Disposable bioreactor sensor interface

Abstract

A bioreactor sensing system is presented. A bioreactor sensing system includes a bioreactor vessel. The biological reaction vessel includes an aperture configured to provide an interface for monitoring contents within the biological reaction vessel. The biological reaction vessel also includes a port coupled to the biological reaction vessel adjacent the aperture. 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 content. 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

[0001] This application is a divisional application, which is based on a Chinese patent application with an application date of December 8, 2016, application number 201611127141.5, and invention name “Disposable Bioreactor Sensor Interface”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application is based upon and claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 265,819, filed on December 10, 2015, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] The present invention relates to a bioreactor sensing system, as well as a method of sealably coupling a sensor to a bioreactor and a sealed sensor interface system for a bioreactor. Background Art

[0005] Bioreactors support biological reactions for many important applications, including cell culture, fermentation, etc. Bioreactions may be susceptible to changes in temperature, pressure, pH, and other factors. In addition, as the bioreaction proceeds, the reaction itself may change various parameters within the bioreaction 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 the bioreaction.

[0006] The life sciences industry is moving away from large, capital-intensive facilities made of stainless steel with large clean-in-place (CIP) infrastructures, and toward smaller facilities that utilize polymer-based bags or containers that serve as single-use bioreactors. Single-use bioreactor bags can be used once and then discarded. Using single-use bioreactors can significantly reduce the capital costs required for a facility. For example, in existing facilities that use stainless steel CIP infrastructure, up to 90% of operating costs can be associated with the CIP infrastructure, including high-end instrumentation 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, such as is required for more targeted drug therapies and other small-scale applications. Summary of the invention

[0007] A bioreactor sensing system is provided. The bioreactor sensing system includes a bioreactor vessel. The bioreactor vessel includes a hole configured to provide an interface or interface for monitoring contents within the bioreactor vessel. The bioreactor vessel also includes a port coupled to the bioreactor vessel adjacent the hole. The bioreactor sensing system also includes a sensing device at least partially disposed within the port such that a sensing element is exposed to the contents. The bioreactor sensing system also includes an external seal configured to be applied to a portion of the sensing device and a portion of the port. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Figure 1 is a schematic diagram of a single-use bioreactor for which embodiments of the present invention are particularly useful.

[0009] Figure 2A and Figure 2B is a schematic diagram of a sensor connected to a disposable bioreactor bag;

[0010] Figure 3 A schematic diagram of a sealed connection between a sensor and a bioreactor port according to one embodiment of the present invention;

[0011] Figures 4A-4D A schematic diagram of a sensor coupled to a port on a bioreactor according to one embodiment of the present invention;

[0012] Figure 5 Flow chart of a method of sealing a sensor to a bioreactor port according to an embodiment of the present invention. DETAILED DESCRIPTION

[0013] A disposable bioreactor may have one or more ports or interfaces or engagement interfaces configured to attach a sensor device capable of monitoring process variables as the reaction proceeds. An instrument interface that facilitates the use and adoption of disposable, single-use bioreactor technology while providing a reliable seal between the instrument and the bioreactor would be a significant benefit to the life sciences industry.

[0014] Figure 1 is a schematic diagram of a disposable bioreactor for which embodiments of the present invention are particularly useful. A sensor device 30 is useful for measuring characteristics of a biological sample within a disposable bioreactor 20, such as pressure, temperature, pH, dissolved oxygen, etc. The sensor 30 can be mounted to the disposable bioreactor 20 and arranged to provide an electrical indication of a parameter of interest relative to the sample 22 located within the bioreactor 20. The sensor 30 is coupled to a suitable analyzer that provides a reading and / or other suitable indication of a parameter of interest to the sample 22.

[0015] In the application of disposable bioreactors, various sensor devices (e.g., sensor 30) can be integrated into or otherwise connected to the bioreactor bag. According to the embodiments described herein, a mechanical interface is provided between the sensor and the bioreactor. The mechanical interface can facilitate the installation of the sensor in the port. The mechanical interface can also provide high reliability integrity. In one embodiment, the mechanical interface can 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 with the body of the sensor and / or at least partially overlaps with the sensor receiving port on the bioreactor. The use of an external seal can provide additional benefits over current systems that rely on internal sealing mechanisms.

[0016] Figure 2A and 2B 4 is a schematic diagram showing one way in which a current sensor device is coupled to a disposable bioreactor bag via port 40. Figure 2A As shown, disposable bioreactor bags typically have so-called "barbed ports". The barbed port 40 typically includes a circular flange 42 that intersects a cylindrical sidewall 44 at an approximately right angle 46. A hose barb 49 is disposed at a distal end 48 of the cylindrical sidewall 44, the hose barb 49 being configured to interfere with a deformable sidewall of a hose (such as a rubber or elastic hose). The barbed port 40 is common on disposable bioreactors to receive a hose coupled to the bioreactor.

[0017] The flange 42 can be attached to the hole in the bioreactor bag in any suitable manner, such as ultrasonic welding, or by using any other suitable method. The flange 42 can be arranged in the bioreactor so that the wall 44 passes through the hole in the bioreactor bag. The flange 42 can also be coupled to the outer surface of the bioreactor bag so that the cylindrical side wall 44 does not pass through the hole in the bioreactor bag. Therefore, the barbed port 40 is very useful and provides flexible connection options for the tube to the disposable bioreactor. Therefore, it is expected that any external sealing mechanism is compatible with the existing barbed port.

[0018] Currently, sensor devices such as sensor device 50 are designed to be located within a barbed port of a disposable bioreactor bag, such as port 40. The outer diameter of sensor 50 is sized so that it can fit within the inner diameter 51 of cylindrical sidewall 44. O-ring 52 is configured to engage inner diameter 51 of cylindrical sidewall 44 so that sensor device 50 is sealed within barbed port 40.

[0019] The sensor 50 may include any suitable sensing device configured to provide an electrical indication of a parameter of interest relative 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 mounted within the cylindrical sidewall 44, the assembly may be as shown. Figure 2B As shown. However, it has been found that the inner surface of the cylindrical sidewall 44 may not have the appropriate quality control to reliably form a seal using the O-ring 52. The main design feature of the barbed port 40 is to connect to a section of tubing and allow fluid to flow therethrough. In order to use the inner surface of the cylindrical sidewall 44 to seal the sensor 50, using only the O-ring 52 may not achieve a robust fluid and / or mechanical seal suitable for all applications. For example, if there is a scratch on the inner diameter 51 of the cylindrical sidewall 44, there is a risk of fluid leaking through the scratch after the sensor device 50 is installed therein. An external seal may provide a more reliable and more robust seal.

[0020] 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. Such an external seal may be used alone to mechanically seal the sensor to the bioreactor, or in addition to the sensor where a redundant seal is desired. Figure 2A and 2B The internal sealing mechanism described is used outside.

[0021] Figure 3 FIG. 1 is a schematic diagram of a sealed connection between a sensor and a bioreactor port according to an embodiment of the present invention. In one embodiment, an external seal can provide additional protection to the current sensor-bioreactor connection structure. For example, the external seal can be placed Figure 2B The upper portion of the sensor-port assembly is shown. In another embodiment, the external seal is used without an additional sealing mechanism between the sensor and the port.

[0022] The external seal can support the use of many different sensor bioreactor bag configurations. The external seal can also provide a more reliable and more robust seal than, for example, an O-ring between a sensor and a port. It may be desirable to isolate the reaction mixture within the bioreactor 102 from the environment 100 outside the bioreactor 102. In one embodiment, the seal 110 can be placed at the interface or connection between the sensor 104 and the sensor port 106 to strengthen or create a barrier between the reaction mixture and the environment 100.

[0023] In one embodiment, the sensor 104 has an outer diameter that is smaller than the inner diameter of the received sensor port 106, and the outer diameter is configured to fit within the inner diameter within the port 106 receiving the sensor. The sensor port 106 can be formed of a material having a certain elasticity so that it can more easily receive the sensor 104 without significant gaps. In one embodiment, at least a portion of the sensor 104 is configured to fit within the sensor port 106. The port coupling portion 116 is configured to receive and couple to the sensor coupling portion 114 at the joint 120. The port portion 116 and the sensor portion 114 are configured to fit together, for example, in corresponding shapes.

[0024] In one embodiment, the seal 110 is configured to overlap at least a portion of the sensor 104 and a portion of the port 106 such that it spans the joint 120. The sensor portion 114 physically interfaces with the port portion 116 at the joint 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 joint 120 extends substantially along the entire circumference of the sensor 104. Along the joint 120, the sensor coupling portion 114 and the port coupling portion 116 can have different possible shapes and structures. In one embodiment, the shape of the sensor portion 114 matches the shape of the port portion 116.

[0025] Figures 4A-4D A sensor coupled to a port on a bioreactor according to an embodiment of the present invention is shown. Figure 4A As shown, 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 substantially located at the edge of the port 140. However, the port 140 may include multiple barbs 149, or include a portion of the barb 149 extending along the length of the port 140 and including one or more portions of the circumference of the port 140. In one embodiment, the barb 149 is a hose barb. In one embodiment, the port 140 is configured to receive the sensing device 160 in the direction indicated by arrow 150, as shown in FIG. Figure 4B Thus, at least some embodiments described herein do not require modification of the barbed port of a disposable bioreactor. This may be useful in order to provide a more substantial seal between the sensor 160 and an existing bioreactor already on the market.

[0026] Figure 4BA sensing device 160 is shown having a sensing end 168 configured to sense one or more parameters associated with a reaction mixture in a bioreactor. In one embodiment, the sensor 160 is cylindrical in shape and is 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 the sensing end 168 and the barb 164 can be selected to allow the sensing end 168 to be exposed to the reaction mixture when fully inserted into the port 140.

[0027] In one embodiment, sensor barb 164 is configured to cooperate with barb 149 on port 140 so that, for example, Figure 4C The outer seal 162 shown in the figure forms a strong mechanical seal between the sensor 160 and the port 140. In one embodiment, the seal 162 includes a flexible and strong material. In one embodiment, the seal 162 includes an elastomeric tube. When the sensing device 160 is installed to the barbed port 140, the elastomeric tube or synthetic rubber tube 162 (elastomeric tubing) is generally slid on the outer diameter of the sensor device 160, preferably in the direction indicated by the arrow 166. In one embodiment, the seal 162 can be attached to the sensor 160 before being inserted into the port 140. In another embodiment, the seal 162 can be attached after the sensor 160 is connected to the port 140.

[0028] In one embodiment, once the elastic tube 162 is positioned so that it extends over and under the barbs 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 so that the barbs 164 abut the barbs 149, for example, as shown in FIG. Figure 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. Figures 4A-4D In the illustrated embodiment, the sensing end 168 is substantially flush with the inner wall portion of the barbed port 40. However, other desired depths of the sensing end 168 are also contemplated. For example, in some embodiments, it may be beneficial for the sensing end 168 to extend substantially within the disposable bioreactor to interact with the reaction mixture therein.

[0029] In at least one embodiment, for example Figure 4DAs shown, barbs 164 have an opposite direction orientation than barbs 149. This opposite directionality allows the sensor 160 / seal 162 assembly to stop upon contact with barbs 149 when sliding in the direction indicated by arrow 150. In one embodiment, when in place, sensor 160 / seal 162 creates a secure mechanical and fluid seal with port 140. However, it is expressly contemplated that embodiments in which barbs 149 and 164 have substantially the same directionality may be implemented. Additionally, although in Figure 4A and 4B The embodiment shown in the figure shows a single barb portion 149 on the port 140 and a barb portion 164 on the sensor 160, in other embodiments, each barb portion may include multiple barb portions. In addition, the tube 160 may include any suitable polymeric material that can be sufficiently deformed and bias itself against the hose barb portions 149 and 164 to create a high reliability seal between the barbed port and the sensor device.

[0030] Figure 5 is a flow chart of a method of sealing a sensor to a bioreactor port according to one embodiment of the present invention. Figure 5 An exemplary method for placing a robust seal between a bioreactor port and the external environment is shown. In one embodiment, the bioreactor is a disposable 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 a barbed sensor port, e.g. Figures 4A-4D However, other port structures that can be coupled to the sensor are also contemplated. For example, in one embodiment, different port structures can be used that can adequately receive the sensing element and the sealing element.

[0031] In frame 210, a sensing element is obtained. The sensing element may be a pressure sensor, a 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 frame 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 port with a barb, and the sensor also includes a corresponding barb. The barbs on the sensor and the port may be oriented in the same direction or in opposite directions.

[0032] In block 220, the port is positioned for connection with the sensing device. The 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, the port is positioned for coupling to the sensing element. The port is positioned so that it has a structure configured to mechanically couple to the selected sensing element.

[0033] In frame 230, the sensing element is positioned in the port of the bioreactor bag. This can include inserting or sliding the sensor into the port. In addition, the sensor can include its own sealing mechanism. In such an embodiment, as shown in frame 234, it may be necessary to place the sealing mechanism as needed. For example, in one embodiment, a sensing element with an O-ring seal can be placed in the port as a second seal. However, in another embodiment, the sensing element does not include a sealing element, as shown in frame 232, and positioning the sensing element includes moving the sensing element to a position in the port before placing the sealing element. In one embodiment, this can include sliding the sensing element along the inner 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 connected to or abuts to a corresponding structure along the edge of the port. For example, in one embodiment, both the sensor and the port include a barb element.

[0034] In block 240, an external seal is provided. Figure 5 As shown, 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 can be set 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 substantially cover equal portions of the sensor and the port.

[0035] 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

1. A bioreactor sensing system, comprising: A bioreactor container, comprising: an aperture configured to provide an interface for monitoring contents in the reaction vessel; and a port coupled to the bioreactor container adjacent the aperture and having a port structure including a port hose barb; a sensing device disposed at least partially within the port to be integrated into the bioreactor container such that a sensing element is exposed to the contents and having a sensor structure including a sensor hose barb; and an external seal configured to extend across the port hose barb of the port structure and the sensor hose barb of the sensor structure, the external seal being a polymer tube and being slidable in the longitudinal direction of the sensor structure to form a mechanical seal between the sensor structure and the port structure by cooperating with the sensor hose barb and the port hose barb, wherein The sensor hose barb of the sensor structure is disposed adjacent to the port hose barb of the port structure, and The port hose barb is formed on an outer surface of the port structure, and the sensor hose barb is formed on an outer surface of the sensor structure, and the sensor hose barb is configured to cooperate with the port hose barb so that the external seal forms the mechanical seal between the sensor structure and the port structure. 2 . The bioreactor sensing system of claim 1 , wherein the outer seal is an elastic tube. 3 . The bioreactor sensing system of claim 1 , wherein the sensor structure and the port structure comprise an interface, and wherein the external seal fluidly seals the interface.

4. The bioreactor sensing system of claim 1, wherein the port hose barb and the sensor hose barb have opposite directionality.

5. A method for sealably coupling a sensor to a bioreactor, comprising the steps of: positioning a port on the bioreactor, the port being configured to receive a sensing element of the sensor, the port having a port structure including a port hose barb, and the port hose barb being formed on an outer surface of the port structure; positioning a sensor within the port such that the sensor is integrated into the bioreactor and the sensing element is exposed to the interior of the bioreactor, wherein the step of positioning the sensor within the port includes positioning a sensor hose barb of the sensor adjacent to the port hose barb of the port structure, the sensor hose barb being formed on an outer surface of the sensor; as well as coupling a sealing element to the sensor and the port such that the sealing element extends across the port hose barb of the port structure and the sensor hose barb of the sensor, wherein The sealing element is a polymer tube and is slidable in the longitudinal direction of the sensor to form a mechanical seal between the sensor and the port structure by cooperating with the sensor hose barb and the port hose barb, and The sensor hose barb is configured to cooperate with the port hose barb such that the sealing element forms the mechanical seal between the sensor and the port structure.

6. The method of claim 5, wherein positioning a sensor structure adjacent to a port structure determines a depth of a sensing element in the port. The method of claim 5 , wherein the sensor structure has an opposite directionality to the port structure.

8. The method of claim 5, wherein the sensor structure and the port structure have the same directionality.

9. The method of claim 5, wherein the step of coupling a sealing element to the sensor occurs prior to actuating the sensor in the port.

10. The method of claim 5, wherein the sealing element is an elastic tube.

11. A sealed sensor interface system for a bioreactor, the sealed sensor interface system comprising: A sealing member, the sealing member comprising: a sensor receiving portion configured to couple to a sensing device, wherein the sensing device is integrated into the bioreactor and has a sensor structure including a sensor hose barb; a port receiving portion configured to couple to a port on the bioreactor, wherein the port has a port structure including a port hose barb; and wherein the seal provides a mechanical interface such that the mixture within the bioreactor is sealed from exposure to the external environment, and the seal extends across the port hose barb of the port structure and the sensor hose barb of the sensor structure, the seal is a polymer tube and is slidable in the longitudinal direction of the sensor structure to form a mechanical seal between the sensor structure and the port structure by cooperating with the sensor hose barb and the port hose barb, wherein the sensor hose barb of the sensor structure is disposed adjacent to the port hose barb of the port structure, and The port hose barb is formed on an outer surface of the port structure, and the sensor hose barb is formed on an outer surface of the sensor structure, and the sensor hose barb is configured to cooperate with the port hose barb so that the seal forms the mechanical seal between the sensor structure and the port structure.

12. The sealed sensor interface system of claim 11, wherein the sensor structure of the sensing device and the port structure of the port are engaged at the mechanical interface.

13. The sealed sensor interface system of claim 11, wherein the tube is an elastic tube.

14. A sealed sensor interface system according to claim 11, wherein the sensor receiving portion is configured to receive the sensor structure on the outer surface of the sensing device, and wherein the port receiving portion is configured to receive the port structure on the outer surface of the port on the bioreactor.

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