Bio-sensing represents one of the most attractive applications of carbon material based electronic devices; nevertheless, the complete integration of bioactive transducing elements still represents a major challenge, particularly in terms of preserving biological function and specificity while maintaining the sensor’s electronic performance. This review highlights recent advances in the realization of field-effect transistor (FET) based sensors that comprise a bio-receptor within the FET channel. A birds-eye view will be provided of the most promising classes of active layers as well as different device architectures and methods of fabrication. Finally, strategies for interfacing bio-components with organic or carbon nano- structured electronic active layers are reported.
Maria D. Angionea, Rosa Pilollia, Serafina Cotronea, Maria Magliuloa, Antonia Mallardib, Gerardo Palazzoa, Luigia Sabbatinia, Daniel Finec, Ananth Dodabalapurd, Nicola Cioffia*, and Luisa Torsia* a Department of Chemistry,University of Bari, Via Orabona, 4, I-70126 Bari, Italy b CNR–IPCF,Istituto per i Processi Chimico-Fisici -Bari, Italy c Department of NanoMedicine and BioMedical Engineering, The University of Texas Health Science Center at Houston, TX, USA d Department of Electrical and Computer Engineering Microelectronics Research Center The University of Texas at Austin, TX USA * E-mail: email@example.com and firstname.lastname@example.org
Recently, increasing medical and biological interest in cheap disposable, analytical, and diagnostic devices has driven research towards the development and adaptation of low-cost electronic sensing devices. While a lot of effort has been devoted to silicon based nanostructured active layers, we focus here on carbonbased materials. Organic semiconductors can be implemented in a platform for flexible devices, including those built on biodegradable and resorbable substrates, while carbon based nano-structured materials, such as carbon nanotubes and graphene sheets, offer higher performance in terms of field-effect mobility and sensitivity. In all cases, the major challenge is to develop active layer materials that allow for the inclusion of biologically active bio-receptors while maintaining electronic performance. The present contribution reviews and compares recent developments in these related fields.
Organic field-effect transistor bio-sensors
Organic transistor-based devices have previously been demonstrated for gas, vapor, and liquid sensing1-5, as well as for the detection of single ions or ensembles of ions in solution6-12. Organic field-effect transistor (OFET) based sensing technologies take advantage of the physical or chemical changes taking place in or around the organic (semi)conducting material when exposed to different analytes in gaseous or aqueous environments. Field-effect transistors (FETs) for their multi-parametric13 response and multi-functionality-related versatility, comprise the primary functional component in an array of sensing platforms proposed in the field of environmental monitoring8, military defense9,10,14-16 and preventative medical care11. The integration of active organic materials into these devices has allowed for the implementation of electronics with plastic substrates, and thus low-cost, lightweight, and flexible sensing devices.
Organic thin-film transistors (OTFTs) are three-terminal electronic devices consisting of a thin organic semiconducting layer, an insulating (dielectric) layer, and three conductive terminals, the source, drain, and gate. The source and drain electrodes are fabricated to be directly in contact with the semiconductor, either on top of the previously deposited organic semiconductor (top-contact), or on the insulating layer to be covered with the semiconductor later (bottom-contact). The “channel” refers to the region in the semiconductor layer between the defined source and drain electrodes12. The active semiconductor layer may consist of small molecules17-22 polymers23,24, or organic nanostructured materials25-27, among others. Contacts are usually composed of gold; although a vast number of conductive materials (e.g., doped conjugated polymers and printed metallic nanoparticles) are actively being used for this purpose28,29. The dielectric layer, which electrically isolates the semiconductor from the underlying gate electrode, may be composed of inorganic oxides30, properly tailored polymers or composites7, or ultrathin self-assembled layers31. Recent advancements in the field of biotechnology have provided systems that are able to efficiently transduce biological events using electronic devices32,33. This progress has led to the improvement of biological sensing platforms demonstrating the potential to be applied for the rapid screening of biological samples and point-ofcare diagnostics. Advancements in biomaterial processing and organic electronic device fabrication have allowed for the potential integration of biomolecules as active components in all of the materials employed in the realization of an organic transistor including the bulk substrate, the dielectric interface, and even the active semiconducting layers and electrodes 34.
Other interesting aspects of biomolecule integration in organic electronic devices have been explored in electrochemical biotransistors35 that have proven to be quite sensitive and selective. Some limitations persist, however, and are connected to their implementation in large area sensor arrays as it is not clear if the need for a reference electrode can be ruled out. Significant effort has also been invested in recent years to develop new hybrid systems in which living cells have been integrated in electronic field-effect devices36,37.The technological impact of these systems is attracting the interest of many research groups as evidenced by the numerous contributions that can be found in the literature38. These studies involve major efforts in assessing biocompatibility and bio-functionality of the materials and the biosystems involved. These aspects are not dealt with here as they would require a review of their own. Only recent advances in processing and integrating natural and synthetic bio-active components into electronic devices based on both organic or carbon nanostructured materials are considered (excluding whole cell implementations). This includes new studies on biodegradable substrates for OFETs as well as bio-species included in gate dielectric materials or on electronic active layers.
OFETs fabricated on resorbable and biodegradable substrates
Efforts to fabricate flexible electronic circuits have routinely focused on developing processes that are compatible with flexible plastic substrate materials such as poly(ethylene terephthalate) (PET)39, poly(imide)40, poly(ether sulfone)41, cellulose42, silk fibroin, or other functional fibers for e-textile development43,44. Various organic polymeric systems composed of biodegradable polymers have demonstrated their usefulness in important applications like temporary medical implants45,46, and biodegradable products47. However, the realization of these systems requires fabrication processes that are compatible with tight substrate compatibility requirements; in particular, in the case of PET, a moderate use of aqueous solvent and low-temperature post processing, must be taken into account as a limiting step in the fabrication procedure. To realize electronic circuits that are not only flexible but also foldable, materials such as aluminum foil48 and paper49 have been explored. Paper films were used as substrates with pentacene-based active layers. This approach was further expanded to create complete circuits using foldable paper-based substrates, motivated by the fact that paper substrates are mechanically flexible and capable of small bending radii. Roll-to-roll processing has also been demonstrated by Siegel and co-workers that allows for the realization of a complete circuit from simple folding and cutting techniques (Fig. 1)34. The relative fragility of paper-based circuits could potentially be utilized in security applications. One specific example is the fabrication of an envelope integrated with a system that, if compromised via destruction of the envelope, will cease to function. Paper-based devices also present distinct advantages in terms of disposability and environmental biodegradability, the latter being extremely important in the context of medical biomaterials. The motivation of this nascent research topic is to improve the compatibility of biomaterials and electronic devices for applications including restorable electronically active medical implants45,46. Mechanically robust, water-insoluble, natural proteins have also been explored as substrates for silicon electronics. A key example is provided by Kim et al.43 who used silk fibroin as a substrate for traditional silicon-based transistors. The performance of these devices is only slightly affected when the substrate is mechanically deformed.
Bao’s group recently investigated materials and fabrication strategies for the realization of organic thin-film transistors using a small-molecule semiconductor in combination with a biodegradable polymeric substrate and dielectric 50. They demonstrated that these devices perform stably after exposure to water and, since they are made of nearly entirely biodegradable materials, are resorbable in a simulated degradation environment in vitro. A schematic image of the device is shown in Fig. 2. The strategy for material selection focused on utilizing materials that are not only biocompatible and biodegradable, but also exhibit adequate electronic properties and a suitable device manufacturing process. The semiconducting molecule utilized in this study, 5,50-bis-(7-dodecyl-9H-fluoren-2-yl)-2,20-bithiophene (DDFTTF), is a robust small-molecule p-channel semiconductor that exhibits excellent device performance and is resistant to harsh aqueous environments. Although the biodegradation of DDFTTF has not been explicitly studied, degradation mechanisms that decompose melanin51,52, a conjugated amorphous semiconductor53,54, could potentially act in a similar manner towards DDFTTF. Poly(vinyl alcohol) was used as the insulating layer. Devices were fabricated with “non-crosslinked” PVA (nPVA) and crosslinked PVA (xPVA) in order to demonstrate the improved performance of the xPVA-based device in terms of leakage current and surface roughness. The substrate, which composed 99.89 % of the total mass, consists of poly(L-lactide-co-glycolide) (PLGA), a linear thermoplastic biodegradable polyester. This polymer contains significant amounts of lactic acid (PLGA 85:15) and thus allows for processing at elevated temperatures due to the high glass-transition temperature, Tg. Thin-film transistors based on p-channel DDFTTF active layers and (PVA) dielectrics exhibited electron mobilities as high as 0.253 cm2s-1V-1 and on/off current ratios (Ion/Ioff) of up to 9.4 × 103. These devices maintained functionality after direct exposure to water and are principally resorbable and biodegradable. To avoid interaction with ionic species eventually present in the analyte aqueous solution, an appropriate encapsulation and packaging of the device was needed. The potential utilization of resorbable organic electronics could serve as a motivating factor for the development of high-performance dielectrics and semiconducting molecules with the additional properties of biocompatibility and biodegradability into nontoxic and environmentally safe monomers.
OFETs dielectrics modified with biomolecules
Improvements of bio-sensor figures of merit have been realized through the development of new high performance dielectrics and device architectures, as well as by tuning device properties via interface engineering. Precise control over the threshold voltage (Vt) of pentacene-based organic thin film transistors, desirable for better integration of OFET devices into electronic circuits, has been achieved by inserting well characterized genetically engineered peptides for inorganics (GEPI) at the semiconductor-dielectric interface55 . Further tuning of the Vt can be achieved by controlling the peptide assembly conditions, such as the pH of the precursor solutions, as demonstrated by the group of A. K-Y. Jen who fabricated pentacene based OTFTs on top of quartz-binding polypeptide (QBP)-modified SiO2/Si substrates with a 50 nm pentacene active layer. The transfer characteristics for these devices are shown in Fig. 3, along with the device structure. A shift in Vt of about 30 V compared to the unmodified SiO2 was observed upon assembly of the peptide in pH-neutral condition. From this point, a positive shift in Vt was observed when the GEPI-QBP was assembled in different concentrations of HCl, while a negative shift in Vt was observed when QBP was assembled from a KOH solution at different concentrations. Although the approach is very interesting, the stability of the system has not been discussed.
OFETs with functional deoxyribonucleic acids (DNAs) as dielectric material have been pioneered by the Grote and Sariciftci groups56-58. Specifically, organic-soluble DNA, such as cetyltrimethylammonium chloride (CTMA)-DNA, have been synthesized and their physical and electronic properties have been elucidated. Since CTMA-DNA is insoluble in water but soluble in alcohol, solution processing methods are suitable for thin-film fabrication. An interesting field-effect carrier transport phenomenon was observed in these devices, although an undesired hysteresis could be seen in the corresponding transfer curves. An additional blocking layer of 5,5’-(9,10-bis((4-hexylphenyl)ethynyl)anthracene-2,6-yl-diyl) bis(ethyne-2,1-diyl)bis(2-hexylthiophene) (HB-ant-THT) molecules was introduced between the organic semiconductor layer and the DNA dielectric, to improve the electrical performance, including a reduction in leakage current. Y. S. Kim59 further reported on the development of photo-crosslinkable DNA-based dielectrics detailing the precise effect of the CTMA units in the copolymer on TFT performance. Particularly, the TFT device with the CTMA-DNA-co-CcDNA dielectric (Fig. 4) has a very high field-effect mobility implying that the long alkyl chains in the CTMA unit help enhance the ordering of the HB-ant-THT molecules.
Bio-functionalization of the organic semiconductor
Many examples have been proposed for the detection of analyte vapors using OTFTs, with numerous reports addressing the ability to identify particular analytes either through the use of a fingerprint response60,61 or by incorporating selective detection layers4,62. On the contrary few examples of chemical and bio-detection in aqueous systems have been demonstrated, the first example being published in 2002 by Someya and co-workers63. Selective in situ detection with OTFTs requires a versatile method for the immobilization of various selective molecular probes within close proximity to the active transport channel. Bao’s et al. reported in 2010 a real-time, in situ selective detection scheme with short-chain DNA targets employing organic transistors as the electrical transducer (Fig. 5) 64 . The device was realized by modifying the OTFT surfaces with a PECVD (plasma-enhanced chemical vapor deposition)-deposited thin maleic anhydride (MA) polymer layer65,66. Such a surface pretreatment allowed for the covalent attachment of the peptide nucleic acid (PNA) strands, which were then used to selectively detect the target DNA molecules within limits approaching 1 nM.
Genetic diagnostic tools have been proposed by Subramaniam’s group that integrate OTFT-based DNA sensors with microfluidic channels. A novel photolithography-based microfluidics fabrication method was used to directly enable on-chip hybridization, a significant advancement in the realization of disposable rapid turn-around tools for field-deployable genetic diagnosis67. Another example of direct semiconductor functionalization was provided by Lim’s group where an organic semiconducting copolymer composed of biotinylatedfluorene and bithiophene was synthesized through a palladium(0)-mediated Suzuki coupling polymerization. OTFTs were fabricated using this p-type polymer and electrically characterized in the presence of avidin (Fig. 6)68 . The binding of avidin-biotin moieties in the polymer were correlated to changes in the channel chemoresistivity and to the on/off characteristics of the OTFTs. Avidin exposure resulted in a lowering of the drain current (Ids) of nearly five orders of magnitude when the device was operated at a drain voltage of −40 V. Detection in this case was done at about 50 ppm, which is quite high considering the specificity of the interaction.
Recently, our group proposed the inclusion of a photosynthetic membrane protein, the bacterial reaction center, into a phospholipid bilayer formed on top of the active layer of an OTFT for herbicide detection69,70. A pictorial view of this sensing device bearing the membrane protein as a bioreceptor is shown in Fig. 7a. The lipid bilayer facilitates a close association of the protein with the carriers (electrons or holes) accumulated in the channel at the semiconductor/ gate-dielectric interface. Atomic force microscopy (AFM) (Fig. 7b) and confocal microscopy (Fig. 7c) have been performed to investigate the structure of the lipid-protein layer deposited on top of the organic semiconductor and shows a very uniform deposition of biomaterials. Very little electronic performance degradation (Fig. 7d) is seen as the bioreceptor containing layer is deposited on top of the channel material.
Another interesting and very recent architecture that explores organic semiconductor functionalization has been presented by Blom’s research group71. Here a dual gate organic field-effect transistor with integrated sulfate binding proteins (SBP) for sensing of sulfate ions is proposed. Fluorescence spectroscopy and tapping mode AFM were used to confirm the covalent coupling of the SBP receptor to the surface of a maleimide functionalized polystyrene layer. This system guarantees protein stability without loss of protein selectivity, as demonstrated by the dissociation constant measurement of SBP after drying and rehydration showing that the protein remains active even after being dried.
Organic nanomaterials for biosensing by FET transduction.
One promising direction for future transistor technology involves “nanoelectronics” in which the active part of the device is composed of nanometer sized materials. In particular the integration of 1D nanomaterials, such as nanowires and nanotubes, into functional electronic devices has received considerable attention for application as highly sensitive tools for biological applications. The comparable sizes of engineered nanomaterials and natural biological systems (e.g., antibodies, enzymes, transport proteins, etc.) make this approach appropriate for creating high throughput sensing probes: shrinking the dimensions of the materials down to the nanometer scale maximizes the effect of biochemical changes at the surface of the device. A single surface binding event will lead to a much larger change in device conductance than planar FETs as a result of the accumulation/depletion of carriers through the entire cross section of the device versus only a thin region near the surface. Nanomaterial based electronic devices thus provide a unique class of biosensor, with intrinsic ultra-sensitivity towards changes in their local chemical environment. These devices behave as both the sensitizing layer and the transducer allowing for the direct conversion of bio-chemical information into an electronic signal without labels allowing for realtime continuous monitoring.
Conducting polymer nanostructures
Given previously reported assessments of three-dimensional conducting polymers as electronic chemical sensors72, 1D conducting polymer (CP) nanomaterials present attractive alternatives to carbon nanotubes and silicon nanowires that merge properties from inorganic, carbonaceous, and polymeric materials: tunable conductivity, chemical diversity, mechanical stability, and biocompatibility73-77. Further advantages include their lightweight, low cost, easy processing/patterning, and scalable production. A crucial factor that needs to be accounted for in designing CP-FET biosensors is the sensitivity of the polymeric nanostructure towards contact resistance variation due to exposure to the liquid phase. Usually, in order to overcome this issue, a functional monomer such as a polymeric derivative with carboxylic side-chain groups78-82 has been integrated into a copolymer scheme. The acid functionality not only provides sufficient immobilization sites for biomolecules, but also assists in the covalent binding of 1D CPs on amine-terminated silanized SiO2 substrates, to form stable contacts with the metal electrodes, as illustrated in Fig. 882. Thrombin78,79, glucose80, human serum albumin81 and odorant molecule82 detection was demonstrated using recognition probes such as aptamers, glucose oxidase enzyme, antibodies and a human olfactory receptor (hOR), respectively. The study by Yoon et al. deserves further mention, since it is the first example of a FET-type bioelectronic nose based on hOR-conjugated CP nanotubes82. The authors developed a reliable chemical immobilization strategy for the fabrication of CPNT-FET devices with quantitative control on the degree of hOR functionalization. Moreover, the feasibility of specific odorant detection down to concentrations as low as tens of femtomoles was assessed.
Since their discovery in 1991 by Ijima83, carbon nanotubes (CNTs) have been regarded as an important nanostructured material derived from bottom-up chemical synthesis. As such, a great deal of effort has been devoted towards understanding their electrical, mechanical, and chemical properties. In this review we will cover the most recent applications in electronic sensing proposed in the literature during the last year. For further details, several previous review papers covering various aspects of carbon nanotube electronics are recommended26,84-88.
The first CNT field-effect transistors (CNT-FETs) were independently obtained in 1998 from both the Dekker group at Delft University89 and the Avouris group at IBM90, with the first biologica l application of CNT-FET proposed by the Dai group in 2003 while investigating specific protein–protein interactions91. Recent rapid development of chemical modification approaches and bio-functionalization methods have allowed a new class of bioactive carbon nanotubes conjugated with proteins, carbohydrates, nucleic acids or aptamers26,83-90,92,93. Single walled CNTs (SWNTs) have usually been preferred because of the availability of each atom in the SWNTs to the surrounding environment leading to maximized electrical coupling.
An interesting advance in functionalizing carbon nanotubes to obtain the detection of protein-receptor interactions is reported in the paper of Star and co-workers94. The authors presented a supramolecular approach based on the noncovalent functionalization of nanotubes, in order to avoid the disadvantage of covalent modification that impairs physical properties of carbon nanotubes. A PEI/PEG polymer coating is used both to attach receptor molecules to the sidewalls of nanotubes and to prevent nonspecific binding of proteins. The biotin-streptavidin binding has been chosen as a model system to demonstrate the effectiveness of the device architecture.
As an alternative to biological molecules conjugated directly to the CNTs, a lipid bilayer-based coating for the CNT channel was proposed95,96. The coating performed tw o key roles acting both as a protective impenetrable barrier between the sensing channel and the surrounding medium, as well as a dispersive matrix for membrane proteins. Usually these devices incorporated passive biological elements which transmitted an environmental change to the CNTs. In 2010 Huang et al. assessed the feasibility of using an adenosine triphosphate (ATP) powered biological pump to control a nanoelectronic circuit96. The authors reported on a hybrid bionanoelectronic transistor in which a local Na+/K+-ATPase protein gate, was embedded in the lipid membrane (Fig. 9). The ion pump modulated the transistor output current by up to 40 % by shifting the pH of the water layer located between the lipid bilayer and the nanotube surface.
Moreover, aligned CNT-FETs have also been proposed as innovative platforms to fabricate biosensors with high sensitivity down to the picomolar range97,98. Aptamer functionalized SWNT-film arrays were deposited by dielectrophoresis and the surface tension associated with a water meniscus; an AC voltage (frequency 1 MHz, amplitude 5 Vp-p) was applied to align SWNTs in solution, which were then compressed by the surface tension of the water meniscus after slow, careful drying. The attachment of the SWNTs to the electrodes was mediated by Van der Waals forces. The resulting SWNT-film, suspended between cantilever electrodes, allowed for a highly specific and real-time detection of thrombin97.
Graphene is highly promising for new types of chemical/biological sensors with excellent sensitivity due to a combination of a high active surface area (i.e., a 2D material with all the carbon atoms exposed to the analyte of interest), exceptional electrical properties, and low noise26,99,100,101. The operational principle of graphene bio-electronic sensors is based on the change of graphene electrical conductivity (σ) due to adsorption of molecules on its surface. The graphene-FET, based on a non-functionalized single-sheet, has been shown to exhibit a proportional increase in conductance upon protein adsorption at a subnanomolar level102. Mohanty and Berry developed a graphene-based bio-sensor capable of single bacterium resolution, investigating for the first time the interaction between chemically-modified graphene and bioentities103. Chemical vapor deposition-grown graphene films have also been used to detect DNA with single-base mismatch sensitivity104, as well as carbohydrates and neurotransmitters105.
Further steps in the development of robust graphene-living cell interfaces have been accomplished in only the last few months. A graphene-FET device detected well-defined extracellular signals while exposed to embryonic chicken cardiomyocytes106. Moreover, hormonal catecholamine molecules and their dynamic secretion from living cells were monitored in real time by biosensors based on a reduced graphene oxide (rGO) film (Fig. 10)107. Noteworthy in this study, the authors focused their attention on competitively alternative materials of graphene, namely rGO, produced by facile and scalable solution processes to extend the applications of graphene for plastic electronics. They proposed the fabrication of centimeter-long, ultrathin (1 – 3 nm), and electrically continuous micropatterns of highly uniform parallel arrays of rGO films on various substrates by using the “micromolding in capillary” method. Remarkable sensitivity was achieved that was shown to be insensitive to substrate binding.
Conclusions and future perspectives
The incorporation of biomaterials into all of the different structural components of organic and nanomaterial based electronic devices has the potential to be applied towards a range of applications in medicine and point-of-care diagnostics. Future efforts will need to be focused on the development of new hybrid biomaterials integrated into electronic devices capable of being processed on flexible substrates. The overall progress of this research field will have enormous implications for both fundamental scientific discovery and technological development. In particular, novel bio-OFETs could be used to study the fundamentals of electron transfer in naturally occurring biomolecules. The investigation of the interface of biomaterials and organic electronics could also lead to the realization of new classes of electronically active medical devices for use in advancing human health.
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