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WO2018218341A1 - Système et procédé de collecte et de conservation d'échantillons de sang pour imagerie ultérieure indépendante des anticorps - Google Patents

Système et procédé de collecte et de conservation d'échantillons de sang pour imagerie ultérieure indépendante des anticorps Download PDF

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Publication number
WO2018218341A1
WO2018218341A1 PCT/CA2018/050607 CA2018050607W WO2018218341A1 WO 2018218341 A1 WO2018218341 A1 WO 2018218341A1 CA 2018050607 W CA2018050607 W CA 2018050607W WO 2018218341 A1 WO2018218341 A1 WO 2018218341A1
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WO
WIPO (PCT)
Prior art keywords
buffer
blood
blood sample
rbc
mixture
Prior art date
Application number
PCT/CA2018/050607
Other languages
English (en)
Inventor
Darin Kurtis FOGG
Original Assignee
Autograph Biosciences, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Autograph Biosciences, Inc. filed Critical Autograph Biosciences, Inc.
Publication of WO2018218341A1 publication Critical patent/WO2018218341A1/fr

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N15/14—Optical investigation techniques, e.g. flow cytometry
    • G01N15/1429—Signal processing
    • G01N15/1433—Signal processing using image recognition
    • A01N1/0231—
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150015—Source of blood
    • A61B5/150022—Source of blood for capillary blood or interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150343—Collection vessels for collecting blood samples from the skin surface, e.g. test tubes, cuvettes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150374—Details of piercing elements or protective means for preventing accidental injuries by such piercing elements
    • A61B5/150381—Design of piercing elements
    • A61B5/150412—Pointed piercing elements, e.g. needles, lancets for piercing the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150374—Details of piercing elements or protective means for preventing accidental injuries by such piercing elements
    • A61B5/150381—Design of piercing elements
    • A61B5/150503—Single-ended needles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/151—Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15142—Devices intended for single use, i.e. disposable
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/30—Staining; Impregnating ; Fixation; Dehydration; Multistep processes for preparing samples of tissue, cell or nucleic acid material and the like for analysis
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/10—Investigating individual particles
    • G01N2015/1006—Investigating individual particles for cytology

Definitions

  • the following relates to systems and methods for collecting and preserving bodily fluids samples, particularly blood samples, for subsequent antibody-independent imaging such as cytometry.
  • a system and method that allows simple and reproducible collection and preservation of WBC from small volumes of blood, which can be stored for long periods (at least several months to one year) without loss of cell integrity or morphometric quality.
  • the method described herein can also be performed by non-experts/non- healthcare professionals at convenient locations, such as, but not limited to, the subject's home. This method can be used alongside recent advances in antibody-independent single cell classification, for example by digital image analysis software, machine-learning-based image analysis and nascent deep learning computing tools. The method thereby allows for reproducible collection and storage of peripheral blood leukocytes at virtually any location that can be subsequently classified and analyzed without the need for staining with fluorochrome-tagged antibodies.
  • a method for a method of preserving blood samples for subsequent antibody-independent imaging comprising transferring a blood sample to a fixative and red blood cell (RBC) lysis buffer.
  • RBC red blood cell
  • kits comprising suitable items, materials and instruments for performing the method.
  • FIG. 1 is a flow chart illustrating operations performed in collecting and preserving bodily fluids samples, particularly blood samples, for subsequent antibody- independent imaging such as cytometry;
  • FIG. 2A illustrates a preparation of working concentration of fixation and RBC lysis buffer according to one preparation method
  • FIG. 2B illustrates a preparation of working concentration of fixation and RBC lysis buffer according to an alternative preparation method
  • FIG. 2C illustrates a transfer of working concentration of fixation and RBC lysis buffer to an empty vessel
  • FIG. 3A is an illustrative view showing blood being drawn from a subject
  • FIG. 3B is a schematic view of a blood sample transferred to a microcentrifuge tube containing the working concentration of fixation and RBC buffer;
  • FIG. 3C is a schematic view of a sample with dilution buffer added prior to storage
  • FIG. 4 provides example Brightfield images of WBC collected one day (left) and four months (right) prior to imaging an image analysis, for heterogeneous WBC populations;
  • FIG. 5 provides example nuclear stained images of WBC collected one day (left) and four months (right) prior to imaging an image analysis, for heterogeneous WBC populations;
  • FIG. 6 provides example darkfield images of WBC collected one day (left) and four months (right) prior to imaging an image analysis, for heterogeneous WBC populations;
  • FIG. 7A provides example image analysis metrics applied to samples collected six weeks prior to image analysis and illustrates Nuclear Symmetry_2 versus Ratio of Nuclear Area to Cytoplasmic Area for each cell in the sample (left), Nuclear Intensity- weighted Aspect Ratio versus Darkfield Intensity-weighted Aspect Ratio (middle), and Nuclear Compactness to Darkfield Intensity (right);
  • FIG. 7B provides example image analysis metrics applied to samples collected four months prior to image analysis and illustrates Nuclear Symmetry_2 versus Ratio of Nuclear Area to Cytoplasmic Area for each cell in the sample (left), Nuclear Intensity- weighted Aspect Ratio versus Darkfield Intensity-weighted Aspect Ratio (middle), and Nuclear Compactness to Darkfield Intensity (right);
  • FIG. 7C provides example image analysis metrics applied to samples collected one day prior to image analysis but underfixed due to low fixation buffer concentration, and illustrates Nuclear Symmetry_2 versus Ratio of Nuclear Area to Cytoplasmic Area for each cell in the sample (left), Nuclear Intensity-weighted Aspect Ratio versus Darkfield Intensity- weighted Aspect Ratio (middle), and Nuclear Compactness to Darkfield Intensity (right);
  • FIG. 7D shows that image analysis metrics can be conserved with cells held at room temperature for a period of time prior to imaging
  • FIG. 8A shows that samples of individual subject's blood leukocytes can be used to train a classifier to recognize main blood cell subsets using supervised machine-learning algorithms, wherein antibody-labelled cells are used to determine features in Brightfield and Darkfield imagery that identify the cell type independent of the antibody labeling;
  • FIG 8B shows that the classifier developed in FIG. 8A can then be used to classify blood cells collected by the current method with the absence of antibody staining;
  • FIG 8C shows that the classification of blood leukocyte subsets identified by the machine-learning algorithms used in FIG 8A results in population percentages similar to those known to be present in human blood (published averages).
  • Described herein is a method for collecting blood or bodily fluids at any location that can be performed by non-experts, in the absence of specialized lab equipment, and that is compatible with short- or long-term storage prior to subsequent image data acquisition and analysis.
  • the method described herein is particularly advantageous for the collection and preparation of WBC from a finger stick blood sample, however the method would apply similarly to blood collected by other methods, such as venipuncture.
  • the ability to obtain blood by finger stick exemplified in this method is particularly advantageous as it allows for use by non-professionals in a safe, repeatable, reproducible, and minimally invasive manner.
  • the method described herein can be applied in several applications, for example the collection and preservation of cells for research or clinical applications with the goal of monitoring an individual's personal immune system homeostasis, or in response to medical treatments, prescriptions, procedures such as cancer chemotherapy, radiation therapy, immunotherapy, anti-microbial agents, vaccinations, or lifestyle changes including but not limited to changes in diet, activity level, tobacco or drug use, environment.
  • Potential applications of the method include cancer, heart disease, autoimmune disorders, pathogenic infections, neurological disorders, etc.
  • Also described herein is a simple, safe, and affordable kit with the necessary components for use by non-experts.
  • This method described herein can be used along with recent advances in antibody-independent single cell analysis, for example by machine-learning-based image analysis.
  • An example of such machine-learning bases image analysis can be found in WO 2015/168026 A2.
  • the fixation of cells prior to antibody labeling destroys or modifies antibody-ligand binding epitopes, resulting in reduced antibody binding (Burel et al, Journal of Immunology 2017, doi 10.4049/jimmunol.1601750). Therefore, this method, which allows for immune cell classification and quantification independent of antibody labeling represents a significant advance in technology. It may be noted that this does not exclude the possibility that in some cases the method could be used in conjunction with antibody labeling, as certain epitopes may be stable to the fixation procedure described herein and thus be targeted by antibody-dependent labeling and analysis if desired.
  • FIGS. 1 -3 illustrate a method for blood collection for WBC fixation/preservation/permeabiliization, RBC lysis, and storage and antibody-free imaging and classification.
  • the method begins at steps 50 and 52 with preparing a working concentration of fixation and RBC buffer (step 50) and collecting a blood sample (step 52).
  • step 50 to an empty, sterile vessel 12a such as a 1 .5ml microcentrifuge tube is added one drop of a mixture of 10x concentrated buffer for WBC fixation and 10x RBC lysis 14 along with 9 drops of water 16, e.g., using a plastic transfer pipette 10 (FIGS. 2A or 2B). 3 drops or 45 - 90 ⁇ of the resulting working concentration of fixation / RBC lysis buffer is added to an empty, sterile vessel 12b as shown in FIG. 2C.
  • sterile vessel 12a such as a 1 .5ml microcentrifuge tube is added one drop of a mixture of 10x concentrated buffer for WBC fixation and 10x RBC lysis 14 along with 9 drops of water 16, e.g., using a plastic transfer pipette 10 (FIGS. 2A or 2B). 3 drops or 45 - 90 ⁇ of the resulting working concentration of fixation / RBC lysis buffer is added to an empty, sterile vessel 12b as shown
  • Fixation in this example is performed with 1 % formaldehyde, however alternative concentrations of formaldehyde, or other fixatives could be used, such as paraformaldehyde (PFA) or formalin.
  • RBC lysis is typically performed using diethylene glycol buffer 14 but could be achieved by alternative means such as hypotonic lysis buffer or water, or ammonium chloride potassium (ACK).
  • Transfer of liquids in this example is performed with a disposable plastic transfer pipette 10 but other means of liquid transfer could be used.
  • the exemplary technique used here includes a commercially available one- step fix/lyse buffer to minimize variability / allow consistency, however other reagents for fixation and RBC lysis or removal may be used.
  • the buffer 14 contains both 10x formaldehyde for fixation and 10X diethylene glycol for RBC lysis. This allows the white blood cells to be fixed and the red blood cells lysed (or otherwise removed).
  • 10x formaldehyde for fixation and 10X diethylene glycol for RBC lysis.
  • This allows the white blood cells to be fixed and the red blood cells lysed (or otherwise removed).
  • the buffer 14 in Figure 2A is one volume of 10x formaldehyde and 10x diethylene glycol. The addition of 9 volumes (in this case each drop is one volume) of water produces the working concentration of both formaldehyde and RBC lysis buffer.
  • the exemplary method for dilution of concentrated fixation / RBC lysis solution uses one drop of the 10x buffer from a plastic transfer pipette added to 9 drops of water to produce 1x (working concentration) buffer.
  • 1x (working concentration) buffer 1x (working concentration) buffer.
  • alternative methods could be used to prepare the working concentration of fixation/RBC buffer.
  • having a defined volume of 10x or other stock concentration of fixation / RBC lysis buffer separated from a defined volume of dilution buffer by a breakable or removeable septum or other barrier 18 as shown in FIG. 2B could be used.
  • the user could break away the barrier by applying pressure to the external surface of the vessel or could otherwise remove the barrier and mix to dilute to the working concentration.
  • Such design would minimize risk of exposure of the subject to the formaldehyde.
  • the area of skin where stick is to be performed should be wiped with a towelette soaked in 70% isopropanol or other disinfectant.
  • a small volume (typically 5 ⁇ - 25 ⁇ but as much as 200 ⁇ ) of blood is drawn by finger stick as illustrated in FIG. 3A.
  • the skin is punctured using a lancing device 22 outfitted with a single use, sterile lancet 20.
  • step 54 one or two drops of blood, totalling 5 ⁇ to 20 ⁇ is wiped from skin at the lancing site to the tube 12 containing the 45 ⁇ - 90 ⁇ of working concentration buffer for WBC cell fixation and RBC lysis.
  • the method described herein should scale linearly. As such, if an application requires collection of a greater number of cells, increasing the volume of blood drawn, along with increasing the volumes of buffer proportionally, can be performed to provide the same result. Larger containment vessels would be required, but the method performed would be the same. For example, it is possible to draw up to 200 ⁇ of blood from a finger stick, and thus as much as 10 times as many cells could be collected if required, for example for rare cell analyses.
  • Blood droplets or a defined volume of blood between 5 ⁇ and 200 ⁇ could be drawn into buffer- containing tubes by microfluidics, capillary tubes or vacuum or other available techniques.
  • step 54 the microcentrifuge tube is recapped and the blood sample is mixed within the fixation / RBC lysis buffer by gentle agitation, for example shaking or flicking the tube, and the sample 24 is set aside for 15 minutes at room temperature in step 56, and shown in FIG. 3B.
  • the incubation period of 15 minutes is exemplary for this method but certain variations in incubation times and temperatures may be acceptable and provide similar results. It has been observed that overly short incubation times, overly dilute fixation buffer, or use of working concentration of fixation buffer that has been stored for too long can have an adverse effect on image quality and reproducibility as shown in the subsequently described figures.
  • phosphate buffered saline which has been stored at 4-10 degrees Celsius in a refrigerator, is then added to the blood sample, e.g., by plastic transfer pipette until a total volume 26 of at least 1 ml is achieved.
  • the tube is recapped and inverted several times to mix the volume 26, and terminate the fixation reaction as shown in FIG. 3C.
  • buffer addition by transfer pipette is exemplary and other methods for transfer may be used.
  • buffer and reagent storage temperatures given herein are exemplary and other storage conditions may be used.
  • buffer volumes and final volume given are exemplary and other volumes may be used.
  • sample storage times and temperatures given are exemplary and other storage conditions may be used.
  • kit can be created to enable the above method to be readily performed by non-experts, e.g., at home or elsewhere in the absence of specialized lab equipment.
  • a kit can include the following elements:
  • FIGS. 4, 5 and 6 provide example images of WBC collected one day (left panels) or 4 months (right panels) prior to imaging and image analysis.
  • Exemplary montages of Brightfield (FIG. 4), nuclear stained (FIG. 5), and darkfield images (FIG. 6) of heterogeneous WBC populations are shown.
  • the image quality, and size, shape, and contrast features of the WBC as observed by Brightfield, darkfield, and nuclear dye staining are preserved during at least 4 months of storage in a household refrigerator. This preservation of WBC is important to allow sample collection at any location, to obviate the need for immediate cryopreservation or immediate cell preparation and analysis typical of existing classification methodologies (Burel et al 2017, J Immunol).
  • FIG. 7A, 7B, and 7C provide dotplots that illustrate the successful preservation of WBC population for six weeks and twenty-four weeks after blood collection, versus the poor preservation of WBC when fixation is improperly performed.
  • the diagrams shown in FIGS. 7A-C demonstrate the clustering of WBC populations using certain image analysis features that can be useful in classifying WBC types without the need for fluorescently- labelled antibodies.
  • FIG. 7A shows cell populations imaged four weeks after initial blood collection by finger stick using this method.
  • FIG. 7B shows cell populations imaged twenty- four weeks after initial blood collection by finger stick using this method.
  • FIG. 7A shows cell populations imaged four weeks after initial blood collection by finger stick using this method.
  • FIG. 7B shows cell populations imaged twenty- four weeks after initial blood collection by finger stick using this method.
  • FIG. 7C illustrates a poorly preserved blood sample where, although the blood sample was collected one day before imaging, the fixation buffer used had expired and was no longer capable of optimally preserving cell morphology and integrity, as evidenced by the spreading out of the cell populations by the ratio of Nuclear Area to Cytoplasmic Area (left plot), the Intensity- weighted Aspect Ratio of the Darkfield signal (middle plot) and the loss of distinct population clusters by Darkfield Intensity (right plot).
  • FIGS. 7A-7C therefore show the image analysis metrics that demonstrate what heterogeneous cells look like after 6 or 24 weeks of storage using the presently described method versus what they may look like when appropriate fixation conditions are not met.
  • FIG. 7D shows that image analysis metrics can be conserved even with cells that were held at room temperature for 24 hours prior to imaging. As such, in at least some implementations, embodiments, or scenarios, refrigeration may not be required.
  • FIGS. 8A, 8B, and 8C provide bar graphs that establish that, in the absence of antibody staining, machine learning algorithms are able to classify many of the normal blood leukocyte subpopulations with high fidelity.
  • FIG. 8A shows that, when machine learning algorithms, such as Gradient Boosting, are applied to images cells acquired in the absence of antibody, high degrees of accuracy in cell type determination can be achieved for some of the major blood cell subsets.
  • machine learning algorithms such as Gradient Boosting
  • Gray Boosting machine learning algorithms
  • FIG. 8A shows that, when machine learning algorithms, such as Gradient Boosting, are applied to images cells acquired in the absence of antibody, high degrees of accuracy in cell type determination can be achieved for some of the major blood cell subsets.
  • machine learning algorithms such as Gradient Boosting
  • FIG. 8B demonstrates that the same classifier used above, trained on samples collected separately from the current method described herein, can be used to classify cells collected using the method described herein, with similar accuracy, in the absence of any antibody-dependent labeling or biomarker staining.
  • blood collected several weeks or months prior to digital image acquisition was analyzed using the classifier developed and describe in FIG 8A. High accuracy of classification was obtained for most subsets, despite the widely differing collection times and procedures.
  • Figure 8C demonstrates that the frequency of cell populations identified using the classifier to predict cell classes using the method described herein is similar to the published average cell frequency of populations in human subjects sampled by traditional blood drawing and antibody-dependent cytometric analysis.

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Abstract

L'invention concerne un procédé de conservation d'échantillons de sang pour une imagerie ultérieure, indépendante des anticorps, qui comprend le transfert d'un échantillon de sang vers un tampon de lyse de globules rouges et de fixateur (RBC). Le procédé peut en outre comprendre le transfert d'un mélange de l'échantillon de sang et du tampon vers un dispositif de réfrigération pour le stockage. Le mélange peut être incubé à température ambiante et comprend un tampon de dilution ajouté à celui-ci pour obtenir un volume cible. Le procédé peut également comprendre la préparation d'une concentration de travail du tampon de lyse de RBC et de fixateur en ajoutant une quantité d'eau qui réduit une concentration du tampon pour produire la concentration de travail. L'échantillon de sang peut être recueilli à l'aide d'une technique de piqûre.
PCT/CA2018/050607 2017-05-29 2018-05-24 Système et procédé de collecte et de conservation d'échantillons de sang pour imagerie ultérieure indépendante des anticorps WO2018218341A1 (fr)

Applications Claiming Priority (2)

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US201762512141P 2017-05-29 2017-05-29
US62/512,141 2017-05-29

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WO2018218341A1 true WO2018218341A1 (fr) 2018-12-06

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019239133A1 (fr) 2018-06-12 2019-12-19 Biorelevant.Com Ltd. Procédé de préparation de solutions tampon pour tester in vitro la solubilité des médicaments, emballage pour produire la solution tampon et kit pour tester les états cliniques
US11399755B2 (en) 2016-08-24 2022-08-02 Becton, Dickinson And Company Device for obtaining a blood sample

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"eBioscience™ 1-Step Fix/Lyse Solution (10X)", SAFETY DATA SHEET, 2 February 2017 (2017-02-02), pages 1 - 10, XP055554287, Retrieved from the Internet <URL:https://www.thermofisher.com/order/catalog/product/00-5333-54> *
"RBC Lysis/Fixation Solution 10X", 17 October 2013 (2013-10-17), XP055554278, Retrieved from the Internet <URL:https://www.biolegend.com/en-us/products/rbc-lysis-fixation-solution-10x-7436> *
KUSNER ET AL.: "Survivin as a Potential Mediator to Support Autoreactive Cell Survival in Myasthenia Gravis: A Human and Animal Model Study", PLOS ONE, vol. 9, no. 7, 22 July 2014 (2014-07-22), pages 1 - 10, XP055554290 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11399755B2 (en) 2016-08-24 2022-08-02 Becton, Dickinson And Company Device for obtaining a blood sample
US11771352B2 (en) 2016-08-24 2023-10-03 Becton, Dickinson And Company Device for the attached flow of blood
US12082932B2 (en) 2016-08-24 2024-09-10 Becton, Dickinson And Company Device for obtaining a blood sample
WO2019239133A1 (fr) 2018-06-12 2019-12-19 Biorelevant.Com Ltd. Procédé de préparation de solutions tampon pour tester in vitro la solubilité des médicaments, emballage pour produire la solution tampon et kit pour tester les états cliniques

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