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WO2023192983A1 - Capteur sans contact pour la mesure de contenus d'un réacteur - Google Patents

Capteur sans contact pour la mesure de contenus d'un réacteur Download PDF

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Publication number
WO2023192983A1
WO2023192983A1 PCT/US2023/065203 US2023065203W WO2023192983A1 WO 2023192983 A1 WO2023192983 A1 WO 2023192983A1 US 2023065203 W US2023065203 W US 2023065203W WO 2023192983 A1 WO2023192983 A1 WO 2023192983A1
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WIPO (PCT)
Prior art keywords
bioreactor
sensor
measured
coil
capacitance
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PCT/US2023/065203
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English (en)
Inventor
Geraint Owen
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Corning Inc
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Corning Inc
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Publication of WO2023192983A1 publication Critical patent/WO2023192983A1/fr
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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/02—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance
    • G01N27/023—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating impedance where the material is placed in the field of a coil
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M41/00—Means for regulation, monitoring, measurement or control, e.g. flow regulation
    • C12M41/30—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration
    • C12M41/36—Means for regulation, monitoring, measurement or control, e.g. flow regulation of concentration of biomass, e.g. colony counters or by turbidity measurements

Definitions

  • This description relates generally to devices, systems, and methods for the measurement of relative permittivity and of other electromagnetic properties which may be used to calculate relative permittivity, and more particularly relates to biomass sensors.
  • a contactless sensor for measurement of contents of a bioreactor may comprise: a resonator comprising a coil disposed around the bioreactor, the coil comprising a cylindrical magnetic coil, and a capacitor connected across the coil; an oscillator electrically coupled to the resonator, the oscillator producing an alternating electric current within the resonator; and a resonance frequency measuring component electrically coupled to the oscillator and to the resonator, the resonance frequency measuring component measuring a measured resonance frequency of the resonator.
  • a second aspect A2 includes the sensor according to the first aspect Al, wherein the measured resonance frequency is indicative of the contents of the bioreactor.
  • a third aspect A3 includes the sensor according to the second aspect A2, wherein the contents of the bioreactor comprise an aggregate biomass quantity.
  • a fourth aspect A4 includes the sensor according to the first aspect Al, wherein the measured resonance frequency is indicative of a permittivity of the bioreactor.
  • a fifth aspect A5 includes the sensor according to the fourth aspect A4, wherein the sensor is configured to measure the permittivity at resonance frequencies in a range from 10 kHz to 1 MHz.
  • a sixth aspect A6 includes the sensor according to the first aspect Al, wherein the measuring of the measured resonance frequency comprises frequency measurement.
  • a seventh aspect A7 includes the sensor according to the sixth aspect A6, wherein the sensor is configured to use inductance in a range of 1 pH to 10 mH.
  • An eighth aspect A8 includes the sensor according to the first aspect Al, wherein the resonance frequency measurement component comprises at least one of: a resistor, a waveform generator, and an oscilloscope; an impedance analyzer; a swept frequency generator and a spectrum analyzer; and a combination thereof.
  • the resonance frequency measurement component comprises at least one of: a resistor, a waveform generator, and an oscilloscope; an impedance analyzer; a swept frequency generator and a spectrum analyzer; and a combination thereof.
  • a ninth aspect A9 includes the sensor according to the first aspect Al, wherein the bioreactor comprises non-magnetic, non-conducting material.
  • a tenth aspect A10 includes the sensor according to the third aspect A3, wherein the aggregate biomass comprises live cells.
  • An eleventh aspect Al l includes the sensor according to the first aspect Al, wherein the bioreactor comprises a fixed bed reactor (FBR).
  • FBR fixed bed reactor
  • a twelfth aspect Al 2 includes the sensor according to the first aspect Al, wherein the coil is wound around a coil former.
  • a thirteenth aspect Al 3 includes the sensor according to the twelfth aspect A 12, wherein the coil former is formed of a rigid, non-magnetic, non-conducting material.
  • a fourteenth aspect Al 4 includes the sensor according to the twelfth aspect A 12, wherein the coil former comprises coil former components, the coil former configured to have the coil wound around the coil former components to form a cylindrical interior cavity configured to receive a reactor.
  • a contactless method for measuring contents of a bioreactor may comprise: positioning a sensor for measurement of the bioreactor, the sensor comprising: a resonator comprising: a coil disposed around the bioreactor, the coil comprising a cylindrical magnetic coil, and a capacitor connected across the coil; an oscillator electrically coupled to the resonator, the oscillator producing an alternating electric current within the resonator; and a resonance frequency measuring component electrically coupled to the oscillator and to the resonator, the resonance frequency measuring component measuring a resonance frequency of the resonator; collecting a measured resonance frequency of the bioreactor using the sensor; and determining the contents of the bioreactor based on the measured resonance frequency of the bioreactor.
  • a sixteenth aspect B2 includes the method according to the fifteenth aspect Bl, wherein the contents comprise an aggregate biomass and wherein determining the contents of the bioreactor comprises determining an aggregate biomass quantity of the bioreactor.
  • a seventeenth aspect B3 includes the method according to the sixteenth aspect B2, wherein the determining the aggregate biomass quantity comprises: identifying at least one corresponding potential resonance frequency of a plurality of potential resonance frequencies, wherein: the at least one corresponding potential resonance frequency corresponds to the measured resonance frequency, and each potential resonance frequency of the plurality of potential resonance frequencies corresponds to a previously-identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities; and identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential resonance frequency.
  • An eighteenth aspect B4 includes the method according to the seventeenth aspect B3, wherein the at least one corresponding potential resonance frequency comprises a first resonance frequency and a second resonance frequency, and wherein the corresponding potential resonance frequency is equal to at least one of the first resonance frequency, the second resonance frequency, or a mathematical combination of at least the first resonance frequency and the second resonance frequency.
  • a nineteenth aspect B5 includes the method according to the seventeenth aspect B3, wherein the collecting the measured resonance frequency further comprises collecting a plurality of measured resonance frequencies, and wherein the at least one corresponding potential resonance frequency corresponds to at least one of the plurality of measured resonance frequencies.
  • a twentieth aspect B6 includes the method according to the sixteenth aspect B2, wherein the determining the aggregate biomass quantity comprises calculating, using the measured resonance frequency, a measured permittivity of the bioreactor.
  • a twenty-first aspect B7 includes the method according to the twentieth aspect B6, wherein the determining the aggregate biomass quantity further comprises: identifying at least one corresponding potential permittivity of a plurality of potential permittivities, wherein: the at least one corresponding potential permittivity corresponds to the measured permittivity, and each potential permittivity of the plurality of potential permittivities corresponds to a previously- identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities; and identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential permittivity.
  • a twenty-second aspect B8 includes the method according to the fifteenth aspect Bl, wherein collecting the measured resonance frequency comprises collecting a plurality of measured resonance frequencies over a period of time to monitor a biomass in the bioreactor over the period of time.
  • a twenty-third aspect B9 includes the method according to the fifteenth aspect Bl, wherein collecting the measured resonance frequency comprises collecting a plurality of measured resonance frequencies to calculate a moving average resonance frequency.
  • a twenty-fourth aspect B10 includes the method according to the fifteenth aspect Bl, wherein the method further comprises filling the bioreactor with cells to be cultured, cell culture media, any additives or supplements for a cell culture experiment, or any combination thereof.
  • a twenty-fifth aspect Bl 1 includes the method according to the twenty-fourth aspect B10, further comprising culturing the cells for a period of time.
  • a twenty-sixth aspect B12 includes the method according to the twenty-fifth aspect B 11 , wherein the method further comprises transmitting the measured resonance frequency from the sensor to a data processor for analysis of the measured resonance frequency, calculation or correlation to a biomass monitoring, display of the biomass monitoring over a period of time, or a combination thereof.
  • a twenty- seventh aspect B13 includes the method according to the fifteenth aspect Bl, wherein the positioning the sensor for measurement of the bioreactor comprises winding the coil of the sensor around an exterior surface of the bioreactor.
  • a twenty-eighth aspect B14 includes the method according to the fifteenth aspect Bl, wherein the positioning the sensor for measurement of the bioreactor comprises winding the coil of the sensor around a coil former configured to receive the bioreactor in an interior cavity of the coil former.
  • a contactless sensor for measurement of contents of a bioreactor may comprise: a resonator comprising a coil disposed around the bioreactor, the coil comprising a cylindrical magnetic coil, and a capacitor connected across the coil; and an impedance measuring component electrically coupled to the resonator, the impedance measuring component measuring a measured maximum impedance of the resonator and the bioreactor and a measured frequency corresponding to the measured maximum impedance.
  • a thirtieth aspect C2 includes the sensor according to the twenty-ninth aspect Cl, wherein the measured frequency is a measure of the contents of the bioreactor.
  • a thirty-first aspect C3 includes the sensor according to the thirtieth aspect C2, wherein the contents of the bioreactor comprise an aggregate biomass quantity of the bioreactor.
  • a thirty-second aspect C4 includes the sensor according to the twenty-ninth aspect Cl, wherein the measured frequency is a measure of a permittivity of the bioreactor.
  • a thirty-third aspect C5 includes the sensor according to the thirty-second aspect C4, wherein the sensor is configured to measure the permittivity at resonance frequencies in a range from 10 kHz to 1 MHz.
  • a thirty-fourth aspect C6 includes the sensor according to the twenty-ninth aspect Cl, wherein the impedance measuring component is an impedance analyzer, an LCR meter, a swept frequency generator and a spectrum analyzer, or some combination thereof.
  • the impedance measuring component is an impedance analyzer, an LCR meter, a swept frequency generator and a spectrum analyzer, or some combination thereof.
  • a thirty-fifth aspect C7 includes the sensor according to the twenty-ninth aspect Cl, wherein the bioreactor comprises non-magnetic, non-conducting material.
  • a thirty-sixth aspect C8 includes the sensor according to the thirty-first aspect C3, wherein the aggregate biomass comprises live cells.
  • a thirty-seventh aspect C9 includes the sensor according to the twenty-ninth aspect Cl, wherein the bioreactor comprises a fixed bed reactor (FBR).
  • FBR fixed bed reactor
  • a thirty-eighth aspect CIO includes the sensor according to the twenty-ninth aspect Cl, wherein the coil is wound around a coil former.
  • a thirty-ninth aspect Cl 1 includes the sensor according to the thirty-eighth aspect CIO, wherein the coil former is formed of a rigid, non-magnetic, non-conducting material.
  • a fortieth aspect C12 includes the sensor according to the thirty-ninth aspect Cl 1, wherein the coil former comprises coil former components, the coil former configured to have the coil wound around the coil former components to form a cylindrical interior cavity configured to receive a reactor.
  • a contactless method for measuring contents of a bioreactor may comprise: positioning a sensor for measurement of the bioreactor, the sensor comprising: a resonator comprising: a coil disposed around the bioreactor, the coil comprising a cylindrical magnetic coil, and a capacitor connected across the coil; an impedance measuring component electrically coupled to the resonator, the impedance measuring component measuring an impedance of the resonator and the bioreactor at a fixed frequency; collecting a measured impedance of the bioreactor using the sensor; and determining an aggregate biomass quantity of the bioreactor based on the measured impedance of the bioreactor.
  • a forty-second aspect D2 includes the method according to the forty-first aspect DI, wherein the contents comprise an aggregate biomass and wherein determining the contents of the bioreactor comprises determining an aggregate biomass quantity of the bioreactor.
  • a forty-third aspect D3 includes the method according to the forty-second aspect D2, wherein the determining the aggregate biomass quantity comprises: identifying at least one corresponding potential impedance of a plurality of potential impedances, wherein: the at least one corresponding potential impedance corresponds to the measured impedance, and each potential impedance of the plurality of potential impedances corresponds to a previously- identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities; and identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential impedance.
  • a forty-fourth aspect D4 includes the method according to the forty-third aspect D3, wherein the at least one corresponding potential impedance comprises a first impedance and a second impedance, and wherein the corresponding potential impedance is equal to at least one of the first impedance, the second impedance, or a mathematical combination of at least the first impedance and the second impedance.
  • a forty-fifth aspect D5 includes the method according to the forty-third aspect D3, wherein the collecting the measured impedance further comprises collecting a plurality of measured impedances, and wherein the at least one corresponding potential impedance corresponds to at least one of the plurality of measured impedances.
  • a forty-sixth aspect D6 includes the method according to the forty-second aspect D2, wherein the determining the aggregate biomass quantity comprises calculating, using the measured impedance, a measured permittivity of the bioreactor.
  • a forty-seventh aspect D7 includes the method according to the forty-sixth aspect D6, wherein the determining the aggregate biomass quantity further comprises: identifying at least one corresponding potential permittivity of a plurality of potential permittivities, wherein: the at least one corresponding potential permittivity corresponds to the measured permittivity, and each potential permittivity of the plurality of potential permittivities corresponds to a previously-identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities; and identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential permittivity.
  • a forty-eighth aspect D8 includes the method according to the forty-first aspect DI, wherein collecting the measured impedance comprises collecting a plurality of measured impedances over a period of time to monitor a biomass in the bioreactor over the period of time.
  • a forty-ninth aspect D9 includes the method according to the forty-first aspect DI, wherein collecting the measured impedance comprises collecting a plurality of measured impedances to calculate a moving average impedance.
  • a fiftieth aspect D10 includes the method according to the forty-first aspect DI, wherein the method further comprises filling the bioreactor with cells to be cultured, cell culture media, any additives or supplements for a cell culture experiment, or any combination thereof.
  • a fifty-first aspect Dl l includes the method according to the fiftieth aspect D10, further comprising culturing the cells for a period of time.
  • a fifty-second aspect D12 includes the method according to the fifty-first aspect Dl l, wherein the method further comprises transmitting the measured impedance from the sensor to a data processor for analysis of the measured impedance, calculation or correlation to a biomass monitoring, display of the biomass monitoring over a period of time, or a combination thereof.
  • a fifty -third aspect DI 3 includes the method according to the forty-first aspect DI, wherein the positioning the sensor for measurement of the bioreactor comprises winding the coil of the sensor around an exterior surface of the bioreactor.
  • a fifty-fourth aspect D14 includes the method according to the forty-first aspect DI, wherein the positioning the sensor for measurement of the bioreactor comprises winding the coil of the sensor around a coil former configured to receive the bioreactor in an interior cavity of the coil former.
  • a contactless sensor for measurement of contents of a bioreactor may comprise: a first electrode plate and a second electrode plate disposed outside of the bioreactor and on opposite sides of a longitudinal axis of the bioreactor; and a capacitance measuring component electrically coupled to the first electrode plate and to the second electrode plate, the capacitance measuring component measuring a measured capacitance of the bioreactor between the first electrode plate and the second electrode plate.
  • a fifty-sixth aspect E2 includes the sensor according to the fifty-fifth aspect El, wherein the measured capacitance is a measure of the contents of the bioreactor.
  • a fifty-seventh aspect E3 includes the sensor according to the fifty-sixth aspect E2, wherein the contents of the bioreactor comprise an aggregate biomass quantity of the bioreactor.
  • a fifty-eighth aspect E4 includes the sensor according to the fifty-fifth aspect El, wherein the measured capacitance is a measure of a permittivity of the bioreactor.
  • a fifty-ninth aspect E5 includes the sensor according to the fifty-fifth aspect El, wherein the capacitance measuring component comprises an LCR meter.
  • a sixtieth aspect E6 includes the sensor according to the fifty-ninth aspect E5, wherein the LCR meter measures the measured capacitance in a range of 0 pF to 100 pF.
  • a sixty-first aspect E7 includes the sensor according to the fifty-ninth aspect E5, wherein the LCR meter comprises a resolution of 0.0001 pf to 1 fF.
  • a sixty-second aspect E8 includes the sensor according to the fifty-fifth aspect El, wherein the bioreactor comprises non-magnetic, non-conducting material.
  • a sixty- third aspect E9 includes the sensor according to the fifty-seventh aspect E3, wherein the aggregate biomass comprises live cells.
  • a sixty- fourth aspect E10 includes the sensor according to the fifty-fifth aspect El, wherein the bioreactor comprises a fixed bed reactor (FBR).
  • FBR fixed bed reactor
  • a sixty-fifth aspect El 1 includes the sensor according to the fifty-fifth aspect El, wherein the sensor further comprises a shielding, wherein the shielding at least partially surrounds the first electrode plate and the second electrode plate.
  • a sixty-sixth aspect E12 includes the sensor according to the fifty-fifth aspect El, wherein at least part of the sensor is fixed in place.
  • a contactless method for measuring contents of a bioreactor may comprise: positioning a sensor for measurement of the bioreactor, the sensor comprising: a first electrode plate and a second electrode plate disposed outside of the bioreactor and on opposite sides of a longitudinal axis of the bioreactor, and a capacitance measuring component electrically coupled to the first electrode plate and to the second electrode plate, the capacitance measuring component measuring a measured capacitance of the bioreactor between the first electrode plate and the second electrode plate; collecting a measured capacitance of the bioreactor using the sensor; and determining an aggregate biomass quantity of the bioreactor based on the measured capacitance of the bioreactor.
  • a sixty-eighth aspect F2 includes the method according to the sixty-seventh aspect Fl, wherein the contents comprise an aggregate biomass and wherein determining the contents of the bioreactor comprises determining an aggregate biomass quantity of the bioreactor.
  • a sixty-ninth aspect F3 includes the method according to the sixty-eighth aspect F2, wherein the determining the aggregate biomass quantity comprises: identifying at least one corresponding capacitance of a plurality of potential capacitances, wherein: the at least one corresponding potential capacitance corresponds to the measured capacitance, and each potential capacitance of the plurality of potential capacitances corresponds to a previously-identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities; and determining the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential capacitance.
  • a seventieth aspect F4 includes the method according to the sixty-eighth aspect F2, wherein the at least one corresponding potential capacitance comprises a first capacitance and a second capacitance, and wherein the corresponding potential capacitance is equal to at least one of the first capacitance, the second capacitance, or a mathematical combination of at least the first capacitance and the second capacitance.
  • a seventy-first aspect F5 includes the method according to the sixty-eighth aspect F2, wherein the collecting the measured capacitance further comprises collecting a plurality of measured capacitances, and wherein the at least one corresponding potential capacitance corresponds to at least one of the plurality of measured capacitances.
  • a seventy-second aspect F6 includes the method according to the sixty-eighth aspect F2, wherein the determining the aggregate biomass quantity comprises calculating, using the measured capacitance, a measured permittivity of the bioreactor.
  • a seventy-third aspect F7 includes the method according to the seventy-second aspect F6, wherein the determining the aggregate biomass quantity further comprises: identifying at least one corresponding potential permittivity of a plurality of potential permittivities, wherein: the at least one corresponding potential permittivity corresponds to the measured permittivity, and each potential permittivity of the plurality of potential permittivities corresponds to a previously-identified aggregate biomass quantity of a plurality of previously- identified aggregate biomass quantities; and identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously- identified aggregate biomass quantity of the at least one corresponding potential permittivity.
  • a seventy-fourth aspect F8 includes the method according to the sixty-seventh aspect Fl, wherein collecting the measured capacitance comprises collecting a plurality of measured capacitances over a period of time to monitor a biomass in the bioreactor over the period of time.
  • a seventy-fifth aspect F9 includes the method according to the sixty-seventh aspect Fl, wherein collecting the measured capacitance comprises collecting a plurality of measured capacitances to calculate a moving average capacitance.
  • a seventy-sixth aspect F10 includes the method according to the sixty-seventh aspect Fl, wherein the method further comprises filling the bioreactor with cells to be cultured, cell culture media, any additives or supplements for a cell culture experiment, or any combination thereof.
  • a seventy-seventh aspect Fl 1 includes the method according to the seventy-sixth aspect F10, further comprising culturing the cells for a period of time.
  • a seventy-eighth aspect F12 includes the method according to the seventy-seventh aspect Fl 1, wherein the method further comprises transmitting the measured capacitance from the sensor to a data processor for analysis of the measured capacitance, calculation or correlation to a biomass monitoring, display of the biomass monitoring over a period of time, or a combination thereof.
  • a seventy-ninth aspect F13 includes the method according to the sixty-seventh aspect Fl, wherein the sensor further comprises a shielding, wherein the shielding at least partially surrounds the first electrode plate and the second electrode plate.
  • FIG. 1 shows a sensor system in accordance with an embodiment described herein.
  • FIG. 2 shows a sensor system in accordance with an embodiment described herein.
  • FIG. 3 shows an image of a sensor system in accordance with embodiments of the present disclosure.
  • FIG. 4 is an electrical schematic of a sensor system with an oscilloscope according to an embodiment described herein.
  • FIG. 5 shows an illustration of sensor operation in accordance with embodiments of the present disclosure.
  • FIG. 6 shows a log-log plot of the cube of frequency v. normalized sensitivity for sensors in accordance with embodiments of the present disclosure.
  • FIG. 7A shows a schematic drawing of a gapped coil system in accordance with embodiments of the present disclosure.
  • FIG. 7B shows an illustration of overall permittivity of a gapped coil system in accordance with embodiments of the present disclosure.
  • FIG. 8 shows a flowchart of sensor system design in accordance with embodiments of the present disclosure.
  • FIG. 9 shows a block diagram of incorporating a coil sensor into an oscillator in accordance with an embodiment described herein.
  • FIG. 10 shows a circuit diagram of a Colpits oscillator in accordance with an embodiment described herein.
  • FIG. 11 A shows a schematic drawing of a sensor system design in accordance with embodiments of the present disclosure.
  • FIG. 1 IB shows a circuit diagram of a sensor system design in accordance with embodiments of the present disclosure.
  • FIG. 12 shows a flowchart of a method according to one or more embodiments described herein.
  • FIG. 13 shows a flowchart of a method according to one or more embodiments described herein.
  • FIG. 14 shows a flowchart of a method according to one or more embodiments described herein.
  • FIG. 15 schematically illustrates components of a system in accordance with embodiments of the present disclosure.
  • FIG. 16 depicts an example of internal hardware that may be used to implement the various computer processes and systems in accordance with embodiments of the present disclosure.
  • a sensor comprising a resonator and a resonance frequency measurement component configured to measure resonance frequency of the resonator.
  • the resonator comprises a coil configured to be wound and disposed around a cylindrical reactor, the coil comprising a cylindrical magnetic coil; and a capacitor connected across the coil.
  • the coil may be a cylindrical coil (L).
  • the capacitor may be an external capacitor (C) connected across the coil.
  • Systems as described in embodiments herein comprise a reactor and a sensor.
  • the reactor comprises a cylindrical shape.
  • the sensor comprises a resonator and a resonance frequency measurement component configured to measure resonance frequency of the resonator, with the resonator comprising a coil configured to be wound and disposed around the reactor, the coil comprising a cylindrical magnetic coil; and a capacitor connected across the coil.
  • the system further comprises a coil former, wherein the coil is configured to wind around the coil former.
  • the coil former is formed of a rigid, non-magnetic, non-conducting material.
  • the coil former comprises coil former components or a frame, the coil former configured to have the coil wound around the coil former components or frame to form a cylindrical interior cavity configured to receive a reactor.
  • cylindrical geometry is compatible with cylindrical reactors, such as the ASCENT bioreactor (Corning Incorporated, Corning, NY), particularly where a need for a non- invasive measurement of biomass within the reactor exists.
  • sensors and systems as described herein do not require a cylindrical coil to be attached to a reactor, thereby making insertion and removal of a reactor within the sensor system much simpler for operators and technicians.
  • biomass refers to cells (e.g., in a cell culture of a bioreactor).
  • viable biomass refers to live cells (i.e., excluding dead cells present in a cell culture, nutrients, or other contents of a reactor not including live cells).
  • a sensor may measure a measured electromagnetic property of a reactor, such as a resonant frequency, impedance, inductance, or capacitance of the reactor, including the contents of the reactor.
  • Electromagnetic properties such as a resonant frequency, impedance, inductance, or capacitance are a measure of permittivity of a material within the reactor, as the permittivity may be derived from such measured electromagnetic properties.
  • the permittivity is a measure of biomass of a material within the reactor.
  • the reactor may comprise non-magnetic, non-conducting material.
  • the permittivity measurement is non-invasive to the reactor.
  • the permittivity measurement comprises inductive permittivity measurement.
  • sensors described herein may be contactless, such that the sensors do not enter an interior of the reactor to measure the contents of the reactor and may, in some embodiments, may not contact the reactor at all.
  • the sensors described herein may be able to measure the permittivity of an entire reactor, rather than, e.g., sample individual regions of the interior of a reactor and extrapolate such findings across the entire volume of the reactor.
  • the sensors described herein may improve ease of measurement, by, e.g., providing a sensor which the reactor need merely be placed inside of, rather than, e.g., requiring the reactor to be opened to admit a sensor or to have inserted a sensor prior to operation.
  • Embodiments of sensors described herein comprise a resonator and a frequency resonance measurement component.
  • the resonator may comprise the high inductance cylindrical coil and an external capacitor connected across the coil.
  • the capacitor may be any suitable capacitor, such as a capacitor up to several thousand pF. The capacitor assists in lowering the resonant frequency.
  • inductive measurement capability at frequencies less than a few MHz were not known to exist and thus conditions for biomass measurement were not optimal.
  • the sensors and systems described herein allow for frequencies much lower than 1 MHz to be used, as such lower frequencies are much better suited to the accurate monitoring of biomass.
  • the sensor may be configured to measure permittivity inductively at resonance frequencies in a range from 10 kHz to 100 MHz.
  • the sensor may be configured to measure permittivity inductively at resonance frequencies in a range from 10 kHz to 10 MHz.
  • the sensor may be configured to measure permittivity inductively at resonance frequencies in a range from 10 kHz to 1 MHz.
  • the sensor may be configured to measure permittivity inductively at resonance frequencies up to and including 100 MHz.
  • the sensor may be configured to measure permittivity inductively at resonance frequencies up to and including 10 MHz.
  • the sensor may be configured to measure permittivity inductively at resonance frequencies from 10 kHz up to and including 1 MHz.
  • the sensor may be configured to measure permittivity inductively at resonance frequencies from 10 kHz to less than 1 MHz.
  • the sensors and systems described herein produce a well-defined measurement volume within the reactor, with reasonably homogenous measurement sensitivity.
  • the present subject matter allows the coil to be separated from the reactor with no electrical connections to the reactor.
  • Sensors described herein limit the risk of contamination by decreasing “hands-on” steps by the user during experimentation and cell culture (e.g., by being contactless sensors). Furthermore, the sensor allows for non-invasive biomass monitoring. In addition, the sensor may be used for the duration of a cell culture experiment. The cell culture experiment may extend for any suitable amount of time to conduct the experiment. As a nonlimiting example, the cell culture process may last hours or weeks, for example from about 72 hours to about 3 weeks. [0114]
  • FIGS. 1 and 2 show a sensor 100 and a sensor system 190, respectively, according to embodiments described herein.
  • FIG. 1 shows a schematic of a reactor 105 (e.g., a bioreactor, a fixed bed reactor (FBR), or other reactor) with a coil 140 wound directly around an exterior surface 107 of the reactor 105.
  • FIG. 2 shows a coil 140 wound on an coil former 145 disposed at an exterior of the reactor 105.
  • the sensor system 190 shown in FIG. 2 allows for the reactor 105 to be inserted or removed without disturbing the reactor itself, making the sensor system 190 easier to use.
  • the system may comprise a coil former 145 around which the coil 140 is wound.
  • the coil 140 may comprise, e.g., a cylindrical coil or wire.
  • the coil former 145 may be configured to be disposed around the reactor 105, such as a bioreactor or FBR. As such, there would not be a need to attach the coil 140 connections to the reactor 105 itself, thereby allowing the reactor 105 to be removably inserted into an interior cavity formed in the coil former 145 once the coil 140 is wound around the coil former 145 frame, thus increasing user-friendliness of the sensor and system.
  • Sensors according to certain embodiments described herein comprise a coil wound around a reactor or bioreactor.
  • the coil may be formed of any suitable material that is conductive and capable of being wound around a cylindrical object.
  • a nonlimiting example of a material suitable for the coil is insulated copper wire.
  • the coil may be wound around an exterior surface of the reactor.
  • the reactor may be cylindrical in shape, having an exterior surface and at least one chamber configured for cell culture within an interior volume of the reactor.
  • the exterior surface of the reactor may be formed of any suitable non-conductive material.
  • the coil may be wound around a coil former configured to receive a reactor.
  • the coil former may be formed of any suitable non-conductive material.
  • the coil former may be formed of a rigid material to allow a reactor to be inserted and removed from an interior space disposed within the coil former once the coil is wound around the coil former.
  • Embodiments of systems described herein further comprise a printed circuit board.
  • the circuit board may comprise mounted electronic components such as resistors, capacitors, inductors, transistors, diodes, and/or integrated circuits.
  • the reactor 105 may comprise a bioreactor.
  • the bioreactor may comprise a fixed bed reactor (FBR).
  • FBR fixed bed reactor
  • a nonlimiting example of an FBR is the CORNING ASCENT bioreactor (Corning Incorporated, Corning, NY).
  • the bioreactor may be configured for cell culture in an internal volume of the reactor.
  • the reactor 105 may alternatively be another type of cell culture device in which cell cultures may grow.
  • Reactors, bioreactors, and/or cell culture devices may be formed of any suitable material.
  • the reactors, bioreactors, and/or cell culture devices are formed of a polymeric material.
  • Nonlimiting examples of polymeric materials include polystyrene, polymethylmethacrylate, polyvinyl chloride, polycarbonate, polysulfone, polystyrene copolymers, fluoropolymers, polyesters, polyamides, polystyrene butadiene copolymers, fully hydrogenated styrenic polymers, polycarbonate PDMS copolymers, and polyolefins such as polyethylene, polypropylene, polymethyl pentene, polypropylene copolymers and cyclic olefin copolymers.
  • an internal or interior surfaces of a bioreactor or cell culture device may be more particularly adapted for cell growth.
  • a cell culture surface of the bioreactor or cell culture device may be treated with a coating to encourage or discourage cells to stick to the cell culture surface.
  • the bioreactor or cell culture device may comprise a cell adherent coating on one or more interior surfaces. Any suitable cell adherent coating may be used, such as the nonlimiting examples of CORNING CELLBIND (Corning Incorporated, Corning, NY), CORNING PRIMARIA (Corning Incorporated, Corning, NY), and CORNING PURECOAT amine and carboxyl (Corning Incorporated, Corning, NY) surfaces.
  • the bioreactor or cell culture vessel may comprise a cell non-adherent coating on one or more interior surfaces.
  • Any suitable cell non-adherent coating may be used as the coating, such as a CORNING Ultra-Low Attachment (Corning Incorporated, Corning, NY) surface.
  • Nonlimiting examples of ultra-low binding materials for coating include one or more of perfluorinated polymers, olefins, agarose, non-ionic hydrogels such as polyacrylamides, polyethers such as polyethyleneoxide, polyols such as polyvinylalcohol or mixtures thereof.
  • FBR fixed bed reactor
  • the embodiment consists of 100 turns and is 65 mm long (i.e., in this embodiment, the length of the coil is 65 mm as measured along the axial length of the reactor as depicted in FIG. 3).
  • the embodiment also comprises a capacitor 120, which is external to the reactor 105 and is connected across the coil 140.
  • the embodiment further comprises a resistor connected to the waveform generator (e.g., an Agilent type 33120A waveform generator) and the combination supplies drive current to the LC resonator. A portion of a 12-inch rule is shown on the left as an approximate scale marker.
  • FIG. 4 shows a schematic view of the sensor system 190 according to an embodiment.
  • the sensor system comprises the sensor 100 comprising a resonator 101 and a electromagnetic property measuring component 103.
  • the electromagnetic property measuring component 103 may comprise or be configured as a resonance frequency measuring component, an impedance measuring component, an inductance measuring component, or a capacitance measuring component.
  • the electromagnetic property measuring component 103 comprises an inductance measuring component
  • the inductance measuring component may be a non-resonant inductance measuring component.
  • a non-resonant inductance measuring component may comprise an LCR meter.
  • a resonance frequency measuring component may comprise an oscillator and at least one of a resistor, a waveform generator, and an oscilloscope; an impedance analyzer; a swept frequency generator and a spectrum analyzer; and a combination thereof.
  • an impedance measuring component may comprise an impedance analyzer, a swept frequency generator and a spectrum analyzer, or some combination thereof.
  • a capacitance measuring component may comprise an LCR meter.
  • an embodiment of the resonator 101 comprises the coil 140 and the capacitor 120.
  • the coil 140 may be wound directly around an exterior surface 107 of the reactor 105.
  • the capacitor 120 is external to the coil 140 and is connected across the coil 140 as indicated in FIG. 4.
  • the capacitor 120 may be connected to the coil by any suitable means. Nonlimiting examples include connecting the capacitor 120 across the coil by soldering, adhesive, or providing the capacitor 120 on a circuit board coupled to the coil.
  • the electromagnetic property measuring component 103 is configured as a resonance frequency measuring component and comprises a resistor 130, a waveform generator 160, and an oscilloscope 170 having display screen 175.
  • the resistor 130 may be connected to a first end 142 or second end 144 of the coil 140 and may be connected to the waveform generator 160.
  • Any suitable oscilloscope may be used, such as a Tektronix TDS2012C. Inputs to the oscilloscope include voltage across the coil and waveform generator output.
  • the display screen 175 may display the voltage developed across the coil (LC resonator) and waveform generator output (voltage across the resistor). All components are connected to ground through a ground connection 150.
  • the resonance frequency measuring component may comprise other elements, as described above.
  • the electromagnetic property measuring component 103 may, in some embodiments, alternatively comprise or be alternatively configured as an impedance measuring component, an inductance measuring component, or a capacitance measuring component and, in such embodiments, the electromagnetic property measuring component may comprise alternative elements or omit certain elements depicted in FIG. 4.
  • the sensor system 190 may not comprise at least one of, if not both of, the capacitor 120 and the resistor 130.
  • the sensor system may further comprise a circuit board 180.
  • the circuit board 180 may, in some embodiments, comprise mounted electronic components such as resistors, capacitors, and/or integrated circuits.
  • FIG. 5 shows a view of an idealized schematic of an embodiment comprising the reactor 105, with relative permittivity £ r , length I, and radius r.
  • This idealized schematic is simplified (compared to, e.g., a real-world embodiment) in that a wall of the reactor 105 is assumed to have a wall of negligible thickness.
  • the reactor 105 is surrounded by the coil 140 which has N turns and carries a current I.
  • a magnetic field (B) is set up along the axis, and this, in turn, generates a circulating electric field (E), as shown in FIG. 5.
  • This circulating electric field stores energy, and as a result, the region inside the coil acts as an internal capacitor.
  • the value of internal capacitance depends, at least in part, on what is inside the reactor.
  • the value of internal capacitance may further depend on other factors, such as, e.g., a turn-to-turn capacitance of the coil, however, in some embodiments, such other factors may be negligible.
  • the internal capacitance would be greater than the instance when air is inside the reactor by a factor of 80.
  • the factor would also be about 80 (as compared to air inside the reactor) with a nutrient such as DMEM inside the reactor. With live cells, the factor would be still greater, perhaps 10 to 200 or more, depending on the number of cells, cell type, and cell maturity.
  • the internal capacitance inside the coil is a proxy for the biomass.
  • the factors of 80, 100, and 200 are known as the relative permittivity (s r ) of the medium or media inside the coil.
  • the coils of the coil 140 described here are not “very long”, and to a reasonable approximation the internal capacitance is about half of the value that the formula in this paragraph would indicate.
  • the internal capacitance would be about 3.7 pF; if the permittivity increased to 100, the capacitance would increase to about 4.6 pF, and the capacitance change would be 0.9 pF.
  • an external capacitor e.g., the capacitor 120
  • a coil e.g., the coil 140
  • live cells e.g., within the reactor 105
  • live cells may be unable to respond strongly (i.e., respond at a level undetectable by, e.g., the sensor 100, due to an insufficient sensitivity of the sensor 100), and the system, as a result, may not be sensitive to viable biomass.
  • the resonant frequency of the system may be lowered, for example to 250 kHz or lower, which may give a much stronger live cell response (i.e., a cell response detectable by, e.g., the sensor 100).
  • biomass detected may include only or predominantly viable biomass, which may provide the benefit of preventing dead cells from influencing biomass measurement or reducing the influence of dead cells on biomass measurement.
  • the resonant frequency of a sensor and reactor system is determined by the sum of the external capacitance and the internal capacitance, as described above. The latter varies with permittivity (and thus also biomass).
  • the low frequency response is relatively small, as the change in internal capacitance as the cells grow will be perhaps only 0.1% of the value of the external capacitor. However, frequency can be measured extremely accurately, and such a change is sufficient to allow for good sensitivity to biomass (and, in particular, viable biomass), as long as noise and drift are kept well under control.
  • the measurements may indicate (directly or indirectly by, e.g., measuring a resonance frequency, inductance, impedance, or capacitance) a permittivity (and, thereby, a biomass) of an entire space defined by the coil.
  • biomass and, particularly in some embodiments, viable biomass
  • biomass may be measured holistically, rather than sampled and extrapolated across a volume (e.g., as might be necessary by measuring with, e.g., a capacitor internal to a reactor). Measurements and calculations have indicated that the volume over which the biomass is sampled is almost completely bounded by the coil and the ends of the coil and is ovoid or substantially ovoid in shape.
  • a biomass (and, particularly in some embodiments, a viable biomass) of the bioreactor may be calculated because, as cells of the biomass grow, the permittivity of the biomass will also change. However, as the cells grow, electrical properties (e.g., conductivity) of nutrients feeding the biomass change, and so the magnitude of changes in the impedance due to cell growth will change as the cells grow.
  • electrical properties e.g., conductivity
  • a method for associating certain impedance values with certain biomass quantities is necessary, as the two values may not linearly correlate.
  • One method for associating impedance values with viable biomass quantities comprises making two measurements with a sensor at two different frequencies.
  • the first measurement may be taken at a frequency of less than 1 MHz, as, at such frequencies, the viable biomass will respond strongly and nutrients and dead cells of the bioreactor may respond weakly to the measurement.
  • the second measurement may be taken at a frequency of much greater than 1 MHz (e.g., between 2 MHz and 30 MHz), as, at such frequency ranges, the nutrients and the dead cells, may be weakly responsive, and the viable biomass will no longer be strongly responsive, but only weakly responsive.
  • a permittivity value of only the viable biomass may be obtained.
  • a bioreactor may position live cells on a fixed mesh and provide a flow of nutrients via the nutrient circulation system of the bioreactor.
  • a second sensor to measure permittivity of the flow of nutrients in the nutrient circulation system (and thereby measuring the permittivity of the nutrients and dead cells, which tend not to adhere to the fixed mesh, without measuring the permittivity of the live cells)
  • the permittivity of the viable biomass can be calculated by comparing the first measurement with the second measurement (via the sensor 100).
  • Either of the above methods or other methods may be used to determine, for a specific biomass and nutrient combination (i.e., a specific organism and a specific nutrient type), an array of values of measured permittivities and associated biomasses (and, particularly in some embodiments, viable biomasses). These measured permittivities and associated biomasses (or, in some embodiments, viable biomasses) may be used to simplify (viable) biomass measurement for future measurement of reactors having the same biomass and nutrient combination.
  • a sensor e.g., the sensor 100
  • future reactors having the same biomass and nutrient combination may be monitored by a sensor (e.g., the sensor 100) by merely calculating a permittivity of the reactor (by, e.g., measuring the resonant frequency, impedance, inductance, or capacitance of the reactor) and comparing the calculated permittivity against the table to determine an associated (viable) biomass quantity for that measured permittivity.
  • Table 1 shows the details of five sensor embodiments that were constructed and tested using different coil designs.
  • Table 1 Sensor Configurations [0134] Each embodiment was assigned an identification (ID) number (#1, #2, #3, #4, or #5). Sensor embodiment #1 and sensor embodiment #2 each had a design of a single layer of 40 turns. Sensor embodiment #3 and sensor embodiment #4 each had a design of a single layer of 100 turns. Sensor embodiment #5 had a design of two layers, each of 100 turns, wound on top of each other. In all cases, the wire used was Daburn 2671/32. Additional details of the sensor coils are provided in Table 1. All except sensor embodiment #1 had external capacitors connected in parallel with the coil.
  • Sensor embodiment #1 had no capacitor and resonated because of stray capacitances (of which the internal capacitance is just one), which were on the order of only 10 pF, hence its high resonant frequency.
  • the resonators were driven by a current source consisting of a 47kQ resistor connected in series with a signal generator (Agilent type 33120A).
  • the last column of Table 1 is a measure of the sensitivity of the resonator in terms of the change in resonant frequency (f res ) caused by a change of one unit in s r .
  • f res change in resonant frequency
  • the resonant frequency and the sensitivity are related by the “universal” theoretical relationship: wherein N indicates the number of turns, L indicates inductance (pH), and I indicates the length (mm) of the coil. C ext indicates external capacitance, and f res indicates resonant frequency.
  • inductance is measured in Henries, length in meters, frequency in Hertz and capacitance in Farads.
  • the value for s 0 is 8.854x1 O' 12 F/m.
  • the relationship predicts that a graph of the cube of the resonant frequency plotted against the “normalized sensitivity” on the left-hand side of the equation will be a straight line.
  • FIG. 6 shows a loglog plot of the resonant frequencies (fres versus the normalized sensitivity for five sensor coils according to embodiments of the present subject matter. Each of the five embodiments was provided with an identification (ID) number as #1, #2, #3, #4, or #5.
  • ID identification
  • the labels on the data points show the ID number of the sensor coil embodiment (labeled #1, #2, #3, #4, #5), the resonant frequency, the inductance, the coil length, and the (un- normalized) sensitivity
  • the dotted line is a best fit to the data points, and the box to the right of the dotted line shows its equation and the coefficient of determination.
  • the darker dashed line represents the theoretical equation, which uses the “long coil” approximation, and the darker box to the left of the dashed line shows its equation and coefficient of determination.
  • the value on the X-axis (“normalized sensitivity”) for the experimental line is about twice as great as for the theoretical line as a result of the approximation.
  • FIG. 7A shows a cross sectional view of an embodiment comprising a gap 141 between the coil 140 and the reactor 105, and the gap may be defined or maintained by, e.g., the coil former 145 (not pictured).
  • An embodiment comprising a gap (e.g., the gap 141) between a sensor coil and a reactor may provide advantages over non-gapped embodiments, including, e.g., improving ease of use by enabling a reactor to be readily inserted or removed from the gap and eliminating the need to manipulate plugs or connectors to configure the sensor coil to the specific geometry of the reactor.
  • the embodiment of FIG. 7A comprises a reactor radius (rr) 142 and a gap radius (rg) 143.
  • a gap between a sensor coil and a reactor may cause a loss of sensitivity of the sensor coil, due to, e.g., the increased radius of the sensor coil.
  • a gap of less than or equal to 20% of a diameter or a reactor will generally cause a loss in sensitivity of the sensor coil of less than 20%.
  • the following limitation may be observed:
  • the difference in sensitivity between a gapped coil system and a non-gapped coil system may be modeled as the sum of two inductances in series.
  • the larger inductance generally, an inductance of the reactor 105
  • Contents of the reactor 105 comprise a permittivity si and a region between the contents of the reactor 105 and the coil 140 comprises a permittivity £2.
  • the region comprises layers including a wall of the reactor 105, the gap 141, the coil former 145, and any other materials between the contents of the reactor 105 and the coil 140. these individual layers have thicknesses 6 and permittivities and there is a total of N layers, then, for N > 1:
  • FIG. 8 shows a flowchart for a process 800 for designing systems according to embodiments described herein.
  • the process 800 comprises steps for the pre-design of the coil/capacitor resonator system.
  • Input parameters are chosen.
  • Input parameters in some embodiments and as depicted in block 802, are a desired resonant frequency, a length of the coil, and a desired sensitivity (df res /ds ).
  • a required inductance may be estimated using the formula:
  • systems or devices used may have a limited range of calculated values for L, and so, in block 820 and in such embodiments, if a calculated value of L is not usable, then the calculated value may necessitate, in block 822, modifying input parameters (e.g., the length of the coil) to adjust the calculated value such that the calculated value is within the limited range of the systems or devices.
  • input parameters e.g., the length of the coil
  • systems or devices used may have a limited range of calculated values for Cext, and so, in block 830 and in such embodiments, if a calculated value of Cext are not usable, then the calculated value may necessitate, in block 822, modifying input parameters to adjust the calculated value such that the calculated value is within the limited range of the systems or devices. If the value of Cext is usable, then the process 800 is complete.
  • the Q factors of the constructed prototype resonators were between 15 and 35. (The “Q” or “Quality” factor determines the sharpness of the resonance peak and higher is sharper. The sharper the peak, the more accurately the resonance frequency can be measured.) In all cases, the Q factors of the prototypes were adequate. Individual Q factors may also be defined for the coil and the capacitor, with a value of at least 50 to 100 for each. The system Q factor is affected by resistive losses, principally the parallel equivalent resistance of the current source used to drive the resonator, and the equivalent parallel loss resistance of the plastic reactor body. For the sensor embodiments provided in Table 1, these were about 47 kQ and 100 kQ respectively, and these values were found to be adequate. The higher these resistances, the better.
  • the LC resonator may be integrated into a system.
  • a manual method was adopted.
  • the manual method used the setup shown in FIG. 4.
  • the oscilloscope displayed two traces. One trace was the voltage across the coil.
  • the other trace was the output voltage of the waveform generator.
  • the traces, or voltages were out of phase. However, at resonance, the traces were in phase. Therefore, the measurement procedure comprised manually adjusting the frequency of the waveform generator until the two traces were in phase, at which point resonance had been achieved.
  • the resonance frequency of the LC coil sensor may be tracked continuously over time. Any suitable method may be used to track the resonance frequency of the LC coil sensor over time.
  • a nonlimiting example of a way to track the resonance includes automating the manual procedure of adjusting the frequency of the waveform generator until the two traces from the oscilloscope (the voltage across the coil and the output voltage of the waveform generator) were in phase, over time.
  • Another nonlimiting example of a way to track the resonance includes using an impedance analyzer.
  • Another nonlimiting example of a way to track the resonance includes incorporating the LC coil sensor into an oscillator and tracking the oscillation frequency (which is equal or substantially equal to the resonant frequency of the LC resonator), which is relatively simple and inexpensive (i.e., compared to using an impedance analyzer).
  • An alternative to resonance tracking is to measure the inductance of a coil surrounding a reactor during cell growth.
  • a nonlimiting example of inductance measurement of a coil surrounding a reactor during cell growth includes using an LCR meter connected directly across the coil sensor (i.e., omitting the capacitor of the previously-described LC circuit) to measure an inductance of the coil sensor.
  • a reactor e.g., a biomass or a viable biomass
  • a permittivity of the reactor may also change, causing, in turn, a measured inductance of the reactor to change.
  • the measured inductance and, thereby, the biomass or the viable biomass of the contents of the reactor
  • an illustrative example of this technique uses a coil of the same type as configuration ID #3 of Table 1, wound on a reactor.
  • Table 2 shows details of the coil of configuration ID #3 used in an inductance-measuring embodiment measuring an empty reactor (in row 1) and a reactor filled with water (in row 2).
  • Table 2 Configuration ID #3 in an Inductance-Measuring Embodiment
  • FIG. 9 shows a block diagram of a resonance frequency measurement component 900 according to an embodiment of systems described herein, namely monitoring cell growth by tracking the resonance frequency of a resonance coil 910 over time using an oscillator 920.
  • the oscillator 920 may be, in some embodiments, a Colpitts oscillator, but, in other embodiments, any suitable oscillator may be used.
  • the resonance coil 910 may form part of an LC oscillator but may be physically external to the rest of the components. As the biomass in a reactor changes, the permittivity changes, which causes the oscillation frequency of the oscillator 920 (when the reactor is positioned within the resonance coil 910) to change.
  • the output of the oscillator 920 is fed to a frequency counter 930, which measures a frequency of the oscillator 920.
  • the frequency counter 930 may be, in some embodiments, a commercial frequency counter (BK Precision 1856D), but, in other embodiments, any suitable frequency counter may be used.
  • the output of the frequency counter 930 is provided to a computer 940 by an electrical coupling (e.g., a RS232 link).
  • the computer 940 may thereby store the frequency data as a function of time and manipulate and display the data in an appropriate form, which may be selected by the user.
  • FIG. 10 shows an embodiment comprising a circuit diagram 1000 of a Colpitts oscillator designed for such a use and oscillated at around 400 kHz.
  • An integrated circuit 1010 as depicted in the embodiment of FIG. 10, is the LT 1227 operational amplifier, obtained from Analog Devices, but, in other embodiments, the integrated circuit 1010 may be any suitable circuit.
  • Outputs i.e., in the embodiment of FIG. 10, a voltage oscillating at the resonant frequency or, in other embodiments, measured values such as a resonance frequency, an impedance, a capacitance, or a permittivity
  • the supply voltage (Vs) of this embodiment may be approximately 9 Volts.
  • the coil 140 may require a constant temperature, e.g. a temperature maintained within 0.1 °C of a target temperature.
  • a Colpitts oscillator may also require a similar constant temperature.
  • an incubator may be used.
  • the coil 140 may be positioned inside of the incubator, and many incubators have temperature control at or near a sufficient level for operation of the coil 140 and associated coil sensor embodiments.
  • Remaining components of an oscillator circuit of the coil sensor embodiment may be positioned within the incubator or, in other embodiments, may be connected to an external circuit board housed in a temperature-controlled enclosure (which may be, in some embodiments, attached to or, in other embodiments, separate from the incubator).
  • FIG. 11 A shows a schematic drawing of an embodiment comprising, rather than a coil sensor wound about the reactor, a capacitor sensor 1100 comprising a first electrode plate 1120 and a second electrode plate 1130 positioned about the reactor 105 and electrically coupled to a capacitance measuring component 1102, which measures a capacitance 1110 of a system comprising the capacitor sensor 1100 and the reactor 105.
  • the electrode plates 1120, 1130 may comprise adhesive copper tape or may comprise other conductive materials.
  • the electrode plates 1120, 1130 may be attached to either the reactor 105 (and, particularly in the embodiment of FIG. 11 A, attached to an outside surface 1156 of a wall 1150 of the reactor 105) or an external former positioned about the reactor 105.
  • the electrode plates 1120, 1130 are attached symmetrically about the reactor 105, such that the first electrode plate 1120 and the second electrode plate 1130 are disposed on opposite sides of a longitudinal axis 1105 (traversing into and out of the page) of the reactor 105.
  • the capacitor sensor 1100 of the capacitance-measuring embodiment of FIGs. 11A-B is used to calculate a permittivity of the reactor 105 by measuring an electromagnetic property of the reactor 105 (in particular, the capacitance of the reactor 105).
  • the relationship between a measured capacitance of the reactor 105 and a permittivity of the reactor 105 may not be linear; instead, the two values exhibit a non-linear relationship.
  • a measured capacitance of the reactor 105 depends on the capacitance of the reactor 105 and the contents of the reactor 105 can be modeled as a capacitor in series (rather than in parallel), and, in addition to environmental capacitance (which may be modeled as a capacitor in parallel), this effect results in a non-linear relationship between the measured capacitance of the reactor 105 and the permittivity of the reactor 105.
  • FIG. 1 IB illustrates a simplified circuit diagram of this embodiment.
  • a capacitance 1111 (Cy) represents the environmental capacitance
  • a capacitance 1112 (C ) represents the capacitance of the contents of the reactor 105
  • a capacitance 1113 (Cj) represents the capacitance of the wall 1150 of the reactor 105 (and, in embodiments using an external former, the capacitance 1113 (Cj) further includes the capacitance of the external former).
  • the capacitance 1110 (C) thereby represents the total capacitance of the system, which may be defined by the following formula:
  • measuring the capacitance of the reactor 105 may require that the resolution of the capacitor sensor 1100 be on the order of 0.001 pF or of a more precise resolution than 0.001 pF, and, due to such a high degree of sensitivity, measures to reduce noise (e.g., electromagnetic interference) may also be necessary.
  • shielding 1140 (comprising, e.g., a non-conductive material) may be placed around the capacitor sensor 1100 and the reactor 105 to shield the capacitor sensor 1100 from noise. In embodiments, the shielding 1140 is grounded. In some embodiments, the shielding 1140 may wholly surround sides of the capacitor sensor 1100 and the reactor 105 (as in the embodiment of FIG.
  • the shielding 1140 may further surround the capacitor sensor 1100 and the reactor 105 from above and/or below.
  • the shielding 1140 may reduce errors produced by environmental effects (e.g., effects of nearby machinery, moving objects or people, or movement of the capacitor sensor 1100) on capacitances measured by the capacitor sensor 1100.
  • vibration of the capacitor sensor 1100 and/or the reactor 105 may affect capacitance measurements of the capacitor sensor 1100.
  • embodiments fix in place any or all of the reactor 105, the capacitor sensor 1100, or any associated electric cables to reduce such vibration or other movement.
  • the capacitance 1113 (C3) is in series with the capacitance 1112 (C2), the capacitance 1113 may degrade the performance of the sensor.
  • the effects of the capacitance 1113 (C3) may be, in some embodiments, mitigated by making a value of the capacitance 1113 (C3) as large as possible, so that a reactance associated with the capacitance 1113 (C3) is as small as possible.
  • Certain such embodiments may, referring again to FIG. HA, comprise making the wall 1150 of the reactor 105 as thin as practically possible (e.g., having a thickness of 1 mm) in regions 1152, 1154 of the wall of the reactor 105 in a vicinity of the electrode plates 1120, 1130, respectively. In the embodiment of FIG.
  • the regions 1152, 1154 of the wall 1150 are portions of the wall in contact with a respective one of the electrode plates 1120, 1130, but, in other embodiments where the electrode plates 1120, 1130 are not in contact with the outside surface 1156 of the wall 1150, the regions 1152, 1154 may instead be regions near the electrode plates 1120, 1130 (e.g., regions of the wall 1150 between the electrode plates 1120, 1130).
  • An alternative embodiment may, instead, use a material (e.g., alumina) having a high relative permittivity (e.g., a permittivity of greater than 3 and less than 1,000) in this region (e.g., alumina with a permittivity of 10).
  • a thin material e.g., alumina with a thickness such as 40 pm
  • a very high relative permittivity e.g., a permittivity of greater than 100,000).
  • the method 1200 begins at the block 1201, with positioning the sensor 100 for measurement of a reactor.
  • the sensor 100 comprises a resonator and a resonance frequency measuring component (e.g., the electromagnetic property measuring component 103).
  • the resonator comprises the coil 140, the capacitor 120, and an oscillator.
  • the coil 140 is disposed around the reactor 105 and comprises a cylindrical magnetic coil, and the capacitor 120 is connected across the coil 140.
  • the oscillator is electrically coupled to the resonator, and the oscillator produces an alternating electric current within the resonator.
  • the resonance frequency measuring component is electrically coupled to the oscillator and to the resonator, and the resonance frequency measuring component may measure a resonance frequency of the resonator.
  • the positioning the sensor for measurement of the reactor 105 may comprise winding the coil 140 of the sensor 100 around an exterior surface of the reactor 105.
  • the positioning the sensor for measurement of the bioreactor comprises winding the coil 140 of the sensor around the coil former 145, and the coil former 145 is configured to receive the reactor 105 in an interior cavity of the coil former 145.
  • the resonance frequency measuring component may comprise the oscillator and at least one of a resistor, a waveform generator, and an oscilloscope; an impedance analyzer; a swept frequency generator and a spectrum analyzer; and any combination thereof.
  • the method 1200 continues at block 1202, with collecting a measured resonance frequency of the reactor 105.
  • the sensor 100 may be configured to measure permittivity at resonance frequencies in a range of 10 kHz to 100 MHz, in a range of 10 kHz to 10 MHz, in a range of 10 kHz to 1MHz, or any range contained therein.
  • the measuring of the measured resonance frequency may comprise frequency measurement, and, in some such embodiments, the sensor 100 may be configured to use inductance in a range of 1 pH to 10 mH.
  • collecting the measured resonance frequency may comprise collecting a plurality of measured resonance frequencies over a period of time to monitor a biomass or a viable biomass in the bioreactor over the period of time.
  • collecting changes in the measured resonance frequency over time changes in the permittivity of the reactor 105 over time can be detected, and, by detecting changes in the permittivity over time, changes in the contents of the reactor 105 may be detected.
  • collecting the measured resonance frequency may comprise collecting a plurality of measured resonance frequencies to calculate a moving average resonance frequency.
  • measured values taken only a short time apart may exhibit changes in measured values (due to, e.g., environmental factors), and so when identifying contents of a reactor, by collecting a plurality of measured resonance frequencies, an average resonance frequency can be calculated to diminish the influence of such changes.
  • Such a moving average resonance frequency may, in some embodiments, be calculated by using tens or hundreds of measurements, and, in embodiments, such measurements may be taken at intervals of several minutes apart.
  • the method 1200 continues at block 1203, with determining the contents of the reactor 105 based on the measured resonance frequency of the reactor 105.
  • the contents of the reactor 105 may comprise an aggregate biomass and, in such embodiments, determining the contents of the bioreactor comprises determining an aggregate biomass quantity of the bioreactor. In embodiments, determining the aggregate biomass quantity may comprise determining an aggregate viable biomass quantity.
  • reactors having the same biomass and nutrient combination may be monitored by a sensor (e.g., the sensor 100) by merely measuring the same electromagnetic property of the reactor 105 (by, e.g., measuring the resonant frequency or permittivity of the reactor 105) and comparing a calculated permittivity or the measured electromagnetic property against the table to determine an associated (viable) biomass quantity for that calculated permittivity or measured electromagnetic property.
  • a sensor e.g., the sensor 100
  • determining the aggregate biomass may comprise identifying at least one corresponding potential resonance frequency of a plurality of resonance frequencies, wherein the at least one corresponding potential resonance frequency corresponds to the measured resonance frequency and each potential resonance frequency corresponds to a previously-identified aggregate biomass quantity of a plurality of previously identified biomass quantities.
  • a measured resonance frequency may be determined to correspond to a previously identified resonance frequency of such a table (by, e.g., picking a closest-in-value previously identified resonance frequency or by an average or weighting formula associated with nearest- in-value previously identified resonance frequencies).
  • determining the aggregate biomass may further comprise identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously- identified aggregate biomass quantity of the at least one corresponding potential resonance frequency.
  • identifying a corresponding previously identified (i.e., potential) resonance frequency a previously identified aggregate biomass quantity (or, an average or otherwise weighted combination of several previously identified aggregate biomass quantity) can be determined to be the measured aggregate biomass quantity of the reactor 105.
  • the at least one corresponding potential resonance frequency may comprise a first resonance frequency and a second resonance frequency, and the corresponding potential resonance frequency may be equal to at least one of the first resonance frequency, the second resonance frequency, or a mathematical combination of at least the first resonance frequency and the second resonance frequency.
  • collecting the measured resonance frequency may comprise collecting a plurality of measured resonance frequencies, and the at least one corresponding potential resonance frequency may correspond to at least one of the plurality of measured resonance frequencies.
  • collecting the measured resonance frequency may comprise collecting a plurality of measured resonance frequencies, and the at least one corresponding potential resonance frequency may correspond to at least one of the plurality of measured resonance frequencies.
  • Either or both embodiments, solely or in combination, may provide a mechanism for determining a corresponding previously identified resonance frequency when a first measured resonance frequency does not exactly equal any previously identified resonance frequency.
  • determining the aggregate biomass quantity when measuring biomass, may further comprise calculating, using the measured resonance frequency, a measured permittivity of the bioreactor. In some such embodiments, and as described above with respect to resonance frequencies, determining the aggregate biomass quantity may further comprise identifying at least one corresponding potential permittivity of a plurality of potential permittivities, wherein the at least one corresponding potential permittivity may correspond to the measured permittivity, and wherein each potential permittivity of the plurality of potential permittivities may correspond to a previously-identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities. In such embodiments, determining the aggregate biomass quantity may further comprise identifying the aggregate biomass quantity of the bioreactor, and the aggregate biomass quantity may correspond to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential permittivity.
  • the method 1200 optionally continues at block 1204, with transmitting the measured resonance frequency from the sensor to a data processor for analysis. Analysis may comprise analysis of the measured resonance frequency, calculation or correlation to a biomass monitoring, display of the biomass monitoring over a period of time, or a combination thereof. [0179] The method 1200 optionally continues at block 1205, with filling the reactor 105. In embodiments, filling the reactor 105 may comprise filling the reactor 105 with cells to be cultured, cell culture media, any additives or supplements for a cell culture experiment, or any combination thereof.
  • the method 1200 optionally continues at block 1206, with culturing the cells for a period of time.
  • an exemplary method 1300 of measuring contents of a reactor is depicted.
  • the method 1300 begins at the block 1301, with positioning the sensor 100 for measurement of a reactor.
  • the sensor 100 comprises a resonator and an impedance frequency measuring component (e.g., the electromagnetic property measuring component 103).
  • the resonator comprises the coil 140 and the capacitor 120.
  • the coil 140 is disposed around the reactor 105 and comprises a cylindrical magnetic coil, and the capacitor 120 is connected across the coil 140.
  • the impedance measuring component is electrically coupled to the resonator, and the impedance measuring component measures an impedance of the resonator and the reactor 105 at a fixed frequency.
  • the fixed frequency may be a frequency near in value to a resonant frequency of the sensor 100.
  • the fixed frequency may be between 50 kHz and 1 MHz. In further embodiments, the fixed frequency may be between 500 kHz and 700 kHz.
  • the positioning the sensor for measurement of the reactor 105 may comprise winding the coil 140 of the sensor 100 around an exterior surface of the reactor 105. In other embodiments, the positioning the sensor for measurement of the bioreactor comprises winding the coil 140 of the sensor around the coil former 145, and the coil former 145 is configured to receive the reactor 105 in an interior cavity of the coil former 145.
  • the impedance measuring component may be an impedance analyzer, an LCR meter, a swept frequency generator and a spectrum analyzer, or some combination thereof.
  • the method 1300 continues at block 1302, with collecting a measured impedance of the reactor 105.
  • the sensor 100 may be configured to measure permittivity at resonance frequencies in a range of 10 kHz to 100 MHz, in a range of 10 kHz to 10 MHz, in a range of 10 kHz to 1MHz, or any range contained therein.
  • the measuring of the measured impedances may comprise frequency measurement, and, in some such embodiments, the sensor 100 may be configured to use inductance in a range of 1 pH to 10 mH.
  • collecting the measured impedance may comprise collecting a plurality of measured impedances over a period of time to monitor a biomass in the bioreactor over the period of time. As described above, by monitoring changes in the measured impedance over time, changes in the permittivity of the reactor 105 over time can be detected, and, by detecting changes in the in the permittivity over time, changes in the contents of the reactor 105 may be detected.
  • collecting the measured impedance may comprise collecting a plurality of measured impedances to calculate a moving average impedance.
  • measured values taken only a short time apart may exhibit changes in measured values (due to, e.g., environmental factors), and so when identifying contents of a reactor, by collecting a plurality of measured impedances, an average impedance can be calculated to diminish the influence of such changes.
  • a moving average impedance may, in some embodiments, be calculated by using tens or hundreds of measurements, and, in embodiments, such measurements may be taken at intervals of several minutes apart.
  • the method 1300 continues at block 1303, with determining the contents of the reactor 105 based on the measured impedance of the reactor 105.
  • the contents of the reactor 105 may comprise an aggregate biomass and, in such embodiments, determining the contents of the bioreactor comprises determining an aggregate biomass quantity of the bioreactor.
  • the aggregate biomass quantity may be an aggregate viable biomass quantity.
  • reactors having the same biomass and nutrient combination may be monitored by a sensor (e.g., the sensor 100) by merely measuring the same electromagnetic property of the reactor 105 (by, e.g., measuring the resonant frequency or permittivity of the reactor 105) and comparing a calculated permittivity or the measured electromagnetic property against the table to determine an associated (viable) biomass quantity for that calculated permittivity or measured electromagnetic property.
  • a sensor e.g., the sensor 100
  • determining the aggregate biomass may comprise identifying at least one corresponding potential impedance of a plurality of impedances, wherein the at least one corresponding potential impedance corresponds to the measured impedance and each potential impedance corresponds to a previously-identified aggregate biomass quantity of a plurality of previously identified biomass quantities.
  • a measured impedance may be determined to correspond to a previously identified impedance of such a table (by, e.g., picking a closest-in-value previously identified impedance or by an average or weighting formula associated with nearest-in- value previously identified impedances).
  • determining the aggregate biomass may further comprise identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential impedance.
  • identifying a corresponding previously identified (i.e., potential) impedance a previously identified aggregate biomass quantity (or, an average or otherwise weighted combination of several previously identified aggregate biomass quantity) can be determined to be the measured aggregate biomass quantity of the reactor 105.
  • the at least one corresponding potential impedance may comprise a first impedance and a second impedance, and the corresponding potential impedance may be equal to at least one of the first impedance, the second impedance, or a mathematical combination of at least the first impedance and the second impedance.
  • collecting the measured impedance may comprise collecting a plurality of measured impedances, and the at least one corresponding potential impedance may correspond to at least one of the plurality of measured impedances. Either or both embodiments, solely or in combination, may provide a mechanism for determining a corresponding previously identified impedance when a first measured impedance does not exactly equal any previously identified impedance.
  • determining the aggregate biomass quantity when measuring biomass, may further comprise calculating, using the measured impedance, a measured permittivity of the bioreactor. In some such embodiments, and as described above with respect to resonance frequencies, determining the aggregate biomass quantity may further comprise identifying at least one corresponding potential permittivity of a plurality of potential permittivities, wherein the at least one corresponding potential permittivity may correspond to the measured permittivity, and wherein each potential permittivity of the plurality of potential permittivities may correspond to a previously-identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities. In such embodiments, determining the aggregate biomass quantity may further comprise identifying the aggregate biomass quantity of the bioreactor, and the aggregate biomass quantity may correspond to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential permittivity.
  • the method 1300 optionally continues at block 1304, with transmitting the measured impedance from the sensor to a data processor for analysis.
  • Analysis may comprise analysis of the measured impedance, calculation or correlation to a biomass monitoring, display of the biomass monitoring over a period of time, or a combination thereof.
  • filling the reactor 105 may comprise filling the reactor 105 with cells to be cultured, cell culture media, any additives or supplements for a cell culture experiment, or any combination thereof.
  • the method 1300 optionally continues at block 1306, with culturing the cells for a period of time.
  • the method 1400 begins at the block 1401, with positioning the sensor 100 for measurement of a reactor.
  • the capacitor sensor 1100 comprises the first electrode plate 1120, the second electrode plate 1130, and the capacitance measuring component 1102.
  • the first electrode plate 1120 and the second electrode plate 1130 are disposed outside of the reactor 105 and on opposite sides of a longitudinal axis of the reactor 105.
  • the capacitance measuring component 1102 is electrically coupled to the first electrode plate 1120 and to the second electrode plate 1130, and the capacitance measuring component 1102 measures measured capacitance of the reactor 105 between the first electrode plate 1120 and the second electrode plate 1130.
  • the capacitor sensor 1100 may further comprise the shielding 1140, wherein the shielding at least partially surrounds the first electrode plate 1120 and the second electrode plate 1130.
  • the capacitance measuring component 1102 may comprise an LCR meter, and, in further such embodiments, the LCR meter may measure capacitance in a range of 0 pF to 100 pF, a range of 0.0001 pF to IfF, or any range contained therein.
  • the method 1400 continues at block 1402, with collecting a measured capacitance of the reactor 105.
  • collecting the measured capacitance may comprise collecting a plurality of measured capacitances over a period of time to monitor a biomass in the bioreactor over the period of time. As described above, by monitoring changes in the measured capacitance over time, changes in the permittivity of the reactor 105 over time can be detected, and, by detecting changes in the in the permittivity over time, changes in the contents of the reactor 105 may be detected. [0199] In embodiments, collecting the measured capacitance may comprise collecting a plurality of measured capacitances to calculate a moving average capacitance.
  • measured values taken only a short time apart may exhibit changes in measured values (due to, e.g., environmental factors), and so when identifying contents of a reactor, by collecting a plurality of measured capacitance, an average capacitance can be calculated to diminish the influence of such changes.
  • a moving average capacitance may, in some embodiments, be calculated by using tens or hundreds of measurements, and, in embodiments, such measurements may be taken at intervals of several minutes apart.
  • the method 1400 continues at block 1403, with determining the contents of the reactor 105 based on the measured capacitance of the reactor 105.
  • the contents of the reactor 105 may comprise an aggregate biomass and, in such embodiments, determining the contents of the bioreactor comprises determining an aggregate biomass quantity of the bioreactor.
  • the aggregate biomass quantity may be an aggregate viable biomass quantity.
  • reactors having the same biomass and nutrient combination may be monitored by a sensor (e.g., the sensor 100) by merely measuring the same electromagnetic property of the reactor 105 (by, e.g., measuring the resonant frequency or permittivity of the reactor 105) and comparing a calculated permittivity or the measured electromagnetic property against the table to determine an associated (viable) biomass quantity for that calculated permittivity or measured electromagnetic property.
  • a sensor e.g., the sensor 100
  • determining the aggregate biomass may comprise identifying at least one corresponding potential capacitance of a plurality of capacitances, wherein the at least one corresponding potential capacitance corresponds to the measured capacitance and each potential capacitance corresponds to a previously-identified aggregate biomass quantity of a plurality of previously identified biomass quantities.
  • a measured capacitance may be determined to correspond to a previously identified capacitance of such a table (by, e.g., picking a closest-in-value previously identified capacitance or by an average or weighting formula associated with nearest-in- value previously identified capacitance).
  • determining the aggregate biomass may further comprise identifying the aggregate biomass quantity of the bioreactor, wherein the aggregate biomass quantity corresponds to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential capacitance.
  • identifying a corresponding previously identified (i.e., potential) capacitance a previously identified aggregate biomass quantity (or, an average or otherwise weighted combination of several previously identified aggregate biomass quantity) can be determined to be the measured aggregate biomass quantity of the reactor 105.
  • the at least one corresponding potential capacitance may comprise a first capacitance and a second capacitance, and the corresponding potential capacitance may be equal to at least one of the first capacitance, the second capacitance, or a mathematical combination of at least the first capacitance and the second capacitance.
  • collecting the measured capacitance may comprise collecting a plurality of measured capacitances, and the at least one corresponding potential capacitance may correspond to at least one of the plurality of measured capacitance. Either or both embodiments, solely or in combination, may provide a mechanism for determining a corresponding previously identified capacitance when a first measured capacitance does not exactly equal any previously identified capacitance.
  • determining the aggregate biomass quantity when measuring biomass, may further comprise calculating, using the measured capacitance, a measured permittivity of the bioreactor. In some such embodiments, and as described above with respect to resonance frequencies, determining the aggregate biomass quantity may further comprise identifying at least one corresponding potential permittivity of a plurality of potential permittivities, wherein the at least one corresponding potential permittivity may correspond to the measured permittivity, and wherein each potential permittivity of the plurality of potential permittivities may correspond to a previously-identified aggregate biomass quantity of a plurality of previously-identified aggregate biomass quantities. In such embodiments, determining the aggregate biomass quantity may further comprise identifying the aggregate biomass quantity of the bioreactor, and the aggregate biomass quantity may correspond to a corresponding previously-identified aggregate biomass quantity of the at least one corresponding potential permittivity.
  • the method 1400 optionally continues at block 1404, with transmitting the measured capacitance from the sensor to a data processor for analysis.
  • Analysis may comprise analysis of the measured capacitance, calculation or correlation to a biomass monitoring, display of the biomass monitoring over a period of time, or a combination thereof.
  • filling the reactor 105 may comprise filling the reactor 105 with cells to be cultured, cell culture media, any additives or supplements for a cell culture experiment, or any combination thereof.
  • the method 1400 optionally continues at block 1406, with culturing the cells for a period of time.
  • the methods 1200, 1300, 1400 for measuring the contents (e.g., a biomass) of a bioreactor of the bioreactor may include measuring or calculating an electromagnetic property of a bioreactor (e.g., the resonance frequency of the bioreactor, the impedance of the bioreactor, the inductance of the bioreactor, the capacitance of the bioreactor, and/or the permittivity of the bioreactor) with a sensor.
  • an electromagnetic property of a bioreactor e.g., the resonance frequency of the bioreactor, the impedance of the bioreactor, the inductance of the bioreactor, the capacitance of the bioreactor, and/or the permittivity of the bioreactor
  • the measured property of the bioreactor may be compared to, for example, a look-up table which includes known properties of the bioreactor (e.g., previously measured resonance frequencies of the bioreactor, previously measured impedances of the bioreactor, previously measured inductances of the bioreactor, previously measured capacitances of the bioreactor, and/or previously calculated permittivities of the bioreactor) indexed according to experimentally determined measurements of contents of the bioreactor for each of the known properties.
  • known properties of the bioreactor e.g., previously measured resonance frequencies of the bioreactor, previously measured impedances of the bioreactor, previously measured inductances of the bioreactor, previously measured capacitances of the bioreactor, and/or previously calculated permittivities of the bioreactor
  • a measured electromagnetic property the bioreactor may be compared to the look-up table, equated to a known property of the bioreactor, and thereby correlated to a measured contents of the bioreactor.
  • FIG. 15 further illustrates additional components of the sensor system 190. These components may be incorporated into the sensor 100.
  • the sensor system 190 may further include a controller 1570 configured to control the various components of the system.
  • the controller 1570 may be configured to control the sensor, distinguish between sensor readings, control the frequency of monitoring or measurements, control the communications module 1550, control the data processor 1560, or any combination thereof.
  • the sensor system 190 may further include a communications module 1550 configured to transfer data from the sensor 100 to a data processor 1560.
  • the communications module 1550 may be configured to communicate through a wired or wireless connection, including, but not limited to, a data connection conforming to one or more of the IEEE 802.11 family of standards (e.g., WiFi), a Bluetooth connection, a cellular network connection, an RF connection, a Universal Serial Bus (USB), an Ethernet connection, or any other data connection.
  • the data processor 1560 may be configured to record and analyze permittivity measurements received from the sensor 100.
  • the communications module 1550, and data processor 1560 may be on a single electronic device or multiple electronic devices, such as one or more desktop computers, laptop computers, tablet PCs, or other computer systems.
  • the controller 1570, communications module 1550, and data processor 1560 may interact so as to provide certain features to the sensor 100.
  • the sensor 100 may be adapted to record the permittivity measurements (and subsequent biomass data indications and/or monitoring in a reactor) in a non-transitory computer readable medium.
  • the sensor system 190 may be adapted to allow a user to record and/or analyze permittivity measurements and data and by proxy, biomass data.
  • the sensor 100 may allow a user to set a monitoring period and/or monitoring frequency, such that permittivity measurement data is recorded and/or analyzed a specified number of times in a predefined time period for a specified duration of time (e.g., a measurement recorded once every 30 minutes over a 24-hour time period).
  • the permittivity measurement data may be recorded and/or analyzed at a defined frequency continuously for an indefinite duration.
  • the sensor 100 may be configured to communicate with a remote user device.
  • remote user devices include a mobile phone device, a tablet computer, a desktop computer, a laptop computer, and/or other computing system.
  • the sensor 100 may be configured to send permittivity measurements and data to the remote user device.
  • the remote user device may be adapted to control the sensor 100, including any of the functionality discussed above.
  • FIG. 16 depicts an example of internal hardware that may be used to contain or implement the various computer processes and systems as discussed herein.
  • the sensor 100 discussed above may include mobile device hardware such as that illustrated in FIG. 12.
  • An electrical bus 500 serves as an information highway interconnecting the other illustrated components of the hardware.
  • the CPU 505 is a central processing unit of the system, performing calculations and logic operations required to execute a program.
  • the CPU 505, alone or in conjunction with one or more of the other elements, is a processing device, computing device or processor as such terms are used within this disclosure.
  • a CPU or “processor” is a component of an electronic device that executes programming instructions.
  • the term “processor” may refer to either a single processor or to multiple processors that together implement various steps of a process.
  • processor includes both the singular and plural embodiments.
  • Read only memory (ROM) 510 and random-access memory (RAM) 515 constitute examples of memory devices, wherein the term “memory device” and similar terms include single device embodiments, multiple devices that together store programming or data, or individual sectors of such devices.
  • a controller 520 interfaces with one or more optional memory devices 525 that serves as data storage facilities to the electrical bus 500.
  • the optional memory devices 525 may include, for example, an external or internal disk drive, a hard drive, flash memory, a USB drive or another type of device that serves as a data storage facility. Such various drives and controllers are optional devices.
  • the optional memory devices 525 may be configured to include individual files for storing any software modules or instructions, auxiliary data, incident data, common files for storing groups of contingency tables and/or regression models, or one or more databases for storing the information as discussed above.
  • the ROM 510 and/or the RAM 515 may store program instructions, software, or interactive modules for performing any of the functional steps associated with the processes as described above.
  • program instructions may be stored on a non-transitory, computer readable medium such as a compact disk, a digital disk, flash memory, a memory card, a USB drive, an optical disc storage medium, and/or other recording medium.
  • the sensor cap may comprise a display screen or display interface.
  • Such an optional display interface 540 may permit information from the electrical bus 500 to be displayed on the display 545 in audio, visual, graphic or alphanumeric format. For example, permittivity measurements over a time period collected by a sensor disposed around a reactor and that correspond to a graphic showing the monitoring of biomass levels in the reactor over that time period may be displayed.
  • Communication with external devices may occur using communication ports 550.
  • the communication port 550 may be attached to a communications network, such as the Internet, a local area network or a cellular telephone data network.
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, embodiments include from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

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Abstract

L'invention concerne des capteurs, des systèmes et des procédés permettant de déterminer les contenus d'un réacteur. Un procédé de détermination de contenus d'un réacteur comprend le positionnement d'un capteur pour la mesure du réacteur, la collecte d'une propriété électromagnétique mesurée du réacteur, et la détermination des contenus du réacteur sur la base de la propriété électromagnétique mesurée.
PCT/US2023/065203 2022-03-31 2023-03-31 Capteur sans contact pour la mesure de contenus d'un réacteur Ceased WO2023192983A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4810963A (en) * 1984-04-03 1989-03-07 Public Health Laboratory Service Board Method for investigating the condition of a bacterial suspension through frequency profile of electrical admittance
GB2260407A (en) * 1991-10-10 1993-04-14 Christopher Barnes Contactless measurement of physical parameters of samples
WO2004023125A2 (fr) * 2002-09-05 2004-03-18 Pendragon Medical Ltd. Systemes et procedes bases sur une spectroscopie d'impedance
US20050074904A1 (en) * 2003-09-10 2005-04-07 Auburn University Magnetostrictive ligand sensor
US20140090454A1 (en) * 2012-09-28 2014-04-03 General Electric Company Sensor Systems for Measuring an Interface Level in a Multi-Phase Fluid Composition
US20200018867A1 (en) * 2017-03-14 2020-01-16 Salunda Limited Sensor for Detecting the Contents of a Bore

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4810963A (en) * 1984-04-03 1989-03-07 Public Health Laboratory Service Board Method for investigating the condition of a bacterial suspension through frequency profile of electrical admittance
GB2260407A (en) * 1991-10-10 1993-04-14 Christopher Barnes Contactless measurement of physical parameters of samples
WO2004023125A2 (fr) * 2002-09-05 2004-03-18 Pendragon Medical Ltd. Systemes et procedes bases sur une spectroscopie d'impedance
US20050074904A1 (en) * 2003-09-10 2005-04-07 Auburn University Magnetostrictive ligand sensor
US20140090454A1 (en) * 2012-09-28 2014-04-03 General Electric Company Sensor Systems for Measuring an Interface Level in a Multi-Phase Fluid Composition
US20200018867A1 (en) * 2017-03-14 2020-01-16 Salunda Limited Sensor for Detecting the Contents of a Bore

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