Biomimetic Sensors Based on Molecularly Imprinted Interfaces

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Biomimetic Sensors Based on Molecularly Imprinted Interfaces Mihaela Puiu1, Nicole Jaffrezic-Renault2 and Camelia Bala1, * 1

University of Bucharest, Bucharest, Romania University of Lyon, Villeurbanne, France *Corresponding author: E-mail: [email protected]

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Contents 1. Polymers as Alternative Recognition Elements to Natural Receptors 2. Polymer Systems and Imprinting Principles 2.1 Selection of functional monomers and imprinting matrices 2.2 Choice of solvent 2.3 Design of molecularly imprinted polymers 2.4 Strategies for template immobilization and removal 2.5 Imprinting techniques 2.5.1 Bulk imprinting 2.5.2 Surface imprinting

1 3 4 7 8 9 13 13 14

3. Physical Form and Configurations of Molecularly Imprinted Polymers 3.1 Monolithic molecularly imprinted polymers 3.2 Molecularly imprinted polymer membranes 3.3 Molecularly imprinted polymers based on molecular self-assembling 3.4 Development of micro- and nanosized molecularly imprinted polymer materials 4. Interfacing Sensors’ Transducers With Molecularly Imprinted Polymers 5. Micro- and Nanostructured Molecularly Imprinted Polymers for Sensing Devices 6. Market Potential of Molecularly Imprinted Polymer Sensors Acknowledgement References

16 16 18 19 20 20 21 26 26 26

1. POLYMERS AS ALTERNATIVE RECOGNITION ELEMENTS TO NATURAL RECEPTORS Molecularly imprinted polymers (MIPs) are synthetic materials mimicking molecular recognition by antibodies, enzymes or other biological receptors [1]. Their artificially generated recognition sites are able to specifically rebind the target molecules, preferentially discerning among other closely related compounds. MIPs are obtained through the polymerization Comprehensive Analytical Chemistry, Volume 77 ISSN 0166-526X http://dx.doi.org/10.1016/bs.coac.2017.05.002

© 2017 Elsevier B.V. All rights reserved.

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of functional and cross-linking monomers around a printed molecule (template), which results in a highly cross-linked three-dimensional network. This technique e molecularly imprinting e involves the formation of complexes between the monomer units and the template molecule through weak, noncovalent interactions such as hydrophobic, ionic or hydrogen bonding [2,3]. Once polymerization is achieved, the extraction of the template molecule progresses and the ‘imprinted’ cavities in the cross-linked matrix feature binding sites with shape, size and functionalities complementary to the target analyte [4,5] (Fig. 1). The fixation of binding groups can be achieved by various chemical reactions (e.g., different condensation and addition polymerizations), as long as these reactions do not disrupt the template-building block complex [6]. The resulted MIPs are chemically and mechanically stable over a broad range of pH; their interaction with the target molecules emulates the interaction of the target with biological molecules (antibodies or nucleic acids) in terms of specificity and selectivity, but without the inherent stability limitations. Moreover, MIPs synthesis is also relatively cheap and easy, making them a clear alternative to the use of natural receptors [8]. MIPs are different from biological receptors because they are large, rigid and insoluble, while their natural counterparts are smaller, flexible and mostly soluble [7,9]. To date, only relatively low molecular weight compounds (sugars, amino acid derivatives, steroids, drugs and pesticides) were used as templates. Thus, the choice of template is limited. There are at least two main reasons preventing the use of macromolecules such as proteins

Figure 1 Schematic representation of molecular imprinting. A template molecule (T) is mixed with functional monomers (M) and a cross-linker (CL) yielding a self-assembled complex (1). The polymerization of the resulting system produces a rigid structure bearing imprinted sites (2). The final removal of the template provides empty cavities that can specifically recognize and bind the target molecule (3). Adapted with permission from K. Haupt, Anal. Chem. 75 (2003) 376Ae383A. Copyright (2008) American Chemical Society.

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and nucleic acids as templates: steric hindering and thermodynamic restriction. The steric effect is caused by the inability of bulky proteins to slip in and out of a polymer matrix [10] and the approaches overcoming these drawbacks were based on the so-called ‘surface imprinting’ methods which use Cu2þ chelating monomers able to bind exposed histidine residues [11]. Alternatively, the use of macroporous MIPs with increased internal surface area (250e500 m2/g) and a broad distribution of large pores (>50 nm) ensures that not only solvents and low molecular weight compounds but also long chain peptides and globular proteins (with 5e10 nm diameter) have access to a significant fraction of the polymer mass [12]. Thermodynamic considerations [8] suggest that the use of nonrigid templates, such as polypeptides or proteins, yield less well-defined recognition sites in MIP [2]. Similarly to their corresponding natural receptors (enzymes, antibodies and hormone receptors), MIPs have found many applications in analytical chemistry and biochemistry areas such as mimics of biomolecules in bio/immunoassays implemented on sensors and biochips; affinity separation materials and enzyme-like catalysts [13]. Regarding the commercialization of MIPs there has been great progress during the last decade, targeting several areas from analytical chemistry and biochemistry such as sample clean-up and preconcentration [14]. Here, the advantages of MIPs over biomacromolecules are obvious [9]. Finally, it can be mentioned that MIP-based materials can have applications ranging from chromatography and solid phase extraction to controlled drug delivery [12].

2. POLYMER SYSTEMS AND IMPRINTING PRINCIPLES The molecularly imprinting is basically a three dimensional effect, namely, the effective control of three-dimensional interactions by the template with surrounding functional monomers and the cross-linked network [15]. However, the performance of MIPs in terms of binding and selectivity is expressed with the aid of two parameters: the binding constant K for comparing different substrates and the selectivity factor a, representing the ratio of binding constant for two substrates. Size or different partitioning effects strongly influence the selectivity factor, and hence the separation of two substrates which are not enantiomers. These effects are mostly due to the differences in polarity, hydrophobicity, ionization state, shape and conformation. The best way to evaluate the imprinting effect is to monitor the binding of a chiral template and its enantiomer, since all

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size and partitioning considerations remain the same, with the only difference being the topological orientation of the molecular scaffolds in threedimensional space [16]. Investigation into the resolving power of MIPs with different distances between the primary binding event and the chiral centre may reveal a distanceegeometry algorithm for molecular recognition [17]. Thus, enantioselectivity of an MIP provides a valuable criterion in the optimization of the imprinting procedures. This is particularly important for comparing the performance of one polymer to another because differences in the polymer morphology and chemical composition lead too differences in the partitioning effects between nonenantiomeric molecules [15].

2.1 Selection of functional monomers and imprinting matrices An essential requirement for obtaining specific binding sites in the MIP’s network is the existence of strong interactions between monomer and template. However, the monomers should not reactively polymerize with the template. They are chosen to play a specific role for structure and function. The monomers can carry basic (e.g., vinylpyridine), acid (e.g., methacrylic acid (MAA)), hydrogen bonding (e.g., methacrylamide) or hydrophobic (e.g., styrene) groups [5,9] (Fig. 2). The preferred method for preparing MIPs is free radical polymerization with MAA and 4-vinylpyridine (4-VPY) as the most used functional monomers. The MAA monomer interacts electrostatically with amines and through hydrogen bonding with amides, carbamates and carboxyl groups. Apparently, the best performance of MIP materials is achieved via electrostatic interactions. Polyurethanes were also used recently but their applications are somehow restricted due to the limited choice of functional monomers [19]. One of the monomeric units is an isothiocyanate that is reacting with alcohol or amine groups present in most biomolecules [20]. The imprinted polymer needs to be cross-linked enough to maintain the binding sites intact after the template’s removal. If the binding sites are too flexible, they might also bind similar molecules. Polymers with crosslink ratios in excess of 80% are often preferred. It has been found that highly cross-linked polymers are best suited for targeting small molecules [15,21], whereas targeting larger molecules is achieved with more flexible polymers [22]. Ethylene glycol dimethacrylate (EDMA) with two vinyl groups is the most used cross-linker. Cross-linkers containing three or four vinyl groups yield polymers with improved load capacity and selectivity than the polymer prepared using EDMA [23]. Pentaerythritol triacrylate (PETRA), EDMA

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Figure 2 Commercially available functional monomers used in imprinting processes. Reproduced with permission of H. Yan, K. Row, Int. J. Mol. Sci. 7 (2006) 155.

and divinylbenzene (DVB) were compared for synthesizing an MIP targeting the caffeic acid [24]. The MIPs were compared in terms of rigidity and selectivity showing the interest of using PETRA because of its higher hydrophilic properties, thus resulting in a higher selectivity of the obtained MIP [25]. The chemical structures of several cross-linkers used in MIP synthesis are summarized in Fig. 3. Solegels such as silica and titanium dioxide have been employed as imprinting matrices recently and they gained importance because solegel matrices seem to yield better results than the common polymethacrylate

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polymers [26]. For the imprinting of molecules on biosensor surfaces, there are different types of molecular imprinting techniques that can be classified in three main categories: bulk imprinting, surface imprinting and epitope imprinting [27]. The most common applications of MIPs are presented in Table 1. The molecular imprinting of bulk amorphous silica with single aromatic molecules with a covalent monomer template complex was used to create shape-selective catalysts [38]. Finally, during the past decade, composite materials have started to appear, which combine the recognition properties of MIPs with the specific mechanical, optical, electrical or other functional properties of a second material [6]. Numerous materials such as responsive polymers, lanthanide ion complexes [39], solegel derived xerogels [40], silica particles [41], quantum dots [42], carbon nanoparticles [43], metals such as gold or silver, can be fused with MIPs in various combinations. Metallic silver and gold particles are used as the core material due to their electronic properties and scattering/plasma behaviour in respect of the light emitted [44]. Metal organic frameworks (MOFs) are crystalline porous hybrid materials that contain coupling units (metal ions or metal-oxo units) coordinated by electron-donating organic ligands. A subgroup of MOFs that

Figure 3 Chemical structures of commonly used cross-linkers in molecularly imprinted polymer synthesis. Reproduced with permission of C. Algieri, E. Drioli, L. Guzzo, L. Donato, Sensors 14 (2014) 13863.

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Table 1 Molecularly imprinted polymer systems according to their applications Polymer Application Method References

Polyacrylate/ polymethacrylates/ polymethylmethacrylate Polyacrylamide Polyurethane Siloxanes Solegels

• Drug delivery • Chromatography • Sensors

• Bulk imprinting • Surface imprinting • Imprinted particles

[28] [29] [30]

• • • • • • •

• Bulk imprinting

[31] [32] [33] [34,35] [29] [36] [37]

Chromatography Crystallization Sensors Chromatography Chromatography Sensors Catalysis

• Surface imprinting • Surface imprinting • Bulk imprinting

Adapted with permission from R. Schirhagl, Anal. Chem. 86 (2014) 250e261. Copyright (2008) American Chemical Society.

consist of pores with dimensions less than 2 nm are microporous metal organic frameworks (MMOFs). MOFs with aromatic ligands generally have a high specific surface area and large pore volume with well-defined pore size, which had been effective for hydrogen and methane adsorption [45]. MIPs are developed mainly for small molecule detection or storage but the real challenge remained the synthesis of MIPs for biomacromolecules [9].

2.2 Choice of solvent The solvent serves to bring all the components in the polymerization process, i.e., template, functional monomer(s), cross-linker and initiator into one phase. When polymerization occurs, solvent molecules occupy space in the polymer network and create pores. For this reason it is quite common to refer to the solvent as the ‘porogen’ [3]. Usually, solvents used for MIP synthesis are methanol, tetrahydrofuran (THF), 2-methoxyethanol, dichloroethane, chloroform, N,N-dimethylformamide (DMF), toluene and acetonitrile [46]. The polarity of porogens affects the template/monomer interaction and consequently the adsorption properties of MIPs, especially in noncovalent interaction systems. The porosity of polymers is dependent on the overall concentration of monomers and cross-linkers in the solution. Pores are required to allow the diffusion of the template out of the network and its subsequent diffusion back into the polymer during recognition. An

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adequate solvent for MIP would create well-developed pores within the network and increase the pore surface area [12], but a large amount of solvent can ultimately lead to the formation of microspheres and nanospheres instead of a large and stable cross-linked network. Moreover, the solvent can be used to dissipate the heat generated by polymerizations especially those which involve acrylate and methacrylate polymers. The heat released in the system may affect the stability of the templateemonomer complex by unduly degrading or denaturing the target molecule. The solvent should not influence the formation of the templateemonomer complex because in this case it may inhibit the formation of the imprinting sites. Therefore, many imprinting systems avoid polar solvents such as water and instead utilize nonpolar solvents to enhance template/monomer interactions [3]. As a result, water is an especially poor solvent for MIP synthesis due to its highly polar nature and the fact that most MIP materials function only in organic solvents. Especially during the noncovalent imprinting water, as both a hydrogen bond donator and hydrogen acceptor, can disrupt the hydrogen bonds established between template and monomer. In addition, many cross-linking agents that are water soluble possess little structural integrity, thus limiting these materials in extraction applications such as high pressure liquid chromatography (HPLC) [12]. More recently, room temperature ionic liquids (RTILs) have been reported to accelerate the synthesis process, improving the selectivity and adsorption of trans-asconitic acid imprinted polymers. Due to the negligible vapour pressures, RTILs can help reduce the problem of MIP bed shrinkage and act as pore templates in the polymerization reaction [47].

2.3 Design of molecularly imprinted polymers Despite their moderately long history, the development of imprinted polymers is not an easy task. Several variable parameters, monomers (more than four thousand monomers are commercially available), solvent, temperature, etc., make the choice of a polymerization protocol difficult [48,49]. Although some excellent materials were prepared through a rational design of the polymerization conditions, improved results could be obtained using combinatorial approaches, where tens, hundreds and even thousands of polymer can be synthesized and tested to select the best one [50]. A solution for MIP design includes the computational screening of a virtual library of functional monomers against a target molecule followed by selection of those able to form the strongest complex with the template. Commercially available software take into account the real polymerization conditions

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(solvent, temperature, etc.), under which polymers have to be prepared and used, and mimicked. The computationally designed polymers possess an affinity comparable with antibodies (Table 2). To speed up the process MIPs for terbutylazine (herbicide) were synthesized in small quantities (‘mini MIPs’- 55 mg) in HPLC autosampler vials [52], allowing for automated processing. During a first round of screening, the selection criteria were based on the amount of template released upon washing with the solvent used as a porogen during polymerization. Therefore, for a certain MIP, a quantitative release of the template indicates that target binding will be weak and the MIP will thus be discarded. In the second screening round, the purpose was to maximize the imprinting effect; thus, the rebinding of the template to the mini MIPs and to nonimprinted polymers was compared. A library of 80 polymers could be synthesized in this manner and evaluated in only 1 week [53,54].

2.4 Strategies for template immobilization and removal Basically, there are four strategies employed for MIP technology depending on the nature of the interactions template/monomer in the prepolymerization step: noncovalent (nonionic and electrostatic interactions), covalent, semi-covalent and metal centre coordination [5] (Fig. 4). The experimental procedure in the noncovalent imprinting is rather simple and there are plenty of commercially available monomers able to interact with almost any kind of template. During the noncovalent approach, the special binding sites are formed by the self-assembly between the template and monomer, followed by a cross-linked copolymerization [18]. The imprinted molecules

Table 2 Comparison of the properties of tunable recognition systems Molecularly Synthetic imprinted molecular polymers Characteristic Antibodies receptors

Preparation time Average binding affinities (M1) Inexpensive preparation Thermal and chemical stability

3e6 months 106e102

1e6 months

1e7 days

103e106

102e103

No No

No Yes

Yes Yes

Reproduced from K.D. Shimizu, C.J. Stephenson, Curr. Opin. Chem. Biol. 14 (2010) 743e750 with permission from Elsevier.

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Figure 4 Molecular imprinting approaches: (i) noncovalent (nonionic), (ii) noncovalent (electrostatic/ionic), (iii) covalent, (iv) semicovalent and (v) metal coordination. An imprint molecule is combined with a specific functional monomer, through noncovalent, covalent or ligand (L) to metal (M) interactions with complementary functional groups on the imprint. A complex of the template (imprint) and functional monomer (IC) is formed (I) by hydrogen bonding or van der Waals interactions, (II) by electrostatic or ionic interactions (the charges on the imprint and functional monomer may be reversed), (III) through a covalent bond, (IV) through a covalent bond with a spacer (orange) or (V) by ligandemetal or metaleligand coordination. The functional monomer contains a functional group, Y, which is able to undergo a cross-linking reaction with an appropriate cross-linker. After polymerization of the complex with a cross-linker to form the solid polymer matrix (grey), the imprinte functional monomer interactions are intact. The imprint is removed through washing, cleavage of chemical bonds or ligand exchange and leaves behind an imprint cavity with functional groups on the walls. Subsequent uptake of a target molecule is achieved by noncovalent interactions (in types i, ii and iv), the formation of a covalent bond (in type iii) or by ligand exchange (in type v) with target molecules that fit into the cavity and possess the correct structure. The matrix may also participate in target recognition and binding through nonspecific surface interactions that result from surface features created around the imprint molecule during cross-linking. Reproduced with permission of J.E. Lofgreen, G.A. Ozin, Chem. Soc. Rev. 43 (2014) 911e933. Copyright (2014) Royal Society of Chemistry.

interact, during both the imprinting procedure and the re-binding, with the polymer via hydrophobic and hydrogen bonding [55]. The main advantage is given by the absence of kinetic limitations related to imprinted molecule/ functional monomer complex (IC) formation and recognition of the target molecule. The predominant limiting factor is diffusion, which can be easy to diminish with carefully chosen system parameters. However, such weak interactions require the use of an excess of functional monomer because the equilibrium of the system does not favour the formation of the IC [56].

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Consequently, the excess of free monomers is randomly incorporated to the polymeric matrix leading to the formation of nonselective binding sites [8]. A major drawback is that the formation of interactions between monomers and the template are stabilized under hydrophobic environments, while polar environments disrupt them easily [55]. Another limit is given by the need of several distinct points of interactions: some molecules characterized by a single interacting group, such as an isolated carboxyl, generally give imprinted polymers with poor molecular recognition properties. Increasing the number of binding interactions in the polymer binding site may provide higher affinity and selectivity to the site. The number of functional groups in the polymer binding site is not determined directly by the solution phase prepolymer complex; rather, it is determined during polymerization. Because of the difficulty to characterize the binding site during and after polymerization, the actual events determining the final structure of the binding site are still challenging. The covalent approach [57] involves the formation of reversible covalent bonds between the template and monomers before polymerization. In this method, the template is bound covalently to functional monomers normally through the use of a vinyl moiety [58]. This strategy often uses readily reversible condensation reactions as those that form boronate esters [57], ketals/acetals [59] and Schiff’s base [60]. The first successful imprinting of this type employed a simple sugar conjugated to a boronic acid derivative. The conjugate was cross-linked using ethylene dimethacrylate. When the ester was cleaved, it was found that the template was bound selectively and strongly [12]. The high stability of templateemonomer interaction leads to a rather homogenous population of binding sites, minimizing the number of nonspecific sites. Moreover, the covalent imprinting, being stoichiometric, ensures that functional monomer residues exist only in the imprint cavities; thus greatly reducing nonspecific interactions. Still, the need for a distinct synthesis step to generate the initial template molecule/monomer complex, the bond cleavage required to remove the imprint and bond formation required to bind a target molecule increase the complexity of this method; the additional kinetic barrier of covalent bond formation may render it slower in target binding [56,61]. The most successful MIP systems are tightly cross-linked polymeric hydrogels that contain acrylic acid or MAA monomers grafted with a polyethylene glycol derivative [62]. These monomers possess anionic acidic groups that can noncovalently bind the template molecule and also allows the template to be removed in mild conditions [63].

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An intermediate option is the semicovalent imprinting. In this case, the template is also covalently bound to a functional monomer, but the template rebinding is based only on noncovalent interactions. This is an optimized approach combining the durability of covalent imprinting and the rapid target uptake of noncovalent imprinting (where the dominant kinetic barrier is diffusion of target species into the imprint sites); after polymerization, the template molecule is cleaved and later rebound through noncovalent interactions. The use of covalent templateemonomer interactions during the polymerization step results in a more homogeneous recognition site distribution. A further development of this, termed the sacrificial spacer approach, was presented by Whitcombe and coworkers for the imprinting of another poorly functionalized template, cholesterol [55,64]. This approach takes into account the steric requirements of the noncovalent rebinding interaction. The small sacrificial spacer fragments, such as carbon dioxide [64], silyl ether or silyl esters [65], add just enough length to the covalent bond holding the template/monomer complex together to facilitate the transition from covalent bonds in the imprinting step to noncovalent interactions in the target assimilation step [55,56]. To date, imprinting technologies based on coordination chemistry are fully exploited, especially in the context of developing biomimetic catalysts, although there is still a lot of potential. Transitionemetal ligand interactions are well suited for molecularly imprinting because coordinative bonds can be thermodynamically stable and at the same time kinetically labile, thus permitting ligand exchange reactions [66]. Metal ions can interfere in the imprinting process in two ways: either they form part of a complex that is covalently bound to an imprint cavity and participate in target recognition through metaleligand bonding (where the target is a ligand for the metal ion) (Fig. 4V), or they can act as the actual imprint when metal ion uptake is the aim. When a metal ion is the centre of a complex bound into an imprint cavity, it can undergo ligand exchange to bind a suitable target molecule. Alternatively, a metal ion can act as an ionic imprint species to create an imprint cavity that can interact with an appropriate target metal ion. Here, the ligands that are covalently bound to the matrix remain, and the metal ion is removed after imprinting. The level of selectivity of this imprinting approach is governed less by the size of the cavity created and more by the partial charge from the cavity and the strength of the interactions between the target metal ion and the ligands in the cavity [56,67]. Liu and Wulff [68] reported the synthesis of imprinted polymers mimicking the activity of carboxypeptidase A, by using an amidinium

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functional monomer and a trialkylamine unit coordinating a Zn(II) atom that was able to coordinate the phosphate template [69]. Recently a new kind of affinity material for the specific recognition of porcine serum albumin (PSA) combining metal coordination with surface molecular imprinting was reported. Herein, metal ions not only work as anchor points for the immobilization of PSA during the formation of cross-linked imprinted layer, enabling the facile removal of template after polymerization, but also serve as recognition elements for the rebinding of target proteins, together with imprinted cavities [70]. However, the removal of the template is a critical step in the preparation of imprinted polymers. In fact, like in the case of noncovalent binding, the interactions between polymer and template can sometimes make difficult the removal of the last traces of template, even after washing the material many times. This is a problem, which may lead to the depletion of the residual template when the polymer is used [23,71]. In addition, it must be taken into account that if there are residual template molecules in the imprinted matrix, less recognition sites will be available for rebinding, thus lowering the polymer efficiency [72]. To achieve complete template removal, Ellwanger and coworkers [73] employed different postpolymerization treatments (Soxlet extraction, microwave-assisted extraction, thermal annealing and supercritical fluid template desorption) aiming to a complete removal of clenbuterol and L-phenylalanine anilide from their respective imprinted polymers. In the case of clenbuterol, the lowest retention level was observed after microwave-assisted extraction. Referring to the MIP imprinted with L-phenylalanine anilide, the lowest retention was found after extensive online washing in solvents containing acid or base additives and after thermal annealing treatment of the polymer [23].

2.5 Imprinting techniques 2.5.1 Bulk imprinting In bulk imprinting, the template is imprinted entirely in the polymer matrix and wholly removed from the molecularly imprinted material after polymerization. In the following step the bulk polymer is ground mechanically into small particles which are afterwards fractionated. By this easy and accessible manner, template-specific 3D interaction sites are obtained within the selective, imprinted polymeric material [74]. This method is preferred for the imprinting of small molecules because, at least in theory, the adsorption and removal of the template molecule are faster and reversible which is an advantage in terms of reusability of the imprinted support for subsequent

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assays [75]. In the case of biomacromolecules, microorganism and living cells, this method exhibits several disadvantages. First is the difficulty in maintaining the conformational stability of proteins; then for large imprinted sites, cross-reactivity with smaller polypeptide may occur [76]. Besides, due to the thick morphology of bulk imprints, big template molecules are deeply embedded in the matrices, which leads to restricted access of the target molecules to the binding sites and consequently to increased response times and poor regeneration [77]. These drawbacks have been overcome by alternative imprinting techniques such as surface and epitope imprinting. 2.5.2 Surface imprinting The surface imprinting method provides MIPs with high affinity recognition sites which are more easily accessible and display favourable binding kinetics [78]. The template/polymer interactions are not diffusion limited to the same extent as it was the case in bulk imprinting [79]. In surface imprinting, lesser template molecules are used compared other conventional imprinting techniques because they are involved only in the surface coating step [77]. One serious disadvantage of this method for biosensing applications is the possibility of lower sensitivity as compared to bulk imprinting owing to the reduced number of imprinted sites [75]. 2.5.2.1 Epitope approach

The epitope approach is based on the recognition between the antibody and an antigenic site of a protein, the epitope. The epitope is a short amino acid sequence complementary to the binding site of antibody [80]; Rachkov and Minoura have developed a new concept for the synthesis of protein recognition polymers [2]. Instead of the whole proteins, a short peptide sequence, often exposed at the protein surface, was used as a template for MIP preparation. Once the matrix has been polymerized the resultant imprinted material was able to recognize and bind the whole protein. The concept is based on the use of a short peptide sequence (three to four residues) as a template (Fig. 5). The surface imprinting technique provides selective sensing layers because the recognition of macromolecular or bioanalytes is exclusively carried out at the surface of a polymeric or a solegel material. The polymer surface is crafted to acquire both geometrical and chemical fit (imprint) of the target molecule [81] and consequently to deliver highly specific recognition events.

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Figure 5 Schematic diagram of epitope imprinting: a short peptide sequence is used as the template to create selective binding sites for a protein. Reproduced from M.J. Whitcombe, I. Chianella, L. Larcombe, S.A. Piletsky, J. Noble, R. Porter, A. Horgan, Chem. Soc. Rev. 40 (2011) 1547e1571. Copyright (2011) Royal Society of Chemistry.

2.5.2.2 Soft lithography

Soft lithography or stamping is a widely used technique for the preparation of biomimetic sensors [75]. Micro and nanoscaled patterns can be prepared by this technique without expensive materials or specialized equipment. This non-photolithographic strategy, introduced by Bain and Whitesides in 1989 [82], uses a soft polymeric stamp to imprint a solution of molecules or biospecies onto a solid substrate and to generate surface patterns with feature sizes ranging from 30 nm to 100 mm [27,75]. A prepolymerized layer is coated onto a transducer’s surface and the template stamp is softly pressed

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over this surface for a certain time, thus creating of patterned surface structures. Self-assembling of template structures including macromolecules or microorganisms on a smooth support are used to produce the template stamps, which are complementary to the template in their structural, geometrical and also chemical features [83]. For the preparation of stamp, one important issue to be considered is the amount of template on the stamp which strongly influences the sensor’s response. Dickert and coworkers [84] demonstrated that multilayer stamps provide better sensor responses than monolayer covered polymers. Regarding the selection of solid support, a glass slide may be preferred owing to its rigid structure which confers mechanical stability [85]. A surface-imprinted polymer layer can selectively recognize the target through its distinct geometry and/or reversible noncovalent interactions. Therefore, the target recognition characteristics can be tuned by adjusting the polarity of a polymer, its composition and processing methodology. A prepolymer matrix usually contains functional monomers or oligomers along with high proportions of cross-linkers, which offer substantial geometrical stability and rigidity so that the imprinted cavities retain their shape and do not collapse after template removal [27,75].

3. PHYSICAL FORM AND CONFIGURATIONS OF MOLECULARLY IMPRINTED POLYMERS As mentioned above, molecular imprinting is generally carried out using irregularly formed porous polymer particles obtained by mechanical grinding, followed by size fractionation to obtain small micrometre-sized particles. This simple and direct procedure leads to size-defined though irregularly shaped material [6] and is used in most imprinting methods. Other applications involve MIPs in defined physical forms, for which specially adapted synthesis methods are required. Therefore, three aspects have been addressed recently: the synthesis of small, spherical particles of below micrometre size, the synthesis of thin layers and the creation of surface imprints [86]. MIP-based materials are built up for specific applications following several formats including MIP beads and in situ prepared monoliths (Table 3) [6].

3.1 Monolithic molecularly imprinted polymers Monolithic MIPs are prepared by a one-step, in situ, free-radical polymerization ‘molding’ process directly within a chromatographic column without the tedious procedures of grinding, sieving and column packing [100].

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Table 3 Various configurations of molecularly imprinted polymers (MIPs) Configuration Characteristics Method of preparation References

Monolith

Bead

Membrane/film

• Physical dimensions of MIPs are controlled by the accessible volume the reaction container provides • Particle size is controlled by addition of surface-active reagents •

Self-assembled monolayer

•

Microscale 3D structure Nanotube, nanowire, nanofibre Dendrimer

•

•

In situ polymerization

• Suspension polymerization • Emulsion polymerization • Precipitation polymerization Thickness is • In situ polymerization controlled by the • Surface-initiated preparation polymerization method • Electrochemical polymerization A monolayer of • Molecular selfself-assembled assembly molecules A well-defined • Soft lithography 3D structure • Microstereolithography • Electrospinning • In situ polymerization inside nanochannels Single binding • Multistep organic side in wellsynthesis defined globular macromolecules

[87]

[88] [89] [90] [91] [92] [93] [94,95]

[96] [97] [98] [78] [99]

Adapted with permission from L. Ye, K. Mosbach, Chem. Mater. 20 (2008) 859e868. Copyright (2008) American Chemical Society.

Monolithic MIP is expected to improve the separation and enable direct analysis with high-speed and high performance after in situ polymerization. Moreover, the preparation of this type of MIP is more cost efficient because the amount of template molecules required is much lower. Their greater porosity, and hence good permeability, and high surface area are well suited for both small molecules and large biopolymers [18].

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Regular beads can be obtained using precipitation polymerization method. This technique allows the formation of imprinted beads with the same reaction mixture used in the bulk method except for the presence of a higher amount of porogen. Polymer chains will continue to grow, precipitating only when they become large enough to be insoluble in the reaction mixture. Then the polymer beads are easily recovered by washing and centrifugation operations [101]. The particle diameters decrease, increasing the porogen volume, probably due to the formation of lesser oligomers under diluted conditions. Mosbach and Mayes [102] prepared spherical beads in liquid perfluorocarbon by suspension polymerization in the presence of a stabilizer and a surfactant. Following their work Zourob and coworkers [103] employed a polycarbonate-based spiral microflow reactor, proving that in mineral oil (far less expensive than perfluorocarbon) the addition of stabilizer or surfactant was not necessary for producing monodisperse MIP beads. Bonini and coworkers [104] reported the synthesis of surface imprinted beads for the recognition of human serum albumin (HSA). They used the covalent immobilization of template for homogeneous population of recognition sites. Thus, the target proteins were immobilized on silica beads that previously modified to introduce imine bonds for appropriate interactions with the amino groups of lysine in HSA. The HSA recognition and binding capacity of surface-imprinted beads were tested in human serum and targeted the removal of HSA from biological fluid without a loss of the other protein.

3.2 Molecularly imprinted polymer membranes In recent years, MIP membranes have attracted tremendous interest. A membrane is defined as a selective barrier interposed between two neighbouring phases and regulates the transport chemical species between the two phases. Membrane-based imprinting processes do not require additives and can be performed at low temperature, thus reducing the energy costs. Compared to other applications of imprinted polymers, molecularly imprinted membranes (MIMs) can operate in a continuous mode by exploiting the characteristics of membrane and molecular imprinting technologies [105]. Most commonly prepared MIMs have flat-sheet configurations and are used for the recognition of a wide range of compounds such as pesticides [106], flavonoids [107], vitamins [108] and proteins [109]. The formation of membrane structure and molecular recognition sites is mainly accomplished by means of the in situ cross-linking polymerization and the so-called alternative molecular imprinting. The first method allows the

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formation of a cross-linked polymeric network produced by thermal or UVinitiated polymerization of a mixture solution of template, functional monomer, cross-linker and initiator in a suitable solvent. Plasticizer agents are also added to the prepolymerization mixture to obtain membranes that are more flexible [23,48]. Membranes are able to selectively bind the template with respect of the structural analogue choramphenicol [109]. MIMs-based sensors take advantage of their high selectivity and stability, which enable their long-term operation under conditions not tolerated by biomolecules without losing sensitivity. Still, there is a need to simplify the imprinting of larger biological molecules.

3.3 Molecularly imprinted polymers based on molecular self-assembling The technique involves the simultaneous sorption of the template and the mercaptan molecules on gold electrode, followed by the extraction of template [50]. The principle of two-dimensional molecular imprinting was later realized using self-assembled monolayers (SAMs) of alkanethiols on gold for the binding of barbiturate [110]. Here, an alkanethiol SAM was formed onto the gold electrode in the presence of the target; the latter was then desorbed. Electrochemical measurements showed selective binding of the corresponding targets. However, the system was unstable; total loss of the receptor properties was already observed after the first adsorption/ desorption cycle [110] or after storage for several hours. Most probably, the cause of this instability was lateral diffusion of molecules in the noncross-linked monolayers, which distorts the receptor structure [111]. A ‘spreader-bar’ approach was suggested to overcome this issue [110]. The method was based on coadsorption of two types of molecules: the ‘template’ molecules, the shape of which is similar to the target but has additional thiol groups providing a strong binding to the surface and the ‘matrix’ molecules (alkanethiols), which also strongly adsorb to the surface forming a monolayer thicker than that of the template. The resulting mixed monolayer is believed to have pores that are the same shape as that of the template molecules This approach can be considered a further extension of the concept of nanoporous monolayers [112], for which there has been a voltammetric investigation of mixed monolayers from a long-chain (nonconductive) alkanethiol and short-chain (conductive) thiocholesterol [113]. Lahav and coworkers [114] produced recognition sites for a naphthacene quinone derivative in a thiol monolayer on gold electrodes through a photochemical imprinting method. Additionally, the low surface energy associated with the methyl

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groups of the alkanethiol monolayer leads to the formation of droplets of hydrophilic compounds on this surface, thus decreasing the number of molecules interacting with the surface. The role of surface hydrophobicity in the permeability of SAMs was also demonstrated by the lower permeability of hydrophobic substances through 11-mercaptoundecanol monolayers in comparison with 18-octadecanethiol monolayer [115]. The permeability of alkanethiol SAMs can be controlled through chemical modification or by formation of multilayers or laterally organized nanostructures [111].

3.4 Development of micro- and nanosized molecularly imprinted polymer materials Micro- and nanosensor chips are embeddable in array systems that are capable of handling a large number of samples at a time. The greatest advantage of micro- and nanostructured MIP materials is not the size itself, but their rapid equilibration with the target, resulting from the limited diffusional length within the object [116]. For multisensor applications, MIP materials have to be suitably patterned on a chip surface interfaced with transducers. Patterning techniques that are compatible with MIP materials are photolithography [117], soft lithography [118] and microspotting techniques [119]. For sensing platforms, thin films of conducting polymers and other types of in situ polymerized and electropolymerized films [120] can be conveniently used as alternative source materials [121]. Arrayed MIP sensors, display low selectivity and there are still unsolved issues regarding the delivery of prepolymerization mixtures, each containing a different template, on a directed transducer surface in a highly precise manner [116].

4. INTERFACING SENSORS’ TRANSDUCERS WITH MOLECULARLY IMPRINTED POLYMERS The main feature of MIP-based sensors is that the MIPs display both recognition and transduction properties; as recognition elements can specifically bind target analytes and transduction elements can generate output signals for detection [122]. Typically, the output detection signals can be classified into three types: optical, electrochemical and piezoelectric according to the transduction mechanism [86,122,123]. And the transducers used are optical transponders, electrodes and piezoelectric crystals. An important aspect in designing MIP-based sensor is to find an appropriate way of interfacing the polymer, in the form of nanometre- or

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micrometre-sized particles, with the transducer. An obvious advantage would be to integrate this step in an automated production process. Thereby, the polymer can either be synthesized in situ at the transducer surface or the surface can be coated with a preformed polymer [86]. MIPs can be synthesized in situ at an electrode surface via electropolymerization. First attempts were made on gold with phenolic monomers, but the layers were thick and uncovered areas had to be blocked with other molecules to prevent nonspecific binding [124]. Significant improvements have been made allowing to depositing films at precise spot of the sensor surface with even a complex geometry [125]. The additional benefit is that the thickness and density can be easily regulated by changing the voltage. The electrodes were stable, responses are reproducible and the selectivity is high, but often detection limits are only in the order of micron/micromolar range, which is often not within the physiologically relevant regime [126]. More applicable are the standard surface coating techniques, spin coating and spray coating, both being used to apply a thin film of monomer solution to acoustic transducer surfaces [127]. With these two techniques, thin layers can be produced, although if radically polymerized vinyl or acrylic systems are used, the coating has to be achieved under inert atmosphere, due to the radical scavenging effect of oxygen which would inhibit the polymerization process [122]. Thus, a suspension of MIP particles in a solution of an inert, soluble polymer (polyvinyl chloride) has been spin-coated onto an acoustic transducer surface [83]. MIPs displaying electrical conductivity facilitate their assembly with an electrochemical transducer in an integrated device. In this context, the preparation of composite materials consisting of an electrically conducting polymer (polypyrrole) and an acrylic MIP is worth mentioning [128]. This method used photo-initiated atom transfer radical polymerization for synthesis of MIPS as monoliths, thin films and nanoparticles. The method was validated with MIPs for testosterone and S-propranolol. The polypyrrole, which was grown into the preformed porous MIP, did not alter its recognition properties; however, in this way MIP particles could be mechanically and electrically connected to a goldcovered silica substrate [123].

5. MICRO- AND NANOSTRUCTURED MOLECULARLY IMPRINTED POLYMERS FOR SENSING DEVICES For multisensor applications, MIP materials have to be suitably patterned on a chip surface interfaced with transducers. However, the low

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fidelity of the imprinting process gives rise to low average binding affinities (102 to 103 M1) and high cross-reactivities [129]. A number of strategies have been developed to enhance the imprinting effect but often detrimental to the efficiency of imprinting. The array format is amenable to the new generation of MIPs without further optimization or modification [51]. Sensor arrays also utilized variety of different signalling mechanisms such as fluorescent competition assays, electrical capacitance, surface plasmon resonance (SPR) and quartz crystal microbalance. Several MIP-based nano- and microsensors and sensor arrays are summarized in Table 4. Table 4 Recent formats for sensor arrays based on micro- and nanostructured molecularly imprinted polymers Sensing materials/ Sensing Template (target) substrates mechanism References

Albuterol

Molecular-imprinting photoresist/Au and Pt electrodes 4,6-Dinitro-o-cresol Electrocopolymerization of aniline and o-phenylenediamine/carbon fibre microelectrode Uracil and 5Free radical thermal fluorouracil polymerization of N-acryloyl-2mercaptobenzamide/Ag electrode electrochemical etching of silver-wire b- estradiol Electropolymerization of N-phenylethylene diamine methacrylamide/Au electrode L-Glutamate, Overoxidized taurocholate, polypyrrole/glassy adenosine carbon, printed triphosphate carbon Fluorescein, 2,4-D 4-Vinylpyridine, trimethylolpropane trimethacrylate/glass

Electrochemistry

[130]

Electrochemistry

Electrochemistry

[131]

Electrochemistry

[132]

Electrochemistry, quartz microbalance, fluorescence Fluorescence

[133] [134] [135] [136]

Adapted with permission from S. Tokonami, H. Shiigi, T. Nagaoka, Anal. Chim. Acta 641 (2009) 7e13. Copyright Elsevier.

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An MIP sensor array selective for carbohydrate analytes was recently developed by Tan and coworkers based on an imprinted mesoporous silica matrix [137]. The MIP array was able to differentiate samples of individual carbohydrates in orange juice. The imprinted mesoporous silica framework was prepared with a phenylboronic acid functionalized triethoxysilane monomer covalently linked to a carbohydrate template (D-fructose or D-xylose). After solegel formation in the presence of channel forming surfactants, the carbohydrate templates were cleaved from the matrix, leaving a surface of free boronic acid binding groups. The binding of carbohydrates to the boronic acid functionalized mesoporous silica was monitored via a competitive binding assay using a catechol-based dye that competes for the boronic acid recognition groups. Binding studies verified the presence of an imprinting effect as all the imprinted materials displayed the highest affinity for their respective templates. This work demonstrates the ability of MIP sensor arrays to distinguish structurally similar nonimprinted analytes. It also highlights one of the key advantages of the array approach, which is the ability to analyse samples without the need to isolate the target from a complex matrix. MIP sensor arrays have been successful in monitoring complex analytes such as monitoring bitterness in tonic water [138], monitoring the headspace above a commercial-type composter [139] and the monitoring of the amount of terpenes emitted by odoriferous plants [51,140]. Metal and semiconductor nanoparticles as optical and fluorescent probes are much more robust in both the repeated and continuous uses than the corresponding organic dyes and can be used as a convenient chemical switch to report analyte uptake when built into an MIP material [116]. Gold nanoparticles (AuNPs) have been most commonly used as a probe material due to its characteristic and intense red colour. Still, there are only a few reports on analytical applications of nanoparticleeMIP systems. Matsui and coworkers reported on the plasmon-band shifts of an MIP-AuNP conjugated film imprinted with adrenaline [141]. The film was prepared by radical polymerization of a mixture consisting of 11-undecanoic acid-protected AuNP (diameter 5.3 nm), N,N-methylenebis(acrylamide), N-isopropylacrylamide, acrylic acid and adrenaline (template). A band shift of 22 nm from 533 nm to 511 nm after equilibration with a 1-mM adrenaline solution was assigned to an increase in the interparticle distance between AuNPs caused by template rebinding. AuNPs were used in the development of an electrochemical MIP based on the noncovalent approach for the detection of 1,3,5-trinitrotoluene (TNT) [142]. The MIP MMOF was formed in situ at the Au electrode surface via electropolymerization of p-aminothiophenol

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(PATP)-functionalized AuNPs in the presence of trinitrotoluene as the template molecule. The construction of the MIP sensor is depicted in Fig. 6. In the first step, a monolayer of PATP is formed at the gold electrode surface via Au/S bonds between gold and thiol groups of PATP. In the next step, the molecularly imprinted MMOF film was deposited on the electrode via electropolymerization in a mixing solution containing PATP-functionalized AuNPs and TNT. The interactions between the electron-poor TNT and the electron-rich PATP promoted the embedding of the host molecules in a three-dimensional polymer-AuNP network. The template was removed from the complex matrix, forming surface imprinted sites. AuNPs have an important role, for the enhancement of the conductivity by increasing the rate of electron transfer, and for the number of imprinted sites, leading to more homogenous distribution of the recognition sites [142]. A linear response was obtained in the range of 4.4 fM to 44 nM, with a detection limit of 0.04 fM.

Figure 6 Schematic representation of the procedure for preparing molecularly imprinted polymer (MIP)-based sensors for 1,3,5-trinitrotoluene (TNT) detection [142].

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Another recent study proposed an approach to the synthesis of magnetic MIPs with high density and accessible recognition sites for the SPR detection of chlorpyrifos (CPF). As depicted in Fig. 7, the magnetic MIPs were synthesized by self-polymerization of dopamine on the surface of Fe3O4 NPs in the presence of template CPF in solution [143]. This method enables the template-imprinting sites to situate at the surface or in the proximity of material’s surfaces; thus, nearly all the recognition sites are accessible to the target and fast association/dissociation kinetics (Fig. 7A) was expected. The results showed that the target molecules were rapidly enriched and separated by the imprinted Fe3O4@polydopamine nanoparticles (Fe3O4@PDA NPs) by an external magnetic field. Integrating the CPF-imprinted Fe3O4@PDA NPs to an SPR chip through the specific interactions between the CPF rebound in the

Figure 7 (A) Schematic illustration of the preparation of magnetic imprinted Fe3O4@ PDA for CPF recognition, (B) schematic illustration of the stepwise preparation process of the sensor surface for CPF detection and (C) illustration of recognition and separation of CPF with imprinted Fe3O4@PDA. CPF, chlorpyrifos; EDC, 1-Ethyl-3(3 dimethylaminopropyl)carbodiimide; MUA, 11-mercaptoundecanoic acid; NHS, Nhydroxysuccinimide. Adapted with permission from G.-H. Yao, R.-P. Liang, C.-F. Huang, Y. Wang, J.-D. Qiu, Anal. Chem. 85 (2013) 11944e11951. Copyright (2013) American Chemical Society.

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recognition cavities in the PDA matrix and the acetylcholinesterase (AChE) immobilized on sensor chip yielded a significant signal amplification due to the high molecular weight of Fe3O4@PDA NPs (Fig. 7B). The biosensor showed a good linear relationship between the SPR angle shift and the CPF concentration over a range from 0.001 to 10 mM with a detection limit of 0.76 nM.

6. MARKET POTENTIAL OF MOLECULARLY IMPRINTED POLYMER SENSORS There are at least three features making the MIP sensors commercially appealing: MIPs are stable and can be autoclaved; they are compatible with microfabrication technology and they are significantly less expensive than antibodies, enzymes or natural receptors [49]. It is also apparent that continuous progress in MIP technology relies on better analytical and rational understanding of MIP synthesis and technology enabling rational design, development and optimization for effective MIPs adaptable to any given target [144]. The most promising areas of MIP sensor applications are diagnostics and health care, as well as security topics (e.g., detecting illegal drugs). Those fields do not necessarily require reversible sensors, but disposable systems. Therefore, they do not particularly require the ruggedness and reusability of biomimetic materials [145]. The market of diagnostic tools is inherently conservative and thus reluctant to replace established techniques with newer ones due to lack of experience or expertise. Apparently, replacing or at least complementing bioreceptors or artificial receptors will not be possible in the immediate future. However, MIPs are amenable to applications requiring long-term stability, such as process control or monitoring air/water quality over extended periods of time [145].

ACKNOWLEDGEMENT The authors would like to acknowledge the financial support of Romanian National Authority for Scientific Research UEFISCDI project 177/2014.

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