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    • 专利摘要:
    DEVICE FOR COLLECTING, TRANSPORTING AND STORING BIOMOLECULES FROM A BIOLOGICAL SAMPLE. The present application provides a sample receiving device comprising a test tube, a receptacle in communication with the vial for receiving the sample and a cap of a pusher, the pusher for mating with the sample receptacle. The receptacle comprises a disruption member to break the sample when the pusher engages with the sample in the receptacle and expels the broken sample into the vial. Typically, the device can be used for collecting faecal samples. A method of preserving a biomolecule on the device using a biomolecule preserving composition is also provided.
    公开号:BR112016026305B1
    申请号:R112016026305-7
    申请日:2015-05-13
    公开日:2021-05-11
    发明作者:Adele Jackson；Maria Mercedes Acero；Evgueni Vladimirovitch Doukhanine；Rafal Michal Iwasiow；Carlos Alberto Merino Hernandez；H. Chaim Birnboim；Jonathan D. Liberty
    申请人:Dna Genotek Inc；
    IPC主号:
    专利说明:

    FIELD
    [001] This application belongs to the field of collection and storage of biological materials. More specifically, the present application relates to a device for collecting, transporting and storing biomolecules from a biological sample, such as feces. BACKGROUND
    [002] There are several means and devices that have been developed for collecting, transporting and analyzing biological samples. Many of these samples are faecal samples obtained from humans and other mammalian species. Stools are a non-invasive and useful type of specimen that can be used for various biological tests, such as parasite screening and fecal occult blood testing (FOBT); both being used for the diagnosis of an acute gastrointestinal (GI) condition. However, there is growing scientific evidence to suggest that screening for nucleic acid in the microbial community of the human GI tract can provide insight into the onset and progression of various human disorders and diseases. These range from obesity and other metabolic disorders (Korecka & Arulampalam 2012) to neurological pathologies (Culligan et al. 2013) and colorectal cancer (CRC, Cole et al. 2003; Osborne et al. 2012).
    [003] Human children are born virtually free of intestinal microbiota, despite the presence of various organisms in the amniotic fluid (DiGiulio et a. 2008). The first fecal samples produced by children after birth have a low microbial density (Palmer et al. 2007). Microbes present in children's intestines are unstable from the first to three years of life, after which the species diversity begins to resemble those found in the adult GI tract (Kostic et al. 2013; Palmer et al. 2007), when the intestinal lumen is populated by trillions of microbiota. Over the past century, and particularly over the last two decades, it has become more and more evident that microbes in the human GI are needed for a wide variety of processes essential to human health (Evans et al. 2013; Korecka & Arulampalam 2012 ). For example, one of the main contributions of gut microbiota to humans is the production of short-chain fatty acids, which is a significant source of energy (Evans et al. (2013). it is an essential part of normal development (Kostic et al. (2013). In order to elucidate the identity and specific roles of the microbial species present in the GI tract, much of the research has focused on metagenomic analysis (the evaluation of the total genetic material (DNA and RNA)) and the group of microbiota present The metagenome of microbiota is generally called the microbiome.
    [004] The first step in metagenomic analysis is the acquisition of a representative sample of the total environment of microbes and that allows the isolation of the total metagenomic DNA/RNA. The methods and devices used to collect and subsequently transport fecal samples must therefore provide a consistent and measurable sample, preserve the diverse profile of organisms represented by the microbiome, and minimize the risk of contamination for the user.
    [005] In the current standard of practice, a small basin or similar container is used by the donor to collect the entire fecal sample; that same container is used for storage and transport. In order to preserve the sample, and by extension the microbiota and microbiome, the entire sample inside this container is packed in a larger box and kept frozen on dry ice (-78°C) during storage and transport to a facility central before the isolation of nucleic acids. Although sample collection takes place directly from the donor's perspective, keeping these samples frozen from the point of collection is understandably inconvenient and very costly to the researcher. Furthermore, from the researcher's point of view, obtaining a secondary sample of consistent size from these collections requires a thaw and a potentially difficult and unpleasant transfer step. A device and/or a collection method that excludes the need for freezing storage and allows for quantitative sampling and simplified postal transport, while maintaining ease of use for the donor, would be a significant improvement in the field. .
    [006] It is important to note that methods with more accessible values, such as collection with a brush/scrub or by transfer with a lesser container, may not only be inappropriate for collecting samples of adequate quality for use in a metagenomic analysis microbiota, but it can also bring unwanted complexity to the donor and the researcher. Due to the necessarily private nature of the production of fecal matter, collection of these samples is usually carried out by the donor, who is likely not familiar with the details of collecting the appropriate specimen. In addition, unpleasant aspects of the stool (particularly the odor and the potential for transmission of infectious organisms) often result in an unwillingness or inability to handle the specimen. Even in the context of initial diagnosis of life-threatening diseases such as CRC, participation in fecal donation can be quite low, especially if complex steps are required (Cole et al. 2003; Osborne et al. 2012).
    [007] In order to overcome some of these difficulties, several devices and methods have been described for the collection and transport of feces. Many of these are specifically aimed at facilitating the screening of parasites or FOBT, whose characteristics often preclude the use of metagenomic analysis of faecal microbiota. For example, in screening for parasites, the aim is to strain the fecal matter (and ultimately dispose of it) to retain and examine adult eggs, larvae, and parasites (usually intestinal worms) that may be present. In terms of FOBT, a common test used in screening for CRC, the Guaiac dye test (eg Hemoccult®) is based on a stool stain applied to a paper pad and allowed to air dry. The lower GI of humans is mainly populated by Bacteroides and Firmicutes, the microbial families comprised mainly of obligate anaerobic species (Korecka & Arulampalam 2012), to which sustained exposure to oxygen is toxic. Thus, faecal samples collected by this method cannot provide an accurate representation of the microbiome.
    [008] Several fecal collection/transport systems that do not have the aforementioned disadvantages involve a main tube and a rod-like or spoon-like collector (which may or may not be integrated with a lid) and a liquid stored in the main tube. Such a collection device, described in US 8,556,826, is based on a fecal specimen collector with delicate features, similar to a brush or stick. In order to obtain a sample, the specimen fecal collector is introduced into the fecal sample, allowing the fecal matter to adhere to the fine elements of the collector. The collector is then introduced into the part of the main tube (test tube body) that contains a diluting liquid. The user seals the top cap on the test tube body and shakes the test tube body to mix the sample with the liquid diluent before reaching the stool diluent mixture. Although this invention allows for the collection of a smaller stool sample, the intended use is microscopic observation of the diluted stool sample or examination by test paper. The invention does not allow for the collection of a quantitatively uniform fecal sample size, a feature that allowed for more reliable data comparison.
    [009] Furthermore, fecal samples can be highly variable in one between individuals, ranging from hard granule-like droplets (Type 1) to a soft semi-solid (Type 4) or to completely fluid (Type 7) (the so-called "Bristol scale" ", Heaton et al. 1992; Lewis & Heaton 1997). Brush-like/rod-like characteristics can limit the ability to collect more rigid, bead-like samples, and relying solely on fluid turbulence to mix can lead to inefficient disruption and, ultimately, to non-homogeneous samples. Furthermore, the role of the liquid in this case is only to dilute the sample, not to preserve biomolecules such as DNA and RNA. This is a significant limitation due to the fact that sample collection approaches can have a wide impact on the microbiome, and measurable mea- genomic differences can be observed within 20 minutes (Couch et al. (2013). for the study of the microbiome that a "photo" of the microbiota be obtained at the time of collection.
    [0010] The second type of fecal sample collector described in US 8,623,665 presents a system comprising a container, a collector (with an optional snap-on filter) and a lid. The user first collects the fecal sample with the collector (which can be shaped like a spoon, mop, fork, etc.), fixes the filter, if used, and finally the sample and collector are inserted into the container and the container is closed with the lid before being sent to the test unit, where a processing fluid is added. When transporting a faecal sample to the processing unit, prior to inserting a processing fluid, the integrity of the sample can be compromised, as described above. Furthermore, in relation to Type 1 samples, there is also a risk of desiccation in the container before processing, which can make it difficult to break up the sample with the processing fluid, a necessary step to ensure that the entire sample (and the associated metagenome ) is available for review.
    [0011] Again in this example, it is not possible to reproducibly collect a sample of a defined quantity, nor is there a means of preservation. An additional complication is transporting the sample in the container, which is secured with a snap closure. This has no problems with harder samples, more like spheres (Type 1); however, there is a considerable risk of leakage with Type 5-7 specimens. The consequence of this is contamination of the outside of the collection container and the possible spread of an infection.
    [0012] In light of the preceding examples, it becomes clear that there is a demand for a device and a method that allow the reproducible collection of a defined quantity of biological sample to perform biomolecule analyses. The present invention addresses these issues and further facilitates rapid and complete disassembly, and subsequent homogenization of the sample with a preservation medium, while providing for leak-proof transport and storage. Additionally, according to the invention, the collection of the sample can be carried out in a convenient and easy way for the donor to carry it out in privacy and without risk of contamination. Finally, the method and device enable a stable, high-quality sample that is easily transported in a cost-effective manner.
    [0013] This background information is provided for the purpose of making known the information believed by the applicant to be of possible relevance to the present invention. No admission is necessarily intended, nor should it be construed, that any of the foregoing information constitutes prior art against the present invention. SUMMARY
    [0014] An object of the present invention aims to provide a device for a better collection, storage and preservation of biomolecules, particularly the collection of nucleic acids from samples, such as feces.
    [0015] According to one aspect of the present invention, there is provided a sample receiving device comprising a test tube, a receptacle in communication with the test tube for receiving the sample and a lid comprising a pusher, the pusher for engaging the sample in the receptacle, wherein the receptacle comprises a cutter member for breaking up the sample when the pusher engages the sample in the receptacle and expels the broken up sample in the test tube.
    [0016] The receptacle may be a volumetric breaker, which stores a particular volume or mass of sample, such as a biological sample. The biological sample can be any suitable biological sample, but it can particularly be a fecal sample, derived from an animal, such as a mammal, including a human. In certain embodiments, the receptacle can store between about 200 mg to 2 g or about 400 mg of sample, particularly when faeces is used.
    [0017] In certain embodiments, the pusher comprises a first end connected to an inner portion of the lid and a second end for engaging the sample and, for example, an inner wall of the receptacle. The pusher may be concave and comprise an edge and a lower end surface. The pusher expels the sample through the breaker member of the receptacle and into the test tube.
    [0018] In certain embodiments, the test tube further comprises a mixing medium, such as one or more balls (including one or more spherical bearings, for example), which can be used to homogenize the sample. The test tube may also comprise a composition to preserve the biomolecules. Exemplary compositions that may be used are described in applicant's U.S. patent application Serial No. 61/949,692, filed March 7, 2014, the entire contents of which are incorporated herein by reference. In certain embodiments, biomolecules are nucleic acids.
    [0019] The present application further provides for a receptacle for receiving a biological sample comprising a first opening end for receiving the sample, a second end for engaging with the test tube and a chopping member for breaking up the sample when the sample is placed on the chopping member. The cutter member may comprise one or more openings therethrough for passing the sample into the test tube and one or more breaker projections for breaking up the sample such as the sample passing through the breaker. In certain embodiments, the cutter member can take any shape suitable for breaking up the sample, but includes openings in the shape of a four-leaf clover, circular or cross, for example.
    [0020] The receptacle may comprise a thread for engaging a lid and/or for engaging a test tube. Typically, the test tube and/or cap has complementary threads that allow the receptacle to engage and secure to the test tube and/or cap. In certain modalities, the receptacle is convex. This facilitates attachment to certain covers that comprise concave pushers as described here.
    [0021] According to another aspect of the present invention, a method of preserving biomolecules in a biological sample is provided, the method comprising: a) obtaining a sample; b) obtaining the device of claim 1; c) remove the lid from the container attached to the test tube; d) place the sample in the container; e) place the lid on the container; f) attaching the lid to the receptacle, thereby coupling the pusher with the receptacle and engaging the sample with the cutting means to expel the sample into the test tube; and g) mixing the extruded sample with a composition in the test tube to preserve the biomolecule within the sample. The mixing step may further comprise homogenizing the expelled sample with a mixing medium such as a metal ball bearing.
    [0022] According to another aspect of the present application, a system for preserving biomolecules from a sample is provided, the system comprising: a test tube, a receptacle for receiving the sample in communication with the test tube, a lid that comprises a pusher, a pusher for engaging the sample in the receptacle, wherein the receptacle comprises a breaker member for breaking up the spherical bearing to further homogenize the sample when expelled from the receptacle into the test tube and a composition in the test tube to preserve the biomolecules in the expelled broken up sample.
    According to another aspect of the present application, a kit comprising the device described herein and instructions for use in preserving biomolecules from a biological sample is provided. In particular embodiments, the sample is a fecal sample and the biomolecules are nucleic acids. BRIEF DESCRIPTION OF THE FIGURES
    [0024] For a better understanding of the present invention, as well as other additional aspects and features thereof, reference is made to the following description which should be used in conjunction with the attached figures, in which:
    [0025] Figure 1 shows an exemplary tube according to the present invention.
    [0026] Figure 2 shows a side view of the tube of Figure 1.
    [0027] Figure 3 shows a tube of Figure 1 that contains a spherical bearing.
    [0028] Figure 4 shows a base of the tube of Figure 1.
    [0029] Figure 5 shows a cap in accordance with the present invention. Figure 5a shows a side view of an embodiment, Figure 5b shows a top angle view of the embodiment of Figure 5a; Figure 5c shows a top view of a different embodiment; Figure 5d shows a bottom view of the embodiment of Figures 5a and 5b; Figure 5e shows a cross section of the embodiment of Figure 5a.
    [0030] Figure 6 shows a cross section of a cover pusher from Figure 5.
    [0031] Figures 7a to c show a cross section of an assembled device of the present invention with a top approximation of the connection between the cap and the volumetric breaker.
    [0032] Figure 8 shows a volumetric breaker in accordance with the present invention. Figure 8a shows a top view and Figure 8b shows a bottom view. Figure 8c shows a top view of a different embodiment of the volumetric breaker.
    [0033] Figures 9a-d show various views of exemplary chopping members of the present invention.
    [0034] Figure 10 shows several views of an embodiment of the assembled device of the present invention. Figure 10a shows an exploded view; Figures 10b and c show the bottom and top views, respectively.
    [0035] Figure 11 shows an exemplary syringe for use with the device of the present invention. DETAILED DESCRIPTION
    [0036] The present application provides for a sample receiving device designed to facilitate the proper collection, storage and transport of biological samples such as faeces. The device is particularly advantageous as it allows the user to collect a desired amount of sample and preserve and store the biomolecules contained therein. Optionally, the device can be used with a composition to preserve and stabilize the biomolecules contained therein, such as nucleic acids.
    [0037] Unless defined otherwise, all technical and scientific terms used in this document have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
    [0038] As used in the specification and claims, the singular forms of "a", "an" and "o", "a" include the plural references unless the context clearly dictates otherwise.
    [0039] The term "comprises" as used herein shall be understood to mean that the following list is non-exhaustive and may or may not include any other appropriate additional articles, for example, one or more additional features, component(s) and/or ingredient(s) as appropriate.
    As used herein, "biomolecules" includes biological molecules and may include molecules such as nucleic acids or proteins, for example.
    As used herein, "biological sample" is any specimen that potentially contains a substance of interest, particularly a nucleic acid and optionally a protein or other biomolecules of interest. The term "sample" can encompass a solution, such as an aqueous solution, cell, tissue, biopsy, powder, or population of one or more thereof. The sample can be a biological one, such as: saliva, sputum, oral swabs sample, serum, plasma, blood, inflammatory layer, pharynx, nasal/nasal pharyngeal or sinus swabs or secretions, throat swabs or scrapings, urine, mucosa, stool/sediment/excrement, rectal swabs, lesion swabs, chyme, vomit, gastric juice, pancreatic juice, gastrointestinal (GI) tract solids or fluids, semen/sperm, urethral swabs and secretions, spinal cerebral fluid, breastfeeding products or menstruation, egg, yolk, amniotic fluid, aqueous humor, vitreous humor, cervical secretions or swabs, vaginal fluid/secretions/swabs or scrapings, bone marrow samples and aspirates, pleural fluid and effusions, sweat, pus, tears, lymph , bronchial or pulmonary lavage or aspirates, peritoneal effusions, cell cultures and cell suspensions, bacteria, viruses, fungi, connective tissue, epithelium, epithelial swabs and stains, mucous membrane, muscle tissue, p tissue lacentary, biopsies, exudates, organ tissue, nerve tissue, hair, skin or nails, wherein the aforementioned samples may be obtained, for example, from a vertebrate, including a mammal. A mammal can be, for example, a human being, a non-human primate, livestock (eg cow, goat or sheep), as well as a dog, cat, horse, etc. The sample may also include soil, effluents or water residues from which to collect microorganisms.
    [0042] In one embodiment, the biological sample is a fecal sample and the individual is a mammal. In another modality, the biological sample is a fecal sample and the individual is a human being.
    [0043] As used herein, "faecal sample" refers to a waste product from an animal's digestive tract, expelled through the anus or cloaca during evacuation. In the case of human faeces, faecal matter can be represented by any of the seven types of faeces on the Bristol faeces scale.
    As used herein, a nucleic acid can be DNA or RNA, including viral mRNA or RNA. In one embodiment, the nucleic acid is DNA, which can be of human, viral, or microbial origin. In another embodiment, the nucleic acid is RNA, which can be of human, viral, fungal or bacterial origin.
    As used herein, "nucleic acid preserving composition" or "biomolecule preserving composition" refers to any composition suitable for preserving and stabilizing biomolecules, such as nucleic acid, in a sample, such as, for example, a fecal sample. Exemplary compositions that may be used are described in applicant's U.S. patent application Serial No. 61/949,692, filed March 7, 2014, the entire contents of which are incorporated herein by reference.
    [0046] When referring to a nucleic acid as "stable", it is meant that at least 50% of the initial amount of high molecular weight nucleic acid contained in a sample is still present after storage of the sample at room temperature (this is, from 15°C to 25°C) for a specific period of time.
    [0047] The device, as presented here, comprises a test tube or collection tube, a receptacle or a lid. Optionally, the device can also comprise mixing means, such as one or more balls (for example metal spherical bearings). The receptacle is referred to here as a volumetric breaker, as it is capable of storing a specific amount of sample for its breakup. The present invention provides for a sample collection system comprising the device plus additional components. For example, the system may comprise a tool for transferring the biological sample to the device's volumetric disruptor. Furthermore, the system may comprise a syringe that replaces the pusher and is attachable to the receptacle. This can be used in place of or added to the cap to add a sample to the receptacle and finally to the test tube or collection tube. The component parts of the device and sample collection system are described below with reference to the figures. Test tube
    [0048] The sample is collected in a test tube or tube, the example of which is shown in Figure 1 as tube 10. Although any suitable test tube can be used, such as sample collection tubes known in the art, it would be desirable to have a tube for sample collection, specifically faecal samples, with certain attributes not found in other tubes and described below.
    [0049] Referring to Figure 2, an exemplary tube 10 in accordance with the present invention generally has a cylindrical shape. The tube has an open end 12 for receiving the sample and a closed end 14 where the sample is collected. Open end 12 is ideally threaded to engage a cap and/or a volumetric breaker as described herein. Tube 10 can be of any desired width, length or density as needed and is made of an inert and durable material such as polyethylene, polypropylene or related plastic. Tube 10 is ideally freestanding and includes a wall 20 that defines a reservoir 16 for receiving the sample. Reservoir 16 is suitable for storing a substance such as a liquid, solid, semi-solid, paste, suspension, powder, colloid, gel, gas, mixtures thereof or the like. The reservoir must have a volume empty enough to hold the sample, plus any composition desired to mix with the sample, and, as mentioned above, a mixing means such as one or more spherical bearings that can be used to facilitate mixing of the sample with the composition and to break or homogenize the sample into discrete components.
    [0050] In certain embodiments, the outer surface of the edge of the opening end can be grooved, as best shown in Figure 2. Groove teeth 13 are particularly useful for biting the volumetric breaker plastic when closing the volumetric breaker in the pipe. The extra grip helps make a connection between the volumetric breaker and the tube more firmly than the connection between the cap and the volumetric breaker. This in turn makes it easier to loosen or remove the volumetric breaker cap than to remove the breaker from the tube. This is highly desirable as on order the donor removes and applies the cap, and generally does not need to remove the volumetric breaker. The cap and volumetric breaker are removed in the laboratory to gain access to the sample:
    [0051] As shown in Figure 3, the interior 15 of the closed end 14 desirably has a rounded shape. This serves a number of purposes. First, the rounded shape eliminates corners where the sample can potentially become trapped/compacted and inaccessible to any composition in the tube, and ultimately for end-user analysis. Second, the rounded bottom is complementary to a mixing medium, such as one or more spherical bearing(s), if these are used, to freely allow the s) bearing(s) fit(s) and break(s) the specimen as possible. Third, the rounded shape is more suitable for centrifugation as it resists centrifugal forces better than a straight-bottomed tube.
    [0052] The outer surface 20 of the tube ideally should be transparent or translucent, so as to allow visualization of the sample when collected. The outer surface 20 may be free of any indicia or other markings, and must be suitable for comfortable handling by the user. However, it can be adorned, if desired, and/or have a tack or raised texture to facilitate handling or have graduated marks to indicate volume.
    [0053] As mentioned above, and if desired, a mixing medium such as one or more spherical bearing(s) may be used. Best shown in Figure 3, the spherical bearing 24 can be any metallic sphere, such as a typical spherical bearing known in the art. However, the spherical bearing can be any solid object, with or without projections, to facilitate sample dissociation. The sphere is typically an inert metallic composition suitable for homogenizing the sample into any composition present in the tube, such as a nucleic acid preservation solution. Exemplary compositions which may be used are described in applicant's U.S. Patent Application Serial No. 61/949,692 filed March 7, 2014, the entire contents of which are incorporated herein by reference. The spherical bearing is sized to fit the tube, fits into the closed end (rounded) bottom 15 of the tube, and has adequate space between the spherical bearing and the inner side walls of the tube. This allows the ball bearing to move freely within the tube and efficiently homogenize the sample during user agitation. Ideally, the tube can include at least one large (5.6-11.1mm, typically 7.9mm) and dense (7.6-15.63 g/cm3) metallic sphere smaller than the inner diameter. of the tube (eg 12.9 mm). Ideally, the densest material possible is selected for the homogenizing media (eg tungsten carbide (15.63 g/cm3) or stainless steel (7.6-8.0 g/cm3). homogenizers are selected with an outer diameter slightly smaller than the inner diameter of the tube or container (for example, when the homogenization medium is a mixing sphere, the mixing sphere will typically have a diameter of about 4-6 mm, typically about 4-5 mm or about 5 mm less than the inside diameter of the mixing tube.) This leaves about 2-3 mm on one side of the ball between the ball and the inner wall of the tube. be selected with a "free space" above the sample and a stabilization solution to allow the homogenization medium to gain momentum during manual shaking.
    [0054] If the homogenization medium/sphere is too small in relation to the tube, the sample passes around the homogenization medium/sphere without dispersing in the stabilization solution. In contrast, if the homogenization medium/sphere is too large (eg > 11.1 mm) relative to the tube (eg 12.9 mm inside diameter), the sample does not disperse or "crush" between the homogenizing medium/sphere and the tube walls, the homogenizing medium/sphere does not gain enough momentum and the sample becomes compacted at one or both ends of the tube. Ideally, when the outer diameter of the homogenization medium (eg 7.9 mm tungsten carbide or stainless steel ball) releases the inner vertical walls of the tube (eg 10 ml tube with an inner diameter of 12.9 mm, above) of about 5 mm (2.5 mm on both sides of the sphere), the homogenization medium effectively functions as a homogenizer, breaking or breaking the samples as a solid, semi-solid stool sample (eg, 400 mg; Bristol scale type 1-7), collected in the present composition (eg 2 ml), to form a homogeneous liquid sample that can be quickly pipetted or manipulated and processed in the laboratory. This homogenization means ensures that the collected biological sample, even solid feces, is quickly and completely broken up and, in doing so, is quickly exposed to the stabilizing composition. It is important to note that it was found that the density of the homogenization medium, not just its diameter, compared to the tube/container, was critical to achieving complete sample disruption in a timely manner (20-30 seconds) by shaking with Simply force the tube by hand. Due to the malleable and often sticky nature of the stool (eg type 4), it is often difficult to achieve complete homogenization of this sample in flat-bottomed or conical-bottom tubes using a spherical homogenization medium. Therefore, a round bottom tube for a spherical homogenization medium is most suitable.
    [0055] Surprisingly, for complete homogenization of the most difficult types of human stool (eg 400 mg; Bristol Scale type 1-2) of the stabilizing composition (eg 2 ml) within a reasonable period of time ( <3 minutes), both the stopping media and the homogenizing media are required. In the absence of the volumetric disruption member, the homogenization means alone is not capable of rapidly disaggregating such hard stools into the composition to form a homogeneous mixture.
    [0056] In certain embodiments, the outer base 22 of the tube has an enhanced anti-rotation feature. This is mainly composed of a reinforced "skirt" of extra-resistant material, such as the plastic used in the rest of the tube, or any other suitable material. Figure 4 illustrates an exemplary skirt when viewed from the bottom of the tube. The skirt may include extra plastic, such as ribs 23a-c, to reinforce the skirt and reduce the likelihood of tube collapse under g-force during centrifugation and to strengthen the tube base to prevent breakage during vigorous shaking, particularly when a mixture such as a metal ball bearing is used. The skirt can also be polygonal in shape, such as triangle, square, hexagonal or the like, to keep the base in a strong position during collection post-processing and prevent tube rotation during leveling and uncapping. The hexagonal shape, for example, can serve as a typical tube-locking e-key holding devices used in robotic and/or manual systems, which would be used to process the sample in the tube. Cover
    [0057] As exemplified in Figures 5a-c, the cap 26 may have any suitable cover that complements the volumetric disruption member or container and the open end of the tube. Ideally, however, an exemplary cap as shown is particularly advantageous. The cap 26 may be cylindrical and made of a durable material such as polyethylene plastic, polypropylene or related. The cap 26 comprises an upper end 28 and an open end 32 which connects with the volumetric disruption member. In some embodiments, the cap can connect directly with the tube, if no volumetric disruption member is used. The cylindrical wall of the cap between the open end and the top end can be any thickness desired, but must be firm to ensure adequate user grip to secure the cap to the volumetric breaker member or tube. The cap can be a generally hollow cylinder, or a solid portion therein. Top end 28 of the lid can be opened or closed as desired and can be marked with any desired indicia.
    [0058] The cap itself can be sized to accommodate the size of a typical user's index finger and thumb. For example, the cap can be relatively tall to accommodate the width of an adult thumb. This is particularly useful to reduce any incidence of unscrewing the volumetric breakage member together with the cap, when only removal of the cap is desired. The outer surface 30 of the lid may be ribbed to facilitate a tightening of the lid. As an alternative and as per the embodiment in Figure 5c, the cap can be polygonal in shape (eg hexagonal) to facilitate adhesion.
    [0059] The open end 32 of the cover is best shown in Figure 5d. The open end 32 comprises a tab 34 and a pusher 36 extending from a location within the cap to the open end 32. In certain embodiments, the lower end of the pusher 36 extends a distance from the inside of the cap, but does not extend. extends beyond tab 34 of open end 32. In certain embodiments, the lower end of the pusher is generally concave in shape. In this embodiment, the lower end has a pusher tab 48 and a lower end surface 50 for cooperating and engaging with the volumetric disruption member. By coupling the cap with the volumetric disruption member, as described in more detail below, the concave nature of the lower end allows for a complementary relationship between the lower end surface 50/pusher tab 48 with the disruption member.
    [0060] Figure 5e shows a cross section of the cover. The lid interior 40 constitutes a platform from which the pusher 36 extends. The pusher 36 has an upper end 38 extending from the lid interior 40 and the lower end as described above, including the pusher lip 48 and the lower end surface 50. Figure 6 provides a closed view of the lower end of the pusher. An interior surface 46 may comprise threading for mating with complementary threading on the volumetric disruption member and/or the tube when the cap is placed on top of either. This threaded region typically extends from the open end flap upward toward and adjacent to the interior 40 of the cap. Inner surface 46 provides a sealing surface when the cap is engaged with the volumetric and/or tube disruption member. The space between one side of the pusher and an open-end 32 inner surface 46 of the cap provides a passage for the tab of the volumetric disruption member (or tube) to engage the inner surface 46.
    [0061] Figures 7a and b show a cap wrapped with a volumetric disruption member and tube in accordance with the present invention. When coupled together, a high-seal cleaner 151 forms a tight seal with the inner wall of the tube to reduce the likelihood of leakage when sample and stabilizing composition are transported into the collection device. In the embodiment shown in Figure 7c, and as described above, there may be teeth 13 at the end of the upper (open) tube, which serve to "bite" into the volumetric disruption member when involved therewith. Teeth 13 press on top wiper seal 151. This also assists with reduction leakage as it creates a tight fit between the volumetric breaker member and the tube. Volumetric disruption member
    [0062] The volumetric disruption member is a removable container for receiving a quantity of sample. The volumetric breakout member is removable from the open end of the tube and is typically used to collect a portion of the sample before introducing the sample into the tube. For example, the volumetric disruption member may receive about 200 mg to 2 g of sample, such as 400 mg stool for example, which is suitable for analysis; however, larger or smaller sizes of the breaking member may be desired to accommodate different sample amounts. The breakout member is usually hollow and generally cylindrical or polygonal (such as hexagonal) in shape, for example, such that it complements the shape of the tube and cap.
    [0063] In an embodiment shown in Figures 8a and b, the volumetric disruption member 51 comprises two main sections: a sample receiving end 50 and a base end 52. The sample receiving end 50 comprises a cylindrical wall 54 having a tab 59. The cylindrical wall 54 extends from the end of the base 52 to the tab 59 and defines a reservoir at the sample-receiving end. An outer surface 53 of the cylindrical wall 54 is desirably threaded to engage the wires with the inner surface of the cap when the cap is engaged with the volumetric disruption member.
    [0064] Figure 8c shows an alternative embodiment of the volumetric disruption member having one end of the hexagonal base 155.
    [0065] The base end 52 of the volumetric disruption member has a cylindrical wall 55 defining an open end which is slightly larger in diameter than the sample receiving end 54. The base end top 52 forms a protrusion 61 from which the cylindrical wall of the sample receiving end extends. When coupled with the cap, the wall of the cap, when placed over the break member, lines up in flow with the wall of the base end. In addition, the open end of the base fits over the tube, thus closing the open end of the tube. To facilitate this, the inner surface 57 of the base is also segmented to engage the thread in the tube. The interior of the base of the volumetric disruption member may include a high wiper seal 151 to ensure the inner tube wall seal thereto. This is particularly advantageous for transporting the sample and stabilizing the composition to ensure a tight seal of the tube with the cap.
    [0066] The base wall 55 may have an indicator, as a flat surface between grooves in the wall, to align with a similar indicator on the lid; once aligned, the complementary signs indicate proper closure of the lid. The wall can also be made of a transparent or translucent material, if desired, to facilitate viewing of the sample and if it has been properly loaded into the volumetric disruption member.
    [0067] As shown in Figures 8a, 8c and more particularly in Figures 9a-d, the volumetric disruption member comprises a disruption member 56. The disruption member is generally positioned within the sample receiving end; for example, it can serve as the base of the sample receiving end reservoir. However, it is envisioned that the disruption member can be positioned at any suitable location within the volumetric disruption member depending on the desired volume and the type of sample to be collected. The breakout member can be of any suitable material to facilitate the breakage of the sample when applied to them. In an embodiment shown in Figure 9a, the breaking member is shaped like clover leaves, but can be other shapes such as cross-shaped, "Y"-shaped, triangle-shaped, square-shaped, or rectangular-shaped. , for example. In the present embodiment, the four "arms" 58a-d of the disruption member are apertures defined by the projections 60a-d therebetween. The 60a-d projections are ideally of a durable material and may include cutting edges to facilitate breaking of the specimen passing through the tearing member. When placed at the sample receiving end of the volumetric disruption member, the sample is in communication with the tube below through the openings in the disruption member. Other modalities of the disruption member are shown in Figures 9b-d, including "radiation symbol" (Figure 9b), "helix" (Figure 9c) and "aim" (Figure 9d). The openings serve to direct or break the sample channel in the tube and keep the sample segments separate.
    [0068] The breaking member is ideally convex and rounded. This allows the breakout member to cooperate via mounting to the concave dimension of pusher 36. With a sample in the volumetric breakout member reservoir, it is ideal for the cap to contact the sample closest to the first wall. This forces the fecal material into and through the center of the tearing limb. This precludes a scenario in which if the pusher is convex and comprises a "dome", the pusher dome would contact the first sample and force the sample outward towards the wall of the volumetric disruption member and reservoir. With the pusher making contact with the wall of the first volumetric disruption member, it allows scraping of the sample wall and forces the sample into the disruption member (and eventually into the tube below). In addition, the pusher frame 36 and the volumetric disruption member reservoir create a seal as the sample is forced through the disruption member and into the tube. The pusher forces from the outside to the inside and scraping the wall creates a relatively clean seal. In addition, a seal is created in the base and side walls of the pusher on the volumetric disruption member. Finally, when the pusher wraps around the bottom of the breakout member, the shape of the pusher deforms the breakout member to deliver the maximum amount of sample in the tube. When the cap is engaged by the user and the pusher exerts a force on the breakout member, the breakout member projections 60a-d flex inward and downward. This allows the projections to come together, inserting the spaces (ie, the "arms" 58a-d separating the projections). As the projections move, arms 58a-d become smaller, forcing the sample through ever-narrower openings. For example, if the stool sample, the sample is made smaller by the action of the pusher, the invasion of the projections and the narrowing of the arms. This facilitates deeper sample disruption and promotes sample homogenization in stabilizing and preserving the composition within the tube.
    [0069] Similar to the bottom of the round tube, the curved surface 153 (best shown in Figure 7a) at the bottom of the volumetric disruption member prevents compaction of the sample by the ball bearing (if used) in potential corner traps and allows the sample effectively mixes with any composition in the tube.
    [0070] Figures 10a-c show various views of the fully assembled device, comprising the cap, volumetric disruption member and tube. EXAMPLES EXAMPLE 1: Use of the present device for collecting and storing a sample
    [0071] In an exemplary use, the tube comprises a ball bearing and composition for the preservation of nucleic acids in a sample. The volumetric breaking member is attached (eg screwed) to the open end of the tube to receive the sample and finger tighten to ensure a seal is formed. A specimen, such as a fecal specimen, is placed within the specimen from the receiving end of the volumetric disruption member. The user can apply the sample with a probe, stick, spoon, cotton swab, tongue depressor, spatula or any other instrument. Sample can also be added using an applicator, such as a syringe, as described in Example 2, below.
    [0072] The sample is placed on top of the disruption member, level with the upper lip of the sample receiving end wall of the volumetric disruption member. Sufficient sample is added to maximize breaker member coverage and "fill" the reservoir within the sample receiving end.
    [0073] Next, the cap is placed over the volumetric disruption member and, when threads exist, the cap is rotated to the volumetric disruption member to ensure a tight fit. By this action, the plug presses down on the sample at the sample receiving end of the volumetric disruption member. The force of the cap interrupts the sample as it is pressed through the breaking member to form parts of the sample that are more easily suspended in any composition present in the tube. The concave orientation of the inner surface of the lid prevents compaction of the sample within the curves of the junction between the pusher and the volumetric disruption member. A tall wiper seal can be used to seal the inner wall of the tube with the volumetric breaking member as described in this document.
    [0074] The user then vigorously shakes the tube by hand with the cap firmly secured over the volumetric disruption member and tube. This allows the ball bearing (if present) to mate with the sample to further interrupt it and to promote complete suspension of the liquid chemical sample within the tube. The user can stir any desired amount of time, typically for about 30 seconds, until the sample is properly mixed with the chemical solution. Although not all particles in the sample will dissolve in the chemical solution, agitation promotes at least a considerable portion of the sample to become dissociated in solution. EXAMPLE 2: Use of the present device with an applicator
    [0075] An applicator, as shown in Figure 11, can also be used. The applicator can be used to extract a portion of a larger sample for addition to the tube. In certain embodiments, the applicator is a modified syringe, comprising a piston 70 and a syringe tube 72. At one end of the piston 70 is a syringe plunger 76 to facilitate expulsion of the sample. In use, the lower end 74 of the syringe tube is placed within the largest amount of the sample and a sample portion of the core is drawn therefrom by pulling up on the first end 78 of the piston 70.
    [0076] In one example, a stool sample is obtained. First the plunger is pulled back a defined distance (indicated by the recoil/restraint in the syringe barrel) to create a volumetric void at the tip of the syringe; the syringe is pushed for the largest amount of sample collected a sample that fills the empty space created in the last step. Ideally, the lower end 74 of the syringe tube is of a suitable and desired volume that adjusts the volume of the volumetric disruption member.
    [0077] Lower end 74 of the syringe tube is then placed over the volumetric disruption member. In certain embodiments, the lower end of the syringe tube is segmented and complements the volumetric disruption member wires. The user then presses down on the piston 70 at the first end 78 to expel the sample from the syringe tube 70. Depressing the piston will push the sample out of the syringe and through the volumetric disruption disruption member into the tube. In effect, the syringe can function as the pusher as described above. It would be particularly advantageous if syringe plunger 76 is likewise concave to complement the convex structure of the disruption member.
    [0078] For liquid samples (eg blood, urine, saliva, cell suspensions), including 7 types of stool, pulling the modified syringe plunger will draw up a known volume of liquid sample that can be expelled into the tube through the limb of volumetric disruption. Hence selection of an appropriate applicator enables volumetric collection of a wide variety of sample types, ranging from liquid (7 stool types) to hard solids (1 stool type).
    The sample can then be processed according to standard protocols to isolate, amplify and store nucleic acids from the sample.
    [0080] All publications, patents and patent applications mentioned in this specification are indicative of the skill level of those skilled in the art to which this invention belongs and are incorporated herein by reference to the same extent as they would be if each publication, patent or application individual patents were specifically and individually indicated to be incorporated by reference.
    [0081] The invention being thus described, it will be obvious that the same can be varied in many ways. Such variations are not to be considered as a departure from the spirit and scope of the invention, and all modifications as would be obvious to a person skilled in the art are intended to be included within the scope of the following claims. The scope of the claims should not be limited to the preferred embodiments in the examples, but the broadest interpretation consistent with the description as a whole should be given. References:
    [0082] Cole SR, Young GP, Esterman A, Cadd B, Morcom J (2003) A randomized trial of the impact of new faecal haemoglobin test technologies on population participation in screening for colorectal cancer. Journal of Medical Screening 10:117-122.
    [0083] Couch RD, Navarro K, Sikaroodi M, Gillevet P, Forsyth CB, Mutlu E, Engen PA, Keshavarzian A (2013) PloS One 8(11):e81163.
    [0084] Culligan EP, Sleator RD, Marchesi JR, Hill C (2013). Meta genomics and novel gene discovery: Promise and potential for novel therapeutics. Virulence 5(3):399-412.
    [0085] DiGiulio DB, Romero R, Amogan HP, Kusanovic JP, Bik EM, Gotsch F, Kim CJ, Erez O, Edvin S, Relman DA (2008) Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: the molecular and culture-based investigation. PloS One 3(8):e3056.
    [0086] Evans JM, Morris LS, Marchesi JR (2013) The gut microbi ome: the role of the virtual organ in the endocrinology of the host. The Journal of Endocrinology 218(3):R37-47.
    [0087] Heaton KW, Radvan J, Cripps H, Mountford RA, Braddon FEM, Huges AO (1992) Defecation frequency and timing, and tool form in the general population: a prospective study. Gut 33(6):818-24.
    [0088] Korecka A, Arulampalam V (2012) The gut microbiome: scourge, sentinel or spectator Journal of Oral Microbiology 4: 1-14.
    [0089] Kostic AD, Howitt MR, Garrett WS (2013) Exploring host - microbiota interactions in animal models and humans. Genes and De-velopment 27: 701-718.
    [0090] Lewis SJ, Heaton KW (1997) Stool form scale as a useful guide to intestinal transit time. Scandinavian Journal of Gastroenterology 32: 920-924.
    [0091] Osborne JM, Wilson C, Moore V, Gregory T, Flight I, Young GP (2012) Sample preference for colorectal cancer screening tests: Blood or stool Open Journal of Preventive Medicine 2(3): 326-331.
    [0092] Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO (2007) Development of the human infant intestinal microbiota. PLoS Biology 5(7): e177.
    权利要求:
    Claims (13)
    [0001]
    1. Sample receiving device, comprising: a test tube (10); a receptacle (51) in communication with the test tube (10) for receiving a sample; and a lid (26) characterized in that the receptacle (51) comprises a first opening end for receiving the sample, and a second end for coupling with the test tube (10), the lid (26) comprising a pusher (36) for coupling with the sample when the sample is in the receptacle (51), wherein the receptacle (51) comprises a tearing member (56) for breaking the sample when the cap (26) engages with the receptacle (51 ) for expelling the interrupted sample into the test tube (10), and wherein the pusher (36) comprises a first end extending from an inner part of the cap (26), and a second end for engaging the sample ; wherein the receptacle (51) comprises a thread for engaging with a complementary thread of the cap (26) to allow the receptacle (51) to engage and secure with the cap (26).
    [0002]
    2. Device according to claim 1, characterized in that the receptacle (51) is a volumetric breaker.
    [0003]
    3. Device according to claim 1 or 2, characterized in that the receptacle (51) has a capacity of about 200 mg to about 2 g of sample, preferably of about 400 mg of sample.
    [0004]
    4. Device according to any one of claims 1 to 3, characterized in that the pusher (36) expels the sample through the breaking member (56) of the receptacle (51).
    [0005]
    5. Device according to claim 1, characterized in that the pusher (36) is concave, preferably wherein the second end comprises a flap (48) and a lower end surface (50).
    [0006]
    6. Device according to any one of claims 1 to 5, characterized in that the test tube (10) further comprises a mixing medium (24), preferably one or more balls, more preferably ball bearings.
    [0007]
    7. Device according to claim 1, characterized in that the breaking member (56) is convex.
    [0008]
    8. Device according to claim 1, characterized in that the breaking member (56) is convex and the pusher (36) is concave.
    [0009]
    9. Method of preserving a biomolecule in a biological sample, the method characterized by the fact that it comprises: a) obtaining a sample; b) obtaining the device as defined in claim 1; c) removing the lid (26) from the receptacle (51) attached to the test tube (10); d) placing the sample in the receptacle (51); e) placing the lid (26) on the receptacle (51); f) secure the lid (26) with the receptacle (51), thereby coupling the pusher (36) with the receptacle (51) and coupling the sample with the breaker means (56) to expel the sample into the test tube ( 10); and g) mixing the expelled sample with a composition in the test tube (10) to preserve the biomolecule within the sample.
    [0010]
    10. Method according to claim 9, characterized in that the step of mixing further comprises homogenizing the expelled sample with a mixing medium (24), preferably one or more ball bearings (24).
    [0011]
    11. System for preserving a biomolecule from a sample, the system characterized in that it comprises: the sample receiving device as defined in claim 6, wherein the disruption member (56) is arranged to disrupt the sample when the pusher (36) couples with the sample in the receptacle (51) to expel the sample into the test tube (10); and a composition in the test tube (10) for preserving the biomolecule in the expelled sample; wherein the mixing means (24) is arranged to homogenize the broken sample once it is expelled from the receptacle (51) within the test tube (10).
    [0012]
    12. System according to claim 11, characterized in that the cap (26) is a syringe comprising a syringe plunger (76) fitted to a piston (70) in a syringe tube (72), and wherein the thread of the receptacle (51) couples with complementary threads disposed on a lower end of the syringe tube (72).
    [0013]
    13. Kit characterized in that the kit comprises: the device as defined in any one of claims 1 to 6, and instructions for use in preserving a biomolecule from a biological sample.
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    同族专利:
    公开号 | 公开日
    RU2696484C2|2019-08-02|
    SG10201810090QA|2018-12-28|
    IL280814D0|2021-04-29|
    AU2020281110A1|2021-01-07|
    MX2016014871A|2017-03-27|
    RU2016146466A|2018-06-14|
    SA516380270B1|2021-03-18|
    IL248634A|2021-02-28|
    US20170072393A1|2017-03-16|
    EP3146307A4|2018-02-28|
    CN106461518B|2021-09-10|
    AU2015258711B2|2020-09-10|
    WO2015172250A1|2015-11-19|
    JP6968538B2|2021-11-17|
    JP2017519975A|2017-07-20|
    SG11201609187YA|2016-12-29|
    AU2015258711A1|2016-11-24|
    RU2016146466A3|2018-12-27|
    JP2020190562A|2020-11-26|
    CN106461518A|2017-02-22|
    CA2948678A1|2015-11-19|
    KR20170012281A|2017-02-02|
    IL248634D0|2017-01-31|
    EP3146307A1|2017-03-29|
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    法律状态:
    2020-03-24| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2021-03-02| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2021-05-11| 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 13/05/2015, OBSERVADAS AS CONDICOES LEGAIS. |
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    US201461992993P| true| 2014-05-14|2014-05-14|
    US61/992,993|2014-05-14|
    PCT/CA2015/050434|WO2015172250A1|2014-05-14|2015-05-13|Device for collecting, transporting and storing biomolecules from a biological sample|
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