WO2009083846A2 - Optical coupling medium - Google Patents

Optical coupling medium Download PDF

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Publication number
WO2009083846A2
WO2009083846A2 PCT/IB2008/055240 IB2008055240W WO2009083846A2 WO 2009083846 A2 WO2009083846 A2 WO 2009083846A2 IB 2008055240 W IB2008055240 W IB 2008055240W WO 2009083846 A2 WO2009083846 A2 WO 2009083846A2
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WO
WIPO (PCT)
Prior art keywords
optical
coupling
medium
medium according
optical coupling
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PCT/IB2008/055240
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French (fr)
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WO2009083846A3 (en
Inventor
Martinus. B Van Der Mark
Antonius W. M. De Laat
Rik Harbers
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Koninklijke Philips Electronics N.V.
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Application filed by Koninklijke Philips Electronics N.V. filed Critical Koninklijke Philips Electronics N.V.
Publication of WO2009083846A2 publication Critical patent/WO2009083846A2/en
Publication of WO2009083846A3 publication Critical patent/WO2009083846A3/en

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    • 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
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47Scattering, i.e. diffuse reflection
    • G01N21/4795Scattering, i.e. diffuse reflection spatially resolved investigating of object in scattering medium
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/0059Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • A61B5/0082Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes
    • A61B5/0091Measuring for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence adapted for particular medical purposes for mammography
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Measuring for diagnostic purposes; Identification of persons
    • A61B5/43Detecting, measuring or recording for evaluating the reproductive systems
    • A61B5/4306Detecting, measuring or recording for evaluating the reproductive systems for evaluating the female reproductive systems, e.g. gynaecological evaluations
    • A61B5/4312Breast evaluation or disorder diagnosis
    • 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
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/47Scattering, i.e. diffuse reflection
    • G01N21/4785Standardising light scatter apparatus; Standards therefor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B2562/00Details of sensors; Constructional details of sensor housings or probes; Accessories for sensors
    • A61B2562/14Coupling media or elements to improve sensor contact with skin or tissue
    • A61B2562/146Coupling media or elements to improve sensor contact with skin or tissue for optical coupling

Definitions

  • the invention relates to an optical coupling medium for coupling optical energy from a light source to a turbid medium, comprising a scattering component and an absorbing component, and use of the optical coupling medium. Moreover, the invention relates to a system and a method for imaging a turbid medium.
  • such an optical examining device includes an optical energy source, a photo detector and a control unit to reconstruct the interior of the turbid medium on the basis of the measured intensities.
  • a holder may be provided with an optical coupling fluid. This fluid serves to provide optical coupling the between the turbid media to be imaged and a fiber coupling to the light source and detectors respectively.
  • the optical coupling fluid should further serve to prevent optical short circuits, being light finding a path from the light source to said detector without traveling though the turbid medium under investigation. It furthermore may function as a reference medium for calibration, eliminates boundary effects due to both holder and turbid medium and provides an optical contact between optodes and breast.
  • the optical properties of said fluid must closely match the turbid medium to be examined.
  • Conventional coupling media are provided as an aqueous fluid that is supplemented with scattering and absorbing components. Such a fluid and use thereof is disclosed in patent application WO 00/56206.
  • Commonly used scatter components comprise TiO 2 particles.
  • Absorbing characteristics of an optical coupling fluid can be adjusted by adding dyes with specific optical absorption properties. Quality and resolution of the obtained images are strongly dependent on the homogeneity and optical properties of the coupling medium. Air gaps, bubbles or inhomogeneities in the coupling medium result in artifacts which may strongly hamper the measurement.
  • an optical coupling medium comprising a scattering component, an absorbing component and a polymeric thickening component.
  • the invention is based on the recognition that stabilization of the scattering particles enhances the quality of the obtained images.
  • scatter particles will not be subject to settling and movement in solid coupling media.
  • solid coupling media are not suitable for use in optical measurements as direct coupling between a light source and the turbid medium to be examined is essential.
  • the dimensions of biological turbid media are not constant and air gaps and free spaces will occur in the holder cup when a solid coupling medium is used.
  • a polymeric thickening component to a liquid optical coupling medium results in an at least partial gelation of the medium.
  • scatter particles can be homogeneously distributed and more importantly, settling and motion of the scatter particles is severely reduced. This consequently reduces the noise in the measurement and the resolution of the obtained images is improved.
  • polymer thickeners are known in the art and several of these polymers are well tolerated by biological tissue and are easy to obtain. An optical coupling medium that can be easily handled, and that additionally stabilizes the scatter particles during measurement is therefore advantageous.
  • the optical coupling medium liquefies upon the application of shear.
  • This shear can be generated by a mechanical treatment of the coupling medium, such as stirring or shaking. It may be favorable if the coupling medium reversibly liquefies.
  • shear-thinning is a principle that is ideal for use in the conventional diffuse optical tomography devices, as shear, e.g. stirring, facilitates liquefaction of the composition so it can be easily pumped into or out of the measurement cup.
  • shear e.g. stirring
  • the medium forms a gel- like state due to the polymeric thickening component and thus stabilizes the scattering particles during measurement.
  • the polymeric thickening component comprises a xanthan gum and/or modified forms thereof.
  • the polymeric thickening component is present in a concentration in the range of 0.2-0.3 wt %.
  • Xanthan gums are examples of such polymeric thickening components.
  • Xanthan gum is a polymeric sugar molecule that is easily soluble in both hot and could water, is highly resistant to enzymatic degradation and is soluble and stable in acidic, neutral and alkaline solutions. Furthermore, it imparts a high solution viscosity at already low polysaccharide concentrations and it works as an effective emulsion or suspension stabilizer. It is easily available and convenient for use in industrial applications.
  • the thickening component is dehydroxanthan gum.
  • Dehydroxanthan gum is a commercially available product with easy handling properties. Low stirring speeds already lead to significant thinning so little to no air bubbles are introduced due to vigorous rotation or shacking.
  • the optical coupling medium according to the invention comprises a scattering component selected from TiO 2 particles, hollow spheres and combinations thereof.
  • the scattering component comprises hollow spheres.
  • Hollow spheres are well suitable for the use as scatter particles. Their density is controllable and ideally constructed to equal that of the matching medium. This reduces the settling of the particles in the suspension. TiO 2 particles that have a density that is approximately 4 times that of the medium are prone to settling.
  • the Brownian motion of the particles is low compared to conventional scatterers such as TiO 2 .
  • they have high scattering properties that are less dependent on wavelength.
  • the scattering component comprises glass hollow spheres.
  • Glass hollow spheres can be filled with a gas, leading to high scattering properties.
  • concentration of the hollow spheres in the medium according to the invention preferably is in the range of 1.5-3 wt % and the size of the hollow spheres according to the invention is preferably between 1-25 microns
  • the scattering component of the medium according to the invention can comprise TiO 2 .
  • the concentration of these TiO 2 particles preferably is in the range of 0.5-2 g/1.
  • TiO 2 particles are scatter particles that are among the most highly effective scatterers known for visible light, without having significant absorbing characteristics. Furthermore, it is possible to control their size to be in the order of half a wavelength resulting in optimal scattering properties at an already low density compared to other scatter particles. An additional advantage of TiO 2 is that this compound has no toxic effects.
  • the optical coupling medium comprises a dye or a combination of dyes.
  • the dye or the selection of dyes is selected from the group having color index (CI): 74220; 74160; 74260; 61570; 75815; 10020; 77268; 75290; 77265; 77266.
  • a color index is a generally used reference number for dyes and pigments which allows identification of the product.
  • two or more dyes could be combined. It has been found that a combination of Sanolin green (CI 61570) and Cosmenyl Black (CI 77266) is particularly well suited, but other combinations are also possible.
  • the optical coupling medium further comprises an alcohol.
  • Addition of an alcohol such as ethanol during the preparation of the medium ensures complete wetting of the polymer thickener without swelling or dissolution.
  • the completely wetted powder is added to water while stirring and forms a homogeneous mixture easily without any lumping. Good reproducibility of the gel strength can be realized in this way.
  • An additional advantage of using an alcohol during the manufacturing process is provided by the disinfecting properties of alcohols.
  • the described advantages and improvements can also be achieved by the use of the optical matching medium according to the invention in a device for examining turbid media. Furthermore, the described advantages and improvements can be achieved by the use of the optical matching medium according to the invention in a device for medical image acquisition and in a device for diffuse optical tomography.
  • aspects of the invention relate to a method of imaging an interior of a turbid medium, comprising the steps of: providing a container comprising a coupling liquid, immersing the turbid medium into the coupling liquid, - at least partially gelatinizing the coupling liquid, illuminating the turbid medium through the at least partially gelatinized coupling liquid by an optical radiation, measuring a part of the optical radiation passing through the turbid medium and the at least partially gelatinized coupling liquid, and - constructing an image based on said measuring.
  • Another aspect of the invention relates to a system for imaging an interior of a turbid medium, comprising: a container arranged for receiving a coupling liquid, the coupling liquid in at least partial gelatinous state - an optical radiation source for irradiating the turbid medium through the coupling liquid, a detector for measuring at least a part of the radiation passing through the turbid medium and the at least partially gelatinized coupling liquid, and a control unit for constructing an image of the interior of the turbid medium on the basis of said measuring.
  • Figure 1 depicts a measurement cup with matching fluid and breast to be imaged.
  • Figure 2 shows the effect of addition of the separate scattering and absorbing components on the optical properties of the optical coupling medium.
  • Figure 3 shows the deviation between two identical optical measurements as a function of signal level.
  • Figure 4 shows reconstructed phantom measurements, using conventional optical coupling fluids in the left panel, and a coupling medium according to the invention in the right panel.
  • Figure 5 shows effects of stability in time on image quality with a conventional coupling fluid and a coupling medium according to the invention using a steel phantom.
  • Figure 6 depicts a system for imaging the interior of a turbid medium.
  • the term light is to be understood to mean electromagnetic radiation, particularly of a wavelength in the range of from 400 to 1400 nm, and more particularly in the range of 650 to 950 nm.
  • a turbid medium is to be understood as a substance consisting of a material having a high light scattering coefficient.
  • An example in this respect is human tissue e.g. a human breast.
  • optical properties cover the reduced scattering coefficient ⁇ ' s and the absorption coefficient ⁇ a .
  • matching optical properties is to be understood as having a similar reduced scattering coefficient ⁇ ' s and the absorption coefficient ⁇ a.
  • gelatinize is meant the process of turning into a gelatinous form which comprises an increase in viscosity.
  • product names and names of the suppliers used in the tables and examples might be subject to trademark rights and are not intended to be used in a generic way but only to define the specific products supplied by the named suppliers.
  • Diffuse optical tomography is a technique that is currently used for the detection of malignant masses in human tissue.
  • One of the challenges for optical mammography is to prevent light from finding a path from the light source to the detector without traveling through the tissue under investigation.
  • optical mammography it has been proven that the application of a so-called coupling fluid is beneficial.
  • a representative picture of a cup used in optical tomography of the female breast is shown in figure 1. The procedure involves that the breast 1 is put inside a container, being in this example a cup 2, that contains optics being a number of light sources 3 and detectors 4, and a fluid 5 is used to immerse the breast.
  • the fluid 5 has several tasks.
  • a serious problem with the immersion fluid based on TiO 2 particles suspended in water is that the particles settle and stick together. Settling of the scattering particles is the result of a difference in specific mass between the particles and the solvent, which is mostly water, and the settling rate is dependent on the viscosity of the solvent.
  • the settling effect can be diminished by an increase of the viscosity of the medium in which the particles are present. Viscosity increase can slow down the settling rate significantly and also reduces the Brownian motion.
  • a disadvantage of high viscosities is the handling of the liquid due to slowness of filling of the cup and, more over, by capture of air bubbles of various sizes which is detrimental to the optical properties of the fluid.
  • Polymer or particle gels can be formulated in such a way that they liquefy upon applying shear and restore to the gel situation after the shear has stopped. This transformation can be instant or can take some time and the process is generally indicated as thixotropy.
  • the transition of low- viscous liquids to gels can be achieved by but is not limited to chemical cross-linking, physical association of polymer chains, particles, or both. It may be preferable to have a low cross-linking density to get a flexible or fluffy gel to facilitate easy removal from the skin and the cup after the measurements. However, the trapping of the scatter particles in the polymeric grid has to be sufficient to reduce the movement and settling of the particles.
  • Xanthan gums impart a high solution viscosity at already low polysaccharide concentrations and work as an effective emulsion or suspension stabilizer. It was investigated at which dehydroxanthan gum concentration, a sufficient trapping of the scatter particles occurred. The drift over 5 minutes in measured values on a conventional optical tomography scanner is used as discriminator for this gel strength. The coupling fluid was poured into the cup directly after heating to 30 0 C to match the eventual measurement situation as much as possible. Results are shown in table 1.
  • optical coupling media stabilized with polymers that have shear thinning capacities can be kept in a storage tank with a stirrer from which the optical coupling medium can be pumped into the measurement cup. In the cup, no shear is applied so the optical coupling fluid is transformed into a gel- like state. This stabilizes the scatter particles during measurement.
  • Another way to avoid settling and motion of scatter particles is to adjust the density of these particles to equal that of the medium. This can for example be achieved by using hollow particles made of a material of larger density than the fluid, filled with air or any other lighter substance, in such a way that the total density is equal to that of the suspending medium.
  • the particles can be made large to reduce Brownian motion. In general, suspensions of large particles, typically larger than microns, show insufficient scattering to mimic the scattering behavior of biological tissue unless the volume fraction of particles is high. They can therefore not be used in as scatterers in coupling fluids.
  • hollow particles can be made highly scattering if they contain a gas, as gasses commonly have low refractive indexes compared to the particle's shell. Hollow spheres with a diameter in the range of 1-25 microns filled with a gas can now be used as scatter particles in the medium according to the present invention.
  • the inside of the particle may contain specific dyes or pigments which may otherwise by insolvable, toxic or otherwise not usable in conventional optical coupling media.
  • Latex particles or glass hollow particles are suitable candidates. These particles are larger as compared to the 250 nm TiO 2 particles and due tot their size have almost no Brownian motion. Also, the use of larger particles makes the scattering power less dependent on the wavelength of the light used, as is the case for (soft) biological tissue. Note that both scattering particles and liquid may have light absorbing characteristics, and may be tuned to the required value.
  • m n/n me d between the scatterers and the surrounding medium, n me d, which determines the scattering properties of the material as a whole. The higher the ratio, the better and in the case of hollow particles, the refractive index step inside the particle greatly enhances the scattering power of the particles.
  • Luxil glass hollow particles provide an example of suitable glass hollow spheres. These particles are 9-13 microns in size and are commonly used in cosmetics. The fact that these particles are hollow glass spheres explains both their special scattering properties and specific mass being close to that of water (between 0.1 and 1.5 g/cm 3 ). Ideally, both shear thinning gels and hollow spheres are combined to create a stable optical coupling medium with sufficient scattering properties.
  • An embodiment of an optical coupling medium according to the invention is a gel-like medium comprising hollow particles with a specific density close to that of the medium. This medium results in measurement fluctuations that are of a similar magnitude as the fluctuations measured on a solid. Equal density of the particles and gel results in absence of or major decrease in settling of the scattering particles. The viscosity of the gel was such that it was still very easy to handle. The particles used in the experiment where typically 10 microns in diameter, and hence their Brownian motion was much smaller than for TiO 2 particles.
  • FIG. 1 shows the effect of addition of the separate scattering and absorbing components on the optical properties of the optical coupling medium.
  • Stars indicate the optical properties of the average breast tissue at the indicated wave lengths. It can be appreciated that the addition of both Cosmenyl black (CI 77266) and Sanolin Greeen (CI 61570) leads to optical characteristics that match the optical characteristics of the average breast.
  • Table 2 shows the addition of both Cosmenyl black (CI 77266) and Sanolin Greeen (CI 61570) leads to optical characteristics that match the optical characteristics of the average breast.
  • Table 2 Preferred composition of an optical coupling medium comprising a polymeric thickening agent and glass hollow spheres.
  • optical properties of the optical coupling medium match the optical characteristics of the turbid medium to be examined. These optical characteristics are determined for a coupling medium with dehydroxanthan gum and hollow spheres according to table 2.
  • the measured values of the attenuation coefficient K and the calculated values of ⁇ s ' and ⁇ a are compared with the average breast values and the spec ranges in table 3. As can be appreciated, the characteristics are comparable to that of average breast tissue.
  • Table 3 The optical properties at 4 wave lengths of the optical coupling medium according to example 3 compared with the average breast values and specification ranges.
  • FIG. 3 shows the deviations for a conventional mammoscope system whose cup is filled with a conventional fluid coupling medium with TiO 2 scatter particles, a coupling medium with composition as shown in table 2 or Delrin.
  • Delrin is a solid diffuse medium mimicking the perfect fluid; a fluid that does not change over time.
  • the deviations that occur between two Delrin measurements are thus related to changes in the system, not in the fluid.
  • the time interval between two measurements, 15 minutes, is chosen because it is a time interval that is typically expected between a reference and a breast measurement in optical mammography.
  • deviations between two Delrin measurements are significantly lower than deviations between two measurements with fluid- filled cups.
  • the performance of the system is thus limited by the fluid.
  • the deviations of the measurements with a coupling medium according to the present invention are approximately five times lower than the deviations measured between two measurements with conventional coupling fluids comprising TiO 2 .
  • the optical coupling medium according to table 2 and a conventional optical coupling fluid with TiO 2 as scatter particles were used to perform two measurements and the resulting reconstructed images are shown in figure 4.
  • the measurements were performed on a 4 mm diameter steel ball phantom.
  • the left frame shows an image obtained from a measurement using a conventional optical coupling fluid with TiO 2 as scatter particles.
  • the right frame shows the result of a similar measurement, but the conventional coupling fluid is replaced with an optical coupling medium according to the invention.
  • increased scatter particle stability due to the coupling medium according to the invention leads to improved reconstructed images.
  • the distribution of the scatter particles in a non-stabilized fluid will become inhomogeneous du e to settling and Brownian motion.
  • a method for imaging an interior of a turbid medium starts with the filling of a container according to figure 1 with a coupling medium, step 1.
  • the turbid medium for example a female breast, is immersed in the coupling medium, step 2. It is also possible to first put the turbid medium into the container and then fill the remaining space with the coupling medium. In step 3, when no shear is applied, the coupling medium is at least partially gelatinized to a gel-like state, thus stabilizing the scatter particles.
  • the turbid medium is then illuminated in step 4 and the optical radiation that has passed through the turbid medium is measured in step 5. Based on the measured intensities and image of the interior of the turbid medium is constructed in step 6.
  • Figure 6 schematically shows a system for imaging an interior of a turbid medium. It comprises a container 11 arranged for receiving a coupling liquid 12. This coupling medium can for example be pumped into the container. In order to stabilize the scatter particles, the coupling liquid has to be in an at least partial gelatinous state.
  • the system further comprises an optical radiation source 13 for irradiating the turbid medium through the coupling liquid. The radiation is then received by a detector 14 for measuring at least a part of the radiation passing through the turbid medium and the at least partially gelatinized coupling liquid.
  • the system comprises a control unit 15 for constructing an image of the interior of the turbid medium on the basis of said measuring.
  • Preparing the coupling medium (amounts for 10 kg batches): calculate the exact amounts needed for each ingredient (depends on dilutions) weigh 9449.85 g of water in the mixing tank (20 1 volume) weigh 200.0 g of water in a separate bottle place the impellor of the dissolver at 1 A of diameter of the mixing tank - weigh 25.0O g of Dehydroxanthan gum and 50.0 g of ethanol prepare a slurry of Dehydroxanthan gum and ethanol with about half the amount of ethanol switch on the dissolver (low speed) add the Dehydroxanthan gum slurry in ethanol to the water quickly - use the remaining part of ethanol to flush all Dehydroxanthan gum into the water cover the vessel with alu foil (keep covered as much as possible) allow the gel to develop strength for about 1 hour while stirring (increase the stirring speed from time to time as the viscosity increases) - weigh 250.00 g of glass hollow spheres and add to the gel reduce the sirring speed (visco
  • the bottles with matching fluid are preferably stored in a cool dark place.

Abstract

The present invention relates to an optical coupling medium that can be used in diffuse optical tomography. By using polymeric thickening components to stabilize the medium and preferably hollow spheres as scattering components, the quality of the optical images is enhanced.

Description

Optical coupling medium
FIELD OF THE INVENTION
The invention relates to an optical coupling medium for coupling optical energy from a light source to a turbid medium, comprising a scattering component and an absorbing component, and use of the optical coupling medium. Moreover, the invention relates to a system and a method for imaging a turbid medium.
Background of the invention
Several methods and devices for examining turbid media, particularly being biological tissue, have been developed. More specific, new devices for the detection of inhomogeneities in these tissues by using light sources have been developed and improved. Examples are optical mammoscopes that use light to detect malignant growth in breast tissue. Detection of such malignancies by using light has the advantage that the object under examination is not exposed to X-ray or other ionizing radiation.
Generally, such an optical examining device includes an optical energy source, a photo detector and a control unit to reconstruct the interior of the turbid medium on the basis of the measured intensities. Furthermore, a holder may be provided with an optical coupling fluid. This fluid serves to provide optical coupling the between the turbid media to be imaged and a fiber coupling to the light source and detectors respectively. The optical coupling fluid should further serve to prevent optical short circuits, being light finding a path from the light source to said detector without traveling though the turbid medium under investigation. It furthermore may function as a reference medium for calibration, eliminates boundary effects due to both holder and turbid medium and provides an optical contact between optodes and breast. In order to achieve these objectives, the optical properties of said fluid must closely match the turbid medium to be examined. Conventional coupling media are provided as an aqueous fluid that is supplemented with scattering and absorbing components. Such a fluid and use thereof is disclosed in patent application WO 00/56206. Commonly used scatter components comprise TiO2 particles. Absorbing characteristics of an optical coupling fluid can be adjusted by adding dyes with specific optical absorption properties. Quality and resolution of the obtained images are strongly dependent on the homogeneity and optical properties of the coupling medium. Air gaps, bubbles or inhomogeneities in the coupling medium result in artifacts which may strongly hamper the measurement.
SUMMARY OF THE INVENTION
Particular and preferred aspects of the invention are set out in the accompanying independent and dependent claims. Features from the dependent claims may be combined with features of the independent claims and with features of other dependent claims as appropriate and not merely as explicitly set out in the claims.
It is an object of the present invention to provide an optical coupling medium which enhances image resolution.
According to the invention, this object is realized by an optical coupling medium comprising a scattering component, an absorbing component and a polymeric thickening component. Without wishing to be bound by any theory, the invention is based on the recognition that stabilization of the scattering particles enhances the quality of the obtained images. Theoretically, scatter particles will not be subject to settling and movement in solid coupling media. However, solid coupling media are not suitable for use in optical measurements as direct coupling between a light source and the turbid medium to be examined is essential. As it can easily be appreciated, the dimensions of biological turbid media are not constant and air gaps and free spaces will occur in the holder cup when a solid coupling medium is used.
The addition of a polymeric thickening component to a liquid optical coupling medium results in an at least partial gelation of the medium. In a gel, scatter particles can be homogeneously distributed and more importantly, settling and motion of the scatter particles is severely reduced. This consequently reduces the noise in the measurement and the resolution of the obtained images is improved. This clearly is beneficial in the use of this imaging technique for diagnostic purposes as better resolution facilitates earlier detection of e.g. malignant tumors. Examples of polymer thickeners are known in the art and several of these polymers are well tolerated by biological tissue and are easy to obtain. An optical coupling medium that can be easily handled, and that additionally stabilizes the scatter particles during measurement is therefore advantageous.
According to a preferred embodiment of the optical coupling medium the optical coupling medium liquefies upon the application of shear. This shear can be generated by a mechanical treatment of the coupling medium, such as stirring or shaking. It may be favorable if the coupling medium reversibly liquefies.
There are polymeric thickeners known in the art that when dissolved thicken a liquid to a gel- like state, but when shear is applied, this gel-like state is transformed to a liquefied or more liquefied state. This can be referred to as shear-thinning. Shear thinning is a principle that is ideal for use in the conventional diffuse optical tomography devices, as shear, e.g. stirring, facilitates liquefaction of the composition so it can be easily pumped into or out of the measurement cup. When no shear force is applied, the medium forms a gel- like state due to the polymeric thickening component and thus stabilizes the scattering particles during measurement.
In another preferred embodiment the polymeric thickening component comprises a xanthan gum and/or modified forms thereof. Preferably, the polymeric thickening component is present in a concentration in the range of 0.2-0.3 wt %. Xanthan gums are examples of such polymeric thickening components. Xanthan gum is a polymeric sugar molecule that is easily soluble in both hot and could water, is highly resistant to enzymatic degradation and is soluble and stable in acidic, neutral and alkaline solutions. Furthermore, it imparts a high solution viscosity at already low polysaccharide concentrations and it works as an effective emulsion or suspension stabilizer. It is easily available and convenient for use in industrial applications. According to another preferred embodiment the thickening component is dehydroxanthan gum. Dehydroxanthan gum is a commercially available product with easy handling properties. Low stirring speeds already lead to significant thinning so little to no air bubbles are introduced due to vigorous rotation or shacking.
The optical coupling medium according to the invention comprises a scattering component selected from TiO2 particles, hollow spheres and combinations thereof. Preferably, the scattering component comprises hollow spheres. Hollow spheres are well suitable for the use as scatter particles. Their density is controllable and ideally constructed to equal that of the matching medium. This reduces the settling of the particles in the suspension. TiO2 particles that have a density that is approximately 4 times that of the medium are prone to settling. Furthermore, due to the size of the hollow spheres, being in the micron range, the Brownian motion of the particles is low compared to conventional scatterers such as TiO2. Furthermore, especially when filled with a gas, they have high scattering properties that are less dependent on wavelength. More preferably, the scattering component comprises glass hollow spheres. Glass hollow spheres can be filled with a gas, leading to high scattering properties. The concentration of the hollow spheres in the medium according to the invention preferably is in the range of 1.5-3 wt % and the size of the hollow spheres according to the invention is preferably between 1-25 microns
The scattering component of the medium according to the invention can comprise TiO2. The concentration of these TiO2 particles preferably is in the range of 0.5-2 g/1. TiO2 particles are scatter particles that are among the most highly effective scatterers known for visible light, without having significant absorbing characteristics. Furthermore, it is possible to control their size to be in the order of half a wavelength resulting in optimal scattering properties at an already low density compared to other scatter particles. An additional advantage of TiO2 is that this compound has no toxic effects.
According to another embodiment, the optical coupling medium comprises a dye or a combination of dyes. Preferably, the dye or the selection of dyes is selected from the group having color index (CI): 74220; 74160; 74260; 61570; 75815; 10020; 77268; 75290; 77265; 77266. A color index is a generally used reference number for dyes and pigments which allows identification of the product. Preferably, in order to achieve matching of the optical characteristics of the coupling medium and the turbid medium, two or more dyes could be combined. It has been found that a combination of Sanolin green (CI 61570) and Cosmenyl Black (CI 77266) is particularly well suited, but other combinations are also possible.
According to another embodiment, the optical coupling medium further comprises an alcohol. Addition of an alcohol such as ethanol during the preparation of the medium ensures complete wetting of the polymer thickener without swelling or dissolution. The completely wetted powder is added to water while stirring and forms a homogeneous mixture easily without any lumping. Good reproducibility of the gel strength can be realized in this way. An additional advantage of using an alcohol during the manufacturing process is provided by the disinfecting properties of alcohols.
The described advantages and improvements can also be achieved by the use of the optical matching medium according to the invention in a device for examining turbid media. Furthermore, the described advantages and improvements can be achieved by the use of the optical matching medium according to the invention in a device for medical image acquisition and in a device for diffuse optical tomography. Other aspects of the invention relate to a method of imaging an interior of a turbid medium, comprising the steps of: providing a container comprising a coupling liquid, immersing the turbid medium into the coupling liquid, - at least partially gelatinizing the coupling liquid, illuminating the turbid medium through the at least partially gelatinized coupling liquid by an optical radiation, measuring a part of the optical radiation passing through the turbid medium and the at least partially gelatinized coupling liquid, and - constructing an image based on said measuring.
Another aspect of the invention relates to a system for imaging an interior of a turbid medium, comprising: a container arranged for receiving a coupling liquid, the coupling liquid in at least partial gelatinous state - an optical radiation source for irradiating the turbid medium through the coupling liquid, a detector for measuring at least a part of the radiation passing through the turbid medium and the at least partially gelatinized coupling liquid, and a control unit for constructing an image of the interior of the turbid medium on the basis of said measuring.
It is noted that all possible combinations of features and measures mentioned in the claims are part of the invention.
These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts a measurement cup with matching fluid and breast to be imaged.
Figure 2 shows the effect of addition of the separate scattering and absorbing components on the optical properties of the optical coupling medium.
Figure 3 shows the deviation between two identical optical measurements as a function of signal level. Figure 4 shows reconstructed phantom measurements, using conventional optical coupling fluids in the left panel, and a coupling medium according to the invention in the right panel.
Figure 5 shows effects of stability in time on image quality with a conventional coupling fluid and a coupling medium according to the invention using a steel phantom.
Figure 6 depicts a system for imaging the interior of a turbid medium.
DETAILED DESCRIPTION OF THE EMBODIMENTS In the context of the present application the term light is to be understood to mean electromagnetic radiation, particularly of a wavelength in the range of from 400 to 1400 nm, and more particularly in the range of 650 to 950 nm. Furthermore, a turbid medium is to be understood as a substance consisting of a material having a high light scattering coefficient. An example in this respect is human tissue e.g. a human breast. Furthermore, optical properties cover the reduced scattering coefficient μ's and the absorption coefficient μa. Furthermore, matching optical properties is to be understood as having a similar reduced scattering coefficient μ's and the absorption coefficient μa.
With the term gelatinize is meant the process of turning into a gelatinous form which comprises an increase in viscosity. It should further be noted that product names and names of the suppliers used in the tables and examples might be subject to trademark rights and are not intended to be used in a generic way but only to define the specific products supplied by the named suppliers.
The invention will be illustrated with reference to the following, non-limiting examples and non-limiting figures.
Diffuse optical tomography is a technique that is currently used for the detection of malignant masses in human tissue. One of the challenges for optical mammography is to prevent light from finding a path from the light source to the detector without traveling through the tissue under investigation. In optical mammography it has been proven that the application of a so-called coupling fluid is beneficial. A representative picture of a cup used in optical tomography of the female breast is shown in figure 1. The procedure involves that the breast 1 is put inside a container, being in this example a cup 2, that contains optics being a number of light sources 3 and detectors 4, and a fluid 5 is used to immerse the breast. The fluid 5 has several tasks. It should prevent optical short circuits, eliminate the boundary effect due to both container and breast and provide stable optical contact between optodes and breast. Furthermore it could function as a homogeneous reference medium for calibration. All of the above mentioned objectives are equally important, and in order to achieve these objectives, the optical properties of tissue and fluid, i.e. scattering, absorption and refractive index, must be equal, or at least very similar. The matching optical properties are reached by the addition of scattering components such as TiO2 and absorbing components such as dyes to an aqueous medium. The scattering particles should form a stable scattering/absorption medium. It needs to be the same in the calibration measurement and therefore the pattern should be statistically homogeneous due to either very slow or very fast moving particles as compared to the time required to do the measurement.
A serious problem with the immersion fluid based on TiO2 particles suspended in water is that the particles settle and stick together. Settling of the scattering particles is the result of a difference in specific mass between the particles and the solvent, which is mostly water, and the settling rate is dependent on the viscosity of the solvent.
The settling effect can be diminished by an increase of the viscosity of the medium in which the particles are present. Viscosity increase can slow down the settling rate significantly and also reduces the Brownian motion. A disadvantage of high viscosities is the handling of the liquid due to slowness of filling of the cup and, more over, by capture of air bubbles of various sizes which is detrimental to the optical properties of the fluid.
It would be advantageous to have an optical coupling medium that has stabilizing properties that will be achieved by increasing the viscosity, but at the same time is easy to handle. This means that the introduction of air bubbles by putting the coupling medium into the cup is limited to small numbers or even absent, and that both filling and emptying of the measurement cup is an easy and fast process.
Polymer or particle gels can be formulated in such a way that they liquefy upon applying shear and restore to the gel situation after the shear has stopped. This transformation can be instant or can take some time and the process is generally indicated as thixotropy. The transition of low- viscous liquids to gels can be achieved by but is not limited to chemical cross-linking, physical association of polymer chains, particles, or both. It may be preferable to have a low cross-linking density to get a flexible or fluffy gel to facilitate easy removal from the skin and the cup after the measurements. However, the trapping of the scatter particles in the polymeric grid has to be sufficient to reduce the movement and settling of the particles. Xanthan gums impart a high solution viscosity at already low polysaccharide concentrations and work as an effective emulsion or suspension stabilizer. It was investigated at which dehydroxanthan gum concentration, a sufficient trapping of the scatter particles occurred. The drift over 5 minutes in measured values on a conventional optical tomography scanner is used as discriminator for this gel strength. The coupling fluid was poured into the cup directly after heating to 30 0C to match the eventual measurement situation as much as possible. Results are shown in table 1.
Table 1: Signal drift in the Boreas scanner with matching fluids of various strengths
Dehydroxanthan gum Drift (%) cone (%wt)
0.30 < 0.1
0.25 < 0.1
0.20 ~ 0.2
0.15 ~ 1
These results indicate that 0.25 % wt dehydroxanthan gum concentration is a suitable concentration to stabilize the scatter particles. In general, optical coupling media stabilized with polymers that have shear thinning capacities can be kept in a storage tank with a stirrer from which the optical coupling medium can be pumped into the measurement cup. In the cup, no shear is applied so the optical coupling fluid is transformed into a gel- like state. This stabilizes the scatter particles during measurement.
Another way to avoid settling and motion of scatter particles is to adjust the density of these particles to equal that of the medium. This can for example be achieved by using hollow particles made of a material of larger density than the fluid, filled with air or any other lighter substance, in such a way that the total density is equal to that of the suspending medium. There are three additional insights regarding this approach. The particles can be made large to reduce Brownian motion. In general, suspensions of large particles, typically larger than microns, show insufficient scattering to mimic the scattering behavior of biological tissue unless the volume fraction of particles is high. They can therefore not be used in as scatterers in coupling fluids. However, hollow particles can be made highly scattering if they contain a gas, as gasses commonly have low refractive indexes compared to the particle's shell. Hollow spheres with a diameter in the range of 1-25 microns filled with a gas can now be used as scatter particles in the medium according to the present invention. Furthermore, the inside of the particle may contain specific dyes or pigments which may otherwise by insolvable, toxic or otherwise not usable in conventional optical coupling media.
Latex particles or glass hollow particles are suitable candidates. These particles are larger as compared to the 250 nm TiO2 particles and due tot their size have almost no Brownian motion. Also, the use of larger particles makes the scattering power less dependent on the wavelength of the light used, as is the case for (soft) biological tissue. Note that both scattering particles and liquid may have light absorbing characteristics, and may be tuned to the required value. Next to the appropriate particle size, it is the so-called contrast of refractive index m = n/nmed between the scatterers and the surrounding medium, nmed, which determines the scattering properties of the material as a whole. The higher the ratio, the better and in the case of hollow particles, the refractive index step inside the particle greatly enhances the scattering power of the particles.
Luxil glass hollow particles provide an example of suitable glass hollow spheres. These particles are 9-13 microns in size and are commonly used in cosmetics. The fact that these particles are hollow glass spheres explains both their special scattering properties and specific mass being close to that of water (between 0.1 and 1.5 g/cm3). Ideally, both shear thinning gels and hollow spheres are combined to create a stable optical coupling medium with sufficient scattering properties.
An embodiment of an optical coupling medium according to the invention is a gel-like medium comprising hollow particles with a specific density close to that of the medium. This medium results in measurement fluctuations that are of a similar magnitude as the fluctuations measured on a solid. Equal density of the particles and gel results in absence of or major decrease in settling of the scattering particles. The viscosity of the gel was such that it was still very easy to handle. The particles used in the experiment where typically 10 microns in diameter, and hence their Brownian motion was much smaller than for TiO2 particles.
In order to fulfill the required optical matching of the medium with the turbid medium, in this case being human tissue, not only the scatter particles are relevant. A suitable dye or combination of dyes is added to the medium to adjust the absorbing properties as well. Figure 2 shows the effect of addition of the separate scattering and absorbing components on the optical properties of the optical coupling medium. Stars indicate the optical properties of the average breast tissue at the indicated wave lengths. It can be appreciated that the addition of both Cosmenyl black (CI 77266) and Sanolin Greeen (CI 61570) leads to optical characteristics that match the optical characteristics of the average breast. A preferred example of a composition of an optical coupling medium according to the invention is shown in table 2.
Table 2: Preferred composition of an optical coupling medium comprising a polymeric thickening agent and glass hollow spheres.
Product Dosage
Dehydroxanthan gum 0.25 %wt
Glass hollow spheres 2.5 %wt
Cl 61570 3.23 mg/kg
Cl 77266 0.9 mg/kg
Ethanol 0.6 %wt
As already mentioned it is essential that the optical properties of the optical coupling medium match the optical characteristics of the turbid medium to be examined. These optical characteristics are determined for a coupling medium with dehydroxanthan gum and hollow spheres according to table 2. The measured values of the attenuation coefficient K and the calculated values of μs' and μa are compared with the average breast values and the spec ranges in table 3. As can be appreciated, the characteristics are comparable to that of average breast tissue.
Table 3: The optical properties at 4 wave lengths of the optical coupling medium according to example 3 compared with the average breast values and specification ranges.
Figure imgf000011_0001
An indication for the stability of the optical matching medium is the deviation between two identical measurements. In a perfect world this deviation is zero. In reality, fluctuations in the system make the deviation finite. Figure 3 shows the deviations for a conventional mammoscope system whose cup is filled with a conventional fluid coupling medium with TiO2 scatter particles, a coupling medium with composition as shown in table 2 or Delrin. Delrin is a solid diffuse medium mimicking the perfect fluid; a fluid that does not change over time. The deviations that occur between two Delrin measurements are thus related to changes in the system, not in the fluid. The time interval between two measurements, 15 minutes, is chosen because it is a time interval that is typically expected between a reference and a breast measurement in optical mammography. As can be seen in Figure 3, deviations between two Delrin measurements are significantly lower than deviations between two measurements with fluid- filled cups. The performance of the system is thus limited by the fluid. The deviations of the measurements with a coupling medium according to the present invention are approximately five times lower than the deviations measured between two measurements with conventional coupling fluids comprising TiO2.
The optical coupling medium according to table 2 and a conventional optical coupling fluid with TiO2 as scatter particles were used to perform two measurements and the resulting reconstructed images are shown in figure 4. The measurements were performed on a 4 mm diameter steel ball phantom. The left frame shows an image obtained from a measurement using a conventional optical coupling fluid with TiO2 as scatter particles. The right frame shows the result of a similar measurement, but the conventional coupling fluid is replaced with an optical coupling medium according to the invention. As is clear from figure 4, increased scatter particle stability due to the coupling medium according to the invention leads to improved reconstructed images. The distribution of the scatter particles in a non-stabilized fluid will become inhomogeneous du e to settling and Brownian motion. This will result in degradation of the measurements and image quality over time. The results of a study on degradation of image quality in time with both a conventional coupling fluid with TiO2 particles (MF v2.1) and an optical coupling medium according to table 2 (MF 4.0) are shown in figure 5. Upper panels indicate measurements with a conventional optical coupling medium and lower panels indicated measurements with an optical coupling medium according to the invention. With MF v2.1 the image quality is gradually decreasing, while with MF v4.0 no changes occur over a period of 60 min.
A method for imaging an interior of a turbid medium starts with the filling of a container according to figure 1 with a coupling medium, step 1. The turbid medium, for example a female breast, is immersed in the coupling medium, step 2. It is also possible to first put the turbid medium into the container and then fill the remaining space with the coupling medium. In step 3, when no shear is applied, the coupling medium is at least partially gelatinized to a gel-like state, thus stabilizing the scatter particles. The turbid medium is then illuminated in step 4 and the optical radiation that has passed through the turbid medium is measured in step 5. Based on the measured intensities and image of the interior of the turbid medium is constructed in step 6.
Figure 6 schematically shows a system for imaging an interior of a turbid medium. It comprises a container 11 arranged for receiving a coupling liquid 12. This coupling medium can for example be pumped into the container. In order to stabilize the scatter particles, the coupling liquid has to be in an at least partial gelatinous state. The system further comprises an optical radiation source 13 for irradiating the turbid medium through the coupling liquid. The radiation is then received by a detector 14 for measuring at least a part of the radiation passing through the turbid medium and the at least partially gelatinized coupling liquid. Furthermore, the system comprises a control unit 15 for constructing an image of the interior of the turbid medium on the basis of said measuring. It is to be understood that although preferred embodiments, specific compositions and materials have been discussed herein for optical coupling medium according to the present invention, various changes, modifications or combinations in form and detail may be made without departing from the scope and spirit of the invention.
EXAMPLE
Preparation and synthesis of an optical coupling medium comprising xanthan gum and glass hollow spheres.
Preparations: heat glass hollow spheres at 130 0C overnight @ < 100 mbar overnight (the reduced pressure assist in avoiding clumping of the particles) - dissolve CI 61570 in 60 %wt ethanol in water to about 2 mg/g dilute CI 77266 in water to about 1 mg/g use sterilized demi water
(filtered over Millipore Steripak GP M20RJ filter - 0.2 μm) use Ph. Eur. grade ethanol for biocompatibility reasons - flush all equipment and bottles with 70 %wt ethanol and allow to dry just before use
Preparing the coupling medium (amounts for 10 kg batches): calculate the exact amounts needed for each ingredient (depends on dilutions) weigh 9449.85 g of water in the mixing tank (20 1 volume) weigh 200.0 g of water in a separate bottle place the impellor of the dissolver at 1A of diameter of the mixing tank - weigh 25.0O g of Dehydroxanthan gum and 50.0 g of ethanol prepare a slurry of Dehydroxanthan gum and ethanol with about half the amount of ethanol switch on the dissolver (low speed) add the Dehydroxanthan gum slurry in ethanol to the water quickly - use the remaining part of ethanol to flush all Dehydroxanthan gum into the water cover the vessel with alu foil (keep covered as much as possible) allow the gel to develop strength for about 1 hour while stirring (increase the stirring speed from time to time as the viscosity increases) - weigh 250.00 g of glass hollow spheres and add to the gel reduce the sirring speed (viscosity decreases) weight 16.150 g of 2.000 mg/g CI 61570 solution and add to the gel weight 9.000 g of 1.000 mg/g CI 77266 solution and add to the gel (use the 200 g of water to flush all solutions into the gel) - continue stirring for about 15 minutes transfer the matching fluid to a 10 1 bottle store overnight on a slowly rotating rollerbench to allow escape of air bubbles
Storage: The bottles with matching fluid are preferably stored in a cool dark place.
Preparation before use:
Place the bottle on a rollerbench overnight to assure good homogeneity.
It is to be understood that the invention is not limited to the embodiments as described hereinbefore. It is also to be understood that in the claims the word "comprising" does not exclude other elements or steps.

Claims

CLAIMS:
1. An optical coupling medium for coupling optical energy from a light source to a turbid medium, comprising a scattering component, an absorbing component and a polymeric thickening component.
2. An optical coupling medium according to claim 1, which liquefies upon applying shear.
3. An optical coupling medium according to claim 1, which reversibly liquefies upon applying shear.
4. An optical coupling medium according to any one of claims 1 to 3, wherein the polymeric thickening component comprises a xanthan gum and/or modified forms thereof.
5. An optical coupling medium according to claim 4, wherein the polymeric thickening component is dehydroxanthan gum.
6. An optical coupling medium according to claim 1, wherein the concentration of the polymeric thickening component is in the range of 0.2-0.3 wt %.
7. An optical coupling medium according to any one of the claims 1 to 6, wherein the scattering component comprises TiO2 particles or hollow spheres or a combination thereof.
8. An optical coupling medium according any one of the claims 1 to 6, wherein the scattering component is hollow spheres and the concentration is in the range of 1.5-3 wt %.
9. An optical coupling medium according any one of the claims 1 to 8, wherein the absorbing component comprises a dye or a combination of dyes.
10. An optical coupling medium according to claim 9, wherein the dye or the
5 selection of dyes is selected from the group having color index (CI): 74220; 74160; 74260; 61570; 75815; 10020; 77268; 75290; 77265; 77266.
11. An optical coupling medium according to any one of claims 1 to 10, which further comprises an alcohol.
10
12. Use of an optical coupling medium according to any one of claims 1 to 11 in a device for examining turbid media.
13. Use of a coupling medium according to any one of claims 1 to 11 in a device 15 for medical image acquisition.
14. Use of a coupling medium according to any one of claims 1 to 11 for diffuse optical tomography.
20 15. A method of imaging an interior of a turbid medium, comprising the steps of: providing a container comprising a coupling liquid, immersing the turbid medium into the coupling liquid, at least partially gelatinizing the coupling liquid, illuminating the turbid medium through the at least partially gelatinized
25 coupling liquid by an optical radiation, measuring a part of the optical radiation passing through the turbid medium and the at least partially gelatinized coupling liquid, and constructing an image based on said measuring.
30 16. A system for imaging an interior of a turbid medium, comprising: a container arranged for receiving a coupling liquid (11), the coupling liquid in at least partial gelatinous state (12) an optical radiation source for irradiating the turbid medium through the coupling liquid (13), a detector for measuring at least a part of the radiation passing through the turbid medium and the at least partially gelatinized coupling liquid (14), and a control unit for constructing an image of the interior of the turbid medium on the basis of said measuring (15).
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