US20060054941A1 - Multifunctional biosensor based on ZnO nanostructures - Google Patents
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Abstract
The present invention provides the multifunctional biological and biochemical sensor technology based on ZnO nanostructures. The ZnO nanotips serve as strong DNA or protein molecule binding sites to enhance the immobilization. Patterned ZnO nanotips are used to provide conductivity-based biosensors. Patterned ZnO nanotips are also used as the gate for field-effect transistor (FET) type sensors. Patterned ZnO nanotips are integrated with SAW or BAW based biosensors. These ZnO nanotip based devices operate in multimodal operation combining electrical, acoustic and optical sensing mechanisms. The multifunctional biosensors can be arrayed and combined into one biochip, which will enhance the sensitivity and accuracy of biological and biochemical detection due to strong immobilization and multimodal operation capability. Such biological and biochemical sensor technology are useful in detection of RNA-DNA, DNA-DNA, protein-protein, protein-DNA and protein-small molecules interaction. It can be further applied for drug discovery, and for environmental monitoring and protection.
Description
- This application claims priority to U.S. Provisional Patent Application No. 60/385,884, which was filed on Jun. 6, 2002.
- This invention was made with Government support under Grant Nos. NSF ECS-0088549 and NSF CCR-0103096, awarded by the National Science Foundation. Therefore, the Government has certain rights in this invention.
- This invention relates generally to biosensor technology, and pertains more particularly to novel multifunctional biosensors based on zinc oxide (ZnO) nanostructures for biological, biochemical, chemical and environmental applications.
- The nanoscale science and engineering have shown great promise for the fabrication of novel nano-biosensors with faster response and higher sensitivity than that of planar sensor configurations, due to their small dimensions combined with dramatically increased contact surface and strong binding with biological and chemical reagents which could have important applications in biological and biochemical research, as well as in environmental monitoring and protection.
- ZnO nanostructures have many advantages. As disclosed in U.S. patent application Ser. No. 10/243,269, nanotip arrays made with insulating or conductive ZnO can be fabricated in a controlled manner to produce tips with a uniform size, distribution and orientation. The ZnO nanotips are made using our chemical vapor deposition (CVD)-based method in a simple process at relatively low temperatures as disclosed by S. Muthukumar*, H. Sheng*, J. Zhong*, Z. Zhang*, N. W. Emanaetoglu*, Y. Lu, “Selective MOCVD Growth of ZnO Nanotips”, IEEE Trans. Nanotech, Vol. 2, n. 1, pp. 50-54 (2003), giving ZnO nanostructures a unique advantage over other wide bandgap semiconductor nanostructures, such as gallium nitride (GaN) and silicon carbide (SiC). Furthermore, through proper doping and alloying, ZnO nanotips can be made as piezoelectric and ferroelectric, transparent and conducting, and magnetic, thus having multifunctional applications.
- Recent advances in genetic sequencing methods are leading to an explosion in the area of biotechnology. Many emerging areas of biotechnology are based upon highly-parallel methods for sequencing and detecting DNA, RNA, and proteins. Many of these areas could benefit greatly by leveraging the emerging nanotechnology, but applying it to develop and utilize new analytical tools for biochemical analysis. A need exists to provide novel biological and biochemical sensors, which have higher sensing efficiency and multiple functionality, thereby having significant advantages in comparison to the existing sensor technology.
- It is the primary objective of this invention to address the novel multifunctional biosensor technology based on ZnO nanotips and nanotip arrays.
- Particularly, it is an objective of this invention to provide conductivity-based biosensors using semiconductive or conductive ZnO nanotips; to provide field-effect-transistor (FET)-based biosensors by using ZnO nanotips as the gate of the FET; to provide surface acoustic wave (SAW)-based biosensors by integrating ZnO nanotips into SAW devices to form highly sensitive and multichannel biosensors; and to provide bulk acoustic wave (BAW)-based biosensors by integrating ZnO nanotips into BAW devices to form highly sensitive and multichannel biosensors.
- As ZnO nanotips can be made semiconducting, transparent and conducting, or piezoelectric, their unique electrical, optical and acoustic properties can serve as the basis for multifunctional sensors. A sensor chip comprising of arrays and combinations of various types of ZnO nanotip-based biosensors also allow for multimodal operation.
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FIG. 1 a shows a schematic of a vertical cross-section view of the device structure for the conductivity-based ZnO nanotip biosensor. -
FIG. 1 b shows a schematic of top view of the conductivity-based ZnO nanotip biosensor structure. -
FIG. 2 shows a schematic of a vertical cross-section of a ZnO nanotip gate metal-insulator-semiconductor field effect transistor (MISFET). -
FIG. 3 a shows a schematic of a vertical cross-section view of a ZnO nanotip SAW sensor. -
FIG. 3 b shows a schematic of a top view of ZnO nanotip SAW sensor. -
FIG. 4 a shows an example of transmission spectra as a function of frequency for test ZnO nanotip SAW sensor devices. -
FIG. 4 b shows a plot of a phase shift as a function of frequency between the reference and test ZnO nanotip SAW sensor devices. -
FIG. 5 shows a schematic of a vertical cross-section of a ZnO nanotip BAW sensor. - A biosensor is a device which is capable of providing analysis of various analytes or biomolecules using biological recognition elements which are combined with a signal transducer. Generally, the sensor will produce a signal that is quantitatively related to the concentration of the analytes.
- The biological recognition elements serve to recognize the analytes. These elements include enzymes, microorganisms, tissues, antibodies, receptors, nucleic acids, organelles or whole cells.
- Transducers are physical components of the biosensor that respond to the products of the biosensing process and outputs the response in a form that can be amplified, stored or displayed. Biosensing occurs only when the analyte is recognized specifically by the biological element. Biological recognition in vivo at a single cell level is characterized by high sensitivity, fast response, specificity and reversibility.
- A “sensor surface” refers to the location upon which a binding partner is immobilized for the purpose of measuring changes in physical properties, such as optical refractive index, electrical conductivity, mass loading, etc. They include, but are not limited to, semiconductor, metal and dielectric surfaces.
- ZnO is a wide bandgap semiconductor having a direct bandgap of 3.32 eV at room temperature and can be made semiconducting, piezoelectric, ferroelectric, ferromagnetic, and transparent and conducting through proper doping. ZnO has an exciton binding energy of 60 meV. It is found to be significantly more radiation hard than silicon (Si), gallium arsenide (GaAs), and GaN.
- ZnO is a polar semiconductor with the (0002) planes being Zn-terminated and the (000{overscore (2)}) planes being O-terminated. These two crystallographic planes have opposite polarity and hence have different surface relaxations energies. This leads to a higher growth rate along the c-axis. The ZnO film grown on many semiconducting, insulating or metallic substrates have a preferred c-axis orientation normal to the surface. Therefore, ZnO growth results in a pillar like structure called ZnO nanotips on these semiconducting, insulating and metallic substrates, while ZnO grown on R-plane sapphire substrates results in a smooth epitaxial film. The ZnO nanotips can be grown at relatively low temperatures, giving ZnO a unique advantage over other wide bandgap semiconductor nanostructures, such as GaN and SiC.
- ZnO is an important multifunctional material, which has wide applications in telecommunications, chemical and biochemical sensors and optical devices. In this application, ZnO nanotips are used as the sensor surface to enhance the immobilization in detection of DNA, protein, and harmful biological agents in the field of biological and biochemical sensors. The use of ZnO nanotip arrays also greatly increases the effective sensing area of the biosensor devices as will be described in greater detail below.
- ZnO nanotips can be grown on various substrates. They can also be selectively grown on patterned layers of materials through substrate engineering. Both cases have been disclosed in U.S. patent application Ser. No. 10/243,269.
- Referring to
FIGS. 1 a and 1 b, a schematic of vertical cross-section view and a top view respectively of a conductivity-basedZnO nanotip biosensor 10 are shown. The biosensor consists of asubstrate 16, a conductivethin film 14, aZnO nanotip array 12 on the conductivethin film 14, andmetal electrode pads 17. A reaction between the immobilized species on ZnO nanotips 12 with the target will result in a change in the total change accumulated on nanotips. This change will cause a transient current across the biosensor device, which will be used as the sensor output, as will be described below. - The
substrate 16 can be a semiconductor substrate, such as Si or GaAs, in which case the biosensor can be integrated with electronic integrated circuits (ICs). In a second embodiment of the invention, thesubstrate 16 can be a transparent insulating substrate, such as glass or sapphire, in which case both electrical and optical sensing mechanisms can be used to realize a multifunctional sensor. In a third embodiment of the invention, thesubstrate 16 can be a piezoelectric substrate, such as quartz or lithium niobate (LiNbO3), in which case the conductivity-based sensor can be integrated with the SAW-based sensor to realize another type of multifunctional sensor as described later in this application. - The conductive
thin film 14 has certain conductivity, and it can be a semiconductor, such as Si with properly designed doping level, a metallic thin film, such as gold (Au), a transparent conductive oxide, such as indium tin oxide (ITO), or even the multilayer thin film. The thin film and the metal bond pads are deposited on thesubstrate 16, then patterned using the standard microelectronic processing techniques. - The ZnO nanotips 12 can be deposited on the
substrate 16 andthin film 14 using the technology, but not limited to metal-organic chemical vapor deposition (MOCVD), then patterned by the standard photolithography and etching process. - These ZnO nanotips serve as DNA or protein molecule binding sites. In other words, the ZnO nanotips 12 are preferably bonded with protein or DNA molecules to make conductivity-based biosensors, as will be described in detail below. Specifically, the conductive
thin film 14 surface, with ZnO nanotips 12 grown on the top, will be designed and fabricated as conductivity-based biosensors. Preferably a probe is attached to said tip to seek the targeted molecule due to bioreaction. The probe may preferably be attached on a binding site or a target molecule preferably has a probe. Any useful probes preferably such as chemiluscence, fluorescence, etc. The dimensions of the conductive pattern, the aspect ratio and doping level of the ZnO nanotips, are optimized to enhance the sensitivity. Due to depletion or accumulation of carriers in the nanotips as a result of bioreactions, the conductance of the patterned tip arrays will change significantly. The depletion (accumulation) of the nanotips will result in a transient current across the line. The amplitude of this current will be a function of the amount of target material detected, and the duration to the reaction time. The similar effect was recently demonstrated using Boron doped silicon nanowire biosensors for detection of protein-protein interactions by Y. Cui, Q. Wei, H. Park, and C. M. Lieber, “Nanowire nanosensors for highly sensitive and selective detection of biological and chemical species”, Science 293, 1289 (2001). - If a transparent substrate, either insulating or piezoelectric, is used, the conductivity based
ZnO nanotip biosensor 10 can be operated in optical mode simultaneously with the conductivity mode. ZnO has an optical cut-off wavelength of approximately 373 nm at room temperature. This optical cut-off wavelength can be extended by using its ternary compound, magnesium zinc oxide (MgxZn1-xO). As MgZn1-xO is transparent down to 240 nm (for x=0.6), the changes in the optical absorption characteristics before and after the bioreactions can also be detected and analyzed. During operation, the device is illuminated with ultra-violet (UV) light from one side (top or bottom), and the light is detected on the other side. Changes in the UV absorption spectra are unique to each chemical, allowing identification of the reactant species. Further more, if the tip array is coated with a thin layer of Au (<100A), it can also be functional for fluorescence biosensing as shown by V. H. Perez-Luna, S. Yang, E. M. Rabinovich, T. Buranda, L. A. Sklar, P. D. Hampton, and G. P. Lopez, “Fluorescence biosensing strategy based on energy transfer between fluorescently labeled receptors and a metallic surface”, Biosens Bioelectron. 17, 71 (2002). - In another embodiment of the present invention, there is disclosed a second type of device, which is a ZnO nanotip-gate field-effect-transistor (FET). FETs have been used for chemical sensors. In a FET, a voltage bias applied to the gate of a FET will modulate the current flowing between its source and drain. There are two major types FETs which can be used with biosensors. The first is a metal-insulator-semiconductor FET (MISFET), composed of a metal gate deposited on a gate insulator layer, which is deposited on the semiconductor. The second is a metal-semiconductor FET (MESFET), composed of a metal gate directly deposited on the semiconductor. If the gate insulator is specifically an oxide, the MISFET device is known as a metal-oxide-semiconductor FET (MOSFET).
- An FET type of biosensor can be realized by depositing ZnO nanotips on the gate region of the FET. Such an FET can be a current existing Si MOSFET, GaAS MESFET, etc. The surface charge changes occurring with the target on the ZnO nanotips will result in a potential difference between the gate and the substrate, and modulate the current flowing between the source and the drain. Unlike the resistor-type conductivity-based sensor described above, the FET type sensor can be used for both transient and steady-state current measurements, making it a more flexible device.
- More specifically, a novel transparent FET sensor is composed of a ZnO nanotip gate and a ZnO FET. Referring to
FIG. 2 , there is shown a schematic of a vertical cross-section view of nanotip gateZnO MISFET biosensor 20. It is composed of a R-plane sapphire (R—Al2O3)substrate 22, a semiconductor ZnO thin epitaxial layer as achannel 24, doped ZnO source and drainregions 25, agate insulator 26,metal electrodes 27 to the source and drainregions 25, the ZnO nanotips 12 deposited on the gate, and anencapsulation layer 28 to protect the device except the nanotip gate area. - In this device, n+-
ZnO 25 regions serve as the source and the drain. When Al is used for themetal contacts 27, it will heavily dope the ZnOthin film 24 under it, resulting in good non-alloyed ohmic contact as developed in H. Sheng, N. W. Emanetoglu, S. Muthukumar, and Y. Lu, “Non-alloyed Ohmic Contacts to MgxZn1-xO”, J. Electronic Materials, 31 (2002). This process will be used to simultaneously dope the source and drain regions and form their ohmic contacts in the ZnO MISFET structure. Athin insulation layer 26 will be deposited, and patterned on top of the n-ZnO 24 thin film.Candidate insulators 26 include, but are not limited to, silicon dioxide (SiO2) and magnesium zinc oxide (MgxZn1-xO) with more than 50% Mg mole percentage composition. The device will be protected with theencapsulating layer 28 from the chemical environments it operates in. The ZnO nanotips 12 will be grown on theinsulator layer 26, patterned and etched to serve as the nanotip-gate. - The operation of the ZnO nanotip-gate
transparent MISFET 20 is simple. When a biological reaction occurs with the target at theZnO nanotips 12, the negative surface charge will change, inducing with a potential difference between the gate and the ZnO film. This potential difference will change the conductivity in the n-type ZnO channel 24 under thegate insulator 26, resulting in a change in the current between the source and thedrain regions 25. - As in the conductivity-type
ZnO nanotip biosensors 10 described above, the ZnO nanotip-gatetransparent MISFET biosensor 20 can be operated in optical mode simultaneously with electrical mode. ZnO nanotips, R—Al2O3, SiO2 and MgxZn1-xO (0.5<x<1) are all transparent to visible light, therefore allow the sensor to be operated in optical mode. - In another embodiment of the present invention, there is disclosed a third type of device which integrates piezoelectric ZnO nanotips with SAW biosensors. Referring to
FIGS. 3 a and 3 b, there is shown a schematic of a vertical cross-section view and a schematic of a top view respectively of ZnOnanotip SAW biosensor 30. The ZnO nanotip SAW biosensor is composed of apiezoelectric substrate 32, an insulatingamorphous layer 34, a metal input interdigital transducer (IDT) 36, ametal output IDT 38, and theZnO nanotips 12. - The
piezoelectric substrate 32 can be, but is not limited to, quartz, LiNbO3, lithium tantalate (LiTaO3), etc. An insulatingamorphous layer 34 is deposited on the piezoelectric substrate and patterned using the standard microelectronic processing techniques. This insulating amorphous layer can be, but is not limited to, SiO2 or Si3N4. - The ZnO nanotips 12 are deposited on the surface of the insulating
layer 34 using MOCVD, or other deposition technology, then patterned and etched to define the nanotip coverage area. The metal IDTs 36 and 38 are then deposited and patterned using standard microelectronic processing techniques. The metal of choice is Al, but other metals can also be used. - The ZnO nanotip
SAW sensor device 30 operates similarly to a planar SAW biosensor. A dualchannel biosensor consisting of two identical devices, one without target coating serving as the reference and the other with target coating serving as the sensor, are used together. As the target binds with the ZnO nanotips 12 on the sensor device, mass loading of the sensor will result in a decrease of the phase velocity under the ZnO nanotips. This will results in a phase difference between the output signals of the reference and the sensor devices. The use of ZnO nanotips dramatically enhances the immobilization of DNA, protein and other small biomolecules, therefore the sensitivity of the biosensors. Our preliminary experimental results demonstrate that the immobilization rate of ZnO nanotips is over thirty times higher than that of smooth surface. It is well known that the rough surface will increase the viscosity of the sensing media on the acoustic path and deteriorate the device performance. Therefore, the ZnO nanosize tip-type structures 12 will have higher electromechanical coupling coefficient to compensate the increased propagation loss as disclosed by K. K. Zadeh, A. Trinchi, W. Wtodarski, and A. Holland, “A novel love-mode device based on a ZnO/ST-cut quartz crystal structure for sensing applications”, Sensors and Actuators A 3334, 1 (2002). - In the refinement of the invention, the SAW based
ZnO nanotip biosensor 30 can be operated in optical and SAW modes simultaneously, if a transparent piezoelectric substrate, such as quartz or LiNbO3, is used. As in the conductive-type nanotip biosensors 10, thesensor 30 is illuminated with UV light on one side (either top or bottom) and the transmitted UV light is detected at the other side. The UV absorption spectrum can be used to identify the reactant species. - In another refinement of the invention, the SAW based
ZnO nanotip biosensor 30 can be operated in electrical and SAW modes simultaneously, if the insulating layer structure is replaced with the resistor-type conductive ZnO nanotip biosensor structure. - In a further refinement of the invention, the ZnO nanotips 12 can be combined with the monolithically integrated tunable SAW (MITSAW) sensors disclosed previously (U.S. Pat. No. 6,559,736 and U.S. patent application Ser. No. 09/905,205), to enhance their performance.
- In preliminary work, SAW delay lines are fabricated on 128° Y-cut LiNbO3 with a ZnO nanotip/SiO2 layer structure deposited on the propagation path. The IDT structure of this prototype device consists of 50 pairs of electrodes, 963 μm long, 3 μm wide and 3 μm apart from each electrode for both IDTs. The phase velocity (v) of the SAW on the 128° Y-cut LiNbO3 is 3668 m/s, and the wavelength (λ) of the test pattern is 12 μm. From the equation fc=v/λ, the expected center frequency is 305 MHz. The bandwidth is BW3db=(0.9/Np)*fc=0.9*305/50=5.49 MHz. On the propagation path of the prototype devices, the sensor region has 600 nm ZnO nanotip/100 nm SiO2 is 1116 μm long and 594 μm wide. Furthermore, the dual channel (reference and sensor channels) device is tested using an Agilent 8573D Network Analyzer. The reference channel has no protein bonding and the sensor channel is bonded with 100 ng protein on the ZnO nanotip over an area of 6.629×10−3 cm2.
- The frequency responses of the reference sensor device and the actual test sensor device are shown in a graph shown in
FIG. 4 a. The X-axis is the frequency and the Y-axis is the S21 transmission spectra of reference and sensor device. As shown inFIG. 4 a, the sensor device has a shift to lower frequency compared with the reference device. An additional insertion loss of 6.14 dB is observed for the protein bonded sample. However, the insertion loss shift depends on a number of factors, and by itself is not a good sensing mechanism. Instead, the phase shift of the signal is preferred for accurate and repeatable measurements. -
FIG. 4 b shows a graph displaying a phase difference between the reference and sensor prototype devices. The X-axis is the frequency and Y-axis is the phase difference between the reference and sensor device. As shown inFIG. 4 b, the sensor device has a 47.680 phase shift at thecenter frequency 305 MHz compared with the reference device. The phase shift increases with increasing frequency, due to the different velocity dispersion characteristics of the SAW propagating in the reference and sensor channels. The phase velocity decreases with increasing frequency, as sensitivity increases with frequency. This phase velocity decrease results with a larger phase difference between the sensor and reference devices with increasing frequency. Nominally, the phase shift should be a monotonically increasing function. However, due to such factors as electromagnetic feedthrough and triple transit interference (TTI), the phase response has ripples. The impact of these secondary effects on sensor performance can preferably be minimized. The proof-of-concept device uses an unoptimized SAW delay line structure. Narrower bandwidths and larger phase shifts can be achieved by optimizing the device parameters and proper choice of substrate. - In another embodiment of the present invention, there is disclosed a fourth type of device which integrates piezoelectric ZnO nanotips with BAW biosensors. Referring to
FIG. 5 , there is shown a schematic of a vertical cross-section view of a ZnO nanotipBAW biosensor 50. The ZnO nanotipBAW biosensor 50 is composed of apiezoelectric material 52, ametal top electrode 54, ametal bottom electrode 56 andZnO nanotips 12. - The
piezoelectric material 52 can be, but is not limited to, quartz, LiNbO3, LiTaO3, etc. Themetal top 54 and bottom 56 electrodes are deposited and patterned using the standard microelectronic processing techniques. - The ZnO nanotips 12 are deposited on the top metal electrode surface using MOCVD, or other deposition technology, and then patterned and etched to define the nanotip coverage area of the BAW sensor.
- In a further embodiment of the ZnO nanotip
BAW sensor 50, the center area of the top surface of the piezoelectric substrate is not metallized. The ZnO nanotips 12 are deposited on the barepiezoelectric substrate surface 52, so that thetop metal electrode 54 surrounds, but does not contact theZnO nanotips 12. - The ZnO nanotip
BAW sensor 50 operates similarly to a BAW resonator device. The BAW resonator will resonate at a specific frequency determined by the piezoelectric substrate material properties and thickness. When bonding of the target occurs on theZnO nanotips 12, mass-loading results with a shift in the resonance frequency of the resonator, directly proportional to the amount of target material bonded to theZnO nanotips 12. - In a further embodiment of the ZnO nanotip
BAW sensor 50, the crystal resonator ofFIG. 5 can be replaced with a thin film resonator structure, including, but not limited to, air gap resonators, solidly mounted resonators and membrane (Film Bulk Acoustic Resonator or FBAR) resonators. The thin film resonator structure includes, but not limited to, an air-gap structure on top surface of the substrate, a membrane structure on the substrate and an acoustic mirror on top surface of the substrate. - In a further embodiment of the present invention, there is disclosed a biochip consisting of ZnO nanotip array as biosensors to simultaneously detect a number of different biological information. For certain clinical and scientific applications it is desirable to use multiple biosensors on a chip for simultaneous detection of several biomolecular targets. For this purpose a biosensor chip having multiple detection units for different targets. As described above, both types of biosensor devices with 1D or 2D arrays on a chip can be fabricated through regular microelectronics fabrication processes.
- The current invention presents a new biochemical sensor technology with high 20 sensitivity and multimodal operation capability. The
sharp ZnO nanotips 12 on four type devices, as discussed above, provide the favorable binding sites to enhance the immobilization, and increase the effective sensing area, therefore, improve the sensing and detection efficiency. - The changes in electrical conductivity, or/and optical absorption, or/and fluorescence in conductive and semiconductive ZnO nanotips will be used to sense the targeted biochemical reactions. The ZnO nanotip SAW or BAW sensors possess both the advantages of SAW or BAW, and nanostructured biosensors.
- The ZnO biosensors described above are used to detect RNA-DNA, DNA-DNA, protein-protein, protein-DNA, and protein-small molecule interactions taking advantage of the enhancement of immobilization of DNA, protein molecules on the ZnO nanotips. The optimum immobilization conditions can be used for the biosensors to further enhance their sensitivities and specify the target molecules.
- For DNA immobilization, a solution of avidin is applied to the clean surface of
ZnO nanotips 12, and then biotinylated oligonucleotide will be attached to the modified nanostructured surface as disclosed by G. Marrazza, I. Chianella, and M. Mascini, “Disposable DNA electrochemical sensor for hybridization detection”, Biosens Bioelectron. 14, 43 (1999). The modified nanostructured surface includes theZnO surface 12 initially coated with Cr, Ti, etc., to help the subsequent Au layer wet the surface. The Au film is then deposited and modified with thiol/dextran, which in turn will allow the covalent attachment of avidin as disclosed by S. Tombelli, M. Mascini, L. Braccini, M. Anichini, and A. P. Turner, “Coupling of a DNA piezoelectric biosensor and polymerase chain reaction to detect apolipoprotein E polymorphisms”, Biosens Bioelectron. 15, 363 (2000). Thiolated DNA oligonucleotides are covalently attached to mercaptosilane-derivatised surface via succinimidyl 4-[malemido-phenyl]butyrate (SMPB) crosslinker as disclosed by T. A. Taton, C. A. Mirkin, and R. L. Letsinge, “Scanometric DNA array detection with nanoparticle probes”, Science 289, 1757 (2000) and L. A. Chrisey, G. U. Lee, and C. E. O'Ferrall, “Covalent attachment of synthetic DNA to self-assembled monolayer films”, Nucleic Acids Res. 24, 3031 (1996). The Thiolated DNA oligonucleotides can serve as the biological recognition elements which recognize the analytes. - For testing the efficiency of DNA immobilization procedures, model oligonucleotides with a radioisotope/fluorescent label are preferably used. For testing and calibration of DNA/RNA ZnO nanotip biosensors, a series of complementary pairs of oligonucleotides (20 and 50 nucleotides in length) which are 30, 50 and 70% GC-reach are synthesized having different percents of complementarity (from no to several mismatches). Basically, preferably light with a particular wavelength (λ) is passed through the
transparent ZnO nanotip 12 and one member of each pair of oligonucleotides is immobilized on a surface ofZnO biosensor 10 and the device is tested in a series of hybridization experiments with the corresponding targets. Different hybridization conditions, as well as different RNA targets are evaluated. These targets may preferably be labeled. As an example of the practical application two sets of experiments are conducted with specific targets. One such target is detection of cold-shock inducible cspA mRNA from E. coli. Some major advances in understanding of the regulatory mechanisms of cspA expression have been made as disclosed by S. Phadtare, J. Alsina, and M. Inouye, “Cold-shock response and cold-shock proteins”, Curr Opin Microbiol. 2, 175 (1999). Another is detection of mutations in the BRCA1 gene. This gene is responsible for 40% of breast cancer cases and 80% of breast-ovarian cancer cases as disclosed by M. O. Nicoletto, M. Donach, A. D. Nicolo, G. Artioli, G. Banna, and S. Monfardini, “BRCA-1 and BRCA-2 mutations as prognostic factors in clinical practice and genetic counseling”, Cancer Treat. Rev. 27, 295 (2001). We preferably use oligonucleotides complementary to the 185delAG and 188del11 mutations of the gene, which are the most common in all reported cases as disclosed by D. Tong, M. Stimpfl, A. Reinthaller, N. Vavra, S. Mullauer-Ertl, S. Leodolter, and R. Zeillinger, “BRCA1 gene mutations in sporadic ovarian carcinomas: detection by PCR and reverse allele specific oligonucleotide hybridization”, Clin. Chem. 45, 976 (1999). So, if we see binding, i.e. we get a signal such as fluorescent light, we know that patient's DNA strength hits breast cancer mutation. - For protein immobilization, strategies similar to those of DNA are used. As mentioned above, proteins may have strong affinity to
ZnO surface 12. The Au coated ZnO surface is modified with thiol/dextran and activated by N-hydroxysuccinimide and N-(3-dimethylaminopropyl)-N-ethylcarbodiimide allowing covalent attachment of the protein as disclosed by N. Barie and M. Rapp, “Covalent bound sensing layers on surface acoustic wave (SAW) biosensors”,Biosens Bioelectron 16, 979 (2001). TheZnO surface 12 will be precoated with polyethylenimine and the protein will be crosslinked to the surface via glutaraldehyde as disclosed by J. Ye, S. V. Letcher, and A. G. Rand, “Piezoelectric biosensor for the detection of Salmonella typhimurium”, J. Food. Sci. 62, 1067 (1997). Also bromocyano-immobilization will be preferably modified in which the shilding layer (polyimide or polystyrene) will be first loaded on theZnO surface 12, following CNBr activation and coupling the protein as disclosed by T. Wessa, M. Rapp, and H. J. Ache, “New immobilization method for SAW-biosensors: covalent attachment of antibodies via CNBr”,Biosens Bioelectron 14, 93 (1999). - In another case, for protein immobilization, a histidine kinase called EnvZ was used. The protein was first phosphorylated with }-[32P] ATP and solution of 32P-labled EnvZ was loaded on the nanotips grown on a square glass plate (5×5 mm). After incubation for 90 minutes, plates were washed extensively at room temperature by changing the washing buffer solution five times. The radioactivity of the plate was then measured. More than 90% of the protein was retained on the surface, indicating a strong affinity of the protein to the ZnO surface. It was also found that EnvZ attached on the nanotip surface retained its biochemical property, as approximately 80% of 32P radioactivity was released when the plate was incubated in a solution containing OmpR, an EnvZ substrate, but no radioactivity was released in the presence of other proteins. This model system is preferably used for analysis of protein-protein interactions via optical techniques, since EnvZ forms a stoichiometric complex with OmpR.
- Fluorescence resonance energy transfer (FRET) is a quantum mechanical process wherein excitation energy is transferred from a donor fluorophore to an appropriately positioned acceptor positioned acceptor fluorophore without emission of a photon. Energy can be transferred this way only over a very limited distance, and the efficiency of the energy transfer varies inversely with the sixth power of the distance separating the donor and acceptor. One of the most important uses of FRET spectroscopy is to study protein-protein interactions.
- For testing protein immobilization in addition of a histidine kinase we use preferably as a model, calmodulin (CaM) fused with two mutant proteins, CFP (a mutant of green fluorescent protein, GFP; cyan fluorescent protein) at the N-terminal end and YFP (another mutant of GFP; yellow fluorescent protein) at the C-terminal end as disclosed by A. Miyawaki, J. Llopis, R. Heim, J. M. McCaffery, J. A. Adams, M. Ikura, and R. Y. Tsien, “Fluorescent indicators for Ca2+ based on green fluorescent proteins and calmodulin”, Nature 388, 882 (1997). This allows us to easily determine concentration of the protein by measurement of fluorescent intensity. Moreover, CaM protein is termed “cameleon”, since it responds to Ca++ causing FRET (fluorescent resonance energy transfer) as mentioned above. It is critical to observe whether Ca++ is close enough to calmodulin (CaM), in order for them to interact. Again, preferably light with a particular λ (i.e. light capable of exciting the GFP) is passed through
transparent ZnO nanotip 12. If the green fluorescent protein fluoresces at its characteristic λ, there is no protein interaction since the protein distance is greater than a specific amount and therefore no FRET occurs. However, if the calmodulin and Ca++ are close enough (within FRET proximity) to interact, the GFP is excited but does not emit a photon. Preferably, a sensitized emission from Ca++ occurs, so FRET occurs. The effect can be monitored directly on theZnO sensor 10. Since the ZnO film is transparent, the cameleon-bound ZnO film can be excited from the bottom and the intensity of the emission spectra recorded. The use of cameleons allows us to evaluate theZnO sensor 10 performance preferably by two mechanisms such as electrical (conductivity) and optical (fluorescence), or acoustic (SAW) and optical (fluorescence). The FRET method monitors real-time protein-protein interaction and/or conformational changes. Therefore, the comparison of our acoustic wave/conductivity measurements with FRET data helps to evaluate signal responsiveness. - The ZnO DNA and protein nanotip array based sensors in this application will further benefit to explore genome-wide gene expression for molecular diagnostics, drug target discovery, and validation of drug effects. The ZnO nanotip-based biosensors can also be applied to development of new methods for the prevention, diagnosis and treatment of diseases. Furthermore, the application of ZnO and its nanostructure-based biosensors can be extended to detection of toxic biochemical agents and hazardous chemicals against bioterrorism and environmental monitoring and protection. Unlike other sensor technologies, ZnO biosensors can operate in multimodes due to its multifunctional material properties (semiconductor, piezoelectric, transparent and conductive, etc.). Nanotips made from ZnO and its ternary compound can be used for UV absorption and fluorescence detection. ZnO nanotip arrays can be highly dense for diagnostic kits and flow-through systems, including ZnO UV biotesting bench (containing emitters, detectors, modulators, and filters), gene chip, lab-on-a chip and living-cell chip.
- While the invention has been described in relation to the preferred embodiments with several examples, it will be understood by those skilled in the art that various changes may be made without deviating from the fundamental nature and scope of the invention as defined in the appended claims.
Claims (18)
1. A method for detecting biological molecules comprising:
providing a conductivity mode ZnO nanotip biosensor including ZnO nanotips having binding sites including at least one biological probe;
exposing said binding site to a sample having a potential target molecule;
detecting a change in conductivity in said ZnO nanotips, wherein said change in conductivity being indicative of a chemical and biochemical reaction of the potential target molecule and the biological probe.
2. The method of claim 1 wherein said ZnO nanotips serve for immobilization of DNA or protein molecules to enhance detection of the corresponding targeted DNA, protein or small biomolecules.
3. The method of claim 2 wherein surface charge of the tips changes due to a biological and biochemical reaction of the immobilized DNA, protein molecules or small biomolecules on the ZnO nanotips with the corresponding targeted DNA or protein molecules.
4. The method of claim 1 wherein said biosensor operates in multiple modes due to multifunctional material properties of the ZnO nanotips such as semiconducting, piezoelectric, or transparent and combinations thereof.
5. A method for detecting biological molecules comprising:
providing a semiconductor FET biosensor including ZnO nanotips having binding sites including at least one biological probe wherein said ZnO nanotips are deposited on gate region of the FET;
exposing said binding site to a sample having a potential target molecule;
detecting a change in conductivity in said ZnO nanotips, wherein said change in conductivity being indicative of a chemical and biochemical reaction of the potential target molecule and the biological probe.
6. The method of claim 5 wherein said ZnO nanotips serve as DNA or protein molecule binding sites to detect presence of the DNA, protein molecules or small biomolecules to be targeted.
7. The method of claim 6 wherein upon said detection of the targeted molecules, a change occurs in the surface charge of the ZnO nanotip-gate resulting in a change in the channel conductance.
8. The method of claim 5 wherein said FET biosensor includes Si MOSFET.
9. The method of claim 5 wherein said FET biosensor includes GAs MESFET.
10. A method for detecting biological molecules comprising:
providing a ZnO based SAW sensor including ZnO nanotips having binding sites including at least one biological probe;
exposing said binding site to a sample having a potential target molecule;
detecting a decrease in phase velocity under said ZnO nanotips, wherein said decrease in phase velocity being indicative of a chemical and biochemical reaction of the potential target molecule and the biological probe.
11. The method of claim 10 wherein upon binding of the targeted molecules with said ZnO nanotips causes a mass loading on a SAW path resulting in said decrease of phase velocity under said ZnO nanotips.
12. The method of claim 10 wherein said ZnO nanotips serve as DNA, protein molecule or small biomolecule binding sites.
13. The method of claim 12 wherein said ZnO nanotips enhance binding strength and immobilization of the targeted DNA, protein molecules or small biomolecules.
14. A method for detecting biological molecules comprising:
providing a ZnO based SAW sensor including ZnO nanotips having binding sites including at least one biological probe;
exposing said binding site to a sample having a potential target molecule;
detecting a change in UV absorption, wherein said change in UV absorption being indicative of a chemical and biochemical reaction of the potential target molecule and the biological probe.
15. The method of claim 14 wherein said ZnO nanotips serve as DNA, protein molecule or small biomolecule binding sides.
16. The method of claim 15 further includes illuminating UV light on said sensor and the change in UV absorption is detectable due to a biological and biochemical reaction of sensor layer of immobilized DNA, protein molecules on the ZnO nanotips with targeted DNA, protein molecules or small biomolecules.
17. A method for detecting biological molecules comprising:
providing a ZnO based BAW sensor including ZnO nanotips having binding sites including at least one biological probe;
exposing said binding site to a sample having a potential target molecule;
detecting a change in resonance frequency of the sensor, wherein said change in resonance frequency being indicative of a chemical and biochemical reaction of the potential target molecule and the biological probe.
18. The method of claim 17 wherein upon binding of the targeted molecules with immobilized biomolecules on said ZnO nanotips causes a mass loading on the BAW resulting in the change in the resonance frequency of the sensor.
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Also Published As
Publication number | Publication date |
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AU2003240561A8 (en) | 2003-12-22 |
AU2003240561A1 (en) | 2003-12-22 |
US20050116263A1 (en) | 2005-06-02 |
US6914279B2 (en) | 2005-07-05 |
WO2003104789A1 (en) | 2003-12-18 |
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