Bioapplications for Molecularly Imprinted Polymers - Analytical

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Bioapplications for Molecularly Imprinted Polymers Romana Schirhagl Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/ac401251j • Publication Date (Web): 14 Aug 2013 Downloaded from http://pubs.acs.org on August 23, 2013

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Analytical Chemistry

Bioapplications for Molecularly Imprinted Polymers Romana Schirhagl* AUTHOR ADDRESS: ETH-Zurich, Physics Department, Schafmattstrasse 16, 8046 Zurich, Email: [email protected] It has been found that highly crosslinked polymers that harden in presence of template molecules keep a memory of the template. This effect, called molecular imprinting, is due to functional monomers that are oriented depending on interacting moieties in the template. This orientation is “frozen” when the polymer is crosslinked and remains even when the template is removed. As a result the respective template molecule will be preferentially incorporated in the cavities later on. Molecularly imprinted polymers (MIPs) are widely used as sensor materials, catalysts as well as stationary phases in chromatography. While small molecule MIPs have been improved and optimized in terms of selectivity the field has been extended towards large and complex molecules. This required new imprinting strategies as surface imprinting or the development of an epitope approach. In this article I am reviewing the state of the art and recent advances in these biological applications. Additionally, I will introduce new fields and applications where MIPs have been implemented recently. Among these are biomimetic antibody mimics, crystallization inducers, drug delivery or discovery and cell culturing. 1. INTRODUCTION TO BIOIMPRINTING: Molecules or coatings with high selectivities, as antibodies or enzymes, are of great importance in chemistry, diagnostics1,2 and biology3. However, these natural receptors are expensive or difficult to produce. Furthermore, since they are biomolecules their lifetime and applicability is

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limited4. Molecular imprinting is one technique that was developed to overcome these limitations. To generate imprints with certain selectivity a prepolymer is simply polymerized in the presence of the desired target molecule5,6,7. When the polymer is cured two things happen simultaneously. First, functional groups in the prepolymer orient towards their counteracting partners in the template. This complex formation has been theoretically investigated in several articles8,9,10.

Figure 1. Imprinting mechanism: (a) When the polymer is cured in presence of the template two things happen simultaneously. First, functional groups within the prepolymer (green) are oriented towards functional groups in the template they can interact with (red circles). Second, polymer chains (grey lines) are formed and cross-linked. (b) When the template is removed, the binding sites remain in shape. Second, the polymer is cross-linked resulting in “freezing” the orientation of the functional groups. This orientation remains even when the template is removed. As a result the remaining cavities reproduce size, shape and surface chemistry of the template molecules. As a consequence molecules of the template species will be incorporated preferentially later on. The resulting polymers are promising since they are relatively cheap, straight forward to make and remarkably robust11. Additionally, due to the high number of different monomers that are commercially available (more than 4000polymerizable compounds)12 their properties can be


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tuned. During the last years the field of molecular imprinting has grown rapidly and become very broad. However, there are still entirely new fields were imprinted polymers have been used just recently. While molecularly imprinted polymers with great selectivities have been synthesized for small molecules13, imprinting with large macromolecules remains challenging14. I would like to review recent advances that have been made in this field. I will focus on discussing similarities and differences of applications and requirements concerning the imprinted polymers. Instead of giving a complete list of the work that has been done (which would be way too long) I am giving a broad overview over the topic using most important or recent illustrative examples. 2. POLYMERS AND IMPRINTING STRATEGIES: The choice of the right polymer is one of the most critical factors in molecular imprinting. While many requirements to the polymer are application specific I would like to point out a few generally applicable points. The most important requirement is that the monomer needs to have functional groups that can interact with the template. These groups can be any groups that form non covalent interactions as charges15,16, dipoles17,18, van der Waals interactions19,20, or ππinteractions21. Which groups suit best is thus directed by groups that are available on the template molecule. An additional requirement to the polymer is that it is not reacting polymerizing with the template. This for example poses a problem for imprinting biomolecules into polyurethanes. One of the monomeric units is an isothiocyanate that is reacting with alcohol or amine groups present in most biomolecules. Table 1. Most commonly used polymer systems and examples for applications Polymer Polyacrylate/ polymethacrylates/

Application Sensors, Chromatography,

Methods Literature Bulk imprinting, Purface [22,23,24] Drug imprinting, Imprinted


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polymethylmethacrylate Polyacrylamide Polyurethane Siloxanes Solgels

delivery Chromatography, Crystalization Sensors Chromatography Chromatography, Sensors, Catalysts

Particles Bulk imprinting

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[25,26,27,]

Surface imprinting, sacrifice [28,29,30,31] layers Surface imprinting [32] Bulk imprinting [33,34,35,36]

Furthermore, the polymer needs to be cross-linked enough to guarantee that the binding sites stay intact after the template is removed. If the binding sites are too flexible they might also bind similar molecules. It has been found that targeting smaller molecules works best with highly cross-linked polymers37. In contrast often targeting larger molecules is achieved with more flexible polymers38,39. Furthermore, it is desirable to use non-toxic polymer building blocks. Additionally, to ease optimization for different templates it is favorable if the viscosity of the polymer can easily be tuned. While this article is about imprinted polymers it is worth mentioning that there are alternative methods for molecular imprinting that do not use polymers. Such alternatives are e.g. self-assembled monolayers that are assembled in presence of a template40,41,42,43 or molten gallium44 that can also be imprinted.

3. THE TEMPLATE: Although the template is usually dictated by the problem that one wants to solve there are some interesting alternatives. Fig. 2 summarizes these for creating molecularly imprinted polymers. For a specialized review articles on different methods I would like to refer to45.


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Figure 2. (a) Traditional bulk imprinting46,47,48, (b) surface imprinting 49,50,51 (c) sub structure imprinting 52 (d) Structural analog imprinting (e) Antibody replicae 53,54 (f) sacrifice layers 55,56 Error! Reference source not found.2 (a) shows the traditional bulk imprinting where a template molecule is simply added to the prepolymer57. As a result, selective cavities are distributed all over the bulk. When the template is very big it might not be possible to diffuse through the cross-linked polymer. For such large templates as e.g. cells or viruses surface imprinting with stamps (Figure 2 (b)) was developed by the group of Prof. Dickert58. The rest of the methods that are summarized in Figure 2 are alternative imprinting strategies where the target molecule is not used as template directly. Figure 2 (c) shows substructure imprinting59,60. This method uses small characteristic substructures instead of the whole molecule. This is similar to natural antibodies which target epitopes instead of whole molecules. This is especially favorable if the analyte has a surface where the arrangement of functional groups is changing. This for example applies to cells where membrane proteins can change their relative position within the membrane. This leads to a decrease in binding affinity if the whole structure is used and limits


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the selectivity that can be generated for large flexible structures. In contrast this does not affect the epitope approach which is more promising in those cases (see Figure 3).

Figure 3. The traditional and the epitope approach for large flexible analytes A difficulty of the method is that one needs to know which substructure of an analyte is present on the surface, which is often nontrivial61,62,63,64. Another alternative are structural analogues that can be used instead of the target molecule65. This can be favorable if the target itself is rare or toxic or not stable under the imprinting conditions. Additionally, this is an interesting approach if the template molecule is hard to remove from the polymer or otherwise inconvenient to use. Another method that was also determined in the Dickert group is antibody replicae (Fig. 2 (e))66. The slightly more complicated method uses natural antibodies for the desired target molecule as starting material. These antibodies are imprinted into a polymer which is then used to imprint another polymer. This results in receptors that mimic the structure of the initial antibody material. Since the receptors mimic natural antibodies they also target epitopes instead


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of the whole structure. Another advantage is that the procedure is easily adaptable to other analytes by changing the starting material to an antibody with a different selectivity. This way, selectivity e.g. for large viruses or hormone molecules could be generated. Disadvantages of the method are that it is more complicated than the standard imprinting technique and that the antibody is needed as starting material. Using a sacrifice layer allows the use of a polymer that would otherwise react with the template. So instead of imprinting with the biomolecule directly one can cover the template with a monolayer of molecules. These both interact with the template and form the binding site and are covalently bound to the polymer. This way the recognition can be further tuned. This approach was successfully used by Shi et all to generate imprinted receptors55.

4. REMOVING THE TEMPLATE: Especially for large biological samples template removal is one of the most critical problems in imprinting. To facilitate template removal the imprinted polymer is usually either washed in solvents67,68,69 acids or bases70,71, or detergents72,73. The polymer can also be heated for template removal74,75,76. Another elegant method for template removal is the addition of digesting enzymes like proteases77. For complex biosamples as e.g. cells osmosis can be used. Remaining template cells shrink when the surface is washed with high ionic strength solution and can thus be removed from the surface. Flushing the surface with an excess of ions or molecules that can compete with the template for binding sites might also be successful78. Furthermore, ultrasonic treatment has shown to be useful48. However, care has to be taken since some polymers might be sensitive to the treatment. Furthermore, some molecules that can potentially be used for template removal or recovery of the imprinted polymer can adhere to the polymer. As a result the template


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removal might be successful but binding sites are blocked by removal molecules. This has been shown for some detergents as SDS 79 and can be circumvented by changing the removal procedure or extensive washing. 5. “TRADITIONAL” APPLICATIONS: 5.1. CHROMATOGRAPHY AND ELECTROPHORESIS: Chromatography was the first application were imprinted polymers were used. Separating components of complex mixtures is a crucial step in analysis and preparation of samples. Since they are relatively easy to make and have high selectivities towards their template imprinted polymers are good separation materials. Another part of separation science where MIPs have proven to be useful is electrophoresis. During electrophoresis the analyte mixture is forced through a stationary phase by an electric field (instead of gravity or pressure in chromatography). A specialized review on this application can be found in 80. Since there are many similarities between chromatography and electrophoresis (especially concerning the requirements for the imprinted material) these two methods are discussed here in one section. To allow a flow of the mobile phase passing through the material it needs to be to some extend porous. Furthermore, the density of binding sites should be maximal. In order to achieve that properties several strategies have been used reviewed in the following sections. Figure 4 summarizes the different options and shows examples for the different column materials.


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Figure 4. Different options for MIP materials in chromatography: (a) Bulk Polymer: the stationary phase is a highly porous polymer81 (b) Irregularly shaped particles82 (c) Regularly shaped particles83 (d) surface imprinting on the wall of the column84 5.1.1. BULK POLYMER: One approach to generate an imprinted stationary phase for separation is a porous polymer material. This approach was used by Deng et al. who used imprinted polymers to separate proteins81. They used an acrylamide based monomer solution containing the template proteins. After the addition of cross-linker, the solution was cooled in an ice bath and cooled radical starter was added. The mixture was then polymerized at -20°C for 24 hours. After the polymerization was completed, the frozen monoliths was thawed at room temperature and washed to remove the template. The result was a monolithic porous polymer that was used in HPLC systems to separate hemoglobin from bovine serum albumin. Li et al. used a similar method to generate selectivity towards enrofloxacin (a commonly used antibiotic)85. To allow the mobile phase to pass through the authors used a porogen to increase porosity within the polymer.


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Using such a non-polymerizing solvent which leads to pores within the polymer is a commonly used strategy86. Interestingly, the authors found that the addition of a “crowding agent” can positively alter the formation of imprints. They used polystyrene beads for this purpose and stated that the addition of crowding agents in the pre-polymerization mixture can shift the rate of polymerization and/or the kinetics of phase separation between the MIP and the solvent. The main disadvantage of this method is that the bulk material is only feasible for small molecules. For large templates template removal poses a problem and the bulk material can hinder the analytes to pass the stationary phase during separation. 5.1.2 GRINDED BULK POLYMERS

An alternative method to allow template molecules to diffuse through the stationary phase is using particles. Such particles can simply be generated by synthesizing a bulk material and grinding it to particles87,88. While for the monolithic approach a very porous material needs to be used the choice of polymer in the particle approach is more flexible. As a consequence the polymer material can be fine-tuned for a certain template easier. However, the resulting particles usually have an irregular shape and a wide particle size distribution89,90. This leads to broad peaks and worse reproducibilities. To improve these two properties the particles are often sieved and only the desired size fraction is taken for the separation91. Walshe et al. used this approach to separate enantiomers by electrophoresis92. To this end the authors synthesized bulk MIPs using N-acryloyl-alanine and ethylene glycol dimethacrylate (EDMA) as functional monomers. The bulk material was then crushed and sieved to obtain irregular particles 20–30 µm in size. Using these particles imprinted against (S)-propranolol, a separation of the enantiomers of propranolol


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was obtained. Solutions of reference polymer (prepared without a template) were tested and found not to affect any chiral resolution. 5.1.3 REGULARLY SHAPED MICRO- AND NANOPARTICLES

A widely used approach is using regularly shaped particles for separation. Over grinded material with random shapes they have the striking advantage to be more reproducible and to produce narrower bands. This is due to their monodispersity and regular shape. Such particles can be generated by precipitation polymerization93, emulsion polymerization94, or can be forced through a porous membrane95 (see Fig. 5).

Figure 5. Different methods to synthesize regularly shaped particles: (a) Precipitation polymerization (b) Emulsion polymerization or suspension polymerisation (c) Core shell polymerization (d) U-tube polymerization To perform a precipitation polymerization the monomers and all ingredients are simply stirred in a solution where they are not well soluble. When the polymer is formed the particles containing the drug will precipitate. As an additive to support the droplet formation within such a solution a detergent can be used which will enclose the particle ingredients. This process is called emulsion


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polymerization. For particle sizes above 1 µm this method, which was historically the first method used to generate regularly shaped MIP particles, is called suspension polymerization96. Alternatively, a particle can be used as core which can also support the formation of a polymer shell around it97,98,99. A recent review article on particle synthesis can be found in 100. Alternatively, an imprinted polymer can be synthesized on the surface of a non-imprinted particle101. Regularly shaped polymer particles with selectivity towards 2,4dichlorophenoxyacetic acid (2,4-D, a common herbicide) were used by Fang et al.83. The MIP microspheres were prepared via precipitation polymerization using a complex mixture containing 4-((4-methacryloyloxy)phenylazo)pyridine (MAzoPy), 2,4-D, ethylene glycol dimethacrylate (EGDMA), azobisisobutyronitrile (AIBN), and acetonitrile as the functional monomer, template, crosslinker, initiator, and porogenic solvent, respectively. The most interesting feature of this polymer material is its photoresponsive affinity towards the template, which decreased upon UV light irradiation. This is caused by the azogroups that undergo photoreaction and thus alter binding sites. The initial binding properties could be recovered be heat treatment. Furthermore, the authors were able to separate the template molecule from structural analogues. The disadvantage of using regularly shaped particles is that the procedure is more complicated and particle size control often is non-trivial102. This makes adapting the method to different templates more challenging. 5.1.4 SEPARATION SURFACE

One drawback of all the above mentioned methods to generate a stationary phase is that it takes long to force the mobile phase through a densely packed column. Additionally, if very large particles should be separated densely packed columns cannot be used since the analyte would


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simply get stuck. An interesting alternative is providing the binding sites only on the surface of the column. Qu et al implemented that technique into a microfluidic chip which could be used for enantiomeric separation of L and D forms of tert-butoxycarbonyl-tryptophan (BOC-Trp)84. They inserted the prepolymer mixture consisting of acrylamide as functional monomer and ethylene glycol dimethacrylate as cross-linker into a microfluidic system. There the mixture was polymerized covering the walls of the chip that was used for separation. They optimized the polymeric composition and were able to sort standard analytes for enantiomeric separation (BocD-Trp, Boc-L-Trp) within 75 s. Recently this method was used to allow a chromatography like separation for bacteria79. The authors were able to separate different strains of cyanobacteria using a microfluidic channel where the floor was imprinted with the respective bacteria strains. Remarkably, even strains that could not be separated by FACS sorting could be separated by the polydimethylsiloxane based imprinted polymer. Ren et al. used the same method to generate surface imprinted channels for the separation of different clinically relevant bacteria (Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Staphylococcus epidermidis)103. They found that the imprinted polymer channels preferentially incorporated template bacteria over other species. As a consequence the template cells were trapped in the chip and thus could be depleted from the cell suspension. Furthermore, the authors investigated the mechanism of the capturing. To this end they coated the binding sites by a thin film of silanes. This treatment alters the surface chemistry but hardly affects the shape of the cavities. They found, that after silanization nearly no selectivity was observed. The authors concluded that the separation was mostly due to chemical interactions and not solely based on different shapes.


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A drawback of the method is that the channels have to be fairly small to minimize diffusion ways and thus achieve reasonable separation. Consequently, the method requires fabrication of microfluidic devices. Additionally, packed columns usually provide a larger separation surface and thus are better suitable for small template molecules.

5.2 CHEMICAL SENSING

Since there is only one capturing event selectivity is even more crucial in sensing applications than in chromatography. MIP based biosensors have been generated for different templates ranging from molecules104 to proteins105, viruses106 or even entire cells107,108. Recent specialized reviews on chemical sensing can be found in 109,110,111. The techniques and requirements to imprinted polymer receptors are substantially different depending on the read out methods. Thus different methods are discussed in the following sections. 5.2.1 OPTICAL READ OUT

Optical read out is relatively straight forward. There are very little requirements to the polymer material. It simply has to be non-fluorescent at the detection wavelengths. Since light usually has to pass the polymer to reach the detector the polymer has to be transparent too. The template has to be either naturally fluorescent or absorbing or it has to be stained in a separate step. This restriction to a certain subset of possible analytes is a disadvantage of the method. Fukazawa et al. used UV fluorescence imaging to detect proteins that were captured on the surface of their imprinted polymers112. They used a surface imprinting approach but immobilized the proteins first on particles and then created the imprints. That way they were able to increase


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the density of receptors on the surface and thus the sensitivity of the sensor. Furthermore, they used a layer of sodium dodecyl sulfate (SDS) in analogy to the previously described sacrifice layer to form the binding sites. As polymer matrix a quite complex photoreactive phospholipid polymer was used providing several different functional groups. The authors reported a good selectivity towards bovine serum albumin over the structurally similar ovalbumin. Some authors developed methods where the polymer itself in fluorescing instead of the template molecule113,114. Incorporation of template can be verified since the fluorescence of the polymer is quenched when the cavities are occupied. An interesting approach using reflectometric interference spectroscopy (RIfS) has been used for optical sensing in the group of Prof. Gauglitz115. RIfS is based on the reflectance of white light at thin layers. A characteristic interference spectrum is observed, which gets shifted as a result of the uptake of template molecules by the sensitive layer. This shift corresponds to changes of the optical thickness (product of physical thickness and refractive index) of the sensitive layer116,117. As a result the method is label-free and applicable to molecules that are not fluorescent. The authors used a nanoparticle film imprinted with L-Boc-phenylalanine anilide. They were able to detect concentrations down to 60 µM of their template. 5.2.2 ELECTRICAL READ OUT Electrical read out is especially useful for charged template molecules that can be detected electrically. However, has a clear disadvantage for the detection of neutral analytes. Detailed review articles about electrical sensors based on imprinted polymers can be found at 118,119,120. In addition I would like to refer to an excellent book about MIP sensors covering that topic121. Conductometric, impedimetric, ion selective field effect transistor (ISFET), amperometric and


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voltammetric transduction have been explored which will be discussed in the following (see figure 6 for a scheme).

Figure 6. Different electrical readout schematics: (a) conductometric sensor, (b) ISFET, (c) voltammetric or amperometric sensor Conductometric and Impedimetric Sensors: Measurements are performed by imposing an alternating voltage between two electrodes, two Pt electrodes for conductometric devices and one reference electrode and the sensor for an impedimetric system. As a result one obtains an alternating current as response. In order to carry out conductometric or impedimetric sensing conductivity has to be carried out through a membrane. Therefore, it is necessary to prepare the imprinted polymer as a membrane which can be challenging. This approach was used by Sergeyev et al. to generate an atrazine (a common pestizide) sensor122. MIP membranes were prepared using atrazine as template, methacrylic acid as functional monomer and tri(ethylene glycol) dimethacrylate as a crosslinker. To fabricate a membrane the mixture was sandwiched between two glass plates at a fixed distance of 60-120 µm. Cross sensitivity towards structural analogues was tested and found to be about a factor of 8


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smaller then the signal for the template. Furthermore sensitivity was found to be quite high (detection limit in buffer 5 nM). ISFET: An ion selective field effect transistor or ISFET is a field effect transistor that is sensitive to ions in a solution. It consists of a source and a drain made of a n-doped semiconducting material that are separated by a p-doped semiconductor. The p-doped semiconductor is separated by an insulating layer from the gate where the imprinted polymer is mounted. If charges are generated in the polymer due to incorporation of the template, moving of charge carriers is allowed within the p-doped semiconductor123. This allows a current to flow between source and gate which is used as measuring signal. This method was used by Tsai et al.124 who generated a sensor for creatinine (an clinically relevant by-product of muscle metabolism). The imprinted polymer was based on poly(ethyleneco-vinyl alcohol) that was surface imprinted simply by dropping the template solution onto the prepolymer film (drop-coating). The authors were able to measure concentrations down to 0.2 mg/mL, within a fairly short time of 20 min. Amperometric Sensor and Voltammetric Sensors: In this type of sensors measurements are performed by applying a potential (variable in voltammetric and fixed in amperometric devices) between the sensor and a reference electrode. The current that flows through the counter electrode and the sensor is continuously monitored and used as a signal. Alizadehet al. used such a voltammetric sensor to detect promethazine in plasma sample125. To generate selectivity they synthesized MIP particles. These were then embedded in a carbon paste electrode in order to prepare the MIP electrode. The detection limit was found to be relatively low (2.8×10-12 M) and no sample preparation was necessary.


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Kriz et al. have generated an amperometric sensor for morphin126. Their detection method of morphine involves two steps. In the first step, morphine binds selectively to the molecularly imprinted polymer in the sensor. In the second step, an electroinactive competitor (codeine) is added in excess. As a result some of the bound morphine is released and can be detected amperometrically. To fabricate the MIP electrode the authors used a platinum wire which was melted into a glass tube. Then the wire was dipped into a suspension containing MIP particles in agarose solution. Finally, the agarose is crosslinked and the template is removed. With this method they were able to achieve a remarkably low detection limit of 0.1 µg/ml with this method. 5.2.3 MASS SENSITIVE DEVICES To detect an analyte with a mass sensitive device the imprinted polymer is simply coated onto the surface of a quartz crystal microbalance or a surface acoustic wave resonator. A comparison between the two techniques is shown in Figure 7.


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Figure 7. Comparison between quartz crystal microbalance (top) and surface acoustic wave resonators (bottom): Both techniques are based on the detection of a frequency change caused by an increase in mass. However, they use different oscillations leading to different appearance and properties. Since an increase in the mass load results in a resonance frequency drop one can very accurately measure the incorporation of an analyte. Since every analyte has a mass this is the most generally applicable detection method. However, there are some requirements to the template and the polymer material that need to be fulfilled. First, in order to generate a frequency shift that is proportional to the analyte concentration the analyte molecules need to be to some extent rigid and mounted to the resonator surface. Second, the polymer has to be rigid127 and fairly thin to have linear concentration dependency. For very thick128 or too flexible polymer layers129,130 or analytes that are not tightly bound131,132 unexpected frequency increases have been reported. In addition, care has to be taken when measuring in liquid phase. Since the frequency response also


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depends on viscosity and ionic strength133 of a measured solution, references have to be measured under the same conditions. An additional drawback of mass sensitive devices is that heavy contaminants can lead to high unspecific responses. Quartz crystal microbalance (QCM): A QCM consists of a quartz plate that is sandwiched between two electrodes (see Figure 7). When a voltage is applied an oscillation is induced in the quartz material that is sensitive to a mass change. Where the imprinted polymer coating can be applied depends on the sample. If the sample is a gas, both electrodes can be coated and exposed to the sample during the measurement134. If the sample is liquid, the backside cannot be exposed to sample to prevent shortings in the electronics. The imprinted polymer is then mounted on one electrode while the voltage is applied from the other side. As an alternative to this simplest electrode geometry several alternative designs have been realized. E.g. the group of Prof. Dickert designed more than one electrode on each side of the quartz. This allows them to include a reference coated with a non-imprinted polymer and a measuring electrode coated with the MIP135,136. Up to four electrodes have been implemented on each side allowing to sense with an array of four different coatings simultaneously137. There are also different possibilities for choosing a quartz resonator. Although the mass sensitivity increases with the resonance frequency of the quartz resonator there are practical limitations. For higher frequency resonators the thickness of the quartz plate is smaller. As a consequence they are more fragile and thus harder to handle. Good compromises are resonators with resonance frequencies between 5 and 20 MHz which are normally used138. In order to mount the imprinted polymer onto the gold electrode one can either coat the prepolymer directly on the gold139,140 or apply an additional coating. Such coatings, that facilitate binding, usually have a functional group (e.g. a thiol group) that binds to the gold and a high affinity to the


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polymer material. Such an adhesion layer might also contain groups that form covalent bonds to the prepolymer141. A quartz crystal microbalance was used by Zhou et al. to fabricate a sensor for domoic acid, an amino acid neurotoxin142. To this end the authors coated the gold electrode of a quartz crystal microbalance with the prepolymer (based on dopamine as monomer units). They achieved an excellent selectivity towards the template over structural analogs. Zhou et al. also obtained remarkably high sensitivities and were to detect 5 ppb of domoic acid. A similar quartz microbalance sensor was used by Alenus et al.143. However, instead of an imprinted polymer layer they used microparticles, obtained by crushing a bulk imprinted polymer, which were then immobilized on thin films of polyvinyl chloride on the surface of a QCM. Surface acoustic wave resonators (SAWs): Compared to QCMs SAWs usually have an order of magnitude higher resonance frequencies leading to an increase in mass sensitivity. As a result, SAWs are perfectly suited for trace gas detection144,145,146. This was e.g. used by Dickert at al. who fabricated a MIP-based sensor for the detection of volatile organic compounds in air147,148. It was observed that MIP coated 433 MHz SAW devices exhibited very low detection limit of 0.1 ppm, for o-xylene vapors. These coatings were further optimized to differentiate between different isomers of xylene. Cao et al. achieved excellent sensitivity (19.4 ppb) towards dimethylmethyl phosphonate DMMP with imprinted 2,5-(thioalkyl-alkoxy)-p-tert-butylcalix[4]arene149. DMMP is a highly relevant substance for chemical sensing due to its analogy to chemical warfare agents. They also tested several vapors, and attributed remarkable selectivity of their sensing layer to the molecular imprinting effect.


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A disadvantage of SAWs is that the propagation of surface acoustic waves require the analyte medium to be moved (see Figure 7). As a result the method is more affected by damping and less applicable for detection in viscous, liquid media then QCM detection. Specialized review articles on mass sensitive devices150 or SAW resonators151 have recently been published. 5.3 CATALYSIS Catalysts are materials that can alter the velocity of chemical reactions without being consumed. They usually achieve that by lowering the activation energy by forming a complex which is stabilizing an intermediate. To achieve this with an imprinted polymer one has to generate a cavity where an important intermediate fits in and thus can be stabilized152. Furthermore, the cavities of an imprinted polymer can protect functional groups or orient two areas where a reaction should happen towards each other. See Figure 9 for a schematic summary of the different options to achieve catalysis. These approaches share the disadvantage that one has to have a quite detailed knowledge of the reaction mechanism.


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Figure 8. Options to catalyze a chemical reaction using an imprinted polymer (the structure that fits into the cavity is circled and the respective polymer is depicted on the right): One option is to remove the favored endproduct from the equilibrium with an imprint that represents the shape of the end product. Another option is orienting groups towards each other that should react or protect groups that should not react with cavities resembling a starting product. The third option is to stabilize an intermediate state. Bonomi et al. achieved catalytic activity by using this approach153. There cavities were able to catalyze the so called Kemp elimination that is shown in figure 9.

BX

X

X

Figure 9. Kemp elimination: indole imprinted cavities are thought to catalyze the ring opening by building a complex with the intermediate. (X=H or Cl) To this end they used a vinylpyrollidone based polymer which can form hydrogen bonds with the N-atom in Figure 9. A slightly different approach was used by Zhang et al. to catalyze a regioselective huisgen 1,3dipolar cycloaddition Reaction154. Huisgen 1,3-dipolar cycloaddition of azides and alkynes has drawn great attention because of its efficiency and versatility to provide fast access to an enormous variety of medicinally interesting triazoles155. However, it usually leads to a mixture of two isomers. To direct the reaction towards the preferred isomer they imprinted a polymer with


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the preferred end product isomer. As a result the cavities were catalyzing the formation of the preferred isomer whereas the wrong isomer formation was sterically hindered. This method was used be Katz et al. who used microporous silica as polymer material156. Their material was found to act as shape-selective base catalysts. The formation of their desired product was monitored by gas chromatographic analysis. 6. NEW APPLICATIONS 6.1 DRUG DELIVERY Many drugs that are known to be effective e.g. against cancer cannot be used due to their severe side effects. Other drugs have very low solubility in body fluids or are degraded by the immune system and thus never reach the area in the body where they are needed. Drug delivery is looking for materials that incorporate the drug, can deliver it to the area where it is needed and release it there. Molecularly imprinted polymers can reversibly incorporate a template molecule. This is a property is highly desired in drug delivery which makes them interesting candidates for that field. To be suitable for drug delivery the polymer material has to meet several additional requirements. While for the previously described applications it is desirable to have a stable polymer, drug delivery polymers should be biodegradable. Additionally, toxicity of the polymer or any building block is much more critical. Specialized review articles on MIPs for drug delivery applications are available from157,158. Puoci et al. used MIPs for the delivery of 5-Fluorouracil which is a widely used anti-cancer drug159. To obtained drug delivery particles the authors first performed bulk imprinting using cross linked methylmethacrylic acid. Then the polymer was grinded and sieved to obtain uniformly sized particles. In their study they achieved a sustained release of the drug. This


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means, that the MIP particles slowly released a constant level of the drug. This behavior is highly favorable since the drugs have to be taken less frequently. This was evaluated by in vitro release studies in gastrointestinal and in plasma simulating fluids. An interesting alternative to drug delivery particles are used for therapeutic contact lenses. A review about this topic can be found in 160. To obtain such contact lenses Alvarez-Lorenzo et al. prepared an hydroxyethyl methacrylate based prepolymer which was injected into a mold161. The prepolymer contained the template molecule timolol which is used in eye drops to treat glaucomas. The authors investigated different polymer compositions and where able to achieve sustained release of timolol from their bulk imprinted polymer. This was evaluated in vitro using artificial lacrimal fluid. Similar imprinted polymer based contact lenses where tested in vivo by Hiratani et al.162. The results of animal experiments (with rabbits) indicate that their imprinted polymers provide greater and more sustained drug concentrations in tear fluid with lower doses than conventional eye drops. An interesting approach was used by Sreenivasan163. His drug delivery particles release a drug in response to certain molecules. This was achieved by using a hydrocortison imprinted polymer that was loaded with testosterone that functions as drug. When the imprinted polymer particles come in contact with their template (hydrocortison), the weakly bound testosterone is released. As a result, the release of testosterone can be triggered by hydrocortisone. Suedee et al. generated a polymer membrane that was able to perform differential release of enantiomers, whereby the release of the more therapeutically active enantiomer is promoted, whilst the release of the less or non-active enantiomer is retarded164. This approach is interesting for racemic drugs, which are often considerably cheaper to produce than the pure enantiomer.


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The incorporation of MIPs within delivery systems is of potential value in the administration of chiral drugs, where significant pharmacological activities are associated with only one enantiomer. They developed a transdermal patch for controlled delivery of the active S-enantiomer from racemic propranolol and tested their performance in vivo on rats. A molecularly imprinted polymer (MIP) thin-layer composited cellulose membrane with selectivity for S-propranolol was employed as the enantioselective-controlled release system. The membrane was found to preferentially deliver the desired enantiomer. Compared with conventional drugs, drug delivery particles (based on MIPs and other materials) have the disadvantage that they are quite complex. This poses not only a problem in particle synthesis but can also cause difficulties when the particle should be approved for the clinic since every building block has to be tested. As a consequence drug delivery particles although having nice advantages over conventional drugs are only used where they are really necessary.

6.2 CRYSTALLIZATION Structure determination of proteins is limited by their ability to form well diffracting and large enough crystals. Unfortunately, many proteins have irregular shapes and thus cannot easily be crystallized. Thus a whole field of crystallography has emerged to solve that problem. A very new application for imprinted polymers is initiating protein crystallization165,166.


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The ability of MIPs to control crystallization was first demonstrated in 167,168. The authors showed that polymers imprinted with calcite, are able to induce the nucleation of calcite under conditions favoring the growth of aragonite (another polymorph of calcium carbonate). Saridakis et al. where the first who used molecularly imprinted polymers to facilitate protein crystallization169. They found that molecularly imprinted polymers can initiate protein crystal growth for several different proteins (lysozyme, trypsin, catalase, haemoglobin, intracellular xylanase IXT6-R217W, alpha crustacyanin, and human macrophage migration inhibitory factor). Among them were also proteins that are difficult to crystallize and thus had not been crystallized before. Furthermore, imprinted polymers have also increased the speed of crystal formation significantly. The same group also investigated the crystal formation ability as a measure for the affinity between different polymers and protein templates166. They compared acrylamide (AA), Nhydroxymethylacrylamide (NHMA), and N-isopropylacrylamide (NiPAM) as functional monomers for protein imprinting. They found that the crystal formation was improved in the order NiPAM < AA < NHMA. They concluded that the affinity to the target proteins where in the same order. 6.3 MIP PARTICLES AS BIOMIMETIC ANTIBODIES In this section we would like to discuss the use of MIP particles as artificial antibodies. The idea is to generate particles with certain selectivity that could be given to patients and replace natural antibodies in an immune response. Many authors name their imprinted polymers artificial


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antibodies. However, we would like to address a specific application here and will discuss the respective articles in sections about sensing applications. First attempts towards achieving this goal where made in the Shea group170. The authors designed their particles to bind a toxic protein called mellitin. This is a hemolytic peptide that lyses red blood cells. They investigated different acrylamide based imprinted nanoparticles. The hemolytic behavior was used to determine the success of the binding reaction. To this end the imprinted particles were mixed with red blood cells and melittin. When the melittin bound it could not lyse the blood cells anymore. Remarkably the authors where able to increase blood cell survival in vitro from 0 to almost 80% (after addition of 30 ug/ml of imprinted polymer). This detoxification from melittin poisoning was also demonstrated in vivo171,172. To test the detoxification with imprinted polymer particles mice were intoxicated with melittin. The authors showed that survival rate of mice was significantly improved when they were treated with the melittin imprinted particles. This effect was not observed with non-imprinted reference particles. Additionally, they found that the particles and the enclosed melittin is directed to the liver (which is the organ where particles are naturally cleared from the blood stream to be excreted). The Shea group also tested potential toxicity of the artificial antibodies independently and found no adverse effects on the mice after injection. The same group also generated artificial receptors that were able to bind the Fc fragment of natural antibodies38. These results establish that engineered synthetic polymer particles can be formulated with an affinity to a specific domain of a large biomacromolecule. To achieve that goal the authors used an iterative approach using different polymer compositions to obtain the optimal binding affinity.


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The affinity of such artificial antibodies towards their target can even be increased by affinity chromatography. Hoshino et al. have demonstrated that they can select particles with high affinity173. To achieve this goal they used a column with immobilized target proteins. While low affinity particles get eluted first, high affinity particles remain on the column longer. 6.4 DRUG DISCOVERY The affectivity of drugs is mostly based on their ability to bind to certain receptors and trigger or inhibit a reaction. Inhibitors are of great interest since they are often potential drugs or have other biological relevance. Review articles about molecular imprinting in drug discovery can be found in174. The group of Prof. Mosbach has found that molecularly imprinted polymers can be used to find potential inhibitors for receptors175. The inhibitors they were interested in are kallikrein inhibitors. Kallikrein is an enzyme with physiological significance in transforming hormone precursors into their active form. Kallikrein is also believed to play a role in cancer and thus can be used as cancer marker. For inhibitor screening they self-assembled new inhibitor structures within the reactive sites of the native enzyme (strategy 1 in Figure 10).


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Figure 10. Strategies to screen for new inhibitors discovered in the Mosbach group175: New inhibitors can be self-assembled within the natural enzyme (strategy 1) or generated by double imprinting (strategy 2). In the double imprinting approach an imprinted polymer is molded around a known inhibitor leading to a cavity that represents the active site of the enzyme. The new inhibitor is then self-assembled within the cavity in a second imprinting step.

The assembled products were removed from the enzyme and their ability to inhibit the enzyme activity was tested. As an alternative strategy they used a double imprinting strategy. (strategy 2 in Figure 12) To this end they first imprinted a known kallikrein inhibitor to generate an artificial enzyme (based on a cross linked divinylbenzene). After extracting the template inhibitor, cavities remain that are similar in structure to the natural enzyme. Then the authors performed a condensation reaction within the cavities of the MIP. The products of this second imprinting step were evaluated for their ability to inhibit kallikrein. The striking advantage of this technique is that there is no need for detailed structural information or isolation of the natural biological


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target. Both approaches lead to the formation of new kallikrein inhibitors and thus potential drugs. 6.5 CELL CULTURING

Surfaces with defined patterns and roughness have been found to improve cell culturing176,177. Since size, density and even surface chemistry of such patterns can be tuned in molecular imprinting molecularly imprinted polymers are an interesting material for this application. DePorter et al. have demonstrated the growth promotion of three different cell types178. HeLa cells (cells from an immortal cancer cell line), HEK-293T (human embryonic kidney cells) and MRC-9 (human embryonic lung cells) grow significantly better on an imprinted polymer In order to create the imprints cells were incubated in a premixed solution consisting of acrylamide, bisacrylamide, tetramethylethylene-diamine (TEMED), and ammonium persulfate (radical starter) at room temperature for 20 min. They performed several careful control experiments to guarantee, that the improved adhesion is caused by imprinting and not simply residues of cell debris on the surface. The authors also showed that the imprinted surfaces adhere more to the respective template cells than to other cells. Zehua et al. also used molecular imprinting for cell growth179. However, instead of a cell imprinted polymer they used sugar fibers as templates. They report that grooves remaining from sugar fiber imprinting direct cell growth (MC3T3-E1) in the same direction. They observed that the cell viability is not negatively affected by the imprinted polymer.

7 CONCLUSION AND OUTLOOK


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Molecularly imprinted polymers have been highly optimized for the traditional applications as chemical sensing or chromatography reaching record selectivities. Starting from small molecules the field of molecularly imprinted polymers has been extended to large biomolecules as proteins, viruses or even entire cells. However, the selectivities and sensitivities that have been achieved still differ a lot depending on the template. Selectivities that have been achieved for large biomolecules are still a lot worse than what was reported for small molecules. Some success has been achieved e.g. for viruses that have a repetitive surface structure or for cells with a relatively rigid cell wall. However, too flexible surface structures as e.g. cells with “fluid” cell membranes are a serious problem for imprinting that has so far not been solved. Several promising new technologies are starting to make use of the high affinities provided by molecularly imprinted polymers. These have been successfully used for drug discovery and drug delivery applications, as enzyme like catalysts, for cell culturing and crystal growth and even as artificial antibodies. There are many applications, mainly in the fields of biology and medicine, where MIPs have just been discovered for very recently. Consequently, there is most likely room for improvement and new innovations in this field.

BIBLIOGRAPHIC INFORMATION: Romana Schirhagl studied Chemistry at the University of Vienna, where she received her Ph.D. degree in 2009. She worked for one year as a postdoctoral researcher in the Department of Chemistry at Stanford University. Currently, she does research at the ETH in Zurich, where her main research focus is in micro- and nanofabrication, and surface chemistry for nanometer scale magnetic imaging, bioanalysis tools and biosensors. She is a nationally ranked chess player.


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For TOC only:


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1 Carrara S.; Bhalla V.; Stagni C.; Benini L.; Ferretti A.; Valle F.; Gallotta A.; Ricco B.; Samorì B.; Sensors and Actuators B, 2009, 136, 163–172 2 Tsai W-C.; Li I-C.; Sensors and Actuators B, 2009, 136, 8–12 3 Scharf L.; West AP.; Gao H.; Lee T.; Scheid JF.; Nussenzweig MC.; Bjorkman PJ.; Diskin R.; Proceedings of the National Academy of Sciences of the United States of America, 2013, 110 (15) , pp. 6049-6054 4 Ye L.; Mosbach K.; Chem Mater, 2008, 20, 859–868 5 Polyakov MV.; Zhurnal Fizieskoj Khimii/Akademiya SSSR, 1931, 2, 799-805 6 Arshady R.; Mosbach K.; Macromolecular Chemistry and Physics, 1981, 182 (2), 687-692 7 Sarhan A.; Wulff G.; Makromolekulare Chemie-Macromolecular Chemistry and Physics, 1982, 183 (7), 16031614 8 O’Mahony J.; Karlsson BCG.; Mizaikoff B.; Nicholls IA.; Analyst, 2007, 132, 1161–1168 9 Wei S.; Jakusch M.; Mizaikoff B.; Anal Bioanal Chem, 2007, 389, 423–431 10 Singh K.; Balasubramanian S.; Amitha Rani BE.; Current Analytical Chemistry, 2012, 8 (4), 562-568 11 Schirhagl R.; Qian J.; Dickert FL.; Sensors and Actuators B: Chemical, 2012, 173, 585–590 12 Piletsky SA.; Turner APF.; Electroanalysis, 2002, 14 (5), 317-323 13 Vlatakis G.; Andersson LI.; Müller RI.; Mosbach K.; Nature, 1993, 361, 645-647 14 Kryscio DR.; Peppas NA.; Acta Biomaterialia, 2011, 8(2), 461-73 15 Levi L.; Srebnik S.; J Phys Chem B, 2011, 115, 14469–14474 16 Latif U.; Mujahid A.; Afzal A.; Sikorski R.; Lieberzeit PA.; Dickert FL.; Anal Bioanal Chem, 2011, 400, 2507– 2515 17 Yu Z.; Yang J.; Zhong J.; Wu S.; Xu Z.; Tang Y.; Journal of Applied Polymer Science, 2012, 126 (4), 1344– 1350, 18 Andersson L.; Mosbach K.; J Chromatography, 1990, 516, 313-322 19 Sellergren B.; Wieschemeyer J.; Boos KS.; Seidel D.; Chem Mater, 1998, 10, 4037–4046 20 Whitcombe MJ.; Rodriguez ME.; Villar P.; Vulfson EN J Am Chem Soc, 1995, 117, 7105–7111 21 Ho W-L.; Liu Y-Y.; Lin T-C.; Environmental Engineering Science, 2011, 28 (6), 421-434 22 Li XX.; Bai LH.; Wang H.; Wang J.; Huang YP.; Liu ZS.; Journal of Chromatography A, 2012, 1251, 141-147 23 Puoci F.; Iemma F.; Muzzalupo R.; Spizzirri UG.; Trombino S.; Cassano R.; Picci N.; Macromol. Biosci., 2004, 4, 22–26 24 Puoci F.; Iemma F.; Cirillo G.; Picci N.; Matricardi P.; Alhaique F.; Molecules, 2007, 12, 805-814 25 DePorter SM.; Lui I.; McNaughton BR.; Soft Matter, 2012, 8, 10403 26 Saifuddin N.; Nur YAA.; Abdullah SF.; Asian Journal of Biochemistry, 2011, 6 (1), 38-54 27 Nematollahzadeh A.; Sun W.; Aureliano CSA.; Lutkemeyer D.; Stute J.; Abdekhodaie MJ.; Shojaei A.; Sellergren B.; Angew Chem Int Ed, 2011, 50, 495 –498 28 Sreenivasan K.; Journal of Applied Polymer Science, 1998, 70 (1), 19-22 29 Dickert FL.; Thierer S.; Advanced Materials, 1996, 8 (12), 987-989 30 Dickert FL.; Tortschanoff M.; Bulst WE.; Fischerauer G.; Analytical Chemistry, 1999, 71 (20), 4559-4563 31 Dickert FL.; Aigner S.; Jungbauer C.; Technisches Messen, 2012, 79 (11), 509-515 32 Glad M.; Norrlow O.; Sellergren B.; Siegbahn N.; Mosbach K.; J Chromatogr, 1985, 347, 11–23 33 Zang D.; Ge L.; Zhao P.; Yu J.; Huang J.; Advanced Materials Research, 2011, 306-307, 663-666 34 Graham AL.; Carlson CA.; Edmiston PL.; Analytical Chemistry, 2002, 74 (2), 458-467 35 Yu J.; Zhang C.; Dai P.; Ge S.; Analytica Chimica Acta, 2009, 651 (2), 209-214 36 Katz A.; Davis ME.; Nature, 2000, 403, 286-289 37 Nicolescu T-V.; Sarbu A.; Ghiurea M.; Donescu D.; U.P.B. Sci. Bull., Series B, 2011, 73(1), 163-172 38 Lee S.-H.; Hoshino Y.; Randall A.; Zeng Z.; Baldi P.; Doong R.; Shea K.J.; J. Am. Chem. Soc., 2012, 134, 15765−15772 39 Lei W.; Meng Z.; Zhang W.; Zhang L.; Xue M.; Wang W.; Talanta, 2012, 99, 966-971 40 Harvey SD.; Mong GM.; Ozanich RM.; Mclean JS.; Goodwin SM.; Valentine NB.; Fredrickson JK.; Analytical and Bioanalytical Chemistry, 2006, 386, 211–219


34

Page 35 of 38

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41 Wang Y.; Zhang Z.; Jain V.; Yi J.; Mueller S.; Sokolov J.; Liu Z.; Levon K.; Rigas B.; Rafailovich MH.; Sensors and Actuators B, 2010, 146, 381–387 42 Turner NW.; Wright BE.; Hlady V.; Britt DW.; Journal of Colloid Interface Science, 2007, 308 (1), 71–80 43 Gültekin A.; Diltemiz SE.; Ersöz A.; Sarıözlü NY.; Denizli A.; Say R.; Talanta, 2009, 78, 1332–1338 44 Bossi A.; Rivetti C.; Mangiarotti L.; Whitcombe MJ.; Turner APF.; Piletsky SA.; Biosensors and Bioelectronics, 2007, 23 (2), 290-294 45 Schirhagl R.; Ren K.; Zare RN.; Science China Chemistry, 2012, 55 (4), 469-483 46 Hansen DE.; Biomaterials, 2007, 28, 4178–4191 47 Dvorakova G.; Haschick R.; Klapper M.; Mullen K.; Biffis A.; Journal of Polymer Science Part A: Polymer Chemistry, 2013, 51 (2), 267–274 48 Nicolescu T-V.; Sarbu A.; Ovidiu Dima S.; Nicolae C.; Donescu D.; Journal of Applied Polymer Science, 2013, 127 (1), 366-374 49 Darder M.; Aranda P.; Burgos-Asperilla L.; Llobera A.; Cadarso VJ.; Sanchez CF.; Ruiz-Hitzky E.; Journal of Materials Chemistry, 2010, 20, 9362–9369 50 Seifner A.; Lieberzeit PA.; Jungbauer C.; Dickert FL.; Analytica Chimica Acta, 2009, 651 (2), 215-219 51 Birnbaumer GM.; Lieberzeit PA.; Richter L.; Schirhagl R.; Milnera M.; Dickert FL.; Bailey A.; Ertl P.; Lab on a Chip, 2009, 9, 3549–3556 52 Nishino H.; Huang CS.; Shea KJ.; Angewandte Chemie International Edition, 2006, 45, 2392 –2396 53 Schirhagl R.; Lieberzeit PA.; Dickert FL.; Advanced Materials, 2010, 22 (18), 2078–2081 54 Schirhagl R.; Seifner A.; Hussain FT.; Cichna-Markl M.; Lieberzeit PA.; Dickert FL.; Sensor Letters, 2010, 8, 399-404 55 Shi H.; Tsai WB.; Garrison MD.; Ferrari S.; Ratner BD.; Nature, 1999, 398, 593-597 56 Dickert FL.; Hayden O.; Bindeus R.; Mann KJ.; Blaas D.; Waigmann E.; Analytical and Bioanalytical Chemistry, 2004, 378, 1929–1934 57 Madhuri R.; Tiwari MP.; Kumar D.; Mukharji A.; Prasad BB.; Adv. Mat. Lett., 2011, 2(4), 264-267 58 Dickert FL.; Hayden O.; Halikias KP.; Analyst 2001 126 (6) , 766-771 59 Titirici MM.; Sellergren B.; Analytical and Bioanalytical Chemistry, 2004, 378, 1913–1921 60 Tai DF.; Lin CY.; Wu TZ.; Chen LK.; Analytical Chemistry, 2005, 77, 5140-5143 61 Moores B.; Drolle E.; Attwood SJ.; Simons J.; Leonenko Z.; PLOS, 2011, 6 (10) 62 Whitcombe MJ.; Chianella I.; Larcombe L.; Piletsky SA.; Noble J.; Porter R.; Horgan A.; Chemical Society Reviews, 2011, 40, 1547–1571 63 Rost B.; Liu JF.; Nucleic Acid Research, 2003, 31 (13), 3300-3304 64 Bossi AM.; Sharma PS.; Montana L.; Zoccatelli G.; Laub O.; Levi R.; Anal Chem, 2012, 84, 4036−4041 65 Kugimiya A.; Babe F.; Polymer Bulletin, 2011, 67 (9), 2017-2024 66 Schirhagl R.; Latif U.; Podlipna D.; Blumenstock H.; Dickert FL.; Analytical Chemistry, 2012, 84 (9), 39083913 67 Schirmer C.; Meisel H.; Analytical and Bioanalytical Chemistry, 2009, 394, 2249–2255 68 Guardia L.; Badıa-Laıno R.; Dıaz-Garcıa ME.; Ania CO.; Parra JB.; Biosensors and Bioelectronics, 2008, 23, 1101–1108 69 Liu J.; Wulff G.; JACS, 2008, 130, 8044–8054 70 Schweitz L.; Andersson LI.; Nilsson S.; Analytical Chemistry, 1997, 69, 1179-1183 71 Rachkov A.; Minoura N.; Journal of Chromatography A, 2000, 889, 111–118 72 Huang CY.; Tsai TC.; Thomas JL.; Lee MH.; Liu BD.; Lin HY.; Biosensors and Bioelectronics, 2009, 24, 2611– 2617 73 Guo TY.; Xia YQ.; Hao GJ.; Song MD.; Zhang BH.; Biomaterials, 2004, 25, 5905–5912 74 Ellwanger A.; Berggren C.; Bayoudh S.; Crecenzi C.; Karlsson L.; Owens PK.; Ensing K.; Cormack P.; Sherrington D.; Sellergren B.; Analyst, 2001, 126, 784–792 75 Bolisay LD.; Culver JN.; Kofinas P.; Biomaterials, 2006, 27, 4165–4168 76 Peng-Ju W.; Jun Y.; Qing-De S.; Yun G.; Xiao-Lan Z.; Ji-Bao C.; Chin J Anal Chem, 2007, 35(4), 484–488 77 Bacskay I.; Takatsy A.; Vegvari A.; Elfwing A.; Ballagi-Pordany A.; Kilar F.; Hjerten S.; Electrophoresis 2006, 27, 4682–4687 78 Lee S.-W.; Ichinose I.; Kunitake T.; Langmuir 1998, 14, 2857-2863 79 Schirhagl R.; Hall EW.; Fuereder I.; Zare RN.; Analyst, 2012, 137 (6):1495-1499 80 Schweitz L.; Spegel P.; Nilsson S.; Electrophoresis, 2001, 22, 4053–4063


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81 Deng QL.; Li YL.; Zhang LH.; Zhang YK.; Chinese Chemical Letters, 2011, 22, 1351–1354 82 Vallano PT.; Remcho VT.; Journal of Chromatography A, 2000, 887(1–2), 125–135 83 Fang L.; Chen S.; Zhang Y.; Zhang H.; J Mater Chem, 2011, 21, 2320-2329 84 Qu P.; Lei J.; Ouyang R.; Ju H.; Analytical Chemistry 2009, 81, 9651–9656 85 Li XX.; Bai LH.; Wang H.; Wang J.; Huang YP.; Liu ZS.; Journal of Chromatography A, 2012, 1251, 141-147 86 Mergola L.; Scorrano S.; Del Sole R.; Lazzoi MR.; Vasapollo G.; Biosensors and Bioelectronics, 2013, 40 (1), 336-341 87 Morais EC.; Correa GG.; Brambilla R.; Dos Santos JHZ.; Fisch AG.; Journal of Separation Science (2013) 36(3), 636-43 88 Ansell RJ.; Kuah JKL.; Wang D.; Jackson CE.; Bartle KD.; Clifford AA.; Journal of Chromatography A, 2012. 1264, 117-123 89 Denderz N.; Lehotay J.; Journal of Chromatography A, 2012, 1268, 44– 52 90 Esfandyari-Manesh M.; Javanbakht M.; Dinarvand R.; Atyabi F.; J Mater Sci: Mater Med, 2012, 23, 963–972 91 Liu H.; Row KH.; Yang G.; Chromatographia, 2005, 61, 429–432 92 Walshe M.; Garcia E.; Howarth J.; Smyth MR.; Kelly MT.; Anal. Commun. 1997, 34, 119–122 93 Yun Y.; Zhu M.; Zhang Z.; Liu C.; Lei J.; Ma G.; Su Z.; Pharm Anal Acta, 2012, 3, 151 94 Zhang H.; Dramou P.; He H.; Tan S.; Pham-Huy C.; Pan H.; Journal of Chromatographic Science, 2012, 50, 499–508 95 Guo P.; Martin CR.; Zhao Y.; Ge J.; Zare RN.; Nano Lett, 2010, 10, 2202–2206 96 Mayes AG.; Mosbach K.; Analytical Chemistry, 1996, 8 (21) , 3769-3774 97 Guo Y.; Yang Y.; Zhang L.; Guo TY.; Macromolecular Research, 2011, 19 (11), 1202-1209 98 Hua K.; Zhang L.; Zhang Z.; Guo Y.; Guo T.; Acta Biomaterialia, 2011, 7 (8), 3086-3093 99 Kim Y.; Jeon JB.; Chang JY.; Journal of Materials Chemistry, 2012, 22 (45), 24075-24080 100 Poma A.; Turner APF.; Piletsky SA.; Trends in Biotechnology, 2010, 28 (12), 629-637 101 Gu J.; Zhang H.; Yuan G.; Chen L.; Xu X.; Journal of Chromatography A, 2011, 1218 (45), 8150–8155 102 Prasad Rao J.; Geckeler KE.; Progress in Polymer Science, 2011, 36 (7), 887–913 103 Ren K.; Zare RN.; ACS-Nano, 2012, 6(5), 4314–4318 104 Schirhagl R.; Latif U.; Dickert FL.; 2011, 21 (38), 14594-14598 105 Schirhagl R.; Podlipna D.; Lieberzeit PA.; Dickert FL.; Chemical Communication, 2010, 46, 3128–3130 106 Jenik M.; Schirhagl R.; Schirk C.; Hayden O.; Lieberzeit P.; Blaas D.; Paul G.; Dickert FL.; Analytical Chemistry, 2009, 81, 5320–5326 107 Hayden O.; Dickert FL.; Advanced Materials, 2001, 13 (19), 1480–1483 108 Qi P.; Wan Y.; Zhang D.; Biosensors and Bioelectronics, 2013, 39 (1), 282-288 109 Hussain M.; Wackerlig J.; Lieberzeit PA.; Biosensors 2013, 3(1), 89-107 110 Sharma, P.S., D'Souza, F., Kutner, W., TrAC - Trends in Analytical Chemistry, 2012, 34, 59-76 111 Shimizu, K.D., Stephenson, C.J.; Current Opinion in Chemical Biology, 2010, 14 (6), 743-750 112 Fukazawa K.; Li Q.; Seeger S.; Ishihara K.; Biosensors and Bioelectronics, 2013, 40, 96–101 113 Rathbone DL.; Ge Y.; Analytica Chimica Acta, 2001, 435, 129–136 114 Kim H.; Kim Y.; Chang JY.; Journal of Polymer Science, Part A: Polymer Chemistry, 2012, 50 (23), 4990-4994 115 Kolarov F.; Niedergall K.; Bach M.; Tovar GEM.; Gauglitz G.; Anal Bioanal Chem, 2012, 402, 3245–3252 116 Mohrle BP.; Kumpf M.; Gauglitz G.; Analyst, 2005, 130, 1634–1638 117 Proll F.; Mohrle B.; Kumpf M.; Gauglitz G.; Anal Bioanal Chem, 2005 382, 1889–1894 118 Suryanarayanan V.; Wu CT.; Ho KC.; Electroanalysis, 2010, 22(16), 1795 – 1811 119 Blanco-Lopez MC.; Lobo-Castanon MJ.; Miranda-Ordieres AJ.; P. Tunon-Blanco.; Trends in Analytical Chemistry, 2004, 23(1), 36-48 120 Malitesta C.; Mazzotta E.; Picca RA.; Poma A.; Chianella I.; Piletsky SA.; Analytical and Bioanalytical Chemistry, 2012, 402 (5) , 1827-1846 121 Li S.; Piletsky SA.; Lunec J.; Molecularly imprinted Sensors: Overview and Applications, Elsevier, 2012 122 Sergeyeva TA.; Piletsky SA.; Brovko AA.; Slinchenko EA.; Sergeeva LM.; Elskaya AV.; Analytica Chimica Acta, 1999, 392, 105-111 123 Kugimiya A.; Kohara K.; Materials Science and Engineering: C, 2009, 29 (3), 959–962 124 Tsai HH.; Lin CF.; Juang YZ.; Wang IL.; Lin YC.; Wang RL.; Lin HY.; Sensors and Actuators B: Chemical, 2010, 144 (2), 407–412 125 Alizadeh T.; Ganjali MR.; Akhoundian M.; Int. J. Electrochem. Sci., 2012, 7, 10427 - 10441


36

Page 37 of 38

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


126 Kriz D.; Mosbach K.; Analytica Chimica Acta, 1994, 300 (1–3),71–75 127 Etchenique RA.; Calvo EJ.; Electrochemistry Communications, 1999, 1:167–170 128 Salomaki M.; Kankare J.; The Journal of Physical Chemistry B, 2007, 111, 8509–8519 129 Grate JW.; Klusty M.; McGill RA.; Abraham MH.; Whiting G.; Adonian-Haftvan JA.; Analytical Chemistry, 1992, 64, 610-624 130 Lucklum R, Behling C, Hauptmann P, Analytical Chemistry, 1999, 71, 2488-2496 131 Latif U.; Can S.; Hayden O.; Grillberger P.; Dickert FL.; Sensors and Actuators B: Chemical, 2013, 176, 825–830 132 Dickert FL.; Jenik M.; Lieberzeit PA.; Grillberger P.; Schirhagl R.; Seifner A.; Paul G.; VDI Berichte, 2011, 4352 133 Salomaki M.; Kankare J.; Langmuir, 2004, 20, 7794–7801 134 Findeisen A.; Wackerlig J.; Samardzic R.; Pitkänen J.; Anttalainen O.; Dickert FL.; Lieberzeit PA.; Sensors and Actuators B, 2012, 170, 196– 200 135 Yaqub S.; Latif U.; Dickert FL.; Sensors and Actuators B: Chemical, 2011, 160 (1), 227–233 136 Lieberzeit PA.; Findeisen A.; Mähner J.; Samardzic R.; Pitkänen J.; Anttalainen O.; Dickert FL.; Procedia Engineering, 2010, 5, 381-384 137 Seidler K.; Polreichova M.; Lieberzeit PA.; Dickert FL.; Sensors 2009, 9, 8146-8157 138 Kobayashi T.; Murawaki Y.; Reddy PS.; Abe M.; Fujii N.; Analytica Chimica Acta, 2001, 435, 141–149 139 Apodaca DC.; Pernites RB.; Ponnapati RR.; Del Mundo FR.; Advincula RC.; ACS Appl. Mater. Interfaces, 2011, 3, 191–203 140 Jenik M.; Seifner A.; Krassnig S.; Seidler K.; Lieberzeit PA.; Dickert FL.; Jungbauer C.; Biosensors and Bioelectronics, 2009, 25 (1), 9-14 141 Piacham T.; Josell A.; Arwin H.; Prachayasittikul V.; Ye L.; Analytica Chimica Acta, 2005, 536, 191–196 142 Zhou WH.; Tang SF.; Yao QH.; Chen FR.; Yang HH.; Wang XR.; Biosensors and Bioelectronics, 2010, 26, 585–589 143 Alenus J.; Galar P.; Ethirajan A.; Horemans F.; Weustenraed A.; Cleij TJ.; Wagner P.; Phys. Status Solidi A, 2012, 209 (5), 905–910 144 Wen W.; Shitang H.; Shunzhou L.; Minghua L.; Yong P.; Sensors and Actuators, B: Chemical, 2007, 125 (2), 422-427 145 Grate JW.; Rose-Pehrsson SL.; Venezky DL.; Analytical Chemistry, 1993, 65 (14), 1868-1881 146 Latif U.; Dickert FL.; Chemistry. Insciences J., 2012, 2(4), 63-79 147 Dickert FL.; Forth P.; Lieberzeit P.; Tortschanoff M.; Fresenius J. Anal. Chem., 1998, 360 (8), 759-762 148 Dickert FL.; Hayden O.; Fresenius J. Anal. Chem., 1999, 364:506-511 149 Cao BQ.; Huang QB.; Pan Y.; Am. J. Anal. Chem., 2012, 3, 664-668 150 Avila M.; Zougagh M.; Rios A.; TrAC Trends in Analytical Chemistry, 2008, 27(1), 54-65 151 Afzal A.; Iqbal N.; Mujahid A.; Schirhagl R.; Analytica Chimica Acta, 2013 in press 152 Liu J.; Wulff G.; J. AM. CHEM. SOC., 2008, 130, l8044–8054 153 Bonomi P.; Servant A.; Resmini M.; J. Mol. Recognit., 2012, 25, 352–360 154 Zhang H.; Piacham T.; Drew M.; Patek M.; Mosbach K.; Ye L.; J. AM. CHEM. SOC., 2006, 128:4178-4179 155 Padwa A.; Huisgen R. Ed. Wiley: New York, 1984, 1-176 156 Katz A.; Davis ME.; Nature, 2000, 403, 286-289 157 vanNostrum CF.; Drug Discovery Today: Technologies Drug delivery/formulation and nanotechnology, 2005, 2 (1), 119-124 158 Hilt JZ.; Byrne ME.; Advanced Drug Delivery Reviews, 2004, 56, 1599– 1620 159 Puoci F.; Iemma F.; Cirillo G.; Picci N.; Matricardi P.; Alhaique F.; Molecules, 2007, 12, 805-814 160 White CJ.; Byrne ME.; Expert Opin. Drug Deliv., 2010, 7(6), 765-780 161 Alvarez-Lorenzo C.; Hiratani H.; Gomez-Amoza JL.; Martínez-Pacheco R.; Souto C.; Concheiro A.; J Pharm Sci., 2002, 91(10), 2182-92. 162 Hiratani H.; Fujiwara A.; Tamiya Y.; Alvarez-Lorenzo C.; Biomaterials, 2005, 26(11), 1293-1298 163 Sreenivasan K.; J. Appl. Polym. Sci., 1999, 71, 1819–1821 164 Suedee R.; Bodhibukkana C.; Tangthong N.; Amnuaikit C.; Kaewnopparat S.; Srichana T.; Journal of Controlled Release, 2008, 129 (3), 170-178 165 Whitcombe MJ.; Nature Chemistry, 2011, 3, 657–658


37


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Page 38 of 38

166 Reddy SM.; Phan QT.; El-Sharif H.; Govada L.; Stevenson D.; Chayen NE.; Biomacromolecules, 2012, 13(12), 3959-3965 167 D'Souza SM.; Alexander C.; Carr SW.; Waller AM.; Whitcombe MJ.; Vulfson EN.; Nature 1999, 398 (6725) , 312-316 168 D'Souza SM.; Alexander C.; Whitcombe MJ.; Waller AM.; Vulfson EN.; Polymer International, 2001, l 50 (4), 429-432 169 Saridakis E.; Khurshid S.; Govada L.; Phan Q.; Hawkins D.; Crichlow GV.; Lolis E.; Reddy SM.; Chayen NE.; PNAS, 2011, 108 (45), 18566-18566 170 Hoshino Y.; Urakami T.; Kodama T.; Koide H.; Oku N.; Okahata Y.; Shea KJ.; small 2009, 5 (13), 1562–1568 171 Hoshino Y.; Koide H.; Urakami T.; Kanazawa H.; Kodama T.; Oku N.; Shea KJ.; J AM CHEM SOC, 2010, 132:6644–6645 172 Hoshino Y.; Koide H.; Furuya K.; Haberaecker WW.; Lee SH.; Kodama T.; Kanazawa H.; Oku N.; Shea KJ.; PNAS, 2012, 109 (1):33–38 173 Hoshino Y.; Haberaecker WW.; Kodama T.; Zeng Z.; Okahata Y.; Shea KJ.; J. AM. CHEM. SOC., 2010, 132, 13648–13650 174 Rathbone DL.; Advanced Drug Delivery Reviews 2005, 57, 1854– 1874 175 Yu Y.; Ye L.; Haupt K.; Mosbach K.; Angewandte Chemie - International Edition, 2002, 41(23), 4459-4463 176 Curtis A.; Wilkinson C.; Biomaterials, 1997, 18, 1573 177 Lim JY.; Donahue HJ.; Tissue Eng., 2007, 13, 1879 178 DePorter SM.; Lui I.; McNaughton BR.; Soft Matter, 2012, 8, 10403 179 Zehua Q.; Jiandong D.; Chin J Chem, 2012, 30, 2292—2296


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Bioapplications for Molecularly Imprinted Polymers - Analytical

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