Method for manufacturing a microneedle array.

Abstract

The invention relates to a method for manufacturing a microneedle array comprising a mold provisioning step, the mold comprising a plate and a matrix of microneedle cavities formed within the thickness of the plate, the plate comprising a first external face, each cavity comprising a base coplanar with the first face and a pointed bottom. The mold comprises lateral vents which are grooves formed in the plate in planes orthogonal to the first face and axial vents communicating with the bottom of each cavity, the cavities being interconnected via the lateral vents, the lateral vents extending over at least a portion of the height of each cavity.And also a step of vacuum-sealing the impression matrix via the lateral and axial vents and injecting material through the base of each impression so as to completely fill the volume of each impression by means of material pressure due to injection and suction through the lateral and axial vents. And finally, a demolding step to obtain a network of microneedles. Figure for the abbreviation: FIG. 6.

Description

Title of the invention: Method for manufacturing a network of microneedles. [0001 ] GENERAL TECHNICAL FIELD

[0002] The present invention relates to a method for manufacturing microneedles, in particular allowing the manufacturing by vacuum injection of a network of microneedles of a sensor suitable for detecting a physiological quantity of the human body.

[0003] STATE OF THE ART

[0004] Certain pathologies such as diabetes require daily monitoring of biochemical parameters of the human body, i.e. concentrations of certain compounds (blood sugar in the example of glucose).

[0005] Today we know of advanced systems that are content to analyze the interstitial fluid, that is to say the fluid that fills the space between the blood capillaries and the cells. It has an ionic composition close to that of blood plasma.

[0006] These advanced systems thus make it possible to monitor the desired biochemical parameters transcutaneously, i.e. without the need to regularly pierce the skin and take samples.

[0007] Devices with microneedles are known, which have the advantage of being less invasive than conventional needles. However, it is important that these microneedles remain in place.

[0008] For this purpose, there are permanent devices where microneedles are held on the skin with an adhesive strip.

[0009] The microneedles used are conventionally obtained by microinjection processes or Micro-Electro-Mechanical Systems technology (equivalent to “MEMS” in English).

[0010] Such methods are well known and consist of injecting material into a mold comprising microneedle impressions and are sometimes associated with suction of material to completely fill the mold impressions.

[0011] Microneedle devices for measuring body sizes require microneedles having a certain height and a pointed end and having a surface quality allowing subsequent precise treatments such as metallization or chemical functionalization of the surfaces of the microneedles. PRESENTATION OF THE INVENTION

[0012] An aim of the invention is to obtain microneedles by vacuum injection whose surfaces are flat and have a pointed shape.

[0013] In this respect, the invention relates, according to a first aspect, to a method for manufacturing a microneedle array comprising a step of providing a mold, the mold comprising a plate and a matrix of microneedle impressions formed in the thickness of the plate, the plate comprising a first external face, each impression comprising a base coplanar with the first face and a pointed bottom. The mold comprises lateral vents which are grooves formed in the plate in planes orthogonal to the first face and axial vents in communication with the bottom of each impression, the impressions being in communication with each other via the lateral vents, the lateral vents extending over at least part of the height of each impression.And also a step of vacuuming the impression matrix via the lateral vents and the axial vents and injecting material through the base of each impression so as to completely fill the volume of each impression via a push of material due to the injection and suction through the lateral and axial vents. And finally a demolding step so as to obtain a network of microneedles.

[0014] The presence of lateral vents over all or part of the height of the impression associated with vacuum suction makes it possible to obtain microneedles which are long, i.e. of a length greater than 500 pm.

[0015] The invention is advantageously supplemented by the following characteristics, taken alone or in any of their technically possible combinations: - each indentation is polyhedral and comprises at least one edge, the indentations being arranged relative to the side vents so that the side vents communicate with the indentations only by the edges; - each imprint extends over a first part taken from the base to a break in the slope at a first height and extends over a second part at the tip taken from the break in the slope to the bottom at the tip at a second height; - the side vents extend at least over a height ranging from half of the first part of each footprint to the break in slope; - the side vents extend from the first face of the plate to the slope break of each impression; - the plate consists of an assembly of plate sections, each impression being in two parts, the lateral vents and the axial vents being formed by junctions between the plate sections.

[0016] According to one embodiment, a network of microneedles is obtained by a manufacturing method in which each microneedle comprises a base, advantageously polyhedral, from which extends a first part having as many of faces and stops that the base presents on the sides then a second part presenting a pyramidal shape up to a point.

[0017] According to one embodiment, a network of microneedles is obtained by a manufacturing method in which each microneedle comprises a base, advantageously circular, from which extends a first cylindrical part, then a second part having a conical shape up to a tip.

[0018] Such a mold makes it possible to solve the problems of burrs induced by vents, the presence of which is inevitable during a molding process. In fact, the presence of burrs is limited to the edges or to the end of each microneedle where they are less harmful than on the flat faces of these microneedles.

[0019] The microneedles thus obtained have faces free of any burrs linked to the vents of the mold, which is essential for the quality of the subsequent processes (metallization). PRESENTATION OF FIGURES

[0020] Other characteristics and advantages of the present invention will appear on reading the following description of a preferred embodiment. This description will be given with reference to the appended drawings in which: - [Fig.l] illustrates a body monitoring device according to one embodiment of the invention; - [Fig.2] illustrates a microneedle of a body monitoring device; - [Fig.3] illustrates a top view of the upper part of a mold used according to one embodiment of the invention; - [Fig.4] illustrates a perspective view of a microneedle array obtained by the invention; - [Fig.5] illustrates the steps of a method of manufacturing a network of microneedles according to the invention; - [Fig.6] illustrates a top view of the upper part of a mold used according to one embodiment of the invention; - [Fig.7] illustrates a sectional view of the mold of [Fig.6]; - [Fig.8] illustrates a perspective view of a microneedle array such as that obtained with a mold of [Fig.6]; - [Fig.9] illustrates a top view of the upper part of a mold used according to one embodiment of the invention;

[0021] Throughout the figures, similar elements bear identical references. DETAILED DESCRIPTION

[0022] General architecture of a body monitoring device

[0023] [Fig.l] illustrates a body monitoring device 100 comprising a housing 200, a sensor 30 and an adhesive patch 50.

[0024] The sensor 30 is here a needle sensor provided to provide a measurement of electric current within the interstitial liquid of the carrier of the device 100.

[0025] Needles 10 are advantageously arranged on an internal face 31 of the sensor 30. This internal face 31 is intended to be placed on the skin of the wearer.

[0026] The sensor 30 is assembled to the adhesive patch 50 and together constitute a capsule. The sensor 30 can also be removable relative to the patch 50. Such a capsule is advantageously removably mounted with the housing 200. In particular, the capsule and therefore the sensor 30 preferably engages in a cavity 210 of the housing 200 located on its face intended to be in contact with the skin. The sensor 30 comprises an external face 32 opposite the internal face 31.

[0027] The housing 200 and the capsule may have complementary shapes, which limits the effort required for the correct insertion of the capsule against the housing 200.

[0028] The patch 50 comprises an adhesive layer, or is itself formed from an adhesive material. The patch therefore allows the capsule to be attached to the wearer's skin, and promotes the maintenance of the needles 10 in the interstitial fluid. The patch 50 has, for example, an annular shape, and covers the capsule.

[0029] The sensor 30 illustrated here is circular in shape with a central orifice 33 but it can take other shapes: rectangular, oblong, ellipsoidal with or without a central orifice. The central orifice 33 makes it possible to correctly position the sensor 30 in the cavity 210 of the housing which includes a central positioning stud (not shown).

[0030] The sensor 30 therefore comprises elements which make it possible to sample the liquid or to bring the signals detected by each microneedle to the housing 200 for processing (not described here).

[0031] The sensor 30 can take the form of a plastic plate, a printed circuit (rigid or flexible silicon), or a non-conductive metal plate such as aluminum.

[0032] The adhesive patch 50 is adapted to be stuck to the skin and supports the sensor 30 and allows the housing 200 to be detached without removing the sensor 30 while keeping it stuck to the body. Such a configuration makes it possible to avoid removing the sensor for certain operations which only involve the housing: recharging the battery, repair, replacement, extraction of data to a computer.

[0033] The case 200 is advantageously in the form of a watch case and comprises means 230 for attaching the device to a user's wrist. This is in particular a bracelet adapted to surround a user's wrist. The bracelet is preferably adjustable.

[0034] The housing 200 houses several elements making it possible to analyze or extract interstitial fluid. In this respect, reference may be made to document WO 2019 / 141743 in the name of the applicant which describes in detail the measurement and detection of a physical quantity from microneedles in contact with a bodily fluid which may or may not be sampled.

[0035] Advantageously, the watch further comprises a wireless communication interface, for example via a 3G and / or 4G and / or 5G and / or Wi-Fi and / or Bluetooth and / or NFC and / or DECT type telecommunications network.

[0036] Also, the watch may include a light indicator such as a diode, which may be used to signal the end of a sensor preparation operation.

[0037] The needles 7 are advantageously microneedles. The sensor 30 preferably comprises between four and fifty microneedles 7 or even four hundred microneedles 7. Of course, a different number can be considered without this limiting the description of the invention given here.

[0038] The height of the microneedles 7 is sufficiently low to avoid contact with a mechanical pain nerve of the wearer when the device is worn.

[0039] The microneedles 7 make it possible to measure a body fluid.

[0040] The microneedles 7 are solid to directly analyze the liquid. To analyze liquid, the microneedles do not sample liquid and integrate the sensor on their surface in the form of a coating such as a biochemical material capable of reacting with the analysis to be carried out on the liquid.

[0041] The length of the needles 7 is thus sufficiently reduced to avoid contact with a nerve of the user, to limit the pain caused by wearing the device 100.

[0042] As illustrated in [Fig. 2], each microneedle 7 has, for example, a pyramidal shape. Each microneedle 7 comprises a base 71, advantageously polygonal, from which extends a first part having as many faces 73 and stops 72 as the base 71 has sides. The first part extends from the base 71 to a first break 74. From this break 74 the needle extends in a pyramidal fashion to a point 75.

[0043] Each microneedle 7 comprises on its surface at least one chemical or biochemical material capable of reacting with the bodily analyte of which a measurement is desired (i.e. here glucose). A material capable of reacting with the bodily analyte is for example an enzyme capable of oxidizing the bodily analyte.

[0044] Advantageously, the sensor 30 comprises several microneedles which consist of a network of microneedles in that they are electrically connected to each other in groups. The microneedles 7 pierce the skin to come into contact with the interstitial liquid when the sensor is in contact with the skin.

[0045] General description of a vacuum injection manufacturing process

[0046] In relation to Figures 3, 4 and 5, a method of manufacturing a network of mi croaiguilles includes a first step El of providing a mold 1 (see [Fig.6]).

[0047] The mold 1 comprises a plate 2 and a matrix 3 of microneedle impressions 4. The matrix is ​​formed in the thickness of the plate 2. The plate 2 comprises a first external face A, orthogonal to a first direction Z. Each impression 4 of the matrix 3 comprises a base 41 coplanar with the first face A and extends in the plate 2 from the face A of the plate 2 and in the first direction Z to a bottom 45 at the tip. Each impression 4 comprises a first part 46, called foot hereinafter, which is the part of the impression 4 closest to the base 41 and a second part 47, called head hereinafter, which is the part of the impression 4 closest to the tip 45. In Figures 2 and 3 the impressions are advantageously represented with polyhedral shapes but other shapes are possible such as cylindrical shapes or different polyhedral shapes.The prints 4 are advantageously distributed in the matrix 3 in an aligned and / or gridded manner.

[0048] The mold 1 also comprises lateral vents 51 and axial vents 52. The lateral vents 51 are formed in the plate 2 in planes orthogonal to the first face A, that is to say collinear with the first direction Z and with another direction orthogonal to the first direction Z. All of the lateral vents 51 connecting cavities 4 of the same alignment between them are advantageously formed in the same plane. In addition, the lateral vents 51 extend over at least a portion of the height of each cavity 4. The axial vents 52 are in communication with the bottom 45 of each cavity 4. Advantageously, the axial vents 52 are aligned in the first direction Z and / or a second direction orthogonal to the first direction Z in order to facilitate the manufacture of the molds 1 and optimize the circulation of air in the mold 1.In addition, the imprints 4 which are adjacent to each other are in communication with each other via the lateral vents 51. All of the lateral vents 51 and axial vents 52 of the plate 2 allow air to be evacuated from the matrix 3 at the time of an injection of material into the mold 1 and will be called vents hereinafter.

[0049] The manufacturing method comprises a second step E2 of placing the die 3 under vacuum and injecting material into the die 3. This step E2 is carried out by means of the lateral vents 51 and the axial vents 52 which allow the air to be evacuated from the cavities 4 of the die 3. The injection of material into the die 3 is carried out by the base 41 of each cavity 4 so as to completely fill the volume of each cavity 4. The cavities 4 are filled with injected material by means of a thrust of material due to the injection and the vacuuming by suction through the lateral vents 51 and axial vents 52. The vacuuming is carried out before either simultaneously or simultaneously with the injection. This vacuum will be assimilated to the principle of suction.

[0050] The filling of the foot 46 of each impression 4 during the injection is particularly due to the thrust of the material due to the injection, that is to say by the injection force. The filling of the head 47 of each impression 4 requires a certain suction. The suction allowing the good filling of each impression 4 is carried out by the lateral vents 51 and / or axial vents 52. In addition, the deeper the impressions 4 are, that is to say the further the head 47 is from the base 41, the weaker the influence of the suction carried out by the axial vents 52. The presence of the lateral vents 51 is then necessary to allow the injected material to properly occupy the entire volume of the head 47 of the impressions 4.

[0051] The majority of microneedles 7 comprise a length between 300 qm and 500 qm. Microneedles with a length greater than 500 qm and up to 2 mm are needles of unusual length and require specific and innovative manufacturing processes.

[0052] The manufacturing method then comprises a third step E3 of demolding. The third step E3 makes it possible to obtain a network 9 of microneedles 7.

[0053] Description of a mold for vacuum injection manufacturing according to another embodiment

[0054] In a complementary manner, and in order to avoid the presence of burrs 8 resulting from the presence of the lateral vents 51 in the plate 2 and opening onto the flat faces of the impressions 4, a mold structure different from that described above is used.

[0055] Indeed, the burrs 8 result from a leak of material through the lateral vents 51 which, by solidifying, leaves on the microneedle 7 an excess of material of the order of 5 to 20%, i.e. for example from 0.1 qm to 50 qm. This excess of material, if it is present on one or more flat faces of the impressions 4, is detrimental to the quality of the flat faces 73 of the microneedles 7. Indeed, the flat faces 73 of the microneedles 7 advantageously have defects less than 0.1 qm in thickness.

[0056] Such burrs on the flat faces 73 prevent subsequent precise processes such as metallization or chemical functionalization of the surfaces of the microneedles involving thicknesses between 0.1 qm and 2 qm. Indeed, these joining defects create a weakening of these processes which can lead to degradation of the expected functions as well as to delamination or breaks of the surface induced by these processes.

[0057] Figures 6 and 7 illustrate a mold 1 used for the vacuum injection manufacturing of microneedles 7 which makes it possible to avoid the presence of burrs on the faces 43 of the impressions 4.

[0058] According to this embodiment, each imprint 4 comprises a polygonal base 41 which is formed on the surface A. The first part, the foot 46, of each imprint 4 extends from the base 41 to a slope break 44 along a first height and the second part, the head 47, extends at a point from the slope break 44 to the bottom at a point 45 along a second height. The first slope break 44 forms a concavity in each imprint 4. The axis of the imprints 4 is parallel to the direction Z. The foot 46 of the wall of the plate 2, which extends between the first face A of the plate 2 and the first break 44, defines several flat faces 43 and several edges 42. There are as many flat faces 43 and edges 42 as the polygonal base 41 comprises sides.

[0059] The lateral vents 51 preferably extend at least over a height ranging from half of the foot 46 to the slope break 44. In Figures 6 and 7, the lateral vents extend along the entire foot 46 of each footprint but they can optionally extend over only a portion of each footprint 4 and / or more precisely over a portion of the foot 46 of each footprint 4.

[0060] The indentations 4 of the die 3 are advantageously arranged with respect to the lateral vents 51 so that the lateral vents 51 communicate with the indentations 4 only by the edges 42 of these indentations. In this way the flat faces 43 of each indentation 4 do not communicate with the vents and do not have burrs 8.

[0061] The injection E3 of material is carried out as previously. According to this embodiment, the lateral vents 51 placed laterally at the foot 46 of each impression 4 allow the material to occupy the entire volume of the impression up to the first break 44 by sucking in air during the injection. The axial vents 52 in communication with the bottom 45 of each impression allow the volume of the head 47 to be completely filled, that is to say between the first break 44 and the bottom 45, forming the tip of each impression 4.

[0062] [Fig. 8] illustrates a network of microneedles 7 obtained according to one embodiment. The microneedles 7 preferably have an obelisk shape. The microneedle 7 extends from a parallelogrammatic base 71 from which a first part then a second part extends. The first part of the microneedle 7 comprises four faces 73 and four edges 72. The first part extends from the base 71 to a first break 74. The second part extends from this break to a tip 75 in a pyramidal manner. The microneedles have a burr 8 on at least one edge 42 as well as on the tip 75. The flat faces 43 of the microneedle 7 are advantageously without burrs 8.

[0063] According to one embodiment, illustrated in [Fig.9], the mold 1 may consist of an assembly of plate sections 2a, 2b, 2c forming a plate 2. The plate 2 thus constituted makes it easier to demould the microneedle network 7 from the mould 1. The mould 1 comprising the plate 2 is then crossed by intersecting joints. The lateral vents 51 are advantageously constituted by the joints between the plate sections 2a, 2b, 2c. The cavities 4 of the matrix 3 are then positioned on either side of the joints so that the joints communicate with the cavities only by edges 42. In this way the flat faces 43 of the cavities 4 are entirely formed in the wall of a single plate section 2a, 2b, 2c. [Fig.9] shows a plate 2 consisting of an assembly of three plate sections (2a, 2b, 2c) but the number of sections can be different and advantageously chosen for example as a function of the number of cavities 4.

[0064] According to one embodiment, each imprint 4 is a cavity formed in the plate 2 of the mold 1. The depth of each imprint, that is to say the distance in the first direction Z, between the base 41 and the bottom 45 is advantageously between 300 μm and 2 mm in length.

[0065] According to one embodiment, the plate 2 of the mold 1 may consist of a single plate 2 crossed by grooves (not shown). The grooves extend along planes parallel to each other and orthogonal to the first face A. The grooves preferably extend from the first face A of the plate 2 to the level of the first break 44. In this way, the lateral vents 51 are constituted by the grooves. The indentations 4 are arranged relative to the grooves constituting the lateral vents 51 so that the grooves communicate with the indentations 4 only by the edges 42 of the indentations 4.

Claims

Claims

1. A method of manufacturing a microneedle array comprising: - a step (El) of providing a mold (1), the mold (1) comprising a plate (2) and a matrix (3) of microneedle imprints (4) formed in the thickness of the plate (2), the plate (2) comprising a first external face (A), each imprint (4) comprising a base (41) coplanar with the first face (A) and a pointed bottom (45), and each imprint (4) being polyhedral and comprising at least one edge (42);the mold (1) comprising lateral vents (51) which are grooves formed in the plate (2) in planes orthogonal to the first face (A) and axial vents (52) in communication with the bottom (45) of each cavity (4), the cavities (4) being in communication with each other via the lateral vents (51), the lateral vents (51) extending over at least part of the height of each cavity (4) and the cavities (4) being arranged relative to the lateral vents (51) so that the lateral vents (51) communicate with the cavities (4) only via the edges (42) of the cavities (4);- a step (E2) of placing the matrix (3) of impressions (4) under vacuum via the lateral vents (51) and the axial vents (52) and of injecting material through the base (41) of each impression (4) so ​​as to completely fill the volume of each impression (4) via a thrust of material due to the injection and the placing under vacuum by suction via the lateral vents (51) and axial vents (52); and - a step (E3) of demolding so as to obtain a network (9) of microneedles (7).;

2. Method according to claim 1, in which each imprint (4) extends over a first part (46) taken from the base (41) to a slope break (44) according to a first height and extends over a second part (47) at a point taken from the slope break (44) to the bottom at a point (45) according to a second height.

3. A method according to claim 2, wherein the side vents (51) extend at least over a height ranging from half of the first part (46) of each imprint (4) to the slope break (44).

4. Method according to any one of claims 2 to 3, in which the lateral vents (51) extend from the first face (A) of the plate (2) to the slope break (44) of each imprint (4).

5. A method according to any one of claims 1 to 4, wherein the plate (2) consists of an assembly of plate sections (2a, 2b, 2c), each imprint (4) being in two parts, the lateral vents (51) and the axial vents (52) being constituted by junctions between the plate sections (2a, 2b, 2c).

6. Network of microneedles obtained by a manufacturing method according to any one of claims 1 to 5, in which each microneedle comprises a base (71), advantageously polyhedral, from which extends a first part (46) having as many faces (73) and stops (72) as the base (71) has sides then a second part (47) having a pyramidal shape up to a point (75).

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