WO2011071551A1 - Sample cell for spectroscopic analysis, systems and uses thereof - Google Patents

Sample cell for spectroscopic analysis, systems and uses thereof Download PDF

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Publication number
WO2011071551A1
WO2011071551A1 PCT/US2010/023324 US2010023324W WO2011071551A1 WO 2011071551 A1 WO2011071551 A1 WO 2011071551A1 US 2010023324 W US2010023324 W US 2010023324W WO 2011071551 A1 WO2011071551 A1 WO 2011071551A1
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WO
WIPO (PCT)
Prior art keywords
sample cell
sample
windows
range
inner ridge
Prior art date
Application number
PCT/US2010/023324
Other languages
French (fr)
Inventor
Pieter Roos
Original Assignee
Molecular Biometrics, Inc.
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Filing date
Publication date
Application filed by Molecular Biometrics, Inc. filed Critical Molecular Biometrics, Inc.
Publication of WO2011071551A1 publication Critical patent/WO2011071551A1/en

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Classifications

    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03Cuvette constructions
    • G01N21/05Flow-through cuvettes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502715Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5027Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502723Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by venting arrangements
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06Fluid handling related problems
    • B01L2200/0684Venting, avoiding backpressure, avoid gas bubbles
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/02Identification, exchange or storage of information
    • B01L2300/021Identification, e.g. bar codes
    • B01L2300/022Transponder chips
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/06Auxiliary integrated devices, integrated components
    • B01L2300/0627Sensor or part of a sensor is integrated
    • B01L2300/0654Lenses; Optical fibres
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0809Geometry, shape and general structure rectangular shaped
    • B01L2300/0816Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/08Geometry, shape and general structure
    • B01L2300/0861Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877Flow chambers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/16Surface properties and coatings
    • B01L2300/168Specific optical properties, e.g. reflective coatings
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01LCHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00Additional constructional details
    • B01L2300/18Means for temperature control
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/01Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03Cuvette constructions
    • G01N2021/0346Capillary cells; Microcells
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00029Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor provided with flat sample substrates, e.g. slides

Definitions

  • sample cell When analyzing samples using spectroscopy, the samples are contained in a vessel which is commonly referred to as a sample cell or cuvette. These vessels typically contain two sides of optical quality material that allow radiation to pass through the sample.
  • sample cells Conventional sample cells are designed for large sample volumes, e.g., on the order of 30-100 microliters and are therefore unsuitable in situations where only small sample volumes are available, e.g., of 10 microliters or less.
  • the amount of radiation absorbed by a sample is proportional to the path length of the sample (i.e., the distance the radiation has to travel through the sample). Without innovative designs, small volumes lead to short path lengths and less sensitive measurements. It is therefore a challenge to retain high sensitivity while
  • the present disclosure provides a sample cell for spectroscopic analysis of fluid samples.
  • the sample cell has a body with windows that are located within recesses of upper and lower surfaces. The windows are spaced from the body surface.
  • An optical chamber passes through the body and is in fluid communication with feed conduits that include channel portions within the recesses.
  • the feed conduits each have an outlet on a surface of the body through which a fluid sample can be introduced into the optical chamber.
  • An inner ridge protrudes from within at least one of the recesses and surrounds the feed conduit. The inner ridge is spaced from its corresponding window.
  • the present disclosure also provides systems that include a sample cell and a spectrometer and uses of such systems.
  • Figure 1 shows an exemplary sample cell 10 in isometric, elevation, plan and cross- sectional view.
  • Figure 2 shows additional views of an exemplary sample cell 10, including optical chamber 12, feed conduit 70, ridges 40, 42, 44, circular support ring 50, support ribs 52, and windows 30, 32 and adhesive 100.
  • Figure 3 shows a cross section of an exemplary sample cell 10, illustrating the relationship between the optical chamber 12, body surfaces 14, 16, recesses 90, 92, feed conduit channel portions 70, 72, ridges 40, 42, 44 and windows 30, 32.
  • Figure 4 shows a detailed end cross section of an exemplary sample cell 10, including feed conduit outlet 62, feed conduit 22 with channel portion 72, body surfaces 14, 16 and recesses 90, 92.
  • the design needs to take into account the wavelength of light used (e.g., UV, visible, infrared, etc.), the sensitivity of the spectrometer and the nature of the spectroscopic technique (e.g., absorption, scattering, etc.).
  • the wavelength of light used e.g., UV, visible, infrared, etc.
  • the sensitivity of the spectrometer e.g., the sensitivity of the spectrometer
  • the nature of the spectroscopic technique e.g., absorption, scattering, etc.
  • the present disclosure provides a sample cell that results from efforts to produce a design that can handle small sample volumes while minimizing the presence of air bubbles.
  • the sample cell has a body with windows that are located within recesses of upper and lower surfaces. The windows are spaced from the body surface.
  • An optical chamber passes through the body and is in fluid communication with feed conduits that include channel portions within the recesses.
  • the feed conduits each have an outlet on a surface of the body through which a fluid sample can be introduced into the optical chamber.
  • An inner ridge protrudes from within at least one of the recesses and surrounds the feed conduit. The inner ridge is spaced from its corresponding window.
  • the reduction of air bubbles in the optical chamber is thought to result from the inclusion of the inner ridge and a small gap between the inner ridge and its corresponding window.
  • This design feature stemmed from the recognition that the differences in surface tension of the fluid sample and air with the surfaces and materials of the sample cell could be used to preferentially allow air bubbles to flow over, and become trapped behind, the inner ridge.
  • the components of an exemplary sample cell are shown in Figures 1-4.
  • the gap between inner ridge 40 and windows 30, 32 is most readily visible in Figure 3. In various embodiments, the gap may range from about 0.01 mm to about 0.25 mm.
  • the gap may range from about 0.01 mm to about 0.05 mm, e.g., from about 0.01 mm to about 0.04 mm, from about 0.01 mm to about 0.03 mm, or from about 0.01 mm to about 0.02 mm.
  • the gap is such that air passes through the gap more easily than the fluid sample to be tested (e.g., any of the fluid samples discussed herein including embryo culture media, amniotic fluid, blood, etc.).
  • the gap is achieved by having an inner ridge 40 with a height lower than the height of a support means for windows 30, 32.
  • the support means comprises one or more raised structures located within the recesses. For example, as shown in Figures 1-4 one or more outer ridges 42, 44, a circular support ring 50, and/or support ribs 52 may form part of a support means.
  • the one or more outer ridges 42, 44 may also serve to contain any fluid sample that leaks over the inner ridge.
  • the one or more outer ridges 42, 44 may further serve to seal the fluid sample and optical chamber 12 from portions of recesses 90, 92 (e.g., to prevent adhesive 100 from mixing with the fluid sample and/or entering the optical chamber 12).
  • inner ridge 40 is generally, but not necessarily, perpendicular to the body surfaces 14, 16 from which it protrudes. In general, inner ridge 40 surrounds the channel portion 70, 72 of feed conduits 20, 22 and one end of optical chamber 12.
  • the height of inner ridge 40 may be any height within the limits of the manufacture and machining of the material of construction of sample cell 10.
  • inner ridge 40 has a height in the range of about 0.05 mm to about 0.25 mm. In some of these embodiments, inner ridge 40 has a height of at least about 0.07 mm, 0.09 mm, 0.1 1 mm, 0.13 mm, or 0.15 mm. In other embodiments, inner ridge 40 has a height of less than about 0.15 mm, 0.13 mm, 0.1 1 mm, 0.09 mm, or 0.07 mm. In any of these embodiments, the height of inner ridge 40 is not necessarily constant along its length. The horizontal distance between the edge of channel portions 70, 72 and the centerline of inner ridge 40 may also vary along its length and may be any distance within the range of manufacture and machining of the material of construction of the sample cell.
  • the distance is in the range of about 0.05 mm to about 2 mm (e.g., at least about 0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 1 mm, or 2 mm).
  • the one or more outer ridges 42, 44 are also generally, but not necessarily, perpendicular to body surfaces 14, 16 from which they protrude.
  • the one or more outer ridges 42, 44 surround inner ridge 40.
  • the inner and outer ridges may merge at one or more points.
  • the height of the one or more outer ridges may be any height within the limits of the method of manufacture and machining of the material of construction of sample cell 10. It is to be understood that the heights of the one or more outer ridges 42, 44 may be the same or different and that they may not be constant along their lengths.
  • the one or more outer ridges 42, 44 have a height in the range of about 0.05 mm to about 0.25 mm.
  • they have a height of at least about 0.07 mm, 0.09 mm, 0.1 1 mm, 0.13 mm, 0.15 mm or 0.20 mm. In other embodiments, they have a height of less than about 0.20 mm, 0.15 mm, 0.13 mm, 0.11 mm, 0.09 mm, or 0.07 mm.
  • the outer ridge 42 that is closest to inner ridge 40 is of approximately the same height as inner ridge 40 (i.e., it is also spaced from the corresponding window). In other embodiments, the outer ridge 42 that is closest to inner ridge 40 is taller than inner ridge 40 and contacts the corresponding window.
  • sample cell 10 includes two outer ridges 42, 44 as shown in Figures 1-4 and both outer ridges 42, 44 are taller than inner ridge 40 and contact the corresponding window. It is to be understood that the sample cell of the present disclosure is not limited to the aforementioned structures, and that the present disclosure encompasses the use of additional structures and ridges as well as alternative geometries and orientations of ridges in a sample cell 10. The distance between any of the ridges (i.e., between inner and outer ridges and between outer ridges) may be within the limits of manufacture and machining of the materials of construction of the sample cell 10.
  • each ridge and windows 30, 32, edges of channels portions 70, 72 or the central axis of optical chamber 12 need not be equal or constant and may vary independently. Additionally, the distances between any of the ridges (e.g., ridges 40, 42, 44) may vary independently.
  • sample cell 10 includes an optical chamber 12.
  • the optical chamber passes through the body 80 of sample cell 10 and exits into recesses 90, 92.
  • Optical chamber 12 can be any cross-sectional shape including circular, oval, square, rectangular, etc.
  • the optical chamber 12 is cylindrical.
  • recesses 90, 92 are designed to accommodate windows 30, 32.
  • the dimensions of optical chamber 12 can be determined to minimize total sample volume, maximize sensitivity during analysis, and accommodate particular radiation wavelengths and radiation beam profiles.
  • the diameter or cross-sectional area of the optical chamber 12 may be selected so that radiation having the wavelength(s) of interest can propagate through optical chamber 12.
  • the length of the chamber will generally be chosen so that it generates consistent results with radiation having the wavelength(s) of interest. It will be appreciated that these dimensions may also need to be adjusted depending on the nature of the fluid sample (e.g., the water content of the fluid sample can dramatically affect infrared absorption levels). These two dimensions then determine the volume of optical chamber 12 and thus have an impact on the fluid sample volume required to fill the optical chamber 12. For certain fluid samples it will be desirable to minimize sample volume due to limited availability of the sample or because the sample is hazardous.
  • optical chamber 12 has a volume in the range of about 2 microliters to about 30 microliters (e.g., about 2 microliters to about 10 microliters, about 2 microliters to about 30 microliters, or about 2 microliters to about 5 microliters).
  • the optical chamber has a diameter or cross-section in the range of about 0.5 mm to about 2 mm (e.g., about 0.75 mm to about 1.25 mm, or about 1 mm).
  • the optical chamber has an optical path length in the range of about 1 mm to about 10 mm (e.g., about 3 mm to about 7 mm, about 4 mm to about 8 mm).
  • the sample cell is only able to accommodate a fluid sample with a volume in the range of about 3 microliters to about 40 microliters (e.g., up to about 40 microliters, 35 microliters, 30 microliters, 25 microliters, 20 microliters, 15 microliters, 10 microliters, or 5 microliters).
  • sample cell 10 can be constructed from any material of construction that is compatible with the fluid sample to be analyzed and the spectroscopic technique being employed. In various embodiments, the material does not absorb the radiation (e.g., infrared radiation) that is used in the spectroscopic technique. In various embodiments, sample cell 10 is made of a moldable material. In various embodiments, sample cell 10 is made of acrylonitrile butadiene styrene (ABS). ABS does not absorb infrared radiation and is therefore particularly suitable for spectroscopic analyses that use infrared radiation. In other embodiments, sample cell 10 is made of TEFLON, polypropylene, aluminum, etc.
  • ABS acrylonitrile butadiene styrene
  • Sample cell 10 includes windows 30, 32 within recesses 90, 92.
  • Recesses 90, 92 can be of any depth within the limitations of manufacturing or machining the material of construction. In various embodiments, each recess has a depth in the range of about 0.5 mm to about 2 mm.
  • body 80 of sample cell 10 is not necessarily a single block of material, but can be constructed by combining two or more blocks of material. It will also be appreciated that body 80 of sample cell 10 is not necessarily a solid block of material and can include various structures, e.g., indentations, protrusions, grooves, ridges, etc. beyond those that are explicitly described herein and in Figures 1-4.
  • Windows 30, 32 are positioned within recesses 90, 92 to enclose optical chamber 12 and adjacent areas of the recess.
  • windows 30, 32 and recesses 90, 92 are circular.
  • windows 30, 32 and recesses 90, 92 are non-circular (e.g., square, rectangular, elliptical, etc.).
  • recesses 90, 92 have dimensions (e.g., diameters) that are larger than the dimensions of windows 30, 32.
  • Each window can be supported by any support means.
  • the support means includes, one or more support ribs 52, one or more outer ridges 42, 44, or any combination of these raised structures.
  • an outer ridge may be in the form of a circular support ring 50 (optionally at the periphery of recess 90, 92).
  • the interface of the raised structure(s) and windows effect to seal optical chamber 12.
  • windows 30, 32 are secured to body surfaces 14, 16 of sample cell 10. Any securing means may be used for that purpose (e.g., pressure fit, snap fit, adhesive, etc.).
  • windows 30, 32 may be secured using adhesive 100 within recesses 90, 92.
  • adhesive 100 is a glue, e.g., an instant cure glue or a UV curable glue. In general, it will be desirable to place adhesive 100 outside inner ridge 40.
  • adhesive 100 may be located on the outside of outer ridges 42, 44.
  • outer ridges 42, 44 may act as a barrier that prevents adhesive 100 from mixing with the fluid sample and entering into optical chamber 12.
  • outlets 60, 62 are located on the same body surface. In various embodiments, outlets 60, 62 are located on a surface of the body that is located between upper and lower body surfaces 14, 16 (e.g., as shown in Figure 2). In various embodiments, outlets 60, 62 are located on different body surfaces, e.g., opposing body surfaces of sample cell 10. In any of these embodiments, outlets 60, 62 may be located in the same plane. In certain embodiments, outlets 60, 62 may be located in a plane that passes through the midsection of sample cell body 80.
  • outlets 60, 62 are circular and have a diameter in the range of about 0.5 mm to about 2 mm. In various embodiments, outlets 60, 62 are sized to accommodate the insertion of a pipette tip, e.g., a standard gel loading pipette tip.
  • Feed conduits 20, 22 also include channel portions 70, 72 within recesses 90, 92. In various embodiments and as shown in Figures 1-4, channel portions 70, 72 may comprise an arcuate loop before terminating at one end of optical chamber 12. Without being bound by any theory, the arcuate loop in channel portions 70, 72 is thought to induce a vortex in the fluid sample so that air is swept away from optical chamber 12, thereby reducing the risk of air bubbles blocking optical chamber 12.
  • channel portions 70, 72 can also be linear and can additionally or alternatively include linear or curvilinear sections. It is also to be understood that the cross-sectional shape of channels portions 70, 72 can be any shape (e.g., rectangular, square, elliptical, semicircular, etc.). In various embodiments, the feed conduits within upper and lower surfaces 14, 16 are mirror images of each other as shown in Figures 1-4.
  • the windows are made of calcium fluoride, borosilicate glass, sapphire optical glass, quartz, poly(methyl methacrylate), polystyrene, poly(carbonate), or an acrylic styrene methyl methacrylate copolymer (e.g., from the NAS polymer series). In various embodiments, the windows are made of calcium fluoride.
  • a scattering material is used in at least one windows 30, 32.
  • the scattering material is a fluoropolymer (e.g., TEFLON, etc.).
  • a reflective material or coating e.g., aluminum is used for the sample cell, or for lining the optical chamber 12. Without being bound by any theory, the scattering of light may increase the interaction between the radiation and the fluid sample contained in optical chamber 12.
  • the present disclosure provides systems that include a sample cell 10 and a spectrometer.
  • spectrometer encompasses any device that is capable of generating and transmitting radiation through a fluid sample in the optical chamber 12 of the sample cell 10 and measuring the amount of radiation that is absorbed or reflected by the fluid sample at one or more wavelengths.
  • the present disclosure is in no way limited to any particular wavelength(s) or type of spectroscopy.
  • the spectrometer may include a source of radiation, a sample cell holder, a detector, and a means for computing the amount of radiation absorbed or reflected by the fluid sample (e.g., a processor that controls the source of radiation and processes signals from the detector in order to compute the amount of radiation absorbed or reflected by the fluid sample).
  • the system also includes a means for outputting and/or displaying the amount of radiation absorbed or reflected by the fluid sample at one or more wavelengths (e.g., a computer screen).
  • the spectrometer operates within the infrared spectrum. In various embodiments, the spectrometer operates within the near-infrared spectrum, e.g., within the range of about 700 nm to about 2200 nm or about 700 nm to about 1400 nm.
  • the system includes a temperature controlled heating block for storing sample cell 10 prior to spectroscopic analysis. In various embodiments, the region of the sample cell holder within the spectrometer is also temperature controlled. The temperatures of the heating block and sample cell holder may be the same or different.
  • the system may also include a suction means for removing a fluid sample from sample cell 10 such as a pump with a connection (e.g., a pipette tip) that can be placed into fluid communication with one of the outlets of feed conduits 60, 62.
  • a suction means for removing a fluid sample from sample cell 10 such as a pump with a connection (e.g., a pipette tip) that can be placed into fluid communication with one of the outlets of feed conduits 60, 62.
  • a fluid sample is introduced into sample cell 10 via one of the outlets 60, 62 of feed conduits 20, 22.
  • the term "fluid sample” includes, without limitation, a homogeneous solution or heterogeneous mixture which may be a liquid, suspension or gel. Any fluid sample may be used in accordance with the present disclosure.
  • effluent liquids from various sources laboratory samples for different purposes including forensic and biological samples may be used (e.g., cell or viral lysates, cell culture media, cell culture components, blood, blood products, blood components, lymph, mucus secretions, saliva, semen, amniotic fluid, follicular fluid, sweat, urine, cerebrospinal fluid, serum, plasma, tears, reconstituted lyophilized feces, etc.).
  • the fluid sample can be introduced into sample cell 10 by any means, e.g., using a syringe, a pipette with a pipette tip that fits within the outlet, a tube, etc.
  • sample cell 10 is empty when the fluid sample is introduced. Once introduced into a feed conduit, the fluid sample flows via the feed conduit into the channel portion, then through optical chamber 12 and on into the other feed conduit. In various embodiments, the volume of the fluid sample is less than the total volume of the sample cell so that feed conduits 20, 22 are not entirely filled with fluid sample. In various embodiments, the volume of the fluid sample is at least sufficient to fill optical chamber 12 and a portion of both feed conduits 20, 22. In various embodiments, sample cell 10 is stored in a temperature controlled heating block prior to spectroscopic analysis. It will be appreciated that the temperature of the heating block will depend on the type of fluid sample and type of spectroscopy.
  • the sample cell holder of the spectrometer may also be temperature controlled at the same or a different temperature.
  • the temperature of the sample cell holder is slightly lower (e.g., about 0.2 C to about 0.9 C lower, about 0.3 C to about 0.5 C lower, or about 0.4 lower).
  • sample cell 10 is placed within the sample cell holder of the spectrometer for spectroscopic analysis.
  • the source of radiation (which may include filters, etc.) produces a narrow beam of radiation (e.g., about 0.3 micrometers to about 0.5 micrometers in diameter).
  • the source of radiation and sample cell holder are designed such that the windows 30, 32 of the sample cell 10 are approximately perpendicular to the beam and the central axis of the beam is approximately aligned with the central axis of the optical chamber 12 (e.g., less than a 0.2 micrometer offset).
  • the spectrometer detector is located across from the source of radiation, on the opposite side of sample cell 10 and in alignment with the beam.
  • the sample cell 10 is removed from the sample cell holder.
  • the sample cell 10 is reused with a different fluid sample, e.g., a control sample.
  • a different fluid sample e.g., a control sample.
  • the second fluid sample may be introduced into the sample cell in the same manner as the first fluid sample.
  • the first fluid sample is flushed out of the sample cell using an excess volume of the second fluid sample. Depending on the type of fluid sample and the pressures involved, this approach may lead to leaks within the sample cell.
  • the first fluid sample may be removed by any means.
  • the first fluid sample may be removed from the sample cell using a suction means (i.e., a device such as a pump that is capable of generating a negative pressure gradient away from the sample cell and that can be connected to one of the outlets 60, 62 of feed conduits 20, 22).
  • the suction means may generate a low pressure in the range of about 0.2 atmospheres to about 0.4 atmospheres (e.g., about 0.25 atmospheres to about 0.3 atmospheres).
  • a system of the present disclosure may be used for the compositional analysis of one or more fluid samples (e.g., a test sample, fractions of a test sample obtained by chromatographic separation, etc.).
  • compositional analysis involves identifying specific molecular markers within a fluid sample. It is to be understood that these methods do not necessarily require the identity of the marker to be known (e.g., in various embodiments, a marker may be identified based on the presence of characteristic peak(s) in the spectrum without determining the identity of the marker). It will be appreciated that
  • compositional analyses may be performed using any spectroscopic technique that is capable of identifying the marker(s) in question. Without limitation, these may include single or multiwavelength optical absorption, Raman scattering, optical fluorescence, etc. and any combination thereof. In various embodiments, optical absorption may be within the infrared range (e.g., near-infrared range). In various embodiments, a chromatographic technique such as HPLC may be combined with one or more of these spectroscopic techniques. In various embodiments, the system may be capable of performing two or more different compositional analyses on any given fluid sample (e.g., using two or more different spectroscopic techniques for identifying the marker(s) of interest).
  • a system of the present disclosure may be used for the spectral analysis of one or more fluid samples (e.g., a test sample, fractions of a test sample obtained by chromatographic separation, etc.).
  • spectral analysis involves making correlations based on spectra of samples without necessarily identifying the specific molecules that are responsible for spectral features in a given sample.
  • correlations may be made using information from an entire spectrum.
  • correlations may be made using information from one or more regions of a spectrum (e.g., one or more wavelength regions in a spectrum, one or more wavelengths in a spectrum, etc.).
  • spectral analyses may be performed using any spectroscopic technique that is capable of producing a spectrum of the sample in question. Without limitation, these may include single or multiwavelength optical absorption, Raman scattering, optical fluorescence, etc. and any combination thereof. In various embodiments, optical absorption may be within the infrared range (e.g., near-infrared range). In various embodiments, a chromatographic technique such as HPLC may be combined with one or more of these spectroscopic techniques. In various embodiments, the system may be capable of performing two or more different spectral analyses on any given fluid sample (e.g., using two or more different spectroscopic techniques).
  • methods of the present disclosure may involve both a spectral analysis and a composition analysis of one or more samples.
  • spectral analysis may be used as an initial sample filter followed by a secondary compositional analysis of samples that satisfy the requirements of the spectral filter.
  • spectral analysis may be used as a secondary filter following a primary compositional analysis.
  • the methods may involve subjecting each sample to both a spectral analysis and a composition analysis.
  • the methods are executed as part of an assisted reproductive procedure, including in vitro fertilization.
  • an assisted reproductive procedure including in vitro fertilization.
  • 20070160973 describes systems and methods which employ spectral analysis of certain fluid samples in order to make predictions about the state of different types of cells involved in in vitro fertilization, including embryos, spermatozoa, oocytes, cells from the uterine wall, etc.
  • U.S. Patent Publication No. 20070160973 and any other publication referred to herein is hereby incorporated by reference in its entirety.
  • the fluid samples are taken from fluids that are exchanging metabolites with the cell(s) in question.
  • a correlation is initially established between the state of a particular type of cell and spectra of a fluid obtained using a chosen analytical modality for a population of cells with known outcome. For the cell being analyzed, a spectrum of the relevant fluid is obtained using the chosen modality.
  • the spectral analysis involves obtaining and then analyzing spectra of body fluids and/or gamete or embryo culture media used in in vitro fertilization procedures.
  • the methods involve predicting the viability of an oocyte based on spectral analysis of follicular fluid or culture media.
  • the methods involve predicting the viability of spermatozoa based on spectral analysis of seminal plasma or culture media.
  • the methods involve predicting the viability of an embryo based on the spectral analysis of culture media.
  • the spectral analysis is performed using single or multiwavelength optical absorption, Raman scattering or optical fluorescence.
  • optical absorption may be within the infrared range (e.g., near-infrared range).
  • the methods may involve determining one or more of: a time to transfer an embryo into a uterus; a time to subject an embryo to short term storage for future transfer into a uterus; a time to subject an embryo to cryopreservation for future transfer into a uterus; an adjustment to the culture medium to continue growing of an embryo; and a time to transfer an embryo into a different culture medium to continue growing of the embryo.
  • the methods are executed as part of a medical diagnostic or prognostic procedure.
  • U.S. Patent Publication No. 20070054347 describes systems and methods which employ spectral analysis of certain fluids in order to make diagnostic and prognostic predictions about various diseases.
  • a correlation is initially established between a particular diagnosis or prognosis and spectra of a fluid obtained using a chosen analytical modality for a population of patients with known diagnosis or prognosis.
  • a spectrum of the relevant fluid is obtained using the chosen modality.
  • the diagnosis or prognosis for the patient is then predicted using the acquired spectrum and the established correlation.
  • the spectral analysis involves obtaining and then analyzing spectra of body fluids (e.g., whole blood, blood plasma, blood serum, cerebrospinal fluid, etc.).
  • the spectral analysis is performed using single or multiwavelength optical absorption, Raman scattering or optical fluorescence.
  • optical absorption may be within the infrared range (e.g., near-infrared range).
  • the methods may involve prognostic predictions (e.g., predicting the likelihood that a patient will respond to a particular type of therapy).
  • the methods involve predicting the likelihood that a patient has Mild Cognitive Impairment (MCI).
  • MCI Mild Cognitive Impairment
  • the methods involve predicting the likelihood that a patient has Alzheimer's Disease. In various embodiments, the methods involve predicting the likelihood that a patient has Vascular Cognitive Impairment (VCI). In various embodiments, the methods involve predicting the likelihood that a patient has Parkinson's Disease. It is to be understood that these methods may also be applied outside the realm of these exemplary diseases.
  • U.S. Patent Publication No. 20060247536 describes methods and systems which employ spectral analysis of amniotic fluid in order to make predictions about the health of a mother and her fetus during pregnancy. Thus, in various embodiments, spectral analysis of amniotic fluid may be used to make predictions about fetal growth and the likely birth weight of the infant.
  • Patent Publication No. 20060247536 also describes compositional analytical methods and systems that use specific molecular markers in amniotic fluid in order to make predictions about the health of a mother and her fetus during pregnancy. Thus, in various embodiments, these markers may be used to make predictions about the likelihood that the mother will develop Gestational Diabetes Mellitus (GDM).
  • GDM Gestational Diabetes Mellitus

Abstract

The present disclosure provides a sample cell for spectroscopic analysis of fluid samples. The sample cell has a body with windows that are located within recesses of upper and lower surfaces. The windows are spaced from the body surface. An optical chamber passes through the body and is in fluid communication with feed conduits that include channel portions within the recesses. The feed conduits each have an outlet on a surface of the body through which a fluid sample can be introduced into the optical chamber. An inner ridge protrudes from within at least one of the recesses and surrounds the feed conduit. The inner ridge is spaced from its corresponding window. The present disclosure also provides systems that include a sample cell and a spectrometer and uses of such systems.

Description

SAMPLE CELL FOR SPECTROSCOPIC ANALYSIS, SYSTEMS AND
USES THEREOF
PRIORITY CLAIM
The present application claims priority to provisional patent application U.S. Serial No. 61/267611 filed December 8, 2009. The entire contents of this priority application are incorporated herein by reference.
BACKGROUND OF THE INVENTION
When analyzing samples using spectroscopy, the samples are contained in a vessel which is commonly referred to as a sample cell or cuvette. These vessels typically contain two sides of optical quality material that allow radiation to pass through the sample. Conventional sample cells are designed for large sample volumes, e.g., on the order of 30-100 microliters and are therefore unsuitable in situations where only small sample volumes are available, e.g., of 10 microliters or less. As is well known in the art, the amount of radiation absorbed by a sample is proportional to the path length of the sample (i.e., the distance the radiation has to travel through the sample). Without innovative designs, small volumes lead to short path lengths and less sensitive measurements. It is therefore a challenge to retain high sensitivity while
simultaneously reducing the size of the sample cell in order to accommodate small sample volumes. Furthermore, the dimensions of small sample cells present filling challenges and are also prone to entrapment of air bubbles that interfere with the spectroscopic analysis.
SUMMARY OF THE INVENTION
The present disclosure provides a sample cell for spectroscopic analysis of fluid samples. The sample cell has a body with windows that are located within recesses of upper and lower surfaces. The windows are spaced from the body surface. An optical chamber passes through the body and is in fluid communication with feed conduits that include channel portions within the recesses. The feed conduits each have an outlet on a surface of the body through which a fluid sample can be introduced into the optical chamber. An inner ridge protrudes from within at least one of the recesses and surrounds the feed conduit. The inner ridge is spaced from its corresponding window. The present disclosure also provides systems that include a sample cell and a spectrometer and uses of such systems.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 shows an exemplary sample cell 10 in isometric, elevation, plan and cross- sectional view.
Figure 2 shows additional views of an exemplary sample cell 10, including optical chamber 12, feed conduit 70, ridges 40, 42, 44, circular support ring 50, support ribs 52, and windows 30, 32 and adhesive 100.
Figure 3 shows a cross section of an exemplary sample cell 10, illustrating the relationship between the optical chamber 12, body surfaces 14, 16, recesses 90, 92, feed conduit channel portions 70, 72, ridges 40, 42, 44 and windows 30, 32.
Figure 4 shows a detailed end cross section of an exemplary sample cell 10, including feed conduit outlet 62, feed conduit 22 with channel portion 72, body surfaces 14, 16 and recesses 90, 92.
DETAILED DESCRIPTION OF VARIOUS EMBODIMENTS OF THE INVENTION
As mentioned above, a number of factors need to be considered and balanced when designing a sample cell. For example, the design needs to take into account the wavelength of light used (e.g., UV, visible, infrared, etc.), the sensitivity of the spectrometer and the nature of the spectroscopic technique (e.g., absorption, scattering, etc.). When only microliter sample volumes are available, designs are further complicated due to the dominance of surface tension forces, energy dissipation, and fluidic resistance, as well as the very low Reynolds numbers that are encountered. The entrapment of air bubbles is also a significant problem at small scales which can introduce inconsistencies into the analytical methods.
Sample cell
In one aspect, the present disclosure provides a sample cell that results from efforts to produce a design that can handle small sample volumes while minimizing the presence of air bubbles. In general, the sample cell has a body with windows that are located within recesses of upper and lower surfaces. The windows are spaced from the body surface. An optical chamber passes through the body and is in fluid communication with feed conduits that include channel portions within the recesses. The feed conduits each have an outlet on a surface of the body through which a fluid sample can be introduced into the optical chamber. An inner ridge protrudes from within at least one of the recesses and surrounds the feed conduit. The inner ridge is spaced from its corresponding window.
Without being bound by any theory, the reduction of air bubbles in the optical chamber is thought to result from the inclusion of the inner ridge and a small gap between the inner ridge and its corresponding window. This design feature stemmed from the recognition that the differences in surface tension of the fluid sample and air with the surfaces and materials of the sample cell could be used to preferentially allow air bubbles to flow over, and become trapped behind, the inner ridge. For purposes of illustration, the components of an exemplary sample cell are shown in Figures 1-4. The gap between inner ridge 40 and windows 30, 32 is most readily visible in Figure 3. In various embodiments, the gap may range from about 0.01 mm to about 0.25 mm. In various embodiments, the gap may range from about 0.01 mm to about 0.05 mm, e.g., from about 0.01 mm to about 0.04 mm, from about 0.01 mm to about 0.03 mm, or from about 0.01 mm to about 0.02 mm. In various embodiments, the gap is such that air passes through the gap more easily than the fluid sample to be tested (e.g., any of the fluid samples discussed herein including embryo culture media, amniotic fluid, blood, etc.). For example, we have found that smaller gaps may be preferable when using fluid samples with low surface tensions (e.g., despite having higher viscosities than water certain embryo culture media may have lower surface tensions than water and may therefore require a smaller gap than a water sample in order to prevent the fluid sample from passing over inner ridge 40). In various embodiments, the gap is achieved by having an inner ridge 40 with a height lower than the height of a support means for windows 30, 32. In various embodiments, the support means comprises one or more raised structures located within the recesses. For example, as shown in Figures 1-4 one or more outer ridges 42, 44, a circular support ring 50, and/or support ribs 52 may form part of a support means. In various embodiments, the one or more outer ridges 42, 44 may also serve to contain any fluid sample that leaks over the inner ridge. The one or more outer ridges 42, 44 may further serve to seal the fluid sample and optical chamber 12 from portions of recesses 90, 92 (e.g., to prevent adhesive 100 from mixing with the fluid sample and/or entering the optical chamber 12). It is to be understood that inner ridge 40 is generally, but not necessarily, perpendicular to the body surfaces 14, 16 from which it protrudes. In general, inner ridge 40 surrounds the channel portion 70, 72 of feed conduits 20, 22 and one end of optical chamber 12. The height of inner ridge 40 may be any height within the limits of the manufacture and machining of the material of construction of sample cell 10. In various embodiments, inner ridge 40 has a height in the range of about 0.05 mm to about 0.25 mm. In some of these embodiments, inner ridge 40 has a height of at least about 0.07 mm, 0.09 mm, 0.1 1 mm, 0.13 mm, or 0.15 mm. In other embodiments, inner ridge 40 has a height of less than about 0.15 mm, 0.13 mm, 0.1 1 mm, 0.09 mm, or 0.07 mm. In any of these embodiments, the height of inner ridge 40 is not necessarily constant along its length. The horizontal distance between the edge of channel portions 70, 72 and the centerline of inner ridge 40 may also vary along its length and may be any distance within the range of manufacture and machining of the material of construction of the sample cell. In various embodiments, the distance is in the range of about 0.05 mm to about 2 mm (e.g., at least about 0.05 mm, 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 1 mm, or 2 mm).
When present, the one or more outer ridges 42, 44 are also generally, but not necessarily, perpendicular to body surfaces 14, 16 from which they protrude. In various embodiments, the one or more outer ridges 42, 44 surround inner ridge 40. In certain embodiments, the inner and outer ridges may merge at one or more points. The height of the one or more outer ridges may be any height within the limits of the method of manufacture and machining of the material of construction of sample cell 10. It is to be understood that the heights of the one or more outer ridges 42, 44 may be the same or different and that they may not be constant along their lengths. In various embodiments, the one or more outer ridges 42, 44 have a height in the range of about 0.05 mm to about 0.25 mm. In some of these embodiments, they have a height of at least about 0.07 mm, 0.09 mm, 0.1 1 mm, 0.13 mm, 0.15 mm or 0.20 mm. In other embodiments, they have a height of less than about 0.20 mm, 0.15 mm, 0.13 mm, 0.11 mm, 0.09 mm, or 0.07 mm. In various embodiments, the outer ridge 42 that is closest to inner ridge 40 is of approximately the same height as inner ridge 40 (i.e., it is also spaced from the corresponding window). In other embodiments, the outer ridge 42 that is closest to inner ridge 40 is taller than inner ridge 40 and contacts the corresponding window. In various embodiments, sample cell 10 includes two outer ridges 42, 44 as shown in Figures 1-4 and both outer ridges 42, 44 are taller than inner ridge 40 and contact the corresponding window. It is to be understood that the sample cell of the present disclosure is not limited to the aforementioned structures, and that the present disclosure encompasses the use of additional structures and ridges as well as alternative geometries and orientations of ridges in a sample cell 10. The distance between any of the ridges (i.e., between inner and outer ridges and between outer ridges) may be within the limits of manufacture and machining of the materials of construction of the sample cell 10. The distances between each ridge and windows 30, 32, edges of channels portions 70, 72 or the central axis of optical chamber 12 need not be equal or constant and may vary independently. Additionally, the distances between any of the ridges (e.g., ridges 40, 42, 44) may vary independently.
As shown in Figures 1-4, sample cell 10 includes an optical chamber 12. The optical chamber passes through the body 80 of sample cell 10 and exits into recesses 90, 92. Optical chamber 12 can be any cross-sectional shape including circular, oval, square, rectangular, etc. In various embodiments, the optical chamber 12 is cylindrical. As discussed below, recesses 90, 92 are designed to accommodate windows 30, 32. The dimensions of optical chamber 12 can be determined to minimize total sample volume, maximize sensitivity during analysis, and accommodate particular radiation wavelengths and radiation beam profiles. For example, the diameter or cross-sectional area of the optical chamber 12 may be selected so that radiation having the wavelength(s) of interest can propagate through optical chamber 12. Additionally, the length of the chamber will generally be chosen so that it generates consistent results with radiation having the wavelength(s) of interest. It will be appreciated that these dimensions may also need to be adjusted depending on the nature of the fluid sample (e.g., the water content of the fluid sample can dramatically affect infrared absorption levels). These two dimensions then determine the volume of optical chamber 12 and thus have an impact on the fluid sample volume required to fill the optical chamber 12. For certain fluid samples it will be desirable to minimize sample volume due to limited availability of the sample or because the sample is hazardous. In various embodiments, optical chamber 12 has a volume in the range of about 2 microliters to about 30 microliters (e.g., about 2 microliters to about 10 microliters, about 2 microliters to about 30 microliters, or about 2 microliters to about 5 microliters). In various embodiments, the optical chamber has a diameter or cross-section in the range of about 0.5 mm to about 2 mm (e.g., about 0.75 mm to about 1.25 mm, or about 1 mm). In various embodiments, the optical chamber has an optical path length in the range of about 1 mm to about 10 mm (e.g., about 3 mm to about 7 mm, about 4 mm to about 8 mm). In various embodiments, the sample cell is only able to accommodate a fluid sample with a volume in the range of about 3 microliters to about 40 microliters (e.g., up to about 40 microliters, 35 microliters, 30 microliters, 25 microliters, 20 microliters, 15 microliters, 10 microliters, or 5 microliters).
In general, sample cell 10 can be constructed from any material of construction that is compatible with the fluid sample to be analyzed and the spectroscopic technique being employed. In various embodiments, the material does not absorb the radiation (e.g., infrared radiation) that is used in the spectroscopic technique. In various embodiments, sample cell 10 is made of a moldable material. In various embodiments, sample cell 10 is made of acrylonitrile butadiene styrene (ABS). ABS does not absorb infrared radiation and is therefore particularly suitable for spectroscopic analyses that use infrared radiation. In other embodiments, sample cell 10 is made of TEFLON, polypropylene, aluminum, etc.
Sample cell 10 includes windows 30, 32 within recesses 90, 92. Recesses 90, 92 can be of any depth within the limitations of manufacturing or machining the material of construction. In various embodiments, each recess has a depth in the range of about 0.5 mm to about 2 mm. It will be appreciated that body 80 of sample cell 10 is not necessarily a single block of material, but can be constructed by combining two or more blocks of material. It will also be appreciated that body 80 of sample cell 10 is not necessarily a solid block of material and can include various structures, e.g., indentations, protrusions, grooves, ridges, etc. beyond those that are explicitly described herein and in Figures 1-4. Windows 30, 32 are positioned within recesses 90, 92 to enclose optical chamber 12 and adjacent areas of the recess. In various embodiments, windows 30, 32 and recesses 90, 92 are circular. In other embodiments, windows 30, 32 and recesses 90, 92 are non-circular (e.g., square, rectangular, elliptical, etc.). In various embodiments, recesses 90, 92 have dimensions (e.g., diameters) that are larger than the dimensions of windows 30, 32. Each window can be supported by any support means. As mentioned above, in various embodiments, the support means includes, one or more support ribs 52, one or more outer ridges 42, 44, or any combination of these raised structures. In various embodiments an outer ridge may be in the form of a circular support ring 50 (optionally at the periphery of recess 90, 92). In various embodiments, the interface of the raised structure(s) and windows effect to seal optical chamber 12. In various embodiments, windows 30, 32 are secured to body surfaces 14, 16 of sample cell 10. Any securing means may be used for that purpose (e.g., pressure fit, snap fit, adhesive, etc.). In various embodiments and as shown in Figures 1 and 2, windows 30, 32 may be secured using adhesive 100 within recesses 90, 92. In various embodiments adhesive 100 is a glue, e.g., an instant cure glue or a UV curable glue. In general, it will be desirable to place adhesive 100 outside inner ridge 40. In various embodiments, adhesive 100 may be located on the outside of outer ridges 42, 44. In various embodiments, outer ridges 42, 44 may act as a barrier that prevents adhesive 100 from mixing with the fluid sample and entering into optical chamber 12.
As illustrated in Figures 2 and 4 for an exemplary sample cell 10, the fluid sample is brought to and from optical chamber 12 via feed conduits 20, 22. Each feed conduit 20, 22, has an outlet 60, 62. In various embodiments, outlets 60, 62 are located on the same body surface. In various embodiments, outlets 60, 62 are located on a surface of the body that is located between upper and lower body surfaces 14, 16 (e.g., as shown in Figure 2). In various embodiments, outlets 60, 62 are located on different body surfaces, e.g., opposing body surfaces of sample cell 10. In any of these embodiments, outlets 60, 62 may be located in the same plane. In certain embodiments, outlets 60, 62 may be located in a plane that passes through the midsection of sample cell body 80. In various embodiments, outlets 60, 62 are circular and have a diameter in the range of about 0.5 mm to about 2 mm. In various embodiments, outlets 60, 62 are sized to accommodate the insertion of a pipette tip, e.g., a standard gel loading pipette tip. Feed conduits 20, 22 also include channel portions 70, 72 within recesses 90, 92. In various embodiments and as shown in Figures 1-4, channel portions 70, 72 may comprise an arcuate loop before terminating at one end of optical chamber 12. Without being bound by any theory, the arcuate loop in channel portions 70, 72 is thought to induce a vortex in the fluid sample so that air is swept away from optical chamber 12, thereby reducing the risk of air bubbles blocking optical chamber 12. It is to be understood that channel portions 70, 72 can also be linear and can additionally or alternatively include linear or curvilinear sections. It is also to be understood that the cross-sectional shape of channels portions 70, 72 can be any shape (e.g., rectangular, square, elliptical, semicircular, etc.). In various embodiments, the feed conduits within upper and lower surfaces 14, 16 are mirror images of each other as shown in Figures 1-4.
During a spectrometric analysis, radiation enters optical chamber 12 after passing through either window 30 or 32 and exits through the opposite window. It will be appreciated that the choice of window material will depend on the wavelength of the radiation and also on the type of spectroscopic technique. In general however, any type of crystal, glass or plastic conducive to spectroscopic analysis may be used. In various embodiments, the windows are made of calcium fluoride, borosilicate glass, sapphire optical glass, quartz, poly(methyl methacrylate), polystyrene, poly(carbonate), or an acrylic styrene methyl methacrylate copolymer (e.g., from the NAS polymer series). In various embodiments, the windows are made of calcium fluoride. In various embodiments, a scattering material is used in at least one windows 30, 32. In various embodiments, the scattering material is a fluoropolymer (e.g., TEFLON, etc.). In various embodiments, a reflective material or coating (e.g., aluminum) is used for the sample cell, or for lining the optical chamber 12. Without being bound by any theory, the scattering of light may increase the interaction between the radiation and the fluid sample contained in optical chamber 12.
Systems and uses thereof
In another aspect, the present disclosure provides systems that include a sample cell 10 and a spectrometer. As used herein, the term "spectrometer" encompasses any device that is capable of generating and transmitting radiation through a fluid sample in the optical chamber 12 of the sample cell 10 and measuring the amount of radiation that is absorbed or reflected by the fluid sample at one or more wavelengths. The present disclosure is in no way limited to any particular wavelength(s) or type of spectroscopy. In various embodiments, the spectrometer may include a source of radiation, a sample cell holder, a detector, and a means for computing the amount of radiation absorbed or reflected by the fluid sample (e.g., a processor that controls the source of radiation and processes signals from the detector in order to compute the amount of radiation absorbed or reflected by the fluid sample). In various embodiments, the system also includes a means for outputting and/or displaying the amount of radiation absorbed or reflected by the fluid sample at one or more wavelengths (e.g., a computer screen). In various
embodiments, the spectrometer operates within the infrared spectrum. In various embodiments, the spectrometer operates within the near-infrared spectrum, e.g., within the range of about 700 nm to about 2200 nm or about 700 nm to about 1400 nm. In various embodiments, the system includes a temperature controlled heating block for storing sample cell 10 prior to spectroscopic analysis. In various embodiments, the region of the sample cell holder within the spectrometer is also temperature controlled. The temperatures of the heating block and sample cell holder may be the same or different. In certain situations we have found it advantageous to use a heating block that is at a slightly higher temperature than the sample cell holder of the spectrometer (e.g., about 0.2 C to about 0.9 C higher, about 0.3 C to about 0.5 C higher, or about 0.4 C higher). As discussed in more detail below, in various embodiments, the system may also include a suction means for removing a fluid sample from sample cell 10 such as a pump with a connection (e.g., a pipette tip) that can be placed into fluid communication with one of the outlets of feed conduits 60, 62.
In operation, a fluid sample is introduced into sample cell 10 via one of the outlets 60, 62 of feed conduits 20, 22. As used herein, the term "fluid sample" includes, without limitation, a homogeneous solution or heterogeneous mixture which may be a liquid, suspension or gel. Any fluid sample may be used in accordance with the present disclosure. In various embodiments effluent liquids from various sources, laboratory samples for different purposes including forensic and biological samples may be used (e.g., cell or viral lysates, cell culture media, cell culture components, blood, blood products, blood components, lymph, mucus secretions, saliva, semen, amniotic fluid, follicular fluid, sweat, urine, cerebrospinal fluid, serum, plasma, tears, reconstituted lyophilized feces, etc.). It is to be understood that the fluid sample can be introduced into sample cell 10 by any means, e.g., using a syringe, a pipette with a pipette tip that fits within the outlet, a tube, etc. In various embodiments, sample cell 10 is empty when the fluid sample is introduced. Once introduced into a feed conduit, the fluid sample flows via the feed conduit into the channel portion, then through optical chamber 12 and on into the other feed conduit. In various embodiments, the volume of the fluid sample is less than the total volume of the sample cell so that feed conduits 20, 22 are not entirely filled with fluid sample. In various embodiments, the volume of the fluid sample is at least sufficient to fill optical chamber 12 and a portion of both feed conduits 20, 22. In various embodiments, sample cell 10 is stored in a temperature controlled heating block prior to spectroscopic analysis. It will be appreciated that the temperature of the heating block will depend on the type of fluid sample and type of spectroscopy. In various embodiments, e.g., when performing near-infrared spectroscopy with fluid samples that include water we have found it advantageous to set the temperature of the heating block in the range of about 23 C to about 25 C (e.g., about 24 C). As mentioned above, in various embodiments, the sample cell holder of the spectrometer may also be temperature controlled at the same or a different temperature. In various embodiments, the temperature of the sample cell holder is slightly lower (e.g., about 0.2 C to about 0.9 C lower, about 0.3 C to about 0.5 C lower, or about 0.4 lower).
Once filled, and optionally stored in the heating block, sample cell 10 is placed within the sample cell holder of the spectrometer for spectroscopic analysis. In various embodiments, the source of radiation (which may include filters, etc.) produces a narrow beam of radiation (e.g., about 0.3 micrometers to about 0.5 micrometers in diameter). In various embodiments, the source of radiation and sample cell holder are designed such that the windows 30, 32 of the sample cell 10 are approximately perpendicular to the beam and the central axis of the beam is approximately aligned with the central axis of the optical chamber 12 (e.g., less than a 0.2 micrometer offset). In various embodiments, the spectrometer detector is located across from the source of radiation, on the opposite side of sample cell 10 and in alignment with the beam.
Once spectroscopic analysis of the fluid sample has been completed the sample cell 10 is removed from the sample cell holder. In various embodiments, the sample cell 10 is reused with a different fluid sample, e.g., a control sample. When the signals being measured in a test sample are weak it may prove advantageous to perform spectroscopic analysis of a control sample using the same sample cell 10 in order to minimize signal fluctuations that could result from slight variations between sample cells. It is to be understood that the second fluid sample may be introduced into the sample cell in the same manner as the first fluid sample. In various embodiments, the first fluid sample is flushed out of the sample cell using an excess volume of the second fluid sample. Depending on the type of fluid sample and the pressures involved, this approach may lead to leaks within the sample cell. Therefore, in various embodiments we have found that it may be advantageous to remove the first fluid sample from the sample cell before introducing the second fluid sample. The first fluid sample may be removed by any means. For example, in various embodiments, the first fluid sample may be removed from the sample cell using a suction means (i.e., a device such as a pump that is capable of generating a negative pressure gradient away from the sample cell and that can be connected to one of the outlets 60, 62 of feed conduits 20, 22). In various embodiments the suction means may generate a low pressure in the range of about 0.2 atmospheres to about 0.4 atmospheres (e.g., about 0.25 atmospheres to about 0.3 atmospheres). In various embodiments, a system of the present disclosure may be used for the compositional analysis of one or more fluid samples (e.g., a test sample, fractions of a test sample obtained by chromatographic separation, etc.). In general, compositional analysis involves identifying specific molecular markers within a fluid sample. It is to be understood that these methods do not necessarily require the identity of the marker to be known (e.g., in various embodiments, a marker may be identified based on the presence of characteristic peak(s) in the spectrum without determining the identity of the marker). It will be appreciated that
compositional analyses may be performed using any spectroscopic technique that is capable of identifying the marker(s) in question. Without limitation, these may include single or multiwavelength optical absorption, Raman scattering, optical fluorescence, etc. and any combination thereof. In various embodiments, optical absorption may be within the infrared range (e.g., near-infrared range). In various embodiments, a chromatographic technique such as HPLC may be combined with one or more of these spectroscopic techniques. In various embodiments, the system may be capable of performing two or more different compositional analyses on any given fluid sample (e.g., using two or more different spectroscopic techniques for identifying the marker(s) of interest).
In various embodiments, a system of the present disclosure may be used for the spectral analysis of one or more fluid samples (e.g., a test sample, fractions of a test sample obtained by chromatographic separation, etc.). In general, spectral analysis involves making correlations based on spectra of samples without necessarily identifying the specific molecules that are responsible for spectral features in a given sample. In various embodiments, correlations may be made using information from an entire spectrum. In various embodiments, correlations may be made using information from one or more regions of a spectrum (e.g., one or more wavelength regions in a spectrum, one or more wavelengths in a spectrum, etc.). It will be appreciated that spectral analyses may be performed using any spectroscopic technique that is capable of producing a spectrum of the sample in question. Without limitation, these may include single or multiwavelength optical absorption, Raman scattering, optical fluorescence, etc. and any combination thereof. In various embodiments, optical absorption may be within the infrared range (e.g., near-infrared range). In various embodiments, a chromatographic technique such as HPLC may be combined with one or more of these spectroscopic techniques. In various embodiments, the system may be capable of performing two or more different spectral analyses on any given fluid sample (e.g., using two or more different spectroscopic techniques).
In various embodiments, methods of the present disclosure may involve both a spectral analysis and a composition analysis of one or more samples. For example, spectral analysis may be used as an initial sample filter followed by a secondary compositional analysis of samples that satisfy the requirements of the spectral filter. Alternatively, spectral analysis may be used as a secondary filter following a primary compositional analysis. In various embodiments, the methods may involve subjecting each sample to both a spectral analysis and a composition analysis.
In various embodiments the methods are executed as part of an assisted reproductive procedure, including in vitro fertilization. For example, U.S. Patent Publication No.
20070160973 describes systems and methods which employ spectral analysis of certain fluid samples in order to make predictions about the state of different types of cells involved in in vitro fertilization, including embryos, spermatozoa, oocytes, cells from the uterine wall, etc. U.S. Patent Publication No. 20070160973 and any other publication referred to herein is hereby incorporated by reference in its entirety. Without limitation, the fluid samples are taken from fluids that are exchanging metabolites with the cell(s) in question. A correlation is initially established between the state of a particular type of cell and spectra of a fluid obtained using a chosen analytical modality for a population of cells with known outcome. For the cell being analyzed, a spectrum of the relevant fluid is obtained using the chosen modality. The state of the cell is then predicted using the acquired spectrum and the established correlation. Thus, in various embodiments the spectral analysis involves obtaining and then analyzing spectra of body fluids and/or gamete or embryo culture media used in in vitro fertilization procedures. In various embodiments, the methods involve predicting the viability of an oocyte based on spectral analysis of follicular fluid or culture media. In various embodiments, the methods involve predicting the viability of spermatozoa based on spectral analysis of seminal plasma or culture media. In various embodiments, the methods involve predicting the viability of an embryo based on the spectral analysis of culture media. In various embodiments, the spectral analysis is performed using single or multiwavelength optical absorption, Raman scattering or optical fluorescence. In various embodiments, optical absorption may be within the infrared range (e.g., near-infrared range). In various embodiments, instead of predicting embryo or gamete viability, the methods may involve determining one or more of: a time to transfer an embryo into a uterus; a time to subject an embryo to short term storage for future transfer into a uterus; a time to subject an embryo to cryopreservation for future transfer into a uterus; an adjustment to the culture medium to continue growing of an embryo; and a time to transfer an embryo into a different culture medium to continue growing of the embryo.
In various embodiments the methods are executed as part of a medical diagnostic or prognostic procedure. For example, U.S. Patent Publication No. 20070054347 describes systems and methods which employ spectral analysis of certain fluids in order to make diagnostic and prognostic predictions about various diseases. A correlation is initially established between a particular diagnosis or prognosis and spectra of a fluid obtained using a chosen analytical modality for a population of patients with known diagnosis or prognosis. For the patient being analyzed, a spectrum of the relevant fluid is obtained using the chosen modality. The diagnosis or prognosis for the patient is then predicted using the acquired spectrum and the established correlation. Thus, in various embodiments the spectral analysis involves obtaining and then analyzing spectra of body fluids (e.g., whole blood, blood plasma, blood serum, cerebrospinal fluid, etc.). In various embodiments, the spectral analysis is performed using single or multiwavelength optical absorption, Raman scattering or optical fluorescence. In various embodiments, optical absorption may be within the infrared range (e.g., near-infrared range). In various embodiments, the methods may involve prognostic predictions (e.g., predicting the likelihood that a patient will respond to a particular type of therapy). In various embodiments, the methods involve predicting the likelihood that a patient has Mild Cognitive Impairment (MCI). In various embodiments, the methods involve predicting the likelihood that a patient has Alzheimer's Disease. In various embodiments, the methods involve predicting the likelihood that a patient has Vascular Cognitive Impairment (VCI). In various embodiments, the methods involve predicting the likelihood that a patient has Parkinson's Disease. It is to be understood that these methods may also be applied outside the realm of these exemplary diseases. For example, U.S. Patent Publication No. 20060247536 describes methods and systems which employ spectral analysis of amniotic fluid in order to make predictions about the health of a mother and her fetus during pregnancy. Thus, in various embodiments, spectral analysis of amniotic fluid may be used to make predictions about fetal growth and the likely birth weight of the infant. U.S. Patent Publication No. 20060247536 also describes compositional analytical methods and systems that use specific molecular markers in amniotic fluid in order to make predictions about the health of a mother and her fetus during pregnancy. Thus, in various embodiments, these markers may be used to make predictions about the likelihood that the mother will develop Gestational Diabetes Mellitus (GDM).

Claims

CLAIMS We claim:
1. A sample cell for spectroscopic analysis of a fluid sample, wherein the sample cell
comprises:
a body with an upper surface and an opposing lower surface;
recesses within the upper and lower body surfaces that each accommodate a window, wherein the windows are spaced from their corresponding body surfaces by way of support means;
an optical chamber that passes through the body between the recesses within the upper and lower body surfaces;
first and second feed conduits in fluid communication with opposite ends of the optical chamber, wherein a portion of the first feed conduit is a channel within the recess of the upper body surface and a portion of the second feed conduit is a channel within the recess of the lower body surface of the body and wherein the first and second feed conduits each have an outlet on a surface of the body through which a fluid sample can be introduced into the optical chamber; and
an inner ridge protruding from within at least one of the recesses, wherein the inner ridge is spaced from its corresponding window and surrounds the feed conduit within the recess.
2. The sample cell of claim 1 , wherein the sample cell comprises an inner ridge within each recess.
3. The sample cell of claim 1, wherein the inner ridge has a height in the range of about 0.05 mm to about 0.25 mm.
4. The sample cell of claim 1, wherein the inner ridge has a height in the range of about 0.07 mm to about 0.25 mm.
5. The sample cell of claim 1, wherein the inner ridge has a height in the range of about 0.09 mm to about 0.25 mm.
6. The sample cell of claim 1, wherein the inner ridge has a height in the range of about 0.11 mm to about 0.25 mm.
7. The sample cell of claim 1 , wherein the inner ridge is spaced from its corresponding window by about 0.01 mm to about 0.05 mm.
8. The sample cell of claim 1 , wherein the inner ridge is spaced from its corresponding window by about 0.01 mm to about 0.04 mm.
9. The sample cell of claim 1 , wherein the inner ridge is spaced from its corresponding window by about 0.01 mm to about 0.03 mm.
10. The sample cell of claim 1 , wherein the inner ridge is spaced from its corresponding window by about 0.01 mm to about 0.02 mm.
11. The sample cell of claim 1 , wherein the windows are spaced from their corresponding body surfaces by about 0.05 mm to about 0.25 mm.
12. The sample cell of claim 1 , wherein the windows are spaced from their corresponding body surfaces by about 0.05 mm to about 0.20 mm.
13. The sample cell of claim 1 , wherein the windows are spaced from their corresponding body surfaces by about 0.05 mm to about 0.13 mm.
14. The sample cell of claim 1 , wherein the windows are spaced from their corresponding body surfaces by about 0.05 mm to about 0.07 mm.
15. The sample cell of claim 1 , wherein the support means that space the windows from their corresponding body surfaces comprise one or more raised structures located within the recesses.
16. The sample cell of claim 1 , wherein the sample cell comprises an inner ridge and an outer ridge within each recess and wherein the outer ridge is or forms part of the support means.
17. The sample cell of claim 16, wherein the outer ridge is located at the periphery of the recess.
18. The sample cell of claim 16, wherein the support means comprises at least two outer ridges of about the same height.
19. The sample cell of claim 16, wherein the difference in height between the inner ridge and the outer ridge is in the range of about 0.01 mm to about 0.05 mm.
20. The sample cell of claim 16, wherein the difference in height between the inner ridge and the outer ridge is in the range of about 0.01 mm to about 0.04 mm.
21. The sample cell of claim 16, wherein the difference in height between the inner ridge and the outer ridge is in the range of about 0.01 mm to about 0.03 mm.
22. The sample cell of claim 16, wherein the difference in height between the inner ridge and the outer ridge is in the range of about 0.01 mm to about 0.02 mm.
23. The sample cell of claim 1 , wherein the sample cell body is made of a moldable material.
24. The sample cell of claim 23, wherein the sample cell body is made of acrylonitrile
butadiene styrene.
25. The sample cell of claim 1 , wherein the sample cell body is made of a material that does not absorb infrared radiation.
26. The sample cell of claim 1 , wherein the recesses and windows are circular.
27. The sample cell of claim 26, wherein the recesses have diameters that are larger than the diameters of their corresponding windows.
28. The sample cell of claim 27, wherein the windows are glued to their corresponding body surfaces.
29. The sample cell of claim 28, wherein the windows are glued to their corresponding body surfaces with an instant cure glue.
30. The sample cell of claim 28, wherein the windows are glued to their corresponding body surfaces with a UV curable glue.
31. The sample cell of claim 2, wherein the windows are glued to their corresponding body surfaces and the glue is located on the outside of the inner ridge.
32. The sample cell of claim 16, wherein the windows are glued to their corresponding body surfaces and the glue is located on the outside of the outer ridge.
33. The sample cell of claim 1 , wherein the windows are made of calcium fluoride,
borosilicate glass, sapphire optical glass, quartz, poly(methyl methacrylate), polystyrene, poly(carbonate), or an acrylic styrene methyl methacrylate copolymer.
34. The sample cell of claim 1 , wherein the optical chamber is cylindrical.
35. The sample cell of claim 1, wherein the central axis of the optical chamber is
approximately perpendicular to both windows.
36. The sample cell of claim 1 , wherein the optical chamber has a volume in the range of about 2 microliters to about 30 microliters.
37. The sample cell of claim 1 , wherein the optical chamber has a volume in the range of about 2 microliters to about 10 microliters.
38. The sample cell of claim 1 , wherein the optical chamber has a volume in the range of about 2 microliters to about 5 microliters.
39. The sample cell of claim 1 , wherein the optical chamber has a diameter or cross-section in the range of about 0.5 mm to about 2 mm.
40. The sample cell of claim 1 , wherein the optical chamber has an optical path length in the range of about 1 mm to about 10 mm.
41. The sample cell of claim 1, wherein the sample cell has a total fluid sample volume in the range of about 3 microliters to about 40 microliters.
42. The sample cell of claim 1, wherein the channel portions of the feed conduits comprise an arcuate loop.
43. The sample cell of claim 42, wherein the first and second feed conduits are mirror images of each other.
44. The sample cell of claim 1, wherein the channel portions of the feed conduits are linear.
45. The sample cell of claim 1, wherein the feed conduit outlets are located on the same body surface.
46. The sample cell of claim 45, wherein the feed conduit outlets are located on a surface of the body that is located between the upper and lower body surfaces.
47. The sample cell of claim 1 , wherein the feed conduit outlets are located on different body surfaces.
48. The sample cell of claim 47, wherein the feed conduit outlets are located on opposing body surfaces.
49. The sample cell of claim 1 , wherein the feed conduit outlets are circular and have a
diameter in the range of about 0.5 mm to about 2 mm.
50. A system comprising a spectrometer and a sample cell of any one of the previous claims.
51. A method comprising a step of using a system of claim 50 to perform a compositional analysis of a fluid sample.
52. A method comprising a step of using a system of claim 50 to perform a spectral analysis of a fluid sample.
PCT/US2010/023324 2009-12-08 2010-02-05 Sample cell for spectroscopic analysis, systems and uses thereof WO2011071551A1 (en)

Applications Claiming Priority (2)

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US26761109P 2009-12-08 2009-12-08
US61/267,611 2009-12-08

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8323177B2 (en) 2009-08-22 2012-12-04 The Board Of Trustees Of The Leland Stanford Junior University Imaging and evaluating embryos, oocytes, and stem cells
US9482659B2 (en) 2010-09-27 2016-11-01 Progyny, Inc. Apparatus, method, and system for the automated imaging and evaluation of embryos, oocytes and stem cells
US9879307B2 (en) 2011-02-23 2018-01-30 The Board Of Trustees Of The Leland Stanford Junior University Methods of detecting aneuploidy in human embryos
US10241108B2 (en) 2013-02-01 2019-03-26 Ares Trading S.A. Abnormal syngamy phenotypes observed with time lapse imaging for early identification of embryos with lower development potential
US11627728B2 (en) * 2017-02-23 2023-04-18 Ryshens Ltd. Devices and methods for determining analytes

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US6983177B2 (en) * 2003-01-06 2006-01-03 Optiscan Biomedical Corporation Layered spectroscopic sample element with microporous membrane

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US5139333A (en) * 1988-11-11 1992-08-18 Automatik Apparate-Maschinebau Gmbh Measuring cell for the spectral analysis of flowing media, in particular plastic melts
US6188474B1 (en) * 1998-05-13 2001-02-13 Bayer Corporation Optical spectroscopy sample cell
US6983177B2 (en) * 2003-01-06 2006-01-03 Optiscan Biomedical Corporation Layered spectroscopic sample element with microporous membrane

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8323177B2 (en) 2009-08-22 2012-12-04 The Board Of Trustees Of The Leland Stanford Junior University Imaging and evaluating embryos, oocytes, and stem cells
US8337387B2 (en) 2009-08-22 2012-12-25 The Board Of Trustees Of The Leland Stanford Junior University Imaging and evaluating embryos, oocytes, and stem cells
US8721521B2 (en) 2009-08-22 2014-05-13 The Board Of Trustees Of The Leland Stanford Junior University Imaging and evaluating embryos, oocytes, and stem cells
US8951184B2 (en) 2009-08-22 2015-02-10 The Board Of Trustees Of The Leland Stanford Junior University Imaging and evaluating embryos, oocytes, and stem cells
US8989475B2 (en) 2009-08-22 2015-03-24 The Board Of Trustees Of The Leland Stanford Junior University Imaging and evaluating embryos, oocytes, and stem cells
US9228931B2 (en) 2009-08-22 2016-01-05 The Board Of Trustees Of The Leland Stanford Junior University Imaging and evaluating embryos, oocytes, and stem cells
US9482659B2 (en) 2010-09-27 2016-11-01 Progyny, Inc. Apparatus, method, and system for the automated imaging and evaluation of embryos, oocytes and stem cells
US9879307B2 (en) 2011-02-23 2018-01-30 The Board Of Trustees Of The Leland Stanford Junior University Methods of detecting aneuploidy in human embryos
US10241108B2 (en) 2013-02-01 2019-03-26 Ares Trading S.A. Abnormal syngamy phenotypes observed with time lapse imaging for early identification of embryos with lower development potential
US11627728B2 (en) * 2017-02-23 2023-04-18 Ryshens Ltd. Devices and methods for determining analytes

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