CN206244792U - Disposable bioreactor sensor interface - Google Patents

Abstract

A bioreactor sensing system is presented. A bioreactor sensing system includes a bioreactor vessel. The bioreactor vessel includes an aperture configured to provide an interface for monitoring the contents of the bioreactor vessel. The bioreactor vessel also includes a port coupled to the bioreactor vessel adjacent the well. The bioreactor sensing system also includes a sensing device disposed at least partially within the port such that the sensing element is exposed to the contents. The bioreactor sensing system also includes an outer seal configured to be applied over a portion of the sensing device and a portion of the port.

Description

Disposable bioreactor sensor interface

Cross References to Related Applications

This application is based upon and claims the benefit of U.S. Provisional Patent Application Serial No. 62/265,819, filed December 10, 2015, the contents of which are incorporated herein by reference in their entirety.

technical field

The utility model relates to a disposable bioreactor sensor interface and a sealed sensor interface system for the bioreactor.

Background technique

Bioreactors support biological reactions used in many important applications, including cell culture, fermentation, and more. Biological reactions may be susceptible to changes in temperature, pressure, pH, and others. Additionally, as the biological reaction proceeds, the reaction itself may change various parameters within the bioreactor vessel, such as dissolved oxygen content and/or pH. Therefore, it may be important to monitor one or more process variables over time to track the progress of a biological response.

The life sciences industry is moving away from large, capital-intensive facilities made of stainless steel with extensive clean-in-place (CIP) infrastructure, and toward smaller facilities utilizing polymer-based bags or containers as single-use bioreactors. Disposable bioreactor bags can be used once and then discarded. The use of single-use bioreactors can significantly reduce the capital costs required for plants. For example, in existing equipment using stainless steel CIP infrastructure, up to 90% of operating costs may be associated with CIP infrastructure, including high-end instruments designed to withstand steam cleaning cycles. By using disposable, single-use bioreactor bags, the CIP portion of the capital cost can be eliminated and the equipment can be flexible and much smaller, which in turn allows for smaller batch production, e.g. for more targeted drugs required for therapeutic and other small-scale applications.

Utility model content

A bioreactor sensing system is presented. A bioreactor sensing system includes a bioreactor vessel. The bioreactor vessel includes an aperture configured to provide an interface or interface for monitoring the contents of the bioreactor vessel. The bioreactor vessel also includes a port coupled to the bioreactor vessel adjacent the well. The bioreactor sensing system also includes a sensing device disposed at least partially within the port such that the sensing element is exposed to the contents. The bioreactor sensing system also includes an outer seal configured to be applied over a portion of the sensing device and a portion of the port.

Description of drawings

Figure 1 is a schematic diagram of a single-use bioreactor for which embodiments of the present invention are particularly useful.

2A and 2B are schematic diagrams of sensors coupled to disposable bioreactor bags;

Figure 3 is a schematic diagram of a sealed connection between a sensor and a bioreactor port according to one embodiment of the present invention;

4A-4D are schematic diagrams of a sensor coupled to a port on a bioreactor according to an embodiment of the present invention;

5 is a flowchart of a method of sealing a sensor to a bioreactor port according to an embodiment of the present invention.

detailed description

A single-use bioreactor may have one or more ports or interfaces or interfaces configured to attach sensor devices capable of monitoring process variables as the reaction proceeds. Promoting the use and adoption of disposable, single-use bioreactor technologies while providing a reliable sealed instrument interface between the instrument and the bioreactor would be of significant benefit to the life sciences industry.

Figure 1 is a schematic diagram of a single-use bioreactor for which embodiments of the present invention are particularly useful. The sensor device 30 is useful for measuring properties of the biological sample within the disposable bioreactor 20, such as pressure, temperature, pH, dissolved oxygen, and the like. Sensor 30 may be mounted to single-use bioreactor 20 and arranged to provide an electrical indication relative to a parameter of interest to sample 22 located within bioreactor 20 . Sensor 30 is coupled to a suitable analyzer that provides a reading of a parameter of interest to sample 22 and/or other suitable indications.

In single-use bioreactor applications, various sensor devices, such as sensor 30, may be integrated into or otherwise coupled to the bioreactor bag. According to embodiments described herein, a mechanical interface is provided between the sensor and the bioreactor. A mechanical interface facilitates mounting the sensor in the port. The mechanical interface also provides high-reliability integrity. In one embodiment, the mechanical interface may include a seal that prevents leakage of bioreactor fluid into the environment and contamination of the bioreaction material by the environment. In one embodiment, the mechanical interface at least partially overlaps the body of the sensor and/or at least partially overlaps the sensor receiving port on the bioreactor. The use of external seals may provide additional benefits over current systems that rely on internal sealing mechanisms.

2A and 2B are schematic diagrams showing one way in which the current sensor device can be coupled to a disposable bioreactor bag through port 40 . As shown in Figure 2A, disposable bioreactor bags often have so-called "barbed ports". The barbed port 40 generally includes a circular flange 42 that meets a cylindrical sidewall 44 at approximately a right angle 46 . Disposed at the distal end 48 of the cylindrical sidewall 44 is a hose barb 49 configured to interfere with a deformable sidewall of a hose, such as a rubber or elastic hose. Barbed ports 40 are common on disposable bioreactors to receive tubing coupled to the bioreactor.

Flange 42 may be attached to the hole in the bioreactor bag in any suitable manner, such as ultrasonic welding, or by using any other suitable method. Flange 42 may be positioned within the bioreactor such that wall 44 passes through a hole in the bioreactor bag. Flange 42 may also be coupled to the outer surface of the bioreactor bag such that cylindrical sidewall 44 does not pass through the hole in the bioreactor bag. Thus, the barbed ports 40 are very useful and provide flexible coupling options for tubing to single-use bioreactors. Therefore, any external sealing mechanism is expected to be compatible with existing barbed ports.

Currently, sensor devices such as sensor device 50 are designed to sit within barbed ports such as port 40 of disposable bioreactor bags. The outer diameter of the sensor 50 is sized such that it can fit within the inner diameter 51 of the cylindrical side wall 44 . O-ring 52 is configured to engage inner diameter 51 of cylindrical sidewall 44 such that sensor device 50 is sealed within barbed port 40 .

Sensor 50 may comprise any suitable sensing device configured to provide an electrical indication relative to a parameter of interest to the biological sample within the bioreactor bag. Such sensors may include temperature sensors, pressure sensors, dissolved oxygen sensors, carbon dioxide sensors, conductivity sensors, pH sensors, colorimetric sensors, or any other suitable sensor configured to detect a parameter of interest. When the sensor 50 is properly installed within the cylindrical side wall 44, the assembly may be as shown in Figure 2B. However, it has been found that the inner surface of the cylindrical sidewall 44 may not have proper quality control in order to reliably form a seal using the O-ring 52 . The main design feature of the barbed port 40 is to couple to a length of tubing and allow fluid to flow therethrough. In order to seal the sensor 50 using the inner surface of the cylindrical sidewall 44, the use of the O-ring 52 alone may not achieve a suitable robust fluid and/or mechanical seal for all applications. For example, if there are scratches on the inner diameter 51 of the cylindrical side wall 44, there is a risk of fluid leaking through the scratches after the sensor device 50 is installed therein. External seals can provide a more reliable and robust seal.

In one embodiment, the sensor coupling structure may include the use of an external seal to prevent fluid from passing through either the sensor 50 or the cylindrical sidewall 44 . This outer seal can be used alone to mechanically seal the sensor to the bioreactor, or in addition to the inner sealing mechanism as described in Figures 2A and 2B where redundant seals are required.

Figure 3 is a schematic diagram of a sealed coupling between a sensor and a bioreactor port according to one embodiment of the present invention. In one embodiment, an external seal may provide additional protection to the current sensor-bioreactor coupling structure. For example, an external seal can be placed on the sensor-port assembly shown in Figure 2B. In another embodiment, an external seal is used without an additional sealing mechanism between the sensor and the port.

The outer seal can support the use of many different sensor bioreactor bag configurations. The external seal may also provide a more reliable and robust seal than, for example, an O-ring between the sensor and the port. It may be desirable to isolate the reaction mixture within the bioreactor 102 from the environment 100 external to the bioreactor 102 . In one embodiment, a seal 110 may be placed at the interface or junction between the sensor 104 and the sensor port 106 to reinforce or create a barrier between the reaction mixture and the environment 100 .

In one embodiment, the sensor 104 has an outer diameter that is smaller than the inner diameter of the receiving sensor port 106 and the outer diameter is configured to fit within the inner diameter within the receiving sensor port 106 . The sensor port 106 may be formed from a material that has some elasticity so that it can more easily receive the sensor 104 without significant gaps. In one embodiment, at least a portion of sensor 104 is configured to fit within sensor port 106 . Port coupling portion 116 is configured to receive and couple to sensor coupling portion 114 at joint 120 . The port portion 116 and the sensor portion 114 are configured to fit together, eg, in corresponding shapes.

In one embodiment, seal 110 is configured to overlap at least a portion of sensor 104 and a portion of port 106 such that it spans junction 120 . The sensor portion 114 physically interfaces with the port portion 116 at a junction 120 . In one embodiment, the sensor portion 114 is physically coupled to the port portion 116, such as by interlocking of corresponding features. In one embodiment, the junction 120 extends along substantially the entire circumference of the sensor 104 . Along the joint 120, the sensor coupling portion 114 and the port coupling portion 116 may have different possible shapes and configurations. In one embodiment, the shape of the sensor portion 114 matches the shape of the port portion 116 .

4A-4D illustrate a sensor coupled to a port on a bioreactor according to an embodiment of the present invention. As shown in FIG. 4A , in one embodiment, the barbed port 140 includes a barb 149 extending along the circumference of the port 140 . In one embodiment, the barb 149 is located substantially at the edge of the port 140 . However, the port 140 may include a plurality of barbs 149 , or include portions of barbs 149 extending along the length of the port 140 , and include one or more portions of the circumference of the port 140 . In one embodiment, barb 149 is a hose barb. In one embodiment, port 140 is configured to receive sensing device 160 in the direction indicated by arrow 150, as shown in FIG. 4B. Accordingly, at least some of the embodiments presented herein do not require modification of the barbed port of the disposable bioreactor. This may be useful in order to provide a more substantial seal between the sensor 160 and existing bioreactors already on the market.

FIG. 4B shows sensing device 160 having sensing end 168 configured to sense one or more parameters associated with the reaction mixture in the bioreactor. In one embodiment, the sensor 160 is cylindrical in shape and configured to fit within the inner diameter 151 of the barbed port 140 . In one embodiment, the sensor 160 includes a hose barb 164 positioned along the length of the outer surface of the sensor 160 . In one embodiment, the barb 164 is located at a distance from the sensing end 168 . The distance between sensing end 168 and barb 164 may be selected to allow sensing end 168 to be exposed to the reaction mixture when fully inserted into port 140 .

In one embodiment, sensor barb 164 is configured to cooperate with barb 149 on port 140 such that outer seal 162 , such as shown in FIG. 4C , forms a robust mechanical seal between sensor 160 and port 140 . In one embodiment, seal 162 comprises a flexible yet strong material. In one embodiment, seal 162 includes a resilient tube. When the sensing device 160 is mounted to the barbed port 140 , an elastic or elastomeric tube 162 (elastomerictubing) generally slides on the outer diameter of the sensor device 160 , preferably in the direction indicated by arrow 166 . In one embodiment, seal 162 may be attached to sensor 160 prior to insertion into port 140 . In another embodiment, seal 162 may be attached after sensor 160 is coupled to port 140 .

In one embodiment, once the elastic tube 162 is positioned such that it extends above and below the barb 164 , the entire sensor 160 /seal 162 assembly is coupled to the port 140 . In one embodiment, the sensor 160/seal 162 assembly can be configured to couple to the port 140 such that the barb 164 abuts the barb 149, such as shown in FIG. 4D. Thus, in one embodiment, the position of the hose barb 164 relative to the sensing end 168 of the sensing device 160 sets the relative depth of the sensing end 168 within the disposable bioreactor. In the embodiment shown in FIGS. 4A-4D , sensing end 168 is substantially flush with the interior wall portion of barbed port 40 . However, other desired depths for sensing end 168 are also contemplated. For example, in some embodiments it may be beneficial for sensing end 168 to extend substantially within the disposable bioreactor in order to interact with the reaction mixture therein.

In at least one embodiment, barbs 164 have an opposite direction orientation than barbs 149, such as shown in FIG. 4D. This opposite directionality is such that the sensor 160 /seal 162 assembly, when slid in the direction indicated by arrow 150 , will stop upon contact with barb 149 . In one embodiment, the sensor 160/seal 162 creates a strong mechanical and fluid seal with the port 140 when in place. However, it is expressly contemplated that embodiments may be practiced in which the barbs 149 and 164 have substantially the same directionality. Additionally, while the embodiment shown in FIGS. 4A and 4B shows a single barb portion 149 on port 140 and barb portion 164 on sensor 160, in other embodiments each barb portion may include multiple barb part. Additionally, tube 160 may comprise any suitable polymeric material that is sufficiently deformable and biases itself against hose barb portions 149 and 164 to create a high reliability seal between the barbed port and the sensor device.

Figure 5 is a flowchart of a method of sealing a sensor to a bioreactor port according to one embodiment of the present invention. Method 200, shown in FIG. 5, illustrates one exemplary method for placing a robust seal between a bioreactor port and the external environment. In one embodiment, the bioreactor is a single-use bioreactor having one or more ports configured to receive one or more sensors to monitor one or more process variables. In one embodiment, the bioreactor bag has barbed sensor ports, such as shown in FIGS. 4A-4D . However, other port configurations capable of coupling with sensors are also contemplated. For example, in one embodiment, a different port configuration can be used that can adequately receive the sensing and sealing elements.

In block 210, a sensing element is obtained. The sensing element may be a pressure sensor, temperature sensor or any other suitable sensor to detect any suitable parameter to monitor the ongoing reaction within the bioreactor. In one embodiment, the sensor obtained in block 210 includes a coupling structure configured to allow mechanical coupling with a port on a bioreactor bag. In one embodiment, the bioreactor bag includes a barbed port and the sensor also includes corresponding barbs. The barbs on the sensor and port can be oriented in the same direction or in opposite directions.

In block 220, a port is positioned for connection with a sensing device. A bioreactor bag may include one or more ports, and different sensors may be more advantageously placed in different ports based on the need to monitor different process variables. In block 220, a port is positioned for coupling to a sensing element. The port is positioned such that it has structure configured to mechanically couple to the selected sensing element.

In block 230, a sensing element is positioned within a port of the bioreactor bag. This can include inserting or sliding the sensor into the port. Additionally, the sensor may include its own sealing mechanism. In such an embodiment, as indicated at block 234, it may be desirable to place the sealing mechanism as desired. For example, in one embodiment, a sensing element with an O-ring seal may be placed within the port as a secondary seal. However, in another embodiment, the sensing element does not include a sealing element, as indicated at block 232, and positioning the sensing element includes moving the sensing element into position within the port prior to placing the sealing element. In one embodiment, this may include sliding the sensing element along the interior edge of the selected port until the sensing element is exposed to the reaction mixture. In one embodiment, the sensor is in place when a structure along the outer edge of the sensor is coupled to or abuts a corresponding structure along the edge of the port. For example, in one embodiment, both the sensor and the port include barb elements.

In block 240, an outer seal is provided. As shown in Figure 5, first the sensor is moved into position in the seal, and the seal/sensor assembly is then connected to the port. However, it is expressly contemplated that the seal may be provided after the sensor is actuated into the port. In one embodiment, the seal is configured to at least partially overlap the port, as shown in box 242 , and/or at least partially overlap a portion of the sensor, as shown in box 244 . In one embodiment, the seal is configured to cover substantially equal portions of the sensor and port.

Although the present invention has been described with reference to preferred embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.

Claims (11)

1. A bioreactor sensing system comprising: A bioreactor, the bioreactor comprising: an aperture configured to provide an interface for monitoring the contents in the reaction vessel; and a port coupled to the bioreactor vessel adjacent the well; a sensing device disposed at least partially within the port such that a sensing element is exposed to the contents; and An external seal configured to be applied over a portion of the sensing device and a portion of the port. 2. The bioreactor sensing system of claim 1, wherein the outer seal comprises an elastic tube. 3. The bioreactor sensing system of claim 1, wherein the sensing device comprises a sensor structure, the port comprises a port structure, and wherein the sensor structure and the port structure comprise an interface, and wherein the The outer seal fluidly seals the interface. 4. The bioreactor sensing system of claim 3, wherein the sensing element comprises a sensor hose barb. 5. The bioreactor sensing system of claim 4, wherein the port structure includes a port hose barb, and wherein the port hose barb and the sensor hose barb have opposite directionality . 6. A sealed sensor interface system for a bioreactor, said sealed sensor interface system comprising: A seal comprising: a sensor receiving portion configured to be coupled to a sensing device; a port receiving portion configured to couple to a port on the bioreactor; and Wherein the seal provides a mechanical interface such that the mixture within the bioreactor is sealed from exposure to the external environment. 7. The sealed sensor interface system of claim 6, wherein the sensing device and the port are engaged at the mechanical interface. 8. The sealed sensor interface system of claim 6, wherein the seal is a tube. 9. The sealed sensor interface system of claim 8, wherein the tube is an elastic tube. 10. The sealed sensor interface system of claim 8, wherein the seal is a polymer tube. 11. The sealed sensor interface system of claim 6, wherein the sensor receiving portion is configured to receive a sensor structure on an outer surface of the sensing device, and wherein the port receiving portion is configured to receive A port structure on the outer surface of the port on the bioreactor.