Nanotechnology-Enabled Chemical
Sensors and Biosensors
by Michael N. Helmus, Peter Gammel, Fred Allen,
and Piero Migliorat...
detectors are typically based on ion
mobility spectrometry (IMS). With
this technique, airborne chemical
compounds pass do...
the gold positive with respect to the
After interaction, the
samples are thoroughly washed in
deionized water. ...
carbon-based sensors and LTPS circuits
is an interesting possibility in view of
the capability of LTPS technology to
monitoring for biohazards and bioterror-
ism. Avian flu is an example of such an
emerging disease that has an immediate
of 5

Nanotech enabled sensors

Published on: Mar 3, 2016

Transcripts - Nanotech enabled sensors

  • 1. Nanotechnology-Enabled Chemical Sensors and Biosensors by Michael N. Helmus, Peter Gammel, Fred Allen, and Piero Migliorato 34 MARCH 2006 • AMERICAN LABORATORY Chemical sensors and biosensors that are sensitive, robust, cost effective, mobile, and compact are a necessity. Prime applications are those in which portability and low cost are paramount, such as clinical monitoring, point-of- care medicine, crime scene forensics, environmental control, and bioterror- ism prevention. The total available market for these applications is over $15 billion and is currently growing at more than 25% annually. Small sensors that employ miniaturized detection methods, such as the field asymmetric ion mass spectrometry (FAIMS) sensor (Owlstone, New York, NY), have applications in chemical and biological warfare detection and can be handheld or wall- or pole-mounted. There has been an explosion of activity in the development of label-free arrays for chemicals, biologic molecules, and DNA detection. Some of these use arrays of electronic detection systems based on metal-oxide semiconductor or field-effect transistors (MOSFETs) devices to which agents have been immobilized. Many of these systems are being enabled by nanodimensioned processes. The miniaturization that results from the use of these nano- dimensioned processes will allow small devices that have low power require- ments to be deployed in the field. The immobilization of biomolecules on nanostructures that have unique elec- tronic properties, e.g., single-walled car- bon nanotubes (SWCNTs), metallic nanowires and tubes, and metal oxide structures, will also permit the develop- ment of revolutionary biosensors. Biosensors will impact the next inno- vation in microarrays and provide a case study in the evolution of next- generation devices. In order to ensure that microarray technology is more widely accessible, microarrays are incorporated into small, less expensive, lightweight, portable instruments with very low spatial and power require- ments. This paper reviews recent results demonstrating the use of low- temperature polycrystalline silicon- thin film transistors (LTPS-TFTs) for the label-free detection of biomolecu- lar interactions. These devices can be particularly useful in the detection of viral RNA and protein–protein inter- actions, in which the use of labels may drastically affect the analyte. LTPS technology allows one to fabricate integrated circuits (ICs) as complex as some conventional ICs on inexpensive substrates such as glass and plastic. In view of the mature level of the enabling technology, it is anticipated that a new generation of inexpensive microarrays, with more than 100,000 parallel channels and fully integrated readout electronics, can be produced using this approach. Chemical sensors In these uncertain times, small, inex- pensive, sensitive, and remotely pro- grammable chemical and biological detectors are critical to ensure the safety of both civilian populations and armed forces. The United States chem- ical and biological detection market in 2004 was $581.5 mil- lion; in 2005 it was $745.9 mil- lion. It will continue to outpace the market in the rest of the world. Double-digit growth is forecast to continue in U.S. gov- ernment spending on chemical detection over the next decade. As a result, a number of elec- tronic noses are in development. Specific examples that under- score the need for high-throughput electronic noses include the following: • Unofficial reports suggest that only 2% of shipping containers entering the U.S. are inspected • On average, U.S. border officials have just one minute to decide whether to admit a vehicle into the country • At least 30 countries around the world have operated or are sus- pected of operating chemical weapons programs • 5.9% of the U.S. population are diabetic and require regular moni- toring of blood glucose levels. Recent studies have shown that diabetes and other diseases such as bladder cancer can be detected and monitored through volatile com- pounds in the breath. A number of exciting technologies are addressing the need for electronic noses. For example, a technology plat- form based on FAIMS (Owlstone) provides reliable, cost-effective chem- ical sensing in a wide array of applica- tions, including Homeland Security, defense, environmental monitoring, industrial processes, transportation, and health care. The technology at the heart of the device overcomes many of the limitations of conven- tional technologies. Today’s chemical Figure 1 Integrated sensor. AL.pg34-38.Helmus.LO 2/28/06 10:20 PM Page 34 Volume 38, Number 6
  • 2. detectors are typically based on ion mobility spectrometry (IMS). With this technique, airborne chemical compounds pass down a length of tub- ing, where they are ionized by a strong electric field. The distinctive drift speed and kinetic signature of each molecule allow the sensor to discrimi- nate between compounds with differ- ent mobilities. IMS suffers from sev- eral disadvantages. In addition to requiring a relatively large physical assembly for the drift tube and ioniz- ing source, the complex physical assembly is fragile and difficult to assemble. The need for a high ionizing voltage also limits the possibilities for battery-powered mobile and handheld applications. These and other limita- tions of IMS have been addressed with FAIMS. Fabricated using standard microelectromechanical system (MEMS) processing recipes, the solid- state detector is a complete analytical sensor built on just two silicon chips plus a separate ionization source. The detector is compact in size and lightweight; it features high reliability, sensitivity, and response speed; low power consumption; reduced false positives; and high versatility. Figure 1 shows the single-chip chemical sensor. The beta-test system platform with display of results is shown in Figure 2. The range of applications for the chemical detection technology is virtu- ally limitless. The compact, dime- sized dimensions, reliability, rapid response time, and low fabrication costs of the detector enable a wide spectrum of commercial possibili- ties for sensing the presence of organic and inorganic chemical agents in extremely low concentra- tions. Low power consumption, compared with conventional IMS sensors, makes the detector partic- ularly suitable for portable and handheld applications. The rugged, solid-state detector requires no maintenance, consumables, or spe- cial handling, and can perform dependably with a shelf life of sev- eral years. From Homeland Secu- rity and defense to personal health care, industrial, automotive, and envi- ronmental applications, the technol- ogy provides a cost-effective platform for the development of real-world, readily commercialized chemical moni- toring and detection solutions. Biosensors Commercially available DNA microarrays are based on optical detection. Known molecules (probes) are immobilized at selected locations. The molecules to be analyzed (targets) are labeled with fluorophors, and interaction with a complementary probe is detected from the presence of fluorescence at the probe’s location. The method is expensive and difficult to implement in portable instrumen- tation. Since electrical detection is suitable for implementation into microsystems, amperometric methods, based on the detection of redox peaks in cyclic voltammetry are being inves- tigated. However, these methods require labeling of the target molecules with redox groups or with a known strand for recognition. Label- free techniques present many advan- tages because they reduce the com- plexity of the overall system; are suitable for mobile applications; and are appropriate for the detection of analytes susceptible to degradation or loss of functionality when labeled, such as viral RNA or proteins. Work at the Cambridge University Department of Engineering (Cam- bridge, U.K.) has demonstrated the label-free electrical detection of DNA hybridization1 based on a novel sensing mechanism employing LTPS-TFTs with a special structure (Figure 3). Single-stranded DNA (ssDNA) oligonucleotides (probes), modified at the 5′ end by HS- (CH2)6-PO4-(CH2CH2O)6-, are immobilized on the gold metal gate. A self-assembly monolayer is used to passivate the regions between strands and to ensure a vertical ori- entation of the DNA oligomers by means of electrostatic repulsion. The device is then exposed to solu- tions containing complementary DNA strands or noncomplementary strands as control. Both probe immobilization and target hybridiza- tion can be accelerated by biasing AMERICAN LABORATORY • MARCH 2006 35 Figure 2 Beta-test system platform. Figure 3 Poly-Si TFT with an extended gate structure, fabricated on laser recrystallized film. The detection pad, electrically connected to the metal gate, is located away from the channel, allow- ing better electrical and chemical isolation of the device. For the TFT, 100 µm, L = 10 µm. AL.pg34-38.Helmus.LO 2/28/06 10:20 PM Page 35 Volume 38, Number 6
  • 3. the gold positive with respect to the solution.2 After interaction, the samples are thoroughly washed in deionized water. The thin film tran- sistor drain current-gate voltage shift ∆VGS curve (TFT ID-VGS) characteristics are measured by applying the gate-source voltage VGS through an Ag/AgCl reference electrode, immersed in an elec- trolyte (5 mM buffer solution, pH 7.4), which is in contact with the functionalized gate. The results are shown in Figure 4. In these devices, VGS is modulated by the electrical dipole χ at the interface between the metal gate and the electrolyte and the potential across the electro- chemical double layer ϕ0. The value of χ is affected by various micro- scopic phenomena, such as charge distribution in the immobilized chemical species and interaction between the functionalized gate and the electrolyte, i.e., chemisorption, physisorption, and ionic exchange. When hybridization occurs, since the total negative charge carried by the double-stranded DNA (dsDNA) is twice that of the single-stranded oligomer, χ and ϕ0 change, resulting in a shift of the I-V characteristics. In contrast, when the device is exposed to a noncomplementary strand, no binding occurs and the above parameters are unchanged. Hence, the hybridization event can be detected by simply recording a shift in the ID-VGS curve. The technique is sensitive enough to detect a mismatch of one base pair, suggesting that with further work, single-nucleotide poly- morphisms (SNPs) could be detected. The reproducibility is due to the sim- ple and well-established covalent immobilization chemistry of thiol- terminated oligomers on gold. The sensitivity results from the in situ sig- nal amplification provided by the tran- sistor. Since the measurement is purely potentiometric, only a two-electrode configuration is needed, instead of the three-electrode potentiostatic arrange- ment required by amperometric detec- tion. This simplifies the array and readout circuit design. The method is applicable to all biomolecular interac- tions that affect the surface dipole at the metal gate/electrolyte interface and can be extended to other chemical and biochemical systems such as pro- teins and cells. Initial results with pro- teins are promising. Nanostructured materials for biosensors The immobilization of biomolecules on nanostructured materials that have unique electronic properties is enabling the development of revolu- tionary biosensors. For example, novel carbon materials are being evaluated as transducers, stabilizers, and media- tors for the construction of ampero- metric biosensors.3 Materials such as fullerenes and carbon nanotubes are promising as electrochemical media- tors and enzyme stabilizers. In addi- tion, porous carbon and porous glassy carbon are found to be excellent transducers for amperometric mea- surements, while providing cavities adequate for enzyme immobilization. At the same time, the sensitivity to peroxide is shown to depend on the activation procedures. Treatment that introduces oxygen groups significantly increases the sensitivity of the carbon- based sensor to hydrogen peroxide. These materials are being used for the construction, mediation, and stabi- lization of a glucose biosensor. Another technology centers on the ability to make highly stable, DNA- modified diamond films.4 Building a sta- ble platform that can constantly sniff for anything unusual, and that can be inte- grated with microelectronic devices, has long been a problem of surface chem- istry. At this point in time, the use of silicon-based technology makes the pro- cess of merging microelectronics with biosensor applications difficult. Silicon technology proves to be unstable or dif- ficult to integrate with materials such as gold, glass, and glassy carbon, and does not permit leaving a surface in contact with water for an extended period of time since it will eventually degrade. While carbon-based electronics are being actively researched, integration of 36 MARCH 2006 • AMERICAN LABORATORY CHEMICAL SENSORS AND BIOSENSORS continued Figure 4 DNA hybridization detected with a poly-Si TFT. Probe: ssDNA, sequence ACCATTTCAGCCTGTGCT; target: sequence TGGTAAAGTCGGACACGA. AL.pg34-38.Helmus.LO 2/28/06 10:20 PM Page 36 Volume 38, Number 6
  • 4. carbon-based sensors and LTPS circuits is an interesting possibility in view of the capability of LTPS technology to provide monolithically integrated ICs on virtually any substrate. The biologi- cally modified diamond films, on the other hand, have proved to be durable—able to withstand multiple cycles of processing DNA, genetic material that can diagnose, for instance, anthrax, ricin, bubonic plague, small- pox, and other molecules that can potentially be used as biological weapons or agents of terror. In addition to carbon, a variety of other nanostructured materials are being inves- tigated for use in biosensors, including polymers, sol–gel materials, crystalline and amorphous metal oxides, and metals. Table 1 lists a few of these materials and their potential biosensor application. Biosensors for avian flu surveillance The ability to develop high-sensitivity electronic handheld or mounted biosen- sors enables the cost-effective surveil- lance of emerging diseases as well as AMERICAN LABORATORY • MARCH 2006 37 Table 1 Nanomaterials for biosensor applications Material Biosensor application Titania nanotubes Self-cleaning hydrogen sensors. Nickel nanowhiskers Biomedical applications in which the sensor’s electrical properties might be used to detect biomolecules in solution, even in low concentrations. By attaching itself to the sensor, each type of biomolecule would impart its own “fingerprint” by changing the electrical signal of the nanocontact. Metallic nanowires and nanospheres “Nanoantennas” that increase the precision of medical diagnostic imaging and devices that detect chemical and biological warfare agents. A nanometer-thin crystal of tin oxide Highly sensitive and stable nerve gas sensor with potential ability to sandwiched between two platinum electrodes detect a single molecule of sarin, the most toxic of biological warfare. Polymer that exchanges electrons with Implantable glucose sensor of glucose oxidase molecules—the enzyme glucose oxide to produce a current, which that reacts to glucose—immobilized in photopolymerized and is the signal that can be monitored from afar microlithographically patterned film. Wireless monitoring of patient’s physiology in the field. Flexible, biocompatible polymers with Nerve gas detector based on a porous silicon chip optical sensor that optical properties of hard crystalline sensors changes color when it reacts to sarin and other nerve agents. Properties could allow a physician to directly see whether the biodegradable sutures used to sew up an incision have dissolved, how much strain is being placed on a newly implanted joint, or how much of a drug implanted in a biodegradable polymer is being delivered to a patient. Note: A silicon wafer is treated with an electrochemical etch to produce a porous silicon chip containing a precise array of nanometer-sized holes. This gives the chip the optical properties of a photonic crystal—a crystal with a periodic structure that can precisely control the transmission of light much as a semiconductor controls the transmission of electrons. A molten or dissolved plastic is cast into the pores of the finished porous silicon photonic chip. The silicon chip mold dissolves, leaving behind a flexible, biocompatible “replica” of the porous silicon chip. Nitric oxide-releasing polymers that include Chemical sensors that can be placed in the bloodstream or under the skin a copper ion-containing complex to continuously monitor oxygen, acidity (pH), or glucose levels. Note: Copper ions act as catalysts to take nitrosothiols found in the bloodstream and generate nitric oxide from them. DNA–gold nanoparticles Highly sensitive and selective colormetric biosensor that functions in much the same fashion as a strip of litmus paper. Note: Using gold nanoparticles laced with DNA, the nanoparticles are hybridized into aggregate clusters that have a characteristic blue color. In the presence of a specific metal ion, the catalytic DNA will break off individual gold nanoparticles, resulting in a dramatic color shift to red. The intensity of the color depends on the initial concentration of contaminant metal ions. Protein-encapsulated SWCNTs Near-infrared nanoscale sensor that detects glucose. The sensor could be implanted into tissue, excited with a laser pointer, and provides real-time, continuous monitoring of blood glucose level. AL.pg34-38.Helmus.LO 2/28/06 10:20 PM Page 37 Volume 38, Number 6
  • 5. monitoring for biohazards and bioterror- ism. Avian flu is an example of such an emerging disease that has an immediate need for the surveillance of waterfowl, which spread the disease, and poultry, which are infected and continue to spread the disease to other poultry, swine, and potentially humans.5 Asia has become the ideal incubator for the disease to allow potential mutations to humans and a potential pandemic like the 1918 Spanish Influenza. Surveillance at points of potential outbreak is required and includes waterfowl in the field, poultry on farms, and imported animals at points of export and import. Surveillance of people includes farm and health work- ers, individuals at points of entry, sites of possible outbreak, and hospital emergency rooms. A field-usable biosensor needs to be accurate, sensi- tive, and rapid (<15 min, preferably a few minutes) in identifying the infec- tious diseases. Ultimately, the genetic identification of the virus strain, e.g., Influenza A (H5N1), would be required. Screening by identification of Influenza A is useful, but requires additional testing to verify the strain. This reduces the utility of a test, par- ticularly when rapid quarantine or culling of the flock is required to pre- vent spread of the disease. Commonly used methods of identification include direct antigen detection, isolation in cell culture, or identification of influenza-specific RNA by reverse transcriptase-polymerase chain reac- tion (RT-PCR).5–8 A real-time RT- PCR that can provide results on avian flu identification within 3 hr has been developed.9 However, these PCR methods require bench devices and are not portable. Handheld PCR sys- tems are under development,5 but more research is required to provide prepackaged reagents with the requi- site shelf life, robustness, and efficacy. There have also been efforts using oligonucleotide microarray hybridiza- tion technology for the identification of influenza viruses.10 This is a potent approach but is limited to the use of laboratory-based equipment. Efforts at developing field-usable biosensors for avian flu detection as part of surveillance efforts are limited.5 Researchers at the Georgia Institute of Technology (Atlanta, GA) are utilizing planar waveguide coated with antibodies in tandem with interferometry.11 Under develop- ment at Advance Nanotech, Inc. (New York, NY) is an avian flu biosensor based on the microarrays of LTPS-TFTs technology. The unique aspect of this development is the incorporation of additional technol- ogy to make the method usable in remote locations, including real-time secure communications. Conclusion Next-generation chemical and biosen- sor development will utilize nano- enabled materials and electronics to cre- ate miniaturized, portable devices for field use and point-of-care diagnoses. Furthermore, small, inexpensive, sensi- tive, and remotely programmable chem- ical and biological detectors are critical to ensure the safety of both civilian pop- ulations and armed forces. The ability to utilize biosensors that incorporate local, wireless communication in combina- tion with proprietary databases will be very powerful for the rapid identifica- tion of infectious diseases in hospitals, emergency rooms, ambulances, surveil- lance, and sites of potential outbreak. The ability to rapidly identify geograph- ical hot spots, for example, the spread of avian flu in poultry in Asia, and its potential to mutate to an infectious human disease, can be met by this new generation of biosensors. References 1. Estrela, P.; Stewart, A.G.; Yan, F.; Migliorato, P. Field effect detection of biomolecular interactions. Elec- trochim. Acta 2005, 50, 4995–5000. 2. Estrela, P.; Migliorato, P.; Takiguchi, H.; Fukushima, H.; Nebashi, S. Biosens. Bioelectron. 2005, 20, 1580–6. 3. Sotiropoulou, S.; Gavalas, V.; Vam- vakaki V.; Chaniotakis, N.A. Novel carbon materials in biosensor systems. Biosens. Bioelectron. 2003, 18(2–3), 211–5. 4. Yang, W.; Auciello, O.; Butler, J.E.; Cali, W.; Carlisle, J.A.; Gerbi, J.E.; Gruen, D.M.; Knickerbocker, T.; Lasseter, T.L.; Russell, J.N.; Smith, L.M.; Hamers, R.J. DNA-modified nanocrystalline diamond thinfilmsasstable,biologicallyactivesub- strates.Nat.Mater.2002,1(4),253–7. 5. The Threat of Pandemic Influenza: Are We Ready? Workshop Summary; Kno- bler, S.L.; Mack, A.; Mahmoud, A.; Lemon, S.M., Eds; Institute of Medicine, National Academies, National Academies Press: Washing- ton, DC, 2005, catalog/11150.html. 6. WHO Recommendations on the Use of Rapid Testing for Influenza Diagno- sis, Jul 2005. 7. Recommended Laboratory Tests to Identify Avian Influenza A Virus in Specimens From Humans. WHO: Geneva, Jun 2005. 8. Ryan-Poirier, K.A.; Katz, J.M. Appli- cation of Directigen FLU-A for the detection of Influenza A virus in human and nonhuman specimens. J. Clin. Microbiol. 1992, 30(5), 1072–5. 9. Durham, S. A new, rapid test for avian influenza. Agricul. Res. Mag. 2003, 51(2). 10. Sengupta, S.; Onodera, K.; Lai, A.; Melcher, U. Molecular detection and identification of influenza viruses by oligonucleotide microarray hybridiza- tion. J. Clin. Microbiol. 2003, 41, 4542–50. 11. Hewett, J. Optical biosensors help spot bird-flu. Lasers, Optics and Pho- tonics Resources and News (Got- tfried, D.), Sept 2005. Dr.Helmus,Dr.Gammel,andDr.Allenarewith Advance Nanotech, Inc., 600 Lexington Ave., 29th Floor, New York, NY 10022, U.S.A.; tel.: 212-583-0080; fax: 212-208-2676; e-mail: Prof. Migliorato is with the Dept. of Engineering, Cam- bridgeUniversity,Cambridge,U.K. 38 MARCH 2006 • AMERICAN LABORATORY CHEMICAL SENSORS AND BIOSENSORS continued AL.pg34-38.Helmus.LO 2/28/06 10:20 PM Page 38 Volume 38, Number 6

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