阅读说明：本技术 用于收集肠液的装置 (Device for collecting intestinal juice ) 是由 雅克·路图 菲利普·辛奎因 唐纳德·基思·马丁 托马斯·索兰佐 让-皮埃尔·阿尔卡拉斯 让 于 2018-10-24 设计创作，主要内容包括：本申请涉及一种用于收集肠液样本的装置,包括：内部聚合物的材料-具有至少部分压缩的开孔结构,具有体积V并且适于通过吸收肠液膨胀到大于或等于1.1×V的体积,所述内部材料包覆在耐消化液的由弹性聚合物制成的外壳内,所述外壳包括至少一个允许将肠液吸入内部材料的开口,适于在37℃的温度下溶于肠液中的耐胃液材料布置在每个开口的顶部；以及至少一个用于关闭开口的机构。(The present application relates to a device for collecting a sample of intestinal fluid, comprising: material of an inner polymer-having an at least partially compressed open-cell structure, having a volume V and adapted to expand to a volume greater than or equal to 1.1 xv by absorption of intestinal fluid, said inner material being enclosed within a casing made of an elastic polymer resistant to digestive fluids, said casing comprising at least one opening allowing intestinal fluid to be absorbed into the inner material, a gastric fluid resistant material adapted to be dissolved in the intestinal fluid at a temperature of 37 ℃ being arranged on top of each opening; and at least one mechanism for closing the opening.)

1. A device for collecting a sample of intestinal fluid, comprising:

-an inner material (2) made of a polymer:

-has an at least partially compressed open cell structure, and

has a volume V_i，

-a housing (1) made of an elastic polymer that is not affected by digestive fluids, said housing (1) comprising at least one opening (3),

-a gastro-resistant material arranged on top of each opening, said gastro-resistant material being adapted to dissolve in intestinal fluid at a temperature of 37 ℃; and

-at least one mechanism for closing the opening,

the aspiration of intestinal fluid inside the device causes the expansion of said inner material (2), thus causing the closure of said means for closing the opening,

it is characterized in that the preparation method is characterized in that,

the inner material (2) is adapted to expand to greater than or equal to 1.1 × V by absorption of intestinal fluid_iA volume of, and

the shell (1) encases the inner material (2), the at least one opening (3) allowing intestinal fluid to be sucked into the inner material such that expansion of the inner material results in elastic deformation of the shell.

2. The device according to claim 1, wherein the polymer of the housing (1) is selected from the group consisting of: latex, vinyl, nitrile, silicone, and mixtures thereof.

3. The device according to any one of the preceding claims, wherein the inner material (2) is adapted to expand to greater than or equal to 2 × V by absorption of intestinal fluid_iPreferably greater than or equal to 6 × V_iThe volume of (a).

4. The device according to any one of the preceding claims, wherein the polymer of the inner material (2) is selected from: at least partially crosslinked polyvinyl alcohol, at least partially crosslinked poly (meth) acrylic acid and salts thereof, at least partially crosslinked polysaccharide, or mixtures thereof.

5. The device according to any one of the preceding claims, wherein the means for closing the opening (3) comprise a shutter (4) not affected by the intestinal fluid, interposed between the casing (1) and the inner material (2) and arranged below the opening (3).

6. The device according to claim 5, wherein the means for closing the opening (3) comprises a membrane (5) or particles (6) having an average diameter between 0.1mm and 2mm, the membrane (5) or particles (6) comprising a polymer adapted to be dissolved in intestinal fluid at a temperature of 37 ℃, the membrane (5) or particles (6) being arranged between the valve (4) and the housing (1), wherein the membrane (5) or particles (6) and the housing (1) together form a channel through which intestinal fluid is adapted to flow and reach the inner material (2).

7. The device according to claim 5, wherein the mechanism for closing the opening (3) comprises:

-a film or particle (7), said film or particle (7) being arranged between said shutter (4) and said housing (1) and comprising a first polymer bearing hydroxyl, carboxylic acid and/or carboxylate functional groups; and

-a film or particle (8), said film or particle (8) being arranged between said film or particle (7) and said shutter (4) and comprising a second polymer bearing hydroxyl, carboxylic acid and/or carboxylate functional groups;

-wherein the film or particle (7) comprising a first polymer, the film or particle (8) comprising a second polymer and the outer shell (1) together form a channel through which intestinal fluid is adapted to flow and reach the inner material (2),

if:

-when the first polymer carries hydroxyl functional groups, the second polymer carries carboxylic acid and/or carboxylate functional groups,

-when the first polymer bears carboxylic acid and/or carboxylic acid salt functional groups, the second polymer bears hydroxyl functional groups,

-the first polymer and the second polymer are adapted to react together to form a polyester during circulation of intestinal fluid in the passageway.

8. The device according to any of the preceding claims, wherein the device is adapted to collect intestinal fluid having a volume between 0.01mL and 1mL, preferably a volume equal to 0.3 mL.

9. A method (P1) for collecting a sample of intestinal fluid, comprising:

i) ingesting at least one device for collecting a sample of intestinal fluid according to any one of the preceding claims;

ii) the at least one device is moved to the intestine to dissolve the gastric juice resistant material such that the opening is opened;

iii) sucking intestinal fluid into the casing through the opening (3) so that the inner material (2) is expanded to 1.1 × V or more by absorbing intestinal fluid_iThe volume of (a);

iv) closing the means for closing the opening (3);

v) withdrawing the device in the faeces.

10. Use of a device according to any one of claims 1-8 for collecting intestinal fluid.

Technical Field

The present invention relates to a device for collecting intestinal fluid samples from a human or animal body, in particular for research and diagnostic purposes.

Background

Knowledge of the digestive system and its microbiota is considered an important topic for human or animal health. For the diagnosis of diseases, it is crucial to be able to qualitatively and quantitatively characterize the microbiota contained in different parts of the digestive system, in particular in the intestinal tract.

Currently, most assays are performed on feces, thus limiting the possibility of observing the microbiota. Despite the ongoing improvements and lower prices of current analytical methods, there is a need for an automated device that does not negatively impact health, is simple and inexpensive, and is useful for sampling microflora from intestinal fluids.

Devices for collecting intestinal fluid are known, in particular from DE19801573 and US5971942, which describe capsules for extracting samples formed by an outer shell defining an inner volume, wherein the inner pressure is low, the intestinal fluid is fed into the capsule by a pressure difference through an opening, and the closure of the capsule is achieved by a balance of the pressure inside and outside the capsule.

The device according to the application US5971942 is characterized by a small internal volume and a low internal pressure. The device according to DE19801573 comprises a mechanism for closing the opening, which mechanism comprises foam which is not in a compressed state.

It is therefore an object of the present invention to provide a device for collecting samples of intestinal fluid at different levels in the intestine.

It is another object of the present invention to provide a device that can collect different volumes of intestinal fluid while being easily swallowed by a patient.

It is another object of the invention to provide such a device which is inexpensive and easy to use and retrieve.

Other objects of the present invention will appear after studying the following description.

Disclosure of Invention

For this purpose, the invention relates to a device for collecting a sample of intestinal fluid, comprising:

-material of the inner polymer:

-has an at least partially compressed open cell structure, and

has a volume V_i，

-an elastic polymeric casing impervious to digestive fluids, said casing comprising at least one opening,

-arranging on top of each opening a gastro-resistant material adapted to dissolve in intestinal fluid at 37 ℃; and

-at least one mechanism for closing the opening.

The aspiration of intestinal fluid into the device causes the inner material to expand, causing the closure of the mechanism for closing the opening.

The inner material is adapted to expand to a volume greater than or equal to 1.1 × Vi by absorption of intestinal fluid.

The housing encloses an inner material, and the at least one opening allows intestinal fluid to be drawn into the inner material.

Thus, the expansion of the inner material results in an elastic deformation of the outer shell.

The invention thus ensures that the volume of intestinal fluid collected can be accurately (pre-) determined, since the expansion force of the inner material is balanced with the force exerted by the housing due to its elastic deformation.

The term "intestinal fluid" refers to the fluid present in the intestine, where the fluid contains a very large number of living microorganisms, commonly referred to as "microbiota". The term "digestive juice" means gastric juice or intestinal juice.

Hereinafter, the expression "between X and Y" represents a range including X and Y. The term "polymeric" is meant to include polymers.

Preferably, the inner material of the polymer comprised in the device has an intestinal fluid solubility of less than or equal to 1 mass%, measured at a temperature of 37 ℃. Preferably, the inner material is insoluble in intestinal fluid at a temperature of 37 ℃. The term "insoluble" means that the inner material does not dissolve (solubility of 0 mass%) throughout the digestion process (preferably for at least 24 hours) after immersion in intestinal fluid at a temperature of 37 ℃.

Advantageously, the polymer of the inner material is selected from: at least partially crosslinked polyvinyl alcohol, at least partially crosslinked poly (meth) acrylic acid and salts thereof, at least partially crosslinked polysaccharide, or mixtures thereof. Among the polysaccharides, mention may be made of dextran or one of its derivatives.

The at least partial crosslinking of these polymers ensures that their solubility in intestinal fluid at a temperature of 37 ℃ is less than or equal to 1 mass%, preferably 0 mass% (insoluble). In fact, the non-crosslinked polymers described above are generally soluble in water and therefore soluble in intestinal fluids at a temperature of 37 ℃.

The polymeric inner material has an open pore structure and a volume V_iThe volume V_iCorresponding to the volume before it is taken. Thus, it exists in the form of a foam or sponge.

The open cell structure of the inner material comprises a plurality of pores separated from each other by polymeric walls, the average thickness of said walls preferably being between 2 μm and 500 μm. The average thickness of the pore walls was measured by scanning electron microscopy.

The pores of the open-porous structure are typically at least partially or completely filled with a gas, preferably air. The apertures may include water.

The open cell structure is at least partially compressed, whereby the inner material is adapted to expand to greater than or equal to 1.1 × V by absorption of intestinal fluid_iIn particular greater than or equal to 2 × V_iPreferably greater than or equal to 6 × V_iThe volume of (a).

The term "elastic shell" means that the shell has elasticity, thereby ensuring that the internal volume expands to greater than or equal to 1.1 × V_iPreferably to 2 × V_iTo 6 × V_iThe volume of (a). Typically, the polymeric sheath is stretchable to 2 to 6 times its original length at a temperature of 25 ℃ under a force of 1N. Preferably, the shore hardness (shore a standard method) of the elastic shell is between 30 and 55. Preferably, the polymer of the shell has a young's modulus between 1.1 and 1.9 MPa.

Preferably, the polymer of the shell is selected from: latex, vinyl, nitrile, silicone, and mixtures thereof, preferably, the polymer of the shell is selected from nitrile polymers such as butadiene acrylonitrile copolymers.

Since the shell encases the inner material, the expansion of the inner material once administered is limited by the elasticity of the shell. Preferably, the shell is in an unstretched state prior to administration.

The term "gastric juice-impervious envelope" means: at 37 ℃, gastric fluid does not flow through the shell except at the site of the opening. The shell is therefore impermeable to gastric juices. Typically, the housing has pores with an average diameter of less than 0.2 μm as measured by scanning electron microscopy. Preferably, the housing is pore-free.

Preferably, the shell is stable with respect to digestive fluids. The term "stable" means that the shell is not damaged, and that the chemical composition and tightness of the shell is not altered by contact with the digestive juices throughout the digestion process (preferably at least 24 hours).

The housing defines an interior space in which the interior material is disposed. The inner material typically occupies at least 80%, in particular at least 90%, preferably at least 95% of the volume of the inner space formed by the housing. Preferably, the pressure difference between the pressure inside the housing (and thus inside the interior material enclosed therein) and the atmospheric pressure is less than 5%, in particular less than 1%, preferably 0%. Typically, the pressure inside the housing (and thus inside the inner material enclosed therein) is atmospheric pressure (1 bar).

Preferably, the housing comprises 1, 2, 3, 4 or 5 openings, preferably a single opening. The opening allows intestinal fluid to be drawn into the device and thus into the inner material.

The housing may include wires for reinforcing the housing so that the housing is better able to withstand peristaltic movement. The metal wire may be disposed in the thickness of the housing. Preferably, the metal line is a ferromagnetic metal line.

The housing may be integrated with coloured markings on its surface to allow identification of the retracted device. Silicon chips, RFID chips, etc. may also be used.

The term "gastric juice resistant material" means a material that does not rupture and dissolve upon contact with gastric juice. The term "adapted to dissolve in intestinal fluid at a temperature of 37" means that the limit of solubility of the gastric resistant material in intestinal fluid at a temperature of 37 ℃ is more than 95 mass%, preferably more than 98 mass%.

Preferably, the gastro-resistant material is adapted to dissolve in intestinal fluids at a given PH. Indeed, the solubility of the gastro-resistant material may essentially depend on the PH of the medium in which the gastro-resistant material is placed. Thus, preferably the gastro-resistant material is insoluble in a medium having an acidic pH (less than 7) at a temperature of 37℃, preferably the gastro-resistant material is insoluble in a medium having a pH of less than 5 at a temperature of 37℃. The term "insoluble" means that the gastric resistant material has a solubility in a medium having a PH of less than 5 of less than or equal to 1% by mass, preferably equal to 0% by mass. The pH of intestinal fluids varies between 5 and 8 depending on the exact location of the intestine in which it is located. As is known to those skilled in the art, a stomach is characterized by a pH between 1.5 and 3 in the fasting state, which pH is between 2 and 5 after a meal and gradually becomes neutral when leaving the stomach. Thus, the pH at the duodenum is between 5.4 and 6.1, the pH at the ileum is between 7 and 8, the pH at the cecum and colon is between 5.5 and 7, and the pH in the rectum is equal to 7. Thus, one skilled in the art will readily appreciate that gastric juice resistant materials are selected according to solubility at the pH at the location where intestinal fluid is to be collected. Preferably, a gastro-resistant material adapted to dissolve in intestinal fluid at a temperature of 37 ℃ is arranged on top of the entire device. For example, a gastric resistant hard capsule adapted to dissolve in intestinal fluid at a temperature of 37 ℃ may cover the assembly formed by the outer shell and the inner material. Such a gastro-resistant material is suitable for complete dissolution in intestinal fluid at a temperature of 37 c when the pH reaches a determined value. Preferably, the gastro-resistant material dissolves rapidly in less than 10 minutes, preferably less than 5 minutes.

Preferably, the gastric juice resistant material is selected from: polymethyl methacrylate, acetyl cellulose phthalate, hydroxymethyl cellulose, hydroxypropyl methylcellulose succinate, polyvinyl acetate phthalate, shellac, and the like. Advantageously, the gastric juice resistant material is selected from: winning wound

Eudragit sold by company

D-55 and Eudragit

A compound is provided.

Advantageously, one or more intermediate layers (typically alginate layers) may be arranged between the opening and the gastro-resistant material. Preferably, there is no intermediate layer between the opening and the gastro-resistant material.

In one embodiment, the outer shell and the inner material are encased in alginate hard capsules, which may be coated with a gastric juice resistant material such as those mentioned above. The alginate hard capsules are completely dissolved in the intestinal fluid at a temperature of 37 ℃, preferably the limit of solubility of the alginate hard capsules in the intestinal fluid at a temperature of 37 ℃ is more than 95 mass%. Since the film is coated with a gastric juice resistant material, the outer surface of the hard capsule is gastric juice resistant.

Advantageously, the device may be in the form of a cylinder, sphere or ellipsoid, preferably a cylinder. Preferably, the device may be a flat cylinder in the form of a half moon.

Preferably, the device is adapted to collect a volume of intestinal fluid between 0.01mL and 1mL, preferably a volume equal to 0.3 mL.

The mechanism for closing the openings can close each opening of the housing by closing the opening. The device may include the same number of mechanisms as the number of openings. Alternatively, a single closing mechanism may close multiple openings.

The following describes different closing mechanisms for closing a single opening, but which can be used to close a plurality of openings. Where the housing includes multiple openings, multiple identical or different closure mechanisms may be used.

Drawings

Various mechanisms for closing the opening of the device will now be described in more detail, using a number of embodiments given by way of non-limiting example, with reference to the accompanying drawings, in which:

fig. 1 shows a first embodiment of a closure mechanism, said mechanism comprising a shutter (clapet);

FIG. 2 shows a first alternative of a second embodiment of a closure mechanism comprising a shutter and a polymer film;

FIG. 3 shows a second alternative to the second embodiment of the closure mechanism, which comprises a shutter and polymer particles;

figure 4 shows a third embodiment of a closing mechanism comprising a shutter and two polymers in powder or film form;

FIG. 5 shows a fourth embodiment of a closure mechanism comprising a shutter comprising contacts;

FIG. 5A shows a top view of the closure mechanism shown in FIG. 5;

FIG. 6 shows a fifth embodiment of a closure mechanism comprising a shutter comprising a snap fastener;

FIG. 6A shows a top view of the closure mechanism shown in FIG. 6;

FIG. 7 shows a sixth embodiment of a closure mechanism comprising a shutter comprising a snap fastener and connected to a housing;

FIG. 7A shows an enlarged view of the closure mechanism shown in FIG. 7;

FIG. 8 shows a seventh embodiment of a closure mechanism including an aperture closure (obturaur);

fig. 9 shows an eighth embodiment of a closing mechanism including a disk-shaped shutter; and

fig. 9A shows a top view of the closure mechanism shown in fig. 9.

Detailed Description

Preferably, the closing mechanism according to embodiments 1 to 7 and 9 includes the shutter 4. The valve is typically resistant to intestinal fluids. The term "a valve unaffected by intestinal fluid" means: at a temperature of 37 ℃, intestinal fluid does not flow through the valve. Preferably, the shutter is made of polyethylene or silicone. The shutter may be in the form of a disc which completely closes the opening 3 once the closure mechanism is closed. Preferably, the shutter is a disc having a thickness between 0.1mm and 0.4 mm. Preferably, the surface area of the shutter is larger than the surface area of the opening.

According to a first embodiment shown in fig. 1, the mechanism for closing the opening (orifice) 3 comprises a valve 4 impermeable to intestinal fluid, interposed between the casing 1 and the inner material 2 and arranged below the opening 3.

According to a second embodiment, the mechanism for closing the opening 3 of the collecting device may comprise:

a shutter 4, unaffected by the intestinal fluid, interposed between the casing 1 and the inner material 2 and arranged below the hole 3;

-a film 5 or a granule 6 having an average diameter between 0.10mm and 2mm, said film 5 or said granule 6 comprising a polymer adapted to dissolve in intestinal fluid at a temperature of 37 ℃, said film 5 or said granule 6 being arranged between the valve 4 and the housing 1,

wherein the membrane 5 or the particles 6 and the outer shell 1 together form a channel, so that intestinal fluid is adapted to flow therethrough and reach the inner material 2.

More particularly, according to a first alternative embodiment to the second embodiment shown in fig. 2, the mechanism for closing the opening 3 of the device comprises:

a shutter 4, unaffected by the intestinal fluid, interposed between the casing 1 and the inner material 2 and arranged below the hole 3;

a membrane 5, said membrane 5 comprising a polymer adapted to dissolve in intestinal fluid at a temperature of 37 ℃, said membrane being arranged between the valve 4 and the housing 1,

wherein the membrane 5 and the housing 1 together form a channel so that intestinal fluid is adapted to flow therethrough and reach the inner material 2.

The polymer of the film 5 is adapted to dissolve in intestinal fluid at a temperature of 37 c in less than 5 minutes.

Preferably, the polymer of the membrane 5 is biocompatible. Preferably, the polymer of the membrane 5 suitable for dissolving in intestinal fluid at a temperature of 37 ℃ is a polymer with hydroxyl, carboxylic acid or carboxylate functional groups, preferably the polymer of the membrane 5 is made of polyvinyl alcohol (PVA). Preferably, the film 5 has an embossed structure.

According to a second alternative embodiment to the second embodiment shown in fig. 3, the mechanism for closing the opening of the collecting device comprises:

a shutter, unaffected by the intestinal fluid, interposed between the casing 1 and the inner material 2 and arranged below the orifice;

-particles 6 having an average diameter comprised between 0.10mm and 2mm, said particles 6 being arranged between the valve 4 and the housing 1 and comprising a polymer adapted to dissolve in intestinal fluid at a temperature of 37 ℃;

wherein the particles 6 together with the casing 1 form a passage, so that intestinal fluid is adapted to flow therethrough and reach the inner material 2.

The average diameter of the particles 6 can be determined by scanning electron microscopy. Preferably, the polymer comprised in the particles 6 is adapted to dissolve in intestinal fluid in less than 5 minutes. Preferably, the polymers included in the particles are biocompatible. Preferably, the polymer of the particles 6 is polyethylene glycol (PEG), generally polyethylene glycol having a molecular weight of less than 20000g/mol, preferably a molecular weight equal to 8000 g/mol. Higher molecular weight PEGs require longer time to dissolve in intestinal fluids and are less suitable for the present invention by comparison.

According to a third embodiment shown in fig. 4, the mechanism for closing the opening 3 comprises:

a shutter 4 unaffected by the intestinal fluid, interposed between the casing 1 and the inner material 2 and arranged below the orifice 3;

-a film or particle 7, said film or particle 7 being arranged between the shutter 4 and the housing 1 and comprising a first polymer bearing hydroxyl, carboxylic acid or carboxylate functional groups; and

-a film or particle 8, said film or particle 8 being arranged between the film or particle 7 and the shutter 4 and comprising a second polymer bearing hydroxyl, carboxylic acid or carboxylate functional groups;

-wherein the film or particle 7 comprising the first polymer, the film or particle 8 comprising the second polymer and form a channel with the outer shell 1, such that intestinal fluid is adapted to flow therethrough and reach the inner material 2.

If:

-when the first polymer carries hydroxyl functionality, the second polymer carries carboxylic acid or carboxylate functionality;

-when the first polymer carries carboxylic acid or carboxylate functional groups, the second polymer carries hydroxyl functional groups;

-the first and second polymers are adapted to react together to form a polyester during circulation of intestinal fluid in the passageway.

Independently, the first and second polymers may be in the form of films or particles 7, 8. The average diameter of the particles may be between 0.10mm and 2mm and is measured by scanning electron microscopy. The thickness of the polymer films 7, 8 may be between 0.1mm and 0.5 mm.

In this embodiment, the first and second polymers are adapted to form a polyester that closes the passageway through which intestinal fluid flows and also closes the opening. The polyester formed is insoluble in intestinal fluid at a temperature of 37 ℃, preferably the limit of solubility of the polyester formed in intestinal fluid at a temperature of 37 ℃ is less than or equal to 1 mass%, preferably 0 mass%. Preferably, the first and second polymers are biocompatible and in a dehydrated state. Preferably, the polymers bearing hydroxyl, carboxylic acid or carboxylate functional groups are hydrophilic and completely soluble in intestinal fluid, i.e. the limit of solubility of the polymers in intestinal fluid at a temperature of 37 ℃ is greater than 95 mass%.

Preferably, the polymer bearing hydroxyl functional groups is polyvinyl alcohol. Advantageously, the polymer bearing carboxylic acid or carboxylate functional groups is chosen from: polyacrylic acid or one of its salts, preferably sodium polyacrylate.

According to a fourth embodiment, illustrated in fig. 5, shutter 4 is molded, the shutter having a circular shape and comprising, on the perimeter, an embedding structure 9, embedding structure 9 being also suitable to be molded. These embedded structures represent the type of contacts and are integral with the shutter 4. Preferably, the shutter 4 (including its embedded structure 9) comprises the same polymer as the housing 1, which ensures good adhesion between the shutter 4 and the housing 1 when the closing mechanism is closed. For example, the polymer of the shutter 4 and the housing 1 is silicone. Typically, the shutter is moulded in silicone with a shore hardness T of 30 to give the shutter elasticity and controlled stiffness and very good adhesion to the silicone housing.

According to a fifth embodiment, shown in fig. 6 and 6A, the shutter 4 comprises, at its centre, an addition in the form of a snap 10, the snap 10 being suitable to be polymeric. The top part of the snap fastener is structured in the form of a radiused channel 11.

According to a sixth embodiment, shown in fig. 7, the shutter 4 comprises at its centre a snap fastener 12, the snap fastener 12 having at its periphery a point connection 13 with the housing 1. The shutter 4 (including its snap 12 and point connection 13) comprises the same polymer as the housing 1, which ensures good adhesion between the shutter 4 and the housing 1 when the closing mechanism is closed. For example, the polymer of the shutter 4 and the housing 1 is silicone. The shutter 4 and the connecting piece 13 may be molded in one piece with the housing 1 so that they do not move laterally. The connecting piece 13 ensures that the snap fastener 12 is always centred facing the opening 3. For example, the portion may be moulded in silicone with a shore hardness T of 30 to give the portion elasticity and controlled stiffness and very good adhesion to the silicone housing.

According to a seventh embodiment shown in fig. 8, the opening 3 is arranged to be able to receive a bead 14, for example made of glass or polystyrene and typically having a diameter of about 1mm, the opening and the bead acting as a closed cell (obturaur) as a whole. The obturator member consists of two chambers, a lower chamber 15 adapted to receive the bead 14 and an upper chamber 16, the lower chamber 15 being wider than the upper chamber 16. The opening is open when the bead is in the lower chamber 15. When the bead is in the upper chamber 16, the opening is closed.

According to an eighth embodiment shown in fig. 9, the shutter 4 has the shape of a concave disk, around which there are perforations 17, the perforations 17 allowing the intestinal fluid to be sucked in through the opening 3.

The different closure systems 5-9 described above may each comprise a membrane 5, 7, 8 or a particle 6, 7, 8, the membrane 5, 7, 8 or the particle 6, 7, 8 comprising a polymer adapted to form a channel with the outer shell, whereby intestinal fluid is adapted to flow through the channel and to the inner material to facilitate the aspiration of intestinal fluid into the device. The film 5, 7, 8 or the granules 6, 7, 8 are made of a polymer as defined in particular in the above examples 2, 3 and 4.

As explained below, by expanding, the inner material facilitates closure of the closure system by exerting a force on one component of the closure system. Preferably, the system for closing the opening of the device does not comprise an inner material.

The invention also relates to a method (P1) for collecting a sample of intestinal fluid, the method comprising:

i) ingesting at least one device for collecting a sample of intestinal fluid as defined above;

ii) the at least one device is moved into the intestine, thereby allowing the dissolution of the gastric juice resistant material and opening of the opening;

iii) sucking intestinal fluid into the casing through the opening, whereby the inner material expands to 1.1 × V or more by absorbing intestinal fluid_iThe volume of (a);

iv) closing the mechanism for closing the opening;

v) withdrawing the device in the faeces.

The method (P1) can be applied to humans or animals.

During step ii) of the method (P1), the device passes through the stomach and is in gastric fluid. The device is stable in gastric fluid, in particular due to the fact that the top of each opening is arranged with a gastric resistant material adapted to dissolve in intestinal fluid at a temperature of 37 ℃ and the casing is not affected by gastric fluid. This means that the device does not deform and does not break due to contact with gastric juices. At the end of step ii) of the method, the device is located in and thus in contact with the intestinal fluid, which results in dissolution of the gastric resistant material and in the intestinal fluid being accessible to the opening to ensure the performance of step iii). During step iii), the opening is at least partially open, preferably fully open. The opening is fully open when all of the gastro-resistant material closing the opening has dissolved due to contact with intestinal fluid.

During step iii), intestinal fluid is sucked into the housing, and more particularly into the open cell structure of the expanded inner material, through the opening to collect intestinal fluid.

Absorption of intestinal fluid into the inner material causes the inner material to expand to greater than or equal to 1.1 × V_iIn particular greater than or equal to 2 × V_iPreferably greater than or equal to 6 × V_iThe volume of (a).

Aspirating intestinal fluid into the collection device during step iii) generates a mobile expansive force. The expansion force is typically calculated to accommodate the reaction force exerted by the outer shell encasing the inner material due to the elasticity of the inner material. This enables precise definition of the size, shape and volume related parameters of the collection device upstream of the method (P1).

The method (P1), in particular step iii) thereof, is thus achieved based on a force balance between the inner material and the outer shell. The at least partially compressed inner material remains in a compressed state prior to ingestion, even without an opposing force. During step iii), the inner material absorbs intestinal fluid and swells. During expansion, the intercommunicating pores of the open-cell structure expand, thereby forming a reservoir unit for intestinal fluid, particularly the microbiota. The intestinal fluid absorbed by the inner material exerts an expansion force in the centrifugal direction, which is continuously compensated by a reaction force in the centripetal direction of the outer shell of the inner material. The expansion pressure reserve of the inner material on the one hand is generally opposite to the stress tension of the outer shell on the other hand, which provides the driving force required for collecting intestinal fluid.

Advantageously, the device is capable of retaining intestinal fluid collected throughout the digestion process and containing the microbiota to be subsequently analyzed. Advantageously, the device is capable of maintaining the viability of the microbiota.

The gastro-resistant material is usually in the form of a layer arranged on top of each opening. Advantageously, the time and location of the collection of the intestinal fluid is predetermined by the PH, the thickness and/or the number of layers of gastric resistant material arranged on top of the outer surface of the opening, thereby determining the duration of its dissolution. Thus, a small layer thickness of the gastric juice-resistant material, or a small amount of this material, ensures a rapid dissolution and thus a rapid collection. Conversely, a thick, or numerous, layer of gastric juice resistant material increases its time to complete dissolution and facilitates slower collection. The combination of the thickness and/or number of layers of gastric resistant material and their solubility according to pH value enables to predetermine the exact location of collection of intestinal fluid.

Typically, step iii) of the implementation method (P1) triggers step iv). In other words, the aspiration of intestinal fluid into the device causes an expansion of the inner material, which causes the closure of the mechanism for closing the opening. Advantageously, step iv) of the method (P1) is triggered when the device is at least partially filled with intestinal fluid. The mechanism for closing the opening is actuated by the inner material expanding in contact with the intestinal fluid. Thus, closing of the closing mechanism is achieved due to the balance of the expansion force and the external force of the housing.

Preferably, the total duration of steps iii) and iv) is less than 5 min.

The closure of the closure mechanism enables the collected intestinal fluid sample to be subsequently uncontaminated during digestion.

In a first embodiment of the mechanism for closing the orifice 3, during step iii), the inner material 2 expands and subsequently exerts a pressure on the shutter 4, the shutter 4 deforming to fit the shape of the housing 1. The greater the volume of intestinal fluid in the inhalation device, the greater the pressure exerted by the inner material 2 on the valve 4, which strengthens the contact between the valve 4 and the housing 1, effectively closing the opening 3. In the particular case where the housing 1 and the shutter 4 are composed of silicone, the polymerization between the shutter 4 and the housing 1 is enhanced by the consistency of the viscosity therebetween and the hydrophobic interaction.

In a first alternative of the second embodiment of the mechanism for closing the opening 3, the membrane 5 and the housing 1 together form a passage through which intestinal fluid is adapted to pass and reach the inner material, which ensures that intestinal fluid is sucked into the device. When intestinal fluid circulates in the channel, the film 5 of polymer dissolves, the channel disappears and the shutter 4 adheres to the opening 3, which results in the closing of the opening 3.

In a second alternative of the second embodiment of the mechanism for closing the opening 3, the particles 6 form together with the housing 1 a passage through which intestinal fluid is adapted to circulate and reach the inner material, which ensures that intestinal fluid is sucked into the device. When intestinal fluid circulates in the channel, the particles 5 of polymer dissolve, the channel disappears and the shutter 4 adheres to the opening 3, which results in the closing of the opening 3.

In a third embodiment of the mechanism for closing opening 3, during step iii) of method (P1), the polymers of films and/or particles 7 and 8 dissolve due to contact with the intestinal fluid and react with each other in an esterified manner. The polyester forms a hard object and is able to effectively close the opening 3. The duration of esterification is long enough to allow collection of intestinal fluids.

In a fourth embodiment of the mechanism for closing the orifice 3, the contact 9 of the shutter 4 is kept at a distance from the housing 1 and the inner material 2, which ensures the entry of intestinal fluid to inflate the inner material 2. Due to the pressure release caused by the expansion of the interior material 2, the shutter 4 is bent to completely fit the shape of the housing 1, so that the opening 3 is completely closed.

In a fourth embodiment of the mechanism for closing the opening 3, the radial channels 11 allow intestinal fluid to enter through the opening 3 while keeping the outer shell 1 separated from the inner material 2. The release of pressure due to the expansion of the inner material ensures that the snap fastener 10 is inserted into the opening 3 and thus irreversibly closes the opening 3, rendering the entire device impervious to intestinal fluids.

In the sixth embodiment of the mechanism for closing the opening 3, the release of the pressure due to the expansion of the interior material can cause the shutter 4 to bend so that the snap fasteners 12 facing the opening 3 are inserted therein and close the opening 3.

In the seventh embodiment of the mechanism for closing the opening 3, when the released pressure increases due to the expansion of the inner material, the bead 14 rises into the chamber 16, thereby closing the opening 3. When the pressure is further increased, the bead 14 cannot pass through the opening 3 and thus irreversibly closes the opening.

In an eighth embodiment of the mechanism for closing the opening 3, the combined action of the expansion of the inner material 2 and the stretching of the casing 1 causes the edge of the shutter 4 to move apart, thus flattening the edge and gradually pushing the shutter towards the casing 1, which reverses its concavity. By pressing on the housing 1, the shutter 4 sealingly covers the opening 3.

Advantageously, the collecting device can be monitored during steps i) to iv) of the method (P1) due to the presence of ferromagnetic metal wires included in the thickness of the casing. The monitoring may be performed by radiography or ultrasonography.

Advantageously, step v) of the method (P1) is facilitated by a ferromagnetic metal wire included in the thickness of the casing, the retraction being carried out by a magnet or any other magnetic means.

Following step v), the intestinal fluid collected in the device may be characterised and the microbiota analysed using any technique known to those skilled in the art. Preferably, the pores of the open cell structure of the retrieved device have an average inner diameter of 10 μm to 3mm as measured by scanning electron microscopy. Advantageously, the maximum size (diameter or height) of the device depends on the object in which the device is used. Thus, after step v), the maximum size of the device is less than 2mm if the device is intended for use on a small animal such as a rat. When the device is used on the human body, the maximum dimension is typically less than 10mm, preferably less than 8 mm.

The invention also relates to the use of the device for collecting intestinal fluids. Advantageously, the collection device may be used to collect intestinal fluid at a predetermined time or location.

The invention also relates to a method (P2) for producing a device, comprising the following steps:

a) providing a compound having V₀Volume of polymer material, V₀Greater than V_i，

b) At least partially compressing the polymeric material to reach a volume V_i，

c) Encasing the at least partially compressed polymeric material obtained in step b) in a housing,

d) a gastro-resistant material adapted to dissolve in intestinal fluid at a temperature of 37 c is applied to the outer surface of each opening,

α) in combination with a mechanism for closing the opening, optionally step α) is carried out before, during or after step c).

The material provided in step a) corresponds to the inner material as defined above, except for its volume V₀Greater than V_i(which represents a lower, preferably uncompressed, degree of compression than the internal material of the device). Preferably, V₀Greater than or equal to 2 × V_iPreferably greater than or equal to 4 × V_i. In general, V₀At 4 × V_iTo 6 × V_iIn the meantime.

Having a volume V₀The polymeric material of (a) is typically a commercial material. Mention may be made, for example, of polyvinyl alcohol materials in the form of foams contained in surgical dressings, which are suitable for absorbing blood during surgical procedures.

Step b) is generally carried out by means of a jig or hydraulic press, depending on the maximum size of the device. The applied pressure was about 5kg/cm². Generally, the at least partially compressed polymeric material obtained at the end of step b) retains the volume Vi at the end of step b), even if no further compressive force is applied. Its shape remains unchanged.

Step c) is generally carried out using any means known to the person skilled in the art.

Step a) of method (P2) may be carried out before, during or after step c). Thus, there may already be openings on the housing during the coating of the polymeric material; or the opening may be formed before or after the housing is disposed.

In general, step d) of the method (P2) is carried out using any means known to the person skilled in the art.

Example (c): preparation of the device according to the invention

The work is performed in a clean, sterile and dust-free environment. The device is made of a polyvinyl alcohol (PVA) sponge porous material, such as that sometimes used by surgeons to wipe the surgical field. A sample of this material having a thickness of 10mm was placed on a solid surface. A 10x10mm cylinder was cut out and removed using a punch with a diameter of 10 mm. The cylinder was then compressed using a jig to obtain a disc in a 10x2mm format. The shutters were cut from a 0.2mm thick polyethylene film covered on a compression plate using the same punch. The whole was placed in a housing consisting of the fingers of a butadiene-acrylonitrile surgical glove. The fingers of the glove are knotted to form a sealed enclosure while the position within the valve is determined. A sharp clamp was used to open a 1mm diameter opening in the butadiene-acrylonitrile copolymer housing above the center of the valve without damaging the valve. The device is characterized by dimensions suitable for animal testing of pigs.

The following volumes were measured:

volume of material V₀＝0.785ml

Volume V after compression_i＝0.157ml

Volume V of expanded material is 0.470ml

The volume V of the collected intestinal juice is 0.310ml

The hardness of the butyronitrile shell is 50 Shore hardness, and the Young modulus is 1.5 MPa. After compression, the average pore size of the PVA inner material is between 7 and 12 μm. After collection of intestinal fluid, the average pore size of the inner material is between 80 and 200 μm. The elongation in the wet state was 250%. The porosity is between 89% and 91%. Pore volume of 0.56cm in the dry state³g^-1。