Microneedle platform developed for use in allergy skin tests

Abstract

The invention relates to a microneedle platform that enables rapid and safe immune reaction assessment by single application of allergens contained in microneedle-containing islets (2) positioned at certain intervals on a biocompatible material developed for use in allergy skin tests. Unlike the methods used in the art, the inventive microneedle platform, which enables the simultaneous application of different allergens, also enables immune cells in different layers of the skin to react against allergens with microneedles of varying sizes within the unit microneedle area.

Description

[0001] MICRONEEDLE PLATFORM DEVELOPED FOR USE IN ALLERGY SKIN TESTS

[0002] Technical Field

[0003] The invention relates to a microneedle platform that enables rapid and safe immune reaction evaluation by single application of allergens of different properties in islets containing microneedles positioned at certain intervals on a biocompatible material developed for use in allergy skin tests.

[0004] Prior Art

[0005] Abnormal reactions defined as IgE antibody -mediated immune response of individuals against different substances in their environment are characterized as allergies. Allergy tests, which are used in the evaluation of allergic reactions to active substances, are diagnostic tools that enable the evaluation of symptoms that occur as a result of IgE antibody -mediated reactions to allergens in individuals. Allergenicity observed against different substances is one of the most important problems in societies and causes a large part of children, adults or elderly individuals to need allergy skin testing at some point in their lives. Allergen tests can be performed as skin prick, patch or intradermal injection according to allergen groups.

[0006] The most commonly used allergy test is the prick test known as skin prick. These tests involve the dripping of the relevant allergen group onto the marked skin areas at certain intervals and the piercing of the allergen-applied areas with the help of special tips. After 15-20 minutes from the application, the reaction areas are examined and evaluated by the specialist. During skin prick allergy tests, it is most important that the clinician (specialist) is well trained during the application of allergens, that the allergen application sites are positioned at 20-25 mm intervals in order to distinguish the reaction to allergens and that the allergen penetrates the skin well. Expert-induced errors occurring during application may cause false allergenicity results. Therefore, there is a need for allergen tests that will minimise application errors and provide highly accurate results.

[0007] Microneedles that can pierce the dermal layer without causing a defect on the skin may include designs of microscale needles in different placement patterns with materials of different composition, specific to the intended use. Microneedles can be produced with metal, silicone and other biocompatible materials by using methods such as micro-milling, wet and dry etching, photolithography, mouldingbased techniques, injection moulding, laser patterning and drawing lithography. Manufacturing strategies vary according to the physical properties and material composition of microneedles. Micro -moulding techniques (laser drilling, injection moulding and casting) and additive manufacturing or 3D printing methods are widely used in microneedle production. In particular, photopolymerisation and stereolithography-based printing techniques are used to produce well-designed microneedle platforms layer by layer. Thanks to all these adjustable features, microneedles are unique tools for the development of painless and minimally invasive application platforms.

[0008] In microneedle-based approaches developed for use in skin allergy tests, skin damage and bleeding may occur at the application site due to design. At the same time, if microneedle-covered platforms are treated with allergens and applied as separate modules, clinician-induced errors can be observed again due to inaccurate adjustment of the dose and distances between the application sites of different allergens.

[0009] In the skin prick allergen test applied against different allergens in the technique, allergens are applied as droplets to the skin areas determined by the clinician and holes are created in the skin in the droplet areas with the help of special tips. The allergic reaction occurring within 15-20 minutes is evaluated by the clinician. Its application requires expertise. Unwanted irritation and bleeding may occur on the skin during application. The error rate in allergen penetration is high. Errors during application may cause errors in allergen-reaction interpretation. It may cause fear and anxiety according to the patient profile, especially in children.

[0010] Another method, the patch test, involves a varying number of allergen sites positioned on a panel that can adhere to the skin. The patch is applied to the patient's skin and the reaction is evaluated after 48 hours. The applicable allergen group is limited. There is no standardisation in the preparation of allergens and therefore allergen-reaction assessment is prone to errors according to the practising clinician.

[0011] EP2119469B1 discloses a platform containing 100-10000 microneedles per cm2coated with a water-soluble polymer containing a hydroxyl group on its surface, which can be applied for peptide and protein allergens. In the document, the needle depth of 50-500 pm may cause allergen penetration problems. It is limited to peptide and protein allergens only. This restricts its application for other allergens with high incidence in the community. The distance between allergen application sites and dose adjustment are under the control of the clinician. Therefore, it is prone to clinician errors.

[0012] In the patent document numbered US7942827B2, it is mentioned that a deposit containing encapsulated allergens is applied with microneedles in cannula or solid form. In the application, microneedle or encapsulated allergens are exposed to pressure with the activation system. As a result of activation, the allergens penetrate the skin with the help of the cannula in the microneedle or by positioning at the tip of the microneedle. The microneedles on the platform have a diameter of 10-80 microns and a height of 50-300 microns. It is possible that a microneedle with these characteristics (height) may not be able to provide antigen penetration at the appropriate dosage and consequently show low efficacy.

[0013] In the patent document numbered US20220105328A1, it is mentioned that allergens from an allergen cartridge are loaded into thin allergen application zones through channels in a polymeric planar platform and the microneedle array designed to pierce through these thin layer zones is applied with pressure. In principle, it is similar to the patent document US7942827B2. The need to determine the microneedle characteristics (height) according to the thickness of the allergen loading platform (1-10 mm) and the compressibility of the allergen loading zones may cause complexity in practice. During the application, applying pressure to coincide with the motifs of the allergen-containing regions using the microneedle array may pose practical difficulties for clinicians.

[0014] In previous skin allergy tests, the use of metals in allergen administration has been proposed, but metals pose a risk of misdiagnosis because they are materials that cause allergic response for some individuals. In some metals that do not pose a risk of allergic reaction, high cost limits the applicability of the tests.

[0015] Previously, needle structures in the range of 0.762-1.524 millimetres were used to puncture the skin in skin allergy tests, but this needle size can cause bleeding as well as causing pain to the patient. In addition, silicone microneedle chips have been produced that can be used as attachments to the tips used in the clinic. Although these approaches provide advantages in increasing allergen penetration, they are prone to errors due to the fact that the distances between the allergen application sites are under the control of the clinician in case of application of different allergens.

[0016] Approaches to the rapid production of biodegradable microneedles using mouldingbased manufacturing methods for use as allergen reservoirs in skin allergy tests have also been provided. However, moulding-based approaches are limited in controlling the physical (topographic) properties of the needles. At the same time, these applications are not suitable methods for the development of systems loaded with biological material as they may require multi-step and complex production processes and in some cases require temperature in production protocols. When the studies in the prior art were examined, it was necessary to develop a microneedle platform that allows rapid and safe immune reaction evaluation by applying allergens in islets containing microneedles positioned at certain intervals on biocompatible material.

[0017] Objectives of the Invention

[0018] The object of the present invention is to develop a microneedle platform that enables rapid and safe immune reaction evaluation by single application of allergens contained in microneedle-containing islets positioned at certain intervals on a biocompatible material.

[0019] Another object of the present invention is to develop a microneedle platform that enables immune cells in different layers of the skin to react against allergens with microneedles of varying sizes within the unit microneedle area, thanks to its design that allows different allergens to be applied simultaneously.

[0020] Detailed Description of the Invention

[0021] A microneedle platform for achieving the objects of the present invention is shown in the attached figures.

[0022] Figures;

[0023] Figure 1: Top view of the inventive microneedle platform.

[0024] Figure 2: A side view of the microneedle arrays used in the inventive microneedle platform.

[0025] Figure 3: A general view of microneedle designs that may be provided in microneedle islets on the inventive microneedle platform.

[0026] Figure 4: A view of the inventive microneedle platform in an exemplary embodiment. The parts in the figures are numbered individually, and the corresponding descriptions are given below.

[0027] 1. Panel

[0028] 2. Islet

[0029] A microneedle platform for rapid and safe immune reaction assessment for use in allergy skin tests, it comprises, panel (1) which is made of any biodegradable or non-biodegradable and high-strength polymeric material that will not cause an allergic reaction, islets (2) containing microneedle arrays containing antigen and evenly spaced on the panel (1).

[0030] The inventive microneedle platform is a panel (1) for use in allergy tests, and the shape of the panel (1) can be rectangular, square, circle or any other shape. The main material of the panel (1) may be any biodegradable (dextran, chitosan, alginate, gelatin, polyvinyl alcohol, polycapronolactone, polyurethane, polylactic acid, polyglycolide, polylactic acid-co-polyglycolide, polyanhydride etc.) polymer and / or its derivatives, natural or synthetic polymer and / or derivatives or combinations of these or similar polymers) or non-biodegradable (polymethacrylic acid, polycarbonate, polycarbonate, polytetrafluoroethylene, polyoxymethylene etc. polymer and / or derivatives or combinations of these or similar polymers), high strength and biocompatible polymeric material. The main material of the panel (1) may be transparent or opaque.

[0031] The antigen-containing islets (2) positioned at equal intervals (at least two cm) on the panel (1) may comprise any biocompatible polymeric material. The shape of the antigen-containing islets (2) containing microneedle arrays may be different geometric shapes other than circular, the size of the panel (1) and the number of antigen-containing microneedle islets (2) may vary. At the same time, these islets (2) can be produced by microneedle moulding, laser processing and additive manufacturing methods (Fused Deposition Modelling -FDM-, Stereolithography- SLA-, Selective Laser Sintering SLS, Digital Light Processing-DLP Inkjet, microextrusion etc.) or by a combination of these manufacturing techniques.

[0032] Each antigen-containing islet (2) on the panel (1) contains microneedle arrays and the distances between the islets can be adjusted to the desired dimensions. The diameters and heights of the microneedle arrays can vary, they can all have the same diameter and height value or they can have different heights, diameters and geometries in the same array in the range of 10-2000 micrometres. However, microneedle diameter and height parameters may vary. The placement patterns of these microneedles with varying topographic features can be designed as microneedle height increasing from inside to outside or from outside to inside. At the same time, microneedle placement patterns and geometries may vary.

[0033] Microneedles in microneedle arrays in antigen islets (2) on panel (1) may include different designs. Microneedles can be antigen-coated on the surface, solid, containing allergens and cannulated to allow allergens to pass through the centre. In addition, microneedles with blunter or sharper tips can be used as topographical features as well as antigen content strategies. Microneedles can be produced by mixing antigens with polymer solution, or the surfaces of microneedles can be coated with antigens by spraying, dipping, etc. techniques. Antigens can be used directly with polymers or can be applied inside or on the surface of microneedles together with a micro / nanoparticle or encapsulated in a micro / nanoparticle. Antigen-loaded micro / nanoparticles can be coated on the surfaces of microneedles by spraying, dipping, etc. techniques.

[0034] The application of the inventive platform, which is designed to be used in allergy testing, is in the form of covering and applying pressure on the skin of the surface containing microneedle arrays containing allergens. Microneedles of varying heights in each antigen-containing islet (2) enable highly efficient antigen application to different layers of the skin. Sufficient distance between the evenly spaced antigen application islets (2) enables highly accurate discrimination between allergic reactions.

[0035] The inventive microneedle platform describes a test panel (1) comprising microneedle islets (2) positioned at equal intervals (at least two cm apart), whose physical (topographical) characteristics and material composition may vary depending on the allergen. The microneedle design (microneedle size, allergen loading / coating / inclusion form and mechanical properties) may vary depending on the allergenic substance. The design can also be changed in terms of the size of the panel (1) and the number and geometry (circle, ellipse, hexagon, square, etc.) of the antigen-containing islets (2).

[0036] In the inventive platform, by using different designs in topographical and compositional features in the designs of microneedles together, it is ensured to perform a skin allergy test that removes the restrictions in allergen diversity in the panel (1) system compared to previous designs, at the same time, it is easy to apply compared to existing applications, minimises clinician application and evaluation errors and provides comfort by preventing skin damage in the patient.

[0037] In the inventive platform, high efficiency antigen application is enabled by stimulating immune cells in different layers of the skin layers by forming arrays containing different topographical features (such as height and diameter) together in an antigen application islet (2). Another novelty is the unique microneedle design in each of the antigen delivery islets (2) on a panel (1).

[0038] The inventive microneedle platform, thanks to its physical (topographical) properties and material composition customised according to allergens, will enable effective allergy testing application due to the fact that it contains different microneedle designs such as conical microneedle islets (2) filled with allergen and microneedle islets (2) with allergen coated surface on a polymeric material. At the same time, it will maximise allergen penetration due to the varying heights and designs of microneedles containing different allergens on the polymeric material, while minimising clinician-induced application and evaluation errors due to the equal distance between these islets (2).

Claims

CLAIMS1. A microneedle platform for rapid and safe immune reaction assessment for use in allergy skin tests, characterized in that, it comprises, panel (1) which is made of any biodegradable or non-biodegradable and high-strength polymeric material that will not cause an allergic reaction, islets (2) containing microneedle arrays containing antigen and evenly spaced on the panel (1).

2. A microneedle platform accoring to claim 1, characterized in that the shape of the panel (1) can be rectangular, square, hexagonal, circular, etc.

3. A microneedle platform accoring to claim 1, characterized in that the biodegradable materials may be natural or synthetic polymers and / or derivatives or combinations of these or similar polymers, such as dextran, chitosan, alginate, gelatin, polyvinyl alcohol, polycapronolactone, polyurethane, polylactic acid, polyglycolide, polylactic acid-co- polyglycolide, polyanhydride, etc.

4. A microneedle platform accoring to claim 1, characterized in that the non- biodegradable materials may be polymers and / or derivatives thereof such as polymethacrylic acid, polycarbonate, polycarbonate, polytetrafluoroethylene, polyoxymethylene, etc. or combinations of these or similar polymers.

5. A microneedle platform according to any preceding claims, characterized in that the distance between the islets (2) comprising the microneedle arrays is at least two cm.

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