Integrated capsule system for real-time bioprocess monitoring and method of using the same

1 . A system for in-situ real-time wireless and continuous monitoring of a product process in a bioreactor, the system comprising:

a bioreactor tank containing a culture media within with a magnetic source disposed about the tank;

an external control device;

a plurality of neutral buoyant devices each independently free-floating within the culture media, each neutral buoyant device comprising:

a leak-proof housing, including a top half and a bottom half, the top half including a bayonet twist connector to form a leak proof seal with the bottom half, the top half including a central cutout;

an electrochemical cell including a bioprocess sensor, the bioprocess sensor including a first end having a plurality of contact pins and a second end having a sensor interface, the electrochemical cell being disposed in the central cutout of the housing with a leak-proof connection therebetween, the contact pins being disposed within the housing and the sensor interface disposed outside the housing and exposed to the culture media to sense a parameter of the product process in the culture media;

a card edge connector interfaced with the sensor, the card edge connector having leak-proof fittings located between the plurality of contact pins and the sensor interface of the bioprocess sensor;

a readout circuit directly interfaced with the sensor via the card edge connector, the readout circuit including an analog front end (AFE) potentiostat;

a power supply contained within the housing; and

an electronics module contained within the housing and in communication with the power supply and the bioprocess sensor, the electronics module comprising:

a wireless communication unit

including a Bluetooth low energy (BLE) chipset having an internal antenna having a defined transmission frequency and a ground plane sized to fit within the housing and modulate the transmission frequency so as to form a Bluetooth mesh network with another neutral buoyant device in the plurality of neutral buoyant devices and the external control device over the modulated transmission frequency and through the culture media; and

a location tracking mechanism for identifying location information including spatial distributions of process parameters and product heterogeneities within the tank, the location tracking mechanism including an RSSI receiver, an on-board pressure sensor, and a magneto-resistive sensor, the RSSI receiver to determine an RSSI signal strength, the pressure sensor to monitor depth within the media and the magneto-resistive sensor to correlate an observed magnetic field between the magneto-resistive sensor and the magnetic source to determine the location of the neutral buoyant device within the tank; and

wherein each of the plurality of devices transmits over the Bluetooth mesh network to the external control device the sensed parameter of the product process, and location information associated with the parameter for identifying spatial distributions of the sensed parameters to target product heterogeneities within the bioreactor.

2 . The system of claim 1 , wherein the housing comprises a first element and a second element joined with a leak-proof fitting.

3 . The system of claim 1 , wherein the housing comprises a biocompatible material.

4 . The system of claim 3 , wherein the housing is formed using 3D printing of the biocompatible material.

5 . The system of claim 1 , wherein the bioprocess sensor comprises a dissolved oxygen sensor.

6 . The system of claim 5 , wherein the dissolved oxygen sensor comprises a Clark electrode bathed in electrolyte solution and covered by a gas-permeable membrane to define the sensor interface; disposed thereon defining a first portion an electrode surface, the electrolyte solution being trapped within a well formed by a electroplating tape, the gas permeable membrane being a fluorinated ethylene propylene gas permeable membrane separating the electrolyte solution from the culture media.

7 . The system of claim 1 , wherein the housing comprises a spherical shape.

8 . The system of claim 7 , wherein a diameter of the housing is in a range of 2 cm to 6 cm.

9 . The system of claim 1 , wherein the electronics module further comprises a power management unit.

10 . The system of claim 1 , wherein the wireless communication unit comprises a transmitter capable of emitting a signal strong enough to be detected by a receiver.

11 . A method for in-situ real-time wireless and continuous monitoring of a product process, the method comprising:

providing a plurality of neutral buoyant devices into a bioreactor tank containing a culture media each neutral buoyant device independently free-floating within the culture media of the bioreactor tank, each neutral buoyant device including:

a leak-proof housing, including a top half and a bottom half, the top half including a bayonet twist connector to form a leak-proof seal with the bottom half, the top half including a central cutout;

an electrochemical cell including a bioprocess sensor having a first end with a plurality of contact pins and a second end having a sensor interface, the electrochemical cell being disposed in the central cutout of the housing with a leak-proof connection therebetween, the contact pins being disposed within the housing and the sensor interface disposed outside the housing;

a card edge connector interfaced with the sensor, the card edge connector having leak-proof fittings located between the plurality of contact pins and the sensor interface of the bioprocess sensor;

a readout circuit directly interfaced with the sensor via the card edge connector the readout circuit including an analog front end (AFE) potentiostat;

a power supply contained within the housing, and

an electronics module contained within the housing and in communication with the power supply and the bioprocess sensor, the electronics module comprising:

a wireless communication unit

including a Bluetooth low energy (BLE) chipset having an internal antenna having a defined transmission frequency and a ground plane sized to fit within the housing; and

a location tracking mechanism including an RSSI receiver, an on-board pressure sensor, and a magneto-resistive sensor,

sensing a parameter of the product process in the culture media by the plurality of neutral buoyant devices;

recording location information using the location tracking mechanism, the location information corresponding to spatial distributions of process parameters and product heterogeneities within the tank, the recording including using the RSSI receiver to determine an RSSI signal strength, using the pressure sensor to monitor depth within the media and using the magneto-resistive sensor to correlate an observed magnetic field between the magneto-resistive sensor and a magnetic source to determine the location of the neutral buoyant devices within the tank;

storing the data regarding the parameter and the corresponding location information in the electronics module of each neutral buoyant device; and

transmitting through the culture media the sensed parameter of the product process and the location information associated with the parameter, the transmitting including modulating the transmission frequency of the internal antenna of one neutral buoyant device with the ground plane of the one neutral buoyant device; and

forming a Bluetooth mesh network with another neutral buoyant device in the plurality of neutral buoyant devices.

12 . The method of claim 11 , wherein the bioprocess sensor comprises a dissolved oxygen sensor, and

wherein sensing a parameter includes measuring dissolved oxygen levels.

13 . The method of claim 11 , wherein sensing a parameter further comprises: measuring the bioprocess parameter at least once per every 60 seconds.

14 . The method of claim 11 , further comprising receiving the information identifying the parameter at a receiver and displaying the information via a user interface of a display to a user.

15 . The method of claim 14 , further comprising making multiple transmissions of information identifying parameters, and receiving the transmissions at a receiver.

16 . The method of claim 15 , further comprising detecting a missing transmission from a given neutral buoyant device and reporting to the user that the sensor has a fault condition.

17 . The method of claim 15 , wherein the user interface displays to the user a visual spatial mapping of the parameters.

18 . The method of claim 15 wherein the user interface alerts the user of a sensed parameter that is outside a predetermined desired range.

19 . The method of claim 13 , wherein sensing the parameter further comprises, for each of the more than one of the plurality of neutral buoyant devices:

measuring a signal output from the bioprocess sensor for a measurement duration to record a first measurement, wherein the measurement duration is about 5 seconds to about 30 seconds, then ceasing to measure such signal;

after a period of not measuring the signal output, measuring the signal output again for another measurement duration to record a second measurement; and

associating the first measurement with location information of the sensor unit indicative of where the neutral buoyant device was located in the bioreactor tank during the associated measurement duration and associating the second measurement with location information of the sensor unit indicative of where the neutral buoyant device was located in the bioreactor tank during the associated measurement duration.

20 . The system of claim 1 , wherein the parameter measurement comprises a measurement duration comprising a duty cycle of about 10% to about 20%.