BONE DEFECT COVER PIECE

Abstract

The present invention relates to a method for manufacturing a cover piece for a bone regeneration device to cover 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 and a wall facing the bone defect, and which cover piece can be fixed in place on a bone by at least one means of fixation, etc.) manufacturing the cover piece, characterized in that said cover piece is made of resorbable polymer by 3D printing, and in that it has: - a thickness of between 0.8 and 1.5 mm, and - micro-perforations.

Description

Title of the invention: BONE DEFECT COVERING PIECE FIELD OF INVENTION

[0001] The present invention relates to a method for manufacturing a covering piece for a bone defect in the context of bone regeneration. ANTERIOR ART

[0002] Bone tissue is the main component of the skeleton. It provides both support for the soft parts of the body and protection for vital organs such as those of the skull and thoracic cavity.

[0003] Despite its mineral characteristics, associated with an abundant extracellular matrix, bone tissue remains a living tissue, composed of thousands of cells dispersed within this matrix, and whose 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.

[0004] Now, a dysregulation within this bone tissue, which may 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 hollow areas within the bone tissue.

[0005] In practice, bone defects are filled in bone surgery using dedicated materials which, in addition to filling, also promote bone healing.

[0006] Generally, the filling 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 has been filled with this filling material, and as described, for example, in German patent DE 4302708C2, a cover piece is positioned over it. This cover piece is fixed to the bone surrounding the bone defect and directs bone growth through the filling material exclusively towards the bone. From this, various cover technologies have been developed.

[0007] A first technological field corresponds to "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). While the application of these membranes is relatively easy for the practitioner, the result of bone regeneration is often less than ideal, due to their flexible structure, which only allows for a rough delineation of bone growth.

[0008] The second technological field corresponds to "rigid" covering pieces that take the form of metal meshes 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 and whose shape precisely matches that of the bone regenerated after filling the bone defect. However, the nature (generally titanium) of these rigid covering pieces makes them expensive, in addition to the greater complexity associated with their implementation. SUMMARY OF THE INVENTION

[0009] Faced with this problem, the inventor has now developed and obtained, by 3D printing, a micro-perforated, resorbable polymer cover piece that combines the advantages of previously known flexible and rigid cover pieces. Thus, the cover piece developed by the inventor offers a particularly advantageous cost, while allowing for good delineation of bone regeneration without being associated with any complexity of implementation for the practitioner and, moreover, without requiring removal due to its biodegradability.

[0010] 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.

[0011] Also, a first object of the invention relates to a method for manufacturing a cover piece for a device intended for bone regeneration for a bone defect in a subject, which method comprises the following steps:

[0012] - recording of a data set representing the bone defect concerned in its three-dimensionality,

[0013] - design of the cover piece using this data set, which cover piece has a wall opposite the bone defect and a wall facing the bone defect, and which cover piece can be fixed in place on a bone by at least one means of fixation, and

[0014] - manufacturing of the cover piece,

[0015] characterized in that said cover piece is made of absorbable polymer by 3D printing, and in that it has:

[0016] - a thickness between 0.8 and 1.5 mm,

[0017] - micro-perforations.

[0018] A second object of the invention relates to a cover piece that can be obtained by such a manufacturing process.

[0019] 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 cover piece as well as at least one means of fixation.

[0020] 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. DETAILED DESCRIPTION OF THE INVENTION

[0021] The bone defect can be of any type, including a bone defect within the bones delimiting the orbital cavities, the jawbones, the bones of the inner ear, or the external ear. Now, according to a preferred embodiment, the bone defect corresponds to a bone defect within the jaw.

[0022] As regards the step of recording the dataset which represents the bone defect concerned in its three-dimensionality, this step is carried out by methods well known to those skilled in the art such as tomography or similar imaging processes.

[0023] The cover piece is 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.

[0024] The cover piece has a three-dimensional shape that allows it to cover the bone defect in the subject so as to ensure harmonious and seamless bone regeneration. This means bone regeneration that results in bone whose shape is that which existed prior to the appearance of the bone defect. Typically, such regeneration shows no discontinuity between the bone surrounding the bone defect and the regenerated bone that has formed within the bone defect.

[0025] Now, the cover piece can optionally incorporate a pre-positioning site for an implant, once bone regeneration has been completed within the bone defect.

[0026] To highlight its particularly advantageous properties, the inventor has indicated that the micro-perforated cover piece must have a thickness between 0.8 and 1.5 mm, preferably between 0.9 and 1.3 mm. More specifically, The inventor was able to show that a cover piece thickness of between 1 and 1.2 mm made it possible to obtain, in 3D printing, a cover piece with optimal properties.

[0027] The inventor has demonstrated that it is possible to use different resorbable polymers, provided that they result in a reduction of less than 50% in the average load of the cover piece within 4 months of its implantation in a subject. Therefore, based on these elements and their general knowledge, a person skilled in the art will be able to adapt the thickness of the cover piece according to the type of resorbable polymer used.

[0028] Preferably, the resorbable polymer is a poly(lactic-co-caprolactone) copolymer [PLCL].

[0029] Particularly advantageously, the resorbable polymer is a PLCL copolymer comprising a proportion of 70% lactic acid and 30% coprolactone.

[0030] 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.

[0031] The micro-perforations in the cover piece are critical in that they allow the supply of nutrients to the regenerating bone within the bone defect, while ensuring the proper delimitation of the bone regeneration.

[0032] By micro-perforations, we mean perforations which have a diameter between 100 and 2000 pm, preferably between 200 and 1000 pm.

[0033] Advantageously, the cover piece also has a border which rests on the healthy bone framing the bone defect.

[0034] Preferably, the edge of the cover piece has a width of at least 1 mm, preferably a width between 2 and 5 mm.

[0035] 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).

[0036] 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 the form of 3 to 5 points of support. Typically, these points of support are equally spaced around the contour of the cover piece.

[0037] Advantageously, the edge of the cover piece contains no micro-perforations. Indeed, the absence of micro-perforations in this area ensures the best possible rigidity of the cover piece without compromising its effectiveness.

[0038] As for the at least one means of attaching the cover plate to the bone, it may take the form of a pin, a screw, a nail, or an adhesive substance for attaching the cover plate to the bone. The cover plate may combine different, distinct means of attachment, for example, at least one screw and at least one adhesive substance.

[0039] In the case of a fastening means taking the form of a screw, the edge advantageously includes an orifice allowing its positioning with preferably a milling adapted to the head of said screw.

[0040] In the case of a fastening means in the form of an adhesive substance, this substance is selected 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.

[0041] Composite-based cement is defined as a material whose characteristics are as defined in ISO 4049, comprising a dispersed phase including the filler (mineral, organo-mineral, or organic) coupled, by means of a silane, to the dispersing phase (organic matrix) comprising at least one monomer derived from methacrylate. The dispersing phase or organic matrix acts as a binder between the fillers. This phase gives the unpolymerized composite a viscosity that varies depending on the methacrylate derivative(s) it contains. It should be noted that it is common to use mixtures of different derivatives to achieve the desired viscosity. However, this dispersing phase, when considered on its own, 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), 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 that vary in size, composition, and percentage. Furthermore, if it is possible to use organic fillers (e.g.,resins) or organo-mineral (organically modified ceramic, these are most often mineral fillers based on silica (in crystalline form (e.g. quartz) or not (e.g. borrosilicate 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 increase radiopacity. Silane is a bifunctional molecule possessing both a mineralophilic and an organophilic end group. Such a molecule allows the polymer to be grafted to the filler. Examples of such functional molecules include methacryloxypropyl-trimethoxy-silane (MPMA) and racryloxypropyl-trimethoxy-silane (APM). A dispersing phase and / or a dispersed phase functionalized by silanization can be used.Silanes are chemical compounds with the formula SinH2n+2, the simplest of which is silane (SiH4), 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.

[0042] This time in connection with cyanoacrylates, these form a family of powerful and fast-drying adhesives used in medicine, industry, and everyday life. The cyanoacrylates usable within the scope 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). In the case of an adhesive substance corresponding to a cyanoacrylate, NBCA may be used, for example, which is marketed under the brand names CUTSEAL, MEDIBOND, MEDICRYL, PERIACRYL, GLUSTITCH, XOIN, GESIKA, GLUEBRAN2, VETGLU, VETBOND, LIQUIVET, INDERMIL, LIQUIBAND, HISTOACRYL, IFABOND, etc.

[0043] According to a specific embodiment, the at least one means of fixation takes only the form of an adhesive substance and the cover plate then does not include any orifice (other than micro-perforations and, possibly, at least one pre-positioning site for an implant).

[0044] Bone regeneration substitutes are well known to those skilled in the art, and such a substitute can be chosen from among those used for filling bone defects in various pathologies. Such a bone regeneration substitute can consist of a synthetic bone substitute material (for example, hydroxyapatite granules), but also of bone particles, which can be taken from the patient on whom bone regeneration is planned. By way of example Examples of bone regeneration substitutes include RE-BONE, BIO-OSS, BIOSORB-DENTAL, CREOS, ADBONE, TEEBONE, SYBONE, etc.

[0045] The following examples are provided for illustrative purposes only and shall not limit the scope of the present invention.

[0046] Determination of the evolution of the mechanical and physico-chemical properties of a 3D printed device over a hydrolytic degradation period of 4 months.

[0047] 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.

[0048] 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.

[0049] The inventor has demonstrated that it is possible to print, particularly with this PLCL, 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 it could be installed by a practitioner, proved to be insufficiently rigid to ensure its proper function over time.

[0050] Regarding the characteristics of the devices obtained, the average post-printing load for devices 0.8 mm thick was found to be 12 N, but with an average load of only 5.7 N after one month of degradation. In the case of a 1.1 mm thick device, the average post-printing load was indeed 15.2 N, but it was still 8 N after one month of degradation.

[0051] In the end, the results showed that the 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).

[0052] At the same time, the resulting cover piece exhibits a "flexibility" that makes it easier for a practitioner to apply compared to known metallic plates. Furthermore, due to its resorbable nature, it is not necessary to remove the cover piece after bone regeneration, thus minimizing trauma to the patient.

Claims

Demands

1. A method for manufacturing a cover piece for a bone regeneration device to cover 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 and a wall facing 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 resorbable polymer by 3D printing, and in that it has: - a thickness of between 0.8 and 1.5 mm, and - micro-perforations.

2. The process according to claim 1, characterized in that the resorbable polymer is a poly(lactic-co-caprolactone) copolymer [PLCL].

3. The method according to claim 1 or 2, characterized in that the micro-perforations correspond to perforations which have a diameter between 100 and 2000 pm, preferably between 200 and 1000 pm.

4. The method according to any one of claims 1 to 3, characterized in that the cover piece has a border which rests on the healthy bone framing the bone defect and whose width is at least 1 mm, preferably this border has a width between 2 and 5 mm.

5. The method according to claim 4, characterized in that the edge of the cover piece has a discontinuous nature and takes the form of 2 to 6 points of support on the healthy bone framing the bone defect, preferably the form of 3 to 5 points of support.

6. The method according to claim 4 or 5, characterized in that the edge of the cover piece does not contain any micro-perforations.

7. A cover piece obtained by a manufacturing process according to any one of claims 1 to 6.

8. A device for bone regeneration for a bone defect in a subject and comprising at least one cover piece according to claim 7 and at least one means of fixation.

9. A device according to claim 8, characterized in that at least one means of fixing takes the form of an adhesive substance allowing the cover piece to be fixed to the bone and in that the cover plate then does not include any opening.

10. 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 8 or 9 and at least one bone regeneration substitute