions, respectively. The resulting surfaces showed both antithrombogenic and clot lysing properties due to the bioactivity of these two ligands in promoting endothelial cell attachment and activation of the fibrinolytic system, respectively. It is important to note that the two functions were not compromised by each other. In a similar work, surfaces having 29



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affinity for both plasminogen and tissue plasminogen activator (to generate plasmin for clot lysis) were constructed via this sequential attachment method using the tissue plasminogen activator (t-PA) affinity ligand peptide ARMAPE (Ala-Arg-Met-Ala-Pro-Glu) and CD-Lysine7.67 This method should be broadly applicable to other combinations of bioactive molecules thereby providing a versatile platform method for engineering of dual- or multi-functional surfaces.

Figure 8. Procedure for preparation of multifunctional surface. (1) Fabrication of vinyl-functionalized polyurethane (VPU). (2) Grafting PHA from VPU. (3) Conjugation of REDV peptide to PHA. (4) Immobilization of CD-Lysine7 on PHA. Adapted with permission from ref. 66. Copyright 2015, John Wiley and Sons.

3.2

Combination of β-CD-containing polymer brushes and functional guest derivatives Another approach for fabrication of supramolecular bioactive surface based on polymer brushes

is to attach biofunctional guest molecules to β-CD modified polymer brushes. Post modification is often used to attach β-CD to polymer brushes as it is relatively difficult to prepare β-CD monomers. For

example,

poly(oligo(ethylene

glycol)

methacrylate)

30


(POEGMA)

was

grafted

from

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poly(dimethylsiloxane) (PDMS) surface via surface-initiated polymerization. The bromide groups on the end of the polymer chains were converted to azido groups, which were used for the conjugation of β-CD via click chemistry (PDMS-β-CD). Ada labeled biotin (Ada-biotin) was then attached to the βCD modified POEGMA brushes to construct a molecular recognition surface based on biotin/Sav interactions.68 In another work, the Azo labeled cell recognition peptide (Azo-REDV) was attached to β-CD-containing polymer brushes for the mediation of cell-substrate interactions and cell migration.69 Since REDV peptide has specific recognition for endothelial cells, this surface showed enhanced adhesion of these cells. Following irradiation with UV, about 50% of the attached cells were released from the surface. The efficiency of cell release in this system may be limited since about 20% of the Azo moieties remain in the trans conformation after UV-light irradiation. To enhance release efficiency, a combination of Ada replacement and UV irradiation was used. This approach resulted in decreases in density, spreading area, and adhesion force of adherent endothelial cells.

4

Supramolecular bioactive surfaces based on multilayered films The fabrication of SAMs- and polymer brushes-based matrices may be restricted by substrate

limitations, the need for harsh reaction conditions and complexity of the preparation process. Thus, a broadly applicable and versatile strategy to construct matrix layers containing β-CD or guest elements would be of great interest. Multilayered films are 3D polymer films that are fabricated by a simple layer-by-layer (LbL) assembly technique.72 Compared with SAMs and polymer brushes, these films have the important advantage of broad applicability, i.e. they can be formed on diverse substrates having different shape, size and surface chemistry in a mild way.73 Incorporation of biofunctional molecules into multilayered films via host-guest interactions may thus be a useful method to fabricate bioactive surfaces with attributes of simplicity, controllability, broad applicability and renewability. 31



Page 32 of 65

Taking advantage of host-guest interactions and LbL technique, we developed a strategy to construct

bioactive

surfaces

with

the

four

attributes

indicated

above.74 A common

polyanion/polycation pair, poly(acrylic acid) (PAA)/poly(allylamine hydrochloride) (PAH) was chosen to fabricate the multilayered films, and β-CD/Ada pair was used for incorporation of bioactive ligands. The procedure is illustrated in Figure 9. First, a PAA-based copolymer with Ada groups (P(AA-Ada)) and PAH was attentively deposited on substrates via LbL technique to form a multilayered film; various functional β-CD derivatives were then incorporated in the multilayered films via host-guest interactions to give different biological functions. The entire procedure was carried out in aqueous solution at room temperature, thereby favoring the maintenance of bioactivity of the ligands. The multilayered polymer film provides a 3D structure for the attachment of biofunctional molecules with high loading capacity. The total amount and surface density of incorporated biomolecules can easily be regulated by changing the thickness of the film and by diluting the ligand modified β-CD with unmodified β-CD, respectively. In addition, renewal of the surface biofunction can be achieved based on the reversible nature of the host-guest interactions. Different biological functions were obtained by varying the ligand on the β-CD.75-77 For example, a regenerable antibacterial surface was prepared using CD-QAS7.78 The resulting surface showed high biocidal activity to kill >95% of attached pathogenic bacteria. Most importantly, almost all of the dead bacteria could be simply removed from the surface by incubation in SDS solution for a short period. Moreover, the surfaces could be regenerated via incubation with fresh CD-QAS7 solution for continuing use. Importantly also, this strategy can be applied for a wide variety of substrates with different surface chemistry including metals and related oxides, polymers, inorganic materials, as well as materials with unique surface topography. Other biological functions such as fibrinolytic activity, protein 32


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immobilization and bacterial capture and release were realized by incorporating CD-Lysine7,74 CDBiotin7,79 and CD-Mannose7,80 respectively. We also demonstrated that multifunctionality can be achieved by co-immobilization of β-CD with different ligands on the multilayered LbL films simultaneously. Surfaces with antibacterial activity and specificity for endothelial cell adhesion were prepared by incorporating CD-QAS7 and mono-mannose substituted REDV peptide (CD-REDV1).78 It is also of interest to introduce additional biofunctions using functional polyanionic or polycationic polymers. In our recent work, a multifunctional surface designed for blood contact was constructed by incorporating CD-Lysine7 on the multilayered films of chitosan/poly(sodium 4-vinylbenzenesulfonateco-Ada) (P(SS-co-Ada)).81 The chitosan and P(SS-co-Ada) were intended to provide antibacterial and heparin-like properties, respectively. In addition, the highly localized lysine moieties in the multilayered films may provide fibrinolytic properties. This multi-functionalization strategy may be conveniently used in the design of biomedical materials more generally. Taken together, our work indicates that the combination of host-guest interactions and LbL deposition provides a universal and versatile strategy to endow surface with desired biofunction by assembling individual molecular building blocks.

33



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Figure 9. Preparation of bioactive surfaces using a combination of LbL deposition and host-guest interactions. Adapted with permission from ref. 74. Copyright 2016, John Wiley and Sons.

Multilayered films may be used not only as matrices for incorporation of functional agents, but may also provide high capacity depots for drugs for controlled release.82 Using this approach, photoswitchable surfaces with the ability to control drug loading and release may be prepared using the photo-responsive β-CD/Azo host-guest pair (Figure 10). For example, the polycation-containing photo-responsive

Azo

dimethoxy)phenoxy]propyl

polymer,

poly

[6-[(2,6-dimethoxyphenyl)azo-4-(2’,6’

dimethylaminoethyl

methacrylate-random-poly(2-(N,N-

dimethylaminoethyl)methacrylate)] (Azo-PDMAEMA) was synthesized and paired with polyacrylic acid (PAA) for the construction of LbL multilayers. A model “cargo”, β-CD decorated with rhodamine B (CD-RhB1), was loaded into the polyelectrolyte film by reaction of the trans-Azo with β-CD. The 34


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trans-to-cis isomerization of Azo is generally achieved by irradiation with UV light, which may damage the biological components. To address this issue, a visible light-responsive Azo derivative, tetra-ortho-methoxy-substituted azobenzene (mAzo) was employed. On irradiation with green light, the trans form of mAzo transitioned to the cis form, thereby dissociating the β-CD/Azo complex and releasing the cargo. The cis-mAzo could be transitioned back to the trans form upon irradiation with blue light, allowing incorporation of CD-RhB1 into the polyelectrolyte film again.83

Figure 10. (a) Chemical structures of Azo-PDMAEMA and PAA. (b) Photo-responsive supramolecular interaction between Azo-PDMAEMA and CD-RhB1. (c) Fabrication of multilayered films via LbL deposition and the light-triggered release of loaded cargo. Reproduced with permission from ref. 83. Copyright 2017, The Royal Society of Chemistry.

35



5

Page 36 of 65

Live cell membrane engineering based on host-guest interaction Cell surfaces evolve naturally to express functional molecules that interact with their surroundings

to stimulate and/or respond to cellular activity, and regulate vital processes such as biotransformation, transportation of matter, and energy transduction.84 As discussed above, multifunctional and stimuliresponsive “artificial” surfaces have been constructed to mimic the natural interactions by incorporating biofunctional molecules via β-CD-based host-guest interactions. It seems possible that cell surfaces could be modified in a similar way to regulate cell activity or to design cell-based therapies. In the following section, we introduce work on incorporation of biofunctional molecules into the surface of living cells using combinations of well-established biological modification techniques and β-CD-based host-guest interactions. Various strategies have been explored to introduce β-CD or guest components into cell membranes. For example, covalent bonding of β-CD with functional groups (e.g. -NH2) on cells or LbL deposition of anionic β-CD and cationic polyelectrolytes (PAH) on negatively charged cells were used for incorporation of β-CD into yeast cells.85 It should be noted that cytotoxic reagents may be involved in covalent bonding reactions, and modifying cell surfaces with polyanion/polycation layers may disrupt the cell membrane, leading to reduced cell function. As an alternative, bio-orthogonal conjugation has been investigated. For example, via ligand-receptor interactions, an Ada-functionalized cyclic AcTZ14011 peptide (Ada-AcTZ14011) as Ada-ligand was attached via chemokine receptor 4 (CXCR4) to overexpressing MDAMB231 × 4 cells to endow the cell surface with “guest” elements.86 However, this method relies on a specific cell receptor and is thus of limited application. Cell-surface modification based on non-covalent, non-receptor-mediated lipid insertion was employed for the incorporation of β-CD into mammalian cells (Figure 11a).87 Although lipid anchoring is simple and 36


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efficient, the “bonds” may be unstable because of the dynamic nature of the phospholipid cell membrane. As an alternative, a combination of the metabolic labelling approach and the click reaction copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC) was used for the attachment of β-CD to cell surfaces (Figure 11b).88 The “metabolic” incorporation of non-natural monosaccharide derivatives into cell-surface glycans could provide stable surfaces with different functional groups, thus solving the instability problem. Modification of live cell surfaces with β-CD and guest molecules is a new area and additional strategies still need to be developed.

Figure 11. (a) Direct anchorage of lipid-PEG-β-CD onto cell membrane via its lipid tail. Adapted with permission from ref. 87. Copyright 2017, Elsevier. (b) Conjugation of alkynyl-PEG-β-CD onto cell membrane via a combination of metabolic labeling method and CuAAC. Adapted with permission 37



Page 38 of 65

from ref. 88. Copyright 2016, Springer Nature.

Some bio-applications of these β-CD/guest molecule-modified cells were also investigated. A simple application is cell patterning on a planar artificial material surface. In recent work by Qu and co-workers, mixed β-CD-labelled MCF-7 cells and Hela cells were seeded on trans-azobenzenepatterned substrate.88 Following culture for 4 h, the β-CD-labelled cells were attached preferentially to the azo-benzene regions via host-guest interactions. Taking the advantage of the photo-responsive properties of the β-CD/Azo pair, about 84% of the original adherent cells could be removed from the substrate by illustration with UV light and further being washing with PBS. In addition to cell patterning, the manipulation of cell-cell interactions using β-CD-modified cells was also explored. For example, a bis-Azo molecule (Azo-PEG-Azo) was used as a linker for light-controllable reversible assembly of β-CD-modified cells (Figure 12a).87 A mixture of β-CD-modified MCF-7 cells labeled (or not) with green cytosolic dye in a 1:1 ratio was used in this work. Without Azo-PEG-Azo the cells were well separated, while addition of trans-Azo-PEG-Azo led to a rapid formation of 3D spheroid assemblies of interconnected cells. Due to the photo-responsive properties of β-CD/Azo, the aggregates could be disassembled to give individual cells by UV irradiation. These results demonstrate that host-guest interactions hold advantages for direction of cellular interactions and emulation of biological systems. Another application is the incorporation of functional molecules such as aptamers into β-CD-modified cells to endow the cells with specific functions. For instance, aptamer-presenting peripheral blood mononuclear cells (PBMCs) were prepared by incorporating an Azo modified aptamer (Azo-Aptamer) into β-CD-labeled PBMCs. Due to the molecular recognition ability of the aptamer, the aptamer labeled PBMCs cells were activated to allow adhesion to mucin 1-overexpressing 38


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cancer cells, MCF-7 cells, leading to enhanced apoptosis (Figure 12b).87 Such regulation of heterotypic cell adhesion provides a new strategy for designing cell-based therapies.

Figure 12. (a) Upper panel: light-induced arrangement of cellular interactions. Lower panel: microscopy images showing light-controlled assembly and disassembly of cells. (b) Upper panel: recognition of aptamer-modified PBMCs (green) with targeting MCF-7 cells (red). Lower panel: representative fluorescence image showing contacts between aptamer-modified PBMCs (stained red) and MCF-7 cells (stained green). Adapted with permission from ref. 87. Copyright 2017, Elsevier.

6

Summary and Perspectives The preparation of bioactive surfaces using β-CD-based host-guest interactions has undergone

rapid development in recent years. The combination of well-established matrices such as SAMs, polymer brushes and multilayered films with components formed by β-CD-based host-guest

39



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interactions is an effective method to construct multifunctional and stimuli-responsive bioactive surfaces. These surfaces not only provide ideal platforms for fundamental investigation of biological processes such as molecular recognition, enzyme catalysis, biosensing, and energy transfer, but also show great potential for practical applications including biomolecule sensing and separation, bloodcontacting materials, and antibacterial surfaces. The attributes of β-CD-based host-guest interactions (simplicity, broad applicability and reversibility) serve to overcome the limitations of traditional covalent bonding methods for fabricating bioactive surfaces. However, our understanding of the complex biological processes at interfaces in biological systems is still incomplete, and the application of these surfaces in practical systems is just beginning. It is also notable that most of the systems realized thus far are based on SAMs; supramolecular bioactive surfaces based on polymer brushes and multilayered films need to be explored further. The modification of live cell surfaces with functional molecules is also an important emerging area which is expected to contribute in important ways to our ability to regulate cell behavior; this approach holds great potential for cell-based therapies.

Author Information Corresponding Author

* E-mail: [email protected]

Author Contributions

Contributions to this review were made by all authors, and all have seen and approved the submitted manuscript.

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Notes

The authors declare no competing financial interest Acknowledgment

This work was supported by the National Natural Science Foundation of China (21774086 and 21334004), the National Key Research and Development Program of China (2016YFC1100402), the Natural Science Foundation of Jiangsu Province (BK20180093), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The authors thank Prof. John Brash for helpful discussion.

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Table of Contents Graphic

49



Fig. 1 219x158mm (201 x 201 DPI)


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Fig. 2 199x208mm (300 x 300 DPI)



Fig. 3 122x34mm (300 x 300 DPI)


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Fig. 4 113x218mm (300 x 300 DPI)



Fig. 5 240x82mm (300 x 300 DPI)


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Fig. 6 179x105mm (300 x 300 DPI)



Fig. 7 119x85mm (300 x 300 DPI)


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Fig. 8 299x97mm (300 x 300 DPI)



Fig. 9 299x213mm (300 x 300 DPI)


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Fig. 10 162x105mm (300 x 300 DPI)



Fig. 11 139x157mm (300 x 300 DPI)


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Fig. 12 236x130mm (300 x 300 DPI)



TOC 250x129mm (300 x 300 DPI)


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Scheme 1 199x113mm (300 x 300 DPI)



Scheme 2 220x117mm (300 x 300 DPI)


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Scheme 3 250x115mm (300 x 300 DPI)


Fabrication of Supramolecular Bioactive Surfaces via Î²-cyclodextrin

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