Methods and systems for real-time sensing of viable and nonviable cells

Abstract

Provided herein are techniques for identification of viable and nonviable cells in a cell culture that include measuring a resonance impedance spectral response of at least one resonator in proximity to the cell culture and correlating the measured response to the concentration of viable cells in cell culture and/or the concentration of nonviable cells in cell culture.

1 . A system, comprising:
 a sensor comprising:
 a dielectric substrate; 
 at least one sensing region; and 
 a plurality of tuning circuits over a frequency range of analysis of a cell culture reaction, wherein the sensor is configured to be compatible with at least one a plurality of cell culture media types; and 
   a reader configured to receive a signal from the sensor across the frequency range of analysis; and   processing circuitry configured to perform the steps of:
 analyzing impedance spectra of the sensor; and 
 determining one or more properties of the cell culture reaction based on the analyzed impedance spectra. 
   
     
     
         2 . The system of  claim 1 , where the system quantifies a concentration of nonviable cells and a concentration of viable cells. 
     
     
         3 . The system of  claim 1 , where the system quantifies a concentration of nonviable cells, a concentration of viable cells, and a size of viable cells. 
     
     
         4 . The system of  claim 1 , wherein the reader is configured to communicate wirelessly with a bioprocess control system controlling the cell culture reaction. 
     
     
         5 . The system of  claim 1 , wherein the sensing pregion is protected from direct contact with the cell culture reaction via a biocompatible dielectric conformal layer. 
     
     
         6 . The system of  claim 1 , wherein the sensor is inserted or mounted to a non-rigid container via mounting device such that the sensor is held aseptically within the internal space of the container and in operational contact with fluid within the container. 
     
     
         7 . The system of  claim 1 , wherein the mounting device comprises a hose barb port. 
     
     
         8 . A system, comprising:
 a bioreactor holding a cell culture reaction;   a sensor comprising at least one sensing region in operational contact with the cell culture reaction;   a reader configured to receive a signal from the sensor, wherein the signal is representative of impedance spectra of the sensing region over a measured spectral frequency range; and   processing circuitry configured to perform the steps of:
 analyzing the impedance spectra of the sensor; and 
 determining one or more properties of the cell culture reaction based on the analyzed impedance spectra. 
   
     
     
         9 . The system of  claim 8 , where the system quantifies a concentration of nonviable cells and a concentration of viable cells. 
     
     
         10 . The system of  claim 8 , where the system quantifies a concentration of nonviable cells, a concentration of viable cells, and a size of viable cells. 
     
     
         11 . The system of  claim 8 , wherein the reader is configured to communicate wirelessly with a bioprocess control system controlling the cell culture reaction. 
     
     
         12 . The system of  claim 8 , wherein the sensing pregion is protected from direct contact with the cell culture reaction via a biocompatible dielectric conformal layer. 
     
     
         13 . The system of  claim 8 , wherein the sensor is inserted or mounted to a non-rigid container via a mounting device such that the sensor is held aseptically within the internal space of the container and in operational contact with fluid within the container. 
     
     
         14 . The system of  claim 13 , wherein the mounting device comprises a hose barb port. 
     
     
         15 . The system of  claim 8 , wherein the sensor comprises a plurality of tuning circuits outside a fluid of the cell culture reaction. 
     
     
         16 . A system, comprising:
 a sensor comprising at least one sensing region in contact with a cell culture reaction;   a reader configured to receive a signal from the sensor, wherein the signal is representative of impedance spectra of the sensing region over a measured spectral frequency range; and   processing circuitry configured to perform the steps of:
 analyzing the impedance spectra of the sensor; and 
 determining one or more properties of the cell culture reaction based on the analyzed impedance spectra. 
   
     
     
         17 . The system of  claim 16 , wherein the sensor comprises at least two electrodes. 
     
     
         18 . The system of  claim 17 , wherein the at least two electrodes form a sensing electrode structure. 
     
     
         19 . The system of  claim 18 , wherein the sensing electrode structure is part of the sensing region. 
     
     
         20 . The system of  claim 17 , wherein the sensor comprises at least one resonant circuit.