Modular system for bioprocess monitoring and method thereof

Abstract

A modular system (100) is provided for bioprocess monitoring. The modular system comprises a container (101) comprising a culture medium (102), at least one sensor (103) configured to be in contact with the culture medium (102), a first connector (104) operably coupled to the at least one sensor (103), and a sealing system (105) encompassing the first connector (104); and a read-out module (106) comprising a second connector (107) and a read-out circuit (108) operably coupled to the second connector (107). In this regard, the first connector (104) and the second connector (107) are configured to be attached in a detachable manner.

Description

[0001] IMEC VZW

[0002] 1

[0003] Modular system for bioprocess monitoring and method thereof

[0004] The invention relates to modular sensor systems for measuring, monitoring or controlling parameters during a bioprocess, especially in sterilizable containers.

[0005] Generally, in order to achieve reproducible results and to fabricate reliable products within bioreactors and other cell culture environment, bioprocess occurring within the containers should be controlled and monitored, which may be performed through a set of sensors. Furthermore, in order to prevent contaminations and to maintain the quality of the products, the containers need to be sterilized. However, the sterilization process must not affect the sensor system functionalities .

[0006] For example, the document US 2019 / 0309255 Al discloses a bioreactor with a sensor port for exchanging different sensors without exposing the interior of the bioreactor. However, the measurements of US 2019 / 0309255 Al are limited to transflection measurements, which may suffer from a reduced accuracy due to the additional noise caused from the distance between the sensors and the content of the bioreactor .

[0007] Accordingly, an object of the invention is to provide a modular system and a method to facilitate the modular system for measuring, monitoring or controlling parameters during a bioprocess with an improved accuracy while maintaining the sterile conditions of the bioprocess monitoring, and further to reuse some o f the components to minimi ze the impact on cost and sustainability .

[0008] The obj ect is solved by the features of the first independent claim for the modular system and by the features of the second independent claim for the method . The dependent claims contain further developments .

[0009] According to a first aspect o f the invention, a modular system is provided for bioproces s monitoring . The modular system comprises a container compris ing a culture medium, at least one sensor configured to be in contact with the culture medium, a first connector operably coupled to the at least one sensor, and a sealing system encompassing the first connector; and a read-out module compris ing a second connector and a read-out circuit operably coupled to the second connector .

[0010] In thi s regard, the first connector and the second connector are conf igured to be attached in a detachable manner . In other words , the read-out module may be detachably attached to the container via the first connector and the second connector, especially to make a connection between the first connector and the second connector during the operation .

[0011] Furthermore, the at least one sensor may be in direct contact with the culture medium within the container . Advantageous ly, the measurement accuracy can be improved . Moreover, at least the read-out module can be reused many times over , thereby minimiz ing the impact on cost and sustainability . Preferably, the first connector and the second connector are configured to facilitate an electrical connection between the first connector and the second connector . In other words , the first connector and the second connector may j oint together electrically .

[0012] Preferably, the first connector and the second connector are configured to facilitate both a mechanical connection and an electrical connection between the f irst connector and the second connector . In other words , the first connector and the second connector may j oint together mechanically and electrical ly .

[0013] Advantageous ly, the mechanical connection and / or the electrical connection between the first connector and the second connector can be formed without posing a risk in terms o f sterility issue to the container .

[0014] Preferably, the first connector comprises at least one maletype connector and the second connector comprises at least one female-type connector . Alternatively, the first connector comprises at least one female-type connector and the second connector comprises at least one male-type connector . For example , the first connector and / or the second connector may additionally comprise a snapping mechani sm activated at the insertion .

[0015] Preferably, the sealing system is conf igured to i solate the first connector from the culture medium . Thi s may advantageous ly ensure that the environment remains sterile . Preferably, the sealing system is configured to encompass a portion of the read-out module inside of the container, and to isolate the first connector and the portion of the read-out module from the culture medium. In this regard, the portion of the read-out module comprises at least the read-out circuit. This may advantageously prevent the culture medium from reaching the electronics, and may further form a barrier between the sterile and the non- sterile environment.

[0016] Preferably, the modular system further comprises a fitting arrangement configured to align the first connector and the second connector. In this regard, the fitting arrangement comprises at least one alignment marker and / or at least one alignment guide. Advantageously, a precise connection between the first connector and the second connector can be formed with ease.

[0017] Preferably, the container is a cell-culture vessel, especially a bioreactor vessel.

[0018] Preferably, the container is a cell-culture bag, especially a bioreactor bag.

[0019] Preferably, the container is a cell-culture tube or a flowcell .

[0020] Advantageously, the requirements in terms of sterility and reusability of components can be fulfilled for different types of containers. Preferably, the at least one sensor is an electrochemical sensor. Additionally or alternatively, the at least one sensor is configured to measure at least one of a physical parameter, a chemical parameter, and a biochemical parameter of the culture medium. The parameters can be defined as but not limited to temperature, pH level, dissolved oxygen, glucose and lactate concentrations, cell density, cell viability, electrical conductivity, oxidation or reduction potential, and proteins concentrations.

[0021] For example, the at least one sensor may comprise or be an array of sensors, e.g., a sensing area comprising a high density of sensors such as ion-sensitive field-effect transistors (ISFETs) , that may use an electrochemical transduction principle for monitor different process parameters, preferably simultaneously.

[0022] Preferably, the container is sterilizable. In other words, the container along with its contents, especially including the at least one sensor, are sterilizable components. Advantageously, the sterile conditions of the bioprocess monitoring can be maintained.

[0023] According to a second aspect of the invention, a method is provided for facilitating a modular system for bioprocess monitoring. The method comprises the steps of providing a container comprising the culture medium, at least one sensor in contact with the culture medium, a first connector operably coupled to the at least one sensor, and a sealing system encompassing the first connector; and providing a read-out module comprising a second connector and a readout circuit operably coupled to the second connector. In this regard, the first connector and the second connector are attached in a detachable manner .

[0024] It is to be noted that the method according to the second aspect corresponds to the modular system according to the first aspect and its implementation forms . Accordingly, the method o f the second aspect may have corresponding implementation forms . Further , the method o f the second aspect achieves the same advantages and ef fects as the modular system o f the f irst aspect and its respective implementation forms .

[0025] Exemplary embodiments o f the invention are now further explained with respect to the drawings by way of example only, and not for limitation . In the drawings :

[0026] Fig . 1 shows a first exemplary embodiment of the modular system according to the first aspect of the invention ;

[0027] Fig . 2 shows a second exemplary embodiment of the modular system according to the first aspect of the invention ;

[0028] Fig . 3 shows a third exemplary embodiment of the modular system according to the first aspect of the invention ;

[0029] Fig . 4 shows a fourth exemplary embodiment of the modular system according to the first aspect of the invention ; and Fig. 5 shows an exemplary embodiment of the method according to the second aspect of the invention.

[0030] Reference will now be made in detail to the embodiments of the present invention, examples of which are illustrated in the accompanying drawings. However, the following embodiments of the present invention may be variously modified and the range of the present invention is not limited by the following embodiments.

[0031] In Fig. 1, a first exemplary embodiment of the modular system 100 according to the first aspect of the invention is illustrated. The modular system 100 may comprise a container 101 that may comprise a culture medium 102, an array of sensors 103 in direct contact with the culture medium 102, a first connector 104 coupled to the array of sensors 103, and a sealing system 105 encompassing the first connector 104.

[0032] The modular system 100 may further comprise a read-out module 106 that may comprise a second connector 107 and a read-out circuit 108 coupled to the second connector 107. The read-out module 106 may further comprise a transmitter 109 operably coupled to the read-out circuit 108. Moreover, the read-out module 106 may further comprise a power source 110, e.g., a battery, to supply electrical energy to the read-out circuit 108 and / or the transmitter 109.

[0033] During operation, the first connector 104 and the second connector 107 may be attached or connected to each other mechanically and electrically. When required, e.g., to reuse the read-out module 106, the first connector 104 and the second connector 107 may be detached or disconnected.

[0034] As such, the array of sensors 103 may monitor different process parameters, such as temperature, glucose concentration, dissolved oxygen, and so on, while being in direct contact with the culture medium 102, and may generate sensing signals.

[0035] For instance, the array of sensors 103 may be realized via a sensor die having a sensing area in direct contact with the culture medium 102, where the sensing area may contain a high density of sensors, such as ISFETs, fabricated with CMOS fabrication technology, and may be able to simultaneously detect or monitor multiple process parameters. Furthermore, the array of sensors 103 may be additionally provided with an AC / DC converter to facilitate digital data transfer, especially to reduce the impact of noise for longer distances.

[0036] For example, the first connector 104 and the second connector 107 may comprise or be a short connector PCB, e.g., wire-boned to the array of sensors 103 and the readout circuit 108, respectively, that may join mechanically and electrically, and may transfer the digital data through multiple channels. The shorter length of the connectors may allow the read-out circuit 108 to be at a shorter distance from the array of sensors 103, which may minimize the sensitivity reduction and induced noise due to the distance.

[0037] In this regard, the first connector 104 may comprise one or more male-type connectors or parts and / or one or more female-tape connectors or sockets. Additionally, the second connector 107 may comprise one or more male-type connectors or parts and / or one or more female-tape connectors or sockets .

[0038] Moreover, the first connector 104 and / or the second connector 107 may comprise a snapping mechanism activated at the insertion, especially to mechanically maintain the electrical connection between the first connector 104 and the second connector 107. The electrical connection status between the first connector 104 and the second connector 107 may be controlled with a self-check mechanism.

[0039] The read-out circuit 108 may read-out the sensing signals, e.g., the digital data, through the first connector 104 and the second connector 107, i.e., the electrical connection formed between the first connector 104 and the second connector 107, and may transfer the read-out signals to the transmitter 109. The transmitter 109 may transmit the readout signals for further processing to an external entity, e.g., a signal processor, by means of a wired transmission, e.g., via a cable, or of a wireless transmission, e.g., via an antenna.

[0040] The container 101 and its contents, e.g., the culture medium 102, the array of sensors 103, the first connector 104, and the sealing system 105 may be sterilized. As such, the monitoring circuitry may be split up into a sterilizable part made up of the array of sensors 103, the first connector 104, and the sealing system 105; and a reusable part that may not need to be sterilized and made up of the second connector 107, the read-out circuit 108, the transmitter 109, and the power source 110.

[0041] In this regard, the sealing system 105 may ensure that the environment remains sterile, especially by forming a barrier between the sterile and the non-sterile environment. The sealing system 105 may further isolate the first connector 104 from the culture medium 102.

[0042] For example, the sealing system 105 may be arranged with respect to the container 101 such that the read-out module 106 may reside partly inside of the sealing system 105. In this regard, the sealing system 105 may encompass the first connector 104, and a portion of the read-out module 112 that may comprise the second connector 107, i.e., while connected to the first connector 104, the read-out circuit 108, and the power source 110, especially to prevent the culture medium 102 from reaching the electronics.

[0043] The sealing system 105 may additionally encompass the transmitter 109 in a manner that the transmissions from the transmitter 109 may not be affected. The sealing system 105 may comprise or be made of impermeable material such as filtering membranes, stainless steel, plastic, glues, and the like.

[0044] The modular system 100 may further comprise a fitting arrangement 111, especially to facilitate the connection between the first connector 104 and the second connector 107 without posing a risk in terms of sterility issue to the container 101. For example, the fitting arrangement 111 may comprise one or more alignment guides 111, e.g., respectively arranged at the read-out module 106 and an inner part of the sealing system 105, which may ensure a correct connection between the first connector 104 and the second connector 107.

[0045] In Fig. 2, a second exemplary embodiment of the modular system 200 according to the first aspect of the invention is illustrated. In this example, the container may correspond to a cell-culture vessel, e.g., a bioreactor vessel 101A, containing the cell-culture medium 102. The array of sensors 103, the first connector 104, the sealing system 105, and the read-out module 106 may respectively correspond to the array of sensors 103, the first connector 104, the sealing system 105, and the read-out module 106 of the modular system 100.

[0046] In this regard, the array of sensors 103, the first connector 104, and the sealing system 105 may be arranged in the bioreactor vessel 101A such that the array of sensors 103 may be in direct contact with the cell-culture medium 102. Furthermore, the array of sensors 103, the first connector 104, and the sealing system 105 may be arranged in the bioreactor vessel 101A while maintaining sterility.

[0047] Moreover, the fitting arrangement 111 may comprise one or more alignment markers 211 in addition to the one or more alignment guides 111 in order to further ensure a correct connection between the first connector 104 and the second connector 107.

[0048] In Fig. 3, a third exemplary embodiment 300 of the modular system according to the first aspect of the invention is illustrated. In this example, the container may correspond to a cell-culture bag, e.g., a single use or a disposable bioreactor bag 101B, containing the cell-culture medium 102. The array of sensors 103, the first connector 104, and the read-out module 106 may respectively correspond to the array of sensors 103, the first connector 104, and the read-out module 106 of the modular system 100.

[0049] In this example, the sealing system 105 may be arranged to encompass only the first connector 104 to isolate the first connector 104 from the cell-culture medium 102. For example, the array of sensors 103, the first connector 104, and the sealing system 105 may form a button-shaped arrangement into the bioreactor bag 101B, where the read-out module 106 may be plugged-on to the button-shaped arrangement via the first connector 104 and the second connector 107.

[0050] In this regard, the array of sensors 103, the first connector 104, and the sealing system 105 may be arranged in the bioreactor bag 101B such that the array of sensors 103 may be in direct contact with the cell-culture medium 102. Furthermore, the array of sensors 103, the first connector 104, and the sealing system 105 may be arranged in the bioreactor bag 101B while maintaining sterility.

[0051] In Fig. 4, a fourth exemplary embodiment of the modular system 400 according to the first aspect of the invention is illustrated. In this example, the container may correspond to a cell-culture tube 101C, e.g., a tubing or a flow line in a perfusion system, or a flow-cell, through which the cell-culture medium 102 may flow or pass. The array of sensors 103, the first connector 104, and the read- out module 106 may respectively correspond to the array of sensors 103 , the first connector 104 , and the read-out module 106 o f the modular system 100 .

[0052] In this example, the sealing system 105 may be arranged to encompass only the f irst connector 104 to isolate the first connector 104 from the cell-culture medium 102 . For example , the array of sensors 103 , the first connector 104 , and the seal ing system 105 may be arranged in the cell-culture tube 101C , where the read-out module 106 may be plugged-on via the first connector 104 and the second connector 107 .

[0053] In this regard, the array of sensors 103 , the first connector 104 , and the sealing system 105 may be arranged in the cell-culture tube 101C such that the array of sensors 103 may be in direct contact with the cell-culture medium 102 flowing through the cell-culture tube 101C . Furthermore, the array of sensors 103 , the first connector 104 , and the seal ing system 105 may be arranged in the cell-culture tube 101C while maintaining sterility .

[0054] In Fig . 5 , an exemplary embodiment o f the method 500 according to the second aspect of the invention is illustrated . In a first step 501 , a container comprising a culture medium, at least one sensor in contact with the culture medium, a first connector operably coupled to the at least one sensor, and a sealing system encompassing the first connector is provided . In a second step 502 , a readout module comprising a second connector and a read-out circuit operably coupled to the second connector is provided, wherein the f irst connector and the second connector are attached in a detachable manner . It is important to note that , in the description as well as in the claims , the word "comprising" does not exclude other elements or steps and the indef inite article " a" or " an" does not exclude a plurality . A single element or other unit may fulfil l the functions of several entities or items recited in the claims . Furthermore , the word "coupled" impl ies that the elements may be directly connected together or may be coupled through one or more intervening elements . Moreover, the disclosure with regard to any of the aspects is also relevant with regard to the other aspects of the disclosure .

[0055] Although the invention has been il lustrated and described with respect to one or more implementations , equivalent alterations and modif ications will occur to others skil led in the art upon the reading and understanding of this speci fication and the annexed drawings . In addition, while a particular feature of the invention may have been disclosed with respect to only one of several implementations , such feature may be combined with one or more other features of the other implementations as may be desired and advantageous for any given or particular appl ication .

Claims

Claims1. A modular system (100, 200, 300, 400) for bioprocess monitoring, comprising: a container (101) comprising a culture medium (102) , at least one sensor (103) configured to be in contact with the culture medium (102) , a first connector (104) operably coupled to the at least one sensor (103) , and a sealing system (105) encompassing the first connector (104) ; and a read-out module (106) comprising a second connector (107) and a read-out circuit (108) operably coupled to the second connector (107) , wherein the first connector (104) and the second connector (107) are configured to be attached in a detachable manner.

2. The modular system according to claim 1, wherein the first connector (104) and the second connector (107) are configured to facilitate an electrical connection between the first connector (104) and the second connector (107) .

3. The modular system according to claim 1 or 2, wherein the first connector (104) and the second connector (107) are configured to facilitate both a mechanical connection and an electrical connection between the first connector (104) and the second connector (107) .

4. The modular system according to any of claims 1 to 3, wherein the first connector (104) comprises at least one male-type connector and the second connector (107) comprises at least one female-type connector, and / orwherein the first connector (104) comprises at least one female-type connector and the second connector (107) comprises at least one male-type connector.

5. The modular system according to any of claims 1 to 4, wherein the sealing system (105) is configured to isolate the first connector (104) from the culture medium (102) .

6. The modular system according to any of claims 1 to 5, wherein the sealing system (105) is configured to encompass a portion of the read-out module (112) inside of the container (101) , and to isolate the first connector (104) and the portion of the read-out module (112) from the culture medium (102) .

7. The modular system according to claim 6, wherein the portion of the read-out module (112) comprises at least the read-out circuit (108) .

8. The modular system according to any of claims 1 to 7, wherein the modular system further comprises a fitting arrangement (111) configured to align the first connector (104) and the second connector (107) .

9. The modular system according to claim 8, wherein the fitting arrangement (111) comprises at least one alignment marker (211) and / or at least one alignment guide (111 ) .

10. The modular system according to any of claims 1 to 9, wherein the container (101) is a cell-culture vessel, preferably a bioreactor vessel (101A) .

11. The modular system according to any of claims 1 to 9, wherein the container (101) is a cell-culture bag, preferably a bioreactor bag (101B) .

12. The modular system according to any of claims 1 to 9, wherein the container (101) is a cell-culture tube or a flow-cell (101C) .

13. The modular system according to any of claims 1 to 12, wherein the at least one sensor (103) is an electrochemical sensor, and / or wherein the at least one sensor (103) is configured to measure at least one of a physical parameter, a chemical parameter, and a biochemical parameter of the culture medium.

14. The modular system according to any of claims 1 to 13, wherein the container (101) is sterilizable.

15. A method (500) for facilitating a modular system for bioprocess monitoring, comprising: providing (501) a container comprising a culture medium, at least one sensor in contact with the culture medium, a first connector operably coupled to the at least one sensor, and a sealing system encompassing the first connector; and providing (502) a read-out module comprising a second connector and a read-out circuit operably coupled to the second connector, wherein the first connector and the second connector are attached in a detachable manner.

Images