Reducing stray light noise in optical Raman probe sensors

Abstract

A cap with a closed end and one or more openings is attached to the tip of the optical Raman probe sensor. The cap serves to prevent stray light noise from entering the tip of the sensor. In this way, Raman spectra can be more accurate and consistent. Furthermore, the cap can be permanently or removably attached to the sensor. In some embodiments, a reflective surface can be provided on the inner surface of the closed end of the cap. This reflective surface can reflect Raman scattered light back toward the tip, 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 optical Raman probe sensors. [Background technology]

[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 various molecular weights such as glucose, lactate, glutamine, ammonium, etc.

[0003] In many situations, this monitoring can be done using Raman spectroscopy. In Raman spectroscopy, a laser is used to direct light of a specific wavelength toward a target molecule. The photons reach the molecule and excite it. When a photon excites a molecule, several outcomes are possible. The most common is that the excitation is transient, causing the molecule to return to its initial energy state. In this mode, the photon is scattered or redirected upon interaction with the molecule. Furthermore, the wavelength of the photon remains unchanged because its energy is not absorbed by the molecule. This phenomenon, called Rayleigh scattering, does not provide any information about the molecule being analyzed.

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

[0005] If the new state is lower in energy than the original, the photon gains energy and therefore increases in frequency. This mode is called anti-Stokes Raman scattering.

[0006] Stokes and anti-Stokes Raman scattering can be used to generate a spectrum, which is usually displayed with the horizontal axis corresponding to wavenumber, which is usually

[0007]

number

[0008] Importantly, each molecule, when excited, produces a unique spectrum that can be used to identify the molecule, and therefore, using this approach, the presence of different molecules can be determined.

[0009] The rate of Stokes Raman scattering is very low compared to Rayleigh scattering, making it very sensitive to noise. For example, ambient light from the sun or indoor lighting can alter the Raman spectrum. Summary of the Invention [Problem to be solved by the invention]

[0010] Therefore, it would be advantageous to have a system and method for reducing the amount of stray light noise that enters an optical Raman probe sensor. [Means for solving the problem]

[0011] A cap with a closed end and one or more openings is attached to the tip of the optical Raman probe sensor. The cap serves to prevent stray light noise from entering the tip of the sensor. In this way, Raman spectra can be more accurate and consistent. Furthermore, the cap can be permanently or removably attached to the sensor. In some embodiments, a reflective surface can be provided on the inner surface of the closed end of the cap. This reflective surface can reflect Raman scattered light back toward the tip, enhancing the received signal by 2 to 100 times.

[0012] According to one embodiment, an apparatus for measuring Raman scattering is disclosed. The apparatus includes an optical Raman probe sensor, a tube surrounding the optical Raman probe sensor, where light from a laser travels through the tube and through a window, and a cap attached to the tube, the cap having a cylindrical body with one or more openings and a closed end. The cap is positioned at the end of the tube so that light from the laser travels toward the closed end. In some embodiments, the openings constitute 25% to 75% of the circumference of the cylindrical body. In some embodiments, the apparatus includes a reflective surface disposed on the inner surface of the closed end. In certain embodiments, the reflective surface comprises a mirror, which may be a concave mirror. In certain embodiments, the reflective surface comprises 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 composed of a material that provides a spectral cutoff for wavelengths between 400 nm and 2000 nm. In certain embodiments, the cap is composed of stainless steel, plastic, or polymer.

[0013] According to another embodiment, a bioreactor system is disclosed, comprising a bioreactor having a bioreactor bag disposed therein and the above-described apparatus, wherein the tubing is disposed within the bioreactor bag.

[0014] According to another embodiment, an apparatus for measuring Raman scattering is disclosed. The apparatus includes an optical Raman probe sensor; a tube, the tube body surrounding the optical Raman probe sensor, through which light from a laser travels; a tube head attached to the tube body, the tube head including a window; and a cap removably attached to the tube, the cap including a cylindrical body with one or more openings and a closed end, the cap being positioned at the end of the tube such that light from the laser travels through the window toward the closed end. In some embodiments, the tube head includes external threads, the threads being positioned on the inner surface of the cylindrical body. In some embodiments, the openings constitute 25% to 75% of the circumference of the cylindrical body. In some embodiments, the apparatus includes a reflective surface positioned on the inner surface of the closed end. In certain embodiments, the reflective surface includes a mirror, and the mirror may be a concave mirror. In certain embodiments, the reflective surface includes a coating applied to the inner surface of the closed end.

[0015] According to another embodiment, a bioreactor system is disclosed, comprising a bioreactor having a bioreactor bag disposed therein and the above-described apparatus, wherein the tubing body is disposed within the bioreactor bag.

[0016] For a better understanding of the present disclosure, reference is made to the accompanying drawings, which are incorporated herein by reference. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 illustrates a bioreactor including a Raman probe sensor. [Figure 2A] FIG. 1 shows an exploded view of an improved Raman probe sensor according to one embodiment. [Figure 2B] FIG. 1 shows a cross-sectional view of an assembled Raman probe sensor according to one embodiment. [Figure 3A] 1 shows an exploded view of an improved Raman probe sensor according to a second embodiment. [Figure 3B]FIG. 1 shows a cross-sectional view of an assembled Raman probe sensor according to a second embodiment. [Figure 4A] 10A-10C show caps with different configurations of openings. [Figure 4B] 10A-10C show caps with different configurations of openings. [Figure 5] FIG. 10 shows a reflective surface disposed on the closed end of the cap. [Figure 6A] 10 shows a graph illustrating the benefit of the cap in reducing stray light noise. [Figure 6B] 10 shows a graph illustrating the benefit of the cap in reducing stray light noise. [Figure 7A] 1 shows the orientation of the cap on the optical Raman probe sensor. [Figure 7B] 1 shows the orientation of the cap on the optical Raman probe sensor. [Figure 7C] 1 shows the orientation of the cap on the optical Raman probe sensor. DETAILED DESCRIPTION OF THE INVENTION

[0018] Embodiments of the present disclosure describe systems and methods for reducing stray light noise in optical Raman probe sensors.

[0019] In many applications, such as bioprocessing applications, careful and accurate monitoring of materials within a bioreactor is important.

[0020] FIG. 1 illustrates a representative bioreactor 1. A bioreactor bag 10 is typically inserted into the bioreactor 1. The bioreactor bag 10 can include multiple ports for introducing various sensors, actuators, spargers, or other mechanisms 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 a 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 within the bioreactor bag 10. The optical Raman probe sensor 20 projects laser light 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 group of molecules. The scattered light travels along a focused field of view and is incident on 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.

[0021] The optical Raman probe sensor 20 is in communication with a Raman analyzer 21 external to the bioreactor 1. The Raman analyzer 21 may include a laser that generates a laser beam that travels through a conduit to the optical Raman probe sensor 20. The conduit may be a fiber optic cable. The Raman analyzer 21 also includes a processing unit for analyzing the output from the photodetector, which is transmitted from the probe through the conduit to the Raman analyzer 21.

[0022] As noted above, Stokes Raman scattering occurs much less frequently than Rayleigh scattering and is highly sensitive to noise. Therefore, ambient light 40 incident on the optical Raman probe sensor 20 can reduce detection accuracy. This ambient light can be sunlight, moonlight, room lighting, or other types of lighting. One way to address this is to reduce the amount of ambient light allowed to enter the optical Raman probe sensor 20. Specifically, the tip of the optical Raman probe sensor 20 can receive light from a wide field of view. Reducing the collection field of view can at least partially eliminate noise without adversely affecting the ability to receive Stokes Raman scattering.

[0023] Figures 2A-2B show one embodiment that achieves these objectives: Figure 2A shows an exploded view of this embodiment, and Figure 2B shows a cross section of the assembled sensor.

[0024] As shown in these figures, a cap 100 can be placed over the tip of the optical Raman probe sensor 20. The cap 100 is constructed of a material that provides a spectral cutoff for wavelengths between 400 nm and 2000 nm. The optical Raman probe sensor 20 can be housed within a cylindrical tube. The tube 25 can be constructed of stainless steel, such as SST316L, or other materials, such as titanium, Hastelloy, or gold. The tube 25 can have a maximum outer diameter of 12 mm. A sapphire window can be placed within the tube 25.

[0025] The cap 100 comprises a cylindrical body 110. The cylindrical body 110 can have a length between 3 mm and 50 mm. In certain embodiments, the length can be less than 20 mm, for example, about 10 mm. The inner diameter of the cylindrical body 110 can be slightly larger than the outer diameter of the tube 25 surrounding the optical Raman probe sensor 20, such that the cylindrical body 110 can slide over at least a portion of the tube 25 surrounding the optical Raman probe sensor 20.

[0026] 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 the end fixed to the tube 25. The tip is the end from which the laser light is irradiated. The cylindrical body 110 further includes one or more openings 130 disposed along the circumference of the cylindrical body 110. The openings can have lengths between 0.1 mm and 50 mm. The openings can have any desired width. In certain embodiments, the opening width is as small as 0.1 mm. In other embodiments, the opening width may be as large as 98% of the circumference of the cylindrical body 110. In most embodiments, the opening width is between 25% and 75% of the circumference of the cylindrical body 110. In one particular embodiment, the total opening width may be equal to 50% of the circumference of the cylindrical body 110. In certain embodiments, there may be two openings 130 disposed on opposite sides of the cylindrical body 110. In this manner, material from within the bioreactor bag 10 can flow through the interior of the cap 100. The opening 130 may be of any suitable size to allow the flow of material such that the material passes through the optical axis 31.

[0027] The 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. Also, light cannot pass through the occlusion of the cylindrical body 110. Therefore, the amount of stray light is limited to the light that can pass through the opening 130 and reach the tip of the optical Raman probe sensor 20.

[0028] 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 manner, the cap 100 becomes permanently fixed to the tube 25 surrounding the optical Raman probe sensor 20.

[0029] However, in certain embodiments, it may be advantageous to remove the cap from the optical Raman probe sensor 20, such as for cleaning or replacement.

[0030] Figures 3A-3B illustrate such an embodiment. Figure 3A shows an exploded view of this embodiment, and Figure 3B shows a cross-section of the assembled sensor. In this embodiment, the optical Raman probe sensor 20 is enclosed in a tube 26 comprising two sections: a tube body 27 and a tube head 28. The tube body 27 may be of a composition similar to the tube 25 described with respect to Figures 2A-2B and comprises a hollow tube. The tube head 28 is secured to the tube body 27, such as by welding. The tube head 28 comprises a sapphire window and an optical lens 29. Additionally, the exterior surface of the tube head 28 comprises threads for receiving a cap 100.

[0031] The ability to remove the cap 100 for cleaning processes may require a removal concept. Also, in some embodiments, the tube head 28 includes threads on its exterior surface near the distal end.

[0032] In this embodiment, the cap 100 is similar to that described above, but also includes threads on the inner surface of the cylindrical body 110. During operation, the cap 100 is threaded onto the tube head 28. The cap 100 may be removed for easy cleaning. Furthermore, in some embodiments, the cap 100 may be considered a disposable component, such that a new cap 100 is installed on the tube head 28 before each use. Furthermore, this configuration allows for the selection of cap designs depending on the application, without modifying other parts of the optical Raman probe sensor 20.

[0033] In these embodiments, the length of the cap 100 can be a design decision. For example, the cap 100 may be designed so that the distance from the tip of the optical Raman probe sensor 20 to the closed end 120 is 1-10 cm, although other dimensions are possible.

[0034] 2A-2B and 3A-3B show the opening 130 as two circular openings. However, the present disclosure is not limited to this embodiment. Rather, the openings may be circular, oval, rectangular, or any other shape. For example, FIG. 4B shows that the opening 130 is rectangular in shape.

[0035] Additionally, the number of openings 130 may vary. In some embodiments, there may be three or more openings. In other embodiments, there is only a single opening, as shown in FIG. 4A. In this embodiment, the openings 130 may occupy more than 180° of the surface of the cylindrical body 110. In fact, the openings 130 may occupy any portion of the circumference of the cylindrical body 110 that is less than 360°. The remaining portion of the cylindrical body 110 is used to hold the closed end 120.

[0036] Additionally, as noted above, the size of the openings 130 may 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. Thus, if the openings 130 are of equal size, each opening must occupy less than 360° / N of the circumference of the cylindrical body 110.

[0037] The number, shape, and size of the openings 130 can be varied based on the application to regulate the flow of material into the interior of the cap 100. Additionally, the number, shape, and size of the openings 130 may also represent a trade-off between minimizing stray light noise and ensuring sufficient flow of material through the interior of the cap 100.

[0038] The closed end 120 can also be used to improve the sensitivity of the optical Raman probe sensor 20. FIG. 5 illustrates an embodiment 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 certain embodiments, a reflective surface 121 may be disposed 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 mirror attached to the inner surface of the closed end 120. In certain embodiments, the reflective surface 121 may be flat or planar. In other embodiments, the reflective surface 121 may be concave to direct scattered light toward the tip of the optical Raman probe sensor 20. This reflective surface can enhance the Raman scattering signal by more than two times, for example, between two and one hundred times.

[0039] Although this disclosure mentions that the cap 100 may be made from stainless steel, other materials may be used. For example, the cap 100 may be plastic or polymer-based. In this case, the cap 100 may be secured to the tube by overmolding, heat sealing, crimping, or seaming. The cap may also be constructed of a Hastelloy alloy or another material with a low Raman signature.

[0040] Additionally, cap 100 is designed without rough surfaces or edges to avoid the accumulation of media, dust, and components and to facilitate cleaning with an ultrasonic bath or other cleaning procedure.

[0041] The embodiments described above in this application can have many advantages. First, the closed end of cap 100 ensures that the laser beam does not exit the bioreactor. Thus, the laser light can be completely confined by cap 100. This reduces the laser exposure of users who may be positioned along optical axis 31.

[0042] Furthermore, in many applications, the optical Raman probe sensor 20 is placed inside a glass bioreactor or plastic bioreactor bag that is not completely opaque to ambient light. The cap 100 enables Raman measurements with significantly reduced interference caused by ambient light. As an example, FIGS. 6A-6B show the results of one experiment conducted to demonstrate this advantage. 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. The graph in FIG. 6A shows a Raman spectrum obtained using a conventional optical Raman probe sensor, in this case a bioreactor placed in a room with a window. Note the sharp peaks 600 in the intensity of the Raman spectrum every 24 hours. This may be caused by sunlight, which is greatest when the sun's position best aligns with the focused field of view. Additionally, note the presence of lower plateaus 610. These lower plateaus 610 correspond to times when the room was illuminated.

[0043] Figure 6B shows the results when the same optical Raman probe sensor is used here with the cap 100 described above. Note that the peaks 650 are significantly lower than those in Figure 6A. In fact, the intensity of these peaks is reduced by 90%. Furthermore, the plateau 660 caused by room lighting is also significantly reduced.

[0044] Reducing stray light noise improves the accuracy of the predictions provided by the Raman analyzer 21 and allows for control of measurement tolerances.

[0045] Another advantage is that it conforms to the 12mm probe diameter standard and is compatible with many standard connectors such as PG13.5.

[0046] Additionally, the cap 100 may be oriented to minimize the amount of stray light noise reaching the tip of the optical Raman probe sensor 20. For example, FIGS. 7A through 7C show three different configurations in which the opening 130 is oriented horizontally, vertically, and at a 45° angle, respectively. Importantly, the orientation angle can be adjusted while still ensuring the necessary airtightness with the bioreactor connector. Furthermore, the orientation angle may be adjusted based on the specific application or laser safety. The azimuthal angle may also be adjusted based on the predominant direction of stray light. In other words, if stray light arrives primarily from a particular direction, the cap 100 may be oriented so that the opening 130 does not coincide with this direction, thereby reducing the amount of stray light noise reaching the tip of the optical Raman probe sensor 20.

[0047] The present disclosure is not limited in scope by the specific embodiments described herein. Indeed, various other embodiments of and modifications to the present disclosure, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description and the accompanying drawings. Accordingly, such other embodiments and modifications are intended to be included within the scope of the present disclosure. Moreover, while the present disclosure has been described herein in the context of particular implementations in particular environments for particular purposes, those skilled in the art will recognize that its utility is not limited thereto, and that the present disclosure may be beneficially implemented in any number of environments for any number of purposes. Accordingly, the claims set forth below should be construed in light of the full scope and spirit of the disclosure as described herein.

Claims

1. A device for measuring Raman scattering, Optical Raman probe sensor, A tube surrounding an optical Raman probe sensor, through which light from a laser travels through the tube and through a window, A cap attached to a pipe, A cylindrical body having one or more openings Closed end and A cap equipped with Equipped with, The device further includes a reflective surface positioned on the inner surface of the closed end, The cap is positioned at the end of the tube so that the light from the laser travels toward the closed end. Device.

2. The apparatus according to claim 1, wherein the opening constitutes 25% to 75% of the circumference of the cylindrical body.

3. The apparatus according to claim 1, wherein the reflective surface is a mirror.

4. The apparatus according to claim 3, wherein the mirror is a concave mirror.

5. The apparatus according to claim 1, wherein the reflective surface comprises a coating applied to the inner surface of the closed end.

6. The apparatus according to claim 1, wherein the cap is welded to the pipe.

7. The apparatus according to claim 1, wherein the cap is made of a material that provides spectral blocking at wavelengths of 400 nm to 2000 nm.

8. The apparatus according to claim 7, wherein the cap is made of stainless steel, plastic, or polymer.

9. A bioreactor system, A bioreactor with a bioreactor bag placed inside, The apparatus according to claim 1 and The tube is positioned inside the bioreactor bag. Bioreactor system.

10. A device for measuring Raman scattering, Optical Raman probe sensor, It is a pipe, A tube body surrounding an optical Raman probe sensor, through which light from a laser travels; A pipe head attached to the main body of a pipe, the pipe head having a window A pipe equipped with, A cap that is detachably attached to a pipe, A cylindrical body having one or more openings Closed end and It has a cap and Equipped with, The cap is positioned at the end of the tube so that light from the laser passes through the window towards the closed end. Device.

11. The apparatus according to claim 10, wherein the pipe head is equipped with a male thread, and the threads are arranged on the inner surface of the cylindrical body.

12. The apparatus according to claim 10, wherein the opening constitutes 25% to 75% of the circumference of the cylindrical body.

13. The apparatus according to claim 10, further comprising a reflective surface disposed on the inner surface of the closed end.

14. The apparatus according to claim 13, wherein the reflective surface is a mirror.

15. The apparatus according to claim 14, wherein the mirror is a concave mirror.

16. The apparatus according to claim 13, wherein the reflective surface comprises a coating applied to the inner surface of the closed end.

17. A bioreactor system, A bioreactor with a bioreactor bag placed inside, The apparatus according to claim 10 and It is equipped with a tube body which is placed inside the bioreactor bag. Bioreactor system.

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