Ocular suction device

Description

Technical domain.

[0001] The present invention relates to a device for collecting a sample of interstitial fluid from a mucous membrane, for example the oral or ocular mucosa, of an animal ( eg . the man) for his analysis.

[0002] The present invention finds applications, for example, in the field of ophthalmology. State of the Technique

[0003] Suction devices used in dermatology create a suction bubble on the skin, from which interstitial fluid samples can be collected. One example is a steel / plexiglass capsule with a hole of a defined diameter (4, 8, 11, or 14 mm) connected to a vacuum pump, which applies a slight negative pressure of 200 to 300 mmHg to the skin surface. After approximately two hours, this allows interstitial fluid to accumulate between the dermis and epidermis, gradually detaching and forming a suction bubble. We can also mention the Cutometer ®< designed to measure the biomechanical properties of the upper layers of the epidermis by applying negative pressure (suction) which deforms the skin on which it is applied so as to aspirate it into a measuring cup of the probe before releasing it inside the probe.The penetration depth is determined by a non-contact optical measurement system consisting of a light source and a light receiver.

[0004] Suction devices are also used in eye surgeries, particularly LASIK. For example, there is the suction ring, which is placed on the surface of the eye and, through suction along its perimeter (depression), adheres to the eye. This allows for the precise creation of a corneal flap by another device (microkeratome) sliding along a rail that forms the upper surface of the suction ring. Due to its design, the suction ring can only access the periphery of the eye and not the surface of the eye itself, which is covered from the outside. vs central area (window) accessible from the outside.

[0005] Furthermore, various types of ocular samples can be taken from the surface of the eye (conjunctival impression), from inside the eye (aqueous humor), and from the lacrimal tissue. In the case of a conjunctival impression, a blotting paper is applied to the surface of the eye to collect conjunctival epithelial cells in a non- or minimally invasive, rapid, and virtually painless manner for biological analysis of ocular surface diseases. This application can be performed using an instrument, such as Eyeprim™ (single-use), which operates on the principle of a syringe: a plunger operated by the thumb pushes a membrane onto the eye, and upon releasing the plunger, this membrane returns to a sealed container and can then be collected at the end of the analysis using forceps.

[0006] US Patent Application 2016 / 0235392 describes a device comprising a fabric liquefaction system associated with a rotating system for abrading said fabric, to cause the dissolution of one or more components of said fabric and their collection. Description of the invention

[0007] The invention is defined in claim 1.

[0008] The inventors have developed a new device for collecting a sample of interstitial fluid from a mucous membrane ( water membrane which lines the cavities of the body (digestive tract, mouth, nasal cavities, bronchi, anus...) which connects with the skin at the level of the natural orifices, and which is lubricated by the secretion of mucus; eg . oral or conjunctival mucosa), particularly of the ocular or conjunctival mucosa, allowing, by creating a suction / aspiration zone on the surface of an animal's mucosa, eg of the conjunctiva ( waterthe transparent mucous membrane that lines the inside of the eyelids as well as the white of the eye in its bulbar part), the collection of a sample of interstitial fluid ( water the intermediate fluid between blood and cell (whose presence promotes interaction between the two) for its analysis.

[0009] The device of the invention comprises a hollow volume, hereinafter referred to as the enclosure, relatively airtight, inside which a first negative pressure can be created. Preferably, the enclosure has transparent parts, in particular the top face (distal surface furthest from the mucosa, eg . of the conjunctiva) and underneath (proximal surface in contact with the mucous membrane, eg(the conjunctiva) so that the operator can see the surgical field. The enclosure may optionally have a magnifying device on the apex of its distal surface to allow for more precise positioning of the enclosure on the mucosal surface. eg of the conjunctiva. The surface of the membrane in contact with the mucous membrane, eg The conjunctiva (proximal surface) is partially hollowed out to create an opening ("window") defining a sampling area. Preferably, this surface is substantially curved and bordered by a material, preferably flexible, serving as a seal between the enclosure and the anterior surface of the mucosa. egof the conjunctiva, in order to adapt in particular to the average curvature of the eye. Different models may exist, adjusted to different eye sizes (especially for children / adults). The window surface, preferably circular, can vary in size depending on the device, generally ranging from 3 to 350 mm². Preferably, the window is constructed on an iris-like structure, allowing the operator, for example, by rotating the base of the enclosure, to adjust the window diameter. The seal bordering the partially hollowed surface is in contact with the mucous membrane. eg The conjunctiva. To aid in sealing, a cream or other suitable substance can be applied to the mucous membrane. egThe conjunctiva, along the joint. This joint can extend substantially in the plane of the partially hollowed surface outside the enclosure, as well as inside the enclosure where it can help define the solid area of ​​the partially hollowed surface. The enclosure is connected via tubing to a system for adjusting the air pressure inside the enclosure. This system may, for example, consist of a vacuum pump and a means of measuring the pressure inside the enclosure, for example a manometer (see...). figure 1Other known systems, manual, mechanical, etc., can also be used to create an initial vacuum in the chamber. For example, a system based on a manually operated piston, such as a syringe, can be used to create this vacuum, with the body of the syringe graduated to indicate the vacuum levels generated in the chamber. Precise and responsive control and adjustment of the vacuum, created gradually in the chamber, is important, particularly due to the sensitivity and fragility of the eye. Alternatively, the system creating the vacuum in the chamber can consist of a Vacutainer®-type device. The advantage of such a system is that it requires only a set of relatively simple components, notably without a vacuum pump, and can therefore be manufactured as a single-use kit.In this mode, negative pressure control can be achieved using a valve system connecting the Vacutainer® to the device and / or a pressure level within the Vacutainer® which, relative to the chamber volume, poses no risk to the patient while creating the desired negative pressure. Settings, standard increments, successive adjustments, and progressive modes for establishing negative pressure can be defined / automated to facilitate / standardize the operator's work and ensure patient comfort. The chamber walls are hollow, creating a space in contact with the mucous membrane. eg . the conjunctiva, around the edge of the window, inside which a second depression can be created using the first depression system or an additional system ( eg(vacuum pump, Vacutainer® or other). The walls of the enclosure may or may not communicate with the interior of the enclosure. In the first case, the negative pressure inside the walls of the enclosure and inside the enclosure are identical. The second negative pressure created inside the walls of the enclosure allows the mucosa to adhere. eg The conjunctiva, along the perimeter of the window, thus defining a zone whose central part, inside the window, is subjected to the first negative pressure created inside the enclosure. This prevents the first negative pressure inside the window from resulting, due to the relatively high elasticity of a mucous membrane ( eg . of the connective tissue), by a displacement of too much mucous membrane, eg. of conjunctiva, inside the cavity, which could potentially line its inner walls; that is to say, too great a distribution of overpressure, so that the initial negative pressure could cause swelling of part of the mucous membrane, eg of the conjunctiva, water . a "bubble" of suction of interstitial fluid that will form inside the enclosure.

[0010] Thus, once the device of the invention is applied to the surface of the mucous membrane, e. g . of the conjunctiva: (i) the first depression created inside the enclosure made possible by the action of the depression system connected to the enclosure and the hermeticity of the enclosure due to the seal (not mandatory), ensures a solidity of the enclosure with the mucosa, e. g . the conjunctiva, as well as a relative overpressure of the part of the mucous membrane, e. g. of the conjunctiva, in contact with the device, in particular that at the level of the window for the formation of a "bubble" of interstitial fluid, and (ii) the second depression created inside the walls of the enclosure ensures that it is completely airtight and that the mucous membrane is fixed, e. g The conjunctiva, in order to stimulate it over a surface area smaller than the surface area surrounding the device, resulting in a localized pressure increase which, without risk of overpressure (intraocular in the case of the conjunctiva), significantly reduces the time required for the formation of the "bubble". This relative / local overpressure created by the device of the invention thus gradually creates, at the level of the mucosal part, e. g . of the conjunctiva, inside the enclosure a "bubble" whose external surface is the mucous membrane, e. gThe conjunctiva, and the interstitial fluid inside, which can then be collected. The device has a means for this purpose to perform a sample at the level of the part of the mucosa, e. gof the conjunctiva, accessible via the window, and in particular to take advantage of the accessibility of the interstitial fluid in the "bubble" due to the relative / local overpressure. The collection of interstitial fluid from the "bubble" is preferably carried out by an additional suction effect at the window using a system operating, for example, on the principle of a Vacutainer®. Based on this principle, the device includes a hollow needle capable of passing through the top of the chamber, pointing towards the window, and such that inside the needle is a one-way valve / flap, ensuring that a gas / liquid can only pass through the needle from the inside of the chamber to the outside.Such a valve also prevents outside air from entering the container when a vacuum is generated within the chamber, and conversely allows the passage of any sample collected with the needle to the outside of the chamber. This needle has two sharpened ends and can be moved along its axis without compromising the airtight seal of its connection to the chamber. The needle can thus be brought closer to the part of the mucosa, e. gThe conjunctiva (suction bubble) is drawn through the window, and the sample can even be penetrated to the depth desired by the operator. The other end of the needle can then, in the manner of a Vacutainer® system, be used to pierce a reservoir placed under negative pressure, such that the internal pressure of said reservoir is lower than the pressure inside the chamber, creating a suction effect that draws the sample into the reservoir. To achieve this, the chamber has a zone at its apex (distal surface), for example made of foam / elastomer, easily pierced by a needle similar to that described above, so that it closes around the needle without allowing air to pass through at the working pressures of the device of the invention. A means for performing a sampling can consist of a tube attached to the apex of the chamber, inside which a reservoir carrying a needle can slide.This tube is airtight and is such that, at rest (off), the needle does not pass through the top of the chamber. The pressure of the reservoir and the tube at rest is such that, when sliding the reservoir towards the chamber (on), the needle thus passes through the top of the chamber and consequently the mucosa, e. g The conjunctiva, forming the outer surface of the suction “bubble”, then the reservoir pressure is equal to Pr, lower than the pressure Pe inside the chamber, which creates a movement of the interstitial fluid that is in the suction “bubble”, towards the interior of the reservoir. This assumes that when the suction “bubble” is created, its apex is very close to, or even in contact with, the apex of the chamber, in order to limit the vacuum generated by the needle when it is inside the chamber but not yet inside the suction “bubble” (cf. figure 2A). The entire device, with the exception of the system(s) creating the vacuum, is for single use only. The operator may have as many needles as reservoirs, and proceed as indicated above (piercing the top of the chamber, bringing the needle tip closer to the part of the mucosa, e. g . of the conjunctiva, passing through the window, puncture of the reservoir to perform the interstitial fluid sampling). The advantage of this sampling method lies in the fact that there is no contamination from one reservoir to another due to the sharing of a needle in case the operator wishes to perform several samplings ( eg (at different depths). Other known "perforation / aspiration" systems are also conceivable for performing the sampling (eg(e.g., syringe, etc.). For such a sampling device, the length of the needle's path is preferably, for safety reasons, such that the needle tip cannot extend beyond the lower part of the device and thus beyond the protrusion formed by the suction bubble. For example, in the case of a needle passing through a sliding reservoir, the length of the sampling needle as it exits the reservoir is, for safety reasons, preferably less than the height of the walls of the enclosure blocking the reservoir's path.

[0011] The sampling of interstitial fluid performed via the device of the invention allows for novel analyses: conducting biochemical examinations ( egpH, osmolarity, and ionogram); detection of inflammatory cells, pharmacokinetic / dynamic studies, for example, on eye drops or systemically administered molecules (both surface and depth); side effects of chemotherapy (previously studied in tears). It also enables immediate "Lab on a Chip" type analyses that allow the study of the concentration of different proteins in the interstitial fluid. The device of the invention can also take advantage of the binding force created by suction to perform, on the area in contact with the surface of the mucosa, e. g . of the conjunctiva, a tissue sample of the conjunctival or epithelial type ( eg. buccal) of full thickness of the mucosa. On the other hand, the space created by the device of the invention, particularly under the conjunctiva, can allow injections of substances into a more limited space than current subconjunctival injections.

[0012] The present invention therefore relates to a device for collecting a sample of interstitial fluid from the mucous membrane of an animal for analysis, said device comprising: (i) an airtight enclosure whose proximal surface in direct contact with the mucosa has an opening defining a sampling zone, and whose distal surface includes at least one orifice connected to a first aspiration system (to create a vacuum inside the airtight enclosure and the formation of a suction bubble through the opening), and (ii) a sampling system consisting of a tube attached to the top of the distal surface of the airtight enclosure, inside which slides a reservoir through which a perforation system is directed towards the mucosa, with regard to the opening; in which the walls of the airtight enclosure are hollow (to promote adhesion to the surface of the mucous membrane and increase localized pressure for a faster formation of the suction bubble and therefore faster production of interstitial fluid while limiting the risk of overpressure of the mucosa (especially the conjunctiva in the case of the eye) and connected to a second suction system.

[0013] According to a particular embodiment of the device of the invention, the mucous membrane is the oral mucosa or the conjunctiva, preferably the conjunctiva.

[0014] According to a particular embodiment of the device of the present invention, the proximal surface of the enclosure is convex.

[0015] According to a particular embodiment of the device of the present invention, all or part of the proximal surface of the enclosure is covered with a flexible sealing gasket. In addition, the part of the device in contact with the surface of the mucosa, e.g., the conjunctiva, can be covered with a membrane allowing for an epithelial impression-type sampling ( eg . buccal) or conjunctival.

[0016] According to a particular embodiment of the device of the present invention, the opening (or window) in the proximal surface of the enclosure has a surface area between 3 and 350 mm², and is optionally adjustable.

[0017] According to a particular embodiment of the device of the present invention, the first suction system, and optionally the second suction system, creates a vacuum of less than about 400 mbar (300 mmHg)

[0018] According to a particular embodiment of the device of the present invention, the distal surface of the airtight enclosure is covered at least on its top with a material that can be pierced by the perforation system and that closes on the latter when pierced to maintain the seal.

[0019] According to a particular embodiment of the device of the present invention, the hermetic enclosure has transparent surfaces, and optionally a magnifying means on the top of its distal surface.

[0020] According to a particular embodiment of the device of the present invention, the reservoir has a capacity ranging from 10 to 300µl, preferably from 20 to 200µl, preferably from 30 to 100µl, most preferably from 40 to 50µl.

[0021] According to a particular embodiment of the device of the present invention, the length of the perforation system exiting the tank is less than the maximum height of the hermetically sealed enclosure.

[0022] An unclaimed method is described, the method being useful for understanding the invention. The method refers to a method for collecting a sample of interstitial fluid from the mucosa of an animal for analysis, said method comprising: the disposition of a device according to the present invention on the surface of the mucosa at the sampling site; the application of a depression in the walls and inside the airtight enclosure so as to form a suction bubble at the opening of the proximal surface of the enclosure; the movement of the reservoir of the sampling system towards the mucosa until the perforation system passes through the distal surface of the airtight enclosure and the suction bubble; the collection of the interstitial fluid sample from the suction bubble into the reservoir.

[0023] According to a particular embodiment of the device of the invention, the mucosa is the oral mucosa or the conjunctiva, preferably the conjunctiva. According to a particular embodiment of the method useful for understanding the invention, the negative pressure applied in the walls and inside the airtight enclosure is less than 400 mbar (300 mmHg of mercury).

[0024] According to a particular embodiment of the process useful for understanding the invention, the perforation system cannot descend beyond the proximal surface of the hermetic enclosure. BRIEF DESCRIPTION OF FIGURES

[0025] There Figure 1 This represents a cross-sectional view of the enclosure, positioned over an eye and connected to a vacuum pump and a pressure gauge. The window is an opening on the face of the enclosure (proximal surface) in contact with the surface of the eye (conjunctiva). Figure 2represents a method of collecting interstitial fluid from the conjunctival surface of the eye passing through the window (bubble) by means of a device of the invention, at rest ( figure 2A (off) and in action ( figure 2B , on). The Figure 3 represents the general principle of the enclosure of the device of the invention. The Figure 4 represents the sequence of use of a device according to the invention. The Figure 5 This represents a prototype of an ocular suction bell without the interstitial fluid sampling device. (1) Opening to the suction system of the outer cylinder (3A) for maintaining contact with the mucosal surface. (2) Opening to the suction system of the inner cylinder (3B) for sampling interstitial fluid or mucosal epithelial tissue. EXAMPLES EXAMPLE 1: EXAMPLES OF EMPLYING A DEVICE OF THE INVENTION AND ITS IMPLEMENTATION The general principle of insertion of the device of the invention in action on the joint (Figure 3):

[0026] To the left of the Figure 3, the enclosure of the device of the invention is applied to the eye.

[0027] To the right of the Figure 3 The depression generated inside the enclosure caused a suction "bubble" / growth of the eye through the window, that is, a bubble whose surface is the conjunctival tissue and whose interior is the interstitial fluid.

[0028] The negative pressure inside the enclosure will create, due to the pressure difference with the outside, a force (Pext) applied to the enclosure towards the eye at the points of contact (seal) between the enclosure and the eye's surface. Symmetrically, there will be an overpressure (Pint) from inside the eye at the window, pushing inwards towards the enclosure. The combination of these two opposing forces will generate the eye's protrusion ( watera bubble whose outer surface is conjunctival tissue and whose inner surface is interstitial fluid) through the window. Illustration of the use of the device of the invention on the joint. (Figure 4):

[0029] The sampling means, the vacuum means, and the enclosure are part of the device of the invention. The latter comprises a three-stage tubular body with hollow walls. Its lower part, defining the first stage, is applied to the conjunctiva and has an upper face comprising a hermetically sealed central portion and a peripheral portion communicating with the walls of the second stage. This second stage comprises hollow walls thicker than the walls of the first stage, communicating with the walls and the interior of the first stage. The center of this second stage has a tubular reservoir that can slide hermetically along the walls, through which a needle passes on its lower face and which extends upwards into an arm. The pressure of the second stage is P2 < atmospheric pressure.The 3rd floor includes conduits communicating with the walls of the 2nd floor and, at its top, a sliding airtight strip, crossed in its center by the arm coming from the tank without air being able to pass through this point.

[0030] The sequence for using this device is as follows: after applying the bottom of the device (proximal surface) to the conjunctiva, the airtight flap of the 3rd stage is slid in to create a vacuum in the walls and inside the 1st stage (via the air communication between the walls of the 1st and 2nd stages and the ducts of the 3rd stage). This vacuum, P1, creates a suction "bubble" on the surface of the eye and is such that P2 <P1. Le bras relié au réservoir est alors appuyé, de manière à ce que l'aiguille prolongeant ce dernier traverse la face supérieure (surface distale) du 1 er< étage et perce la « bulle » de succion, provoquant le prélèvement de liquide interstitiel. Une fois que le prélèvement a eu lieu, le retrait du dispositif peut être effectué en rabaissant le 3 ème< étage, ce qui annule la dépression.

[0031] To the left of the Figure 4The device of the invention is affixed to the eye. The first floor, serving as an enclosure, has hollow walls and a window.

[0032] In the middle of the Figure 4 The elevation of the third floor creates, via a network of hollow walls and conduits, a negative pressure in the first floor (interior and walls) which acts as an enclosure. This elevation can be facilitated by handles that support the operator's fingers while holding the body of the device with the other hand. The suction bubble then forms.

[0033] To the right of the Figure 4 The pressure on the arm pushes the reservoir and the needle through the suction bubble. Due to the pressure difference between the first stage and the reservoir, the interstitial fluid contained in the suction bubble is drawn into the reservoir.

Claims

1. A device for collecting a sample of interstitial fluid from the mucosa of an animal for analysis, said device comprising: (i) an airtight enclosure whose proximal surface in direct contact with the mucosa has an opening defining a collection area, and whose distal surface comprises at least one port connected to a first suction system, and (ii) a collection system consisting of a tube joined to the top of the distal surface of the sealed enclosure, inside which a reservoir slides that is passed through by a perforation system oriented toward the mucosa, opposite the opening; wherein the walls of the sealed enclosure are hollow, and connected to a second suction system.

2. The device according to claim 1, where the mucosa is the conjunctiva.

3. The device according to claim 1 or 2, wherein the proximal surface of the enclosure is domed.

4. The device according to any one of claims 1 to 3, wherein the proximal surface of the enclosure is covered by a flexible seal.

5. The device according to any one of claims 1 to 4, wherein the opening in the proximal surface of the enclosure has an area of between 3 and 350 mm2, and is optionally adjustable.

6. The device according to any one of claims 1 to 5, wherein the suction system creates a vacuum of less than 400 mbar (300 mmHg).

7. The device according to any one of claims 1 to 6, wherein the distal surface of the sealed enclosure is covered at least on its top with a material that can be pierced by the perforation system and closes over the latter when pierced to maintain the seal.

8. The device according to any one of claims 1 to 7, wherein the sealed enclosure has transparent surfaces, and optionally a magnification means on the top of its distal surface.

9. The device according to any one of claims 1 to 8, wherein the reservoir has a capacity ranging from 10 to 300 µl.

10. The device according to any one of claims 1 to 9, wherein the length of the perforation system emerging from the reservoir is less than the maximum height of the sealed enclosure.