Process for manufacturing micro-devices having thin parts or extensions, especially for delivering a bioactive substance to a mammal

Abstract

The process of the invention is intended to produce devices of millimetric or sub-millimetric overall size. The device has thin parts or extensions or arms extending outward of the surface of the device body. The device can have the ability to puncture microholes into a biological tissue such as skin. The process comprises the steps of shaping ceramic devices by casting a slurry, containing ceramic material as well as selected additives, into molds. The process steps and parameters and the slurry composition allow for the making of high-quality, high-resistance devices with high shape conformity and low breaking during manufacture and / or during use.

Description

PROCESS FOR MANUFACTURING MICRO-DEVICES HAVING THIN PARTS OR EXTENSIONS, ESPECIALLY FOR DELIVERING A BIOACTIVE SUBSTANCE TO A MAMMAL CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Application No.63 / 689,218, filed August 30, 2024, the entirety of which is incorporated herein by reference. TECHNICAL FIELD

[0002] This Disclosure relates to the field of manufacturing micro-devices with thin partsor extensions, for example for facilitating the delivery of an active substance through a biological tissue. BACKGROUND

[0003] Animals, especially mammals, are usually protected by a thick layer, such as anepidermis or skin. Such layer provides a protection against external elements. Such elements can be of any type, for example abrasion, pressure or cuts. That protection is also effective against the penetration of liquids, gaseous or solid substances into the body of the animal. The absorption of external substances is therefore heavily impacted by the protective layer. If this is a positive protection for the animal, such protective layer also impairs the absorption of desirable compounds or actives through the skin.

[0004] Many methods and devices have been designed to help the absorption of thepassing of compounds, especially active compounds through the protective layers and through the skin of the mammals for example.

[0005] One of the most common methods and devices may be the injection devices usingsharp hollow needles able to penetrate the skin and transfer liquid containing an active component into the body.

[0006] Other more sophisticated methods and devices use, for example, patches whichsurface are covered with microneedles able to penetrate slightly the upper layers of the skin and in which the patches are impregnated with the bioactive component which would pass through the skin. Alternatively rigid macrostructures have been described to induce a transdermal drug delivery for example as described in U.S.20130144261.

[0007] More recent methods have used microneedle particles of very small size which canbe incorporated into a matrix containing the bioactive. Such microneedles obliterate / create DB1 / 161834162.2small punctures or micropores in the skin upon rubbing and somewhat facilitate the transfer of the bioactive. Such microneedle particles, substantially flat, have been described in WO2017151745. Other microneedle devices, substantially spherical, have been described in U.S.20200121900A1. Such devices and methods are however of limited efficiency and improvements are needed. The process of manufacture for spherical devices can be for example complex and / or cost ineffective.

[0008] All these methods and devices have however disadvantages: low efficiency oftransfer, superficial depth of transfer of the bioactive, inconvenience or pain, complexity, low surface area of transfer, need of a trained operator, low absorption into the body, etc.

[0009] Additionally, these methods making use of devices of very small size (often in therange of 0.5 to 10 mm in overall size), the resistance to mechanical fracture or damage during the manufacturing process as well as the resistance to mechanical fracture or damage of the devices in use are of extreme importance.

[0010] Similarly, in other fields of technology, many instruments and equipment makeuse or comprise parts or devices of small size. Those are often of complex shapes with thin portions or extensions. Those parts, often millimetric or sub-millimetric in size must be produced with the highest possible precision, highest possible accuracy of their dimensions and shapes, and highest reproducibility. For example, many tiny parts, gears, cogs, levers and wheels in the watch industry must comply with these requirements. Many (micro)mechanical mechanisms from various technical fields also make use or comprise such parts (for example measuring devices, sensors, audio devices, automotive parts, aeronautical parts, locksmith parts, actuators, micro-sensors or effectors of the electronic industry, etc.). In many instances those parts do not have a simple shape (e.g. rounded, spherical, ovoid, or parallelepipedic shape) but comprises a core / body and extensions or elongations, possibly extending outwardly form the core. Typical examples of such part would be a sub-millimetric clock / watch cog or micro-switches in the electronic industry. The complexity of their shape, their three-dimensionality, the presence of elongated or thin sub-parts, or the presence of extensions, all make these devices fragile, easily breakable or easily deformable.

[0011] There are indeed substantial disadvantages (e.g. complexity of manufacture, cost,safety, etc.) linked to the breaking of such devices. For example, during manufacturing, the breaking induces the creation of dust and a higher cost. Similarly, during use, the breaking of the devices may challenge the performance of the devices (such as the efficiency of the bioactive transfer) and the presence of the broken parts is most often undesirable (In case of DB1 / 161834162.2microneedle devices for delivering an active substance, the broken parts can even get potentially stuck in the skin).

[0012] Also, the manufacturing steps can impart some deformation of the micro-devicebeing manufactured. High temperature, heat transfer parameters of the materials or of the equipment, pressure (positive or vacuum), and other factors all potentially impact the shape, the dimensions and resistance of the final product. For example, the material contraction or expansion during the manufacturing steps must be taken into consideration and accounted for when designing the devices (or the molds for such devices). Only the fine balance between (i) the nature and amount of materials & components entering into the process, (ii) the equipment used (e.g., mold), (iii) the nature of the process steps used (e.g., laser ablation, sintering, etc.) and (iv) the process parameters (e.g., temperature, process steps duration, pressure, heat rate, etc.) can lead to the end-products (devices) of the desired shape and quality (e.g., most accurate dimensions, shape, volumic mass, homogeneity and resistance).

[0013] The shape and structure of the devices is of the highest importance for theirfunction. The manufacturing of carefully designed and configured devices, in millimeter or sub-millimeter size, at high efficiency, high accuracy, low cost and high quality remains to be optimized.

[0014] There is a need to produce devices and other millimeter size or sub-millimeter sizedevices or parts in a material that is most suited for the intended use and presenting the best mechanical and / or volumic mass characteristics and / or material homogeneity for the intended use. There is a need to produce devices with desired and particular homogeneity in the material mass, for example to ensure a smooth movement of the parts of an apparatus, and / or insuring a particular inertia and momentum.

[0015] There is a need to produce devices and other sub-millimeter size devices or partsin a reproducible way with high efficiency, and high accuracy of dimension and shape.

[0016] There is a need to produce devices and other sub-millimeter size devices or partsin the most economical way, at low cost, and by a process which is environmentally friendly.

[0017] There is a need to produce devices and other millimeter size or sub-millimeter sizedevices or parts using reusable equipment and / or without undesirable substances or with the lowest possible energy consumption.

[0018] There is a need to produce microneedle devices and other millimeter size or sub-millimeter size devices or parts in a way that creates identical or nearly identical plurality of devices of the desired shape and structure, with the lowest possible variations in shape, size and the lowest possible making of broken or incomplete devices or parts. DB1 / 161834162.2

[0019] There is a need to produce microneedle devices and other millimeter size or sub-millimeter size devices or parts with the highest possible precision of shape and dimensions. SUMMARY OF INVENTION

[0020] The present invention proposes an optimized manufacturing process formillimetric or sub-millimetric devices. Such devices have preferably thin parts, and / or extensions and / or arms and / or microneedles and / or cogs.

[0021] The device can comprise one or a plurality of thin parts, arms or extensionsconfigured in a way promoting the desired function. Such function can for example include the creation of micro-punctures / micropores by the microneedles at the distal end of arms (in particular when the devices are applied to a biological tissue and facilitates the passing of a bioactive substance through a biological tissue). Such function can for example also include the transmission of a movement (e.g., actuators effector devices, watch cogs), the transmission of a signal (e.g., sensors), or the connection or association between parts (e.g., the engagement of the arms or extension of the device with other parts of an apparatus).

[0022] In one aspect, the invention relates to the manufacture of a millimetric or sub-millimetric device that has a remarkable tridimensional shape and has thin extensions pointing outwardly from the body of the device and / or has sharp edges.

[0023] In one aspect, the invention relates to the manufacture of a microneedle device thathas a particular tri-dimensional shape and has a concave and / or a convex surface as well as a plurality of microneedles arranged at the distal end of each arm.

[0024] In one aspect, the invention relates to a millimetric or sub-millimetric devicehaving a plurality of thin parts (and / or extensions) useful in the watch industry or micromechanic industry.

[0025] In one aspect, a plurality of devices of the invention are connected to each other'sby their thin parts to form, for example, a net or a mesh. BRIEF DESCRIPTION OF THE FIGURES

[0026] Figure 1 represents a microneedle device having three microneedles produced bythe process of the invention.

[0027] Figure 2 represents a microneedle device having three microneedles and oneadditional arm produced by the process of the invention. DB1 / 161834162.2

[0028] Figure 3 shows the images of different intermediate products (= green bodies)made with different slurry compositions.

[0029] Figure 4 shows test results illustrating the importance of the additives in the slurryof the invention.

[0030] Figure 5 illustrates the importance of the degassing step and of the degassingadditive. DETAILED DESCRIPTION

[0031] In one embodiment, the invention relates to the making of millimetric or sub-millimetric devices or microneedles devices. Preferably the device has a body (= core) and thin parts, and / or arms or extension, optionally pointing outwardly from the body.

[0032] The invention can however extend to related parts or devices having the claimedphysical characteristics but intended for various uses.

[0033] In the present document, the terms «microneedle device» or « device » are used asthey may represent some of the preferred embodiment of the invention. The terms are however to be understood in this document as « any device or part of a millimeter or submillimeter overall size » and having preferably a plurality of thin extensions or arms, regardless of the intended use. The terms can be used interchangeably.

[0034] Device

[0035] The device made by the process of the invention can be encompassed in a circle of50 mm, 25 mm, 20 mm, 10 mm, 8 mm, 5 mm, 2 mm, 1 mm, 800 micrometers, 500 micrometers, 200 micrometers, 100 micrometers, 50 micrometers, or 20 micrometers in diameter. It is therefore said to be of millimeter or submillimeter overall size. The device can have any shape or three-dimensional configuration falling in the claims of the present invention.

[0036] In one embodiment, the device made by the process of the invention has a core (ora body) and one or a plurality of thin parts and / or one or a plurality of extensions or arms.

[0037] The thin parts are thin in comparison to the size of the body, for example theircross-sectional dimension (or their maximum cross-sectional dimension) is smaller than the cross-sectional dimension of the body (or of the maximum cross-sectional dimension of the body). Preferably that dimension is less than 1.5 times, less than 2 times, less than 5 times, less than 10 times, or less than 25 times compared to the body. In one embodiment the cross- sectional dimension or maximum cross-sectional dimension of the thin parts (or of at least one thin part) is less than 5 mm, less than 2 mm, less than 1 mm, less than 500 micrometers, less DB1 / 161834162.2than 250 micrometers, less than 100 micrometers, less than 50 micrometers, less than 25 micrometers, less than 10 micrometers, less than 5 micrometers, less than 2 micrometers or less than 1 micrometers. Each thin part is associated, linked, juxtaposed or connected with the body.

[0038] The extensions or arms extend or elongate from the body (or core). In oneembodiment, extensions or arms extend or elongate outwardly from the body.

[0039] In one embodiment, the body is hollow, and the extensions or arms extend orelongate inwardly from the body. In one embodiment, the body comprises recesses or voids. This feature may be of importance to reduce the weight of the devices for some applications, especially when the devices will be animated during use.

[0040] In one embodiment, the core itself is of extremely limited size and is defined bythe point attaching the extensions or arms together.

[0041] The device can comprise a body having two opposing surfaces and a geometricalcenter, at least three arms and at least three microneedles. In one embodiment, the number of extensions or arms or microneedles is one, two, three, four or more. In one embodiment, one of the opposite surfaces is convex, and / or one of the opposite surfaces is concave.

[0042] Each arm or extension has a distal end and proximal end. The proximal end isattached, part of, linked, associated or connected to the body. Each arm or extension extends from, elongates from or protrudes from, the body. Preferably the arms or extensions point to different directions separated by an angle of more than 20 degrees, 30 degrees, 40 degrees, 50 degrees, 60 degrees, 90 degrees, or 110 degrees.

[0043] The preferred number of arms or extensions or thin parts is one, two or three.However, in some embodiments, the number of arms, extensions or thin parts can be four, five, six, seven, eight, nine, or ten. In one embodiment, the plurality of arms, extensions or thin parts is less than 5, less than 10, less than 20, less than 50, or less than 100. In one embodiment, the corresponding number of microneedles can be 1, 2, 3, 4, 5, 6, 7, 8, or 10. In one embodiment, the number of arms (or extensions) and / or the number of microneedles is less than 10 or less than 5. Having a limited number of arms extensions reduces the risk of deformation or breaking during process and improves the precision and quality of the devices.

[0044] As a distal end of each arm, a microneedle may be arranged. Each microneedle hasa general direction, most often similar to the direction of the arm, pointing outward and away from the center of the body of the microneedle device. The angle between two of the general directions of the microneedles is at least 30, at least 40, at least 60, at least 70 or at least 90 degrees (measured as projected in the plane formed by three microneedles). In some DB1 / 161834162.2embodiments, the microneedles are integral part of the arms and / or represent the end or tip of the arm.

[0045] When having a concave surface and / or a convex surface the device is not flat buthas a remarkable three-dimensional shape. The convex surface for example can induce a better sliding of the devices when rubbing against a biological tissue, and thus a better dispersion of the devices or microneedles (and therefore of the microholes created). However, such surface may be much more difficult to manufacture compared to substantially flat surface.

[0046] In one embodiment, the surfaces of the device are substantially flat, or one of thesurfaces is substantially flat. In application where mechanical movements are desired, a flat surface may present advantageous effect (for example the reduction of the friction).

[0047] In one embodiment, the device of the invention is substantially elongated and has aconvex or a concave surface. In one embodiment of the invention, the device of the invention is not substantially spherical or not totally spherical. In one embodiment, the device is spherical, substantially spherical or ovoid.

[0048] In one embodiment, the device comprises one or more microneedles (=microneedle device). In one embodiment, the device of the invention does not comprise any microneedle.

[0049] In one embodiment, the device of the invention comprises a plurality of thin partsand / or extensions, the plurality of devices is connected or associated to each other by their body or preferably by their thin parts or extensions. Most preferably a void is left between the bodies or thin parts. The plurality of devices can form a net, a webbing, a mesh or a lace. Such a plurality of devices can for example be useful to screen, filter or sieve different solids, gaseous or liquid materials, or more generally in the physical spacing of components or materials.

[0050] In one embodiment, the process of the invention is for manufacturing a deviceconsisting of or comprising at least one mechanical part. The mechanical part can be static or non-static (intended to be in movement during use). The mechanical part is preferably a part of high precision (manufacturing tolerances lower than 0.1 mm, or lower than 0.01 mm or lower than 0.001 mm). The mechanical part or the device can be of small dimension (i.e., maximum dimension lower than 20 mm, lower than 15 mm, lower than 10 mm, lower than 5 mm, lower than 2.35 mm, lower than 1 mm, lower than 0.1 mm, lower than 0.05 mm, or lower than 0.01 mm). DB1 / 161834162.2

[0051] The device or the mechanical part can consist of or can comprise an optical device,preferably with at least one structured surface. In one embodiment, the device or mechanical part has 1, 2, 3 or 4 structured surfaces. In one embodiment the optical device comprises ceramic and / or glass. In one embodiment, the optical device comprises nanoparticles modulating the refractive index. In one embodiment the optical device does not comprise nanoparticles for modulating the refractive index.

[0052] The device or the mechanical part can consist of or can comprise a membraneand / or a filter, preferably having pores or micropores. The pores or the micropores are preferably sub-millimetric or sub-micrometric pores (i.e., average diameter of the pores below 1 mm, below 0.05 mm, below 0.01 mm, below 5 micrometers, below 1 micrometer, below 0.1 micrometer, below 0.01 micrometer, or below 0.001 micrometer). In one embodiment, the device or the mechanical part can comprise or can consist of a time-keeping apparatus, a watch or a part of a watch.

[0053] In one embodiment, the device made by the present invention is or comprises anyof a cog, a gear, an actuator, a lever, an effector, a wheel or a sensor. The thin part of the device can itself be or comprise a cog, a gear, an actuator, a lever, an effector, a wheel or a sensor.

[0054] In one embodiment, the device manufactured by the process of the invention, or aplurality of the devices, consists of, or comprises or forms a structured surface. The structured surface can have frictional and / or tribological properties and / or can comprise a lubricating agent reservoir. In one embodiment, the structured surface is characterized by comprising structures having dimensions from 0.01 micrometer to 100 micrometers or from 0.1 micrometers to 10 micrometers.

[0055] In one embodiment, the device manufactured by the process of the inventioncomprises at least one surface structure. The surface structure has preferably optical functionality selected from the list: light scattering, wavelength selective coupling gratings, specific reflectivity properties, projecting images based on diffractive optical elements, or a combination thereof. The surface structure being preferably of micrometric scale (for example, between 0.1 micrometer and 10 micrometers, less than 50 micrometers, or less than 10 micrometers).

[0056] In one embodiment, the device manufactured by the process of the inventioncomprises mechanical functionality, preferably selected from the list: fixing optical fibers, guiding optical fibers, orientating optical fibers into positions, maintaining or placing optical fibers at desired angles to one another. Optionally such functionality relates to the DB1 / 161834162.2transportation of information or being used in information transportation couplers and / or separators.

[0057] In one embodiment of the invention, the process can be used for manufacturing adevice for use in medical or non-medical treatment of pathological or non-pathological conditions. In one embodiment such treatment consists or comprises the step by rubbing said device or a plurality of devices on the skin of a mammal together with a bioactive substance or a medicament. The step induces the passing of the bioactive substance or medicament through the skin of the mammal. In one preferred embodiment, the device is used in a plurality of devices, preferably in an ointment or gel matrix, and is particularly suitable for creating micro-punctures into the skin. Non-medical treatments can include cosmetic or aesthetical uses. Medical treatments can include dermatological uses and / or the passing of an active medicament through the skin (comprised for example in the ointment or gel) for a local or a remote action of the drug.

[0058] Device Material

[0059] In one embodiment, the device is made of, comprises or consists of, a moldableplastic material, or a metal or a ceramic material.

[0060] In one preferred embodiment, the devices are made of alumina (Al2O3) and / orzirconia (ZrO2) and / or hydroxyapatite (Ca10(PO4)6(OH)2) and / or calcium phosphate (Ca3(PO4)2) and / or calcium sodium phosphosilicate and / or silica (SiO2) and / or silicon nitride (Si3N4) and / or stabilized zirconia and / or yttrium aluminum garnet (YAG) and / or magnesium aluminum spinel (MgAl2O4) and / or aluminum nitride (AlN) and / or silicon nitride (SiC), or any combination or derivative thereof (including stable and metastable phases that can occur).

[0061] The material can be pure or doped such as to alter the microstructure during theprocess (e.g., during sintering) or such as to stabilize or meta-stabilize the structure.

[0062] The material of the devices is sufficiently resistant to preserve its integrity withoutbreakage and / or undesired deformation during manufacturing and / or during use. It can be also sufficiently hard to have microneedles of enough sharpness and that can penetrate the biological tissue.

[0063] Device Shape

[0064] In one embodiment, the device has regions between the arms or extensions that donot present any (or only very few) angular edge nor angular angles (especially when observed from a plane formed by three of the arms or extensions tips). In other words, the regions between the arms or extensions have rounded or smooth boundaries. This geometrical DB1 / 161834162.2characteristic has been shown to induce less breakage, during manufacturing and / or use, due to the absence of any angular point or line creating weakness.

[0065] In one embodiment, the device has one, two, or three or at least one additionalarms and / or additional microneedles protruding from the convex or from the concave surface (or both) of the body. In one embodiment, the additional arm(s) are protuberances extending outwardly from the surface, with or without additional microneedles at their distal end. Preferably the additional arm(s) (or additional microneedle(s) when present) points into a direction that is perpendicular to the surface and / or a direction that is perpendicular to the plane formed by three microneedles. Such additional microneedle(s), when present, can have an advantageous effect on the ability of the device to puncture the tissue and create microholes. The additional arm(s) can have the ability for the device to enhance the rolling or sliding on the surface of the biological tissue (enhancing dispersion upon use and the surface area of the microholes).

[0066] In one embodiment, the microneedle device comprises microneedles that aresufficiently thin and sharp, -while keeping a good resistance to breakage-, to easily puncture the biological tissue or skin. A thin microneedle is preferred. A sharp microneedle is also preferred. The extremity of a microneedle can be encompassed by a circle of less than 25, less than 15 micrometers, less than 10 micrometers, or less than 6 micrometers in diameter (or in cross sectional maximum dimension). Alternatively, or additionally, the extremity or distal end of the microneedles or of the arms or of the extensions can be encompassed by a cone having an angle of less than 45 degrees, less than 30 degrees, less than 20 degrees, less than 10 degrees, less than 5 degrees, or less than 2.5 degrees. A smaller angle means for example that the microneedle is sharp and thin at its extremity, promoting a good penetration in the tissue or skin.

[0067] In one embodiment, the device has a small overall dimension. The device of theinvention can be encompassed by a circle of less than 20 mm, less than 15 mm, than 10 mm, less than 5 mm, less than 1500 micrometers, less than 1000 micrometers, less than 900 micrometers or preferably less than 600 micrometers or less than 500 micrometers diameter. In some embodiments of the invention, the encompassing circle is between 1 mm and 15 mm, between 500 micrometers and 1500 micrometers, or between 600 micrometers and 100 micrometers.

[0068] In one embodiment, the distance between the center of the body of the device andany microneedle (or distal extremity thereof) is less than 800 micrometers, less than 700 micrometers, less than 600 micrometers, less than 500 micrometers, or less than 400 DB1 / 161834162.2micrometers. In some embodiments, such distance is between 400 micrometers and 800 micrometers.

[0069] The device has a defined thickness of material. That thickness is defined by thedistance between the opposite surfaces of the device, especially at its body center (measured perpendicularly to the surfaces). In one embodiment, that thickness of material of the device is constant in all, substantially all, or the majority of the surface area of the surface of the device. In one embodiment, the thickness of material varies along one or more dimension of the device. In one embodiment, the material thickness is between micrometers 50 and 500 micrometers or between 100 micrometers and 350 micrometers. In one embodiment, said thickness is 150 micrometers, 200 micrometers, or 300 micrometers. The thickness of material must be sufficient to enhance the resistance of the device and avoid undesired deformation (during manufacturing and / or during use) while being thin enough to allow for its function (for example a good dimensional fit in a small-size apparatus or a good sharpness and ability to puncture the tissue of the microneedles).

[0070] The device in the invention has a particular three-dimensional structure. Thepresence of arms or extensions or thin parts, possible of a convex or concave surface and possibly of microneedles extending outward can induce a curved body (on contrary to a generally flat body). The distance between the plane defined by the distal ends of three of the arms or extensions or microneedles and the center of the opposite surface of the device represents the 3D thickness of the device. In one embodiment, it is at least 50 micrometers, at least 100 micrometers, at least 250 micrometers, at least 500 micrometers, or at least 1000 micrometers. In one embodiment, the 3D thickness of the device is less than 1000 micrometers, less than 800 micrometers, less than 500 micrometers, less than 200 micrometers, less than 100 micrometers, or less than 50 micrometers. A larger 3D thickness of the device may impact positively the device function (for example, its ability to puncture the tissue or the ability to roll / slide on the biological tissue). However, the high tridimensionality (large 3D thickness of the device) makes the device more difficult to produce in good quality and without breaking.

[0071] The three-dimensional structure of the device, the spatial orientation of the arms,extensions, thin parts or optional microneedles as well as the possible concavity and convexity of the surfaces can result either from the original design of the manufacturing mold (for example, by having themself convex and concave surfaces and / or particular arm directions or by having corresponding 3D cavities of the corresponding dimensions) and / or can result from the controlled shrinkage of the device during some steps of the manufacture of DB1 / 161834162.2the device (for example, during the drying, sintering or heat treatment). Similarly, the spatial orientation of the arms or extensions or thin parts or microneedles can be dictated either by the shape of the molds (or of its cavities) or by the controlled shrinkage of the material during or after manufacture. The materials, the composition of the slurry (ceramic and / or additives), the shape of the molds (and / or of its cavities) and the process parameters (e.g., temperature and / or time of drying, debinding, sintering) have been selected to obtain the desired three- dimensional shape, size and configuration of the device at the end of the manufacturing process.

[0072] Manufacturing process of the invention

[0073] The devices made by the present invention can be produced by some steps ofconventional ceramic molding / demolding and / or laser milling or ablation (as for those presented in WO 2017151745 and WO 2021081260), when associated with the critical, unique and inventive process steps of the present invention.

[0074] The process of the invention comprises the following steps. The steps a, b, c, e, f,g, h, i, j, k are sequential steps. The step d may be performed non sequentially and independently of the other steps. It is obviously understood that the step of preparation of the slurry (step d) is executed prior to (or together with) the steps e to j.

[0075] a. Optionally, engraving a master-mold. The master mold can comprise or consistof a polymeric material. The engraving can comprise or consist of a step of laser milling, or any other conventional suitable engraving. Without being bound to the theory, for laser fabrication of the mold, Excimer laser mask projection direct ablation offers unique advantages as compared to other laser milling processes as it offers higher resolution of the laser light exposure resulting in a higher precision and sharpness of the molds. Edge curvatures of the mold can easily reach curvature radii of less than 5 micrometers, less than 2 micrometers, or even smaller than 0.5 micrometers. High aspect ratio structures width to depth of smaller than 1 micrometer, smaller than 0.5 micrometer, or even smaller than 0.2 micrometer can be achieved in a cost-effective rapid process not needing a clean room or comparable large facility equipment. Such laser technology can be used in a preferred embodiment of the invention.

[0076] b. Optionally reproducing the master-mold into a shim. The shim can comprise orconsist of nickel material (Ni). The reproduction step can comprise or consist of electro- formation or any conventional suitable method. Such methods have been described for example in the book « Hot Embossing », author Matthias Wargull, Elsevier Inc., 2009, ISBN 978-0-8155-1579-1, in particular Chapter 9 on electroforming. DB1 / 161834162.2

[0077] c. Optionally creating a mold, preferably a multiple use mold, and preferably byhot embossing a polymeric material with the shim. In one embodiment, the mold is created by cross-linking a silicone directly from the master-mold. The mold is configured to mold the desired shape of the device. The mold material is a polymeric material. In one embodiment, the polymeric material preferably comprising or consisting of polypropylene (PP), or polycarbonate (PC), or polyethylene (PE), or polyterafluorethylene (PTFE) or any other thermoplastic polymer. Alternatively, photoresist polymers or thermally or photolytically hardening acrylates or silicone polymers could also be used. Alternatively, a hot embossed polymeric material may be treated with cross-linking agents to provide thermal shape stability. The process for creating the mold can be any suitable convention process, in particular those described in the above reference book « Hot Embossing ». The mold is preferably a reusable mold. By carefully selecting the material of the mold and the conditions of the hot embossing and of the later processes, it is possible to produce a mold that is sufficiently resistant to be used in multiple productions, without deformation or impairment, while still producing devices of high quality.

[0078] d. Non-sequentially preparing a slurry. The slurry may comprise:i. ceramic material, preferably in powder form. The ceramic material used in the invention is preferably alumina (Al2O3) and / or zirconia (ZrO2) and / or hydroxyapatite (Ca10(PO4)6(OH)2) and / or calcium phosphate (Ca3(PO4)2) and / or calcium sodium phosphosilicate and / or silica (SiO2) and / or silicon nitride (Si3N4) and / or stabilized zirconia and / or yttrium aluminum garnet (YAG) and / or magnesium aluminum spinel (MgAl2O4) and / or aluminum nitride (AlN) and / or silicon nitride (SiC), or any combination or derivative thereof (including stable and metastable phases that can occur). In some embodiments the amount ( % w / w) of ceramic in the slurry is between 30% and 95%, or between 50% and 85%, or between 60% and 80%, or between 65% and 75%, or is 70%, or at least 50%, or is at least 60%, or at least 65% or at least 69%, or at least 80% or at least 90% or at least 95% or at least 98%. The inventors have observed that the curvature of the final device is influenced by the solid loading of the ceramic material in the slurry. The inventors have found that an optimum curvature (of the opposite surfaces of the device) can be obtained by selecting a proper % of ceramic material in the slurry. Similarly, the lack of curvature can be helped / obtained by selecting a particular % of ceramic material in the slurry.

[0079] Ceramic materials are described in « Fundamental biomaterials: Ceramic » authorsSabu Thomas, Preetha Balakrishnan and M.S. Skreekala, Elsevier Ltd., ISBN 978-0-08- 102203-0. DB1 / 161834162.2ii. A sol-gel additive. The sol-gel additive used in the invention preferably contains a colloidal dispersion of nanoparticles or precursors (such as metal alkoxides or metal salts) of zirconia (ZrO2) and / or alumina (Al2O3) and / or silica (SiO2), and / or calcium sodium phosphosilicate. The concentration is preferably between 1 to 20 wt% or between 3 and 10 wt%, or 6 wt % relative to mass of the ceramic material. Sol-Gel additives have been described in Material Matter, by Sandra Kay Young, 2006, 1.3,8., also available at www.sigmaaldrich.com / CH / de / technical-documents / technical-article / materials-science-and- engineering / solid-state-synthesis / sol-gel-science-for. The sol-gel additive can be or can comprise, in one embodiment of the invention, nanoparticles in the form of a colloidal or nano-colloidal solution. The nanoparticles may be crystalline, or amorphous, or a combination thereof. The sol-gel reaction forming or activating the sol-gel additive can be performed before the addition of the sol-gel additive or in the slurry or in mold. The sol-gel additive helps providing resistance / strength to the intermediate (so-called green body) and / or final product. The resistance of the intermediate product (for example just before demolding) is of importance as insufficient resistance would provoke damage to the products during the process (in particular during the demolding step). The resistance / strength and physical characteristics of the intermediate product (green body) is selected to enable the reusability of the mold. Difficult demolding could result in damage to the mold or to the product being made. The resistance of the final products is not only crucial during its intended use, but also during the handling of final product and / or additional manufacturing, packaging, or transportation steps. In one embodiment of the invention, the sol-gel additive is replaced, is in the form of, or comprises single powder compounds (such as those listed in the ceramic list above) having a particle size of less than 250 nm, less than 150 nm, less than 100 nm, or less than 80 nm. Without being bound to the theory, it is thought that small particle size (in particular when below 150 nm) enhances the quality of the intermediate product (green body) and / or enables an adequate quality of the end product, and / or allows for an adequate molding and demolding. In some embodiments, the sol-gel additive is replaced, or is in the form of, or comprises an organic binder (e.g. polyvinyl alcohol PVA, polyethylene glycol PEG), and / or inorganic binder (e.g. alkoxides), and / or nanoparticles synthesized for example through sol route or else. The sol-gel additive may be optional in some embodiments. iii. Optionally a dispersant additive, comprising preferably electrolytes such as citric acid, and / or polyelectrolytes such as polyacrylic acid, and / or surfactants such as Polysorbate 20 (Tween 20, available from MERCK, Germany). The dispersant additive can be neutralized or partially neutralized with NH4OH prior to incorporation. The dispersant DB1 / 161834162.2additive may be aqueous suspensions or non-aqueous suspensions. Examples of non-aqueous suspensions, like dicarboxylic acids, can be found in “Surface modification of alpha-Al2O3with dicarboxylic acids for the preparation of UV-curable ceramic suspensions; S Zhang, N. Sha and Z. Zhao; Journal of the European Ceramic Society, 2017, vol 37, issue 4, pages 1607- 1616, WOS:00039482700049; DOI:10.1016 / jeurceramsoc.2016.12.013. The dispersant additive is preferably in concentrations between 0.2 to 5.0 wt%, or between 0.3 and 2 wt%, or between 0.4 and 1 wt%, or is 0.6 wt% relative to mass of the slurry. The dispersant additive has been found to help the dispersion of the powders in the slurry, to help reduce the viscosity of the slurry, which allows the coating / filling of the mold by the slurry and / or to avoid air bubbles in the mold. This induces better quality devices. iv. Optionally, a crack-prevention additive. The cracking-prevention additive preferably comprises of or consists of ethylene glycol, polyethylene glycol, or glycerol. The concentration is between 2 to 15 wt% or between 3 to 12 wt%, or between 5 to 10 wt% or is 7 wt% relative to mass of said ceramic material. The cracking prevention additive has been found to help the resistance of the device during the manufacturing process and avoid the breaking of the devices. Also, the cracking prevention additive enables to incorporate finer powders into the slurry (e.g., ceramic powders). Finer powders are associated with a better filling of the mold. Without being bound to the theory, it is thought to increase the capillary pressure in the intermediate product during drying. v. Optionally a wetting additive. The wetting additive is preferably any low surface energy water soluble volatile liquid for example an alcohol with an aliphatic chain, preferably octanol ( for example 1-octanol, 2-octanol 3-octanol or 4-octanol, available for example from Sigma Aldrich Chemie GmbH), preferably in concentrations between 1 to 20 wt% or between 3 to 10 wt% or is 7 wt% relative to mass of said ceramic material. The wetting additive has been found to help the complete filling of the mold and to avoid air bubbles when filling the mold. vi. Optionally a degassing additive. A degassing agent comprises preferably a mixture of alkyl poly(alkoxy esters) and fatty esters. The additive Foamaster NO 2365 or Foamaster NO 2306 (available from BASF, Ludwigshafen, Germany) are suitable for the invention. The concentration between 0.1 to 10 wt%, or between 0.2 to 5 wt% or between 0.3 to 3 wt% or between 0.4 to 1 wt%, or is 0.5 wt% relative to mass of said ceramic material. The degassing additive helps the degassing step, thus helping to reduce the formation of air bubbles in the cast ceramic parts. Without being bound to the theory, it is thought that the degassing additive reduces the surface tension of the slurry, hence enabling the gas to escape DB1 / 161834162.2(Thus avoiding gas bubbles). Also, it is thought to improve the wetting of the mold (thus promoting better filling of the slurry into the mold). The preparation of the slurry optionally comprises the steps of: 1. mixing the ceramic material with the sol-gel, dispersant, wetting, and crackprevention additives 2. then submitting the mixture to an ultrasound treatment3. then adding the degassing additive4. then submitting the mix to a pressure below atmospheric pressure or a vacuum fordegassing. The degassing may include submitting the mixture to a pressure below atmospheric pressure or may include submitting the mixture to gravitational or centrifugal mixing forces.

[0080] e. Filling a mold with said slurry. The mold is selected and designed to be reusable / multiple use mold. The mold may be made of polypropylene (PP), polycarbonate (PC), polyethylene (PE), polymethylmethacrylate (PMMA), polytetrafluoroethylene (PTFE), or any other thermoplastic polymer or polymer blend. Photocurable polymers can also be used. The mold can be or is configured to mold a plurality of devices at once.

[0081] f. Optionally removing excess material with a single pass or multiple passes of awiper, said wiper being made of or comprising rubber and / or silicone and / or a metal. The removing can be achieved by any conventional method suitable for the purpose.

[0082] g. Optionally drying the mold comprising the slurry. The drying temperature maybe between 20 °C and 40 °C, between 20 °C and 30 °C, or about 25 °C. The drying time may be for a duration of 5 minutes to 180 minutes, 5 minutes to 90 minutes, 10 minutes to 60 minutes, 20 minutes to 50 minutes, 25 minutes to 40 minutes, or about 30 minutes. Without wishing to be bound by any particular theory, it was observed that covering the mold after casting may allow for a slow evaporation of the solvents and may result in a smoother compaction of the ceramic particles.

[0083] h. Demolding the devices. Demolding can be efficiently promoted by submittingthe mold and the devices being formed to an ultrasound treatment, preferably at relatively low power.

[0084] i. Optionally debinding the devices in a furnace at temperatures from 400 °C to900 °C, between 500 °C and 800 °C, or from 300 °C to 700 °C, or a about 700 °C. It has been found of importance for the quality of the devices to execute this step at heating rates from 0.5 °C / min. to 10 °C / min., or from 1 °C / min to 2 °C / min. Together with the below sintering, this DB1 / 161834162.2provides for an optimally controlled shrinkage of the device with reduced breaking or cracking. The debinding step may preferably be performed with intermediate dwell.

[0085] j. Sintering the devices at temperatures from 900 °C to 2500 °C, or from 1200 °Cto 1600 °C, or from 1400 °C to 1600 °C, or from 1000 °C to 1200 °C, or from 900 °C to 1600 °C, or from 800 °C to 1800 °C. Sintering of the device may be done at a temperature of about 1550 °C, of about 1400 °C, or of about 1200 °C. The sintering step may be executed with a heating rate from 0.5 °C / min to 12 °C / min, from 1 °C / min to 10 °C / min, from 2 °C / min to 7 °C / min, or at 5 °C / min. The duration of the sintering step may be from 0.1 hours to 24 hours, from 0.1 hours to 10 hours, from 0.5 hours to 5 hours, from 1 hour to 3 hours, or about 2 hours. The sintering provides resistance of the devices together with the optional debinding, without creating breaking or cracking.

[0086] k. Optionally, isolating the devices from residues, preferably by sieving.

[0087] In one embodiment of the invention, the process comprises a post-sintering stepperformed after the sintering step -j- . The post-sintering step may be hot isostatic pressing at temperatures below or equal to the sintering temperatures. The post-sintering step can consist or comprise applying pressure on the parts in a hot isostatic press to modify the final density or reach near full density, at a temperature typically equal or lower than the sintering temperature.

[0088] In one embodiment of the invention, an impregnation step by a sol-gel mixture canbe performed (e.g., after any of steps -e-, -f- , -g- or -h-). The steps -f- (removing excess material) and / or -g- (drying) can then be repeated after that impregnation.

[0089] In one embodiment of the invention, the machining step is performed beforedemolding. The machining step can comprise grinding the pieces to flatten the exposed surface of the device in the mold. It is understood that such machining step, performed on the devices in the mold, can erode or abrade the mold, although it may be preferred to not alter the mold (especially by a precise guiding of the machining). In one embodiment, the machining step is performed after demolding and / or after sintering.

[0090] The devices may comprise a body (or core) and at least three arms, each armelongating from the center of the body, and each arm having a microneedle at its distal end.

[0091] In one embodiment, the invention is based on the selection of the slurrycomposition (ceramic and additives) in order to obtain devices that have the desired shape and resistance. Both the nature of the materials (of the ceramic or of the ceramic mix), the nature of the additives, the sequence of the process steps and their relative amounts have been optimized to produce high quality devices of the invention. Without being bound to the DB1 / 161834162.2theory, each additive has more than one advantageous effect and the cited advantageous effects of each additive all play together in a synergistical manner to deliver the quality product made by the invention. Such quality can for example be measured by the precision of the devices of very small sizes made by the invention, by their resistance and strength, by the repeatability and robustness of the process to make identical or quasi-identical devices, or by their ability to preserve their thin and sharp shapes.

[0092] Similarly, the process parameters have been optimized for the same optimumeffect (for example the temperature, duration or rate of heating).

[0093] Plurality of devices made by the process of the invention – configuration of themold.

[0094] In one embodiment, the device made by the process of the invention is a stand-alone device (i.e. a separated unit). In one embodiment, a plurality of devices made by the process of invention at the same time or in one process run (e.g., a plurality of devices can be made out of one unique mold, the mold comprising a plurality of cavities, each cavity corresponding to a device). In one embodiment of the invention, plural devices are attached or linked to each other. In one embodiment of the invention, plural devices are made or are mutually associated. In one embodiment, the mold can comprise separated cavities and / or a plurality of cavities linked together, for example by an extension of some of or all the cavities. In one embodiment, all the cavities of the mold are linked by extensions, leading to a plurality of devices all linked together. EXAMPLES Example 1: Slurry

[0095] Figure 1 shows a microneedle device having 3 arms and 3 microneedles. Themicroneedles are pointing outward of the device in a configuration that is especially suitable for the intended use (e.g., for creating microholes / punctures on the surface of a biological tissue). The microneedles are elongated, thin and sharp.

[0096] Figure 2 shows a microneedle device having 3 arms and 3 microneedles as well asan additional arm. The 3 microneedles are pointing outward of the device in a configuration that is especially suitable for the intended use (e.g., for creating microholes / punctures on the surface of a biological tissue). The microneedles are elongated, thin and sharp. The additional arm points outward of the convex surface. It also helps the rolling, sliding, and / or gliding of the device on the biological tissue, together with potentially creating additional micropunctures on the tissue upon pressure. In this experiment, different slurries were DB1 / 161834162.2prepared and used to cast (fill) the PP molds, according to the invention. The images show the intermediate products (green bodies) before sintering. The images were taken before and after drying. As it can be seen in the images of Figure 3, without additives, it is not possible to fill completely the molds, specifically the tips (microneedles). After drying, this slurry composition leads to cracks and holes in the intermediate product (green bodies). The addition of Foamaster and ZrO2gel allows filling the molds properly and eliminating the holes after drying. However, the cracks are still present. Thus, the importance of adding ethylene glycol in combination with the other additives is evident in the last test, where a perfect intermediate product (green body) is obtained without cracks or holes.

[0097] Figure 4 shows the results of a test illustrating the importance of the amount ofadditives and of the process conditions. In this example, various amounts / concentrations of ethylene glycol, as an additive (e.g., as cracking prevention additive) mixed in the slurry, have been tested in the manufacturing of devices according to the invention. "Arm width at 10 µm from the tip" (referring in a way to the tip curvature / sharpness) and “tip-to-tip length” (= total length) of the devices made have been measured from different concentrations of ethylene glycol. The results show that slight changes in concentration or amount can have a significant effect on the shape and three-dimensional conformation of the device.

[0098] The experiment was performed as follows: slurries containing Al2O3 + ZrO2 gel +Foamaster + octanol were prepared with different amounts of ethylene glycol and were used for casting in the PP molds. Then, the green parts (intermediate products before sintering) were demolded and analyzed.

[0099] The use of ethylene glycol (in the presence of the other additives – ZrO2 gel,Foamaster, and octanol) allows obtaining the full reproduction in the ceramic parts of the desired shape on the polymeric molds, by a better filling of the molds and drying without cracks and breakage. This is important to ensure the sharpness (smaller tip length) of the microneedles.

[0100] The process of the invention was performed with and without degassing step(Figure 5). This experiment was performed by casting PP molds with slurries containing Al2O3+ ZrO2gel + Foamaster + ethylene glycol. In the first device, there is no octanol used and for the second device, octanol was used. The images show the devices obtained after sintering.

[0101] The use of octanol as a degassing agent and “lubricant” for demolding is importantsince bubbles in the slurry and in the mold after casting can cause defects in the devices, making them fragile and prone to breakage. DB1 / 161834162.2

[0102] In one embodiment the slurry to use in the process of the invention is as follows:Amount Ceramic material Al2O3 70 wt%Sol-gel additive ZrO2, and / or Al2O3,6 wt% with respect to the and / or calcium sodium weight of Al2O3phosphosilicate. Dispersant additive Polyacrylic0.6 wt% with respect to (neutralized with the weight of Al2O3NH4OH) Cracking prevention additive Ethylene glycol and / or7 wt% with respect to the Polyethylene glycol weight of Al2O3and / or Glycerol Wetting additive Foamaster NO23650.5 wt% with respect to (BASF) and / or the weight of Al2O3Polysorbate 20 Degassing additive Octanol 7 wt% with respect to theweight of Al2O3Water H2O to 100%Example 2: Process Conditions

[0103] In this example the process steps are performed as follows:

[0104] The mold is made of polypropylene (PP). Removal of the excess material isperformed with multiple passes of a rubber wiper at the surface of the mold.

[0105] The mold with the slurry encounters a drying step at 25 °C and for a duration of 30minutes.

[0106] Demolding is performed using an ultrasonic device at low power.

[0107] Debinding is performed in a furnace at 700 °C for 30 minutes with a heating rateof 1.5 °C / min.

[0108] Sintering is performed at 1550 °C with a heating rate of 5 °C / min. The duration ofthe sintering step is 2 hours. After sintering, the devices are isolated from residues by sieving. DB1 / 161834162.2

Claims

CLAIMS1. A process of manufacturing a device comprising one or more of steps selected from a,b, c, e, f, g, h, i, j, k, and d: a. Engraving a master-mold, the master-mold comprising or consisting of apolymeric material, preferably the engraving comprising or consisting of laser milling; b. Reproducing the master-mold into a shim, the shim preferably comprising orconsisting of Ni material; c. Creating a mold, preferably a reusable mold, preferably by hot embossing apolymeric material with the shim, or by cross-linking a silicone directly from the master-mold; the mold being configured to mold the shape of a plurality of embodiments of the device; d. Preparing a slurry comprising:(i) a ceramic material, preferably in powder form, preferably alumina(Al2O3) and / or zirconia (ZrO2), and / or stabilized zirconia and / or hydroxyapatite (Ca10(PO4)6(OH)2) and / or calcium phosphate (Ca3(PO4)2) and / or calcium sodium phosphosilicate and / or silica (SiO2) and / or yttrium aluminum garnet (YAG) and / or magnesium aluminum spinel (MgAl2O4) and / or aluminum nitride (AlN) and / or silicon nitride (Si3N4), or any combination or derivative thereof (including stable and metastable phases that can occur); (ii) a sol-gel additive, preferably containing nanoparticles of zirconia(ZrO2), and / or alumina (Al2O3), and / or silica (SiO2), and / or calcium sodium phosphosilicate, and / or precursors or metal alkoxides or metal salts thereof, preferably in concentrations 1 wt% to 20 wt% relative to mass of said ceramic material, or an organic binder or an inorganic binder or nanoparticles optionally synthesized through sol route; and one or more of (iii)-(vi): (iii) a dispersant additive, comprising preferably of polyacrylic acid (partially neutralized with NH4OH), preferably in concentrations 0.2 wt% to 5.0 wt% relative to mass of powder; DB1 / 161834162.2(iv) a crack-prevention additive, comprising preferably of ethyleneglycol, polyethylene glycol, or glycerol in concentrations between 2 wt% to 10 wt% relative to mass of said ceramic material; (v) a wetting additive, comprising preferably of octanol or of a mixture ofalkyl poly(alkoxy esters) and fatty esters, or of surfactants such as a polysorbate, preferably in concentrations between 0.1 wt% to 10 wt% relative to mass of said ceramic material; (vi) degassing additive, preferably octanol or defoamer agents,preferably in concentrations between 1 wt% to 20 wt% relative to mass of said ceramic material; e. Filling a mold with the slurry, the mold being preferably reusable, the moldbeing configured to mold the shape of a plurality of embodiments of the device; f. Removing excess material with a single pass or multiple passes of a wiper, thewiper preferably being made of or comprising of rubber and / or of silicone and / or of a metal; g. Drying the mold comprising the slurry, at temperatures from 20 °C to 40 °C for5 minutes to 180 minutes, preferably for 5 minutes to 60 minutes; h. Demolding the plurality of embodiments of the device, preferably by submittingthe mold and devices to an ultrasound treatment, preferably at low power; i. Debinding the devices in a furnace at temperatures from 300 °C to 900 °C,preferably from 400 °C to 700 °C, at heating rates from 0.5 °C / min to 10 °C / min; j. Sintering the devices at temperatures from 80 °C to 1800 °C, preferably withheating rates from 0.5 °C / min to 10 °C / min for 0.5 hour to 5 hours; k. Isolating the devices from any residues, preferably by sieving.

2. The process of claim 1, wherein a device comprises a body and one or more thin parts,and / or one or more extensions or arms, each extension or arm extending or elongating from the body, each thin part being associated with, or connected to or linked with the body, and wherein the device can be encompassed in a circle of 20 mm, 5 mm, 2 mm, 1 mm, 800 micrometers, 500 micrometers, or 200 micrometers in diameter.

3. The process of claim 1 or 2, wherein at least two or more of steps a, b, c, e, f, g, h, i, j, andk are performed sequentially. DB1 / 161834162.

24. The process of any one of claims 1 to 3, wherein step d is performed non-sequentially.

5. The process of any one of claims 1 to 4, wherein the device comprises microneedles onthe distal end of each extension or arm, preferably the number of extensions, arms and microneedles being three.

6. The process of any of the preceding claims, wherein the device comprises oppositesurfaces, one surface preferably being concave and / or the other surface preferably being convex.

7. The process of any of the preceding claims, wherein the device is or comprises any of acog, a gear, an actuator, a lever, an effector, a wheel or a sensor.

8. The process of any of the preceding claims, wherein the device, or a plurality of thedevices, comprises or forms a structured surface; preferably wherein the structured surface has frictional or tribological properties or comprises a lubricating agent reservoir.

9. The process of any of the preceding claims, wherein the device comprises at least onesurface structure, preferably with optical functionality selected from light scattering, wavelength selective coupling gratings, specific reflectivity properties, projecting images based on diffractive optical elements, or a combination thereof; the surface structure being preferably of micrometric scale.

10. The process of any of the preceding claims, wherein the device comprises mechanicalfunctionality, preferably selected from fixing optical fibers, guiding optical fibers, orientating optical fibers into positions, maintaining or placing optical fibers at desired angles to one another, optionally such functionality relating to the transportation of information or being used in information transportation couplers and / or separators.

11. The process of any of the preceding claims, wherein the slurry preparation step –dcomprises one or more steps selected from: mixing the ceramic material with the sol-gel or organic binder or inorganic binder or nanoparticles, dispersant, wetting, and crack prevention additives; submitting the mixture to an ultrasound treatment; DB1 / 161834162.2adding the degassing additive; and submitting the mix to a pressure below atmospheric pressure or a vacuum for degassing.

12. The process of any of the preceding claims, wherein the mold is made of polymericmaterial preferably comprising or consisting of polypropylene (PP), polycarbonate (PC), or polyethylene (PE).

13. The process of any of the preceding claims, wherein the reproduction step -b- comprisesor consists of electro-formation.

14. The process of any of the preceding claims, further comprising a post-sintering stepperformed after the sintering step -j- , preferably by hot isostatic pressing, preferably at temperatures below or equal to the sintering temperatures.

15. Use of the process of any of the preceding claims, for making devices for use in medicalor non-medical treatment of pathological or non-pathological conditions by rubbing said device on the skin of a mammal together with a bioactive substance or a medicament and thus inducing the passing of said bioactive substance or medicament through the skin of the mammal.

16. Use of the process of any of claims 1 to 14, wherein the device consists of or comprises amechanical part, preferably of high precision, or an optical device with at least one structured surface, or a membrane or a filter, said membrane or filter preferably having sub-millimetric or sub-micrometric pores. DB1 / 161834162.2

Images