• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    PROCESS FOR THE CHARACTERIZATION OF TRANSPARENT OBJECTS IN A TRANSPARENT MEDIUM AND COMPUTER PROGRAM The present invention relates to a process for the characterization of transparent objects (2, 3) in a transparent medium (1), presenting said transparent objects (2, 3) ) an optical focal area (5, 6), said process comprising the steps of: - illuminating a sample comprising the objects (2, 3) to be characterized by means of a directional light source (7), thereby inducing peaks of light intensity (5,6) in the focal area of said transparent objects; - determining at least one characteristic of the light intensity peak (5,6) induced by said object to be characterized, determining, from said light intensity peak (5,6), at least one property of said object.
    公开号:BR112013010262B1
    申请号:R112013010262-4
    申请日:2011-11-09
    公开日:2022-01-25
    发明作者:Frank Dubois；Catherine Yourassowsky
    申请人:Universite Libre De Bruxelles；
    IPC主号:
    专利说明:

    Domain of invention
    [0001] The object of the present invention is an optical process for the characterization of particles. State of the art
    [0002] Counting small transparent particles in a transparent medium is a well-known problem in many technical fields. It may refer to counting the number of particles of a dispersed phase in scientific material, counting the number of cells in a biological culture, counting the number of micelles in a latex in chemistry or polymer synthesis.
    [0003] The first attempt to solve this problem is to use transparent standard grids (grids), followed by manually counting, in a microscope image, the number of particles in each square defined by the grid. These manual counting processes suffer from several disadvantages. First of all, they are highly time-consuming, have poor statistical validity for small numbers, and typically have limited reliability.
    [0004] Therefore, image analysis is sometimes used to automate this counting. In these processes, microscope images are normally transformed by standard processes such as threshold level use, segmentation, dilation and erosion transformation, threshold detection. The individual particles are then counted using more or less complex algorithms. These automated processes typically have several disadvantages. For example, if the image obtained has a limited contrast or if there are particles that overlap, the algorithms may not accurately separate the different particles and the count has poor reliability.
    [0005] Other known methods for counting particles flowing in a liquid rely on shading or light scattering effects. Such processes, widely used, for example, in the pharmaceutical field, also have several disadvantages. The first of all is the fact that normally it is not possible to discriminate between bubbles and solid particles. This is particularly critical when evaluating the cleanliness or purity of physiological buffered solutions containing a large amount of dissolved CO2, which disrupts the measurement. In this type of measurement, there is no information about the nature of the particles that can be extracted from the results. Objectives of the invention
    [0006] The present invention aims to provide a process for characterizing and/or counting transparent spheroid particles, in a transparent medium, which does not have the disadvantages of the prior art.
    [0007] The advantages of the present invention will be evident from the description that follows. Summary of the Invention
    [0008] The object of the present invention is a process for the characterization of at least one property of transparent objects that have a focal area (point of focus), said object being in a transparent medium, said process comprising the steps of: - illumination of a sample comprising the objects to be characterized by means of a directional light source, thereby inducing light intensity peaks in the focal area of said transparent objects, - determination of at least one characteristic of the light intensity peaks, - determination, from there, of at least one characteristic of the light intensity peaks and therefore of at least one property of said objects.
    [0009] By transparent object, which has a focal area (point of focus), it is understood, in this document, an object capable of concentrating light in that focal area when it is illuminated by a directional light source, forming the concentrated light a peak of light intensity. In the present invention, said light intensity peaks are induced directly by the interaction between the object and directional light, irrespective of the apparatus producing the image (i.e., the light peaks exist even when they are not being observed).
    [0010] According to particular preferred embodiments, the process of the present invention comprises one or an appropriate combination of at least two of the following characteristics: - the process further comprises the step of: a. recording a holographic representation of the illuminated sample; B. reconstructing, from said holographic representation, a three-dimensional representation of the intensity of the light field induced by said sample; ç. screening the three-dimensional representation of the light field strength to determine the area of light peaks having an intensity greater than a predetermined threshold, each of said light peaks corresponding to a particle; - at least one characteristic of the objects comprises the number of said objects, the characteristic of the light intensity peaks comprising the number of peaks; - objects are selected from the group consisting of gas bubbles, vesicles of liquid in an emulsion, solid beads, live cells, dead cells and their mixtures; - objects are selected in the group consisting of live cells, dead cells and their mixtures; - at least one of said peak characteristics comprises at least one peak characteristic selected from the group consisting of distance between the light peak and the corresponding object, light peak area and light peak intensity; - the peak characteristic is used to classify said objects into at least two subsets of objects; - a subset of objects corresponds to live cells and a second subset of objects corresponds to dead cells; - the characterization process takes place dynamically in successive holographic representations; - the transparent medium consists of a flowing liquid that transports the objects; - the holographic representation is obtained by means of a holographic microscope; - the microscope is used according to a differential mode; - the microscope is used in dark field mode; - the light source is partially coherent; - the microscope is used off-axis.
    [0011] Another aspect of the present invention relates to a computer program that implements the process of the present invention or a preferred embodiment of the present invention. Brief description of drawings
    [0012] Fig. 1 schematically represents the basic principles of the present invention.
    [0013] Fig. 2 schematically represents the measurement of contact angles using a process according to the present invention.
    [0014] Fig. 3 schematically represents the digital holographic microscope used to generate the data of the examples.
    [0015] Fig. 4a represents an “in focus” intensity image of live cells.
    [0016] Fig. 4b represents the focal areas of the transparent cells of figure 4-a that concentrate the illuminating light rays, which form the light intensity peaks.
    [0017] Fig. 5 represents a histogram of the number of peaks as a function of the dimensions of the peaks (areas) of a cell culture, before and after heat treatments that induce cell death. Numbers key 1: Transparent medium 2, 3: Transparent spheroid objects 4: Transparent sample vessel walls 5, 6: Focal areas of the transparent objects (2,3) which concentrate the illuminating light rays (7), which form the peaks of light intensity 7: Illumination light rays 8: Flux direction of the transparent medium Detailed description of the invention
    [0018] The object of the present invention is analytical processes that use an optical characteristic common to many transparent objects when they are illuminated by light. This common feature consists in the fact that many transparent objects act as a lens, concentrating the light in a real posterior focal area (5) or in a virtual anterior area (6) of said object.
    [0019] This focal area can be induced, for example, by objects shaped like spheroids or transparent ellipsoids (2-3) with a refractive index different from the surrounding medium. Such particles can be, for example, oil droplets dispersed in an aqueous solution, gas bubbles (3) in a liquid, living or dead cells, droplets of a liquid in a gaseous stream.
    [0020] By transparent, it is understood, in this document, a medium that maintains the light in a directional way sufficient to observe the focus peaks. This transparency can be characterized, for example, by measuring the fog (ASTM D 1003). The problem arises when a large fog constitutes an increase in backlight and an added difficulty in discriminating between the background and the peaks.
    [0021] To observe the peaks of light focus intensity, the particles preferably have dimensions greater than the wavelength of the incident light, more preferably, greater than three times the wavelength of the light. In the case of visible light, the particles are preferably larger than one micrometer in size.
    [0022] Transparent particles that induce a focal area are not limited to spheroid particles in free flow, but also include particles fixed on a smooth surface such as liquid droplets or bubbles in contact with glass or the like.
    [0023] A consequence of the existence of these focal points/areas is that each of these particles, when illuminated, produces a peak of light intensity that can be easily detected by tracing the light intensity distribution in three dimensions.
    [0024] Advantageously, the process of the present invention is carried out by first recording a digital holographic representation of an illuminated sample comprising the particles to be analyzed. Screening and analysis are then preferably performed on a representation of a light field induced by the 3D reconstructed illuminated sample.
    [0025] Even a single particle can be characterized by the process of the present invention, and the possibility of automating the process makes it particularly suitable for large sets of particles. The particles to be characterized may be present simultaneously in the field of representation or may be present at a subsequent time.
    [0026] Preferably, the digital holographic representation is recorded by a digital holographic microscope (MHD). Said MHD may advantageously be of the type described in EP1399730 which is incorporated herein by reference.
    [0027] In a preferred embodiment, the MHD may be a differential holographic microscope, such as that described in EP1631788 which is incorporated herein by reference.
    [0028] Advantageously, the MHD operates in a dark field mode as described in WO/2010/037861. The advantage of this darkfield mode is that it facilitates peak light detection by reducing the average light background.
    [0029] The use of an off-axis MHD as described in the international patent application number PCT/EP2010/64843 has the advantage of quickly recording dynamic events, such as particles flowing in a fluid.
    [0030] Preferably, the peak light intensity is determined by detecting the light intensity of a predetermined threshold in the volume of the 3D representation.
    [0031] A first application of this focusing point determination is a process for counting spheroid particles in a flowing medium. In this process, the peak light intensity number corresponds to the number of spheroid particles in the sample. An advantage of this counting process is that the area of focused light is much smaller than the particle size, so that even in the case of high particle density, the light peaks will be easily resolved and well separated. This is a key advantage over the overlapping particle counting process in a 2D representation.
    [0032] Particle counting uses only peak detection, but other characteristics of the light peak, such as shape, intensity and position, can also be used to advantage. This information is characteristic of the lens equivalent to each particle. These lens characteristics are themselves determined by the geometric shape and refractive index of the particles.
    [0033] For example, gas bubbles in a liquid will act as a diverging lens, giving rise to focal points in front of the bubbles, in contrast to particles with a high refractive index which will act as a converging lens, giving rise to a focal point. behind the particle. Therefore, in a preferred process, the particles are classified according to the relative position of the corresponding light peak area. This classification makes it possible to easily discriminate between different classes of particles such as bubbles and particles with a high refractive index.
    [0034] By high or low refractive index is meant, in the present document, respectively, a higher or lower refractive index than the refractive index of the medium surrounding the particles.
    [0035] As another example of particles differing in their optical properties, it was surprisingly demonstrated that the process of the present invention was able to discriminate between live and dead cells flowing in a liquid medium, based on the characteristics of the light peaks. that correspond to the cells.
    [0036] In the experimental example shown below, as in fig. 5, peak size was used as the discrimination criterion (ie, the volume or area where the light intensity is greater than the threshold). It has also been found that other criteria can be used, such as absolute peak intensity (i.e., the maximum intensity or the integral intensity of light within the peak).
    [0037] As the process can be easily automated and performed automatically in consecutive time series, the process of the present invention can advantageously be used to study the displacement of individual cells.
    [0038] Still as a dynamic application of the present invention, spray drying processes using various peak characteristics can be studied. In these studies, the pulverized particles are counted by the process described above, their individual movements in the stream can be accurately determined, the particle size as a function of time can be determined simultaneously by analyzing the reconstructed particle (image “in focus” ”) and the concentration of the solution can be calculated from the refractive index of the particles, determined from the correlation between the shape of the particle and the position of the peak of light intensity in the focal area. One of the advantages brought by this method would be, for example, the ability to determine the phenomenon of supersaturation and the corresponding processes of nucleation and growth.
    [0039] Another advantageous application of determining the focal point of transparent objects is the precise determination of geometric parameters of liquid droplets on a flat transparent surface. These geometric parameters can then be used to accurately calculate, for example, contact angles.
    [0040] More generally, the following parameters may be of interest: number of peaks, peak shapes and peak dimensions, peak intensities (integral and/or maximum value), relative positions from the corresponding particles .
    [0041] These peak parameters can be advantageously correlated with the shape and position of the corresponding particle.
    [0042] Correlations with corresponding fluorescence data originating from the particles can also be used to advantage to characterize the particles. Such fluorescence correlation may utilize the process described in US 2004/156098 which is incorporated herein by reference.
    [0043] From these parameters, the following characteristics can be advantageously inferred: viability of live cells, solution concentration, cell type, particle movement, etc. EXAMPLE
    [0044] Cell cultures have been characterized using the process of the present invention.
    [0045] A microscope was used, as shown in fig. 3 to record digital holograms. The hologram sampling rate was 2.5 Hz and 200 holograms were made in one sequence.
    [0046] As shown in fig. 1, the sample holder 4 was a cell in a stream where the liquid samples in stream 8 and particles were dynamically observed.
    [0047] Figure 4a represents a reconstructed image of one of the holographic records obtained. Figure 4b represents the corresponding projection of the focus peaks. It can be seen in fig. 4b , that even the cells in contact are well resolved when considering the light peak rather than the corresponding representation of the cells. It should be noted that for ease of representation, the peaks have been represented in two dimensions. In the real representation, they are resolved in depth.
    [0048] The number of cells, as determined by the present procedure, was 3.72 million cells/mL. In comparison, a Bürker cell count was 3.71 million cells/mL. This very good agreement was confirmed even in the case of very high cell concentrations. In the latter case, the usual automated counting processes give inaccurate results.
    [0049] In another experiment, the process of the present invention was used first to count the number of cells in a culture. In a second step, the culture medium was subjected to a 3 h heat treatment at 42.5 °C. This treatment is known to reduce cell viability. [0050] The size distribution of the observed light peaks was then determined before and after the heat treatment. The results are illustrated in fig. 5. As can be seen in this figure, the peak size distribution is strongly correlated with cell viability.
    权利要求:
    Claims (15)
    [0001]
    1. Process for characterizing transparent objects in a transparent medium, said transparent objects (2.3) having a focal optical area (5.6), said process being characterized by the fact that it comprises the steps of: illuminating a sample comprising the objects (2,3) to be characterized by means of a directional light source (7), thus inducing light intensity peaks (5,6) in the focal area of said transparent objects (2, 3); said focal area being a real focal area behind (5) said objects (2, 3) or a virtual focal area in front (6) of said objects (2, 3); - determining at least one characteristic of the induced light intensity peaks (5, 6), - determining from said at least one light intensity peak characteristic (5, 6), in at least one property of said objects ( 2.3); - recording a holographic representation of the illuminated sample; - reconstructing, from said holographic representation, a three-dimensional representation of the intensity of the light field induced by said sample; and - tracking the three-dimensional representation of the light field intensity to determine the light intensity peaks (5,6) that have an intensity greater than that of a predetermined threshold, each of said light peaks (5,6) corresponding to an object (2,3).
    [0002]
    2. Process according to claim 1, characterized in that the holographic representation is obtained by means of a holographic microscope.
    [0003]
    3. Process according to claim 2, characterized in that said microscope is operated according to a differential mode.
    [0004]
    4. Process according to claim 2, characterized in that said microscope is operated in a dark field mode.
    [0005]
    5. Process according to claim 2, characterized in that said light source is partially coherent.
    [0006]
    6. Process according to claim 5, characterized in that said microscope is operated out of axis.
    [0007]
    7. Process, according to claim 1, characterized in that at least one characteristic of the particles comprises the number of said objects (2,3).
    [0008]
    8. Process according to claim 1, characterized in that said objects (2, 3) are selected from the group consisting of gas bubbles, liquid vesicles in an emulsion, solid beads, live cells, dead cells and their mixtures .
    [0009]
    9. Process according to claim 1, characterized in that said objects are selected from the group consisting of live cells, dead cells and their mixtures.
    [0010]
    10. Process according to claim 1, characterized in that at least one peak characteristic is determined, said peak characteristic being selected from the group consisting of the distance between the light intensity peak and the corresponding object, area of the peak light intensity (5.6) and the intensity of the peak light intensity (5.6).
    [0011]
    11. Process according to claim 10, characterized in that said peak characteristic is used to classify said objects into at least two subsets of objects (2,3).
    [0012]
    12. Process according to claim 11, characterized in that a subset of objects (2,3) correspond to live cells and a second subset of objects (2, 3) correspond to dead cells.
    [0013]
    13. Process according to claim 1, characterized in that said characterization process is performed dynamically in a successive holographic representation.
    [0014]
    14. Process according to claim 1, characterized in that the transparent object has enough light directionally to observe the focus peaks.
    [0015]
    15. Process according to claim 1, characterized in that the transparent objects (2, 3) are spheroidal; where the transparent medium is as follows; wherein at least one characteristic of the induced light intensity peaks is the number of induced light intensity peaks; at least one characteristic of said object is the number of spheroidal objects.
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    法律状态:
    2020-08-18| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2020-08-25| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-08-03| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|
    2021-11-30| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2022-01-25| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 09/11/2011, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |
    优先权:
    申请号 | 申请日 | 专利标题
    EP10190977|2010-11-12|
    EP10190977.8|2010-11-12|
    EP11161884.9|2011-04-11|
    EP11161884|2011-04-11|
    PCT/EP2011/069746|WO2012062805A1|2010-11-12|2011-11-09|Optical method for characterising transparent particles|
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