Temperature regulation of measurement arrays

Information

  • Patent Grant
  • 9110478
  • Patent Number
    9,110,478
  • Date Filed
    Tuesday, October 18, 2011
    13 years ago
  • Date Issued
    Tuesday, August 18, 2015
    9 years ago
  • CPC
  • Field of Search
    • US
    • 422 068100
    • 422 082010
    • 422 082120
    • 422 407000
    • 422 551000
    • 422 552000
    • 422 560000
    • 422 109000
    • CPC
    • G05D23/2026
    • G05D23/2029
    • G05D23/2034
  • International Classifications
    • G05D23/00
    • G05D23/20
    • Term Extension
      474
Abstract
A system for regulating a temperature of a measurement array is disclosed. The system includes a measurement array including a plurality of sensors, wherein the plurality of sensors are integrated onto an integrated circuit die. The system includes a thermal sensor integrated onto the integrated circuit die, wherein the thermal sensor senses a temperature associated with the plurality of sensors. The system further includes a heat pump coupled to the integrated circuit die, wherein the heat pump is controlled by a feedback control circuit including the thermal sensor.
Description
BACKGROUND OF THE INVENTION

Advances in micro-miniaturization within the semiconductor industry in recent years have enabled biotechnologists to begin packing their traditionally bulky sensing tools into smaller and smaller form factors, onto so-called biochips. It would be desirable to develop techniques for biochips.





BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the invention are disclosed in the following detailed description and the accompanying drawings.



FIG. 1 is a diagram illustrating the short time duration variability in the temperature in a biochemical measurement array in which a bang-bang temperature control mechanism is used.



FIG. 2A is a diagram illustrating the top view of a biochemical measurement chip 200.



FIG. 2B is a diagram illustrating the side view of the same biochemical measurement chip as shown in FIG. 2A.



FIG. 2C is a diagram illustrating an embodiment of a temperature regulating system for the biochemical measurement chip 200 as shown in FIGS. 2A and 2B.



FIG. 3 is a diagram illustrating an embodiment of a linear feedback control circuit 300 for driving Peltier device 214 in FIG. 2C.



FIG. 4 is a diagram illustrating a thermal model for temperature regulating system 220.





DETAILED DESCRIPTION

The invention can be implemented in numerous ways, including as a process; an apparatus; a system; a composition of matter; a computer program product embodied on a computer readable storage medium; and/or a processor, such as a processor configured to execute instructions stored on and/or provided by a memory coupled to the processor. In this specification, these implementations, or any other form that the invention may take, may be referred to as techniques. In general, the order of the steps of disclosed processes may be altered within the scope of the invention. Unless stated otherwise, a component such as a processor or a memory described as being configured to perform a task may be implemented as a general component that is temporarily configured to perform the task at a given time or a specific component that is manufactured to perform the task. As used herein, the term ‘processor’ refers to one or more devices, circuits, and/or processing cores configured to process data, such as computer program instructions.


In various embodiments, the techniques described herein are implemented in a variety of systems or forms. In some embodiments, the techniques are implemented in hardware as an application-specific integrated circuit (ASIC) or a field-programmable gate array (FPGA). In some embodiments, a processor (e.g., an embedded one such as an ARM core) is used where the processor is provided or loaded with instructions to perform the techniques described herein. In some embodiments, the technique is implemented as a computer program product which is embodied in a computer readable storage medium and comprises computer instructions.


A detailed description of one or more embodiments of the invention is provided below along with accompanying figures that illustrate the principles of the invention. The invention is described in connection with such embodiments, but the invention is not limited to any embodiment. The scope of the invention is limited only by the claims and the invention encompasses numerous alternatives, modifications and equivalents. Numerous specific details are set forth in the following description in order to provide a thorough understanding of the invention. These details are provided for the purpose of example and the invention may be practiced according to the claims without some or all of these specific details. For the purpose of clarity, technical material that is known in the technical fields related to the invention has not been described in detail so that the invention is not unnecessarily obscured.


Biochemical sensors are devices that can measure a variable biochemical quantity and transform the measurement into output signals, e.g., an electrical signal or a light signal, according to certain rules. Biochemical sensors may be electrochemical sensors or optical sensors. Biochemical sensors may be employed in a variety of applications; for example, they may be used for nucleotide sequencing, medical diagnosis, patient monitoring, and the like.


A nanopore array is one example of measurement arrays that use biochemical sensors for biochemical measurements. A nanopore array for nucleotide sequencing may contain thousands or millions of single cells or measurement sites. Each cell contains a nanopore, which is a small hole in an electrically insulating membrane that can be used as a single-molecule sensor. A nanopore may be formed using a biological material, such as α-hemolysin or MspA. A nanopore may be formed using a solid-state material, such as a semiconductor material. When a small voltage is applied across a nanopore, an ionic current through the nanopore can be measured to provide information about the structure of a molecule transiting the nanopore. In a single cell of a nanopore array, an electrical circuit may be used for controlling the electrical stimulus applied across a lipid bilayer which contains the nanopore, and for sensing the electrical patterns, or signatures, of a molecule passing through the nanopore.


In some applications, biochemical measurement arrays may be used to take precise biochemical measurements; however, their performance can be affected by the temperature at the site of the measurements. Typically, biochemical sensors are mounted on, or are an integral part of, an integrated circuit. Since the measurements made by the biochemical sensors are taken directly from the surface of integrated circuits which may produce heat, the accuracy and variability of the temperature at the site of the measurements need to be carefully controlled; otherwise, performance degradation will result.


Temperature regulation of biochemical measurement arrays is challenging for several reasons. Transducing temperature at the exact point of biochemical measurements is difficult. Furthermore, any temperature difference between the point of thermal measurement and the point of biochemical measurement will translate into errors in regulating the temperature at the point of biochemical measurement.


In some temperature regulation schemes, a bang-bang control mechanism is employed. A bang-bang controller is a feedback controller that switches abruptly between two states. For example, a cooling or heating element is turned either full on or full off, without being run at any intermediate levels. This technique simplifies the temperature regulation circuitry, but introduces short time duration variability (ripples) in the temperature at the site of the biochemical measurements.



FIG. 1 is a diagram illustrating the short time duration variability in the temperature in a biochemical measurement array in which a bang-bang temperature control mechanism is used. As shown in FIG. 1, these ripples may fluctuate in a temperature range in excess of half a degree centigrade over a period that lasts from milli-seconds to minutes. However, in order to achieve precise control of the temperature at the site of the biochemical measurements, the temperature fluctuation should be much less than half a degree centigrade over all time scales.



FIG. 2A is a diagram illustrating the top view of a biochemical measurement chip 200. FIG. 2B is a diagram illustrating the side view of the same biochemical measurement chip as shown in FIG. 2A. With reference to FIG. 2A and FIG. 2B, a biochemical measurement array 202 is located in the central region of the top surface of an integrated circuit die 204. The biochemical measurement array 202 has multiple columns and rows of biochemical measurement sites. A plurality of bonding pads situated at the peripheral of integrated circuit die 204, are electrical contacts for communicating with the biochemical measurement array 202. A reservoir 208 may be mounted on integrated circuit die 204 to hold a liquid which covers the surface of biochemical measurement array 202. The liquid which covers the surface of biochemical measurement array 202 may be introduced through a channel 210.



FIG. 2C is a diagram illustrating an embodiment of a temperature regulating system 220 for the biochemical measurement chip 200 depicted in FIGS. 2A and 2B. The biochemical measurement chip 200 is mounted on a thermally conductive material 212. A first side 214A of a Peltier device 214 is mounted on the bottom surface of integrated circuit die 204. A second side 214B of Peltier device 214 is mounted on a convection heat sink 216, which may include pin-fins 218. A Peltier device, also known as a Peltier heat pump, solid state refrigerator, or thermoelectric cooler (TEC), is a solid-state, active heat pump which transfers heat from one side of the device to the other side against the temperature gradient (from cold to hot), with consumption of energy. When DC current runs through a Peltier device, heat is removed from one side to the other. Therefore, a Peltier device can be used either for heating or for cooling, and it can also be used as a temperature controller that either heats or cools.


In some embodiments, the first side 214A of Peltier device 214 has a surface large enough to cover the entire bottom surface of integrated circuit die 204 or the entire biochemical measurement array 202, such that the temperature of the entire integrated circuit die 204 or the entire biochemical measurement array 202 can be maintained at a predetermined operating temperature. In some embodiments, the predetermined operating temperature is configurable and is selected from a plurality of operating temperatures.



FIG. 3 is a diagram illustrating an embodiment of a linear feedback control circuit 300 for driving Peltier device 214 in FIG. 2C. As shown in FIG. 3, a thermal measurement transistor 302 (e.g., a diode connected transistor) is coupled with an amplifier 304. The output of amplifier 304 is fed as an input to a thermoelectric cooler controller chip 306 (e.g., LTC1923 from Linear Technology), and the output of thermoelectric cooler controller chip 306 is used to drive Peltier device 214.


Typically, a biochemical measurement chip may include as many as one million biochemical measurement sites. Since each biochemical measurement site may consume as much as 3.3 μW (1 μA at 3.3 V), a total of 3.3 W may be consumed by the entire biochemical measurement chip. In the absence of temperature regulating system 220, which efficiently pumps heat away from the die, the power consumed by the circuitry of the biochemical measurement chip may cause the die to overheat.


With reference to FIG. 2B and FIG. 3, the thermal measurement transistor 302 is integrated into die 204. The advantage of integrating thermal measurement transistor 302 into die 204 is that direct measurements of the die temperature can thereby be made. As described above, heat is generated within the die itself. If the thermal measurement transistor is external to the die, the thermal resistance between the die and the thermal measurement transistor will increase, causing a large thermal gradient to be established across the distance between the die and the thermal measurement transistor. Consequently, an accurate measurement of the temperature of the die cannot be made. Note that in some embodiments, more than one thermal measurement transistor 302 can be integrated into die 204. The example with a single thermal measurement transistor 302 is provided for illustration purposes only; accordingly, the present application is not limited to this specific example only: the temperature sensor could be a transistor, a diode, a temperature-sensitive resistor or other temperature sensitive device included on the die.


The temperature regulating system 220 as described in the present application provides an asymptotically Lyapunov stable linear control loop for regulating the temperature of biochemical measurement chip 200. In particular, the mechanical arrangement of the various components in temperature regulating system 220 ensures that the system thermal time constants are asymptotically Lyapunov stable.



FIG. 4 is a diagram illustrating a thermal model for temperature regulating system 220. In FIG. 4, “R” denotes thermal resistance (in Kelvins/Watt). For example, Rdie-ambient ambient is the thermal resistance between die 204 and the ambient air surrounding the die. “C” denotes thermal capacitance (in Joules/Kelvin), and “T” denotes temperature (in Kelvin) at a specific location. In order to achieve closed loop stability, the thermal capacitance C and thermal resistance R for various components satisfy a set of criteria as shown at the bottom of FIG. 4. In particular, the thermal capacitance of convection heat sink 216 should be several times larger (e.g., ten times larger) than the thermal capacitance of Peltier device 214 and the thermal capacitance of die 204. The thermal resistance between the die and the ambient air surrounding the die, Rdie-ambient, should be several times (e.g., ten times larger) larger than Rambient-sink, Rsink-peltier, and Rpeltier-die.


Although the foregoing embodiments have been described in some detail for purposes of clarity of understanding, the invention is not limited to the details provided. There are many alternative ways of implementing the invention. The disclosed embodiments are illustrative and not restrictive.

Claims
  • 1. A system for regulating a temperature of a measurement array, comprising: a measurement array including a plurality of sensors, wherein the plurality of sensors are integrated onto an integrated circuit die;a thermal sensor integrated onto the integrated circuit die, wherein the thermal sensor senses a temperature associated with the plurality of sensors; anda heat pump coupled to the integrated circuit die and coupled to a heat sink, wherein the heat pump is controlled by a feedback control circuit including the thermal sensor; wherein the feedback control circuit includes an amplifier coupled to the thermal sensor and further includes a thermoelectric controller; andwherein thermal behaviors of the system are represented by a thermal model including a plurality of thermal parameters, wherein the thermal parameters comprise thermal resistances and thermal capacitances measured with respect to a plurality of components of the system, including the heat pump, the heat sink, and the integrated circuit die, and wherein the system forms an asymptotically Lyapunov stable linear control loop based at least in part on satisfying a plurality of relationships between two thermal parameters associated with the thermal model, the plurality of relationships comprising:a thermal capacitance associated with the heat sink is substantially larger than a thermal capacitance associated with the heat pump; anda thermal capacitance associated with the heat sink is substantially larger than a thermal capacitance associated with the integrated circuit die.
  • 2. The system of claim 1, wherein the measurement array comprises a biochemical measurement array, and wherein each of the plurality of sensors comprises a biochemical sensor.
  • 3. The system of claim 1, wherein the feedback control circuit is configured to maintain the temperature associated with the plurality of sensors at a predetermined temperature, and wherein the predetermined temperature is configurable.
  • 4. The system of claim 1, wherein sensing the temperature associated with the plurality of sensors comprises sensing a temperature associated with the integrated circuit die.
  • 5. The system of claim 1, wherein the heat pump comprises a Peltier heat pump.
  • 6. The system of claim 1, wherein the heat pump includes a first surface in contact with the integrated circuit die and a second surface in contact with the heat sink, and wherein heat is transferred from one surface to another.
  • 7. The system of claim 1, wherein the feedback control circuit is configured as a linear feedback control circuit.
  • 8. The system of claim 1, wherein the plurality of relationships comprises a relationship between a first thermal resistance and a second thermal resistance, and wherein the first thermal resistance comprises a thermal resistance between the integrated circuit die and ambient air surrounding the integrated circuit die, and wherein the second thermal resistance comprises a thermal resistance between the heat sink and ambient air surrounding the heat sink.
  • 9. The system of claim 8, wherein the first thermal resistance is substantially larger than the second thermal resistance.
  • 10. The system of claim 1, wherein the plurality of relationships comprises a relationship between a first thermal resistance and a second thermal resistance, and wherein the first thermal resistance comprises a thermal resistance between the integrated circuit die and ambient air surrounding the integrated circuit die, and wherein the second thermal resistance comprises a thermal resistance between the heat sink and the heat pump.
  • 11. The system of claim 10, wherein the first thermal resistance is substantially larger than the second thermal resistance.
  • 12. The system of claim 1, wherein the plurality of relationships comprises a relationship between a first thermal resistance and a second thermal resistance, and wherein the first thermal resistance comprises a thermal resistance between the integrated circuit die and ambient air surrounding the integrated circuit die, and wherein the second thermal resistance comprises a thermal resistance between the heat pump and the integrated circuit die.
  • 13. The system of claim 12, wherein the first thermal resistance is substantially larger than the second thermal resistance.
  • 14. The system of claim 1, wherein the thermal sensor includes one of the following: a thermal transistor, diode, or other on-chip temperature sensor.
  • 15. The system of claim 1, wherein the feedback control circuit is configured as a bang-bang control circuit.
CROSS REFERENCE TO OTHER APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 61/436,948 entitled TEMPERATURE REGULATION OF BIOCHEMICAL MEASUREMENT ARRAYS filed Jan. 27, 2011 which is incorporated herein by reference for all purposes.

US Referenced Citations (186)
Number Name Date Kind
2656508 Coulter Oct 1953 A
4121192 Wilson Oct 1978 A
4859945 Stokar Aug 1989 A
5198543 Blanco et al. Mar 1993 A
5302509 Cheeseman Apr 1994 A
5308539 Koden et al. May 1994 A
5457342 Herbst, II Oct 1995 A
5569950 Lewis et al. Oct 1996 A
5576204 Blanco et al. Nov 1996 A
5756355 Lang et al. May 1998 A
5770367 Southern et al. Jun 1998 A
5795782 Church et al. Aug 1998 A
5804386 Ju Sep 1998 A
5814454 Ju Sep 1998 A
5869244 Martin et al. Feb 1999 A
5876936 Ju Mar 1999 A
5912155 Chatterjee et al. Jun 1999 A
5939301 Hughes, Jr. et al. Aug 1999 A
5952180 Ju Sep 1999 A
6012291 Ema Jan 2000 A
6014213 Waterhouse et al. Jan 2000 A
6015714 Baldarelli et al. Jan 2000 A
6046005 Ju et al. Apr 2000 A
6082115 Strnad Jul 2000 A
6210896 Chan Apr 2001 B1
6217731 Kane et al. Apr 2001 B1
6232103 Short May 2001 B1
6255083 Williams Jul 2001 B1
6261797 Sorge et al. Jul 2001 B1
6265193 Brandis et al. Jul 2001 B1
6321101 Holmstrom Nov 2001 B1
6362002 Denison et al. Mar 2002 B1
6383749 Bochkariov et al. May 2002 B2
6399320 Markau et al. Jun 2002 B1
6399335 Kao et al. Jun 2002 B1
6413792 Sauer Jul 2002 B1
6485703 Cote et al. Nov 2002 B1
6607883 Frey et al. Aug 2003 B1
6616895 Dugas et al. Sep 2003 B2
6627748 Ju et al. Sep 2003 B1
6664079 Ju et al. Dec 2003 B2
6673615 Denison et al. Jan 2004 B2
6686997 Allen Feb 2004 B1
6699719 Yamazaki et al. Mar 2004 B2
6723513 Lexow Apr 2004 B2
6746594 Akeson et al. Jun 2004 B2
6762048 Williams Jul 2004 B2
6794177 Markau et al. Sep 2004 B2
6800933 Mathews et al. Oct 2004 B1
6824659 Bayley et al. Nov 2004 B2
6880346 Tseng et al. Apr 2005 B1
6891278 Muller et al. May 2005 B2
6916665 Bayley et al. Jul 2005 B2
6952651 Su Oct 2005 B2
7033762 Nelson et al. Apr 2006 B2
7041812 Kumar et al. May 2006 B2
7052839 Nelson et al. May 2006 B2
7057026 Barnes et al. Jun 2006 B2
7074597 Ju Jul 2006 B2
7153672 Eickbush et al. Dec 2006 B1
7189503 Akeson et al. Mar 2007 B2
7223541 Fuller et al. May 2007 B2
7229799 Williams Jun 2007 B2
7238485 Akeson et al. Jul 2007 B2
7244602 Frey et al. Jul 2007 B2
7279337 Zhu Oct 2007 B2
7321329 Tooyama et al. Jan 2008 B2
7368668 Ren et al. May 2008 B2
7405281 Xu et al. Jul 2008 B2
7446017 Liu et al. Nov 2008 B2
7452698 Sood et al. Nov 2008 B2
7622934 Hibbs et al. Nov 2009 B2
7625701 Williams et al. Dec 2009 B2
7626379 Peters et al. Dec 2009 B2
7710479 Nitta et al. May 2010 B2
7727722 Nelson et al. Jun 2010 B2
7745116 Williams Jun 2010 B2
7777013 Xu et al. Aug 2010 B2
7777505 White et al. Aug 2010 B2
7871777 Schneider et al. Jan 2011 B2
7897738 Brandis et al. Mar 2011 B2
7906371 Kim et al. Mar 2011 B2
7924335 Itakura et al. Apr 2011 B2
7939259 Kokoris et al. May 2011 B2
7939270 Holden et al. May 2011 B2
7947454 Akeson et al. May 2011 B2
7948015 Rothberg et al. May 2011 B2
7973146 Shen et al. Jul 2011 B2
7989928 Liao et al. Aug 2011 B2
8022511 Chiu et al. Sep 2011 B2
8058030 Smith et al. Nov 2011 B2
8058031 Xu et al. Nov 2011 B2
8133672 Bjornson et al. Mar 2012 B2
8137569 Harnack et al. Mar 2012 B2
8148516 Williams et al. Apr 2012 B2
8192961 Williams Jun 2012 B2
8252911 Bjornson et al. Aug 2012 B2
8257954 Clark et al. Sep 2012 B2
8324914 Chen et al. Dec 2012 B2
20020030044 Brown Mar 2002 A1
20030027140 Ju et al. Feb 2003 A1
20030054360 Gold et al. Mar 2003 A1
20030101006 Mansky et al. May 2003 A1
20030166282 Brown et al. Sep 2003 A1
20030198982 Seela et al. Oct 2003 A1
20040122335 Sackellares et al. Jun 2004 A1
20040185466 Ju et al. Sep 2004 A1
20050032081 Ju et al. Feb 2005 A1
20050091989 Leija et al. May 2005 A1
20050127035 Ling Jun 2005 A1
20050186576 Chan et al. Aug 2005 A1
20050208574 Bayley et al. Sep 2005 A1
20050221351 Ryu Oct 2005 A1
20050239134 Gorenstein et al. Oct 2005 A1
20060057565 Ju et al. Mar 2006 A1
20060105461 Tom-Moy et al. May 2006 A1
20060252038 Ju Nov 2006 A1
20060278992 Trezza et al. Dec 2006 A1
20070173731 Meka et al. Jul 2007 A1
20070190542 Ling et al. Aug 2007 A1
20070196846 Hanzel et al. Aug 2007 A1
20070275387 Ju Nov 2007 A1
20080101988 Kang et al. May 2008 A1
20080108082 Rank et al. May 2008 A1
20080199932 Hanzel et al. Aug 2008 A1
20080218184 White et al. Sep 2008 A1
20080221806 Bryant et al. Sep 2008 A1
20080286768 Lexow Nov 2008 A1
20080318245 Smirnov Dec 2008 A1
20090029477 Meller et al. Jan 2009 A1
20090066315 Hu et al. Mar 2009 A1
20090073293 Yaffe et al. Mar 2009 A1
20090087834 Lexow et al. Apr 2009 A1
20090099786 Oliver et al. Apr 2009 A1
20090102534 Schmid et al. Apr 2009 A1
20090136958 Gershow et al. May 2009 A1
20090167288 Reid et al. Jul 2009 A1
20090215050 Jenison Aug 2009 A1
20090269759 Menchen et al. Oct 2009 A1
20090298072 Ju Dec 2009 A1
20100025238 Gottlieb et al. Feb 2010 A1
20100025249 Polonsky et al. Feb 2010 A1
20100035260 Olasagasti et al. Feb 2010 A1
20100047802 Bjorson et al. Feb 2010 A1
20100072080 Karhanek et al. Mar 2010 A1
20100075328 Bjornson et al. Mar 2010 A1
20100075332 Patel et al. Mar 2010 A1
20100078777 Barth et al. Apr 2010 A1
20100092952 Ju et al. Apr 2010 A1
20100093555 Bjornson et al. Apr 2010 A1
20100121582 Pan et al. May 2010 A1
20100122907 Stanford et al. May 2010 A1
20100148126 Guanet et al. Jun 2010 A1
20100243449 Oliver Sep 2010 A1
20100261247 Hanzel et al. Oct 2010 A1
20100297644 Kokoris et al. Nov 2010 A1
20100301398 Rothberg et al. Dec 2010 A1
20100320094 White et al. Dec 2010 A1
20110005918 Akeson et al. Jan 2011 A1
20110053284 Meller et al. Mar 2011 A1
20110059505 Hanzel et al. Mar 2011 A1
20110165652 Hardin et al. Jul 2011 A1
20110168968 Yang et al. Jul 2011 A1
20110174625 Akeson et al. Jul 2011 A1
20110189659 Clark et al. Aug 2011 A1
20110192723 Chen et al. Aug 2011 A1
20110193249 Chen et al. Aug 2011 A1
20110193570 Chen et al. Aug 2011 A1
20110218414 Kamath et al. Sep 2011 A1
20110244447 Korlach Oct 2011 A1
20110287414 Chen et al. Nov 2011 A1
20120034602 Emig et al. Feb 2012 A1
20120040869 Meller et al. Feb 2012 A1
20120052188 Chen et al. Mar 2012 A1
20120094278 Akeson et al. Apr 2012 A1
20120094332 Lee et al. Apr 2012 A1
20120115736 Bjornson et al. May 2012 A1
20120160681 Davis et al. Jun 2012 A1
20120160687 Akeson et al. Jun 2012 A1
20120160688 Davis et al. Jun 2012 A1
20120187963 Chen Jul 2012 A1
20120188092 Chen Jul 2012 A1
20120262614 Chen Oct 2012 A1
20130015068 Chen et al. Jan 2013 A1
20130207205 Chen Aug 2013 A1
20130244340 Davis et al. Sep 2013 A1
Foreign Referenced Citations (29)
Number Date Country
9106678 May 1991 WO
9321340 Oct 1993 WO
9732999 Sep 1997 WO
9746704 Dec 1997 WO
0222883 Mar 2002 WO
0229003 Apr 2002 WO
0229003 Jul 2002 WO
02079519 Oct 2002 WO
2004007773 Jan 2004 WO
2004055160 Jul 2004 WO
2005084367 Aug 2004 WO
2006020775 Dec 2005 WO
2007002204 Jan 2007 WO
2007053702 May 2007 WO
2007053719 May 2007 WO
2007062105 May 2007 WO
2007127327 Nov 2007 WO
2007146158 Dec 2007 WO
2008034602 Mar 2008 WO
2008069973 Jun 2008 WO
2008102120 Aug 2008 WO
2008124107 Oct 2008 WO
2009051807 Apr 2009 WO
2011097028 Aug 2011 WO
2011106459 Sep 2011 WO
2012009578 Jan 2012 WO
2012088339 Jun 2012 WO
2012088341 Jun 2012 WO
2012121756 Sep 2012 WO
Non-Patent Literature Citations (103)
Entry
Aksimentiev, et al. Microscopic Kinetics of DNA Translocation through synthetic nanopores. Biophys J. Sep. 2004;87(3):2086-97.
Andersen. Sequencing and the single channel. Biophys J. Dec. 1999; 77(6):2899-901.
Ashkenasy, et al. Recognizing a single base in an individual DNA strand: a step toward DNA sequencing in nanopores. Angew Chem Int Ed Engl. Feb. 18, 2005:44(9):1401-4.
Atanasov, et al. Membrane on a chip: a functional tethered lipid bilayer membrane on silicon oxide surfaces. Biophys J. Sep. 2005;89(3):1780-8.
Baaken, et al. Planar microelecrode-cavity array for hig-resolution and parallel electrical recording of membrane ionic currents. Lab Chip. Jun. 2008;8(6):938-44. Epub Apr. 16, 2008.
Bai, et al. Design and synthesis of a photocleavable biotinylated nucleotide for DNA analysis by mass spectrometry. Nucleic Acids Res. Jan. 26, 2004;32(2):535-41. Print 2004.
Benner, et al. Sequence-specific detection of individual DNA polymerase complexes in real time using a nanopore. Nat Nanotechnol. Nov. 2007;2(11):718-24. Epub 200 Oct. 28.
Bezrukov, et al. Counting polymers moving through a single ion channel. Nature. Jul. 28, 1994;370(6487):279-81.
Bezrukov, et al. Dynamic partitioning of neutral polymers into a single ion channel. In NATO Advanced Research Workshop: Structure and dynamics of confined polymers. Kulwer Press. 2002; 117-130.
Bezrukov, et al. Dynamics and free energy of polymers partitioning into a nanoscale pore. Macromolecules. 1996;29:8517-8522.
Bezrukov, et al. Neutral polymers in the nanopores of alamethicin and alpha-hemolysin. Biologicheskie Membrany 2001, 18, 451-455.
Boireau, et al. Unique supramolecular assembly of a redox protein with nucleic acids onto hybrid bilayer: towards a dynamic DNA chip. Biosens Bioelectron. Feb. 15, 2005;20(8):1631-7.
Bokhari, et al. A parallel graph decomposition algorithm for DNA sequencing with nanopores. Bioinformatics. Apr. 1, 2005;21(7):889-96. Epub Nov. 11, 2004.
Buchmann, et al. Electrochemical release from gold-thiolate electrodes for controlled insertion of ion channels into bilayer membranes. Bioorg Med Chem. Mar. 15, 2004;12(6):1315-24.
Butler et al. Of RNA orientation during translocation through a biological nanopore. Biophys J. Jan. 1, 2006;90 (1):190-9. Epub Oct. 7, 2005.
Butler et al. Single-molecule DNA detection with an engineered MspA protein nanopore. Proc Natl Acad Sci U S A. Dec. 30, 2008;105(52):20647-52. Epub Dec. 19, 2008.
Butler, et al. Ionic current blockades from DNA and RNA molecules in the alphahemolysis nanopore. Biophys J. Nov. 1, 2007;93(9):3229-40. Epub Aug. 3, 2007.
Chandler, et al. Membrane surface dynamics of DNA-threaded nanopores revealed by simultaneous single-molecule optical and ensemble electrical recording. Langmuir. Feb. 3, 2004;20(3):898-905.
Churbanov, et al. Duration learning for analysis of nanopore ionic current blockades. BMC Bioinformatics. Nov. 1, 2007;8 Suppl 7:S14.
Clarke, et al. Continuous base identification for single-molucule nanpore DNA sequencing. Nat Nanotechnol. Apr. 2009;4(4):265-70. Epub Feb. 22, 2009.
Cockroft, et al. A single-molecule nanpore device detects DNA polymerase activity with single-nucleotide resolution. J am Chem Soc. Jan. 23, 2008;130(3):818-20. Epub Jan. 1, 2008.
Danelon, et al. Cell membranes suspended across nanoaperture arrays. Langmuir. Jan. 3, 2006;22(1):22-5.
Deamer, et al. Characterization of nucleic acids by nanopore analysis. Acc Chem Res. Oct. 2002;35(10):817-25.
Derrington, et al. Nanopore DNA sequencing with MspA. Proc Natl Acad Sci U S A. Sep. 14, 2010;107(37):16060-5. Epub Aug. 26, 2010.
Einstein. Investigations on the theory of Brownian movement. Dover, New York. 1956.
Ervin, et al. Simultaneous alternating and direct current readout of protein ion channel blocking events using glass nanopore membranes. Anal Chem. Mar. 15, 2008;80(6):2069-76. Epub Feb. 23, 2008.
Flusberg, et al. Direct detection of DNA methylation during single-molecule, real-time sequencing. Nat Methods. Jun. 2010;7(6):461-5. Epub May 9, 2010.
Fologea, et al. Detecting single stranded DNA with a solid state nanopore. Nano Lett. Oct. 2005;5(10):1905-9.
Fologea, et al. Slowing DNA translocation in a solid-state nanopore. Nano Lett. Sep. 2005;5(9):1734-7.
Gu, et al. Stochastic sensing of organic analytes by a pore-forming protein containing a molecular adapter. Nature. Apr. 22, 1999;398(6729):686-90.
Haas, et al. Improvement of the qualiity of self assembled bilayer lipid membrances by using a negative potential. Bioelectrochemistry. Aug. 2001;54(1):1-10.
Halverson, et al. Asymmetric blockade of anthrax protective antigen ion channel asymmetric blockade. J Biol Chem. Oct. 7, 2005;280(40):34056-62. Epub Aug. 8, 2005.
Harlepp, et al. Probing complex RNA structures by mechanical force. Eur Phys J E Soft Matter. Dec. 2003;12(4):605-15.
Heins, et al. Detecting single porphyrin molecules in a conically shaped synthetic nanopore. Nano Lett. Sep. 2005;5(9):1824-9.
Heng, et al. Stretching DNA using the electric field in a synthetic nanopore. Nano Lett. Oct. 2005;5(10):1883-8.
Heng, et al. The electromechanics of DNA in a synthetic nanopore. Biophys J. Feb. 1, 2006;90(3):1098-106. Epub Nov. 11, 2006.
Henrickson, et al. Driven DNA transport into an asymmetric nanometer-scale pore. Phys Rev Lett. Oct. 2, 2000;85(14):3057-60.
Henrickson, et al. Probing single nanometer-scale pores with polymeric molecular rulers. J Chem Phys. Apr. 7, 2010;132(13):135101. doi: 10.1063/1.3328875.
Holden, et al. Direct introduction of single protein channels and pores into lipid bilayers. J Am Chem Soc. May 11, 2005;127(18):6502-3.
Holden, et al. Direct transfer of membrane proteins from bacteria to planar bilayers for rapid screening by single-channel recording. Nat Chem Biol. Jun. 2006;2(6):314-8. Epub May 7, 2006.
Hromada, et al. Single molecule measurements within individual membrane-bound ion channels using a polymer-based bilayer lipid membrane chip. Lab Chip. Apr. 2008;8(4):602-8. Epub Feb. 29, 2008.
International Preliminary Report on Patentability issued Dec. 24, 2008 in connection with International Application No. PCT/US2007/013559.
International search report and written opinion dated Mar. 18, 2013 for PCT/US2012/063099.
International search report and written opinion dated May 3, 2012 for PCT/US2012/020827.
International search report and written opinion dated May 9, 2013 for PCT/US2013/028058.
International search report and written opinion dated May 16, 2013 for PCT Application No. US2013/022273.
International search report and written opinion dated May 16, 2013 for PCT Application No. US2013/026514.
International search report and written opinion dated Jul. 8, 2011 for PCT/US2011/064490.
International search report and written opinion dated Aug. 28, 2012 for PCT/US2011/066627.
International search report and written opinion dated Aug. 28, 2012 for PCT/US2011/066632.
International search report and written opinion dated Oct. 29, 2007 for PCT/US2007/013559.
International search report and written opinion dated Nov. 5, 2012 for PCT/US2011/064490.
International search report dated Feb. 24, 2013 for PCT/US2011/065640.
Ito, et al. Simultaneous determination of the size and surface charge of individual nanoparticles using a carbon nanotube-based Coulter counter. Anal Chem. May 15, 2003;75(10):2399-406.
Ju, et al. Cassette labeling for facile construction of energy transfer fluorescent primers. Nucleic Acids Res. Mar. 15, 1996;24(6):1144-8.
Ju, et al. Energy transfer primers: a new fluorescence labeling paradigm for DNA sequencing and analysis. Nat Med. Feb. 1999;2(2):246-9.
Ju, et al. Fluorescence energy transfer dye-labeled primers for DNA sequencing and analysis. Proc Natl Acad Sci U S A. May 9, 1995;92(10):4347-51.
Ju, et al. Four-color DNA sequencing by synthesis using cleavable fluorescent nucleotide reversible terminators. Proc Natl Acad Sci U S A. Dec. 26, 2006;103(52):19635-40. Epub Dec. 14, 2006.
Jurak, et al. Wettability and topography of phospholipid DPPC multilayers deposited by spin-coating on glass, silicon and mica slides. Langmuir. Sep. 25, 2007;23(20):10156-63. Epub Aug. 28, 2007.
Kang, et al. A storable encapsulated bilayer chip containing a single protein nanopore. J Am Chem Soc. Apr. 18, 2007;129(15):4701-5. Epub Mar. 22, 2007.
Kasianowicz, et al. Characterization of individual polynucleotide molecules using a membrane channel. Proc Natl Acad Sci U S A. Nov. 26, 1996;93(24):13770-3.
Kasianowicz, et al. Physics of DNA threading through a nanometer pore and applications to simultaneous multianalyte sesnsing. In NATO Advanced Research Workshop: Structure and dynamics of confined polymers. Kluwer Press. 2002; 141-163.
Kasianowicz, et al. Simultaneous multianalysis detection with a nanopore. Anal. Chem. 2001; 73:2268-2272.
Kasianowicz. Nanometer-scale pores: potential applications for analyte detection and DNA characterization. Dis Markers. 2002;18(4):185-91.
Kasianowicz. Nanopores: flossing with DNA. Nat Mater. Jun. 2004;3(6):355-6.
Kawano, et al. Controlling the translocation of single-stranded DNA through alphahemolysin ion channels using viscosity. Langmuir. Jan. 20, 2006;25(2):1233-7.
Krasilnikov, et al. A simple method for the determination of the pore radius of ion channels in planar lipid bilayer membranes. FEMS Microbiol Immunol. Sep. 1992;5(1-3):93-100.
Krasilnikov, et al. Single polymer molecules in a protein nanopore in the limit of a strong polymer-pore attraction. Phys Rev Lett. Jul. 7, 2006;97(1):018301. Epub Jul. 5, 2006.
Krasilnikov, et al. Sizing channels with neutral polymers. In NATO Advanced Research Workshop: Structure and dynamics of confined polymers. Kluwer Press. 2002; 97-116.
Kullman, et al. Transport of maltodextrins through maltoporin: a single-channel study. Biophys J. Feb. 2002;82(2):803-12.
Kumar, et al. PEG-labeled nucleotides and nanopore detection for single molecule DNA sequencing by synthesis. Sci Rep. 2012;2:684. Epub Sep. 21, 2012.
Kutik, et al. Dissecting membrane insertion of mitochondrial beta-barrel proteins. Cell. Mar. 21, 2008;132(6):1011-24.
Lee, et al. Enhancing the catalytic repertoire of nucleic acids: a systematic study of linker length and rigidity. Nucleic Acids Res. Apr. 1, 2001;29(7):1565-73.
Li, et al. A photocleavable fluorescent nucleotide for DNA sequencing and analysis. Proc Natl Acad Sci U S A. Jan. 21, 2003;100(2):414-9. Epub Jan. 6, 2003.
Li, et al. Ion-beam sculpting at nanometre length scales. Nature. Jul. 12, 2001;412(6843):166-9.
Linear Technology, High Efficiency Thermoelectric Cooler Controller, 2001.
Low Noise, Dual Switched Integrator, Burr-Brown Corporation, Sep. 1994.
Lundquist, et al. A new tri-orthogonal strategy for peptide cyclization. Org Lett. Sep. 19, 2002;4(19):3219-21.
Madampage, et al. Nanopore detection of antibody prion interactions. Anal Biochem. Jan. 1, 2010;396(1):36-41. Epub Aug. 21, 2009.
Mathe, et al. Nanopore unzipping of individual DNA hairpin molecules. Biophys J. Nov. 2004;87(5):3205-12. Epub Sep. 3, 2004.
Mathe, et al. Orientation discrimination of single-stranded DNA inside the alpha-hemolysin membrance channel. Proc Natl Acad Sci U S A. Aug. 30, 2005;102(35):12377-82. Epub Aug. 19, 2005.
Maurer, et al. Reconstitution of ion channels in agarose-supported silicon orifices. Biosens Bioelectron. May 15, 2007;22(11):2577-84. Epub Nov. 13, 2006.
McNally, et al. Optical recognition of converted DNA nucleotides for single-molecule DNA sequencing using nanopore arrays. Nano Lett. Jun. 9, 2010;10(6):2237-44.
Meller, et al. Rapid nanopore discrimination between single polynucleotide molecules. Proc Natl Acad Sci U S A Feb. 1, 2000;97(3):1079-84.
Meller, et al. Single molecule measurements of DNA transport through a nanopore. Electrophoresis. Aug. 2002;23(16):2583-91.
Mohammad, et al. Controlling a single protein in a nanopore through electrostatic traps. J Am Chem Soc. Mar. 26, 2008;130(12)4081-8. Epub Mar. 6, 2008.
Movileanu, et al. Partitioning of a polymer into a nanoscopic protein pore obeys a simple scaling law. Proc Natl Acad Sci U S A. Aug. 28, 2001;98(18):10137-41. Epub Aug. 14, 2001.
Movileanu, et al. Partitioning of individual flexible polymers into a nanoscopic protein pore. Biophys J. Aug. 2003;85(2):897-910.
Nakane, et al. A Nanosensor for Transmembrane Capture and Identification of Single Nucleic Acid Molecules, Biophysical Journal, vol. 87, Issue 1, Jul. 2004, pp. 615-621, ISSN 0006-3495.
Office action dated Feb. 25, 2013 for U.S. Appl. No. 13/396,522.
Office action dated Apr. 11, 2013 for U.S. Appl. No. 12/658,603.
Office action dated Apr. 26, 2012 for U.S. Appl. No. 12/658,591.
Office action dated Apr. 26, 2012 for U.S. Appl. No. 12/658,601.
Office action dated Jun. 15, 2012 for U.S. Appl. No. 12/658,604.
Office action dated Jun. 28, 2012 for U.S. Appl. No. 12/308,091.
Office action dated Aug. 3, 2012 for U.S. Appl. No. 12/658,602.
Office action dated Oct. 2, 2012 for U.S. Appl. No. 12/658,603.
Office action dated Oct. 16, 2012 for U.S. Appl. No. 12/658,601.
Office action dated Oct. 25, 2012 for U.S. Appl. No. 12/658,591.
Office action dated Nov. 26, 2011 for U.S. Appl. No. 12/308,091.
Akeson, et al. Microsecond time-scale discrimination among polycytidylic acid, polyadenylic acid, and plolyuridylic acid as homopolymers or a s segments within single RNA molecules. Biophys J. Dec. 1999; 77(6):3227-33.
Author Unknown, Linear Technology, High Efficiency Thermoelectric Cooler Controller, 2001.
Rotem et al., Temperature Measurement in the Intel Core Duo Processor, 2007.
Related Publications (1)
Number Date Country
20120196759 A1 Aug 2012 US
Provisional Applications (1)
Number Date Country
61436948 Jan 2011 US