Flow Cell System for Optical Fluid Analysis and Bioreactor System

Abstract

A flow cell system for an optical fluid analysis comprises a disposable flow cell having at least one flow chamber comprising a fluid pathway, and at least one pair of opposed light transmitting windows along the fluid pathway, an external flow cell holder for holding the flow cell, at least one light source, and an external detection device couplable with at least one of the flow cell holder and the flow cell for bringing the external detection device in optical communication with the flow cell, the device having at least one optical detection unit. The external detection device is configured to conduct optical measurements of the fluid that flows in the flow cell through at least one pair of windows from externally under illumination by the at least one light source.

Claims

1-20. (canceled)

21. A flow cell system (6) for an optical fluid analysis, comprising a disposable flow cell (8, 70, 80, 100, 122) having a flow cell inlet (10), a flow cell outlet (12) and at least one flow chamber (14) comprising a fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112), and at least one pair of opposed light transmitting windows (20) arranged along the fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112), an external flow cell holder (38, 98) for holding the disposable flow cell (8, 70, 80, 100, 122), a first bypass line (16) connectable to an apparatus containing a fluid to be analyzed and the flow cell inlet (10), and a second bypass line (18) connectable to said apparatus and the flow cell outlet (12), at least one light source (30, 90, 102, 116), and an external detection device (24, 104) couplable with at least one of the flow cell holder (38, 98) and the flow cell (8, 70, 80, 100, 122) for bringing the external detection device (24, 104) into optical communication with the flow cell (8, 70, 80, 100, 122), the external detection device (24, 104) having at least one optical detection unit (26, 28, 84, 86, 88, 92), wherein the external detection device (24, 104) is configured to conduct optical measurements of the fluid that flows in the flow cell (8, 70, 80, 100, 122) through at least one pair of windows (20) from externally underneath the illumination by the at least one light source (30, 90, 102, 116).

22. The system (6) of claim 21, wherein the flow cell (8, 70, 80, 100, 122) comprises a plurality of consecutive flow chambers (14), each of the consecutive flow chambers having a pair of opposed windows (20), and wherein individual optical characteristics of the respective flow chambers in the plurality of flow chambers (14) differ from each other.

23. The system (6) of claim 22, wherein individual distances (d.sub.1, d.sub.2, d.sub.3 d.sub.4) between the opposed windows (20) or an associated width of the respective flow chambers (14) in the plurality of flow chambers (14) differ from each other.

24. The system (6) of claim 21, wherein the system (6) comprises at least one illumination source as the light source (30, 90, 102, 116) that emits light into one of the pair of windows (20) of a respective flow chamber (14).

25. The system (6) of claim 24, wherein the at least one illumination source comprises at least one light emitting diode (30, 90, 102, 116).

26. The system (6) of claim 25, wherein the at least one light emitting diode (30, 90, 102, 116) comprises an array of light emitting diodes (30, 90, 102, 116) that emit light with different wavelengths.

27. The system (6) of claim 26, wherein individual light emitting diodes (30, 90, 102, 116) of the array can be triggered independently to influence a light wavelength emitted into the respective flow chamber (14).

28. The system (6) of claim 21, further comprising at least one wavelength dispersing device arranged between the at least one light source (30, 90, 102, 116) and the respective window (20) for influencing the wavelength of the light supplied to the at least one flow chamber (14).

29. The system (6) of claim 21, further comprising at least one light guiding device (22) for guiding light from or to at least one of the windows (20).

30. The system (6) of claim 21, wherein the flow cell (8, 70, 80, 100, 122) comprises a flow deflection device arranged in the fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112), such that fluid flowing in the fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112) impinges the flow deflection device, and wherein the flow deflection device influences the flow direction of the fluid for mixing the fluid or for directing the fluid to an inner surface of at least one of the windows (20) for cleaning said inner surface.

31. The system (6) of claim 21, wherein the at least one detection unit (26, 28, 84, 86, 88, 92) is configured to conduct at least one optical analysis from a group of optical analyses consisting of: spectroscopic analysis, optical image recording, turbidity measurement, fluorescence measurement, absorption measurement, and scattering measurement.

32. The system (6) of claim 21, wherein the at least one detection unit comprises at least one optical path for the analysis of the fluid, the optical path being perpendicular to the respective fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112).

33. The system of claim 21, wherein the at least one detection unit (26, 28, 84, 86, 88, 92) comprises at least one optical path for the analysis of the fluid, the optical path being not perpendicular to the respective fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112).

34. The system (6) of claim 21, further comprising a heating device thermally couplable to the flow cell (8, 70, 80, 100, 122) for controlling a temperature of the flow cell (8, 70, 80, 100, 122).

35. The system (6) of claim 21, wherein the flow cell (8, 70, 80, 100, 122) further comprises an additional segregated flow chamber (14) in fluid communication with the fluid path for conducting an optical reference measurement.

36. The system (6) of claim 21, wherein the flow cell (8, 70, 80, 100, 122) further comprises an additional flow path guiding as a part of the at least one flow chamber (14) for reducing the flow rate in the at least one flow chamber (14).

37. The system (6) of claim 21, further comprising at least one electrode having a first end and a second end, wherein the first end is arranged in an interior space of the at least one chamber, the second end is arranged at an exterior space, and a remaining section of the electrode is sealed from the interior space, and wherein the detection device (24, 104) is configured to perform one or more of (i) applying an electrical voltage or an electrical current to the at least one electrode, and (ii) measuring one or more of an electrical voltage, an electrical current, an electrical resistance and an impedance of the fluid.

38. The system (6) of claim 21, wherein the flow cell (8, 70, 80, 100, 122) is sterilizable by a chemical sterilizing process or by a Gamma ray sterilizing process.

39. The system (6) of claim 21, wherein the external flow cell holder (38, 98) is configured for holding the at least one light source (30, 90, 102, 116) and the optical detection device (24, 104), and for retaining the flow cell (8, 70, 80, 100, 122) in a predetermined alignment to the at least one light source (30, 90, 102, 116) and the optical detection device (24, 104).

40. A bioreactor system (2), comprising a disposable bioreactor (4) and a flow cell system (6) for an optical fluid analysis, comprising a disposable flow cell (8, 70, 80, 100, 122) having a flow cell inlet, a flow cell outlet and at least one flow chamber comprising a fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112), and at least one pair of opposed light transmitting windows arranged along the fluid pathway (15, 72, 74, 76, 78, 106, 108, 110, 112), an external flow cell holder (38, 98) configured to holding the flow cell (8, 70, 80, 100, 122), a first bypass line (16) connectable to the bioreactor (4) containing a fluid to be analyzed and the flow cell inlet (10), and a second bypass line (18) connectable to the bioreactor (4) and the flow cell outlet (12), at least one light source (30, 90, 102, 116), and an external detection device (24, 104) couplable with at least one of the flow cell holder (38, 98) and the flow cell (8, 70, 80, 100, 122) for bringing the external detection device (24, 104) into optical communication with the flow cell (8, 70, 80, 100, 122), the external detection device (24, 104) having at least one optical detection unit (26, 28, 84, 86, 88, 92), wherein the external detection device (24, 104) is configured to conduct optical measurements of the fluid that flows in the flow cell (8, 70, 80, 100, 122) through at least one pair of windows (20) from externally underneath the illumination by the at least one light source (30, 90, 102, 116).

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The present invention may be better understood, and its numerous objects and advantages will become apparent to those skilled in the art, by reference to the accompanying drawings wherein like reference numerals refer to like elements in the several figures and in which:

[0035] FIG. 1 is an overview on a bioreactor system,

[0036] FIG. 2 is a first view and a first cross-sectional view onto the holder,

[0037] FIG. 3 is a second view and a second cross-sectional view onto the holder,

[0038] FIGS. 4 and 5 is the flow cell in a lateral view and two cross-sectional views,

[0039] FIG. 6 is a further overview of the flow cell system,

[0040] FIGS. 7 to 12 show further exemplary embodiments in various views.

DETAILED DESCRIPTION

[0041] FIG. 1 schematically shows a bioreactor system 2 comprising a disposable bioreactor 4 as well as a flow cell system 6 for an optical fluid analysis. In the bioreactor 4, a bio process is conducted. However, the bioreactor 4 may simply act as an example for an apparatus comprising containing a fluid to be analyzed.

[0042] The flow cell system 6 comprises a disposable flow cell 8 having a flow cell inlet 10 and a flow cell outlet 12. Between the flow cell inlet 10 and the flow cell outlet 12, at least one flow chamber 14 is provided, which is explained in further detail below. A first bypass line 16 is connected to the flow cell inlet 10, while a second bypass line 18 is collected with a flow cell outlet 12. Both bypass lines 16 and 18 are also connected to the bioreactor 4. Thus, fluid from the bioreactor 4 is guided into the disposable flow cell 8 and back into the bioreactor 4.

[0043] The flow chamber 14 exemplarily comprises a pair of opposed, light transmitting windows 20, which are coupled with light guiding devices 22. An external detection device 24 is coupled with the flow cell 8 for emitting light into one of the windows 20, and obtaining optical information through another one of the windows 20. Light is guided by the light guiding devices 22 for achieving this. The external detection device 24 is indicated with dashed lines and may include components that enable the system 2 to conduct the optical fluid analysis.

[0044] The external detection device exemplarily comprises an absorption detection unit 26 as well as a scattering detection unit 28. These are merely examples for one or several optical detection units integrated into the external detection device 24.

[0045] For an illumination of the fluid that flows through the flow chamber 14, exemplarily one or several LEDs 30 are provided, which emit light and illuminate the interior of the flow chamber 14 through the light guiding device 22. As an example, a monitoring photodiode 32 is provided, which monitors the frequency and brightness of the light that is emitted by the LEDs. Through an LED driver 34, the brightness and color of the light can be controlled. The intensity and frequency can be changed preferably for each LED 30. Several LEDs 30 can be combined to a multi-wavelength device. For example, this may be conducted by an electronics unit 36, such as a PC or a microcomputer, which is preferably equipped with a user interface. The electronics unit 36, the LED driver 34, the monitoring photodiode 32 and the LEDs 30 may or may not be a part of the external detection device 24, depending on the desired setup. If they are not a part of the external detection device 24, they may be provided separately.

[0046] The detection units 26 and 28 and the LED driver 34 are coupled with the electronic unit 36 and together lead to conducting the analysis. For example, these components may be integrated into the electronics unit 36 or they may be provided as one or multiple external devices, which are couplable with the electronics unit 36.

[0047] In FIG. 2, an external flow cell holder 38 is shown. It exemplarily comprises a base 40 for placing the holder 38 onto a table or another surface. The holder 38 comprises a housing 42 with a recess 44, which is designed to enclose the flow cell 8 in a plier-like manner. The flow cell inlet 10 and the flow cell outlet 12 are shown as a duct. At the sides of the housing 42, a first optical coupling 46 and a second optical coupling 48 are arranged. These are aligned with the opposed windows 20 of the flow cell 8 in its installed position. Here, the optical light guiding devices 22 illustrated in FIG. 1 can be attached.

[0048] At a top portion of the flow cell holder 38, a lid 50 is provided, which has an opening 52 for leading the flow cell outlet 12 through and for retaining the flow cell 8 in the recess 44. For this, the opening 52 has a smaller width than the recess 44. The lid 50 can be secured to the remaining part of the holder 38 by thumb screws 54, which are easy to release.

[0049] In the lower part of FIG. 2, a cross-sectional view indicated by the letters A is shown. Here, it is apparent that the flow cell 8 snugly fits into the recess 44. The flow chamber 14 provides a fluid pathway 15, which will be filled with the fluid to be analyzed. The two opposed windows 20 are in line with the flow chamber 14 and the optical couplings 46 and 48. In this view it can be seen that the holder 38 has a C-like cross-sectional surface in the section comprising the recess 44. The flow cell 8 can easily be taken out of the recess 44 and be disposed of and replaced. For retaining the flow cell 8 in a lateral direction, the recess 44 comprises undercuts 56.

[0050] FIG. 3 shows a top view in the bottom section and a cross-sectional view of the holder 38 in the top section of the figure. The orientation of the cross-sectional view of the flow cell 8 and the holder 38 is indicated by the letters B in the top view. In the cross-sectional view, the holder 38 and the flow cell 8 are shown in detail. In the flow cell 8, the two opposed windows 20 are visible. The flow cell 8 may be a 3-D printed or casted part as a single piece, with the windows 20 being attached as separate parts. They may be made from another material for improving the optical characteristics and may be glued into the flow cell 8.

[0051] For aligning the lid 50, it comprises centering cavities 58, which are to be aligned with complimentary shaped centering protrusions 60. The optical couplings 46 and 48 may be screwed into the housing 42. The recess of 44 extends far below the flow cell inlet 10 for allowing to easily house a hose or duct that is attached to the flow cell inlet 10.

[0052] FIG. 4 shows the flow cell 8 in another perspective, from which the flow chamber 14 is visible. The translucent windows 20 are arranged parallel to the viewing plane of this figure and provide an optical axis 62, which in this case is perpendicular to the fluid pathway 15, which extends perpendicular to the viewing plane of FIG. 4 with regard of the cross-section at the bottom of FIG. 4. The viewing direction of an enlarged cross-sectional illustration at the bottom of the figure is indicated with the letters D. Here, it is possible to view from the flow chamber 14 through the flow cell inlet 10 downwards. FIG. 5 shows the flow cell 8 in a cross-sectional illustration, the viewing direction of which is indicated with the letters C in FIG. 4.

[0053] FIG. 6 shows a part of the system 2 in a schematic overview. Here, the flow cell 8 is shown with a heating device 64, which is thermally coupled with the flow cell 8. The heating device 64 may be controllable in order to set and maintain a predetermined temperature in the flow cell 8. Further, the flow cell 8 is shown to comprise several consecutive flow chambers 14a, 14b, 14c and 14d, which are arranged along the fluid pathway 15. The fluid to be analyzed flows through the flow chambers 14a, 14b, 14c and 14d one after another. The flow chambers 14a, 14b, 14c and 14d each comprise a distance d.sub.1, d.sub.2, d.sub.3 and d.sub.4 between opposed windows 20, which differ from each other. In the example shown, the distances d.sub.1, d.sub.2, d.sub.3 and d.sub.4 increase along the flow pathway 15.

[0054] The light source 30 in the form of a multi LED unit emits light into the windows 20 of the flow chambers 14a, 14b, 14c and 14d. At an opposed side of the flow cell 8, the light leaves the respective windows 20 and is routed to a detection unit 66, which may exemplarily comprise a plurality of absorption detection units 26 or any other suitable detection units. By this, several optical paths 62a, 62b, 62c, 62d are created, which are perpendicular to the fluid pathway 15. This is further depicted in a magnified section in FIG. 6.

[0055] Further downstream, another flow chamber 14e is provided. Here, besides absorption detection, also a scattering detection may be conducted. Thus, there may be a perpendicular optical path 62e, as well as an optical path 62f, which is not perpendicular to the fluid pathway 15. A detection unit 68 may be provided, which is inter alia capable of providing the scattering detection.

[0056] FIG. 7 shows a multi-path-length absorption flow cell 70 with a plurality of fluid pathways 72, 74, 76 and 78, which are flown through in a consecutive manner by a fluid to be analyzed. In this particular example, the lengths of the pathways 72, 74, 76 and 78 increase successively. The second pathway 74 has a greater length than the first pathway 72. The length of the third pathway 76 exceeds the length of the second pathway 74 and so on. Merely as an example, the pathway lengths may be about 3 mm, 5 mm, 10 mm and 20 mm. Light is directed through the fluid pathways 72, 74, 76 and 78 as indicated with the arrows running from the left to the right in the viewing plane. Each fluid pathway 72, 74, 76 and 78 comprises a pair of translucent windows 20 are arranged parallel to each other and perpendicular to the respective fluid pathway 72, 74, 76 or 78, in analogy to the illustration in FIG. 5.

[0057] It is conceivable to provide other flow cells with another number of fluid pathways and/or different dimensions. Furthermore, the direction of flow may also be opposite, such that the pathways 72, 74, 76 and 78 with successively decreasing pathlengths are flown through. Also, the light emitted into the various fluid pathways 72, 74, 76 and 78 may comprise different wavelengths.

[0058] FIG. 8 shows a cross-sectional view of a flow cell 80, which may be the same as flow cell 8 of the previous figures and which may comprise the scattering flow chamber 14e indicated in FIG. 6. Here, the viewing plane is perpendicular to a main extension axis, in analogy to the indication D-D in FIG. 4. A ray of light 82, which may be emitted by an LED, in particular a laser LED, enters the flow chamber 14e and impinges onto the fluid to be analyzed. Three detection units are provided, which include a first detection unit 84 at an angle of 180° (shine through), a second detection unit 86 at an angle of 160° and a third detection unit 88 at an angle of 90°. Of cause, detection units may be other angles, when required. In analogy to the above, the detection units 84, 86 and 88 are provided externally and are thus only indicated by dashed lines for clarification. While the first detection units 84 is primarily provided for detecting light absorption, the second detection unit 86 and the third detection unit 88 are provided for detection of light scattering.

[0059] FIG. 9 shows the flow cell 80 held in the flow cell holder 38. Here, an LED 90 is provided to emit the ray of light 82 shown in FIG. 8. In addition to the flow cell 80, also a reference detection unit 92 is provided, onto which a reflected ray of light 94 is directed, which does not run through the fluid to be analyzed. Hence, a reference value may be generated to increase the detection accuracy. For this purpose, a mirror 96 is provided, which is partially transparent.

[0060] FIG. 10 shows a flow cell holder 98, which is exemplarily adapted for holding the flow cell 70 shown in FIG. 7. Here, the flow cell holder 98 comprises four first optical couplings 46a to 46d as well as four second optical couplings 48a to 48d. Here, the couplings 46a to 48d are merely illustrated as openings or seats for introducing dedicated devices for holding glass fibers 99, i.e. light guiding devices 22 (schematically illustrated), that lead light from an external light source to the flow cell or that lead light to an external detection unit for conducting the optical measurement. Also, the optical couplings 46a to 48d may be used for providing the respective light sources/LEDs or detection units.

[0061] FIG. 11 shows a flow cell 100 together with a multi LED unit 102 as well as a detection device 104 having a plurality of detection units, in particular for providing turbidity measurements. The flow cell 100 comprises four fluid pathways 106, 108, 110 and 112, wherein each of the pathways 106 to 112 is associated with a light source 90 as well as a detection unit 114 in the form of a photo diode each for measuring absorption. Furthermore, a laser diode 116 is provided, which emits a laser into a section 118 of the flow cell, which leads to scattering the light. Here, a further detection unit 120 is provided, which is designed for measuring scattered light in an angle of 180° to the laser diode 116. Further detection units are possible, in analogy to FIG. 8.

[0062] FIG. 12 shows another flow cell 122, which comprises a detection unit 124 for optical fluorescence measurement in an angle of 90° to a ray of light 82 entering the flow cell 122. Also, a detection unit 84 may be provided for detecting absorption, in analogy to FIG. 8.

[0063] The invention is not limited to one of the aforementioned embodiments, but can be modified in many ways.

[0064] All features and advantages resulting from the claims, the description and the figures, including constructive details, spatial arrangements and procedural steps, may be essential for the invention, both in themselves and in various combinations.

REFERENCE NUMERALS

[0065] 2 bioreactor system [0066] 4 bioreactor/apparatus [0067] 6 flow cell system [0068] 8 disposable flow cell [0069] 10 flow cell inlet [0070] 12 flow cell outlet [0071] 14 flow chamber [0072] 15 fluid pathway [0073] 16 first bypass line [0074] 18 second bypass line [0075] 20 window [0076] 22 light guiding device [0077] 24 external detection device [0078] 26 absorption detection unit [0079] 28 scattering detection unit [0080] 30 LED/light source [0081] 32 monitoring photodiode [0082] 34 LED driver [0083] 36 electronics unit [0084] 38 flow cell holder [0085] 40 base [0086] 42 housing [0087] 44 recess [0088] 46, 46a-46d first optical coupling [0089] 48, 48a-48d second optical coupling [0090] 50 lid [0091] 52 opening [0092] 54 screw [0093] 56 undercut [0094] 58 centering cavity [0095] 60 centering protrusion [0096] 62, 62a, 62b, 62c, 62d, 62e, 62f optical axis [0097] 64 heating device [0098] 66 detection unit [0099] 68 detection unit [0100] 70 flow cell (absorption) [0101] 72 fluid pathway [0102] 74 fluid pathway [0103] 76 fluid pathway [0104] 78 fluid pathway [0105] 80 flow cell (scattering and absorption) [0106] 82 ray of light [0107] 84 first detection unit [0108] 86 second detection unit [0109] 88 third detection unit [0110] 90 LED/light source [0111] 92 reference detection unit [0112] 94 reflected ray of light [0113] 96 mirror [0114] 98 flow cell holder [0115] 100 flow cell [0116] 102 multi LED unit/light source [0117] 104 detection device [0118] 106 fluid pathway [0119] 108 fluid pathway [0120] 110 fluid pathway [0121] 112 fluid pathway [0122] 114 detection unit [0123] 116 laser diode/light source [0124] 118 section [0125] 120 detection unit [0126] 122 flow cell [0127] 124 detection unit [0128] d.sub.1, d.sub.2, d.sub.3 d.sub.4 distance between opposed windows