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Carbon based materials for electronic bio-sensing 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 nanostructured 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 protected] and [email protected] Recently, increasing medical and biological interest in cheap active layer materials that allow for the inclusion of biologically disposable, analytical, and diagnostic devices has driven research active bio-receptors while maintaining electronic performance. The towards the development and adaptation of low-cost electronic present contribution reviews and compares recent developments sensing devices. While a lot of effort has been devoted to silicon in these related fields. based nanostructured active layers, we focus here on carbon- 424 based materials. Organic semiconductors can be implemented Organic field-effect transistor bio-sensors in a platform for flexible devices, including those built on Organic transistor-based devices have previously been demonstrated biodegradable and resorbable substrates, while carbon based for gas, vapor, and liquid sensing1-5, as well as for the detection of nano-structured materials, such as carbon nanotubes and graphene single ions or ensembles of ions in solution6-12. Organic field-effect sheets, offer higher performance in terms of field-effect mobility transistor (OFET) based sensing technologies take advantage of the and sensitivity. In all cases, the major challenge is to develop physical or chemical changes taking place in or around the organic SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 ISSN:1369 7021 © Elsevier Ltd 2011 Carbon based materials for electronic bio-sensing REVIEW (semi)conducting material when exposed to different analytes in systems involved. These aspects are not dealt with here as they would gaseous or aqueous environments. Field-effect transistors (FETs) for require a review of their own. Only recent advances in processing and their multi-parametric13 response and multi-functionality-related integrating natural and synthetic bio-active components into electronic versatility, comprise the primary functional component in an array of devices based on both organic or carbon nanostructured materials are sensing platforms proposed in the field of environmental monitoring8, considered (excluding whole cell implementations). This includes new military defense9,10,14-16 and preventative medical care11. The studies on biodegradable substrates for OFETs as well as bio-species integration of active organic materials into these devices has allowed included in gate dielectric materials or on electronic active layers. 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 OFETs fabricated on resorbable and biodegradable substrates devices consisting of a thin organic semiconducting layer, an insulating Efforts to fabricate flexible electronic circuits have routinely focused on (dielectric) layer, and three conductive terminals, the source, drain, developing processes that are compatible with flexible plastic substrate and gate. The source and drain electrodes are fabricated to be directly materials such as poly(ethylene terephthalate) (PET)39, poly(imide)40, in contact with the semiconductor, either on top of the previously poly(ether sulfone)41, cellulose42, silk fibroin, or other functional deposited organic semiconductor (top-contact), or on the insulating fibers for e-textile development43,44. Various organic polymeric layer to be covered with the semiconductor later (bottom-contact). systems composed of biodegradable polymers have demonstrated The “channel” refers to the region in the semiconductor layer between their usefulness in important applications like temporary medical the defined source and drain electrodes12. The active semiconductor implants45,46, and biodegradable products47. However, the realization layer may consist of small molecules17-22 polymers23,24, or organic of these systems requires fabrication processes that are compatible nanostructured materials25-27, among others. Contacts are usually with tight substrate compatibility requirements; in particular, in the composed of gold; although a vast number of conductive materials case of PET, a moderate use of aqueous solvent and low-temperature (e.g., doped conjugated polymers and printed metallic nanoparticles) post processing, must be taken into account as a limiting step in are actively being used for this purpose28,29. The dielectric layer, the fabrication procedure. To realize electronic circuits that are not which electrically isolates the semiconductor from the underlying gate only flexible but also foldable, materials such as aluminum foil48 and electrode, may be composed of inorganic oxides30, properly tailored paper49 have been explored. Paper films were used as substrates with polymers or composites7, or ultrathin self-assembled layers31. pentacene-based active layers. This approach was further expanded Recent advancements in the field of biotechnology have provided to create complete circuits using foldable paper-based substrates, systems that are able to efficiently transduce biological events using motivated by the fact that paper substrates are mechanically flexible electronic devices32,33. This progress has led to the improvement and capable of small bending radii. Roll-to-roll processing has also of biological sensing platforms demonstrating the potential to be been demonstrated by Siegel and co-workers that allows for the applied for the rapid screening of biological samples and point-of- realization of a complete circuit from simple folding and cutting care diagnostics. Advancements in biomaterial processing and organic techniques (Fig. 1)34. The relative fragility of paper-based circuits electronic device fabrication have allowed for the potential integration could potentially be utilized in security applications. One specific of biomolecules as active components in all of the materials employed example is the fabrication of an envelope integrated with a system in the realization of an organic transistor including the bulk substrate, that, if compromised via destruction of the envelope, will cease to the dielectric interface, and even the active semiconducting layers and function. Paper-based devices also present distinct advantages in electrodes34. terms of disposability and environmental biodegradability, the latter Other interesting aspects of biomolecule integration in organic being extremely important in the context of medical biomaterials. electronic devices have been explored in electrochemical bio- The motivation of this nascent research topic is to improve the transistors35 that have proven to be quite sensitive and selective. Some compatibility of biomaterials and electronic devices for applications limitations persist, however, and are connected to their implementation including restorable electronically active medical implants45,46. in large area sensor arrays as it is not clear if the need for a reference Mechanically robust, water-insoluble, natural proteins have also been electrode can be ruled out. Significant effort has also been invested in explored as substrates for silicon electronics. A key example is provided recent years to develop new hybrid systems in which living cells have by Kim et al.43 who used silk fibroin as a substrate for traditional been integrated in electronic field-effect devices36,37.The technological silicon-based transistors. The performance of these devices is only impact of these systems is attracting the interest of many research slightly affected when the substrate is mechanically deformed. groups as evidenced by the numerous contributions that can be found Bao’s group recently investigated materials and fabrication in the literature38. These studies involve major efforts in assessing strategies for the realization of organic thin-film transistors using a biocompatibility and bio-functionality of the materials and the bio- small-molecule semiconductor in combination with a biodegradable SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 425 REVIEW Carbon based materials for electronic bio-sensing (a) (a) (b) (b) (c) (c) 426 Fig. 1 Paper-based circuits demonstrate remarkable mechanical flexibility and versatility. (a, b) Trimming and burning fiber-based electronic circuits; in (b), the paper circuit burned in 3 s. (c). A paper airplane circuit shown unfolded (top left) and folded (top right) with battery-powered red/green light-emitting diode (LED) wingtips. The circuit weighs less than 1 g. Electronic traces for both circuits are comprised of metallic wires (100 % In, thickness = 2 mm, width = 1 mm, length = 30 – 60 mm total) patterned on Yasutomo origami paper substrates. Reprinted from34. © Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. Fig. 2 A representation of the device structure and degradation time of the devices reported by Bao, et al. (a) The chemical structure of the semiconductor 5,5-bis-(7-dodecyl-9H-fluoren-2-yl)-2,2 - bithiophene (DDFTTF), the dielectric (PVA) and the substrate (PLGA). (b) The top-contact configuration of the OTFT devices. (c) In vitro degradation studies of the PLGA substrates. Although initially resistant to mass degradation and water uptake, significant mass loss and water uptake can be observed after 30 days. Near-total mass loss and 100 % device hydration were observed at 70 days. Reprinted from50. © Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. polymeric substrate and dielectric50. They demonstrated that these explicitly studied, degradation mechanisms that decompose melanin51,52, devices perform stably after exposure to water and, since they are a conjugated amorphous semiconductor53,54, could potentially act made of nearly entirely biodegradable materials, are resorbable in a in a similar manner towards DDFTTF. Poly(vinyl alcohol) was used as simulated degradation environment in vitro. A schematic image of the the insulating layer. Devices were fabricated with “non-crosslinked” device is shown in Fig. 2. The strategy for material selection focused on PVA (nPVA) and crosslinked PVA (xPVA) in order to demonstrate the utilizing materials that are not only biocompatible and biodegradable, improved performance of the xPVA-based device in terms of leakage but also exhibit adequate electronic properties and a suitable device current and surface roughness. The substrate, which composed 99.89 % manufacturing process. The semiconducting molecule utilized in this of the total mass, consists of poly(L-lactide-co-glycolide) (PLGA), a linear study, 5,50-bis-(7-dodecyl-9H-fluoren-2-yl)-2,20-bithiophene (DDFTTF), thermoplastic biodegradable polyester. This polymer contains significant is a robust small-molecule p-channel semiconductor that exhibits amounts of lactic acid (PLGA 85:15) and thus allows for processing at excellent device performance and is resistant to harsh aqueous elevated temperatures due to the high glass-transition temperature, Tg. environments. Although the biodegradation of DDFTTF has not been Thin-film transistors based on p-channel DDFTTF active layers and (PVA) SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 Carbon based materials for electronic bio-sensing REVIEW dielectrics exhibited electron mobilities as high as 0.253 cm2s-1V-1 and conditions, such as the pH of the precursor solutions, as demonstrated on/off current ratios (Ion/Ioff) of up to 9.4 × 103. These devices maintained by the group of A. K-Y. Jen who fabricated pentacene based OTFTs on functionality after direct exposure to water and are principally resorbable top of quartz-binding polypeptide (QBP)-modified SiO2/Si substrates and biodegradable. To avoid interaction with ionic species eventually with a 50 nm pentacene active layer. The transfer characteristics for present in the analyte aqueous solution, an appropriate encapsulation and these devices are shown in Fig. 3, along with the device structure. packaging of the device was needed. The potential utilization of resorbable A shift in Vt of about 30 V compared to the unmodified SiO2 was organic electronics could serve as a motivating factor for the development observed upon assembly of the peptide in pH-neutral condition. From of high-performance dielectrics and semiconducting molecules with the this point, a positive shift in Vt was observed when the GEPI-QBP was additional properties of biocompatibility and biodegradability into non- assembled in different concentrations of HCl, while a negative shift toxic and environmentally safe monomers. in Vt was observed when QBP was assembled from a KOH solution at different concentrations. Although the approach is very interesting, the OFETs dielectrics modified with biomolecules Improvements of bio-sensor figures of merit have been realized stability of the system has not been discussed. OFETs with functional deoxyribonucleic acids (DNAs) as dielectric through the development of new high performance dielectrics and material have been pioneered by the Grote and Sariciftci groups56-58. device architectures, as well as by tuning device properties via Specifically, organic-soluble DNA, such as cetyltrimethylammonium interface engineering. Precise control over the threshold voltage (Vt) chloride (CTMA)-DNA, have been synthesized and their physical of pentacene-based organic thin film transistors, desirable for better and electronic properties have been elucidated. Since CTMA-DNA integration of OFET devices into electronic circuits, has been achieved is insoluble in water but soluble in alcohol, solution processing by inserting well characterized genetically engineered peptides for methods are suitable for thin-film fabrication. An interesting inorganics (GEPI) at the semiconductor-dielectric interface55. Further field-effect carrier transport phenomenon was observed in these tuning of the Vt can be achieved by controlling the peptide assembly devices, although an undesired hysteresis could be seen in the corresponding transfer curves. An additional blocking layer of (a) (e) 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 (b) 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 (c) chains in the CTMA unit help enhance the ordering of the HB-ant-THT (f) molecules. Bio-functionalization of the organic semiconductor Many examples have been proposed for the detection of analyte (d) 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 Fig. 3 A schematic representation of a peptide-modified thin-film transistor. (b) Assembly in water produces no ions to pair with the peptide termini. (c) When assembled in an HCl solution, the N-termini pair with chloride ions. (d) When assembled in a KOH solution, the C-termini pair with potassium ions to produce a dipole pointing toward the substrate surface. The source-drain current vs source-drain bias (e) and the square root of the source-drain current vs the gate source voltage (f) for pentacene OTFTs assembled on SiO2 under basic (green diamonds), neutral (blue circles), and acidic (red triangles) conditions, as well as with and without peptide (purple squares), are also depicted. Reprinted with permission from55. © 2010, American Institute of Physics. 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 SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 427 REVIEW Carbon based materials for electronic bio-sensing Fig. 4 A depiction of an OTFT device configuration along with the chemical structures of HBant- THT, CcDNA, and CTMADNA-co-CcDNA. Capacitance plots for metal insulator metal devices fabricated with CcDNA and CTMADNA-co-CcDNA. Reprinted with permission from59. © 2010, American Institute of Physics. maleic anhydride (MA) polymer layer65,66. Such a surface pretreatment Genetic diagnostic tools have been proposed by Subramaniam’s allowed for the covalent attachment of the peptide nucleic acid (PNA) group that integrate OTFT-based DNA sensors with microfluidic strands, which were then used to selectively detect the target DNA channels. A novel photolithography-based microfluidics fabrication molecules within limits approaching 1 nM. method was used to directly enable on-chip hybridization, a significant (a) (b) (c) Fig. 5 A schematic representation of an OTFT sensor fabrication process. (a) Fabrication of OTFT with a PVP-HDA (20 nm) dielectric layer, DDFTTF organic semiconductor (15 nm), and source-drain (S-D) electrodes. (b) PNA and DNA 15-mer sequences and the chemical structure of DDFTTF. (c) Schematics of the surface modification to immobilize the PNA-15mer probe. Reprinted from64. © Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. 428 SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 Carbon based materials for electronic bio-sensing (a) (c) (b) (d) REVIEW Fig. 6 (a) SEM and (b) AFM images of a biotinylated F8T2-polymer film coated onto an SiO2/Si substrate. (c) Plot of source-drain current versus gate voltage at a drain voltage of −60 V for biotinylated F8T2 OTFTs. The inset represents the I-V characteristics at various gate biases. (d) Plot of drain current versus gate voltage at a drain-voltage of −60 V for biotinylated F8T2 OTFTs annealed within a temperature range of 150 °C to 280 °C. © ETRI Journal. Reprinted with permission from68. advancement in the realization of disposable rapid turn-around tools Recently, our group proposed the inclusion of a photosynthetic for field-deployable genetic diagnosis67. Another example of direct membrane protein, the bacterial reaction center, into a phospholipid semiconductor functionalization was provided by Lim’s group where an bilayer formed on top of the active layer of an OTFT for herbicide organic semiconducting copolymer composed of biotinylatedfluorene detection69,70. A pictorial view of this sensing device bearing the and bithiophene was synthesized through a palladium(0)-mediated membrane protein as a bioreceptor is shown in Fig. 7a. The lipid Suzuki coupling polymerization. OTFTs were fabricated using this bilayer facilitates a close association of the protein with the carriers p-type polymer and electrically characterized in the presence of avidin (electrons or holes) accumulated in the channel at the semiconductor/ (Fig. 6)68. The binding of avidin-biotin moieties in the polymer were gate-dielectric interface. Atomic force microscopy (AFM) (Fig. 7b) and correlated to changes in the channel chemoresistivity and to the on/off confocal microscopy (Fig. 7c) have been performed to investigate the characteristics of the OTFTs. Avidin exposure resulted in a lowering structure of the lipid-protein layer deposited on top of the organic of the drain current (Ids) of nearly five orders of magnitude when the semiconductor and shows a very uniform deposition of biomaterials. device was operated at a drain voltage of −40 V. Detection in this Very little electronic performance degradation (Fig. 7d) is seen as case was done at about 50 ppm, which is quite high considering the the bioreceptor containing layer is deposited on top of the channel specificity of the interaction. material. (a) (b) (c) (d) Fig. 7 (a) A schematic representation of a phospholipid embedded membrane protein based OTFT. (b) A confocal microscopy image. (c) An AFM image. (d) Currentvoltage characteristics of the supported bilayer OTFT. The gate biases range from 0 V to −100 V in steps of −20 V. Reprinted with permission from69, © 2009, IEEE. SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 429 REVIEW Carbon based materials for electronic bio-sensing Another interesting and very recent architecture that explores organic (a) 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. (b) 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 (c) 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, 430 Fig. 8 (a) A schematic illustration of a human olfactory receptor (hOR) conjugated polypyrrole NT-FET. (b-c) Real-time changes of normalized ISD upon addition of target odorant (amyl butyrate, AB) and non-target odorants (butyl butyrate, BB; propyl butyrate, PB; hexyl butyrate, HB), measured at VSD = 50 mV. Reprinted from82. © Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. and polymeric materials: tunable conductivity, chemical diversity, functionality not only provides sufficient immobilization sites for mechanical stability, and biocompatibility73-77. Further advantages biomolecules, but also assists in the covalent binding of 1D CPs on include their lightweight, low cost, easy processing/patterning, and amine-terminated silanized SiO2 substrates, to form stable contacts scalable production. A crucial factor that needs to be accounted for with the metal electrodes, as illustrated in Fig. 882. Thrombin78,79, in designing CP-FET biosensors is the sensitivity of the polymeric glucose80, human serum albumin81 and odorant molecule82 detection nanostructure towards contact resistance variation due to exposure to was demonstrated using recognition probes such as aptamers, glucose the liquid phase. Usually, in order to overcome this issue, a functional oxidase enzyme, antibodies and a human olfactory receptor (hOR), monomer such as a polymeric derivative with carboxylic side-chain respectively. The study by Yoon et al. deserves further mention, groups78-82 has been integrated into a copolymer scheme. The acid since it is the first example of a FET-type bioelectronic nose based SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 Carbon based materials for electronic bio-sensing on hOR-conjugated CP nanotubes82. The authors developed a reliable chemical immobilization strategy for the fabrication of REVIEW (a) 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. Carbon nanotubes 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, (b) 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 biological application of CNT-FET proposed by the Dai group in 2003 while investigating specific protein–protein interactions91. Recent rapid development of (c) 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 (d) 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 two 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 Fig. 9 (a) A schematic illustration of an experimental setup in which a carbon nanotube channel is covered by a lipid bilayer incorporating a Na+/K+-ATPase ion pump. Inset: a cross-section of the device showing the directions of the ion fluxes. (b) A scanning electron microscopy image of the S-D region of the CNT transistor with a single nanotube bridging the two electrodes. Inset:a photograph of the device chip (2 × 1 cm) with a PDMS microfluidic channel. (c) The normalized nanotube conductance recorded over time for the devices covered with a lipid bilayer with (red trace) and without (blue trace) Na+/K+-ATPase ion pump incorporated, after the injection of 10 mM ATP solution. (Applied gate voltage Vg= −0.05 V). (d) The normalized conductance of the Na+/K+-ATPase containing CNT device recorded at different ATP concentrations. (Applied gate voltage Vg = −0.2 V). Reprinted with permission from96, © 2010, American Chemical Society. SEPTEMBER 2011 | VOLUME 14 | NUMBER 9 431 REVIEW Carbon based materials for electronic bio-sensing (a) (c) (b) (e) (d) Fig. 10 (a) A schematic illustration of the experimental setup of a graphene-FET for biosensing applications. (b) A photograph of a patterned reduced graphene oxide (rGO) sensing device on a polyethylene terephthalate (PET) film. An optical image (c) and schematic illustration (d) of PC12 cells grown on a poly-L-lysine coated rGO-FET fabricated on a PET substrate. (e) The real-time response of the rGO-FET to the vesicular secretion of neurotransmitters from PC12 cells stimulated by a high K+ concentration solution. (Vds = 100 mV, Vg = 0 V, distance between D and S electrodes in the device fixed at 1 cm). Reprinted with permission from107, © 2010, American Chemical Society. 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 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 deposited by dielectrophoresis and the surface tension associated with cells were monitored in real time by biosensors based on a reduced a water meniscus; an AC voltage (frequency 1 MHz, amplitude 5 Vp-p) graphene oxide (rGO) film (Fig. 10)107. Noteworthy in this study, the was applied to align SWNTs in solution, which were then compressed authors focused their attention on competitively alternative materials by the surface tension of the water meniscus after slow, careful drying. of graphene, namely rGO, produced by facile and scalable solution The attachment of the SWNTs to the electrodes was mediated by processes to extend the applications of graphene for plastic electronics. Van der Waals forces. The resulting SWNT-film, suspended between They proposed the fabrication of centimeter-long, ultrathin (1 – 3 nm), cantilever electrodes, allowed for a highly specific and real-time and electrically continuous micropatterns of highly uniform parallel detection of thrombin97. arrays of rGO films on various substrates by using the “micromolding in capillary” method. Remarkable sensitivity was achieved that was Graphene shown to be insensitive to substrate binding. Graphene is highly promising for new types of chemical/biological 432 sensors with excellent sensitivity due to a combination of a high active Conclusions and future perspectives surface area (i.e., a 2D material with all the carbon atoms exposed The incorporation of biomaterials into all of the different structural to the analyte of interest), exceptional electrical properties, and low components of organic and nanomaterial based electronic devices has noise26,99,100,101. The operational principle of graphene bio-electronic the potential to be applied towards a range of applications in medicine sensors is based on the change of graphene electrical conductivity (σ) and point-of-care diagnostics. Future efforts will need to be focused on due to adsorption of molecules on its surface. The graphene-FET, based the development of new hybrid biomaterials integrated into electronic on a non-functionalized single-sheet, has been shown to exhibit a devices capable of being processed on flexible substrates. The overall proportional increase in conductance upon protein adsorption at a sub- progress of this research field will have enormous implications for both nanomolar level102. Mohanty and Berry developed a graphene-based fundamental scientific discovery and technological development. In bio-sensor capable of single bacterium resolution, investigating for the particular, novel bio-OFETs could be used to study the fundamentals of first time the interaction between chemically-modified graphene and electron transfer in naturally occurring biomolecules. 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