Electricity: measuring and testing – Impedance – admittance or other quantities representative of... – Lumped type parameters
Reexamination Certificate
2001-12-13
2004-12-07
Deb, Anjan (Department: 2858)
Electricity: measuring and testing
Impedance, admittance or other quantities representative of...
Lumped type parameters
C324S660000, C324S661000
Reexamination Certificate
active
06828800
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates to single molecule detectors, methods of manufacturing same and methods of detecting single molecules using same. More particularly, the present invention relates to detectors suited for detecting the presence, motion and/or length of one or more molecules, methods of manufacturing same and methods of detecting the presence, motion and/or length of one or more molecules at a resolution, as high as, a nanometer resolution.
Single-molecule experimental techniques provide fascinating possibilities for studying systems in which molecular individuality matters. This is particularly true when the molecule forms a part of a complex environment which substantially affects its behavior, or when the molecule itself has an intricate internal structure resulting in a complex energy landscape. Because single-molecule experiments offer unique information on macromolecular interactions and chemical dynamics, unattainable by ensemble-averaged measurements, such experiments have had a remarkable impact on many scientific and technological disciplines. Single molecule studies on biological systems have already yielded important information relevant to problems that involve macromolecular motion and confirmational dynamics, photo biology, protein folding and enzyme mechanics. Undoubtedly, single-molecule studies will remain central to the biological sciences in years to come.
Single-molecule studies, as oppose to ensemble-based experiments, refer to a class of measurements where the behavior of individual molecules is followed. One advantage of such studies is the ability to determine the distribution of molecular properties by conducting many sequential measurements, hence affording the investigation of inhomogeneous systems. Another advantage of single-molecule studies is that single-molecule trajectories are direct records of the system's fluctuations, and as such they provide dynamical and statistical information that is hidden in ensemble-averaged results. In addition, single-molecule measurements permit real-time observation of rarely populated transients, which are otherwise difficult or impossible to capture using conventional methods.
Several basic experimental approaches and their derivatives, which allow for single-molecule experiments, are known in the art. These include scanning force microscopy (SFM), optical trapping and optical microscopy and spectroscopy. SFM and optical trapping require that an external, time-varying load be applied to the substrate to enable measurement. Although SFM may be used as an imaging tool, its functionality as such is slow. Furthermore, when used as a force sensor, SFM can reliably probe motions only parallel to the scanning tip, whereas other motions cannot be detected effectively. In addition, when used as a characterization tool, SFM has a low throughput and requires highly trained personal.
Optical techniques are comparatively fast allowing the recording of molecular trajectories down to the 10-100 millisecond time-scales, and can achieve center-position accuracy of a few nanometers.
One optical technique of single molecule detection is based on flow cytometry, where an analyte solution is delivered into a rapidly flowing sheath fluid and hydrodynamically focused into a narrow sample stream. Another approach is based on analyte movement through a capillary. In flow cytometry, a sample stream passes through the center of a probe volume defined by the diameter of the focused excitation laser beam and a spatial filter placed in the image plane of a light collecting objective. Single fluorescent molecules are detected by the bursts of photons emitted as they flow through the detection volume one-at-a-time. However, focused laser beams, can generate a notable trapping potential for sizable molecules, which may affect the accuracy of the measurements. More important since these techniques rely heavily on fluorescence, they are prone to a number of photoinduced artifacts, such as triplet trapping and photobleaching. The latter dictates that observation times have to be short. Furthermore, extracting data from fluorescent and optical trapping techniques often requires complex image analysis.
Electrostatic, or capacitive, sensing is one of the most important and oldest precision sensing mechanisms. Macroscopic capacitive sensors and transducers of many shapes have been implemented. They are used for liquid level sensing, touch sensing, key switches, light switches and proximity detection.
Electret microphones implemented in telephones and tape recorders use capacitive sensing, as do Silicone accelerometers that deploy the air bag in a car. A key feature of capacitive sensors is their ability to detect the presence of material at a distance through variation in the dielectric constant. Some of the advantages of capacitive sensors are their sensitivity, accuracy and temperature stability. Furthermore, capacitive sensors are less noisy than resistive sensors and consume very little power.
On the microscopic level, the use of capacitive sensors is increasing rapidly. Use of microscopic level capacitive sensing are known in the art, for example Sohn, L. L., Saleh, O. A., Facer, G. R., Beavis, A. J., Allan, R. S. and Notterman, D. A., PNAS 97, 10687-10690 (2000), disclosed a devise intended to measure dielectric constant using a parallel plate capacitor. However, the device disclosed by Sohn et. al. fails to have any sensitivity to position. In addition, the resolution of this device is limited by the physical size of the device, hence it lacks the capability of a single molecule detection.
Capacitive sensors capable of single molecule detection have not yet been described in the art.
There is thus a widely recognized need for, and it would be highly advantageous to have, a single molecule detector and a method of detecting a single molecule, based on capacitive sensing.
SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a detector, for determining presence, number, length concentration, position and/or motion of at least one particle present in a fluid and having a dielectric coefficient other than a dielectric coefficient of the fluid, the detector comprising: (a) a capacitor, comprising a first conductive plate and a second conductive plate defining an inter-plate volume having a longitudinal axis; and (b) at least two electrical contacts, connecting each of the first and second conductive plates to a capacitance measuring device; the capacitor being characterized by at least one variable parameter so as to allow determination and/or monitoring of presence, number, length concentration, position and/or at least one motion characteristic of the at least one particle placed within the inter-plate volume of the capacitor.
According to another aspect of the present invention there is provided A motion detection method comprising placing at least one particle present in a fluid and having a dielectric coefficient other than a dielectric coefficient of the fluid, within an inter-plate volume of a capacitor, being characterized by at least one variable parameter, and determining and/or monitoring presence, number, length concentration, longitudinal position and/or at least one motion characteristic of the at least one conductive particle, by determining a change in capacitance of the capacitor.
According to yet another aspect of the present invention there is provided a particle presence, number, length or concentration detector comprising; (a) a capacitor, comprising a first conductive plate and a second conductive plate substantially parallel to the first conductive plate, the first and second conductive plates defining an interplate volume having a longitudinal axis; and (b) at least two electrical contacts, connecting each of the first and second conductive plates to a capacitance measuring device; the capacitor being designed and constructed for allowing a determination of a presence, number or concentration of particles placed within the inter-pla
Kapon Ruti
Reich Ziv
Shahar Dan
Benson Walter
Deb Anjan
G. E. Ehrlich (1995) Ltd.
Yeda Research and Development Co. Ltd.
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