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Recent advances in molecular imprinting technology: current status, challenges and highlighted applications Downloaded by Library of Chinese Academy of Sciences on 20 July 2011 Published on 28 February 2011 on http://pubs.rsc.org | doi:10.1039/C0CS00084A

Lingxin Chen,*a Shoufang Xuab and Jinhua Lia Received 18th August 2010 DOI: 10.1039/c0cs00084a Molecular imprinting technology (MIT) concerns formation of selective sites in a polymer matrix with the memory of a template. Recently, molecularly imprinted polymers (MIPs) have aroused extensive attention and been widely applied in many fields, such as solid-phase extraction, chemical sensors and artificial antibodies owing to their desired selectivity, physical robustness, thermal stability, as well as low cost and easy preparation. With the rapid development of MIT as a research hotspot, it faces a number of challenges, involving biological macromolecule imprinting, heterogeneous binding sites, template leakage, incompatibility with aqueous media, low binding capacity and slow mass transfer, which restricts its applications in various aspects. This critical review briefly reviews the current status of MIT, particular emphasis on significant progresses of novel imprinting methods, some challenges and effective strategies for MIT, and highlighted applications of MIPs. Finally, some significant attempts in further developing MIT are also proposed (236 references).

a

Key Laboratory of Coastal Environmental Processes, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai 264003, China. E-mail: [email protected]; Fax: +86-535-2109130; Tel: +86-535-2109130 b Graduate University of Chinese Academy of Sciences, Beijing 100049, China

1. Introduction

Lingxin Chen received his PhD in analytical chemistry from Dalian Institute of Chemical Physics, Chinese Academy of Sciences, China, in 2003. After two years postdoctoral experience in the Department of Chemistry, Tsinghua University, China, he joined first as a BK21 researcher and then as a research professor in the Department of Applied Chemistry, Hanyang University, Ansan, Korea, in 2006. Lingxin Chen Now he is a professor in Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences. His current research interests include chromatographic separation techniques and optical sensor technologies for environmental analysis using novel properties of materials such as functionalization nanoparticles and molecularly imprinted polymers.

Shoufang Xu received her master degree in materials science from East China University of Science and Technology, China, in 2005. She joined the Laboratory of Environmental Microanalysis and Monitoring in Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, as doctoral candidate, in 2009. Her current research interests focus on the preparation of molecularly imprinted Shoufang Xu polymers (MIPs) and application of MIPs in chromatographic separation and analysis of typical organic pollutants.

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Molecular imprinting is known as a technique for creation of tailor-made binding sites with memory of the shape, size and functional groups of the template molecules. The concept of molecular imprinting was first proposed by Polyakov in 19311

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The Royal Society of Chemistry 2011

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Fig. 1 Schematic diagram of the molecular imprinting process by non-covalent imprinting method.

as ‘‘unusual adsorption properties of silica particles prepared using a novel synthesis procedure’’. These ‘‘unusual adsorption properties’’ have been displayed by numerous polymers, which are defined as molecularly imprinted polymers (MIPs).2 MIPs can be synthesized by copolymerization of the functional monomers and cross-linkers in the presence of template molecules. After removal of the template molecules, recognition cavities complementary to the template molecule in shape, size and chemical functionality were formed in the highly cross-linked polymer matrix, which can selectively rebind the template molecules from a mixture of closely related compounds, as shown in Fig. 1.3,4 Compared to other recognition systems, MIPs possess many promising characteristics, such as low cost and easy synthesis, high stability to harsh chemical and physical conditions, and excellent reusability. Consequently, MIPs have become increasingly attractive in many fields, particularly as selective adsorbents for solid-phase extraction (SPE),5–8 chromatographic separation,9 and chemical sensors.10–20

Jinhua Li

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Jinhua Li received her doctorate in analytical chemistry from the Department of Chemistry, Hong Kong Baptist University, Hongkong, in 2009. In the same year, she joined the Laboratory of Environmental Microanalysis and Monitoring in Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, as an assistant professor. Her current research interests focus on chromatographic micro-separation and analysis of typical water pollutants.


There are two main methods to form molecular imprinting, one relying on reversible covalent bonds introduced by Wulff,21 and the other involving non-covalent interactions proposed by Mosbach,22 between imprinted molecules (templates) and functional monomers. In covalent imprinting, typically the templates are bound to appropriate monomers, such as 4-vinylphenylboronic acid and 4-vinylbenzylamine, by covalent bonds. After polymerization, the covalent linkage is cleaved and the template is removed from the polymer. Upon rebinding of the guest molecule by MIPs, the same covalent linkage is formed. Owing to the greater stability of covalent bonds, covalent imprinting protocols yield a more homogeneous binding sites distribution. However, covalent imprinting is also considered as a less flexible method since the formation of identical rebinding linkages requires rapidly reversible covalent interactions between templates and functional monomers. Therefore, templates suitable for covalent imprinting are limited. Moreover, it is very difficult to reach thermodynamic equilibrium due to the strong nature of the covalent interactions and consequent slow binding and dissociation. In contrast, non-covalent imprinting has no such restrictions. In an appropriate solvent, template–monomer complexes are formed relying on various interactions, such as hydrogen bonding, ionic interactions, van der Waals forces, p–p interactions, etc. After polymerization and removal of the template, the functionalized polymeric matrix can then rebind the target (template) via the same non-covalent interactions, so the range of applicative compounds which can be imprinted is greatly expanded. Besides the above-mentioned advantages, a further factor is simplicity in operation since only mixing of templates and monomers in a suitable solvent is required.23 Currently, non-covalent imprinting has become the most popular and general synthesis strategy for MIT. Interestingly, after a covalently bonded template is removed, non-covalent rebinding can also be achieved,24 which is defined as a semi-covalent approach, attributed to Whitcombe et al.25 This method offers an intermediate alternative in which the template is bound covalently to functional monomer as in the covalent approach, but the template rebinding is based on non-covalent interactions. It is characterized by both the high affinity of covalent binding and mild operation conditions of non-covalent rebinding, which will be discussed in detail in section 4.2. Although MIT enjoys significant benefits and diverse applications, it is also associated with many problems such as template leakage, incompatibility in aqueous media, low binding capacity and slow mass transfer. In the present review, we focus on the current status of MIPs (including reagents, traditional synthesis methods), existing problems and several new appealing strategies to those challenges (involving some significant advances in preparing well-designed MIPs, e.g., surface imprinting, semi-covalent imprinting and dummy molecular imprinting), as well as highlighted applications of MIPs. Some novel techniques related to the preparation of MIPs, such as controlled/living radical polymerization (CLRP), block copolymer self-assembly, ionic liquid as solvent, and microwave-assisted heating are also summarized. Finally, we also make some attempts to explore the future development direction of MIT. Chem. Soc. Rev., 2011, 40, 2922–2942

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2. Reagents for molecular imprinting Polymerization reaction is known as a very complex process, which could be affected by many factors, such as type and concentration of the monomer, cross-linker and initiator, temperature and time of polymerization, the presence or absence of magnetic field, and volume of the polymerization mixture. In order to obtain the ideal imprinted polymer, a variety of factors should be optimized. Thus synthesis of MIPs is a time-consuming process. In order to prepare MIPs with perfect properties, numerous attempts have been made to investigate such effects on the recognition properties of the polymeric materials.26 The selection of appropriate reagents is a crucial step in the molecular imprinting process. The synthesis, characteristics, effect of molecular recognition and different preparation methods of MIPs before 2006 have been briefly discussed,27 so more emphasis is placed here on the development of MIPs in recent years. Generally, template molecules are target compounds in analytical processes. An ideal template molecule should satisfy the following three requirements. First, it should not contain groups involved in or preventing polymerization. Second, it should exhibit excellent chemical stability during the polymerization reaction. Finally, it should contain functional groups well adapted to assemble with functional monomers. Most templates applied in molecular imprinting are derived from widespread environmental pollutants, which can be grouped into three broad categories, including endocrine disrupting chemicals (EDCs), pharmaceuticals and toxic metal

Fig. 2

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ions. EDCs have attracted extensive attention when referring to global environmental problems because they can lead to the disturbance of central regulatory functions in humans and wildlife. Worse still, some EDCs are even suspected to cause human infertility or stunt growth of children. Among those EDCs, hormone drugs,28–31 triazine pesticides,32–35 and bisphenol A (BPA)36 are the most widely concerning pollutants used in preparation of MIPs. Pharmaceuticals, including veterinary and human antibiotics, anti-inflammatory agents and b-blockers, have gained increasing attention and interest in the last few years due to their continuous release in the environment, mainly through excretion, disposal of unused or expired drugs, or directly from pharmaceutical discharge.15 In addition, they can cause selective survival of drug-resistant pathogens which may result in various drug-resistant micro-organisms that would become dominant species in the environment, causing great harm to ecosystems as well as mankind. Because of strong polarity and low volatility, aquatic environments are their primary reservoirs. Therefore, preparing water compatible MIPs is a significant development direction for MIT. At present, water compatible MIPs for determination of quinolones in urine,4,37 milk,38 river water,39 and serum40 have been synthesized. Besides quinolones, propranolol,41–44 tetracycline,45,46 digoxin,47,48 dopamine,49 and sulfonamides50,51 imprinted polymers have also been prepared. Heavy metal ions are always the focus of attention owing to their difficulty of degradation and ease of bio-enrichment. Ionic imprinted polymers are an important branch of MIPs.

Structures of commonly used functional monomers and cross-linkers.

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Up to now, ionic imprinted polymers for the determination of Cu2+,52–54 Eu2+,55 Pd2+,56 Sm3+,57 Cd2+,58 Ni2+,59 Zr4+,60 and Zn2+ 61 have been synthesized and displayed excellent recognition ability to template ions. The role of the monomer is to provide functional groups which can form a complex with the template by covalent or non-covalent interactions. The strength of the interactions between template and monomer affects the affinity of MIPs52,62 and determines the accuracy and selectivity of recognition sites.63 The stronger the interaction is, the more stable the complex is, resulting in the higher binding capacity of the MIPs, and therefore, correct selection of the functional monomers is very important. Tedious trial-and-error tests are often required to select a suitable monomer. In order to perform rational design and convenient synthesis of MIPs, several strategies, such as spectroscopic measurement (e.g., nuclear magnetic resonance,64–67 UV-vis,68,69 Fourier-transform infrared spectroscopy),70,71 computer simulation,72 and isothermal titration calorimetry73 have been employed to select optimal functional monomers capable of forming more stable complexes with templates. Research on how to choose and evaluate appropriate functional monomers has been reviewed recently.74 Commonly used monomers for molecular imprinting include methacrylic acid (MAA), acrylic acid (AA), 2- or 4-vinylpyridine (2- or 4-VP), acrylamide, trifluoromethacrylic acid and 2-hydroxyethyl methacrylate (HEMA). Structures of several typical monomers are listed in Fig. 2. MAA has been used as a ‘‘universal’’ functional monomer due to its unique characteristics, being capable to act as a hydrogen-bond donor and acceptor, and showing good suitability for ionic interactions.75 Attempts have been made to seek new functional monomers adapted to the synthesis of MIPs. Due to their special structures, b-cyclodextrins (b-CDs) have aroused extensive interest as attractive candidate monomers for molecular imprinting. b-CDs are a series of cyclic oligosaccharides with a hydrophilic exterior and a hydrophobic cavity,76 which have some unique superior features when compared with traditional functional monomers. For example, b-CDs can form complexes with the template through various interactions, such as hydrogen bond interaction, van der Waals forces, hydrophobic interaction, or electrostatic affinity. The hydroxyl group on b-CDs can act as a polymerization terminal and then form a stable polymer matrix by virtue of a suitable cross-linker. b-CDs have been used as functional monomers or co-monomers to imprint various compounds, such as cholesterol,77 tryptophan,78 ursolic acid,79 bilirubin,80 dextromethorphan,81 and cyclobarbital.82 Generally, the molar ratios between template and monomer in the synthesis process affect the affinity and imprinting efficiency of MIPs. Lower molar ratios induce less binding sites in polymers due to fewer template–monomer complexes, but over-high ones produce higher non-specific binding capacity, diminishing the binding selectivity. So, in order to gain high imprinting efficiency, the molar ratio of templates to monomers should be optimized. The role of the cross-linker is to fix functional groups of functional monomers around imprinted molecules, and thereby form highly cross-linked rigid polymer. After removal This journal is

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of templates, the formed holes should completely complement to target molecules in shape and functional groups. Types and amounts of cross-linkers have profound influences on selectivity and binding capacity of MIPs. When the dosage of cross-linkers is too low, MIPs cannot maintain stable cavity configurations because of the low cross-linking degree. However, over-high amounts of cross-linkers will reduce the number of recognition sites per unit mass of MIPs. Commonly used cross-linkers involve ethylene glycol dimethacrylate (EGDMA), trimethylolpropane trimethacrylate (TRIM), N,N-methylenebisacrylamide (MBAA) and divinylbenzene (DVB), etc. Their structures are displayed in Fig. 2. Porogenic solvent plays an important role in polymerization. It acts as not only a porogen but also solvent in preparation process. Besides, it also influences the bonding strength between functional monomers and templates, the property and morphology of polymer, especially in non-covalent interaction system. Aprotic and low polar organic solvents, such as toluene, acetonitrile and chloroform are often used in non-covalent polymerization processes in order to obtain good imprinting efficiency. It is notable that MIPs prepared in organic solvent work poorly in aqueous media because of the ‘‘solvent memory’’. The development of water-compatible MIPs is a notable area and will be discussed in section 4 ‘‘Challenges for MIT’’.

3. Synthesis methods of MIPs The mechanism of MIP formation includes free-radical polymerization and sol–gel process. Considering the advances in sol–gel process have been reviewed recently by Gupta,83 here we put more emphasis on free radical polymerization. Bulk polymerization is the most popular and general method to prepare MIPs due to its attractive properties, such as rapidity and simplicity in preparation, with no requirement for sophisticated or expensive instrumentation, and purity in the produced MIPs. However, the monolithic polymer obtained by bulk polymerization has to be crushed, ground and sieved to an appropriate size, which is time-consuming and would reduce polymer yield (only 30–40% of polymer recovered as usable material). In addition, grinding operation results in irregular particles in shape and size, and some high affinity binding sites are destroyed and changed into low affinity sites. Bulk polymerization yields polymers with a heterogeneous binding site distribution which thus greatly confines the use of MIPs as chromatographic adsorbents.84 In order to overcome these drawbacks of bulk polymerization, a variety of attractive polymerization strategies have been proposed, such as suspension polymerization,46 emulsion polymerization,85,86 seed polymerization82 and precipitation polymerization. Since the post-treatment steps required in bulk polymerization are not necessary when the alternative polymerisation strategy is used, a more homogeneous binding site distribution should be obtained.87 Among the mentioned polymerization methods, typically, MIPs were prepared by conventional suspension polymerization, where water is used as a continuous phase to suspend a droplet of pre-polymerization mixtures in the presence of a stabilizer or surfactant.88,89 There are some very successful suspension Chem. Soc. Rev., 2011, 40, 2922–2942

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polymerization reports, widely applied for covalent and non-covalent MIT.88–91 However, the MIPs prepared by suspension polymerization are polydisperse in size (a few to a few hundred micrometres). Moreover, MIP microspheres made by suspension polymerization displayed poor recognition. The reason may be that water can weaken the non-covalent interactions, such as hydrogen bonding and electrostatic interactions between template molecules and functional monomers. Moreover, stabilizer or surfactant could interfere with interactions between template molecules and functional monomers. In view of this, recently, two new suspension polymerization techniques based on droplets of pre-polymerization mixtures in liquid perfluorocarbon92 or mineral oil (liquid paraffin)93 have been developed. Liquid perfluorocarbons immiscible with almost all organic solvents, monomers and cross-linkers, which are employed for MIPs preparation, could be utilized.92 However, perfluoro polymeric surfactant is required. As for the droplet formation of mineral oil, no stabilizers or surfactants were required.93 However, neither chloroform, nor dichloromethane, nor toluene, which is generally used as porogen in molecular imprinting, could be used with mineral oil because these solvents are miscible with mineral oil. Both methods give polydispersed beads as well as suspension polymerization in water. As for emulsion polymerization, it has long been regarded as an effective method to produce high-yield, monodispersed polymeric particles.85 It is successfully employed for protein imprinting.85,86 On the other hand, emulsion polymerization also suffers from the presence of remnants of surfactant. Another method termed seed polymerization, a typical multi-step swelling and polymerization, is readily used to prepare monodispersed MIPs and to perform in situ modification.82,94 However, the use of water as a continuous phase interferes with the interactions between template molecules and functional monomers. In addition, the multistep procedure is time-consuming. Precipitation polymerization, enjoying some advantages in synthesizing spherical particles such as stabilizers and free of surfactant, in one single preparative step and with excellent control over the particle size, is a most promising approach to produce high-quality, uniform and spherical imprinted particles. The four-above mentioned polymerization methods mostly used to prepare spherical particles all have a number of advantages and disadvantages. The former three polymerization methods have been comprehensively reviewed,16,94 whereas reviews on precipitation polymerization are relatively few. Therefore, here, more emphasis has been placed on precipitation polymerization. Then, as a newer and competitive synthesis method, surface imprinting is also discussed comprehensively. The other novel polymerization method associated technologies including controlled/living free radical polymerization (CLRP), block copolymer selfassembly, microwave-assistant heating and ionic liquid as porogen, are also summarized. In order to illustrate different polymerization methods clearly, schematic diagrams concerning the different polymerization methods are displayed in Fig. 3. 2926

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3.1 Precipitation polymerization In precipitation polymerization (PP), more porogen (495%, wt) is used than in bulk polymerization method. The growing polymer chains do not overlap or coalesce but continue to grow individually by capturing newly formed oligomers and monomers in this diluted reaction system and then were separated from the solution with microspherical morphologies.46 Table 1 summarizes MIPs synthesized by PP.8,46,84,95–111 To satisfy different application purposes, MIPs with well controlled physical conformations in different size ranges are highly desirable. Many attempts have been made to evaluate the effect of factors upon sizes and shapes of the obtained particles during PP.97,98 According to Wang et al.,112 an adequate match between the solubility parameters of the developing polymer and the polarity of the porogen enables preparation of polymer beads with permanent pore structures and highly uniform particle sizes. As a rule of thumb, the solubility parameter of solvent should be 3–5 (MPa)0.5 away from that of polymer in order to obtain uniform particles. Another factor affecting the particle size is the cross-linker used in polymerization. By changing the ratio of TRIM to DVB, the particle size of the racemic propranolol imprinted polymer beads altered in the range of 130 nm to 2.4 mm.107 In addition, polymerization temperature has a profound impact on the particle size. For poly(MAA-co-TRIM) particles prepared by PP, when the polymerization temperature was increased from 4 to 83 1C, the particle diameter decreased from several micrometres to several nanometres.113,114 Stirring speed also can affect the mean diameter size of the sedimented polymer according to classical fluid mechanics. An increase in the stirring speed considerably increases the amount of bigger-sized polymer particles.96 It has been pointed out that the diameter of the particles decreased with increasing of porogen volume because under dilute conditions less oligomer and nuclei were formed during polymerization, and therefore, less radical monomer and cross-linker diffused to the surface of nuclei and grew up into the particles.107,115 Interestingly, even under the same synthesis conditions, the size and size dispersibility of MIPs are not identical with those of non-imprinted polymers (NIPs),84,107 which can be explained by that the template altered the solubility of the growing polymer chain by forming template–monomer complexes, and thereby influenced the nucleation and growth process of the cross-linked particles. The template used in polymerization has a direct influence on the final morphology of the polymer obtained, as reported by Cacho et al.97 Fenuron imprinted polymer displayed discrete uniformly sized microspheres while propazine imprinted polymer consisted of agglomerates of different sizes. The same conclusion was obtained by Tamayo et al.98 when they prepared MIPs by PP for the extraction of phenylurea herbicides by using linuron or isoproturon as template. In addition to template, the functional monomer used in polymerization also has profound influence on the morphology of obtained polymer. Sambe et al.100 synthesized MIPs for nicotine via PP by using MAA or TFMAA as functional monomer and DVB as cross-linker in a mixture of toluene This journal is

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While PP enjoys some advantages, this process is not without its problems. One problem is that a large volume of porogen (495%, wt) is necessary during PP, which will also increase the cost and lead to environmental pollution. Jin et al.104 proposed a new method to prepare narrowly dispersed molecularly imprinted microspheres by a modified PP method by using a smaller amount of porogen (about 50 wt%). The modified PP used ultraviolet radiation to initiate the process and used a mixture of mineral oil and toluene as porogen. The prepared MIPs possess similar binding selectivity and higher binding capacity compared to microspheres synthesized by traditional precipitation polymerization (TPP). Another problem associated with PP is the long polymerization time. Long polymerization time was used in order to increase the rigidity of the polymer structure and facilitate the formation of imprinted cavities with better defined shapes.27 However, propranolol-imprinted nanoparticles were obtained in less than 3 h by using distillation precipitation polymerization (DPP) proposed by Yang et al.114 Unlike TPP performed at lower temperature for 24 h, DPP was carried out in neat acetonitrile under refluxing conditions, with half of the reaction solvent being distilled off in the latter phase of the polymerization. Fig. 3 Schematic diagrams of the molecular imprinting process for bulk polymerization (1); suspension polymerization or emulsion polymerization (2a); surface imprinting (3) and hollow imprinted polymers (4a). Template removal and rebinding in solid spherical MIPs, core–shell structured MIPs and hollow MIPs are shown in 2b, 3 and 4b, respectively. (m, black, templates in MIPs; & recognition sites shaped in MIPs after removal of templates; m, red, rebound templates in recognition sites).

and acetonitrile. The nicotine imprinted MAA-co-DVB polymers were monodisperse microspheres, while the TFMAAco-DVB ones were gel-like.

Table 1

3.2 Surface imprinting There are several compelling reasons to use surface imprinting approach. Most importantly, extraction of the original templates located at interior area of the bulk materials is quite difficult due to the high cross-linking nature of MIPs, which will result in incomplete template removal, small binding capacity, and slow mass transfer, as can be seen from Fig. 3. Fortunately, this problem can be resolved by surface imprinting, in which the imprinted templates are situated at the surface or in the proximity of the material’s surface.116 Compared to traditional MIPs, surface imprinted polymers possess not only

MIPs synthesized via precipitation polymerization

Template molecule

Target molecule(s)

Monomer/cross-linker/porogen

Tetracycline Carbamazepine Malachite green Thiabendazole Thiabendazole Propazine Linuron or isoproturon BPA (S)-Nicotine Ciprofloxacin Nickel(II) 4-Nitrophenol Theophylline or caffeine BPA, TBZ or estradiol 2,4-D 17b-Estradiol R-Propranolol Cinchonidine Hydroquinone

TC antibiotics CBZ, OCBZ MG/GV Benzimidazole compounds Benzimidazole fungicides Triazinic herbicides Phenylurea herbicides BPA Nicotine Fluoroquinolone antibiotics Nickel(II) 4-Nitrophenol Theophylline or caffeine BPA, TBZ or estradiol 2,4-D Sterol compounds Propranolol Cinchonidine Hydroquinone

MAA/TRIM/methanol–ACN MAA/DVB/ACN–toluene MAA/EDMA/ACN MAA/EDMA or DVB/ACN–toluene MAA/DVB/ACN–toluene MAA/EDMA/toluene MAA or TFMAA/EDMA/toluene 4-VP/TRIM/ACN MAA or TFMAA/DVB/ACN–toluene MAA/EDMA/methanol 4-VP/DVB/ACN–toluene MAA/EDMA/ACN MAA/DVB/ACN–toluene 4-VP/EDMA/mineral oil–toluene 4-VP/EDMA/methanol–water TFMAA/TRIM/ACN MAA/DVB + TRIM/ACN MAA + HEMA/DVB/ACN–toluene MAA/TRIM/ACN–toluene

p-Acetaminophenol b-Estradiol

p-Acetaminophenol b-Estradiol

MAA + GMA/DVB/ACN–toluene MAA/DVB or TRIM/ACN–toluene

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Application method

Sample source

MISPE MISPE MISPE-HPLC MISPE On-line MISPE

Foodstuffs Human urine Aquatic product Tap, river, well water Tap, river, well water

Ref.

46 84 8 95 96 97 MISPE Corn 98 HPLC Tap, lake water 99 On-line HPLC Cigarette smoke extract 100 MISPE Soil 101 MISPE Seawater 59 On-line MISPE Water 102 — — 103 — — 104 — — 105 MISPE Milk powder 106 — — 107 HPLC — 108 Electrochemical — 109 sensor — — 110 MISPE Surface water 111

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higher binding capacity but also faster mass transfer and binding kinetics. Several strategies for surface imprinting have been examined, such as use of immobilized template,117 initiator on supporting matrix,118 and combined surface imprinting with CLRP.119 Many particles have been used as supports in the surface imprinting process, such as activated silica gel,51,120 Fe3O4 magnetic nanoparticles,34,121 chitosan,122 activated polystyrene beads,118 quantum dots (QDs),123,124 and alumina membranes.125–127 Among the above-mentioned support particles, activated silica gel shows promising characteristics, because it is a non-swelling inorganic material, and is stable under acidic conditions. Besides, activated silica gel has high thermal resistance. Surface imprinting using silica gel as support has been applied to imprint EDCs,120,128 pharmaceuticals,129,130 protein,131 and metal ions.58,132 It has been well established that magnetic separation is an effective technique for separation of complicated samples, based on its fast recovery, high efficiency, low cost, and direct purification of crude product from a mixture without any pretreatment. In recent years, magnetic composite modified MIPs have become a hotspot based on the significant advantages of magnetic separation over conventional methods.45,85,121,125,133 Generally preparation of MIPs-coated magnetic nanoparticles (MNPs) such as Fe3O4 MNPs involves three consecutive steps: (1) preparation of Fe3O4 MNPs; (2) surface modification of Fe3O4 MNPs for hydrophobicity to favor surface polymerization, with TEOS, oleic acid, ethylene glycol or poly(vinyl alcohol) and (3) synthesis of surface imprinted MNPs using a sol–gel process or free radical polymerization. For example, Wang et al.121 synthesized MIP-coated MNPs by a sol–gel method for the separation of estrone. Fe3O4 MNPs were first prepared by coprecipitation using FeCl24H2O and FeCl36H2O as raw materials. Then the Fe3O4 MNPs obtained their hydrophobic shell by reaction with TEOS. Estrone-imprinted MNPs were synthesized by condensation of TEOS and IPTS in the presence of estrone. After binding the target molecule, the black MNPs can be easily separated by using an external magnetic field to replace the centrifugation and filtration step in a convenient and economical way. Compared to silica surface imprinting, the MNPs surface imprinting had the remarkable superiority of magnetic separation besides surface imprinting. The advent of the magnetic surface imprinting technique opens up a new approach for surface imprinting, and therefore has promoted the development of MIT. In recent years, MIT have experienced an explosion towards nanotechnology motivated by enormous advantages offered by nanoscale materials. Considering that nanotubes have also been employed for a broad range of important applications in biosensors, biocatalysis, biorecognition and drug delivery, molecular imprinting in nano-porous alumina membranes (NP AMs) is an effective way to develop MIPs.117,119,125–127 Synthesis of silica nanotubes or nanowires involves several successive steps.116 First, inner walls of AM pores with a mean diameter of 100 nm were commonly modified to immobilize imprinting templates within the pores of AMs. Then templateimmobilized AMs were immersed into the prepolymer mixture comprised of functional monomer and cross-linker. After 2928

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polymerization and removal of AMs and template, molecularly imprinted nanotubes were produced. Because the binding sites were situated at the surface of nanotubes, the mass transfer in imprinted nanotubes is faster. As reported by Xie et al.,126 2,4,6-trinitrotoluene (TNT)imprinted silica nanotubes were synthesized using the sol–gel reaction of 3-aminopropyltrimethoxysilane (APTS) and TEOS in the pores of AMs. First, AMs were chemically modified by APTS, leading to the formation of APTS monolayers on the alumina pore walls. Then APTS-modified AMs were immersed into sol–gel precursors comprised of template molecule (TNT), APTS and TEOS. After the gelation process, followed by dissolving AMs with aqueous phosphoric acid and removal of template, a high density of recognition sites to TNT molecules were created on the walls of highly uniform silica nanotubes. Because the inside and outside surface of silica nanotubes are open to analytes and the wall thickness of the nanotubes is only 15 nm, most of the binding sites on the surface or in the proximity of surface, provide good site accessibility and low mass-transfer resistance. The binding capacity of imprinted nanotubes (5.6%) is about 8.0 fold that of non-imprinted nanotubes (0.7%), while the maximum uptake capacity of the nanotubes is nearly 3.6 times that of bulk particles. To further increase the binding capacity and improve binding kinetics, single-hole hollow polymer microspheres for specific uptake of TNT were prepared by the same group.134 In this process, carboxyl-capping polystyrene beads were used as adsorbed substrates for precipitation polymerization. Then a consecutive two-step procedure including pre-polymerization and polymerization was carried out, which resulted in hollow MIPs with a single hole in the shell. The target molecule can easily diffuse into the interior sites of hollow MIPs through the open holes, leading to a higher binding capacity and faster kinetics for the uptake of target molecule than that of solid microspheres. Other strategies for surface imprinting, such as the use of CLRP method, immobilization of imprinting templates on matrix, and sacrificial supports, will be discussed in section 3.3 and 4.1, respectively. 3.3 Novel technologies for MIPs Besides the above-mentioned synthesis strategies, many more novel technologies have also been introduced into MIT for preparing attractive and competitive well-designed MIPs over the latest years. Controlled/living free radical polymerization (CLRP). CLRP techniques including reversible addition-fragmentation chain transfer (RAFT) polymerization, metal-catalyzed atom transfer radical polymerization (ATRP), nitroxide-mediated polymerization (NMP) and iniferter, have been extensively studied and exploited for the production of well-defined polymers with well defined molecular weight, low polydispersity, controlled composition and functionality.135 CLRP involves a thermodynamically controlled process with negligible chain termination and much slower rate for the polymer chain growth over conventional free radical polymerization. This greatly improves the match between the chain growth and chain relaxation rates, and therefore produces a homogeneous This journal is

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polymer network with a narrow distribution of the chain length. Recently, CLRP technique has been utilized to synthesize MIPs owing to its intrinsic advantages over conventional free radical polymerization, which opens a new way to develop MIT.136–139 As discussed in section 3.2, surface imprinting is a most appealing way to prepare MIPs with cavities at the material surface or close to the surface, facilitating the mass transfer of template. However, this procedure is still confronted with a severe challenge on issues of gelation due to the persistence of initiator in solution. To overcome this problem, Sulitzky et al.140 proposed a new way to graft MIP films on silica supports containing surface-bound free radical initiators. However, it was associated with the problem that the solutionphase radical species led to heterogeneous sites, and peak tailing was serious when the obtained MIPs were used as stationary phase. Afterward, an improved method by using photoiniferter (initiator transfer agent terminator) as initiator was proposed by the same group.141 Under UV irradiation, the iniferter decomposes into active radical, which bonded to the support surface and initiates polymerization, and the non-active radical remaining in solution mainly reacts with the growing radical to form a ‘‘dormant species’’. Therefore, the stable dithiocarbamate radical in solution did not initiate solution-phase polymerization, and thus gelation could be avoided effectively, significantly different from those of traditional initiators. So, the method is highly recommended. Due to its good control over molecular weight and dispersity of the product, a good tolerance for functional groups, and a broad selection of monomers, ATRP has become a popular means for preparing graft polymer brushes. Wang et al.119 grafted ATRP initiator and 2-bromo-2-methylpropionyl bromide onto APTS silanized porous anodic alumina oxide (AAO) membrane, then the AAO membrane was used as macroinitiator to initiate a prepolymer mixture comprised of b-estradiol as template, 4-VP as functional monomer, and EGDMA as cross-linker in the presence of CuBr and 1,4,8,11tetraazacyclotetradecane as organometallic catalyst. The ATRP initiated MIP nanotubes have 11-fold higher binding capacity compared to traditionally formed bulk MIPs. The result shows that the ATRP route is an efficient way to prepare MIPs with uniform pores and adjustable thickness. Recent years have witnessed that RAFT is an ideal candidate for CLRP, not only due to its versatility and simplicity, but also because the polymerization products are free from the contamination of metal catalysts used in ATRP. RAFT has been applied for preparation of MIPs by bulk polymerization,139 precipitation polymerization,105 and surface imprinting.136,142 Titirici et al.136 synthesized thin films of MIPs via RAFT polymerization for determination of L-phenylalanine anilide. The effect of the RAFT agent is well illustrated in Fig. 4.136 Particles prepared by RAFT mediated grafting appear smooth and show no agglomeration (Fig. 4A and B). By contrast, during the polymerization in the absence of chain transfer agent, solution polymerization might easily occur, which leads to complete immobilization of the silica particles at higher conversions (Fig. 4C and D). Lu et al.143 reported a general protocol for preparing surface-imprinted core–shell nanoparticles via surface RAFT This journal is

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polymerization using RAFT agent functionalized silica nanoparticles as the chain-transfer agent by copolymerization of 4-VP and EDMA in the presence of 2,4-D as template. Pan et al.105 prepared MIPs by RAFT precipitation polymerization for determination of 2,4-D. The RAFT route is established as an efficient procedure for the preparation of MIPs, which can be ascribed to the intrinsic mechanical characteristics of RAFT. Block copolymer self-assembly. Recently, polymer selfassembly, especially block polymer self-assembly has been rapidly developed. The self-assembly of block copolymers in selective solvents has been comprehensively reported.143,144 Block copolymers form micelles in the selective solvent with insoluble block as core and soluble block as shell. Based on this principle, it is possible to design molecularly imprinted core–shell nanoparticles via self-assembly of block polymers in selective solvents. Fig. 5 shows the schematic diagram of the preparation process for MIP-nanospheres by diblock copolymer self-assembly.145 First, the diblock copolymer was synthesized with one block containing functional groups for both hydrogen bond formation and cross-linking. After forming a hydrogen-bonding complex with the template, the block copolymer was allowed to self-assemble to form spherical micelles in a selective solvent. Then the desired structure was locked by cross-linking. After removing template, complement sites to the template were formed in the core–shell structured nanospheres. Li et al.145 prepared uniform spherical core–shell nanostructured MIPs by combining molecular imprinting and the block copolymer technique. First, the diblock copolymer, poly[(tert-butylmethacrylate)-block-(2-hydroxylethyl methacrylate)], was synthesized by CLRP. Then, 2-acrylamide6-carboxylbutyl amidopyridine and the cross-linkable methacryloyl side group was introduced. The resulting diblock copolymers formed hydrogen bonded complexes with 1-alkyluracil or 1-alkylthymine derivatives. After self-assembly in cyclohexane followed by cross-linking, a uracil or thymine template was embedded within the core. After removal of template, the resultant MIPs demonstrated higher rebinding capacity, faster and complete removal of template, and better dispersibility in solvent than traditional bulk MIPs. It should be noted that MIPs with different properties such as water solubility can be synthesized by adjusting the length, polarity and sequences of the blocks. To our knowledge, there are few reports on MIPs synthesized by the block copolymer self-assembly technique due to the complicated procedure. However, the use of block copolymer self-assembly to prepare MIPs is considered advantageous for method development. Microwave-assisted heating. Microwave heating technique has experienced extensive development and application. Due to the property of heating speed, integrity, selectivity and efficiency, microwave heating has been widely applied in synthesis, sintering, sterilization and other areas. A kind of novel magnetic MIP (mag-MIP) beads were synthesized,34 via suspension polymerization by microwave heating, for separation of trace triazines in spiked soil, soybean, lettuce and millet Chem. Soc. Rev., 2011, 40, 2922–2942

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solvent by combining sol–gel process with sacrificial spacer MIT.120 A homogeneous mixture solution was formed in the sol–gel procedure, showing excellent solvation quality of ionic liquid. The imprinted silica particles possessed high specific recognition property and binding capacity towards testosterone. Subsequently, RTIL was used by Xu et al.152 when they prepared dichlorvos imprinted polymers. The drawback of traditionally prepared MIPs, such as their tendency to shrink or swell when exposed to different solvents and the morphology change of the polymer network, could be avoided. Furthermore, ionic liquids with designable structures are more environmentally friendly than traditional organic solvents due to their negligible vapor pressure. Using ionic liquid as porogenic solvent has provided new promising opportunities for the preparation of MIPs.

4. Challenges for MIT Fig. 4 SEM microphotographs of MIP particles prepared in the presence (A and B) or absence (C and D) of chain transfer agent. Adapted from ref. 136.

As mentioned above, appealing features of MIPs might retain the affinity and selectivity of antibodies, enzymes or biological receptors, while adding several benefits including greater stability, ease of production, and lower cost.87 Meanwhile, at present, MIT still faces severe challenges, such as imprinting biological macromolecules, template leakage, low binding capacity, and incompatibility with aqueous media. To address the existing problems of MIT and to improve the performances of MIPs, significant attempts have been made during recent years. 4.1 Protein imprinting

Fig. 5 Schematic representation of the preparation process for MIPnanospheres by diblock copolymer self-assembly. Adapted from ref. 145.

samples. The produced mag-MIP beads are suitable to prepare samples for trace analysis in complicated matrices. Interestingly, the polymerization time was dramatically shortened by using microwave heating in polymerization, which was less than one tenth that by conventional heating. Moreover, the mag-MIP beads prepared by microwave heating showed a remarkably improved imprinting efficiency compared to that prepared by conventional heating. The microwave heating technique was proved a novel, advantageous and simple integrated technique for molecular imprinting. Ionic liquid as porogen. Room-temperature ionic liquids (RTILs) are substances with melting points at room temperature, composed solely by ions. RTILs have some excellent characteristics, such as low melting point and saturated vapor pressure, non-flammability, good thermal stability, tunable viscosity, miscibility with water and organic solvent, RTILs have been widely employed in many aspects, such as extraction and separation,146,147 catalysis,148,149 and electrochemistry.150,151 Now the use of RTILs has been extended as solvents in MIPs preparation process. Molecularly imprinted silica particles for selective recognition of testosterone were prepared using 1-butyl-3-methylimidazolium tetrafluoroborate as porogenic 2930

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Imprinting water-soluble biological macromolecules is very challenging in the molecular imprinting field since they need to be imprinted under conditions close to their natural environments to ensure conformational integrity. Apart from this, large structures of biological macromolecules might also result in restricted mobility within highly cross-linked polymer networks, and poor rebinding efficiency. Many strategies have been proposed to prepare biological macromolecule-imprinted polymers, especially protein-imprinted polymers, such as surface imprinting,127,131 epitope-mediated imprinting,153–155 micro-contact imprinting,156 metal coordination procedure,157,158 and protein imprinted hydrogel.159 Progress achieved in protein imprinting before 2007 have also been summarized by Bossi,160 Janiak,161 Turner,162 and Hansen.163 Among the techniques used for protein imprinting, surface imprinting is currently the most popular and general method to solve the problem of diffusion limitation caused by large size of protein. Controlling the template molecules to locate at the surface of imprinted materials is typically carried out by the covalent immobilization of template molecules at the surface of solid substrates, which has some advantages. For example, templates insoluble in the prepolymerization mixture can be easily imprinted through this method while template aggregation could be minimized and thereby binding sites could be more homogeneous. Commonly, the process of protein immobilized imprinting involves five consecutive steps, as shown in Fig. 6. First, amino-groups are introduced into the support surface followed by introduction of aldehyde groups via the reaction of amino and glutaraldehyde. Polymerization This journal is

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Fig. 6 Schematic diagram for protein immobilized surface imprinting process.

occurs after the template protein is immobilized on the support surface by a covalent bond. After removal of template, specific binding sites for protein will be generated at the surface of imprinted materials. This method has been used for protein imprinting on various particles such as silica,131,164 MNPs,86 and chitosan.165 A novel surface imprinting approach combining immobilized template with sacrificial support, has proven to be an effective technique for protein imprinting by Yang et al.127 when they used nanoporous alumina membranes as sacrificial support to synthesize surface imprinted nanowires for the detection of protein. Because the imprinted sites were located at the surface, the imprinted nanowires exhibit good site accessibility toward target protein. Meanwhile, the large surface area of nanowires resulted in large binding capacity. The disadvantage of this kind of protein imprinting method is that it requires a multistep treatment of the support matrix before attaching the protein. To simplify this process, Menaker et al.166 presented a new approach; instead of nanoporous alumina membranes, polycarbonate membrane filter with cylindrical pores (F = 8 mm) was used as a sacrificial microreactor since polycarbonate membrane is hydrophobic in nature and can adsorb protein molecules, which offers a straightforward method for fixing the target protein on the pore walls by simple physical adsorption. Relying on antibody–antigen interaction mechanism, using an exposed protein fragment (a short peptide or amino acid residue (histidine)) as template is another efficient way for protein imprinting, denoted as epitope-mediated imprinting.153,167 Those imprinted polymers having recognition ability for peptide or histidine also display selective recognition for the corresponding proteins. Fig. 7 shows the differences between epitope-mediated imprinting and protein-engaged imprinting.154 Epitope-mediated imprinting has several intrinsic advantages, such as avoidance of embedding of target protein and minimal nonspecific interactions between MIPs and proteins. Moreover, all of the proteins bonded to the MIPs are arranged in suitable orientation. This proposed method allowing capturing target protein is mainly based on genomic information in comparison with other mentioned protocols. Epitope imprinting facilitates This journal is

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the removal of the template after the polymerization and reduces the fabrication cost because it does not require high-purity protein for the imprinting. However, the access of macromolecules is still hindered in the highly cross-linked MIPs. Proteins are water-soluble biological macromolecules, so it is invaluable to prepare protein imprinted polymers with recognition property in aqueous media. There have been new developments to imprint proteins in water in recent years. Considering that water can weaken the hydrogen interaction between templates and monomers, metal-chelates155,157,158 and hydrophobic interactions168 were employed when imprinting in aqueous media. The former is based on the fact that strong metal chelating interactions exist between amino acids on the protein surface and metal ions, and in terms of strength, specificity, and directionality, metal coordination interaction is stronger than hydrogen bonding or electrostatic interaction in water. For example, O¨zcan et al.155 prepared MIPs for selective separation of cytochrome c (surface histidine exposed protein) using N-methacroloyl-(L)-hisdidine-copper as a new metal-chelating monomer via metal coordination interaction and histidine template. Subsequently, N-(4-vinyl)benzyl iminodiacetic acid, forming a coordination complex with the template protein in the presence of Cu ions, was used as functional monomer to prepare macroporous thermosensitive imprinted hydrogels for recognition of lysozyme.158 The results indicated that the imprinted polymer with metal coordinate interaction had higher adsorption capacity than that of both the imprinted polymer without the coordinate interaction and the nonimprinted polymers. However, this approach was restricted to protein targets that have exposed histidine residues on their surface. Hydrophobic interaction, together with shape recognition mechanism, can provide satisfactory selectivity toward the template protein as reported by Tan et al.168 4.2 Heterogeneous binding sites Heterogeneous binding sites often exist in MIPs formed by non-covalent interactions because the pre-polymerization step is a non-well defined process, which results in the formation of complexes with different ratios of template to monomer, and then leads to different binding sites. On the other hand, excess monomers are used in order to form template–monomer complexes, which also might cause the formation of nonselective binding sites.102 To overcome this limitation, a semi-covalent approach was proposed,169 also known as sacrificial spacer method, in which the template is bound covalently to a functional monomer as in the covalent approach, but the template rebinding is only based on non-covalent interactions. Because of the coupled advantages of covalent binding (strict control of functional group location and more uniform distribution) and non-covalent binding (reduced kinetic restriction during rebinding), the semi-covalent approach shows strong template binding and efficient rebinding.170 The commonly used semi-covalent binding is the thermally reversible urethane bond formed between an isocyanate and a phenol which is stable at room temperature, but reversible Chem. Soc. Rev., 2011, 40, 2922–2942

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Fig. 7 Comparison of epitope-mediated imprinting and proteinengaged imprinting. Adapted from ref. 154.

cleavage occurs at elevated temperatures.171 Various functional groups can be introduced into the binding cavities via using different nucleophiles during the removal of the template. The isocyanato group is converted to an amino group in the presence of H2O, while it was possible to introduce hydroxyl groups by adding ethylene glycol instead of H2O. An elegant example of this approach is that Ki et al.171 used this thermally reversible urethane bond to imprint estrone on the surface of silica spheres. The monomer–template complex was prepared by the reaction of IPTS and estrone, then the estrone imprinted polymers were prepared by sol–gel process. In subsequent years, the same thermally reversible urethane bond was used for imprinting of testosterone,120 estrone121 and active diosgenin.172 The template can reach the imprinting sites easily and quickly during the rebinding step in the form of non-covalent binding. In addition to the above mentioned semi-covalent imprinting methods, some others were also exploited. For example, semi-covalent imprinted polymers were prepared by using propazine methacrylate as a template molecule, EGDMA as cross-linker and toluene as porogen via PP for clean-up of triazines in soil and vegetable samples.24 Propazine methacrylate was synthesized by the reaction of propazine and methacryloyl chloride in the presence of triethylamine at room temperature under argon atmosphere. After polymerization, the propazine-template was removed by hydrolysis in basic conditions, and the functional group –COOH capable of interacting with propazine during the rebinding process was introduced after acid hydrolysis of the polymer. It was indicated that the better definition of the template–monomer complex during the pre-polymerization step yielded a polymer with fewer non-specific binding sites. 2932

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The sacrificial spacer method has also been used to imprint poorly-functionalized pyridine. Traditionally, imprinting of nitrogen-containing species employed MAA as functional monomer to combine the nitrogen base via a carboxylic acid hydrogen bond (O–H N). However, the specific binding of pyridine was exclusively attributed to only one hydrogen bond being formed. To overcome this limitation, Kirsch et al.170 synthesized MIPs for pyridine via a sacrificial spacer method by using (4-vinyl)phenylbenzoate or phenyldimethylsilylmethacrylate as templates. The polymer prepared using silyl ester as template displayed higher selectivity while the carboxylic imprinted polymer lacked selectivity. The results revealed that the bond length in the template is crucial in establishing specificity of rebinding, and appropriate choice of template is vital for imprinting simple N-heterocycles. In addition to improve homogeneous binding sites, the semi-covalent imprinting approach also can avoid template leakage.121 Even if a small amount of template was left in polymer during removal of the template, it is difficult to elute this from the polymer by organic solvent in a later eluting process because of the strong interaction between template and polymer. Polymers prepared by the semi-covalent approach can fundamentally solve template leakage. However, application of the semi-covalent approach is restricted by some limitations, such as the covalent bond formed between monomer and template should be strong enough to withstand the polymerization conditions, at the same time, it also must be readily cleaved for template removal. The covalent bond should be well designed so that a functional group can act as a hydrogen bond donor and therefore can be retained in the polymer after a cleavage step. Combining the concept of molecular micelles with MIT, a remarkably clever approach to ensure homogeneous binding sites was described by Feliciano et al.,42 which is based on substitution of functional monomer with a surfactant monomer by mini-emulsion polymerization. Imprinted nanoparticles for rac-propranolol analysis were prepared by using (S)-propranolol, sodium N-undecenoyl glycinate and EGDMA as template, surfactant monomer and cross-linker, respectively. Owing to the formation of micelles, all the binding sites located homogeneously at the surface of nanosized MIPs. When the obtained nanosized MIPs were used in capillary electrochromatography, no peak tailing was observed, which can be attributed to the homogeneous interactions between template and imprinting sites. Furthermore, to reduce heterogeneous binding sites and improve binding homogeneity, several successful strategies have been developed, such as selective chemical modification of low affinity sites, and stoichiometric noncovalent imprinting by using very strong binding contacts, which are also reviewed by Zimmerman et al.87 4.3 Incompatibility with aqueous media MIPs synthesized in organic solvent show poor recognition ability for the target in aqueous environments because the presence of polar solvent can disturb the hydrogen bond formed between template and functional monomer. However, many applications require MIPs capable of working in polar This journal is

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solvents, such as aqueous media. For this purpose, many methodologies have been developed in recent years. One strategy was to adopt a two-step extraction method. Commonly, liquid–liquid extraction (LLE) was applied prior to MIPs-SPE. However, the procedures are complicated and time-consuming. Hu et al.133 developed a simple and low organic solvent-consuming method for enhancing selectivity of MIPs in aqueous samples. The method integrated MIPs extraction and micro-liquid–liquid extraction (MLLE) into one step. Target molecules in aqueous media were extracted into organic phase by MLLE and then bonded to the solid phase of MIPs. The specificity was significantly improved in a dual-phase solvent extraction system, as compared to pure aqueous media. This approach exhibits great potential to broaden the range of MIPs applications in biological and environmental samples. Another practical strategy focuses on the development of water-compatible MIPs, in which hydrophilic monomers are employed, such as HEMA, b-CDs.4,9,80,173 Another representative approach is to use water as porogenic solvent because of a solvent memory effect. For example, water-compatible MIPs have been prepared in water–methanol systems for selective extraction and separation of ciprofloxacin from human urine samples, and the resulting MIPs displayed higher affinity for ciprofloxacin in aqueous environment.37 To further achieve recognition in aqueous media, hydrophilic modification of MIPs surface was proposed, which involved a two-step polymerization procedure.114,174 Fig. 8 displays the synthesis process of restricted access material MIPs (RAM-MIPs). Glycidyl methacrylate was chosen as the co-monomer because its oxygen atom bonded to two carbons has lower capacity to form hydrogen bonds than a free hydrogen group, which can lessen interferences in the formation of the pre-polymerization complex. Moreover, the epoxide ring opening induces a hydrophilic behavior to the imprinted particles. As expected, the hydrophilic external layer formed by the glycidyl methacrylate epoxide ring opening on the polymeric surface reduced the non-specific hydrophobic interactions and increased water compatibility. Ye et al.114 proposed a dramatically ingenious approach to synthesize core–shell structured hydrophilic molecularly imprinted nanoparticles by one-pot distillation precipitation polymerization, where the hydrophobic core contained prorpanolol-imprinted binding sites and the hydrophilic shell was nonimprinted. The hydrophilic shell was

Fig. 8

Schematic illustration of RAM-MIPs. Adapted from ref. 174.

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grafted to the core particles via copolymerization of the residual CQC bond remaining in the core with the hydrophilic monomers added in the second phase. This new kind of hydrophilic core–shell nanoparticles is expected to reduce nonspecific protein adsorption while small organic molecules are permitted to enter specific binding sites in the core, which opens up a promising way for biological sample analysis. Specific solutions to the problem of water compatibility can be adopted for some special template molecules. One typical example is the synthesis of MIPs for effective recognition of hexachlorobenzene in water.175 Both hydrophobic and electron-poor characteristics of these molecules provided targeted interactions for recognition in aqueous environments because the template was lipophilic and inherently aromatic. 1,4-Diacryolyloxybenzene was used as functional monomer to imprint hexachlorobenzene because it can provide an electronrich environment to accommodate the template by p-electron stacking. In terms of strength, specificity and directionality, the metal coordination interaction is closer to a strong covalent interaction rather than hydrogen bonding or electrostatic interactions in water. Thus metal coordination can be used to prepare highly specific polymers for the recognition of templates in aqueous media. An 8-hydroxy-2-deoxyguanosine imprinted quartz crystal microbalance (QCM) sensor was prepared for selective determination of 8-hydroxy-2deoxyguanosine in serum samples by using methacryloyl aminoantipyrine-Fe(III) and methacryloyl histidine-Pt(II) as metal-chelating monomers based on double metal coordination and chelation interactions.176 The double metal chelate monomer was found to be effective for molecular imprinting in the aqueous phase. 4.4 Leakage of template molecules In general, MIPs are synthesized by using the detected object as template. However, the potential risk of template leakage during the usage of MIPs can not be ignored, especially the deleterious effects produced during determining the trace compounds by virtue of MIP-SPE. Various strategies have been proposed to resolve this problem, such as isotope molecular imprinting,177 parallel extraction on blank samples,178 postpolymerization treatments (thermal annealing, microwaveassisted extraction, supercritical fluid extraction),179 and dummy molecular imprinting. To date, the dummy molecular imprinting technique, using a structural analog of the targeted compound as template, has been considered more effective to prepare MIPs than other methods. Even though leakage of the ‘‘dummy template’’ occurs during recovery of samples, it will not affect the accuracy of the method. According to the structures of used dummy molecules, this imprinting technique can be divided into fragment imprinting180–182 and interval immobilization.183–185 Fragment imprinting utilizes a part of the target molecule as a pseudo-template to synthesize MIPs. Kuto et al.181 prepared MIPs for selective separation of hydroxyl polychlorinated biphenyl by structural recognition using fragment imprinting technique; p-tert-butylphenol, p-tert-butylbenzoic acid, biphenyl-4-ol and biphenyl-4carboxylic acid were used as template molecules. The results Chem. Soc. Rev., 2011, 40, 2922–2942

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of both the experimental evaluations and molecular modeling indicated that the molecular volumes and pKa values of the template molecules were related to the retention factor of hydroxyl polychlorinated biphenyl, and MIPs prepared with those pseudo-templates displayed selective separation ability for hydroxyl polychlorinated biphenyls.181 Fragment imprinting is used not only for imprinting targeting molecules with inflexible and relatively rigid chemical structures, but also for compounds having flexible chemical structures. Nenoto et al.180 developed a simple and effective MIT for a flexible structure compound of domoic acid using fragment imprinting polymers. o-Phthalic acid, 2,3- or 2,6-naphthalene dicarboxylic acid, and diphenylether-4,4 0 dicarboxylic acid, propane-1,2,3-tricarboxylic acid, etc. were respectively used as template molecules, because they possess the same carboxylic acid groups as the target compounds. Imprinting results suggested that multipoint recognition ability was closely relevant to the structure and spatial distance of the carboxylic acid group of the template molecules. Fragment imprinting can also be used for the determination of some compounds with relatively large molecular weight that cannot be easily imprinted, such as in protein imprinting.186 Interval immobilization imprinting involves synthesizing MIPs by using compounds with similar distances between two functional groups to target molecule as a dummy template. By means of this technique, functional monomers are immobilized at regular distances and those immobilized groups specifically recognize target molecules with functional groups separated by the same distance as the template. Watabe et al.187 prepared uniformly sized MIPs for BPA with immobilized intervals of functional monomers afforded by utilizing 4,4 0 -methylenebisphenol as a dummy template, as shown in Fig. 9. Because of the closely related structure to BPA, 4,4 0 -methylenebisphenol was chosen as the pseudotemplate, which formed a complex with the functional monomer of 4-VP. Appropriate intervals of 4-VP were created by removing 4,4 0 -methylenebisphenol after polymerization and effective hydrogen bonding between 4-VP and BPA occurred; the resulting polymers showed significant selectivity for BPA. Interval immobilization imprinting has also been employed to synthesize MIPs for cylindrospermopsin183 and shellfish paralytic poison saxitoxin,185 by using tributyl(4carboxybenzyl)ammonium and 4-(tributylammonium-methyl)benzyltributylammonium chloride as the pseudo-template, respectively. Dummy templates were also used in the synthesis of MIPs for dopamine,188 organophosphorus nerve agents,189 cyproheptadine190 and 2,4,6-trinitrotoluene.191 In addition to solve the problem of template leakage, the use of dummy template also provides an alternative procedure under the following conditions: (1) when the original template is very expensive or involves safety consideration in manipulation and (2) when the condition used to polymerize could result in unwanted compound degradation, or the low solubility of the targeted analytes does not allow its use for synthesis of MIPs.192 It should be pointed out that although the dummy template imprinting has many advantages, the search for suitable molecules is not yet straightforward. 2934

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Developing novel imprinting or eluting methods, by which templates can be eluted from the imprinted polymer completely, is another way to solve the problem of template leaking fundamentally. For example, by using a novel surface imprinting method employing immobilized template and sacrificial support, all of the imprinting sites are located on the surface, and templates can be removed easily.127 Semi-covalent imprinting approach also can avoid template leakage, as discussed in section 4.2. The enormous advantages offered by the applications of nanotechnology have motivated the development of nano-based imprinted materials. The main advantages recognized up to now in the use of nanomaterials arise from their characteristics of large surface area to volume ratio which contributes to achieving favourable mass transfer, as well as entire removal of template. Imprinted nanospheres, nanorods, nanowires, nanofibers, nanofilms and nanoarrays have been prepared in the past several years and displayed superiority in removal of template. In parallel, in recent years, porous polymers have experienced an explosion in development, such as hollow polymers and cage-like polymers. Thanks to the advances of porous polymers, imprinted porous polymers, such as imprinted hollow microspheres have been prepared and displayed superiority in removing template entirely.134 At present, Soxhlet extraction is the most popular method to remove template from crosslinked polymer matrices. Some novel elution methods require to be further exploited for more effective removal of template. 4.5 Hydrophilic compound imprinting Because of insolubility in non-polar organic solvents, imprinting of hydrophilic compounds such as water-soluble alkaloids is another challenge in molecular imprinting. Conversion of the hydrophilic template to a hydrophobic one by alkyl chain attachment is a way to solve the problem of insolubility of target molecules in organic solvent.193 However, the corresponding chemical synthesis and separation of the target molecules is time-consuming, moreover some functional groups are consumed during chemical reactions, which limits the practical applications of this approach. Interestingly, using a hydrophobic target analogue, instead of the original hydrophilic target molecule as template, assisted to realize the determination of a water-soluble compound in a more facile way.194 However, to find the appropriate analogue is not straightforward. To date, the simplest method for water-soluble molecular imprinting is using ion-pairs as template. Alizadeh et al.195 coupled sodium dodecyl sulfate to pyridoxine (target molecule) by ion-pair formation and extracted the ion-pair complex from water to organic solvent by LLE, and then the ion-pair complex was used as template to prepare MIPs for determining water-soluble vitamin B6. Tominaga et al.185 used the ion-pair complex formed between p-styrenesulfonic acid sodium salt (SSA) and 4-(tributylammonium-methyl)benzyltributylammonium) as template to prepare MIPs for the determination of shellfish paralytic poison saxitoxin. The synthesis concept and procedure is shown in Fig. 10. Because of the formation of an ionic complex, shellfish paralytic poison saxitoxin with inherent hydrophilic nature can be easily dissolved in organic solvent. This journal is

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Fig. 9 Schematic diagram of interval immobilization imprinting using MBP as the dummy template for determination of BPA. 1: chemical structures of 4,4 0 -methylenebisphenol and BPA; 2: polymers prepared using 4,4 0 -methylenebisphenol as dummy template molecule; 3: recognition sites with fixed intervals were created by removal of the 4,4 0 -methylenebisphenol template molecules; 4: the obtained recognition sites can bind BPA based on the fact that BPA has a similar size as 4,4 0 -methylenebisphenol). Adapted from ref. 187.

Probably, searching for new monomers and developing novel imprinting methods in aqueous media are the easiest and most direct way for imprinting water-soluble molecules in the future. For helpful understanding the possible solutions to the existing problems of MIPs as mentioned above, we summarized those strategies in Table 2.

5. Highlighted applications MIPs were most frequently utilized as affinity-based separation media for sample preconcentration and separation, via molecularly imprinted solid-phase extraction (MISPE) and molecularly imprinted solid-phase micro-extraction (MISPME). In recent years, articles about MIPs used in sensors, artificial antibodies and catalysts have been increasing in number. Considering that the highlighted applications of MIPs as separation media have been summarized in ref. 196–208, more emphasis is placed here on the application of MIPs in sensors, artificial antibodies and catalysts. Table 3 summarizes the relevant studies reported209–225 about applications of MIPs as separation sorbents, which are divided into four broad categories: environmental, bioanalytical, food and pharmaceutical applications. Various compounds such as estron, nonylphenol, This journal is

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Fig. 10 Schematic concept of polymer preparation using ionic complex by interval immobilization technique. 1: porous polymer as polymerization matrix; 2: ionic complex is formed between functional monomer SSA and dummy template TBTA; 3: ionic complex is immobilized in MIPs after polymerization; 4: recognition sites are shaped in MIPs after removal of dummy template and anions remain in recognition cavities; 5: template can bind onto recognition sites based on interval immobilization mechanism. Adapted from ref. 185.

sulfamerazine, fluoroquinlones and triazines have been extracted from environmental samples (e.g., tap, river, well, lake, surface, waste, pond water samples, and coastal sediments), biological samples (e.g., urine, plasma, serum, blood) and/or food matrices (e.g., pork, milk, tomato, egg). MIPs have been widely used as the recognition elements for some sensor technologies, such as QCM sensors,15 electrode-type sensors,10,13 and optical sensors,17,18 and some breakthroughs have also been achieved. For example, polymeric membrane ion-selective electrodes (ISEs) have been used for the determination of ionic species, but they have been working poorly for uncharged molecules. Now this limitation has been eliminated by Qin et al.13 in our institute. They proposed a novel strategy for selective and sensitive detection of neutral species, chlorpyrifos, using polymeric membrane ISEs, which was based on uniform-sized MIPs as sensing element for molecular recognition and a charged compound, 3,5,6-trichloro2-pyridyloxyacetic acid, with a structure similar to that Chem. Soc. Rev., 2011, 40, 2922–2942

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Solutions to existing challenges for MIPs

Table 2


Problem

Possible solutions

Protein imprinting

(1) (2) (3) (4)

Incompatibility with aqueous media

(1) Two-step extraction (2) Polymerization in aqueous phase using hydrophilic monomers or non-hydrogen interaction (metal chelate or hydrophobic interactions) (3) Surface modification of MIPs (RAM-MIP)

Leakage of template molecules

(1) Dummy molecular imprinting (2) Nanostructured imprinted polymer (3) Porous imprinted polymer

Heterogeneous binding sites

(1) Semi-covalent imprinting or covalent imprinting (2) Selective chemical modification of low affinity sites

Hydrophilic compound imprinting

(1) Dummy molecular imprinting (ion-pair as template) (2) Imprinting in aqueous media

of the analyte as an indicator ion for the transduction of potential signal. This work may provide a novel methodology for detecting non-ionic species at trace levels by using ISEs. Arrays of carbon-nanotube tips with an imprinted non-conducting polymer coating can recognize protein with subpicogram per litre sensitivity using electrochemical impedance spectroscopy have been prepared recently,226 which can overcome the limitation of electronic nanosensors for protein recognition, such as (1) MIP film may attenuate signals generated in response to template binding due to the large thickness; (2) the detection mechanisms do not readily allow for effective signal conversion; (3) the sensor platforms do not support highly sensitive detection. Fig. 11 shows a schematic diagram for fabrication of this nanosensor. Vertically aligned nanotubes were prepared on titanium-coated glass substrates, followed by embedding in photoresist by spin-coating, and mechanically polishing to expose the tips. Polyphenol film was deposited on the exposed nanotube tips by cyclic voltammetry. To entrap template protein in the polyphenol film, the corresponding template protein was added to the polyphenol deposition buffer. Extraction of template resulted in the reduction of sensor electrical impedance due to electrical leakage. Subsequent rebinding of template protein led to an increase in impedance due to the lower conduction of the protein. This ultrasensitive, label-free electrochemical detection of protein offers an alternative to biosensors based on biomolecule recognition. In addition to the commonly used electrochemical sensors, a new kind of sensor, a label free colorimetric sensor has been developed based on colloidal crystals and imprinted polymer. Fig. 12 shows the protocol for the preparation of photonic MIP films. From the color change, detection of target compound can be easily realized by the naked eye. This method has been used for chiral recognition,19 and excellent determination of ephedrine,20 cholic acid227 and atrazine.228 Quantum dots (QDs) have attracted intense research interest in scientific and technological fields owing to their novel optical properties, such as sharp emission band with broad

excitation, and strong resistance to photobleaching. A number of QD-based sensors have been reported. The synergetic combination of the optical property of QDs with the merits of surface imprinting polymer can improve the selectivity of QD sensors. Surface molecularly imprinted polymers embedded QDs have been used to detect pentachlorophenol,124 pyrethroids229 and 4-nitrophenol230 based on roomtemperature phosphorescence optosensing, chemiluminescence and fluorescence quenching mechanism of electron transfer, respectively. The general process used to prepare MIPs capped QDs sensors include the following steps. First, water-soluble QDs were prepared by refluxing, then silica capped QDs (QDs@SiO2) were prepared by reverse microemulsion methods. MIPs embedded QDs can obtained by polymerizing on the surface of modified QDs via a sol–gel process or a free-radical polymerization process. As reported,124 the combination of the room-temperature phosphorescence property of Mn-doped ZnS QDs with surface imprinted polymers not only improves the selectivity of QDs but also makes the MIP-based optosensor applicable for selective detection of non-phosphorescent analytes without the need for any inducers and derivatization. A latest review article about MIPs based chemosensors, including optical chemosensors (UV-vis spectroscopic chemosensors, photoluminescent chemosensors, surface plasmon resonance chemosensor), piezoelectric chemosensors, and electrochemical sensors (conductometry, capacitance and impedance measurements, potentiometry, chronoamperometry and voltammetry) is very comprehensive,231 and is recommend for reading here. Immunoassays are a class of analytical techniques based on the selective affinity of a biological antibody for its antigen. MIPs have been shown to possess binding characteristics in terms of affinity and specificity similar to those of antibodies and biological receptors. Thus MIPs have shown great potential as replacements for biological antibodies, and have been used for drug assays, assembly of biomimetic sensors, and screening of combinatorial libraries. Two attractive review articles about MIPs used as artificial antibodies have been

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Surface imprinting (immobilized template) Epitope-mediated imprinting Metal coordination procedure Polyacrylamide soft gel imprinting

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Table 3

Selected application examples of MIPs as separation sorbent

Environmental application

Tap water, wastewater Tap, river, well water River water Well water, lake water Tap, river, lake water Water Wastewater

Cibacron reactive red dye Red dye

MAA/EDMA/chloroform/bulk

MISPE

209

Benzimidazole fungicides Ethynylestradiol Estrone Diphenylguanidene Parachion Polybrominatediphenyl ethers Antiepileptics

Thiabendazole Ethynylestradiol Estrone Diphenylguanidene Parachion BED-209

MAA/DVB/ACN–toluene/PP MAA/EDMA/ACN/bulk APTS/TEOS/surface imprinting MAA/EDMA/chloroform/bulk MAA/EDMA/chloroform/PP PTMOS/TEOS/sol–gel process

MISPE MISPE MISPE MISPE MISPE SPME

96 210 211 212 213 214

Cyclobarbital

4-VP/EDMA/multi-step swelling

Benzimidazole Estrone Diclofenac

Thiabendazole Estrone Diclofenac


Tap, river, well water Drinking water Surface water, waste water River water Sludge Ponder water, Coastal sediments, Waste water Water Human serum

Fluoroquinlones Enrofloxacin Nonylphenol and ethoxy- Nonylphenol lated derivates Sulfamerazine Sulfamerazine PAHs 16 PAH compounds Nonylphenol Nonylphenol

HPLC column MAA/EDMA/ACN–toluene/PP MISPE AAm/MPTS/DMSO–toluene/bulk MISPE 2-VP/EDMA/toluene/bulk MISPE

82 95 215 65

MAA/EDMA/ACN/bulk MAA or 4-VP/DVB/toluene/PP

MISPE MISPE

39 216

MAA/EDMA/THF/PP MAA/EDMA/ACN/bulk

MISPE MISPE

37 217

TFMAA/EDMA/ACN/bulk

MISPE

218

Enrofloxacin

MAA/EDMA/ACN/bulk

MISPE

9

Human serum Urine

Fluoroquinolone antibiotics Metronidazole Nicotine

Metronidazole Nicotine

MAA/EDMA/DMF/bulk MAA/EDMA/ACN/bulk

219 220

Tissue

TC antibiotics

Oxytetracycline

Urine, plasma Human urine

Beta-blockers CBZ, OCBZ

Propranolol Carbamazepine

SPME MISPE

44 84

Fishery Human serum, blood Human plasma Serum

17b-Estradiol Isoxicam Ephedrine and analogues Fluoroquinolones

17b-Estradiol Isoxicam Ephedrine Ofloxacin

MISPE MISPE MISPE SPD

7 6 221 40

Human urine

Ciprofloxacin

Ciprofloxacin Ofloxacin Ciprofloxacin Fenitrothion

HPLC column MISPE MISPE MISPE

4

Quinolones Fluoroquinolones Fenitrothion

37 222 223

TC antibiotics

TC

MAA/DVB/water/surface imprinting MAA/TRIM/ACN/coating MAA/DVB + EDMA/ACN– toluene/PP MAA/EDMA/ACN/bulk MAA/EDMA/DMF/bulk MAA/EDMA/chloroform/bulk MAA/EDMA/methanol–water/ bulk MAA/EDMA/methanol–water/ Bulk MAA/TRIM/methanol–water/bulk MAA/EDMA/methanol/PP MAA/EDMA/dichloromethane/ bulk MAA/TRIM/methanol–ACN/PP

MISPE On-line MISPE extraction

MISPE

46

Triazines

Atrazine

Triazine herbicides Malachite green, violet

Ametryn Malachite green

Ractopamine

Ractopamine

Milk

ENF, CIP

Ofloxacin

Citrus

Thiabendazole

Thiabendazole

Herb

Diosgenin

Diosgenin

Urine Food application Baby food Tomatoes Lobster, duck, egg, honey, Soybean, millet, lettuce Rice, maize, onion Grass carp, shrimp, shellfish Pork

Pharmaceutical

Application method Ref.

Target molecule

River water

Bioanalytical application

Monomer/cross-linker/porogen/ Template molecule preparation method

Application field

MAA/TRIM + DVB/toluene/ suspension MAA/EDMA/ACN/monolith MAA/EDMA/ACN/PP

45

Extraction 34 SPME MISPE

32 224

ATPES/TEOS/surface sol–gel process HEMA/EDMA/methanol–water/ bulk MAA/EDMA/toluene–water/ monolith

On-line MISPE MISPE

129 38

MIP-CEC

225

IPTS/TEOS/Sol–gel process

MISPE

14

1

Abbreviations: CIP, ciprofloxacin; DMF, dimethyl formamide; DMSO, dimethyl sulfoxide; ENF, enrofloxacin; OCBZ, oxycarbamazepine; SPE, solid-phase extraction; PTMOS, phenyltrimethoxysilane; MPTS, 3-methylacryloxyprolyl trimethoxysilane.

published by Ansell232 and Ye,233 respectively. No futher examples are thus discussed here. Significant research efforts have been made in the field of enzyme-based biosensors, which have been successfully This journal is

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applied to the detection and quantification of numerous biologically-relevant molecules. However, in some cases the limitations of enzyme-based biosensors are primarily those imposed by the nature of the enzyme itself, such as lack of Chem. Soc. Rev., 2011, 40, 2922–2942

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Fig. 11 Schematic diagram for nanosensor fabrication and template protein detection. The supporting polymer is spin-coated on a glass substrate containing nanotube arrays. Template proteins trapped in the polyphenol (PPn) coating are removed to reveal the surface imprints. Inset: hypothetical sensor impedance responses at critical stages of fabrication and detection. Adapted from ref. 226.

native enzymes corresponding to a target analyte, poor availability and highly specific conditions—so artificial enzymes are required. A comprehensive review about artificial enzyme-based biosensors was given by Vial et al.234 As a promising material, MIPs have been employed to mimic natural enzyme systems with catalytically active arrangements in designed receptors. Enzymes are basically composed of substrate-binding sites and catalytic sites which are close to each other and cooperatively accelerate specific reactions. Molecular imprinting method is an effective way to synthesize artificial enzymes by orderly placing of these two sites. For example, Takeuchi et al.235 synthesized an artificial enzyme for decomposition of atrazien by copolymerization of MAA, 2-sulfothyl methacrylate and EGDMA. Using a transition-state analog as a template to prepare catalytic antibodies is another development direction for mimicking catalytic antibodies. Increasing the transition-state binding and correctly incorporating and positioning the functional groups is essential for the construction of an effective enzyme model. Liu et al.236 reported new MIPs which exhibited strong enhancement for carbonate hydrolysis by oriented amidinium group and Zn2+ in a transition-state analog imprinted cavity. This is the first example in which molecularly imprinted catalysts is clearly much more efficient than catalytic antibodies. 2938

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Fig. 12 Schematic representation for preparation of imprinted photonic polymers: (A) SiO2 colloidal crystals on glass substrate; (B) infiltration of complex solution into colloidal template followed by photopolymerization; (C) photonic MIP film after the removal of SiO2 nanoparticles and template molecules; (D) complex of monomer and template molecule; (E) imprinted molecules within the polymer matrix; and (F) imprinted cavities with complementary shape and binding sites to the template molecule.

6. Conclusions and outlook The current status, challenges, and highlighted applications of MIPs have been described in this critical review. Much work have been performed to resolve the problems hindering the development of MIT during past years. Protein imprinting has been achieved by surface imprinting and epitope-mediated imprinting techniques, while heterogeneous binding sites can be overcome by a semi-covalent imprinting approach. The combining of water-soluble functional monomer with nonhydrogen interactions is an effective approach to solve the problem of MIPs working poorly in aqueous media. For the challenge of template leakage during trace analysis process, dummy molecule imprinting is the most widely used approach. Owing to their high selectivity, high sensitivity, low cost, and ease of preparation, MIPs have been extensively utilized as chromatographic media, sensors, and artificial antibodies to detect various compounds in environmental, bioanalytical, pharmaceutical and food samples. Although remarkable achievements have been attained in MIT, there are still substantial development challenges and opportunities. We attempt to tackle some important exploration initiatives as follows: (1) to explain the molecular imprinting and recognition mechanism at the molecular level with the aid of advanced equipment; (2) to transfer the imprinting process from organic phase to aqueous phase, reaching the level of natural molecular recognition; (3) to design and synthesize new monomers in order to imprint those molecules without functional groups, broadening the application field of MIT; (4) to exploit new polymerization methods for molecular imprinting for higher imprinting efficiency and binding This journal is

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capacity; and (5) to broaden imprinting targets from small molecules to proteins, and even to living cells, in order to make molecular imprinting a truly practical approach for molecular recognition.


List of abbreviations and acronyms AA AAO APTS ATRP b-CDs CLRP DPP DVB EDCs EGDMA HEMA IPTS LLE ISEs MAA MBAA MIPs MNPs MIT MISPE MISPME

acrylic acid anodic alumina oxide 3-aminopropyltrimethoxysilane atom transfer radical polymerization b-cyclodextrins controlled/living radical polymerization distillation precipitation polymerization divinylbenzene endocrine disrupting chemicals ethylene glycol dimethacrylate 2-hydroxyethyl methacrylate 3-isocyanatopropyltriethoxysilane liquid–liquid extraction ion-selective electrodes methacrylic acid N,N-methylenebisacrylamide molecularly imprinted polymers magnetic nanoparticles molecular imprinting technology molecularly imprinted solid-phase extraction molecularly imprinted solid-phase microextraction nanoporous alumina membranes nitroxide-mediated polymerization precipitation polymerization quantum dots quartz crystal microbalance reversible addition-fragmentation chain transfer restricted access material MIPs room-temperature ionic liquids solid-phase extraction tetraethoxysilane traditional precipitation polymerization trimethylolpropane trimethacrylate 2- or 4-vinylpyridine 2,4-dichlorophenoxyacetic acid

NP Ams NMP PP QDs QCM RAFT RAM-MIPs RTILs SPE TEOS TPP TRIM 2- or 4-VP 2,4-D

Acknowledgements Financial support from the National Natural Science Foundation of China (20975089), the Innovation Projects of the Chinese Academy of Sciences (KZCX2-EW-206), the Department of Science and Technology of Shandong Province of China (2008GG20005005) and the 100 Talents Program of the Chinese Academy of Sciences is gratefully acknowledged.

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