Medical devices based on bioceramics, their use as synthetic bone grafts and methods for their preparation

Abstract

The invention relates to a medical device manufactured using an additive manufacturing process (3D printing). The present invention relates to a medical device, preferably for use as a bone graft, consisting of a porous structure of a bioceramic based on beta-tricalcium phosphate (beta-TCP) or hydroxyapatite, the composition of which may contain or do not contain nanostructures, ), for example: carbon nanostructures (graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc., as well as stem cells and polymer membranes in preferred embodiments. The invention further relates to the use of the device as a bone graft and to a method for producing the device.

Description

Technical Field

[0001] The present invention relates to a medical device manufactured by an additive manufacturing process (3D printing). It is a medical device used as a bone graft, consisting of a porous structure based on bioceramics, β-tricalcium phosphate (β-TCP) or hydroxyapatite (HA), which may or may not contain carbon nanostructures (graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.), and in a preferred embodiment, it can carry stem cells.

[0002] Furthermore, the invention relates to the use of the device as a bone graft and to a method for producing the device. Background Art

[0003] Filling materials and synthetic bone substitutes made of porous bioceramics have excellent physical, chemical and biological properties and are classified as bioactive and osteoconductive, which means that osteoblasts are able to use the material as a scaffold to initiate bone formation in the area. Bioceramics based on calcium phosphate Ca3(PO4)2 stand out due to their chemical composition and crystal structure similar to inorganic substances in the human body. The crystal phases are hydroxyapatite (HA) and tricalcium phosphate (β-TCP), the most commonly used in biological systems, in the form of particles or blocks.

[0004] Compared with particulate synthetic bone substitutes, calcium phosphate blocks have superior mechanical and morphological properties. The interconnected pores and high porosity facilitate cell migration for bone reconstruction, diffusion of nutrients, and can even serve as a vehicle for the controlled release of drugs and molecules.

[0005] We highlight below some of the prior art teachings relating to this subject:

[0006] Document US Pat. No. 9,079,357 discloses an improved method for layering molded bodies made of highly viscous light-curing materials, wherein possible use in the dental industry is mentioned.

[0007] Document US 9,403,726 describes a method for preparing high-strength photopolymerizable ceramic wedges that can be used as ceramic molded parts or articles, dental inlays, onlays, veneers, crowns, bridges and structures. The method uses a paste based on a free-radically polymerizable binder, a polymerization initiator and a filler, which contains at least one acidic photoinitiator monomer and ceramic and / or glass-ceramic particles. The above-mentioned ceramic and glass-ceramic particles have dental applications and can be used to prepare dental restorations, such as inlays, onlays, veneers, crowns, bridges or frameworks.

[0008] Document CN 105943406 discloses a 3D printing composite material for oral rehabilitation and a method for preparing and using the 3D printing copy material. The 3D printing composite material for oral rehabilitation has a small healing recovery, a short healing time and high antibacterial properties, and is suitable for manufacturing dentures.

[0009] Document PI0912499-3 describes the use of tricalcium phosphate and hydroxyapatite biomaterials in surgeries requiring bone substitutes, such as transplants or other indications.

[0010] The document PFAFFINGER, M. et al. "Stabilization of tricalcium phosphate slurries against sedimentation for stereolithographic additive manufacturing and influence on the final mechanical properties." International Journal of Applied Ceramic Technology, v.14, no.4, p.499-506, 2017 discloses the use of low molecular lithography (LCM) to produce ceramic parts, and emphasizes the use of a paste filled with tricalcium phosphate.

[0011] The document EBRAHIMI M. & BOTELHO M. "Biphasic calcium phosphates (BCP) of hydroxyapatite (HA) and tricalcium phosphate (TCP) as bone substitutes: Importance of physicochemical characterizations in biomaterials studies." (2017) pages 93-97 discloses the use of tricalcium phosphate as a tissue engineering substitute, mainly for bone regeneration.

[0012] The document TAPPA, K., JAMMALAMADAKA, U. "Novel biomaterials used in medical 3D printing techniques". Journal of Functional Biomaterials, v.9, no.1, 2018 describes the ability to build patient-specific implants (including customized implants) using 3D printing technology. It also describes various biomaterials currently used in medical 3D printing, including metals, ceramics, polymers, and compounds for tissue engineering and regenerative medicine.

[0013] Therefore, there is no solution in the prior art that is equivalent to the solution proposed by the present invention that combines technical differences, quality, safety and reliability.

[0014] Purpose of the Invention

[0015] Therefore, the present invention aims to provide a solution for patients in need of bone grafts, primarily in the craniomaxillofacial region, but also in other areas of the body requiring bone grafts.

[0016] Another object of the present invention is to provide an application of additive manufacturing in the production of medical devices, constituting a technical difference.

[0017] Another object of the present invention is to provide a technology related to providing products and treatment methods that can be applied to regenerative medicine.

[0018] Another object of the present invention is to provide a customization technique produced by additive manufacturing.

[0019] Another object of the present invention is to provide a technique that can produce patient-specific medical devices as well as medical devices having predetermined shapes and sizes.

[0020] Furthermore, another object of the present invention is to provide a medical device that can contain stem cells.

[0021] Another object of the present invention is to provide a porous medical device that can promote improved bone integration.

[0022] Another object of the present invention is to provide a bioceramic medical device comprising carbon nanostructured elements to improve performance.

[0023] Further, another object of the present invention is to provide a medical device that is a solution for patients in need of bone grafts, which combines a device made of bioceramics and a membrane made of PDO. Summary of the invention

[0024] The present invention achieves these and other objects by a medical device, particularly indicated for use as a synthetic bone graft, consisting of a synthetic bioceramic consisting of β-tricalcium phosphate or hydroxyapatite; produced by additive manufacturing; and optionally personalized.

[0025] The present invention achieves these and other objects by a method for preparing the above-mentioned medical device as a patient-specific device, the method comprising the following steps:

[0026] - Obtain patient imaging studies (e.g., computed tomography, DICOM files) using CAD software;

[0027] - Carry out planning and generate planning report, which will be sent to the client (dentist or doctor) for approval;

[0028] - After approval, the said file in STL format (binary coding) is imported by the print preparation software, to which the parameters related to the raw material are added and sent to the printer via a wireless or wired connection;

[0029] - Producing said personalized medical device (customized or patient-specific) by additive manufacturing.

[0030] The present invention achieves these and other objects by a method for preparing the above-mentioned medical device having a predetermined shape of the device, the method comprising the steps of:

[0031] - Technical drawings of standard models (block, wedge and cylinder)

[0032] - Archive. STL is ready and approved by the project team and technical lead;

[0033] -Customization of the graft according to the anatomy of the receiving bed with the help of a drill and sterile surgical / prosthetic discs for straight pieces;

[0034] - Give adequate surface finish without sharp edges to avoid flap perforation;

[0035] -Adapt the block to the recipient bed without leaving a step, aligning all sides of the graft with the bone defect.

[0036] Furthermore, the present invention achieves these and other objects by a method for inserting the above-mentioned medical device, the method comprising the following steps:

[0037] a. Initial field assessment (clinical deficiencies);

[0038] b. Tissue separation to expose the surgical bed;

[0039] c. Prior use of a polymer guide (bone graft analog) to verify the suitability of the device of the present invention;

[0040] d. Perforating the surgical bed to allow blood perfusion and nutrition of the instrument;

[0041] e. Fit the above medical instruments onto the operating table and fix them with screws.

[0042] In a second preferred embodiment, the invention comprises graphene or other compounds made of carbon, such as nanocarbon and carbon tubes. The presence of these components increases the mechanical strength of the device of the invention and also imparts antibacterial properties.

[0043] In a third preferred embodiment, the present invention comprises stem cells, which are preferably autologous adult mesenchymal stem cells obtained from a dermal puncture of a patient.

[0044] In a fourth preferred embodiment of the invention, the invention comprises carbon nanostructures (graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.) and stem cells. Finally, the invention achieves these and other objectives by using the above-described device as a bone graft for volume augmentation / reconstruction of craniomaxillofacial or other bone defects and for space maintenance, which is gradually replaced by newly formed bone.

[0045] In a fifth preferred embodiment of the present invention, the present invention is combined with a poly(dioxanone) membrane to improve and accelerate guided bone regeneration. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1 An embodiment of the device of the present invention applied to personalized facial bones (patient-specific medical device) is shown;

[0047] Figure 2 An embodiment of the device of the present invention applied to a personalized neurocranium is shown (a patient-specific medical device);

[0048] Figure 3 The use of the device of the invention in a personalized jaw (patient-specific medical device) is shown;

[0049] Figure 4 A porous structured solid based on a gyroid surface is shown;

[0050] Figure 5 The present invention (A) mesenchymal stem cell-dermal perforation is shown in detail;

[0051] Figure 6 The present invention is shown in detail (A) mesenchymal stem cell-dermal perforation and (B) osteogenesis;

[0052] Figure 7A preferred embodiment of the invention is shown: disk; cylinder; disk 5x2 mm;

[0053] Figure 8 It is shown Figure 7 a graph showing characteristics of the illustrated embodiment;

[0054] Fig. 9 is a micrograph of the sample of the present invention at 25x magnification;

[0055] Fig.10 are photomicrographs of samples of the present invention at magnifications of: (2a) 25x; (2b) 37x; (2c) 1.000x and (2d) 2.000x.

[0056] Fig.11 It is a production process flow chart of the present invention;

[0057] Fig.12 The shape of the present invention is shown.

[0058] Fig.13 1 and 2 show the results of image inspection of an embodiment of the present invention including graphene. DETAILED DESCRIPTION

[0059] The present invention relates to a medical device used as a synthetic bone graft, preferably composed of a synthetic bioceramic consisting of resorbable β-tricalcium phosphate (≥95% β-TCP) or hydroxyapatite (≥95% HA). The device is intended to be a synthetic bone substitute for use as a bone graft for volume augmentation / reconstruction and space maintenance of craniomaxillofacial or other bone defects, and is gradually replaced by newly formed bone.

[0060] Bioceramics such as calcium phosphates (hydroxyapatite and β-TCP) are materials that induce a controlled reaction with the host tissue in a physiological environment, thereby accelerating the healing process (tissue neoplasia). They also facilitate cellular mechanisms by colonizing stem cells of the respective tissue to be repaired / regenerated.

[0061] Bioceramics promote cell proliferation and differentiation to form new tissue by interacting / binding with the surface of medical devices. Despite this, they are still resorbable.

[0062] The invention targets osteoconductive and biomimetic properties, making its structure conducive to cell recognition and tissue regeneration.

[0063] It serves as a framework that mimics the microstructure of trabecular bone, allowing for efficient vascularization and bone formation.

[0064] Some of the properties of the bioceramics used in the present invention are highlighted below:

[0065] -Through Ca 2+ The release of ions promotes the increase in pH;

[0066] - The elevated pH stimulates alkaline phosphatase activity in both pre-existing osteoblasts and newly differentiated active osteoblasts;

[0067] -Alkaline pH induces the synthesis of type I collagen and non-collagen proteins as well as alkaline phosphatase;

[0068] - Gradual remodeling of the pH at the material-tissue interface by enzymatic action and nucleation of calcium phosphate crystals in collagen fibers (osteoid) until they form a chemically more stable phase (primary bone);

[0069] -Contains HCO 3- The biological buffering effect of ions is beneficial to the precipitation of apatite carbonate.

[0070] In this sense, the present invention is a resorbable synthetic bone graft for reconstruction and / or guided regeneration of bone defects. The macroscopic and microscopic structure, surface area and chemical composition impart effective osteoconductivity, high hydrophilicity, and controlled resorption / dissolution of the crystalline components of the bone graft, which is gradually resorbed by the body and replaced by new bone tissue during the repair or regeneration of bone tissue.

[0071] The present invention is a technology applicable to produce predefined medical devices as well as patient-specific medical devices with customized dimensions, manufactured by additive manufacturing processes (3D printing). The medical device is classified as a bone graft, consisting of a porous structure based on bioceramics, preferably β-tricalcium phosphate (β-TCP).

[0072] In a preferred embodiment of the present invention, the structure of the medical device is as follows:

[0073] The following structure:

[0074]

[0075] Figure 1 and Figure 2 The embodiments of the devices shown in the figure are classified as patient-specific medical devices, which are virtually designed and constructed using virtual 3D models and CAD / CAM technology using data obtained from computer tomography or magnetic resonance imaging. Subsequently, the customized product is obtained through additive manufacturing technology using this file generated in the planning.

[0076] The virtual / digital planning and design of the device is obtained by planning with software that processes images in DICOM format (Digital Imaging and Communications in Medicine) originating from imaging studies (Computed Tomography), wherein the device is designed with complex geometries and faithful to the anatomy of the bone tissue to be reconstructed. In this process of planning the device of the invention, an STL (Standard Triangle Language) file is obtained, which is associated with the additive manufacturing technology to produce these parts with complex geometries, supporting personalized medical devices, subcategorized as "patient-specific".

[0077] A patient-specific medical device is a "medical device that is compatible (or made compatible) with the patient's anatomy using scaling techniques based on anatomical references or using anatomical features obtained from imaging examinations, typically in batches that can be produced by a verifiable and reproducible process under the responsibility of the manufacturer, even if the project may be developed in conjunction with qualified health professionals".

[0078] In more detail, the virtual planning of the model of the medical device of the present invention includes the following steps:

[0079] - Examination of patient images obtained using CAD software (e.g. computed tomography, DICOM files);

[0080] - Perform planning and generate planning report to send to client (dental surgeon) for approval;

[0081] -After approval, the print preparation software imports the STL format (binary coded) file, where parameters related to the raw material are added and sent to the printer via wireless or wired connection.

[0082] The device of the present invention is suitable for filling and / or reconstructing bone defects in the craniomaxillofacial region or other regions. The device of the present invention can also be used for alveolar ridge augmentation / reconstruction or other craniomaxillofacial defects associated with resorbable or non-resorbable membranes, meshes or fabrics for guided tissue regeneration.

[0083] The device of the present invention is used as a bone substitute, which is beneficial to the three-dimensional reconstruction or spatial maintenance of bone defects and provides defect regeneration. The device of the present invention is slowly resorbed by the body, which is beneficial for new bone tissue to replace the graft during tissue repair or regeneration.

[0084] Preferred embodiments of the device of the present invention comprise an internal filling, preferably in the form of Figure 4 The spiral form shown.

[0085] In this embodiment, the infill pattern of the custom block consists of a honeycomb architecture, preferably detailed in CAD, intended to mimic bone tissue. A helical structure model is a good example of a pattern that has been successfully applied to 3D printing due to its high strength and low weight.

[0086] Regarding the predetermined shape of the embodiment of the present invention, Fig.12 As shown, some shapes and sizes are described below:

[0087]

[0088]

[0089] In a preferred embodiment of the present invention, the medical device may contain carbon nanostructures (graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.) Preferably, the medical device contains graphene in a concentration of 0.001% to 0.01%.

[0090] In a preferred embodiment of the present invention, the medical device may comprise a PDO membrane (poly(dioxanone) membrane). Further, in a preferred embodiment of the present invention, the medical device may comprise a PDO membrane and stem cells. The composition has an excellent potential to improve and accelerate guided bone regeneration. In addition, the use of stem cells in the present invention optimizes the bioceramics by increasing their osteoinductive and osteogenic cell capabilities, even with the resorption of the present invention.

[0091] Application of the device of the present invention

[0092] The present invention is a single-use, invasive, implantable product that will be in contact with bone tissue, soft tissue and long-term (>30 days) contact with body fluids in the craniomaxillofacial region. Its application can be performed in an outpatient or operating room environment (hospital) by a surgeon (dentist or doctor) qualified to perform bone reconstruction / regenerative surgery in the craniomaxillofacial region. The technique of using and applying the device of the present invention varies according to the preferences and techniques recommended by the surgeon, and the patient-specific medical device (geometry, size and positioning of the product to the receiving bed) selected by the surgeon for the treatment method and approved by the surgeon for the previously virtually planned and approved by him.

[0093] Therefore, it is not advisable to use common surgical techniques in all patients. The surgical plan must be based on the surgeon's references and previous experience, always considering the most appropriate choice of bone graft, technique, order of grafting, and the use of membranes, meshes or fabrics, always based on traditional and sacred therapeutic techniques of guided tissue regeneration and bone grafting when necessary.

[0094] Before use, the quantity and quality of soft tissue in the transplant area should be analyzed in advance. Whether the adjacent soft tissue is sufficient to cover the device of the present invention without tension on the flap, due to the selection or planning of the device to be used by the customer's incorrect approval, as well as the indications of bone tissue or soft tissue, operation, preparation errors and installation of the product, physical structure damage and product contamination may occur, and lead to product failure.

[0095] It is very important to properly prepare the site (recipient bed) to which the device of the present invention is to be applied. The entire area to be treated must be prepared to facilitate vascularization of the recipient bed. If necessary, the recipient bed is decorticated or some perforations are made with a drill up to 2 mm in diameter to promote vascularization and nutrition to the device, control bleeding, and allow the bone graft to fit perfectly to the recipient bed and achieve the desired result.

[0096] Insertion of the device of the present invention

[0097] Insert the device of the present invention into Figure 3 The indicated location shown contains the following steps:

[0098] a. Initial field assessment (clinical deficiencies);

[0099] b. Tissue separation to expose the surgical bed;

[0100] c. Prior use of polymer guides (bone graft analogs, also produced by additive manufacturing) to verify the fit of the device of the present invention;

[0101] d. Perforating the surgical bed to allow blood perfusion and nutrition of the instrument;

[0102] e. Adapt the instrument of the present invention to the operating table and fix it with screws.

[0103] It is important to emphasize that the device of the present invention must be used by qualified professionals under sterile operating field conditions and with adequate preoperative sterilization to avoid the risk of contamination of the sterile product.

[0104] The device of the present invention is suitable for:

[0105] - Implantology: bone reconstruction for horizontal and / or vertical augmentation;

[0106] - Periodontology: filling of intrabony defects;

[0107] - Craniomaxillofacial care: Traumatology and bone reconstruction (facial skeleton and neurocranium) for horizontal and / or vertical augmentation;

[0108] - General clinical: filling of intraosseous bone defects or bone reconstruction of long bones or spine.

[0109] Compared with the prior art, the present invention has many technical and economic advantages, some of which are as follows:

[0110] - The device of the invention is suitable for guided tissue regeneration, augmentation / reconstruction and filling of atrophic bones or intrabony defects, facial bones, neurocranial bones, spine, long bones or bone defects caused by congenital, post-traumatic, post-surgical problems, which are not inherent to the stability of the bone structure;

[0111] - The device of the present invention is designed and manufactured to ensure safety and efficacy with respect to toxicity;

[0112] - The device of the present invention is designed and manufactured to ensure safety and effectiveness related to biocompatibility. Physicochemical analysis and preclinical testing ensure that its properties meet the performance requirements for its intended use;

[0113] - According to the tests for identification of trace elements and systemic toxicity, the device of the invention is an ingestible product and does not present risks caused by the substances it releases;

[0114] - It is a product that does not present a risk of injury due to its physical and ergonomic characteristics. It is a patient-specific product that must be perfectly adapted to the bone defect / receiver bed according to each clinical case.

[0115] - In addition to the huge gains in surgical procedure agility, the product also brings a better quality of life to patients because it uses customized synthetic materials to reconstruct lost tissue without removing bone tissue from other parts of the patient's body or using grafts from other sources, such as human and animal sources, in a non-personalized manner. As a result, the product is precise, predictable and greatly reduces surgical procedures and complications, such as patient infection or product rejection.

[0116] - The standardized three-dimensional macro and micro structures through additive manufacturing of the present invention impart effective osteoconductivity, high hydrophilicity, and control of the absorption / dissolution of the crystalline components of the bone graft, which is gradually absorbed by the body and replaced by new bone tissue during bone tissue repair or regeneration.

[0117] - The compressive strength properties of these bone grafts ensure a mode of use that allows drilling by a drill and fixation by screws. The adjacent contact of the present invention adjacent to the recipient bed increases the contact area between them, promotes vascular regeneration and provides osteoblast migration into the bone graft. Generally, absorbable synthetic materials for bone regeneration are the materials of choice; because these materials do not contain possible contaminants or organic moieties from homogeneous and heterogeneous grafts, which may cause an immune response. In this way, synthetic materials can minimize the risk of infection, inflammation and other complications in the postoperative period.

[0118] - Furthermore, histological analysis of the biocompatibility testing performed on the present invention showed that the design of the projected extrinsic porosity imparts the product with properties of osteoconduction and integration into adjacent bone tissue, as observed in implantation tests using newly formed healthy bone tissue inside the macropores.

[0119] -The relevant basic performance requirements of the present invention include:

[0120] a) Filling and / or reconstruction of bone defects in the craniomaxillofacial region;

[0121] b) As a bone substitute, it helps maintain the space of bone defects, thereby providing defect repair or even increasing bone volume;

[0122] c) is reabsorbed by the body and replaced by new tissue during the process of bone tissue repair or regeneration.

[0123] -The relevant basic safety requirements of the present invention include:

[0124] (a) Chemical composition (raw materials);

[0125] (b) sterilization;

[0126] (c) Mechanical strength;

[0127] (d) biocompatibility;

[0128] (e) Clinical safety-adverse reactions.

[0129] - Clinical studies have been conducted to augment the atrophic maxilla;

[0130] - The present invention acts as a bone substitute, facilitating the maintenance of space in bone defects, thereby providing repair of the defect or even increasing bone volume.

[0131] - The present invention provides for augmentation of the maxillary bone as well as maintenance of this augmentation / volume.

[0132] - The present invention is reabsorbed by the body during bone tissue repair or regeneration and replaced by newly formed tissue.

[0133] - Further, 8 months after surgery, newly formed tissues were observed within and adjacent to the present invention.

[0134] test

[0135] A. The following tests refer to embodiments of the present invention as patient-specific medical devices

[0136] Test 01. Mechanical test

[0137] Mechanical testing is based on evaluating the compressive strength provided by the product when subjected to force. The compressive strength property ensures that the product can be drilled through a drill and fixed by screws without unexpected breakage (failure mode). The better the fixation next to the recipient bed, the larger the contact area for vascularization and osteoconduction.

[0138] For the composition of β-tricalcium phosphate, the test results show that the average maximum force achieved is 508.42±72.84N. The calculated average compressive strength is 25.89±3.71MPa, which is higher than the porous ceramic blocks of similar products that have been commercialized: ChronOSTM (DepuySynthes) and Adbone (Medibone). For hydroxyapatite, the average maximum force achieved is 81.83±23.09N, resulting in a compressive strength of 4.17±1.18MPa.

[0139] Test 02. Chemical / material characterization

[0140] The raw materials used for the production of the device of the invention are composite resins based on calcium phosphate bioceramics (in the crystalline phase β-tricalcium phosphate, β-TCP, or hydroxyapatite, HA), and after the sintering process only the inorganic phase (bioceramic) is obtained.

[0141] Tests performed to ensure the quality of the raw materials used in the manufacturing process, as well as the composition of the final product:

[0142] Trace Elements: The selected quantitative analyses employed sensitive and indicative methods to determine the limits of specific trace elements, namely arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb) and the sum of heavy metals. In the samples analyzed, all the results of the quantitative analytes were below the LQ (Limit of Quantification), both for the composition of β-tricalcium phosphate and hydroxyapatite, leading to the conclusion that, regarding the residual quantification of trace elements (toxicity to heavy metals), the ceramic prototype in question can be safely used as a bone graft.

[0143] Qualitative and quantitative determination of crystalline phase: The mass fraction of β-tricalcium phosphate phase was quantified by the Rietveld method. The composition of the three batches analyzed was confirmed to be β-tricalcium phosphate, showing a composition of β-TCP>95%. In addition, the purity of the crystalline phase was evaluated by infrared region spectroscopy (FTIR). At the same time, the composition of the three batches of certified hydroxyapatite was HA>95% and calcium oxide <1%.

[0144] Chemical analysis and characterization of crystallinity and phase purity. FTIR analysis confirmed that the sample analyzed consisted of β-tricalcium phosphate (β-TCP), since the identified bands were consistent with the spectrum of this compound in the literature. It was also concluded that the purity of β-TCP met the appropriate requirements, since the characteristic bands of α and β forms of calcium pyrophosphate were demonstrated in the spectrum, namely: 434 cm -1 , 757cm -1 , 1210cm -1 , 1185cm -1 , 723cm -1 and 454cm -1 .

[0145] Shape and size: For both compositions, the analyzed samples presented dimensions appropriate to the geometry proposed in the project for the samples submitted for additive manufacturing. During the sintering of the green body, the burning of organic matter and the rearrangement of the ceramic powder particles occur, forming strong bonds or necks at the contact points of the particles. As the contact increases, the porosity decreases drastically and the particles approach each other, causing the part to shrink. By analyzing the microscopic images of the sintered parts, we can estimate the sintering stage, relative density and grain formation profile of the part. The analyzed samples seem to be in the final stage of sintering, with normal grain growth, as the pores are almost completely closed and the grains are well-formed and uniform.

[0146] Porosity: Although the theoretical density of β-TCP is 3.14 g / cm 3 The average density of the three batches with β-TCP composition was 3.61 ± 0.09 g / cm 3 The average surface area is 0.23 ± 0.09 m 2 / g, revealing that the sintering process used in the process increases the relative density value. In addition, since mercury cannot penetrate under compression of 0-5000PSI, pores smaller than 51μm cannot be determined, indicating that these blocks do not have a large amount of intrinsic pores between 51μm and 0.02μm. The average density of the triplicate samples printed with the hydroxyapatite composition was 3.3745±0.03037g / cm 3 The average surface area is 0.1345±0.0820m 2 / g. The average porosity determined by mercury intrusion porosimetry was 11.06±2.58% and the average diameter was 0.56μm. These data reveal the reproducibility and reliability of the manufacturing process in the post-processing stage.

[0147] It is well known that the properties of the graft structure (e.g., porosity, interconnectivity, pore size, permeability, and pore shape) affect in vivo bone formation. In the analyzed samples, the interconnectivity porosity and diameter were estimated by mercury intrusion porosimetry. The calculated values ​​for total porosity (micropores) were 28.66% and permeability was 0.026 (cm 3 / g), 80% of the interconnected pores measured 5.47-0.39 μm (micropores) and an average pore size of 0.70 μm. To calculate the porosity, the actual density was determined by helium pycnometer measurement (3.213 ± 0.022 g / cm 3 In addition, the mean surface area (0.243 ± 0.2 m 2 / g).

[0148] The porosity of 28.66% is similar to the results reported in other studies using printed β-TCP samples with 400 μm pores in the filling structure. However, modifications to the filling geometry and unit cell size may lead to significant changes in porosity. Therefore, it is concluded that the complex geometry of these samples (spirals with macropores: theoretical value of and actual value of 404 ± 0.0238 μm) adds to the characteristics of the microstructure determined by these analyses, demonstrating that the inherent porosity and the presence of interconnected micropores are favorable for fluid adsorption, adhesion, and cell proliferation, making this microstructure an excellent factor for cell scaffolds.

[0149] Dissolution and pH changes: For both compositions, the pH change of the TRIS-HCl buffer solution during the determination did not exceed 0.2 relative to the initial value. The calcium content of the solution was analyzed by ICP-OES, and the results showed that the calcium ion concentration gradually increased during the analysis. The mass loss was not significant enough to be quantified (<LQ 0.1%), (LQ, limit of quantification).

[0150] In this way, these determinations ensure the compliance of the product with pH changes during implantation, as significant pH changes after implantation can induce an exacerbation of the inflammatory response and interfere with the regeneration process and tissue formation. Additionally, it is desirable for biomaterials used for bone filling / transplantation to degrade at a rate close to that of new bone tissue formation. The degradation of materials mainly depends on their chemical composition and physical properties, and the higher the Ca / P molar ratio, the lower the solubility of the material.

[0151] Test 03. Cytotoxicity assay

[0152] The cytotoxicity of a test substance is determined by the percentage of cells that remain viable after exposing a given cell population to an extract of the test substance at a certain concentration.

[0153] Under the test conditions, the device of the present invention did not promote a significant decrease in cell viability (>30%) in any test group, showing a cell viability of 96%. Therefore, the test items (β-TCP, ≥95%) do not have cytotoxic potential. Under the same test conditions, the test item (HA ≥95%) did not reduce cell viability.

[0154] Test 04. Genotoxicity assay

[0155] The micronucleus test detects chromosomal changes during cell division and aims to evaluate the genotoxic potential of a substance. Under the test conditions, the device samples of the present invention did not show genotoxic (mutagenic) effects in short-term treatment (with or without metabolic activation) and continuous treatment. Therefore, under the described conditions, both compositions (hydroxyapatite and β-TCP) are considered non-mutagenic.

[0156] Test 05. Maximized dermal sensitization

[0157] The maximal dermal sensitization assay involves analyzing the ability of a material to elicit an immune-mediated skin reaction to a substance, characterized by the appearance of edema and erythema. The maximal method uses an adjuvant capable of stimulating an immune response to enhance the sensitivity of the method (Freund's Complete Adjuvant - FCA). The LLNA (Local Lymph Node Assay) method evaluates the potential for dermal sensitization in rodents.

[0158] Under the conditions studied, the tested items in both compositions (hydroxyapatite and β-TCP) were classified as non-sensitizing.

[0159] Test 06. Intradermal Reactivity

[0160] The intradermal reactivity test involves the evaluation of local adverse reactions occurring after a single intradermal inoculation of a substance. Under the conditions studied, the test items in both compositions (hydroxyapatite and β-TCP) did not induce intradermal reactivity in rabbits.

[0161] Test 07. Acute systemic toxicity

[0162] Acute systemic toxicity testing is an evaluation of the health risks and adverse reactions that may result from a single exposure to a substance. These studies provide information about systemic toxic effects and serve as a basis for evaluating the safety of the substance. Under the conditions of this study, the test items in both compositions (hydroxyapatite and β-TCP) met the requirements of no acute systemic toxicity.

[0163] Test 08. Subchronic toxicity

[0164] Subchronic toxicity testing evaluates the possible toxicity and systemic effects of materials implanted in animal species. In this sense, this test was designed to evaluate the possible toxicity and systemic effects of bone implants in rabbits exposed to the test item for 90 days. Under the conditions studied, for both compositions (hydroxyapatite and β-TCP), no systemic or toxic signs were found in daily clinical evaluations, body weight changes, weekly feed consumption, ophthalmological examinations, and biochemical, hematological and anatomical pathological measurements related to subchronic (90 days) systemic exposure to implants of the test item. In this way, the test item can be classified as non-toxic.

[0165] Test 09. Chronic toxicity

[0166] The chronic systemic toxicity test evaluates the possible toxicity and systemic effects of materials implanted in animal species. In this sense, this test was designed to evaluate the possible toxicity and systemic effects of bone implants exposed to the test items for 180 days in rabbits. Under the conditions of the study, no systemic or toxic signs were found in daily clinical evaluations, body weight changes, weekly feed consumption, ophthalmic examinations, and biochemical, hematological and anatomical pathological measurements related to chronic systemic exposure (180 days) to the implants tested. In this way, both the test items (hydroxyapatite and the composition of β-TCP) can be classified as non-toxic.

[0167] Test 10. Testing in Animal Models

[0168] The bone implantation assay evaluates the local effects of materials after implantation in animal species. In this sense, this study aims to characterize the history and evolution of tissue reactions after implantation of medical devices, assessing their biosafety and clinical performance similar to the intended purpose of use. Under the conditions studied, no local or toxic signs were found in the anatomical pathological evaluation of implants of the test item in relation to chronic systemic exposure (26 weeks). The sum of the results obtained in this study indicates that the test item (composed of hydroxyapatite and β-TCP) has a non-irritating character.

[0169] Test 11. Tests of embodiments of the present invention involving mesenchymal stem cells

[0170] The integration of MSCs in the ceramic blocks and their osteogenic differentiation capacity were analyzed by electron microscopy. To this end, cells were plated on the scaffolds in duplicate at a density of 106 cells, and one of the samples was induced to undergo osteogenic differentiation.

[0171] The structure of the blocks showed strong tropism points for the cells, where they covered almost the entire structure, and morphological changes in the samples exposed to osteogenic differentiation medium, indicating calcification points ( Figure 5 and 6 ).

[0172] Test 12. Clinical Study of Block Bone Transplantation

[0173] Title: Use of the present invention for increasing the thickness of atrophic maxillary bone compared with autologous block grafts. Randomized split-mouth clinical study

[0174] Objective: The objective of this study was to evaluate the safety and efficacy of bone neoplasia in the anterior maxillary region by comparing the use of the present invention with the use of autologous block grafts.

[0175] method

[0176] - All participants underwent cone beam computed tomography (CBCT) before surgery;

[0177] - The files from the computed tomography scan are sent together with the information on which side of the maxilla the personalized block graft will be used. From these files, drawings (virtual planning) of the customized blocks of the test group are made in a specific software and then made by additive manufacturing in a 3D printer suitable for ceramic printing. The customized pieces (the present invention) are made using a lithography-based ceramic manufacturing (LCM) technology, the process of which consists in printing the virtual piece in a resin (slurry) containing the desired bioceramic, in this case β-tricalcium phosphate (β-TCP).

[0178] - Preparation and installation of autologous grafts;

[0179] - Installation of the invention;

[0180] - After surgery;

[0181] - Biopsy: Participants underwent a new biopsy 8 months after the bone graft procedure.

[0182] - Analysis: Resorption was calculated by subtracting the result obtained after 8 months from the immediate result. The resorption rate (% resorption) was calculated using the resorption in relation to the initial volume.

[0183] -Comparison of CT scan images shortly after implantation (immediately) and after an 8-month repair / regeneration period.

[0184] result:

[0185] Bone volume was evaluated for autologous bone and the present invention in 15 patients at the time of insertion (immediately after surgery) and eight months after surgery (8 months after surgery). The results are shown in the following table.

[0186] Table 1. Results of bone volume and resorption of autologous bone and the present invention at the time of insertion (PO immediately) and eight months after surgery (PO 8 months).

[0187] Descriptive

[0188] Tables 1 and 2 show the results of the statistical analysis. The results show that although there was no difference in the immediate volume and the volume at 8 months, after 8 months, the resorption rate of the present invention was 8.8 percentage points lower than that of autologous bone. Therefore, in terms of volume maintenance, the present invention is superior to autologous bone (p<0.05).

[0189] Table 1. Comparison of bone volume using ANOVA test with repeated measures.

[0190]

[0191]

[0192] Results: In terms of volume maintenance, the present invention showed superiority over autologous bone.

[0193] Test 13. Macropores - Scanning Electron Microscopy

[0194] The diameter specifications of the micropores and macropores were determined by measurement from micrographs obtained by SEM (scanning electron microscopy) of a cross section of the material and at locations where the pores touch each other so that virtual boundaries between the pores have to be established.

[0195] The technology of the fabrication process makes it feasible to produce complex porous architectures, therefore the same packing structure was applied to the samples used in the present invention, which were spirals with a unit cell of 2.4 mm, resulting in macropores with a theoretical diameter of 400 μm.

[0196] Fig. 9 A micrograph of the evidence body is shown at a magnification of 25X. From the figure, the average diameter of the macropores was determined using ImageJ software (Wayne Rasband and contributors, National Institutes of Health).

[0197] The calculated average diameter of 404 ± 0.0238 μm is consistent with the theoretical diameter of 400 μm of the pores in the helical structure ( Figure 4 ). The size of the helical macropores was designed for osteoconduction, as results showed that in order to increase bone formation, the pores of the 3D printed ceramic implant architecture must be larger than 300 μm with an upper limit of 500 μm.

[0198] The images generated from the scanning electron microscope (SEM) technique allowed the diameter of the large pores present in the complex architecture (with a helical structure) to be measured. The average macropore diameter was 404 ± 0.0238 μm, a value that confirms the theoretical diameter of 400 μm predicted in CAD.

[0199] Test 14. Micropores - Scanning Electron Microscopy (SEM)

[0200] Fig.10 Images of the evidence body at different magnifications are shown.

[0201] The micropores were measured on the surface of the witness body with an average value of 0.69 μm and on the cross section (inside the sample) with an average value of 0.61 μm. Mercury intrusion porosimetry tests confirmed the results obtained by SEM, since the average pore size value for the entire workpiece was 0.70 μm.

[0202] The geometry presented by the printed and sintered samples was analyzed according to the design (STL) submitted for additive manufacturing. The images show surface cracks, although they do not break the workpiece or completely pass through it, but cracks can also be observed internally in the cross-section cut images of the workpiece. In addition to the analysis of the surface and apparent porosity, another objective of this determination is to determine the average diameter of the micropores, where the pores on the surface and in the cross section (interior) of the sample can be measured, with average values ​​of 0.69 μm and 0.61 μm, respectively.

[0203] B. The following tests refer to embodiments of the present invention as predefined shapes of the present invention.

[0204] Test 01. Mechanical properties

[0205] Tests taking into account mechanical stress were carried out to ensure the efficacy and safety of the product. The compressive strength characteristics ensure that the product can be drilled by a drill and fixed by screws without accidentally breaking (failure mode). Taking into account the area of ​​the spiral structure in the cross section, the calculated compressive strength is 18.83 ± 1.51 MPa, which is higher than the mechanical strength value of similar ceramic blocks that have been commercialized.

[0206] Test 02. Chemical properties of materials (raw materials)

[0207] The raw material used to produce the present invention is a resin based on calcium phosphate bioceramics (in the crystalline phase β-tricalcium phosphate), and only the inorganic phase β-tricalcium phosphate (β-TCP) is obtained after the sintering process. The tests performed to ensure the quality of the raw materials are:

[0208] Trace Elements: The results for all quantified elements were below the specified limits.

[0209] Qualitative and quantitative determination of crystalline phases: It was concluded that the mass fraction of the quantitative β-tricalcium phosphate phase was within the specified limits.

[0210] Porosity: It is concluded that complex geometries, with The helicity of the macropores, coupled with the properties of the microstructure determined by these analyses, demonstrates the presence of intrinsic porosity of interconnected micropores that is favorable for fluid adsorption, adhesion, and cell proliferation, making this combination of macro- and microstructures an excellent candidate for a cellular framework.

[0211] Dissolution and pH changes: The results show a gradual increase in calcium ion concentration during the analysis period. In this way, these tests guarantee the consistency of the product in relation to pH changes upon implantation, since significant changes in pH after implantation can cause an increased inflammatory response and interfere with the regenerative process and tissue formation.

[0212] Biocompatibility: The results of characterization tests indicate that the present invention is safe and free from adverse and deleterious effects of comparable products directly and indirectly related to raw materials / chemical composition.

[0213] Dissolution and pH Change: Within specifications.

[0214] Cytotoxicity: Non-cytotoxic product.

[0215] Genotoxicity: Non-genotoxic product.

[0216] Dermal Sensitization - LLNA: Allergenic product.

[0217] Intradermal Reactivity: Non-irritating product.

[0218] Acute Systemic Toxicity: Product does not cause acute toxicity.

[0219] Bioburden: The average microbial load detected in three different batches was less than 1 CFU / unit, indicating that substances from Gram-positive bacteria and fungi have a low potential to cause pyrogenic reactions.

[0220] Bacterial endotoxins (clotting gel): within the limits set by the FDA for medical devices.

[0221] Subchronic systemic toxicity: Non-toxic product.

[0222] Chronic systemic toxicity: Non-toxic product.

[0223] Implantation (90 days): Non-irritating product.

[0224] Implantation (rabbit 180 days): Non-irritating product.

[0225] C. Testing of Embodiments of the Invention Including Graphene

[0226] The compositions of the present invention containing 0.01% and 0.005% graphene were tested to verify properties such as viscosity and shear rate. Some samples were made of Figure 7 The compositions tested were as follows:

[0227]

[0228] The viscosity x shear rate curves for the resins with and without graphene have the same profile and are very close in value, indicating that graphene does not cause a significant change in this property, as can be seen from Figure 8 It can be seen in.

[0229] Adding graphene or other carbon structures to the composition of the medical device of the present invention improves the mechanical properties of the device and also makes the device more radiopaque, which aids in the visualization of the implant in imaging, thereby Fig.13 Can be verified.

[0230] D. The following tests pertain to embodiments of the present invention comprising a PDO membrane

[0231] The bioactivity of the medical device of the present invention with a PDO membrane was evaluated for guided bone regeneration in severe skull defects in rats using cell-based tissue engineering.

[0232] Methods: Male rats were divided into three groups: (1) medical device (β-tricalcium phosphate) + PDO membrane, (2) medical device containing stem cells (β-tricalcium phosphate + adipose-derived stem cells (ASC)) + PDO membrane, and (3) medical device containing stem cells (β-tricalcium phosphate + adipose-derived stem cells (ASC)) + PDO membrane containing stem cells.

[0233] A surgical defect was created in the right parietal bone and filled with the graft described above. Animals were euthanized 7, 14, and 30 days after surgery for histomorphometry and immunolabeling analysis.

[0234] Results: Cell-based therapy promoted bone formation at the defect edge and defect center, especially in group 3.

[0235] Conclusion: The combination of PDO membranes associated with cell-based therapies using this medical device has excellent potential to improve and accelerate guided bone regeneration. Furthermore, the use of ASCs optimized the bioceramics by increasing their osteoinductive and osteogenic progenitor cell capacity, even in the presence of resorption of the printed scaffold.

[0236] At the end of the experiment, 30 days after surgery, group 1 showed the presence of bone tissue formation in the defect edge area, but there was still a significant presence of connective tissue, which migrated into the defect interior along with the extensively resorbed biomaterial. Group 2 showed a scaffold that was almost resorbed and filled with highly vascularized connective tissue. Large bone tissue formed at the defect border and also migrated into the central area of ​​the defect. Group 3 showed a large amount of bone tissue formation in the defect edge area and migrated into the central area, with the presence of cavities filled with osteocytes, characterizing the organization and maturity of the bone. The presence of highly organized connective tissue, with precursor cells for bone formation, extended to the central area, replacing the highly resorbed scaffold.

[0237] Table 3. Percentage of bone, connective tissue and biomaterial area in Group 1 at 7, 14 and 30 days.

[0238]

[0239] The results obtained from the histomorphometric analysis are expressed as percentages (%).

[0240] Table 4. Percentage of bone, connective tissue and biomaterial area in Group 2 at 7, 14 and 30 days.

[0241]

[0242] The results obtained from the histomorphometric analysis are expressed as percentages (%).

[0243] Table 5. Percentage of bone, connective tissue and biomaterial area in Group 3 at 7, 14 and 30 days.

[0244]

[0245] The results obtained from the histomorphometric analysis are expressed as percentages (%).

[0246] Table 6. Scores for immunolabeling analysis of TCP / PG (Group 1), TCPasc / PG (Group 2) and TCPasc / PGasc (Group 3). Antibodies against IL-6, OPN and OCN.

[0247]

[0248] Scores were assessed at the border / center of the defect. Discrete marking (+), moderate marking (++), and intense marking (+++).

[0249] Preparation method of the present invention

[0250] In summary, the method for preparing the present invention comprises the following steps:

[0251] A. Patient-Specific Medical Devices

[0252] a) Customer requests for customized products, patient-specific models

[0253] b) Send imaging examination (.DICOM)

[0254] c) DICOM processing

[0255] d) Planning and virtual modeling of patient-specific bone grafts

[0256] e) Approval of planned / modeled product by the client (doctor or dentist)

[0257] f) Generate .STL for printing

[0258] B. Medical devices with predetermined shapes

[0259] a) Technical drawing of the standard models (block, wedge and cylinder)

[0260] b) Archive. STL is ready and approved by the project team and technical leader

[0261] c) Custom-made implants (devices with fixed shapes) and adapted to the receiving bed:

[0262] ○ Depending on the anatomy of the receiving bed, with the help of a drill and a sterile surgical / prosthetic disc for straight parts (e.g. 702 drill, Maxicut series model and diamond blade);

[0263] ○ Give adequate surface treatment without sharp edges to avoid flap perforation;

[0264] o Fit the block to the receiving bed without leaving a step, aligning all sides of the graft with the bone defect.

[0265] Furthermore, after the above steps:

[0266] -Primary and secondary assembly;

[0267] - Gamma irradiation sterilization;

[0268] -examine;

[0269] - Outer packaging assembly, and

[0270] - Labeling and inventory.

[0271] Brief description of the preparation process steps

[0272] The method for preparing the present invention is as follows Fig.11 As shown and described in detail below:

[0273] Virtual planning: Virtual planning of models of patient-specific medical devices is performed by a professional technical team of the project to model the plans proposed and approved by the customer. Patient images (e.g., computed tomography, DICOM files) are checked using CAD software to plan and model the patient-specific product, and once the planning is completed, a planning report is sent for approval by the customer (dentist or doctor). After approval, the file in STL format (binary encoding) is imported by the print preparation software, in which parameters related to the raw material are added and sent to the printer via a wireless connection or cable.

[0274] The automatic dispenser is responsible for feeding the raw material (ceramic-based resin with β-TCP crystal phase) into the tank during printing, preserving the necessary thickness for each layer to be photopolymerized (printed), without intervention during the printing process. In this way, the manufacturing process is identical for both series, by adopting lithography-based ceramic manufacturing (LCM) technology and additive manufacturing with the same raw materials.

[0275] Post-processing: When printing is completed, the part is removed from the printing platform and cleaned with an organic solvent to remove excess uncured resin from its surface. Subsequently, to ensure the cleanliness of the internal porous structure, the part is immersed in a solvent and subjected to a heated ultrasonic bath. After the external and internal cleaning steps, the excess solvent is removed with a jet of compressed air and then stored in a drying oven for 24 hours. After the drying process, the employees place the manufactured parts (determined by the production order, either special or standard) on an alumina plate and select the sintering program in an automatic muffle furnace with an exhaust system and a catalyst. The heat treatment (sintering) ensures the combustion of organic matter and the sintering of ceramic particles at 1200°C.

[0276] Having described an example of a preferred embodiment of the present invention, it should be understood that the scope of the present invention encompasses other possible variations of the described inventive concept, being limited only by the content of the appended claims, including the possible equivalents therein.

Claims

1. A medical device, particularly suitable for synthetic bone grafts, characterized in that: - consisting of a synthetic bioceramic consisting of β-tricalcium phosphate or hydroxyapatite; - Produced by additive manufacturing; -Porosity is multi-functional, and the porosity is planned and distributed as needed; -Shapes are either personalized or predefined.

2. The medical device according to claim 1, characterized in that It includes carbon nanostructures (graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.).

3. The medical device according to claim 2, characterized in that Contains graphene in a concentration of 0.001% to 0.01%.

4. The medical device according to any one of claims 1 to 3, characterized in that Has the following structure:

5. The medical device according to any one of claims 1 to 4, characterized in that It contains stem cells.

6. The medical device according to claim 5, characterized in that The stem cells are autologous adult mesenchymal stem cells obtained from a dermal puncture of the patient.

7. The medical device according to claim 1, characterized in that The synthetic bioceramic consists of β-tricalcium phosphate (≥95% β-TCP) or hydroxyapatite (≥95% HA).

8. The medical device according to any one of claims 1 to 7, characterized in that It is a patient-specific medical device that is virtually planned and constructed based on data acquired from computed tomography or magnetic resonance imaging using virtual 3D models and CAD / CAM technology.

9. The medical device according to any one of claims 1 to 7, characterized in that It is a medical device of predefined shape which should then be customized by the surgeon.

10. The medical device according to any one of claims 1 to 9, characterized in that It contains internal filling.

11. The medical device according to claim 10, characterized in that The inner filler has a spiral shape.

12. The medical device according to any one of claims 1 to 9, characterized in that A poly(dioxanone) polymer film is included.

13. A method for preparing a medical device as defined in any one of claims 1 or 8, characterized in that It includes the following steps: - Examination of patient images obtained using CAD software (e.g. computed tomography, DICOM files); - Perform planning and generate planning report, which will be sent to the client (dental surgeon) for approval; - After approval, the file in STL format (binary encoding) is imported through the print preparation software, where the parameters related to the raw material are added and sent to the printer via wireless or wired connection; -Production of medical devices through additive manufacturing.

14. A method for preparing a medical device as defined in any one of claims 1 or 9, characterized in that It includes the following steps: a. Technical drawing of the standard models (block, wedge and cylinder) b. Archived, STL is ready and approved by the project team and technical leader c. Customize the graft to the anatomy of the recipient bed with the aid of a drill and a sterile surgical / prosthetic tray for the straight piece d. Provide adequate surface treatment without sharp edges to avoid flap perforation; e. Fit the block to the receiving bed without leaving any steps, aligning all sides of the graft with the bone defect.

15. A method of inserting a medical device as defined in any one of claims 1 to 12, characterized in that It includes the following steps: a. Initial field assessment (clinical deficiencies); b. Tissue separation to expose the surgical bed; c. The fit of the device of the present invention was previously verified using a polymer guide (bone graft analogue also produced by additive manufacturing); d. perforating the surgical bed to allow blood perfusion and nutrition of the instrument; e. Adapting the medical device defined in any one of claims 1 to 5 to the operating bed and screw-stabilizing it.

16. Use of a medical device as defined in any one of claims 1 to 12, characterized in that It is used as a bone graft for volume augmentation / reconstruction of craniomaxillofacial, neurocranial, long bone and spinal defects, and for maintenance of space that is gradually replaced by newly formed bone.

17. The use according to claim 16, characterized in that It is suitable for horizontal and / or vertical augmentation of bone reconstruction, filling of intrabone defects; for horizontal and / or vertical augmentation of traumatology and bone reconstruction; filling of intrabone bone defects.

18. Use of a medical device produced according to the method defined in claim 13 or 14, characterized in that It is used as a bone graft for volume augmentation / reconstruction of craniomaxillofacial, neurocranial, long bone and spinal defects, and for maintenance of space that is gradually replaced by newly formed bone.

19. The use according to claim 18, characterized in that It is suitable for horizontal and / or vertical augmentation of bone reconstruction, filling of intrabone defects; for horizontal and / or vertical augmentation of traumatology and bone reconstruction; filling of intrabone bone defects.

Images