Reducing stray light noise in optical Raman probe sensors

Abstract

A cap having a closed end and one or more openings is attached to the tip of the optical Raman probe sensor. The cap is used for preventing stray light noise from entering the end of the sensor. In this way, the Raman spectrum can be more accurate and consistent. In addition, the cap may be permanently or detachably attached to the sensor. In some embodiments, a reflective surface may be included on an inner surface of the closed end of the cap. The reflective surface may reflect Raman scattered light toward the tip, thereby enhancing the received signal by 2 to 100 times.

Description

Technical Field

[0001] Embodiments of the present disclosure relate to systems and methods for reducing stray light noise in an optical Raman probe sensor. Background Art

[0002] In many applications, such as bioprocessing applications, it is important to carefully and accurately monitor the composition of materials. For example, in a bioreactor, it can be important to monitor the amount of various molecules such as glucose, lactate, glutamine, ammonium, and other molecules.

[0003] In many cases, this monitoring can be accomplished using Raman spectroscopy. In Raman spectroscopy, a laser is used to direct a specific wavelength of light toward a target molecule. The photons reach the molecule and excite it. Once the photons excite the molecule, several possible outcomes can occur. The most common is that the excitation is temporary and the molecule returns to its initial energy state. In this mode, the photons are scattered or redirected due to the interaction with the molecule. Additionally, the wavelength of the photons is unchanged because its energy is not absorbed by the molecule. This phenomenon is called Rayleigh scattering and does not provide any information about the molecule being analyzed.

[0004] In another mode, the molecule is excited by the photon and moves to a different vibrational or rotational state. If this new state is a higher energy state than the original energy state, the photon loses energy, which results in a decrease in frequency. In this way, the total energy is conserved. This mode is called Stokes Raman scattering.

[0005] If this new state is a lower energy state than the original energy state, the photon gains energy, which results in a higher frequency. This pattern is called anti-Stokes Raman scattering.

[0006] Stokes Raman scattering and anti-Stokes Raman scattering can be used to produce a spectrum. The spectrum is usually displayed with a horizontal axis corresponding to wave number, which is usually defined as: Here, λ0 is the wavelength of laser light, and λ1 is the wavelength of Raman scattered light. The vertical axis is used to represent intensity.

[0007] Importantly, each molecule, when excited, produces a unique spectrum of light that can be used to identify that molecule. Therefore, the presence of different molecules can be determined in this way.

[0008] Compared to Rayleigh scattering, Stokes Raman scattering has a very low percentage and is very sensitive to noise. For example, ambient light from the sun or indoor lighting can alter the Raman spectrum.

[0009] Therefore, it would be advantageous to have a system and method for reducing the amount of stray light noise entering an optical Raman probe sensor. Summary of the invention

[0010] A cap having a closed end and one or more openings is attached to the tip of an optical Raman probe sensor. The cap is used to block stray light noise from entering the tip of the sensor. In this way, the Raman spectrum can be more accurate and consistent. In addition, the cap can be permanently attached to or removably attached to the sensor. In some embodiments, a reflective surface can be included on the inner surface of the closed end of the cap. This reflective surface can reflect Raman scattered light toward the tip, thereby enhancing the received signal by 2 to 100 times.

[0011] According to one embodiment, a device for measuring Raman scattering is disclosed. The device includes: an optical Raman probe sensor; a tube surrounding the optical Raman probe sensor, wherein light from a laser propagates through the tube and through a window; and a cap, the cap being attached to the tube, the cap including: a cylindrical body having one or more openings; and a closed end, wherein the cap is disposed on one end of the tube so that the light from the laser propagates toward the closed end. In some embodiments, the opening includes 25% to 75% of the circumference of the cylindrical body. In some embodiments, the device includes a reflective surface disposed at an inner surface of the closed end. In some embodiments, the reflective surface includes a reflector, and the reflector may be a concave mirror. In some embodiments, the reflective surface includes a coating applied to the inner surface of the closed end. In some embodiments, the cap is welded to the tube. In some embodiments, the cap is constructed of a material that provides spectral blocking for wavelengths from 400 nanometers (nm) to 2000 nanometers. In certain embodiments, the cap is constructed of stainless steel, plastic, or a polymer.

[0012] According to another embodiment, a bioreactor system is disclosed, which includes: a bioreactor having a bioreactor bag disposed therein; and the aforementioned device, wherein the tube is disposed in the bioreactor bag.

[0013] According to another embodiment, a device for measuring Raman scattering is disclosed. The device includes: an optical Raman probe sensor; a tube, the tube including: a tube body surrounding the optical Raman probe sensor, wherein light from a laser propagates through the tube body; and a tube head attached to the tube body, wherein the tube head includes a window; and a cap detachably attached to the tube, the cap including: a cylindrical body having one or more openings; and a closed end, wherein the cap is disposed on one end of the tube so that the light from the laser propagates through the window and toward the closed end. In some embodiments, the tube head includes an external thread, and threads are provided on the inner surface of the cylindrical body. In some embodiments, the opening includes 25% to 75% of the circumference of the cylindrical body. In some embodiments, the device includes a reflective surface disposed at the inner surface of the closed end. In some embodiments, the reflective surface includes a reflector, and the reflector may be a concave mirror. In some embodiments, the reflective surface includes a coating applied to the inner surface of the closed end.

[0014] According to another embodiment, a bioreactor system is disclosed, which includes: a bioreactor having a bioreactor bag disposed therein; and the aforementioned device, wherein the tube body is disposed in the bioreactor bag. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] For a better understanding of the present disclosure, reference is made to the accompanying drawings, which are incorporated herein by reference, and wherein:

[0016] Figure 1 A bioreactor including a Raman probe sensor is shown;

[0017] FIG. 2A to FIG. 2B An exploded view of an improved Raman probe sensor and a cross-section of an assembled Raman probe sensor are respectively shown according to one embodiment;

[0018] FIG. 3A to FIG. 3B 10 respectively show an exploded view of an improved Raman probe sensor and a cross section of an assembled Raman probe sensor according to a second embodiment;

[0019] FIG. 4A to FIG. 4B A cap having two different opening configurations is shown;

[0020] Figure 5 showing a reflective surface disposed at the closed end of the cap;

[0021] FIG. 6A to FIG. 6B Two graphs are shown which illustrate the benefit of the cap in reducing stray light noise; and

[0022] 7A to 7C Three orientations of the cap on the optical Raman probe sensor are shown. DETAILED DESCRIPTION

[0023] Embodiments of the present disclosure describe systems and methods for reducing stray light noise in optical Raman probe sensors.

[0024] In many applications, such as bioprocessing applications, it is important to carefully and accurately monitor the material (feed) within the bioreactor.

[0025] Figure 1 A representative bioreactor 1 is shown. A bioreactor bag 10 is typically inserted into the bioreactor 1. The bioreactor bag 10 may have a plurality of ports to allow various sensors, actuators, spargers, or other mechanisms to be introduced into the interior of the bioreactor bag 10. In this illustration, an optical Raman probe sensor 20 enters the interior of the bioreactor bag 10 through port 11. The optical Raman probe sensor 20 includes a tube with a sapphire window. The optical Raman probe sensor 20 also includes a connecting thread compatible with the bioreactor, such as PG13.5. In some embodiments, the tube of the optical Raman probe sensor 20 has a maximum outer diameter of 12 mm. The optical Raman probe sensor 20 is immersed in the material contained in the bioreactor bag 10. The optical Raman probe sensor 20 projects a laser beam along an optical axis 31. The laser beam passes through the tube, the sapphire window, and enters the bioreactor bag 10. The optical Raman probe sensor 20 also receives scattered light from a target 30, which may be a molecule or a group of molecules. The scattered light propagates along the collection field of view and enters the tip of the optical Raman probe sensor 20. The optical Raman probe sensor 20 may include an optical detector such as a CCD or a photodetector.

[0026] The optical Raman probe sensor communicates with a Raman analyzer 21 located outside the bioreactor. The Raman analyzer 21 may include a laser that generates a laser beam that is transmitted through a conduit to the optical Raman probe sensor 20. Such a conduit may be a fiber optic cable. The Raman analyzer 21 also includes a processing unit for interpreting the output from the optical detector, which is transmitted from the probe to the Raman analyzer 21 through the conduit.

[0027] As described above, Stokes Raman scattering occurs at a much lower frequency than Rayleigh scattering and is therefore very sensitive to noise. Therefore, ambient light 40 entering the optical Raman probe sensor 20 can have an adverse effect on the accuracy of detection. This ambient light may be sunlight, moonlight, indoor lighting or other types of lighting. One way to solve this problem is to reduce the amount of ambient light that can enter the optical Raman probe sensor 20. Specifically, the end of the optical Raman probe sensor 20 can receive light from a wide field of view. By reducing the collection field of view, the ability to receive Stokes Raman scattering will not be adversely affected, and noise can be at least partially eliminated.

[0028] FIG. 2A to FIG. 2B One embodiment that achieves these goals is shown. Figure 2A An exploded view of this embodiment is shown, and Figure 2B A cross section of the assembled sensor is shown.

[0029] As shown in these views, a cap 100 can be disposed above the end of the optical Raman probe sensor 20. The cap 100 is constructed of a material that provides spectral blocking for wavelengths from 400 nanometers to 2000 nanometers. The optical Raman probe sensor 20 can be enclosed in a cylindrical tube. The tube 25 can be constructed of stainless steel such as SST 316L or other materials such as titanium, Hastelloy or gold. The maximum outer diameter of the tube 25 can be 12 millimeters. A sapphire window can be disposed in the tube 25.

[0030] The cap 100 has a cylindrical body 110. The length of the cylindrical body 110 may be between 3 mm and 50 mm. In some embodiments, the length may be less than 20 mm, for example, about 10 mm. The inner diameter of the cylindrical body 110 may be slightly larger than the outer diameter of the tube 25 surrounding the optical Raman probe sensor 20, so that the cylindrical body 110 may slide on at least a portion of the tube 25 surrounding the optical Raman probe sensor 20.

[0031] The cap 100 also includes a closed end 120 disposed at the distal end of the cylindrical body 110. The distal end is the end opposite to the end attached to the tube 25. In addition, the distal end is the end to which the laser beam is directed. In addition, the cylindrical body 110 includes one or more openings 130 disposed along the circumference of the cylindrical body 110. The length of the opening can be between 0.1 mm and 50 mm. The opening can have any desired width. In some embodiments, the width of the opening can be as small as 0.1 mm. In other embodiments, the width of the opening can be as large as 98% of the circumference of the cylindrical body 110. In most embodiments, the width of the opening is between 25% and 75% of the circumference of the cylindrical body 110. In a specific embodiment, the total width of the opening can be equal to 50% of the circumference of the cylindrical body 110. In some embodiments, two openings 130 can be provided, which are disposed on opposite sides of the cylindrical body 110. In this way, material from within the bioreactor bag 10 is able to flow through the interior of the cap 100. The opening 130 may be any suitable size to allow material to flow such that the material passes through the optical axis 31.

[0032] Use of the cap 100 reduces the amount of stray light that can reach the tip of the optical Raman probe sensor 20. Specifically, light cannot pass through the closed end 120. In addition, light cannot pass through the closed portion of the cylindrical body 110. Therefore, the amount of stray light is limited to light that can pass through the opening 130 and reach the tip of the optical Raman probe sensor 20.

[0033] In one embodiment, the cap 100 may be made of stainless steel and may be laser welded to the tube 25 surrounding the optical Raman probe sensor 20. In this way, the cap 100 is permanently attached to the tube 25 surrounding the optical Raman probe sensor 20.

[0034] However, in some embodiments, it may be advantageous to remove the cap from the optical Raman probe sensor 20, for example for cleaning or replacement.

[0035] FIG. 3A to FIG. 3B Such an embodiment is shown. Figure 3A An exploded view of this embodiment is shown, and Figure 3B 2 shows a cross section of an assembled sensor. In this embodiment, the optical Raman probe sensor 20 is enclosed in a tube 26, which includes two parts; a tube body 27 and a tube head 28. The tube body 27 can be similar in structure to that described with respect to FIG. 2A to FIG. 2BThe tube 25 is described and comprises a hollow tube. A tube head 28 is attached to the tube body 27, for example by welding. The tube head 28 comprises a sapphire window and an optical lens 29. In addition, the outer surface of the tube head 28 comprises a thread for receiving the cap 100.

[0036] The ability to remove the cap 100 for cleaning may require a removable concept. In addition, in some embodiments, the tube head 28 has threads on its outer surface near the distal end.

[0037] In this embodiment, the cap 100 is similar to the cap described above, but also includes threads on the inner surface of the cylindrical body 110. In operation, the cap 100 is screwed onto the tube head 28. The cap 100 can be removed to make it easier to clean. In addition, in some embodiments, the cap 100 can be considered a disposable component so that a new cap 100 is installed on the tube head 28 before each use. In addition, this configuration allows the possibility of selecting the cap design according to the application without changing other parts of the optical Raman probe sensor 20.

[0038] In these embodiments, the length of the cap 100 may be design-determined. For example, the cap 100 may be designed such that the distance from the tip of the optical Raman probe sensor 20 to the closed end 120 is between 1 cm and 10 cm, but other dimensions are possible.

[0039] FIG. 2A to FIG. 2B and FIG. 3A to FIG. 3B The openings 130 are shown as two circular apertures. However, the present disclosure is not limited to this embodiment. Rather, the openings may be circular, oval, rectangular, or any other shape. For example, Figure 4B The opening 130 is shown as being rectangular in shape.

[0040] Furthermore, the number of openings 130 may vary. In some embodiments, there may be more than two openings. In another embodiment, for example Figure 4A 1, with only a single opening. In this embodiment, the opening 130 may occupy more than 180° of the surface of the cylindrical body 110. In fact, the opening 130 may occupy any portion of the circumference of the cylindrical body 110 that is less than 360°. The remainder of the cylindrical body 110 is used to hold the closed end 120.

[0041] In addition, as described above, the size of the openings 130 can vary. For example, if there are N openings, the area occupied by these openings must occupy less than 360° of the circumference of the cylindrical body 110. Therefore, if the openings 130 are equal in size, each opening must occupy less than 360° / N of the circumference of the cylindrical body 110.

[0042] The number, shape, and size of the openings 130 may vary depending on the application of regulating the flow of material into the interior of the cap 100. In addition, the number, shape, and size of the openings 130 may also represent a trade-off between minimizing stray light noise and allowing sufficient material flow through the interior of the cap 100.

[0043] The closed end 120 can also be used to increase the sensitivity of the optical Raman probe sensor 20 . Figure 5 An embodiment is shown in which the closed end 120 is used to reflect more Stokes Raman scattering toward the tip of the optical Raman probe sensor 20. In some embodiments, a reflective surface 121 can be provided on the inner surface of the closed end 120. In some embodiments, the reflective surface 121 is a treatment or coating applied directly to the inner surface of the closed end 120. In another embodiment, the reflective surface 121 is a reflector attached to the inner surface of the closed end 120. In some embodiments, the reflective surface 121 can be flat or planar. In other embodiments, the reflective surface 121 can be concave to direct the scattered light toward the tip of the optical Raman probe sensor 20. Such a reflective surface can enhance the Raman scattering signal by more than 2 times, for example, between 2 times and 100 times.

[0044] Although the present disclosure notes that the cap 100 can be made of stainless steel, other materials can also be used. For example, the cap 100 can be plastic or polymer-based. In this case, the cap 100 can be fixed to the tube by overmolding, heat sealing, crimping or sewing. The cap can also be constructed of Hastelloy or other materials with low Raman signatures.

[0045] Furthermore, the cap 100 is designed to avoid any rough surfaces or edges to prevent the accumulation of media, dust, components, and to facilitate cleaning using an ultrasonic bath or other cleaning procedures.

[0046] The embodiments described above in the present application may have many advantages. First, the closed end of the cap 100 ensures that the laser beam does not leave the bioreactor. Therefore, the laser beam can be completely contained by the cap 100. This reduces the laser exposure of users who may be positioned along the optical axis 31.

[0047] Furthermore, in many applications, the optical Raman probe sensor 20 is placed in a glass bioreactor or plastic bioreactor bag that is not completely opaque to ambient light. The cap 100 allows Raman measurements to be made with significantly reduced effects of interference caused by ambient light. As an example, FIG. 6A to FIG. 6BThe results of an experiment conducted to demonstrate this benefit are shown. In these graphs, the vertical axis represents the sum of all Raman frequency intensities measured by the optical Raman probe sensor 20. The horizontal axis represents time. Fig. 6A The graph in shows a Raman spectrum obtained using a conventional optical Raman probe sensor, where the bioreactor is set up in a room with windows. Note that every 24 hours, there is a spike 600 in the intensity of the Raman spectrum. This is likely caused by sunlight, which is strongest when the sun is positioned in the best alignment with the collection field of view. In addition, note that there are also lower plateaus 610. These lower plateaus correspond to the times when the room is illuminated.

[0048] Figure 6B The results are shown when the same optical Raman probe sensor is now used with the cap 100 described above. Note that peak 650 is now significantly lower than Fig. 6A In fact, the intensity of these peaks is reduced by 90%. In addition, the plateau 660 caused by the indoor lighting is also significantly reduced.

[0049] The reduction in stray light noise allows for better consistency in the predictions provided by the Raman analyser 21, thereby providing controlled measurement tolerances.

[0050] Another advantage is that it meets the standard probe diameter, i.e. 12 mm, and is compatible with many standard connectors, such as PG13.5.

[0051] Additionally, the cap 100 may be oriented to minimize the amount of stray light noise that reaches the tip of the optical Raman probe sensor 20. For example, 7A to 7C Three different configurations are shown, wherein the opening 130 is oriented horizontally, vertically, and at a 45° angle, respectively. Importantly, the orientation angle can be adjusted while ensuring the necessary tightness with the bioreactor connector. In addition, the orientation angle can be adjusted according to the specific application or laser safety. In addition, the orientation angle can be adjusted according to the main direction of stray light. In other words, if the stray light arrives mainly from a certain direction, the cap 100 can be oriented so that the opening 130 is not aligned with this direction, thereby reducing the amount of stray light noise reaching the tip of the optical Raman probe sensor 20.

[0052] The present disclosure is not limited in scope by the specific embodiments described herein. In fact, in addition to those embodiments described herein, various other embodiments and modifications of the present disclosure will be apparent to those of ordinary skill in the art based on the above description and the accompanying drawings. Therefore, these other embodiments and modifications are intended to fall within the scope of the present disclosure. In addition, although the present disclosure is described in the context of a specific implementation in a specific environment for a specific purpose, a person of ordinary skill in the art will recognize that its usefulness is not limited thereto, and the present disclosure can be beneficially implemented in any number of environments for any number of purposes. Accordingly, the claims listed below should be interpreted in accordance with the full breadth and spirit of the present disclosure described herein.

Claims

1. A device for measuring Raman scattering, comprising: Optical Raman probe sensor; a tube surrounding the optical Raman probe sensor, wherein light from the laser propagates through the tube and through the window; and A cap is attached to the tube, the cap comprising: a cylindrical body having one or more openings; and Closed end, wherein the cap is disposed on one end of the tube so that the light from the laser propagates toward the closed end.

2. The device according to claim 1, characterized in that The opening comprises 25% to 75% of the circumference of the cylindrical body.

3. The device according to claim 1, characterized in that The device also includes a reflective surface disposed at an inner surface of the closed end.

4. The device according to claim 3, characterized in that The reflective surface comprises a mirror.

5. The device according to claim 4, characterized in that The reflecting mirror is a concave mirror.

6. The device according to claim 3, characterized in that The reflective surface includes a coating applied to the inner surface of the closed end.

7. The device according to claim 1, characterized in that The cap is welded to the tube.

8. The device according to claim 1, characterized in that The cap is constructed of a material that provides spectral blocking of wavelengths from 400 nanometers to 2000 nanometers.

9. The device according to claim 8, characterized in that The cap is constructed of stainless steel, plastic or a polymer.

10. A bioreactor system comprising: a bioreactor having a bioreactor bag disposed therein; as well as The device of claim 1, wherein the tube is disposed within the bioreactor bag.

11. A device for measuring Raman scattering, comprising: Optical Raman probe sensor; A tube, the tube comprising: a tube body surrounding the optical Raman probe sensor, wherein light from the laser propagates through the tube body; and a tube head attached to the tube body, wherein the tube head includes a window; and a cap removably attached to the tube, the cap comprising: a cylindrical body having one or more openings; and Closed end, wherein the cap is disposed on one end of the tube so that the light from the laser passes through the window and propagates toward the closed end.

12. The device according to claim 11, characterized in that The tube head includes an external thread, and the inner surface of the cylindrical body is provided with a thread.

13. The device according to claim 11, characterized in that The opening comprises 25% to 75% of the circumference of the cylindrical body.

14. The device according to claim 11, characterized in that The device also includes a reflective surface disposed at an inner surface of the closed end.

15. The device according to claim 14, characterized in that The reflective surface comprises a mirror.

16. The device according to claim 15, characterized in that The reflecting mirror is a concave mirror.

17. The device according to claim 14, characterized in that The reflective surface includes a coating applied to the inner surface of the closed end.

18. A bioreactor system comprising: a bioreactor having a bioreactor bag disposed therein; as well as The device according to claim 11, wherein the tube body is disposed within the bioreactor bag.

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