# US 2021/0340486 A1 · System and Method for Centralized Fluid Management and Culture Control

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- Number: US 2021/0340486 A1
- Document ID: US20210340486A1
- Status: Published application
- Kind: A1
- Application number: 17/243,324
- Filed: 2021-04-28
- Published: 2021-11-04
- Earliest claimed: 2020-05-01
- Assignees: DEKA Products Limited Partnership
- Applicants: DEKA Products Limited Partnership
- Inventors: Richard E. Andrews; Dave D.B. Cannan; Alekhya Akkapeddi; Andrew G. Remec; Bryan A. Finseth; Kevin Kim
- Web page: https://patentgrep.com/patent/US20210340486A1

## CPC

- C12M 41/48: {Automatic or computerized control (automatic analysis G01N35/00)}
- C12M 23/28: {disposable or single use}
- C12M 23/42: {Integrated assemblies, e.g. cassettes or cartridges}
- C12M 23/44: {Multiple separable units; Modules}
- C12M 23/58: {Reaction vessels connected in series or in parallel (combinations of bioreactors with other apparatus, C12M43/00)}
- C12M 27/18: {Flow directing inserts}
- C12M 29/00: {Means for introduction, extraction or recirculation of materials, e.g. pumps (pumps per se F04B)}
- C12M 29/20: {Degassing; Venting; Bubble traps (means for collection or storage of gas C12M23/36; gas collection apparatus for laboratory use B01L5/02)}
- C12M 41/12: {of temperature (controlling the temperature of chemical or physical processes B01J19/0013, heating or cooling apparatus for laboratory use B01L7/00)}
- C12M 41/14: {Incubators; Climatic chambers (per se B01L1/00)}
- C12M 41/16: {by recirculation of culture medium at controlled temperature}
- C12M 41/32: {of substances in solution}
- C12M 41/34: {of gas}
- 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}

## Abstract

System and method for providing biocompatible, nutrient filled media to the Human Cells, Tissues, and cellular and tissue-based Products (HCT/P) while removing wastes. The present teachings provide for sensing the characteristics of the media, and modifying the characteristics when necessary. The present teachings can also provide components that can provide fluid pumping integrated with fluid gas exchange, and sensing of fluid characteristics at consistent times during the fluid flow cycle. System and method control multiple bioreactors from a centralized media reservoir, while fluidically isolating the bioreactors from cross-contamination.

## Claims

### Claim 1

A thermal enclosure for growing tissue comprising:
a plurality of bioreactors isolated from each other;
a plurality of pumping cassettes fluidically coupled with the plurality of bioreactors, the plurality of bioreactors being prevented from providing backflow into the plurality of pumping cassettes by a first of an at least one check valve;
at least one media reservoir fluidically coupled with the plurality of pumping cassettes, the at least one media reservoir providing media to the plurality of pumping cassettes, the plurality of pumping cassettes pumping the media to the plurality of bioreactors;
a waste line fluidically coupled with the plurality of bioreactors, the waste line being prevented from providing backflow into the plurality of bioreactors by a second of the at least one check valve; and
a sample line fluidically coupled to each bioreactor, the sample line being prevented from providing backflow by a third of the at least one check valve,
wherein the at least one media reservoir fluidic coupling, the plurality of pumping cassettes, and the plurality of bioreactors form a fluid path.

### Claim 2 (depends on 1)

The thermal enclosure as in claim 1 wherein the first of the at least one check valve comprises:
at least one valve completely sealing the fluid path when the first of the at least one valve is exposed to neutral pressure or backflow.

### Claim 3 (depends on 1)

The thermal enclosure as in claim 1 further comprising:
a chilled media enclosure providing chilled media to the at least one media reservoir, the chilled media being fluidically isolated from the at least one media reservoir by a third of the at least one check valve.

### Claim 4 (depends on 3)

The thermal enclosure as in claim 3 wherein the at least one check valve comprises at least one spring style check valve.

### Claim 5

A method for automatic centralized fluid management and culture control comprising:
(a) automatically, by a system controller, monitoring temperature, nutrient concentration, and dissolved gas concentrations of a cell or tissue culture media;
(b) automatically, by the system controller, maintaining the temperature of the cell or tissue culture media in a media reservoir at a first pre-selected value;
(c) automatically, by the system controller, adjusting the temperature, the nutrient concentration, and the dissolved gas concentrations of the cell or tissue culture media to second pre-selected values prior to delivery to a user-supplied device;
(d) automatically, by the system controller, delivering the temperature, the nutrient concentration, and dissolved gas concentration-adjusted cell or tissue culture media to the user-supplied device;
(e) automatically, by the system controller, recirculating the temperature, the nutrient concentration, and the dissolved gas concentration-adjusted cell or tissue culture media through the user-supplied device;
(f) automatically, by the system controller, adjusting the temperature, the nutrient concentration, and the dissolved gas concentrations of the cell or tissue culture media to the second pre-selected values prior to the delivery to the user-supplied device;
(g) automatically, by the system controller, monitoring the temperature-adjusted cell or tissue culture media through the user-supplied device;
(h) if the temperature, or the nutrient concentration, or the dissolved gas concentrations of the cell or tissue culture media meet the second pre-selected values, automatically, by the system controller, repeating steps (e)-(g); and
(i) if the temperature, or the nutrient concentration, or the dissolved gas concentrations of the cell or tissue culture media do not meet the second pre-selected values, automatically, by the system controller, delivering the recirculated temperature-adjusted cell or tissue culture media to a waste vessel or a sample vessel.

### Claim 6 (depends on 5)

The method as in claim 5 wherein the user-supplied device comprises a bioreactor.

### Claim 7 (depends on 5)

The method as in claim 5 wherein the automatic delivering of the temperature, the nutrient concentration, and the dissolved gas concentration-adjusted cell or tissue culture media comprises delivering through a sterile flow path including disposable hardware.

### Claim 8 (depends on 7)

The method as in claim 7 wherein the disposable hardware comprises sterilizable hardware.

### Claim 9 (depends on 5)

The method as in claim 5 wherein the first pre-selected value comprises a range of 0-8° C.

### Claim 10 (depends on 5)

The method as in claim 5 wherein the second pre-selected values comprise a range of 32-40° C.

### Claim 11 (depends on 5)

The method as in claim 5 wherein the automatically maintaining the temperature comprises heating elements in a pumping manifold and a holding container.

### Claim 12 (depends on 11)

The method as in claim 11 wherein the recirculating comprises a flow path including the media reservoir, a reservoir line, a reservoir module cassette, the holding container, a module line, and a bioreactor module cassette.

### Claim 13 (depends on 11)

The method as in claim 11 wherein the recirculating comprises a sterile flow path including the media reservoir, a reservoir line, a reservoir module cassette, the holding container, a module line, a bioreactor module cassette, and the user-supplied device.

### Claim 14 (depends on 12)

The method as in claim 12 wherein the monitoring comprises using disposable sensors and non-invasive sensors.

### Claim 15 (depends on 14)

The method as in claim 14 wherein the disposable sensors comprise integration into the bioreactor module cassette and the reservoir module cassette.

### Claim 16 (depends on 12)

The method as in claim 12 wherein the adjusting comprises temperature control using the heating elements, gas diffusion through semi-permeable plastics, or replacement of the cell or tissue culture media.

### Claim 17

A method for producing a plurality of independent tissue constructs simultaneously in a bioreactor system, the bioreactor system including a plurality of bioreactors, at least one waste line conducting waste from the plurality of bioreactors, at least one media line conducting a media towards the plurality of bioreactors, the at least one media line, the at least one waste line, and the plurality of bioreactors being coupled by a fluid path, the method comprising:
fluidically isolating each of the plurality of bioreactors from each other and from other components of the bioreactor system, each of the plurality of bioreactors producing one of the plurality of independent tissue constructs; and
feeding the plurality of independent tissue constructs with the media conducted from a central media reservoir through the at least one media line to the plurality of independent tissue constructs.

### Claim 18 (depends on 17)

The method as in claim 17 wherein the fluidically isolating each of the plurality of bioreactors comprises:
preventing waste line backflow from the at least one waste line to the plurality of bioreactors using a first of an at least one check valve;
preventing bioreactor backflow from the plurality of bioreactors to the at least one media line using a second of the at least one check valve;
preventing sample backflow from a plurality of sample lines to the plurality of bioreactors using a third of the at least on check valve; and
fluidically isolating a chiller media enclosure from the bioreactor system using a fourth of the at least one check valve.

### Claim 19 (depends on 18)

The method as in claim 18 wherein the at least one check valve comprises:
at least one valve completely sealing the fluid path when the at least one valve is exposed to neutral pressure or backflow.

### Claim 20

A system for alternating a direction of a fluid flow of a fluid entering, exiting, or both entering and exiting a pumping cassette without changing the direction of the fluid flow past at least one on-cassette inline sensor and at least one gas exchange surface, the system comprising:
a pumping chamber including a pumping chamber cassette membrane, the pumping chamber being associated with a corresponding pumping valve; and
a fluidic pathway analogous to an h-bridge enabling applying pneumatic pressure to the pumping chamber cassette membrane, the corresponding pumping valve being open, the pneumatic pressure enabling pumping the fluid in a first flow path past the at least one on-cassette inline sensor if a first valve is open, pumping the fluid into a gas exchange zone if a second valve is open, and pumping the fluid into a sample line if a third valve is open, the fluidic pathway enabling isolating the pumping chamber by closing a valve corresponding to a second flow path by blocking the pumped fluid in the second flow path, the second flow path traveling in an opposite direction to the first flow path, the fluidic pathway enabling routing the fluid to the pumping chamber using a fourth valve or a fifth valve, the fluidic pathway enabling tying the first valve and the fourth valve together, and the second valve and the fifth valve together.