US-12624331-B2 - Bioreactor including probe for electrical or electromagnetic measurements

US12624331B2US 12624331 B2US12624331 B2US 12624331B2US-12624331-B2

Abstract

A bioreactor includes a rigid-walled vessel for containing a biological medium, the vessel having a lid. The bioreactor further includes a probe passing through an aperture in the lid and having a sensing end inside the vessel and a remote end outside the vessel. The sensing end has plural electrodes for immersion in the biological medium, and the remote end is configured for coupling to external devices and transmission thereto of electrical or electromagnetic measurements made by the electrodes. One of the lid and the probe has one or more resiliently deformable mechanisms and the other of the lid and the probe has one or more respective complementary surfaces. The resiliently deformable mechanisms and the complementary surfaces are configured such that, on insertion of the probe through the aperture to assemble the probe to the lid, the one or more resiliently deformable mechanisms are first deformed on sliding against the one or more complementary surfaces and then resile when the probe reaches a predetermined insertion position relative to the lid to secure the probe to the lid. One of the lid and the probe carries a sealing element which seals the probe to the lid when the probe is secured at the predetermined position.

Inventors

Paul Grant
Adrian SALARIU
Jochen Scholz
Stuart TINDAL

Assignees

THE AUTOMATION PARTNERSHIP (CAMBRIDGE) LTD.

Dates

Publication Date: 20260512
Application Date: 20211005
Priority Date: 20201015

Claims (12)

1 . A bioreactor including: a rigid-walled vessel for containing a biological medium, the vessel having a lid; a probe passing through an aperture in the lid and having a sensing end inside the vessel and a remote end outside the vessel, the sensing end having plural electrodes for immersion in the biological medium, and the remote end being configured for coupling to external devices and transmission thereto of electrical or electromagnetic measurements made by the electrodes; wherein one of the lid and the probe has one or more resiliently deformable mechanisms and the other of the lid and the probe has one or more respective complementary surfaces, the resiliently deformable mechanisms and the complementary surfaces being configured such that, on insertion of the probe through the aperture to assemble the probe to the lid, the one or more resiliently deformable mechanisms are first deformed on sliding against the one or more complementary surfaces and then resile when the probe reaches a predetermined insertion position relative to the lid to secure the probe to the lid; and wherein one of the lid and the probe carries a sealing element which seals the probe to the lid when the probe is secured at the predetermined position; wherein the probe further includes a flange on a first side of the probe and a shoulder on a second side of the probe opposite the first side, wherein the flange is offset from the shoulder along an insertion direction of the probe so the probe can adopt only one angular orientation around the insertion direction of the probe when the probe is located at the predetermined position.
2 . The bioreactor according to claim 1 , wherein the one or more resiliently deformable mechanisms and the one or more complimentary surfaces form a snap-fit connector.
3 . The bioreactor according to claim 1 , wherein the one or more resiliently deformable mechanisms are one or more flexible members or one or more spring-loaded detent mechanisms.
4 . The bioreactor according to claim 1 , wherein the probe and the lid are configured such that the one or more resiliently deformable mechanisms are deformable by a user to allow the probe to be withdrawn from the lid and reinserted multiple times.
5 . The bioreactor according to claim 1 , wherein a top surface of the flange and a bottom surface of the lid interact to prevent the probe being over-inserted beyond the predetermined position.
6 . The bioreactor according to claim 5 , wherein the sealing element is sandwiched between the top surface of the flange and the bottom surface of the lid and seals to the top surface of the flange and the bottom surface of the lid to seal the probe to the lid when the probe is located at the predetermined position.
7 . The bioreactor according to claim 1 , wherein the probe has a lateral projection at its sensing end which rests against a side wall of the vessel to enforce a minimum stand off distance between the probe and the side wall along a length of the probe from the lid to the projection.
8 . The bioreactor according to claim 1 , wherein the probe is part of a multi-purpose assembly inserted through the aperture in the lid, the multi-purpose assembly also containing either or both of (a) a sparger for conveying sparging gas to the biological medium, and (b) further electrodes forming a pH sensor for sensing the pH of the biological medium.
9 . The bioreactor according to claim 1 , wherein the lid is removably replaceable from the vessel.
10 . The bioreactor according to claim 1 which is a single-use bioreactor.
11 . The bioreactor according to claim 1 , wherein the probe is a capacitance, impedance, permittivity or conductivity probe.
12 . The bioreactor according to claim 1 , wherein a first top surface of the flange and a second top surface of the shoulder cooperate with a corresponding bottom surface of the lid so the probe can adopt the only one angular orientation around the insertion direction of the probe when the probe is located at the predetermined position.

Description

RELATED APPLICATIONS This application is a 35 U.S.C. § 371 national phase application of PCT/EP2021/077401 (WO-2022/078815-A1), filed on Oct. 5, 2021, entitled “BIOREACTOR INCLUDING PROBE FOR ELECTRICAL OR ELECTROMAGNETIC MEASUREMENTS”, and claims priority to EP-20202136.6 filed on Oct. 15, 2020, both of which are incorporated herein by reference in their entirety. This application claims priority from EP 20202136.6 filed 15 Oct. 2020, the contents and elements of which are herein incorporated by reference for all purposes. FIELD OF THE INVENTION The present invention relates to a bioreactor including a probe for electrical or electromagnetic measurements. BACKGROUND Cell culture is a process for growing cells in an artificial environment such as a bioreactor. Often, the cells are grown whilst suspended in a culture growth medium. Monitoring and/or controlling the environment to which the cells are exposed in the bioreactor is important in order to control the physiology of the cells and the amount of target produced. Specifically, the monitoring of various parameters of the cells and/or the culture growth medium within the bioreactor is key to their control. Example bioreactor systems suitable for cell culture are described in US 2016/0152936 and WO 2014/020327. Monitoring of parameters of the cells can be achieved offline by taking samples and/or in-line by measuring various characteristics of the cells directly in the process. In-line monitoring is becoming increasingly important, as it facilitates process control and process automation. In-line monitoring generally uses a sensor inserted directly into the culture growth medium contained in a vessel. For example, electrical or electromagnetic measurements made by electrodes immersed in growth media can be used to measure quantities such as capacitance, impedance, permittivity, conductivity etc. These measurements may then be subject to analysis techniques such as impedance spectroscopy in order to derive, for example, cell concentration. Probes carrying such electrodes need to be arranged so that they can be connected to electronics and communications outside the vessel bioreactor, while ensuring that the sensing end of the probe is properly immersed in the cell culture in the vessel. Other considerations are: speed of assembly, and low risk of introducing contaminants into the cell culture The present invention has been devised in light of the above considerations. SUMMARY OF THE INVENTION The present invention provides a bioreactor including: a rigid-walled vessel for containing a biological medium, the vessel having a lid;a probe passing through an aperture in the lid and having a sensing end inside the vessel and a remote end outside the vessel, the sensing end having plural electrodes for immersion in the biological medium, and the remote end being configured for coupling to external devices and transmission thereto of electrical or electromagnetic measurements made by the electrodes;wherein one of the lid and the probe has one or more resiliently deformable mechanisms and the other of the lid and the probe has one or more respective complementary surfaces, the resiliently deformable mechanisms and the complementary surfaces being configured such that, on insertion of the probe through the aperture to assemble the probe to the lid, the one or more resiliently deformable mechanisms are first deformed on sliding against the one or more complementary surfaces and then resile when the probe reaches a predetermined insertion position relative to the lid to secure the probe to the lid; andwherein one of the lid and the probe carries a sealing element which seals the probe to the lid when the probe is secured at the predetermined position. By securing the probe to the vessel through the lid in this way, correct location of the sensing end in the vessel can be assured, even though the probe is a non-integral part of the lid, or indeed of the vessel. Moreover, assembly by insertion through the lid of the vessel and mechanical joining via the resiliently deformable mechanisms and complementary surfaces is compatible with fast assembly. The mechanical joining approach also allows glues or other adhesive-based fixing techniques to be avoided, such techniques carrying risks of contamination by contact of the cell culture with glues or glue residuals. Optional features of the present invention will now be set out. The invention includes the combination of the optional features described except where such a combination is clearly impermissible or expressly avoided. Conveniently, the one or more resiliently deformable mechanisms and the one or more complimentary surfaces may form a snap-fit connector. The one or more resiliently deformable mechanisms may be one or more flexible members, for example formed of flexible plastic. Another option, however, is for the resiliently deformable mechanisms to be one or more spring-loaded detent mechanisms, e.g. in which the or