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Advanced sensing materials based on molecularly imprinted polymers towards developing point-of-care diagnostics devices/Sensormaterjalid molekulaarselt jaljendatud polumeeridest patsiendimanusteks testideks.

List of main abbreviations

BDNF     Brain-derived neurotrophic factor
BDNF-    SPE modified by MIP film with molecular
MIP/SPE  imprints of BDNF
CDNF     Cerebral dopamine neurotrophic factor
C/LR     Controlled/living radical
CV       Cycling voltammetry
DPV      Differential pulse voltammetry
EIS      Electrochemical impedance spectroscopy
HSA      Human serum albumin
IF       Imprinting factor
LOD      Limit of detection
LOQ      Limit of quantitation
MANF     Mesencephalic astrocyte-derived
         neurotrophic factor
mCD48    Mouse recombinant cluster of
         differentiation 48
MIP      Molecularly imprinted polymer
NF       Neurotrophic factor
NIP      Non-imprinted polymer
PBS      Phosphate buffer saline
PoC      Point-of-care
SPE      Screen-printed electrode
WE       Working electrode


1. INTRODUCTION

Nowadays, healthcare is facing an increasing demand for fast and reliable analytical methods suitable for achieving appropriate sensitivity and selectivity with low limit of detection (LOD) while being low-cost, portable, and capable of in situ real-time monitoring.

The occurrence and use of point-of-care (PoC) devices have steadily increased in Europe [1] as well as globally for facilitating rapid testing in medical diagnostics, and thus clinical decisions [2,3]. Most of the current biosensing systems including PoC devices utilize labile biological recognition elements that offer high selectivity towards a target analyte, but limit the shelf life of the device and increase cost and analysis time. Growing interest in the replacement of biological receptors with wholly synthetic analogues such as molecularly imprinted polymers (MIPs) has made a substantial contribution to the expansion of the field [4,5]. Molecular imprinting is one of the state-of-the-art techniques to generate MIPs--materials with antibody-like ability to bind and discriminate between molecules [6]. The technique can be defined as the process of template-induced formation of specific molecular recognition sites in a polymer matrix. The main benefits of MIPs are related to their synthetic nature, i.e. excellent chemical and thermal stability coupled with their reproducible and cost-effective fabrication. MIPs have been shown to be a promising alternative to natural receptors in biosensors [7-10].

The sensors based on electrochemical transduction mechanisms seem to be prospective for diagnostics purposes since they combine real-time monitoring of an analyte binding event, simplicity in handling, and sufficient sensitivity at reduced cost [11,12]. Furthermore, screen-printed electrode (SPE) sensors, being fully compatible with large-scale fabrication and multiplexing technologies and the ease in their integration with microfluidic systems, represent an ideal starting point to realize low cost and portable sensing platforms suitable for PoC devices [13]. Therefore, robust interfacing of a MIP film with a SPE provides a considerable option to build a cost-effective but reliable PoC device [14,15].

In clinical diagnostics, the research aimed at the discovery and detection of biomarkers of human diseases, especially neurological and mental disorders, has become of great demand due to the increase in the prevalence of these diseases over the last decades and the need for early stage diagnosis [16]. For example, neurotrophic factor (NF) proteins, which are a family of proteins secreted from neurons and neuron-supporting cells, were found to be associated with a number of neurological and mental diseases [17-20]. There is a large number of publications associating brain-derived neurotrophic factor (BDNF) levels with various conditions affecting brain functioning, including depression and neurodegeneration (Alzheimer's and Parkinson's diseases) [21-23]. Therefore, BDNF can be considered as a potential biomarker for the pre-symptomatic diagnostics of these diseases or for monitoring therapies.

The application of MIP-based sensors for diagnostics has been extensively studied. Thus, the detection of cancer biomarkers (such as prostate specific antigen [24], epithelial ovarian cancer antigen-125 [25], carcino-embryonic antigen [26]), and cardiovascular disease biomarkers (myoglobin [27,28] and cardiac troponin T [29]) by MIP-modified sensors has been reported. In addition, MIP receptors for selective extraction of an Alzheimer's disease biomarker, [alpha]-Amyloid peptides, has been studied by Sellergren's group [30]. Although the selective recognition of a growth factor family protein, vascular endothelial growth factor, by hybrid MIP nano-particles as well as by MIP thin layer on surface plasmon resonance (SPR) and screen-printed electrodes (SPEs) has been reported [31-33], to the best of our knowledge, there are no reports on the MIP designed for the recognition of NF proteins.

When synthesizing a MIP for sensing macromolecules such as proteins, it is essential that the synthesis strategy prevent the entrapment of the protein in the polymer matrix during the polymerization process and lead to a robust interfacing of the MIP with the surface of a sensor, i.e. to an efficient transduction of the binding event of this macromolecular analyte by the MIP into useful analytical signals. To address the issues, the implementing of surface-initiated controlled/living radical (C/LR) polymerization was shown to be a prospective solution [34,35]. The method of surface-initiated polymerization allows the formation of covalent bonding between the polymer film and the surface, which ensures a perfect interfacing between the MIP recognition layer and a sensor transducer. Moreover, the C/LR polymerization offers the capability of the film thickness control, uniform coating of surface, control over composition, and high density of grafting [36]. To perform surface initiated C/LR photopolymerization, an initiator, also called iniferter (initiator--transfer agent-terminator), was attached to a sensor surface using different techniques by Ahmad et al. [37].

In the present work, for the first time the MIP-based sensor for the detection of BDNF was prepared on a SPE by C/LR photopolymerization initiated from the surface. The main analytical characteristics of the BDNF-MIP/SPE sensor, such as its limit of detection (LOD) and limit of quantification (LOQ), were determined. The BDNF-MIP/SPE sensor was studied in terms of its recognition capability and selectivity towards the target protein through the analysis of the responses of the BDNF-MIP-modified SPE sensors to the interaction of the target (BDNF) and interfering (cerebral dopamine neurotrophic factor (CDNF), mesencephalic astrocyte-derived neurotrophic factor (MANF), mouse recombinant cluster of differentiation 48 (mCD48)) proteins.

2. EXPERIMENTAL

2.1. Chemicals and materials

3,5-Dichlorophenyl diazonium tetrafluoroborate (3,5-DClPDT), sodium diethyldithiocarbamate (Na-DEDTC), acetonitrile (ACN), (3-glycidyloxypropyl)trimethoxysilane (3-GPS), N,N'-methylenebis(acrylamide) (BAA), diethyl-aminoethyl methacrylate (DEAEM), and human serum albumin (HSA, 66.5 kDa) were obtained from Sigma-Aldrich. Tetrabutylammonium tetrafluoroborate ([Bu.sub.4][NBF.sub.4], 99.0%,) was obtained from Fluka. Human recombinant BDNF (13.5 kDa, pI 9.43), human recombinant CDNF (18.5 kDa, pI 7.68), human recombinant MANF, (18.1 kDa, pI 8.55), and mCD48 antigen (cluster of differentiation 48, 22.2 kDa, pI 9.36) were provided by Icosagen AS (Tartu, Estonia). Ultrapure water (resistivity 18.2 M[ohm] x cm, Millipore, USA) was used for the preparation of all aqueous solutions. Phosphate buffered saline (PBS) solution (0.01 M, pH 7.4) was used to prepare analyte solutions. The screen-printed electrodes (SPEs) were obtained from BVT Technologies a.s. (Praha, Czech Republic). The SPEs (catalogue #AC1.W1.R2) include a gold working electrode (WE) (1 mm diameter), an AgCl covered silver reference electrode, and a gold counter electrode.

2.2. Synthesis of BDNF-MIP films

The BDNF-MIP films were synthesized directly on the WE of the SPE using the following main stages (Fig. 1): (a) functionalization of SPE with 3,5-DClPD, (b) grafting of the iniferter to 3,5-DClPD, (c) coating of the SPE with the solution containing a mixture of the functional (DEAEM) and crosslinking (BAA) monomers and the target protein (BDNF), (d) photopolymerization of the monomers under UV-irradiation, and (e) removing BDNF from the polymer to form BDNF-MIP on the surface of the SPE.

The WE of the SPE was cleaned electrochemically by placing a drop of 0.1 M [H.sub.2][SO.sub.4] solution on it and cycling the potential from 0.1 to 1.15 V at a scan rate of 100 mV/s for 15 cycles. The modification of the WE with the 3,5-DClP layer was performed electrochemically applying an ACN solution containing 1 mM 3,5-DClPDT and 0.1 M [Bu.sub.4][NBF.sub.4] and cycling the potential of the WE between the -0.1 V and 0.5 V vs Ag/AgCl/KCl electrode at a rate of 50 mV/s. The modified surface was washed with tetrahydrofuran (THF) and ultrapure water to remove the physisorbed loosely bound layers of a 3,5-DClP [38] and dried under a nitrogen flow. The resulting SPE sensor with a 3,5-DClP layer grafted on the WE was immersed in ethanolic solution of 2 mM Na-DEDTC and vortexed (600 rpm) overnight at room temperature in the dark. Finally, the SPE was thoroughly rinsed with ethanol and ultrapure water and dried with a nitrogen flow.

The charge transfer blocking behaviour of the 3,5-DClP layer was investigated by electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The EIS and CV were conducted in 1 M KCl solution containing a 4 mM redox probe [K.sub.3][[Fe(CN).sub.6]]/[K.sub.4][[Fe(CN).sub.6]] by an electrochemical workstation (Reference 600, Gamry Instruments, USA). The CV was performed scanning the potential between 0 and 0.5 V at a scan rate of 50 mV/s. The EIS was performed in the frequency range between 100 kHz and 0.1 Hz at open circuit potential with AC amplitude of 10 mV. Every CV and EIS was repeated 3 times. The EIS spectra were fitted to an equivalent electrical circuit using Echem Analyst software (Gamry Instruments, USA). The BDNF-MIP film on the DEDTC-modified WE of the SPE was generated by C/LR photopolymerization by using UV-irradiation.

The prepolymerization solution was prepared by mixing 12.5 [micro]g/mL BDNF, 2.5 mM functional monomer, DEAEM, and 15 mM cross-linking monomer, BAA, in 0.05 M PBS. The prepolymerization solution (10 [micro]L) was dropped onto the DEDTC-modified SPE sensor and left for 30 min. Then the SPE was covered by a mask with a hole 20% larger than the diameter of the WE and irradiated under UV light (500 W/[m.sup.2], 365 nm) during 30 min at room temperature. The optimum polymerization time was determined by comparing the normalized signals of the sensors after polymerization for 15, 30, and 45 min. The normalized signals were determined during incubation in 5 ng/mL BDNF solution in PBS. After photopolymerization the mask was removed and the SPE sensor was alternately immersed in aqueous solution of 0.2 M NaOH and 5% acetic acid and vortexed (600 rpm) for 30 min to remove the protein from the polymer matrix. The resulting BDNF-MIP/SPE sensor was washed with Milli-Q water and dried under nitrogen flow. The reference non-imprinted polymer (NIP) film was produced in the same way except that the prepolymerization solution was prepared without the addition of BDNF. The surface morphology of the BDNF-MIP and NIP films was characterized by high-resolution scanning electron microscope (HR-SEM Zeiss Merlin) equipped with an In-Lens SE detector for topographic imaging. Measurements were made at an operating voltage of 2.00 kV.

2.3. Rebinding, reusability, and selectivity studies of the BDNF-MIP/SPE sensor

The binding affinity and selectivity of the BDNF-MIP/SPE toward the target analyte BDNF were determined by means of differential pulse voltammetry (DPV). Measurements were performed in the 1 M KCl solution containing a 4 mM redox probe [K.sub.3][[Fe(CN).sub.6]]/[K.sub.4][[Fe(CN).sub.6]]. The DPV was conducted in the range 0-0.4 V with the pulse amplitude of 0.025 V, pulse time of 0.05 s, and step potential of 0.005 V. The DPV was performed after 30 min incubation of BDNF-MIP- and NIP-modified SPE sensors in solutions with increasing concentrations of the analyte (from 0.1 to 100 ng/mL of BDNF in PBS solution). After that, the unbound protein was removed by washing twice in PBS vortexed (600 rpm) for 5 min. The optimal incubation time was determined by incubating the BDNF-MIP/SPE sensor in the BDNF solution (2 ng/mL) for various times (5, 10, 15, 20, 30, 40, 60 min). The binding affinity of the BDNF-MIP films toward the target was measured by means of DPV. The DPV curves were recorded after the incubation of BDNF-MIP- and NIP-modified SPEs in solutions with increasing concentrations of the analyte (from 0.1 to 100 ng/mL of BDNF in PBS). The response signals of the BDNF-MIP/SPE were its normalized DPV current peaks, [B.sub.n], calculated according to Eq. (1):

[B.sub.n] = [I.sub.0] - [I.sub.c]/[I.sub.0] (1)

where [I.sub.0] is DPV current peak measured after the incubation of the SPE in blank PBS solution, [I.sub.C] is the DPV current peak measured after the incubation the SPE in PBS containing a particular concentration (C ) of BDNF.

The binding isotherms were generated using [B.sub.n] values. The values of the dissociation constant ([K.sub.d]) and the maximum binding response at saturation ([B.sub.max]) were derived from fitting the binding isotherm to Langmuir adsorption models (Eq. 2):

B = [B.sub.max]C/[K.sub.d] + C (2)

The reusability of the BDNF-MIP/SPE sensor was tested by measuring its responses after the regeneration procedure and repeated incubation in BDNF solution (2 ng/mL). The regeneration procedure was performed in the same way as the procedure for the removal of the protein from the polymer matrix employed after the synthesis of the BDNF-MIP film. The selectivity of the BDNF-MIP/SPE sensor was assessed by comparing the responses of the BDNF-MIP/SPE sensor towards BDNF with those of the interfering proteins CDNF, MANF, and mCD48. The selectivity test was conducted at different concentrations of the proteins in the presence of 0.8 mg/mL HSA.

3. RESULTS AND DISCUSSION

3.1. Preparation of BDNF-MIP films

In this study the BDNF-MIP films were prepared by the surface-initiated C/LR polymerization technique directly on the WE of the SPE. First, the WE of the SPE was modified by a 3,5-dichlorophenyl (3,5-DClP) layer using the electrochemical reduction of the corresponding aryldiazonium salt, 3,5-DClPDT. This is a well-known method and widely used to modify metal surfaces by organic molecules providing the formation of a stable molecular layer as a result of covalent bonding of the aryl radical to the metal surface [39,40]. Figure 2 illustrates CV of the electrodeposition process of 3,5-DClP. The first cycle reveals well-defined reduction peaks, which can be attributed to the electrochemical reduction of 3.5-DClPDT to its corresponding radicals. The reduction peaks disappear during the second cycle, which corresponds to the formation of a blocking layer preventing further access of the diazonium species to the electrode surface [41].

The success of the modification of the WE by 3,5 DClP was confirmed by CV and EIS recorded in the presence of a [Fe(CN).sup.3-/4-.sub.6] redox pair. Figure 3a shows that the intensity of the pair of the current peaks associated with the redox activity of [Fe(CN).sup.3-/4-.sub.6] and defined well on the bare gold electrode, greatly diminished after the grafting of the diazonium salt on the gold electrode. This confirms the insulating nature of the deposited organic monolayers. The charge transfer resistance, as estimated from the width of the semicircle in the Nyquist plot (Fig. 3b), increased from 68 [ohm]/c[m.sup.2] (the bare gold electrode) to 2.3 k[ohm]/[cm.sup.2] (after modification by the 3.5-DClP layer). The increase in the charge transfer resistance is a direct consequence of the partial passivation of the bare gold electrode, which reduces the ability of the redox probe to access its surface. The attachment of the iniferter DEDTC to the 3,5-DClP-modified surfaces by electrophilic substitution was discussed in detail in our previous work [35], where the successful functionalization of the gold electrode by a DEDTC layer was additionally confirmed by X-ray photoelectron spectroscopy data.

To synthesize a protein-selective MIP film, it is essential to prevent the entrapment of protein in the polymer matrix during the polymerization process. Therefore, in order to avoid the overgrowing of the polymer around the BDNF molecules, the thickness of the photopolymerized polymer film was controlled by the UV exposure time. The optimal exposure time was determined by calculating the imprinting factor (IF) (Eq. 3), which characterizes the relative adsorption capacity of MIP.

IF = [B.sub.n]MIP/[B.sub.n]NIP, (3)

where [B.sub.n]MIP and [B.sub.n]NIP are normalized signals after protein adsorption on MIP and NIP, respectively; IF reflects the quality of the imprinting effect, as a larger value of IF represents the availability of more binding sites with high affinity in the resulting polymer. As can be seen in Fig. 4, the BDNF-MIP shows a higher IF value after 30 min of photopolymerization. The UV irradiation of 500 W/[m.sup.2] was chosen as the optimal intensity that does not cause significant damage to the protein structure within 30 min of exposure [35].

3.2. Analytical performance of a BDNF-MIP/SPE sensor

The binding affinity of the BDNF-MIP/SPE toward the target analyte BDNF was determined by means of DPV recorded after the incubation of the sensor in the solution with an increased concentration of the analyte. Firstly, in order to select the optimal binding conditions, the relationship between the sensor signal [B.sub.n] and the incubation time in the range of 5-60 min was studied. The current increased rapidly within the first 20 min of incubation and reached the saturation value after 30 min (Fig. 5), indicating that the adsorption equilibrium was reached. Thus, the optimal incubation time of 30 min was chosen for the rebinding study.

The [B.sub.n] values calculated from Eq. (1) were used to plot the binding isotherms (Fig. 6). The BDNF-MIP/SPE sensor showed a hyperbolic response as a function of the BDNF concentrations. To describe the equilibrium binding events happening on the sensor surface, the Langmuir adsorption model was used in this study. The Langmuir binding model was previously successfully applied to fit the adsorption isotherm of MIPs by other authors [27,29,42]. According to the model, when all binding sites are occupied by molecules, no further adsorption will occur on the surface and the saturation response ([B.sub.max]) will be obtained. The fitting results showed that BDNF-MIP bound the target protein, BDNF, with the dissociation constant [K.sub.d] of 1.12 ng/mL and had an about 5.8 times higher binding capacity than NIP as judged by the respective [B.sub.max] values (0.92 vs 0.16 a.u.).

The BDNF-MIP/SPE sensor showed a pseudo-linear response to the BDNF in the concentration range from 0.01 to 0.06 ng/mL and a fixed concentration of HSA (0.8 mg/mL), the main plasma protein (Fig. 7). The linear regression in this concentration range gives the coefficient of determination, R-squared, equal to 0.991 and LOD and LOQ values, determined as 3 and 10 times the standard deviation (SD) divided by the slope of the regression line, 6 pg/mL and 20 pg/mL, respectively.

3.3. Selectivity and reusability study

The BDNF-MIP/SPE sensor was characterized in terms of its capability to rebind selectively the target protein, BDNF, with respect to the interfering proteins of slightly different size and isoelectric point (pI) such as CDNF, MANF, and mCD48. Selection of CDNF and MANF as interfering analytes was stipulated by their permanent presence in a human serum and thus, they can interfere with the sensor response along with the target protein (BDNF). The third interfering analyte--mCD48--has the molecular weight and pI value similar to those of BDNF. The selectivity of the sensor was studied in the presence of HSA at a concentration of 0.8 mg/mL, corresponding to a 50-fold dilution of its physiological norm in diluted human serum. For the selectivity study, the concentration of the interfering proteins was selected close to their LOQ value (0.02-0.06 ng/mL). The response of the BDNF-MIP/SPE sensor to the BDNF was higher than that to the interfering proteins (Fig. 8). The difference between the responses of the sensor upon the interaction with the BDNF and the interfering proteins increased with the increasing concentration, and at 0.06 ng/mL the BDNF caused about a two times higher response as compared to the interfering proteins. At the same time the responses to the interfering proteins remained at approximately the same level for all tested concentrations.

As to the possibility of regenerating and repeatedly using a sensor, protein-MIP based sensors have been considered to have a significant advantage over conventional antibody-based biosensors. Therefore, we examined the ability of the prepared BDNF-MIP/SPE sensor to withstand the regeneration procedure. The treatments in the acidic and alkaline solutions efficiently disrupting possible multiple hydrogen and electrostatic bonds between the protein and the MIP surface were assessed to regenerate the surface of the sensor. It was found that the response of the BDNF-MIP/SPE sensor was greatly reduced already after the first regeneration cycle (Fig. 9), indicating a poor reusability of the sensor. However, taking into account that a SPE-based sensor is expected to be used as a disposable sensor, its reusability is obviously not of great importance. On the other hand, comparison of the signals of three freshly prepared BDNF-MIP/SPEs showed that a good reproducibility of the sensor response (standard deviation 0.026) was achieved.

4. CONCLUSIONS

In the present study, we have developed for the first time a MIP synthetic receptor capable of selective binding of BDNF integrated with an inexpensive and disposable SPE. Surface-initiated C/LR photopolymerization was demonstrated to be a suitable method to prepare stable BDNF-MIP films directly on a SPE sensor. The prepared BDNF-MIPs were capable of binding BDNF with the dissociation constant, [K.sub.d], of 1.12 ng/mL and had about 5.8 times higher binding capacity than the reference film, NIP. The BDNF-MIP/SPE sensor could detect BDNF with the LOD value of 6 pg/mL and quantify BDNF with the LOQ value of 20 pg/mL in the presence of HSA as a highly abundant serum protein. Moreover, it was able to discriminate BDNF among analogous molecules, i.e. CDNF and MANF, and a molecule of a similar size, i.e. mCD48. Although further research is required, the presented approach to the preparation of a cost-effective MIP-SPE sensor capable of selective detection of a NF-family protein could be a promising route towards the development of innovative PoC diagnostics devices for the early-stage diagnostics of neurological diseases or for monitoring therapies.

ACKNOWLEDGEMENTS

This work was supported by the Estonian Research Council (grant PRG307) and Tallinn University of Technology (development project SS425). The authors thank Icosagen AS and Prof. M. Ustav personally for kindly providing us with the neurotrophic factor proteins. The publication costs of this article were covered by the Estonian Academy of Sciences.

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Anna Kidakova, Jekaterina Reut, Roman Boroznjak, Andres Opik, and Vitali Syritski (*)

Department of Materials and Environmental Technology, Tallinn University of Technology, Ehitajate tee 5, 19086 Tallinn, Estonia

Received 20 December 2018, accepted 2 March 2019, available online 16 April 2019

(*) Corresponding author, vitali.syritski@taltech.ee

https://doi.org/10.3176/proc.2019.2.07
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Title Annotation:MATERIALS ENGINEERING
Author:Kidakova, Anna; Reut, Jekaterina; Boroznjak, Roman; Opik, Andres; Syritski, Vitali
Publication:Proceedings of the Estonian Academy of Sciences
Article Type:Report
Geographic Code:4EXES
Date:Jun 1, 2019
Words:5137
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