Part for covering a bone defect

Abstract

The present invention relates to a method for manufacturing a covering part for a device intended for bone regeneration, in order to cover a bone defect in a patient, which method comprises the steps of a) recording a set of data representative of the stated bone defect in three dimensions; b) designing the covering part using this set of data, which covering part has a wall opposite the bone defect and a wall facing the bone defect, and which covering part is able to be fastened in place on a bone by at least one fastening means; and c) manufacturing the covering part, wherein the covering part is made from a resorbable polymer by 3D printing, has microperforations, and has a thickness of between 0.8 and 1.5 mm.

Description

[PIECE FOR COVERING A BONE DEFECT [

[0001] This patent application claims priority from French patent application FR 2405245 filed on 22 / 05 / 2024, incorporated herein by reference. Scope of the invention

[0002] The present invention relates to a method for manufacturing a cover piece for a bone defect in the context of bone regeneration. Previous art

[0003] Bone tissue is the main component of the skeleton. It provides support for the soft parts of the body and protects vital organs such as those in the skull and thoracic cavity.

[0004] Despite its mineral composition and abundant extracellular matrix, bone tissue remains a living tissue, composed of thousands of cells dispersed within this matrix. Its regulation—known as bone homeostasis—is a particularly complex and dynamic process. Bone tissue undergoes constant remodeling, a process whose main cell types are osteocytes, osteoblasts, and osteoclasts.

[0005] Now, a dysregulation within this bone tissue, which can have a traumatic, infectious, or tumoral origin, can result in an alteration of its structure or even its destruction. While bone healing generally follows this destruction, in some cases this healing may prove insufficient to regenerate the integrity of the bone tissue, leading to the appearance of bone defects. Such bone defects then take the form of hollows or depressions within the bone tissue.

[0006] In practice, bone defects are filled in bone surgery using dedicated materials which, in addition to filling, also promote bone healing.

[0007] Typically, the bone graft material used consists of either synthetic bone substitute material (e.g., hydroxyapatite granules) or natural bone particles. Once the cavity corresponding to the bone defect is filled with this material, and as described, for example, in patent DE 4302708C2, a cover piece is positioned over it. This cover piece is fixed to the bone surrounding the defect and directs bone growth through the graft material exclusively towards the bone. From this starting point, various grafting technologies have been developed.

[0008] A first technological field involves "flexible" covering pieces in the form of woven materials whose mesh allows nutrients to pass through. For example, US patent 4,816,339 describes a flexible covering piece in the form of a flexible, synthetic, multilayer woven membrane (a PRF-type membrane). Similarly, European patent application EP 3882006 A1 describes a resorbable membrane for alveolar bone regeneration, including a 3D FDM printing step of a polymer film (e.g., polycaprolactone / PCL) followed by a "controlled pressing" step of the printed piece. While the implementation of these membranes is relatively easy for the practitioner, the result of bone regeneration is often imperfect, due to their flexible structure, which only allows for a rough delineation of bone growth.

[0009] The second technological field involves "rigid" covering pieces that take the form of metal mesh bonded to the covering material. For example, patent EP 2 536 446 B1 describes such a rigid covering piece manufactured specifically for a given individual, its shape precisely matching that of the bone regenerated after filling the bone defect. Due to difficulties encountered during the removal phase of such a rigid plate, which sometimes resulted in the avulsion of part of the regenerated bone, some manufacturers have developed covering plates incorporating break points to facilitate their removal. withdrawal (e.g., US 2017360565). Now, the nature (usually titanium) of these rigid cover pieces makes them expensive, in addition to the greater complexity associated with their implementation and the difficulty of withdrawal. Summary of the invention

[0010] To address this problem, the inventor has now developed and obtained, through 3D printing, a micro-perforated, resorbable polymer covering that combines the advantages of previously available flexible and rigid coverings. This covering offers a particularly advantageous cost, while providing clear delineation of bone regeneration without adding complexity for the practitioner and, moreover, without requiring removal due to its biodegradability.

[0011] These properties of the resulting cover piece were not obvious in themselves and require the use of resorbable polymers adapted for 3D printing, obtaining a very specific thickness and, above all, the presence of micro-perforations within the cover piece.

[0012] Also, a first object of the invention relates to a method for manufacturing a micro-perforated cover piece for a device intended for bone regeneration for a bone defect in a subject, which method comprises the following steps:

[0013] - recording of a dataset representing the bone defect in question in its three-dimensionality,

[0014] - design of the cover piece using this data set, which cover piece has a wall opposite the bone defect, a wall facing the bone defect, and a three-dimensional shape enabling it to cover the subject's bone defect so as to ensure bone regeneration that results in a bone whose shape is that which existed prior to the appearance of the bone defect, and which cover piece can be fixed in place on a bone by at least one means of fixation, and

[0015] - manufacturing of the cover piece,

[0016] Where said cover piece is made of absorbable polymer by 3D printing, and in that it presents:

[0017] - a thickness between 0.8 and 1.5 mm, and

[0018] - at least one surface covering the entire bone defect, with a length between 5 and 100 mm, a width between 3 and 20 mm, and consisting of microperforations which:

[0019] • allow the supply of nutrients to the regenerating bone within the bone defect, while ensuring proper delimitation of bone regeneration and

[0020] • have a diameter between 100 and 2,000 pm.

[0021] Due to its resorbable nature, the microperforated cover plate has no predefined breaking points for removal. As such, its surface, covering the entire bone defect, consists of microperforations (and nothing else).

[0022] A second object of the invention relates to a micro-perforated cover piece that can be obtained by such a manufacturing process.

[0023] A third object of the invention relates to a device for bone regeneration for a bone defect in a subject and comprising at least one such micro-perforated cover piece as well as at least one means of fixation.

[0024] A fourth object of the invention relates to a kit for bone regeneration for a bone defect in a patient and comprising at least one device as described above and at least one bone regeneration substitute.

[0025] A fifth object of the invention relates to a method for regenerating a bone defect in a patient, which method comprises the steps of:

[0026] 1) Opening of a patient's gum, then filling of a bone defect in a jawbone of said patient with a bone substitute,

[0027] 2) placement of a cover plate over the said bone defect,

[0028] 3) closure of the gum,

[0029] This method uses a cover plate as described previously and therefore does not require reopening the gum in order to remove the cover plate once bone regeneration is complete. Detailed description of the invention

[0030] The bone defect can be of any type, including a defect within the bones delimiting the orbital cavities, the jawbones, the bones of the inner ear, or the outer ear. Now, according to a preferred embodiment, the bone defect corresponds to a bone defect within the jaw.

[0031] The data acquisition stage, which captures the three-dimensional representation of the bone defect, is performed using methods well-known to those skilled in the art, such as tomography or similar imaging techniques. This stage allows for the precise positioning of the bone defect within the jaw, including its dimensions (length, width, depth) and, at a minimum, the dimensions of the surrounding bone.

[0032] As for the design phase of the cover piece, this step is carried out using modeling methods well known to those skilled in the art. These methods take into account both the three-dimensional shape of the bone defect and the surrounding healthy bone within the jawbone, as well as the nature and characteristics (particularly in terms of strength) of the resorbable polymer subsequently used during 3D printing. This design phase allows, in particular, for the precise positioning of the micro-perforations within the cover piece, at a minimum, on the surface of the piece covering the bone defect.

[0033] The cover piece is then manufactured by 3D printing, typically by fused filament deposition, for example with an ULTIMAKER S7 printer. Such 3D printing typically uses a resorbable polymer filament with a diameter between 1 and 5 mm, generally between 1.5 and 3 mm.

[0034] The cover piece has a three-dimensional shape that allows it to cover the patient's bone defect in such a way as to ensure harmonious and seamless bone regeneration. This means bone regeneration that results in a bone whose shape is that which existed before the bone defect appeared. Typically, such regeneration shows no discontinuity between the bone surrounding the defect and the regenerated bone within it.

[0035] Now, the cover piece can potentially incorporate a pre-positioning site for an implant, once bone regeneration within the bone defect is complete.

[0036] To highlight its particularly advantageous properties, the inventor emphasized that the micro-perforated cover piece should have a thickness between 0.8 and 1.5 mm, preferably between 0.9 and 1.3 mm. More specifically, the inventor demonstrated that a cover piece thickness between 1 and 1.2 mm allows for 3D printing a cover piece with optimal properties.

[0037] The inventor demonstrated that it is possible to use different resorbable polymers, provided they result in a reduction of less than 50% in the average load of the cover piece within four months of implantation in a patient. Therefore, based on this information and their general knowledge, a person skilled in the art will be able to adjust the thickness of the cover piece according to the type of resorbable polymer used.

[0038] Preferably, the resorbable polymer is a poly(lactic-co-caprolactone) [PLCL] copolymer.

[0039] Particularly advantageously, the resorbable polymer is a PLCL copolymer comprising a proportion of 70% lactic acid and 30% coprolactone.

[0040] The cover piece has at least one surface covering the entire bone defect, which surface has a length between 5 and 100 mm, preferably between 10 and 50 mm, and a width between 3 and 20 mm, preferably between 5 and 10 mm.

[0041] The micro-perforations in the cover piece are critical because they allow nutrients to reach the regenerating bone within the bone defect, while ensuring proper delimitation of bone regeneration.

[0042] Micro-perforations are preferably understood to mean perforations with a diameter between 200 and 1 000 µm and, particularly preferably, between 400 and 800 µm.

[0043] Advantageously, the cover piece also has a border that rests on the healthy bone surrounding the bone defect.

[0044] Preferably, the edge of the cover piece has a width of at least 1 mm, preferably a width between 2 and 5 mm.

[0045] This border can be continuous (in which case it rests on the entire healthy bone surrounding the bone defect) or discontinuous (in which case it corresponds to one or more points of support on the healthy bone surrounding the bone defect).

[0046] Preferably, the edge of the cover piece has a discontinuous nature, advantageously taking the form of 2 to 6 points of support on the healthy bone surrounding the bone defect, preferably 3 to 5 points of support. Typically, these points of support are equally spaced around the perimeter of the cover piece.

[0047] Even more advantageous, the edge of the cover piece contains no micro-perforations. Indeed, the absence of micro-perforations in this area allows for the best possible rigidity of the cover piece without compromising its effectiveness.

[0048] As for the at least one means of attaching the cover plate to the bone, it can take the form of a pin, a screw, a nail, or an adhesive substance used to fix the cover plate to the bone. Now, the cover plate itself can combine different, distinct means of attachment, for example, at least one screw and at least one adhesive substance.

[0049] In the case of a fastening means taking the form of a screw, the edge advantageously includes an opening allowing its positioning with preferably a milling adapted to the head of said screw.

[0050] In the case of a fixing medium in the form of an adhesive substance, this substance is chosen from the group comprising or consisting of composite-based cements, cyanoacrylates, or any other biocompatible adhesive or cement. Regarding the packaging of the adhesive substance, a squeezable tube, a syringe, or a two-component syringe for controlled mixing and dispensing of two-component materials may be chosen.

[0051] Composite cement is defined as a material whose characteristics are as defined in ISO 4049. It comprises a dispersed phase consisting of the filler (mineral, organo-mineral, or organic) coupled, by means of a silane, to the dispersing phase (organic matrix) containing at least one methacrylate monomer. The dispersing phase, or organic matrix, acts as a binder between the fillers. This phase imparts a viscosity of varying degrees to the unpolymerized composite, depending on the methacrylate derivative(s) it contains. It is common practice to use mixtures of different derivatives to achieve the desired viscosity. However, this dispersing phase, when used alone, exhibits low mechanical strength.A person skilled in the art can easily determine, based on their general knowledge, which methacrylate derivatives are suitable for use in dispersing phases for composite-based cements as required by the invention. Examples of such methacrylate derivatives include bisphenol A glycidyl methacrylate (bis-GMA), urethane dimethacrylate (UDMA), and methyl methacrylate. (MMA), bisphenol A ethyloxy methacrylate (bis-EMA), ethylene glycol dimethacrylate (EGDMA), diethylene glycol dimethacrylate (DEGDMA), triethylene glycol dimethacrylate (TEGDMA), phosphoric acid methacrylate, or a mixture thereof. Regarding the dispersed phase consisting of fillers, current composites contain a wide variety of filler particles varying in size, composition, and percentage. Now, while it is possible to use organic fillers (e.g., resins) or organo-mineral fillers (organically modified ceramics), these are most often silica-based mineral fillers (in crystalline form (e.g., quartz) or non-crystalline form (e.g., borax glass), or heavy metal glasses (barium, strontium, zirconium, yttrium, or ytterbium glass). These fillers are physically and chemically bonded to the organic matrix and ensure the mechanical and optical properties of the cement.In terms of mechanical properties, these fillers increase resistance to compression, tension, bending, and wear, and also enhance radiopacity. A silane is a bifunctional molecule possessing both a mineralophilic and an organophilic end. Such a molecule allows the polymer to be grafted to the filler. Examples of such functional molecules include methacryloxypropyl-trimethoxy-silane (MPMA) and acryloxypropyl-trimethoxy-silane (APM). A dispersing phase and / or a dispersed phase functionalized by silanization are available. Silanes are chemical compounds with the formula Si. nH₂n⁺², the simplest of which is silane, with the formula Si₂PL₂, which is the silica-based structural analog of methane. Methane belongs to the family of hydrides composed of silicon and hydrogen, which can be considered the silica-based analogs of alkanes. The dispersing phase may consist of silane acrylates or methacrylates. The dispersed phase may consist of fillers that have undergone industrial silanization processing; this is referred to as sizing.

[0052] This time, in connection with cyanoacrylates, these form a family of powerful and fast-setting adhesives used in medicine, industry, and everyday life. The cyanoacrylates usable within the framework of the present invention include n-butyl cyanoacrylate or enbucrylate (n-BCA, NBCA), isobutyl cyanoacrylate or bucrylate (ICA), ethyl cyanoacrylate (ECA), and octyl cyanoacrylate (OCA).

[0053] Preferably, the cyanoacrylate used is NBCA or OCA.

[0054] In the case of an adhesive substance corresponding to a cyanoacrylate, NBCA can be used for example, which is marketed under the brands CUTSEAL, MEDIBOND, MEDICRYL, PERIACRYL, GLUSTITCH, XOIN, GESIKA, GLUEBRAN2, VETGLU, VETBOND, LIQUIVET, INDERMIL, LIQUIBAND, HISTOACRYL, IFABOND, etc.

[0055] According to a specific embodiment, at least one means of fixation takes only the form of an adhesive substance and the cover plate then does not include any openings (other than micro-perforations and, possibly, at least one site for pre-positioning an implant).

[0056] Bone regeneration substitutes are well known to those skilled in the art, and such a substitute can be chosen from those used for filling bone defects in various pathologies. A bone regeneration substitute may consist of a synthetic bone substitute material (e.g., hydroxyapatite granules) or bone particles, which may be taken from the patient for the bone regeneration procedure. Examples of bone regeneration substitutes include RE-BONE, BIO-OSS, BIOSORB-DENTAL, CREOS, ADBONE, TEEBONE, SYBONE, etc.

[0057] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. Examples

[0058] Determination of the evolution of the mechanical and physico-chemical properties of a 3D printed device over a hydrolytic degradation period of 4 months.

[0059] The operating conditions made it possible to simulate, in less than 5 days, a degradation equivalent to that observed over a period of 4 months in real time.

[0060] Various resorbable polymers were tested, including a PLCL (poly(lactide-co-caprolactone)). In addition, different part thicknesses were tested, namely 0.8 mm, 1.1 mm, and 1.3 mm.

[0061] The inventor demonstrated that it was possible to print, particularly with this PLCL (Printable Linear Plate), a cover plate with micro-perforations. It should be noted, however, that obtaining micro-perforations proved difficult for both the 0.8 mm and 1.3 mm thicknesses. At the same time, the results showed that a cover plate with a thickness of 0.8 mm or 1.3 mm, while usable by a practitioner, was insufficiently rigid to ensure its proper function over time.

[0062] Regarding the characteristics of the resulting devices, the average post-printing load for devices 0.8 mm thick was 12 N, but the average load was only 5.7 N after one month of degradation. For a 1.1 mm thick device, the average post-printing load was indeed 15.2 N, but it remained at 8 N after one month of degradation.

[0063] In the end, the results showed that devices with a thickness of 1.1 mm showed high mechanical resistance and were fully satisfactory to ensure a covering function over time, particularly with regard to bone regeneration of a bone defect within the jaw (complex environment).

[0064] At the same time, the resulting cover piece has a flexibility that makes it easier for a practitioner to apply compared to traditional metal plates. Furthermore, due to its resorbable nature, it is not necessary to remove the cover piece after bone regeneration, thus minimizing trauma for the patient.

[0065] Regarding the placement of the microperforated overlay plate, its bonding to the jawbone demonstrated excellent adhesion until resorption, both with a cyanoacrylate adhesive (HISTOACRYL®) and with a composite adhesive containing a mineral filler (RELYX™ UNICEM 2 Automix, cement with TEGDMA). Other types of adhesive did not exhibit sufficient strength.

Claims

DEMANDS 1. A method for manufacturing a microperforated cover piece of a bone regeneration device for covering a bone defect in a subject, which method comprises the following steps: a) recording a data set representing the bone defect concerned in its three-dimensionality, b) designing the cover piece using this data set, which cover piece has a wall opposite the bone defect, a wall facing the bone defect, and a three-dimensional shape enabling it to cover the bone defect of the subject so as to ensure bone regeneration that results in bone having the shape that existed prior to the appearance of the bone defect, and which cover piece can be fixed in place on a bone by at least one means of fixation, and c) manufacturing the cover piece, Characterized in that said cover piece is made of absorbable polymer by 3D printing, and in that it exhibits: - a thickness between 0.8 and 1.5 mm, and - at least one surface covering the entire bone defect with a length between 5 and 100 mm, a width between 3 and 20 mm, and consisting of micro-perforations which: allow the supply of nutrients to the regenerating bone within the bone defect, while ensuring the proper delimitation of bone regeneration and have a diameter between 100 and 2,000 pm.

2. The process according to claim 1, characterized in that the resorbable polymer is a poly(lactic-co-caprolactone) [PLCL] copolymer, 3. The process according to claim 2, characterized in that the poly(lactic-co-caprolactone) copolymer [PLCL] comprises a proportion of 70% lactic acid and 30% coprolactone.

4. The method according to claim 2 or 3, characterized in that the micro-perforated cover piece has a thickness between 1 and 1.

2.

5. The method according to any one of claims 1 to 4, characterized in that the cover piece has an edge which rests on the healthy bone framing the bone defect and whose width is at least 1 mm, 6. The method according to claim 5, characterized in that the edge of the cover piece has a width between 2 and 5 mm.

7. The method according to any one of claims 5 or 6, characterized in that the edge of the cover piece has a discontinuous nature.

8. The method according to claim 7, characterized in that the discontinuous nature of the edge of the cover piece takes the form of 2 to 6 points of support on the healthy bone framing the bone defect.

9. The method according to claim 8, characterized in that the discontinuous nature of the edge of the cover piece takes the form of 3 to 5 points of support on the healthy bone framing the bone defect.

10. The method according to any one of claims 5 to 9, characterized in that the edge of the cover piece does not contain any micro-perforations.

11. A micro-perforated cover piece obtainable by a manufacturing process according to any one of claims 1 to 10.

12. A device for bone regeneration for a bone defect in a subject and comprising at least one micro-perforated cover piece according to claim 11 and at least one means of fixation.

13. A device according to claim 12, characterized in that at least one means of fixation takes the form of an adhesive substance enabling the cover piece to be fixed to the bone and in that the micro-perforated cover plate then does not include any orifice.

14. The device according to claim 13, characterized in that the adhesive substance is a composite-based cement comprising a dispersed phase comprising a mineral, organo-mineral or organic filler coupled, by means of a silane, to a dispersing phase consisting of the organic matrix, which comprises at least one monomer derived from methacrylate.

15. The device according to claim 13, characterized in that the adhesive substance is a cyanoacrylate selected from the group comprising n-Butyl cyanoacrylate or enbucrylate (n-BCA, NBCA), isobutyl cyanoacrylate or bucrylate (ICA), Ethyl cyanoacrylate (ECA) and Octyl cyanoacrylate (OCA); preferably NBCA or OCA.

16. A kit for bone regeneration for a bone defect in a subject and comprising at least one device as defined in any one of claims 12 to 15 and at least one bone regeneration substitute.