Molecular recognition by synthetic receptors: Application in field-effect transistor based chemosensing

Biosensors and Bioelectronics 109 (2018) 50–62

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Biosensors and Bioelectronics journal homepage: www.elsevier.com/locate/bios

Molecular recognition by synthetic receptors: Application in field-effect transistor based chemosensing☆ ⁎

T

⁎

Zofia Iskierko, Krzysztof Noworyta , Piyush Sindhu Sharma

Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland

A R T I C LE I N FO

A B S T R A C T

Keywords: Synthetic receptor Molecularly imprinted polymer Electrical transduction Field-effect transistor Extended-gate field-effect transistor

Molecular recognition, i.e., ability of one molecule to recognize another through weak bonding interactions, is one of the bases of life. It is often implemented to sensing systems of high merits. Preferential recognition of the analyte (guest) by the receptor (host) induces changes in physicochemical properties of the sensing system. These changes are measured by using suitable signal transducers. Because of possibility of miniaturization, fast response, and high sensitivity, field-effect transistors (FETs) are more frequently being used for that purpose. A FET combined with a biological material offers the potential to overcome many challenges approached in sensing. However, low stability of biological materials under measurement conditions is a serious problem. To circumvent this problem, synthetic receptors were integrated with the gate surface of FETs to provide robust performance. In the present critical review, the approach utilized to devise chemosensors integrating synthetic receptors and FET transduction is discussed in detail. The progress in this field was summarized and important outcome was provided.

1. Introduction Preparation of novel man-made materials capable to mimic functioning of biorecognition systems, such as enzymes, nucleic acids, or antibodies, signifies the most challenging task that has recently gained large scientific interest (Mahon and Fulton, 2014). The activity of bioreceptors is governed by selective analyte molecular recognition through weak reversible binding. Generally, biosensor activity engages the receptor recognition sites and the analyte binding sites in a particular shape and size configuration that is only one of its kind. The preparation and fabrication of tailor-made biorelevant receptor compounds featuring desired recognition properties require perception and understanding of functioning of the biological systems, in which they operate. Several bio-receptors exhibit specific recognition of organic molecules. This recognition can be explained via the mechanism of “lock and key” (Jones et al., 1995; Liao et al., 2013) and “induced fit model” (Boehr et al., 2009; Sawada et al., 2014). This awareness leads to designing and fabricating novel nature-inspired synthetic receptors

in molecular recognition. Molecular imprinting is a rapidly developing technique used to fabricate synthetic receptors with a great potential in many applications, particularly in the health and life sciences (Figueiredo et al., 2016; Iskierko et al., 2016a; Ndunda and Mizaikoff, 2016; Schirhagl, 2014; Tang, 2018). With this technique, new artificial recognition systems, capable of mimicking features of the corresponding biological recognition systems, are being devised (Chen et al., 2016b; Yoshikawa et al., 2016). The imprinting offers appreciable affinity, selectivity, and robustness at a relatively low cost (Whitcombe et al., 2011). In imprinting, a target analyte is first used as a template. For that, it is complexed by functional monomers in solution of a porogenic solvent. Then, this complex is co-polymerized with an excess of a cross-linking monomer in order to wrap it up in a permeable molecularly imprinted polymer (MIP) shell. The subsequent template removal results in the formation of the nanometer and sub-nanometer-size molecular cavities in the polymer. These cavities are complementary in size, shape, and orientation of their recognizing functionalities and, therefore, capable

List of abbreviations: ACh+, Acetylcholine; AOCB[6], (Allyloxy)12 cucurbit[6]uril; AFM, Atomic force microscopy; cAMP, 3’,5’-Cyclic monophosphate; ChemFET, Chemical field-effect transistor; CB[6], Cucurbit[6]uril; DDFTTF, 5,5′-Bis-(7-dodecyl-9Hfluoren-2-yl)-2,2′-bithiophene; ENFET, Enzyme field-effect transistor; EG-FET, Extended-gate field-effect transistor; FET, Field-effect transistor; HEMT, High-electron-mobility transistor; HSA, Human serum albumin; ISFET, Ion selective field-effect transistor; LOD, Limit of detection; MIP, Molecularly imprinted polymer; MOSFET, Metal oxide field-effect transistor; MOF, Metal-organic framework; NGAL, Neutrophil gelatinase-associated lipocalin (or Human lipocalin-2); NW, Nanowire; OFET, Organic field-effect transistor; PVC, Poly(vinyl chloride); POC, Point-of-care; PPi, Inorganic pyrophosphate; SAM, Self-assembled monolayer; TESBA, triethoxysilybutyraldehyde; TOF-SIMS, Time-of-flight secondary ion mass spectrometry ☆ Dedicated to Prof. Wlodzimierz Kutner, on his 70th birthday, for his contribution in the field of electroanalytical chemistry and molecular imprinting. ⁎ Corresponding authors. E-mail addresses: [email protected] (K. Noworyta), [email protected] (P.S. Sharma). https://doi.org/10.1016/j.bios.2018.02.058 Received 27 November 2017; Received in revised form 24 February 2018; Accepted 26 February 2018 Available online 06 March 2018 0956-5663/ © 2018 Elsevier B.V. All rights reserved.

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and the other to the drain electrode. In the n-channel FET, electrons are majority charge carriers while holes are charge carriers in the p-channel FET. An additional metal-over-dielectric gate electrode, deposited on the semiconducting channel, controls effective electrical diameter of the channel (Liu and Guo, 2012). A small variation in gate voltage is responsible for the observed change in the current flowing from the source to the drain. This conducting gate region can be coated with a membrane or another sensing element to provide selectivity, which is a much desired property for sensing. Bergveld et. al fabricated the first ion-sensitive field effect transistor (ISFET) (Bergveld, 1970). Several pH-sensitive ion-selective membranes, including SiO2 (Berg et al., 1985), Al2O3 (Chen et al., 2011b), Si3N4 (Liu et al., 1989), Ta2O5 (Branquinho et al., 2011), and SnO2 (Cheng et al., 2008) were devised and used afterwards. Depending on the type of modification of the gate surface, FET devices are known as ChemFETs if the charge on the gate electrode is generated by a chemical process (Bergveld, 2003), ENFETs if these devices use enzymes for specific recognition of bio-molecular compounds (Belkhamssa et al., 2016; Dzyadevych et al., 2003; Melzer et al., 2016), or OFETs if a channel of the transistor consists of an organic semiconductor (Liu et al., 2015a). In order to isolate the FET from the chemical environment, an extended-gate field-effect transistor (EGFET) was also devised (Chen et al., 2011a; Sakata et al., 2005; Yin et al., 2000). For a similar purpose, a high-electron mobility transistor (HEMT) has been used for sensor development (Schalwiga et al., 2002). When a sufficiently high gate voltage (VG) is applied, the FET device is turned to the “on” state. Then, the gate voltage generates an electric field across gate and channel. This field controls the source-drain current flow (Banica, 2012), which is characterized as the transfer curve. The saturation region current measured during transistor characteristic can be expressed as

of selective binding of the molecules of the target analyte. The selectivity, owing to the three-dimensional structure of the cavities, is due to multiple supramolecular bindings, such as the ion-ion, ion-dipole, and hydrogen bonding, as well as hydrophobic and van der Waals interactions. Although, separately, each interaction is weak, collectively they afford a relatively strong selective capture of the analyte. Due to these advanced features, the MIPs have become promising materials as recognition units for fabrication of chemical sensors for both low- and high-molecular-weight compounds (Chen et al., 2016b). In contrast, organic macrocyclic receptors, synthesized by common synthetic approaches, are excellent hosts for recognition of a range of low-molecular-weight small guest biocompounds and inorganic ions (Beer and Schmitt, 1997; Chinai et al., 2011; Dun et al., 2017; Klärner et al., 1999; Mahon and Fulton, 2014). Typically, for a chemo- or biosensor, the recognition element, containing artificial or natural receptor cavities, respectively, is assembled in an intimate contact with the transducer surface to generate an output detection signal (Nakamura and Karube, 2003). Preferential binding of the analyte by the receptor sites induces changes in the physicochemical properties of the sensing system. Those changes are detected using proper signal transducers. Usually, the target analyte binding by selective recognition unit is transduced to generate an electrochemical (Holthoff and Bright, 2007; Kumar et al., 2008), optical (Chen et al., 2015; Henry et al., 2005), piezoelectric (Liu et al., 2003b; Lu et al., 2012), and electric using field-effect transistor (FET) signals (Iskierko et al., 2016b, 2015). Among these transducers, FET is an attractive platform for the rapid and accurate determination of various analytes (Nehra and Singh, 2015). The real time results are monitored with low cost meters (Chen et al., 2017). Moreover, the FET-based transducers are easy to miniaturize and capable to produce low-cost diagnostic tools for health care (Gao et al., 2016). The FET transducer is built to meet microelectronic fabrication principle and operates on the basis of an electrostatic field induced modulation of carrier mobility across a biased semiconductor. When a gate surface of the FET is coated with a film of a synthetic receptor, then this receptor provides selectivity to the resulting sensing system. In the present review, the approach, utilized to devise chemosensors integrating FET transducers with synthetic receptors, including macrocyclic and MIP receptors, is discussed in detail. Moreover, these approaches aiming at selective chemosensor development are herein summarized and critically evaluated.

Id,max  =  

µ oCox W  ×    ×   (Vref − VT )2 (1 + λVds) 2 L

(1)

where µo is the electron mobility in the channel, λ is the channel length modulation factor, Cox is the dielectric oxide layer capacity per unit area, W/L is the channel width-to-length ratio, VT, Vref, and Vds is the threshold voltage, applied reference electrode voltage and the drainsource voltage, respectively. The FET can be operated in either a constant-current or constantvoltage mode. For the former, the change in the gate-source voltage must be exactly equal to the change in the threshold voltage. When molecules of the target analyte are bound by a synthetic receptor, the surface potential changes and, therefore, the channel conductance is changed. These conductance changes can be recorded and further processed by an electric measurement system. In the simplest case, when the negatively charged analyte molecules are captured by the receptor immobilized on an n-type semiconductor channel, the number of electron carriers decreases and, hence, electrical conductance is

2. Fundamentals of FET operation in chemical sensing The standard FET can be either of the n- or p-type (Scheme 1). The n-type FET is prepared by forming a channel of an n-type material in a p-type semiconducting substrate and, vice versa, p-type FET is prepared by forming a channel of a p-type material in an n-type semiconducting substrate. One end of this channel is connected to the source electrode

Scheme 1. Illustration of (a) n-channel and (b) p-channel FET.

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Scheme 2. Illustration of the working hypothesis of n-channel FET transducers integrated with a synthetic receptor. (a) Recognition of a negatively charged analyte decreases the sourcedrain current while (b) recognition of a positively charged analyte increases the source-drain current.

In most of reports covered by the present review, commercial FETs have been used (Table 1). Nowadays, these commercial devises are cheap and easily available in bulk quantities. Majority of the reports described integration of biomimetic receptors with the metal oxide gate of commercial ISFETs by using different techniques including drop and/ or spin coating (Table 1). Apparently, the major efforts of these works were focused on improvement of the selectivity of the sensing system, one of major prerequisites of sensing. Several reports confirmed a need for chemical surface modification or immobilization of selective receptors to capture the target analyte. Without this additional functionalization, both the analyte and interferences were able to diffuse to the channel region and contribute to changes in the detection signal. Few reports described development of OFETs with a high work-function metal, e.g., Au or Ag, to produce the source and drain electrodes (Xu et al., 2015). These electrodes were selected for their theoretically predicted small barriers to hole injection as well as easy metal deposition using thermal evaporation in vacuum. Moreover, these metal surface allowed depositing SAMs of receptor molecules in a direct contact with the transducer (Wipf et al., 2013). Several review articles described in detail common approaches used to enhance sensitivity of FETs (Lowe et al., 2017; Matsumoto and Miyahara, 2013; Xu et al., 2015; Zhang and Lieber, 2016). A perspective article (Xu et al., 2015) provided a clear overview of printing technologies and high performance printable organic semiconductors. Moreover, these articles examined all of the device components and discussed the related limitation and challenges in bio-sensing (Lowe et al., 2017; Matsumoto and Miyahara, 2013). Therefore, in the current review, we focused on the approach used to devise selective chemosensors integrating FET transducers with synthetic receptors, including macrocyclic and MIP receptors. So, the present review emphasizes development of the selective recognition unit part rather than the transducer part, i.e., FET, of the sensor.

decreased (Scheme 2a). On the other hand, however, if positively charged analyte molecules bind to the receptor, the number of electron carriers in the semiconductor channel increases, thus resulting in the conductance increase (Scheme 2b). In that case, a size of the target molecule with respect to the Debye length of the electric double layer at the gate/electrolyte solution shall be taken into consideration. Especially, if the devised sensor should operate under conditions predominating in body fluid (Huang et al., 2015). Moreover, the Donan effect should be invoked to account for the mechanism of FET sensor operation (Huang et al., 2015). Formation of an ion-permeable recognition membrane on the FET gate, which allows for small ion movement, may lead to development of the ion concentration gradient and, hence, generation of the Donan potential. This in turn would affect FET channel conductance. The operation mechanism of sensors without a dielectric oxide layer, such as graphene, carbon nanotube, or inorganic nanowire sensors, is anticipated to be different to that with the dielectric layer. Binding or adsorption of analytes over these semiconducting materials can change the electronic properties of the FET via the following mechanisms: (1) surface charge-induced gating, (2) doping or charge transfer between nanomaterials and biocompounds, (3) a scattering potential generation across nanomaterials, and (4) modification of the Schottky barrier between nanomaterials and metal electrodes (Liu and Guo, 2012; Lowe et al., 2017). The advantages of electronic transducers are evidenced by a number of review articles published in past decades. Several recent reviews described application of graphene and other two-dimensional nanomaterials for enhancing sensitivity of the FET sensors (Adzhri et al., 2016; Chandran et al., 2017; Li et al., 2014; Zhang and Lieber, 2016; Zhang et al., 2017) as well as unidimensional materials, such as carbon nanotubes and different nanowires (Nehra and Singh, 2015; Shen et al., 2014; Zhao et al., 2015). Beside these pristine nanomaterials, biological materials are also integrated with the FET transducer to devise biosensing devices; several reviews cover these topics (Chen et al., 2016a; Zhang et al., 2017). 52

53

Polydopamine Conducting thiophene polymer

1.97 µg L 0.1 mM

0.1 pg mL−1 13 µM

0.02–20 mg L 0.1 mM to 0.1 M 0.1 pg mL−1 to 1 ng mL−1 13–100 µM

5.0 4.0, 7.0, 10.0 7.4 -

-OH, HN < -COOH

−1

0.1 µM

120 nM

−1

0.1–7.5 µM

–

Thymine and adenine moieties (WatsonCrick pairing) -N+(CH3)3 -COOH

0.1–0.9 μM

–

–OH

0.12 mM

–

–B(OH)2

0.12–1.00 mM

0.2 mg mL−1 10 µM 0.62 µM

0.2–1.3 mg mL−1 10–40 µM 0.5–50 μM

– – –

-OH -NH-CS-NH2 –B(OH)2, –N < , and –NH2

0.4 µM 0.2 µM 0.1 µM 0.2 µM 0.1 mM

0.5–80 µM 0.3–70 µM 0.1–50 µM 0.2–100 µM

0.4 µM 0.2 µM 0.1 µM 0.2 µM

15 µM 15 µM 0.8 µM 20 µM 0.8 µM

500 µM 10 µM

Limit of detection

0.1–1.0 mM

7.3

0.5–80 µM 0.3–5 µM 0.1–50 µM 0.3–100 µM

30 µM to 5 mM 40 µM to 2 mM 2 µM to 0.5 mM 10 µM to 5 mM 1 µM to 0.8 mM

0.5–6 mM 0.1–9.0 mM

Concentration range (measured)

8.0

-NH-CS-NH2

-CONH-B(OH)2

7.2

7.0

–B(OH)2

-CONH-B(OH)2

7.2

pH

-OH

Recognition sites of MIP

EG-FET EG-FET

AlGaN/GaN HEMT ISFET

EG-FET

EG-FET

EG-FET

ISFET ISFET EG-FET

ISFET

ISFET MOSFET

ISFET

ISFET

ISFET

Type of the transistor (or electronic transduction)

(Tamboli et al., 2016) (Iskierko et al., 2017)

(Jia et al., 2016a) (Rayanasukha et al., 2016)

(Sannicolo et al., 2016)

(Iskierko et al., 2016b)

(Dabrowski et al., 2016)

(Kugimiya and Kohara, 2009) (Tsai et al., 2010) (Kugimiya and Babe, 2011) (Iskierko et al., 2015)

(Petrukhin et al., 2007)

(Pogorelova et al., 2003)

(Sallacan et al., 2002)

(Lahav et al., 2001)

Ref.

cAMP – cyclic adenosine 3′,5′-cyclic monophosphate, NAD+ – β-nicotinamide adenine dinucleotide, NADP+ – β-nicotinamide adenine dinucleotide phosphate, NADH – 1,4-dihydro-β-nicotinamide adenine dinucleotide, NADPH – 1,4-dihydro-βnicotinamide adenine dinucleotide phosphate, PSA – prostate specific antigen.

Phosphate ions Urea

TATAAA

NGAL

D-arabitol

PSA D-phenylalanine, L-phenylalanine

Acrylic polymer

NAD+, NADP+, NADH, NADPH

Acrylic polymer Acrylic polymer Conducting thiophene polymer Conducting thiophene polymer Conducting thiophene polymer Conducting thiophene polymer Acrylic polymer Acrylic polymer

Acrylic polymer

NAD+, NADP+, NADH, NADPH

Creatinine Diphenyl phosphate Inosine

Acrylic polymer

Adenosine 5’-monophosphate, Guanosine 5’-monophosphate, Cytosine 5’-monophosphate Uridine 5’-monophosphate, Glucose

Acrylic polymer

Metal oxide (TiO2)

4-Chlorophenoxy acetic acid 2,4-Dichlorophenoxy acetic acid

cAMP

Type of polymer/imprinting matrix

Template/analyte

Table 1 Molecularly imprinted polymers (MIPs) as recognition units integrated with field-effect transistors (FETs).

Z. Iskierko et al.

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3. Synthetic receptors in FET chemosensing

conventional (crown ether)-based ion-selective electrodes (Moody et al., 1989). However, because of a limited number of interactions with guest molecules, these organic receptors are merely reasonably selective. Moreover, these receptors show only limited selectivity or no selectivity at all if the guest molecules are similar in their structure, shape, and size. One of possible ways to increase selectivity of these receptors is to increase the number of interaction sites by further chemical derivatization of these receptors. For instance, for recognition of electron-rich compounds, such as anionic biocompounds, metal coordination complexes are often employed (Qin et al., 2016). Therefore, other than the receptors with predefined cavity sizes, synthetic chemists succeeded in designing a new class of anion selective receptors. One of these receptors was based on neutral uranylsalophene building blocks (Antonisse et al., 1997). The anion-binding selectivity of these salophenes was governed by properties of the electron-accepting uranyl center. This receptor was integrated with the gate surface of a chemFET using PVC and o-nitrophenyl n-octyl ether to fabricate an electric chemosensor selective for the phosphate anion (Antonisse et al., 1997). Moreover, this receptor became selective to the fluoride anion when additional recognizing sites were introduced close to the anion recognizing sites in the neutral uranylsalophene. However, constant fear of peeling off the plasticizer film forced developing an alternative procedure to immobilize these receptors. Towards that, a new pyrophosphate receptor was designed and synthesized (Liu et al., 2011). This receptor had three components, vis., a recognizing site, a linker, and a handle (Scheme 4a). The recognizing site provided the desired selectivity, while the linker between the handle and the recognizing site provided flexibility (Scheme 4a). The handle part of the receptor helped to immobilize the receptor molecule on a suitable surface. Chelator immobilization was confirmed by time-of-flight secondary ion mass spectrometry (TOF-SIMS) (Scheme 4b). When this chelator-immobilized FET device was exposed to 25 µM inorganic pyrophosphate (PPi) in Tris buffer (pH = 8.0), the drain current versus gate potential curve shifted toward more negative potentials (Scheme 4c). By using FETs with a thin gold gate contact coated with different metalloporphyrins (Scheme 5a–d), different electric characteristics on exposure to various vapors were obtained (Andersson et al., 2001). The presence of a delocalized π-aromatic system in these macrocycle molecules resulted in an interesting electrical property when they were deposited as solid films. That is, the presence of peripheral substituents makes these molecules less planar, thus decreasing the stacking interactions and the possibility of charge transfer among the macrocycles (Andersson et al., 2001). Sensitivity of these devices was dependent upon thickness of the porphyrin film. That is, a thin and continuous porphyrin film was essential for high FET performance. For thicker films, the sensitivity of the fabricated chemosensors was lower because of longer analyte diffusion time. To solve this problem, a monolayer of zinc tetraarylporphyrin was deposited on a gold surface of a transistor using the Langmuir-Blodgett (LB) technique (Takulapalli et al., 2008). Thus, the spatial relationship of the site of ligand binding to the underlying oxide was well defined and, therefore, the device sensitivity was improved. Another approach utilized a SAM strategy for coating FETs with stable thin metalloporphyrin molecular receptor films for fabrication of an NO gas sensor (Natale et al., 2009). For that, non-conducting sensing films of a thiol-modified cobalt tetraphenylporphyrin were formed. The receptor coating was confirmed by AFM morphological characterization of the gate surface before and after film deposition. A porous gold surface before film coating turned smooth and nonporous after deposition of the porphyrin SAM. Presumably, sensor exposure to the NO gas resulted in coordination of the NO molecule to the porphyrin molecule. This coordination was stronger than that to other species including aniline, toluene, ethanol, and triethylamine. However, selectivity of the sensor toward CO was low, possibly because of similar

Synthetic receptors can easily be categorized based on their molecular cavity origin depending on whether a synthetic receptor featured a molecular cavity of a pre-defined size or the cavity was generated via molecular templating. The former approach includes the use of macrocyclic compounds, such as cyclodextrins (Fujita et al., 2017; Liu et al., 2015b), crown ethers (Han et al., 2014; Liu et al., 2003a), cucurbit[n] urils (Barrow et al., 2015; Urbach and Ramalingam, 2011), calixarenes (Coquiere et al., 2009; Ni et al., 2012; Singh et al., 2007) which have already predefined molecular cavity capable of binding small ions or molecules, thus discriminating them preferentially with respect to their size. In this case, the cavity size is fixed. However, selectivity of such a system can be tuned by functionalizing those cavities. The latter strategy includes formation of MIPs, where cavities for certain analytes are generated in their presence as templates during polymerization (Chen et al., 2016b; Ndunda and Mizaikoff, 2016; Uzun and Turner, 2016; Yoshikawa et al., 2016). This strategy provides flexibility in tuning molecular cavity complementarity to the shape, size and moreover, chemical nature of the analyte targeted (Eersels et al., 2016; Iskierko et al., 2016a; Peltomaa et al., 2018). 3.1. Application of receptors with a pre-defined cavity size in FET based chemosensors Molecular receptors with a pre-defined cavity size, such as crown ethers (Wipf et al., 2013; Zhang et al., 2007) cyclodextrins (Li et al., 2005), calixarenes (Puchnin et al., 2017), metalloporphyrins (Takulapalli et al., 2008), valinomycin (Chang et al., 2012) and other ionophores have been used to prepare ISFETs (Mefteh et al., 2014). Three main types of weak reversible receptor-analyte interactions guide this recognition, namely, hydrogen, ionic, and metal-coordination bonding. Hydrogen bonds are formed with three atoms preferably arranged linearly, while metal-coordination bonds are formed via ligand substitution. To translate these interactions into a useful analytical signal effectively, it is important to integrate these receptors with the transducer surfaces. In several examples, a poly(vinyl chloride) (PVC) plasticizer was used to drop-coat films of molecular receptors on the gate surface (Chang et al., 2012). Chemosensors fabricated that way were highly sensitive to alkali earth metal cations. However, the lifetime of chemosensors with the PVC membranes is limited because of the problem of film peeling off (Kimura et al., 1997). This time was even shorter if measurements were performed above room temperature (35–38 °C) (Abramova et al., 2000). Therefore, alternatively, siliconbased polymer siloprene was used (Cao et al., 2015). In this polymer, two different ionophores IV were embedded to result in chemosensors for K+ and Na+. Following a similar approach aiming at fabrication of a stable immobilized film, thiol-modified crown ether was used (Wipf et al., 2013). For that, a thin gold film coated nanowire (NW) helped to functionalize the gate surface with a SAM of crown ether for detection of certain analytes (Scheme 3). For preparation of these NWs, a 5-nm thick chromium adhesion layer, and then a 20-nm thick gold film was evaporated onto an Al2O3 dielectric layer. Scheme 3 shows a sketch of the measurement setup (Scheme 3a) and the cross-sectional view (Scheme 3b), respectively, of the FET device. Nearly 99% of non-oxidized gold surface atoms were functionalized with the crown ether (Scheme 3c). The chemosensor fabricated that way was selective to Na+ with the ~44 mV per decade of Na+ concentration signal in the presence of hydrogen ions (Scheme 3d). Another report used a glutaraldehyde condensation chemistry to covalently bind crown ethers to silicon nanowires (Zhang et al., 2007). With these crown ethers, the resulting chemosensors recognized Na+ and K+ according to their complexation ability. The chemosensors were highly selective and capable of achieving an ultra-low limit of detection (LOD) down to 50 nM. The LOD reached was by three orders of magnitude lower than those of 54

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Scheme 3. (a) Illustration of the FET measurement setup. (b) Nanowire (NW) cross-sectional view showing layers of different thickness. (c) Immobilization of Na+-selective crown ether on the gold surface. (d) Differential threshold voltage (ΔVth) of gold-coated NWs against the electrolyte concentration and solution pH. Adapted with permission from Wipf et al. (2013). Copyright (2013) American Chemical Society.

Scheme 4. (a) Surface immobilization of inorganic pyrophosphate (PPi)-chelator. (b) Confirmation of immobilization of a chelator molecule by time-offlight secondary ion mass spectrometry (TOF-SIMS). by a che(c) Label-free detection of 25 µM PPi lator-modified FET device in Tris buffer (pH = 8.0) with Zn2+, compared to overlapping response in the same buffer (•) before PPi exposure and after rinsing PPi with dilute acid. The inset in (c) is an optical microscopy image of the FET device used for these measurements. TESBA – triethoxysilybutyraldehyde. Adapted with permission from Liu et al. (2011). Copyright (2011) Royal Chemical Society.

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Scheme 5. Structural formulas of metalloporphyrins (a–d) used to devise chemosensors, (e) the response of chemFETs with four different metalloporphyrin recognizing elements to saturated vapors of methanol. Adapted with permission from Andersson et al. (2001). Copyright (2001) Elsevier.

with this receptor from a methanol solution. During recognition, AOCB [6] formed a complex with ACh+, i.e., the carbonyl group of AOCB[6] partially donated electrons to the positively charged quaternized primary amine group of ACh+, and these charge–dipole interactions tended to increase the electron-withdrawing characteristics into the channel region, thereby leading to an increase in the hole current of the p-channel of sensor devices. Unlike other ion-selective biosensors, this chemosensor determined ACh+ down to 1 pM.

coordinative binding (Natale et al., 2009). Operation of FET chemosensors in aqueous systems demonstrates a vast potential in the health and environmental monitoring. However, it still faces many challenges (Wang et al., 2016). Because of chemosensor application in an aqueous system, a water-stable p-channel semiconductor, 5,5′-bis-(7-dodecyl-9Hfluoren-2-yl)-2,2′-bithiophene (DDFTTF) layer, was chosen as a support before applying a final recognition layer (Jang et al., 2015). This p-channel semiconductor was functionalized with the cucurbit[6]uril (CB[6]) derivative, vis., perallyloxyCB[6] (allyloxy)12 CB[6], AOCB[6], receptor molecule. The CB [6] carbonyl group-fringed hydrophobic cavity (~0.5 nm in diameter) showed high binding efficiency and selectivity to acetylcholine (ACh+) (Jang et al., 2015). This receptor was readily soluble in alcohol but insoluble in water. Therefore, p-channel semiconductor was coated

3.2. Application of biomimetic receptors in FET-based chemosensors To provide selectivity, a tailor-made recognition unit must carefully be designed (Culver et al., 2017; Sharma et al., 2015). Affinity and selectivity of MIPs are nearly as high as those of natural receptors 56

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Scheme 6. (a) Illustration of the AlGaN/GaN FET setup. (b) Current response of an AlGaN/GaN HEMT sensor to phosphates of different concentrations. Adapted with permission from Jia et al. (2016a). Copyright (2016) Nature Publishing Group.

MIP triggered electronic transduction of the ISFET. The cAMP linear dynamic concentration range in aqueous solution was 0.1–1.0 mM (Table 1). Other literature on MIPs integrated with FETs described chemosensors for selective determination of creatinine (Tsai et al., 2010), diphenyl phosphate (Kugimiya and Babe, 2011), and ethanol (Alizadeh and Rezaloo, 2013). In all of these reports, the transistor gates were coated with non-conducting acrylic polymer matrices. Performance of these acrylic MIP materials was superior in many applications (Schirhagl, 2014), however, their application in FET devising suffered from a long response time, low reproducibility of the binding performance, and limited sensitivity. Another promising step toward devising (MIP-FET)-based chemosensors of superior performance involved integration of these MIPs with the AlGaN/GaN based HEMTs (Jia et al., 2016a, 2016b). These HEMTs featured a conducting two-dimensional electron gas channel. This channel is located close to the surface. Mobility of charge carriers in this channel is extremely sensitive to adsorption of analytes (Chaniotakis and Sofikiti, 2008; Chu et al., 2010a, 2010b; Lee et al., 2015). In the past few years, devising and fabricating ion-selective sensors based on AlGaN/GaN HEMTs attracted world-wide attention. Due to the excellent chemical and physical stability in water solutions (Hung et al., 2008; Ito et al., 2008), ion-sensitive AlGaN/GaN HEMTs are highly advantageous in ion sensing. Towards that, the gate region of the AlGaN/GaN HEMT was coated with a phosphate anion imprinted polymer capable of phosphate recognizing (Scheme 6a) (Jia et al., 2016a). The recorded current response showed that the fabricated chemosensor was very sensitive to phosphate (Scheme 6b) without revealing measurable response to interfering anions, e.g., permanganate, sulfate, etc. Subsequently, an interesting approach was developed using an extension of the gate electrode (Batista and Mulato, 2005; Batista et al., 2006; Chi et al., 2000). The resulting sensing EG-FET system was composed of two parts. The sensing part was electrically connected to the gate of a commercial MOSFET device (Scheme 7a). All changes of potential at the extended gate were transferred to the transistor gate leading to changes of the source-drain current, exactly as if the potential changes would take place on the gate itself. Although an EG-FET was earlier used as the transducer (Chen et al., 2011a; Chi et al., 2000; Yin et al., 2000), a recent research described its first application in development of MIP-based chemosensors (Iskierko et al., 2015). In EG-

(Medlock et al., 2017; Suriyanarayanan et al., 2012). Like most polymer materials, MIPs are processable. That is, they are compatible with the fabrication techniques and engineering conditions like micromachining, laser ablation, and surface patterning. Evidently, a low manufacturing cost and inexpensive preparation made MIPs interesting for fabrication of so-called “plastic antibodies”. In recent years, the field of MIPs has attracted significant interest, revealed in several reviews (Figueiredo et al., 2016; Holthoff and Bright, 2007; Iskierko et al., 2016a; Ndunda and Mizaikoff, 2016; Piletsky and Turner, 2002; Schirhagl, 2014; Sharma et al., 2012). A list of MIP-based FET chemosensors have been summarized in Table 1. An interesting result was obtained by integrating a molecularly imprinted material with a FET transducer (Lahav et al., 2001). The SiO2 gates of ISFETs were coated with TiO2 films, featuring imprinted molecular cavities templated with 4-chlorophenoxy or 2,4-dichlorophenoxy acetic acid. Both these ISFETs revealed impressive selectivity in sensing of the imprinted compounds as analytes, i.e., 4chlorophenoxy and 2,4-dichlorophenoxy acetic acid. The LOD for the former chemosensor was 0.5 mM in the concentration range of 0.5–6.0 mM (Table 1). The LOD of the latter chemosensor was 10 µM in the concentration range of 0.1–9.0 mM. After this successful attempt of integration artificial antibodies with the FET transduction unit, another similar report appeared (Pogorelova et al., 2003). In this report, recognition sites selective to the NAD(P)+ and NAD(P)H cofactors were imprinted in a film of the cross-linked acrylamide-acrylamidophenylboronic acid copolymer. The signal transduced by the ISFET devices was a potentiometric voltage output originating from both the generation of the boronate complex of the substrate with the recognition sites and from the change in the local pH at the solution-gate interface. The integrated with the ISFETs films of MIPs allowed determining respective analytes with high sensitivity (Table 1). A biomimetic sensor for adenosine 3′,5′-cyclic monophosphate (cAMP), which is an important intracellular regulator of many cellular processes, was fabricated by combining a FET transducer with a cAMPimprinted polymer as the recognition unit (Kugimiya and Kohara, 2009). This polymer was prepared using 1-allyl-2-thiourea as the functional monomer. It interacted with both adenine and cyclic phosphate group in cAMP. The recognizing site of the thiourea group in the cAMP-imprinted polymer distinguished the chemical structure of adenine from that of cyclic phosphate of cAMP. The cAMP binding to the 57

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Scheme 7. (a) A sketch of the experimental setup based on the EG-FET design. An Au plated glass slide coated with the surface developed NGAL-templated MIP film was used as the gate (working electrode, W) and a Pt wire as the reference electrode (R). The G, D, and S symbols stand for the gate, drain, and source components of the FET structure, respectively. (b) The histogram of the drain current change of the EG-FET corresponding to the NGAL analyte binding by a thin and surface developed MIP or NIP film. Concentration of the NGAL analyte was 0.6 µM. (c) Selectivity test of the MIP-MOF chemosensor based on the EG-FET. Gate voltage was kept at 1.50 V. HSA – human serum albumin, MOF – metal-organic framework, NGAL – neutrophil gelatinas-assosiated lipocalin. Adapted with permission from Iskierko et al. (2016b). Copyright (2016) American Chemical Society.

was applied for improving sensitivity of the (MIP-FET)-based chemosensors for a kidney disease biomarker, neutrophil gelatinas-assosiated lipocalin (NGAL) protein. In one example, the active surface area of an MIP film was enhanced by utilization of a sacrificial metal-organic framework (MOF) underlayer (Iskierko et al., 2016b). This area enhancement allowed for relatively fast diffusion of the analyte into the MIP (Scheme 7a). The chemosensor sensitivity with the surface developed MIP film was ~4 times that of the chemosensor with a continuous MIP film (Scheme 7b). Importantly, the chemosensor response was nearly negligible to human serum albumin (HSA), an interfering protein (Scheme 7c). For 0.9 µM HSA, the chemosensor response was similar to that for 0.1 µM NGAL (Scheme 7c). A recent report described application of a colloidal crystal as the solid support for synthesis of a highly porous hierarchical MIP film (Dabrowski et al., 2017). An enhanced surface area of this MIP film together with a precise control of imprinting of cavities provided both easy access for the target HSA analyte to these imprinted cavities and its selective binding (Scheme 8). Combination of a precisely controlled porous synthetic recognition film with the sensitive EG-FET transducer allowed determining HSA in an impressively low femtomolar concentration range, i.e., the range much lower than that reached by surface enhancement with the MOF sacrificial scaffold (Iskierko et al., 2016b). The possible reason of this detectability improvement in the former might originate from much developed MIP surface area. This more porous surface (Scheme 8) enhanced diffusion of the HSA analyte to its molecular cavities.

FETs, the recognition unit is deposited on the surface of the gate extended from the FET. The experimental setup prepared is greatly advantageous with respect to flexibility in the gate shape (Chi et al., 2000). Favorably, minute changes in potential at the gate surface because of the presence of charged analyte molecules can be transduced into detectable electric signals without a need of using expensive instruments and reagents. Additionally, the stability of FET characteristics in the ambient environment is greatly improved and, more importantly, packing and transporting of such a setup for field measurements applications is easy (Iskierko et al., 2015). Moreover, this MIP-(EG-FET) combination allowed positioning of molecular cavities close to the gate surface (Iskierko et al., 2015). The derivatized thiophene-based functional monomers provided interaction sites for selective recognition of inosine. After successful fabrication of the inosine MIP chemosensor, this fabrication procedure was further extended to devise similar detection systems for such analytes as D-arabitol (Dabrowski et al., 2016), human lipocalin-2 (NGAL) (Iskierko et al., 2016b), prostate specific antigen (Tamboli et al., 2016), hexanucleotide with the nucleobase sequence of TATAAA (thymine-adenine-thymine-adenine-adenine-adenine) (Sannicolo et al., 2016), as well as D- and L-phenylalanine (Iskierko et al., 2017). One of the main goals in devising chemosensors with artificial recognition elements is to improve an early medical diagnosis. Nowadays, several known biomarkers of dangerous diseases can be detected only when it is already too late for the dedicated, successful treatment. Therefore, devising not only selective but also very sensitive diagnostic tools is of great importance. One way to improve the sensor response is to enlarge its working surface area (Sharma et al., 2013). This approach

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Scheme 8. Illustration of the steps of the poly(2,3′-bithiophene) inverse opal imprinting with HSA. Step I – preparation of a colloidal crystal template of SiO2 nanoparticles using the Langmuir-Blodgett (LB) technique. Steps II and III – derivatization of template molecules of HSA with bithiophene functional monomers and then their immobilization on SiO2 nanoparticles. Step IV – deposition of poly(2,3′-bithophene) film by electropolymerization Step V – removal of the nanoparticles and HSA from the resulting MIP for preparation of the final polymeric inverse opal material. Step V shows side view SEM image of macroporous MIP film. Adapted with permission from Dabrowski et al. (2017). Copyright (2017) Elsevier.

4. Conclusions and future prospects

molecular receptors involved expertise of researchers from different disciplines, such as organic synthesis and coordination chemistry. However, MIP-based receptors needed a wider community contribution for designing selective molecular cavities compatible with bio-receptors including, among others, computational, synthetic, polymer, and analytical chemists. Several interesting reports confirmed this cooperation for development of MIP-based nanoparticles toward drug delivery and biomedical applications (Alvarez-Lorenzo and Concheiro, 2004; Hoshino et al., 2012). The complex stability constants of such synthetic MIP receptors were very high and comparable with those of corresponding bio-receptors. The application of FETs and synthetic receptors together with the nanomaterial, such as carbon nanomaterials, nanowires, and metal nanoparticles, have not been studied broadly. Moreover, these studies are surprisingly rare in comparison to nanomaterials and (bio-receptor)-based FETs. Therefore, we expect that research in this direction will be increasingly developed, especially, if considering stability limitations of bio-receptors and their non-availability for each target analyte. Another important issue, which is widely studied for (bio-receptor)based FETs but not much reported for (synthetic receptor)-based FETs,

Herein, we described recent progress made in the field of (synthetic receptor)-integrated FET sensing. The FET transducer appeared suitable to translate efficiently molecular recognition signal into electric analytical signal with the use of either natural or synthetic receptors. Derivatization of synthetic receptors with suitable functionalities helped to immobilize them on active gate areas of FETs. High reproducibility and durability of these chemosensors in comparison to biorecognition systems confirmed suitability of these procedures developed for chemosensor fabrication. Moreover, integration of recognition films with these FETs made the resulting sensing systems highly selective with respect to a particular analyte. Besides, combination of EG-FET transduction and synthetic receptor recognition appeared much appealing (Iskierko et al., 2015). This combination provides a way to integrate recognition films much easier than in classical FETs because it does not require engaging complicated and costly processing. The EG-FET can easily be adapted to operate in both organic and aqueous solutions, which is important from the point of view of both sensor fabrication and subsequent practical applications. Noticeably, the anion and/or biomolecule recognition through 59

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is the study of the ionic screening effect on the sensor performance. For instance, the Debye screening length of 1 M NaCl solution is reported to be 0.3 nm while in pure water this length is of the µm range (Lowe et al., 2017; Luo and Davis, 2013). Noticeably, any recognition/binding above this length cannot be sensed by a FET system. Therefore, in final application of chemosensors to determine analytes in real samples where ion concentration exceeds 0.1 M, this charge screening should be avoided or overcome. Hence, careful control of thickness of a synthetic receptor film is necessary. Alternatively, more advanced measurement techniques need to be developed to overcome or reduce this effect. There are interesting reports (Kulkarni and Zhong, 2012) suggesting that the use of the nanoelectronic sensing platform operating at drain voltage, modulated at high frequency, can overcome the ionic screening effect. Principally, this procedure detects dipole changes of molecules due to binding effect instead of their charge. Because of different time constants of the dipole movement in biomolecules and that of diffusion of ions in solution, measurements at megahertz modulated voltage allow for effective minimization of the ion screening effect. For successful applications of synthetic receptor-FETs as commercial clinical diagnostic tools, high reproducibility in the device performance is required. Additionally, it requires reliable and easy fabrication method for a large-scale manufacturing of these devices. Therefore, continuation of studies in this direction is desired. Moreover, the future of FET transducers lies in the nanoscale integration, miniaturization and in wireless point-of-care (POC) diagnostics. Indeed, it will be a huge step forward in the area of clinical diagnostics to develop FET based wireless miniaturized POC devices for monitoring continuously biomarkers, drugs, and their metabolites among others.

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