Medical device based on bioceramics, its use as a synthetic bone graft and its preparation method

Abstract

The present invention relates to a medical device manufactured using a layered manufacturing method (3D printing). This medical device comprises a porous structure based on bioceramics based on β-tricalcium phosphate (β-TCP) or hydroxyapatite and is preferably used as a bone graft. Its composition may or may not include nanostructures, for example, carbon nanostructures (graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.), and in a preferred embodiment, stem cells and a polymer membrane. The present invention also relates to the use of this device as a bone graft and the manufacturing process of this device.

Description

Technical Field

[0001] The present invention relates to medical devices manufactured from additive manufacturing processes (3D printing). The present invention is a medical device used as a bone graft comprising a porous structure based on bioceramics, β-tricalcium phosphate (β-TCP) or hydroxyapatite (HA). In a preferred embodiment, it may or may not include carbon nanostructures (such as graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.) and may carry stem cells.

[0002] The present invention also relates to the use of this device as a bone graft and a method for preparing this device.

Background Art

[0003] Fillers and synthetic bone substitutes made of porous bioceramics have excellent physical, chemical and biological properties and are classified as bioactive and osteoconductive. That is, osteoblasts can use the material as a scaffold to initiate bone formation at that site. Bioceramics mainly composed of calcium phosphate (Ca3(PO4)2) are prominent because their chemical composition and crystal structure are similar to those of the inorganic substances in the human body. The crystal phases thereof are hydroxyapatite (HA) and tricalcium phosphate (β-TCP), which are the most commonly used in biological systems, and are in the form of particles or blocks.

[0004] Calcium phosphate blocks have excellent mechanical and morphological properties compared to particulate synthetic bone substitutes. Interconnected pores and high porosity promote cell migration and nutrient diffusion for bone reconstruction and also function as a vehicle for the controlled release of drugs and molecules.

[0005] Some teachings of the prior art referred to in this case are specifically noted below.

[0006] Document US9,079,357 discloses an improved method for laminating a shaped body made of a highly viscous photocurable material, and mentions the potential for use in the dental industry.

[0007] Document US9,403,726 describes a method for preparing a high-strength photopolymerizable ceramic wedge that can be used as a ceramic shaped part or product, dental inlay, onlay, veneer, crown, bridge, and structure. In this method, a paste based on a radically polymerizable binder, a polymerization initiator, and a filler is used, and this paste contains at least one acidic photopolymerization initiator monomer and ceramic particles and / or glass ceramic particles. The aforementioned ceramic particles and glass ceramic particles have dental applications and can be used in the preparation of dental restorations such as inlays, onlays, veneers, crowns, bridges, or frameworks.

[0008] Document CN105943406 discloses a 3D printing composite material for oral rehabilitation, and a preparation method and a usage method of the 3D printing composite material. The 3D printing composite material for oral rehabilitation has a small healing shrinkage, a short healing time, a high antibacterial property, and is suitable for the manufacture of dental prostheses.

[0009] Document PI0912499-3 describes the use of tricalcium phosphate and hydroxyapatite biomaterials in surgeries that require bone substitutes such as transplantation and other indications.

[0010] In the literature "Stabilization of tricalcium phosphate slurries against sedimentation for stereolithographic additive manufacturing and influence on the final mechanical properties." by PFAFFINGER, M. et al., published in the International Journal of Applied Ceramic Technology, v. 14, no. 4, p. 499 - 506, 2017, the use of lithography (LCM) for the manufacture of ceramic pieces is disclosed, and the use of pastes filled with tricalcium phosphate is emphasized.

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

[0012] In the literature "Novel biomaterials used in medical 3D printing techniques" by TAPPA, K., JAMMALAMADAKA, U., published in the Journal of Functional Biomaterials, v. 9, no. 1, 2018, the ability to construct patient - specific implants, including custom implants, using 3D printing techniques is described. Also described in the same literature is that a wide variety of biomaterials, such as metals, ceramics, polymers, compounds, etc., are used in medical 3D printing for the purposes of tissue engineering and regenerative medicine.

Summary of the Invention

Problems to be Solved by the Invention

[0013] As described above, there is no solution in the prior art that has technical differences, quality, safety, and reliability equivalent to the present invention presented in this specification.

[0014] Therefore, the object of the present invention is mainly to provide a solution for patients who need bone grafting in the craniofacial region, but it is also applicable to other regions of the body that require bone grafting.

[0015] Another object of the present invention is to provide the use of additive manufacturing in the production of medical devices (medical equipment) that constitute technical differences.

[0016] Another object of the present invention is to provide a technology that includes products and treatment approaches applicable to regenerative medicine.

[0017] Another object of the present invention is to provide a customization technology manufactured by additive manufacturing.

[0018] Another object of the present invention is to provide a technology that can provide medical devices with predefined shapes and dimensions, together with patient-specific medical devices.

[0019] Furthermore, another object of the present invention is to provide a medical device that may contain stem cells.

[0020] Another object of the present invention is to provide a porous medical device that can promote improved bone integration.

[0021] Another object of the present invention is to provide a bioceramic medical device containing carbon nanostructure elements from the perspective of improving characteristics.

[0022] Another object of the present invention is to provide a medical device that is a solution for patients in need of a bone graft that combines a device made of bioceramic and a membrane made of PDO.

Means for Solving the Problems

[0023] The present invention achieves these and other objects by a medical device particularly used as a synthetic bone graft. The medical device includes a synthetic bioceramic made of β-tricalcium phosphate or hydroxyapatite, is manufactured by additive manufacturing, and is optionally personalized.

[0024] The present invention achieves the above and other objects by a method for manufacturing the medical device dedicated to a patient. The manufacturing method includes - a step of examining an image of a patient (e.g., computed tomography, DICOM file) using CAD software, - a step in which a plan is executed and a plan report is created, and the report is sent for approval by a client (dentist or surgeon), - a step in which, after approval, a file in STL format (binary encoding) is imported into printing production software, parameters regarding raw materials are added, and it is sent to a printer via a wireless or cable connection, - a step in which the personalized medical device (custom-made or patient-dedicated) is manufactured by additive manufacturing and includes.

[0025] The present invention achieves the above and other objects by a method for manufacturing the medical device defined in advance. The manufacturing method includes a. technical drawings of standard models (blocks, wedges, and cylinders), b. an archive in which STL is ready and has already been approved by the project team and the technical responsible person, c. Using a drill for the straight piece and a sterilized surgical / orthopedic disk, customizing the graft according to the anatomical structure of the receiving bed; d. To avoid perforating the flap, performing appropriate finishing without leaving sharp edges or corners; e. Leveling all sides of the graft with respect to the bone defect and fitting the block to the receiving bed without leaving a step; and including.

[0026] Furthermore, the present invention achieves the above and other objects by the method of inserting the medical device. The insertion method includes: a. An initial site evaluation (clinical defect); b. Dissecting the tissue to expose the surgical field; c. Using a polymer guide (bone graft analog) in advance to confirm the compatibility of the device of the present invention; d. Drilling the surgical field to enable blood perfusion and nutrition supply of the device; e. Fitting the device to the surgical field and stabilizing it with screws. and comprising.

[0027] In a second preferred embodiment, the present invention comprises graphene or other compounds (made from carbon such as nanocarbons and carbon nanotubes). The presence of these components adds mechanical strength and antibacterial properties to the device of the present invention.

[0028] In a third preferred embodiment, the present invention comprises stem cells, preferably autologous adult mesenchymal stem cells obtained from a patient's skin punch.

[0029] In a fourth preferred embodiment of the present invention, the present invention comprises a carbon nanostructure (such as graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.) and stem cells. Finally, the present invention achieves the above and other objectives by the method of using the above device. In the method of use, the device functions as both a bone graft for increasing / reconstructing the volume of craniofacial or other bone defects and for maintaining the space gradually replaced by the newly formed bone.

[0030] In a fifth preferred embodiment of the present invention, the present invention improves and promotes bone regeneration induction in combination with a polydioxanone membrane.

Brief Description of the Drawings

[0031]

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Embodiments for Carrying Out the Invention

[0032] The present invention relates to a medical device (medical instrument) used as a synthetic bone graft, preferably composed of a synthetic bioceramic consisting of β-tricalcium phosphate (β-TCP of 95% or more) or hydroxyapatite (HA of 95% or more), and is resorbable. This device is intended to be a synthetic bone substitute that functions as both a bone graft for augmentation / reconstruction of craniofacial defects or other bone defects and for maintaining a space that is gradually replaced by new bone.

[0033] Bioceramics such as calcium phosphate (hydroxyapatite and β-TCP) are materials that induce a controlled reaction with host tissue in a physiological environment and promote the healing process (neogenesis of tissue). In addition, the colonization of stem cells of each tissue to be repaired / regenerated promotes the cell mechanism.

[0034] Bioceramics promote the growth and differentiation of cells that form new tissue through interaction / binding with the surface of the medical device. Also, bioceramics are absorbable.

[0035] The present invention aims at osteoconductivity and biomimicry, and its structure is advantageous for cell recognition and tissue regeneration.

[0036] The present invention functions as a framework that mimics the microstructure of cancellous bone and enables effective angiogenesis and osteogenesis.

[0037] Some of the properties of the bioceramics used in the present invention are described below. - Ca 2+ The release of ions promotes an increase in pH. - The increase in pH stimulates alkaline phosphatase activity in existing osteoblasts and newly differentiated active osteoblasts. - The basic pH induces the synthesis of type I collagen, non-collagen proteins, and further alkaline phosphatase. - The pH at the material-tissue interface is gradually re-established until a chemically more stable phase (primary bone) is formed by enzymatic action and the nucleation of calcium phosphate crystals in collagen fibers (osteoid). - HCO 3- The action of the biological buffer containing ions promotes the precipitation of apatite carbonate.

[0038] In this sense, the present invention is a resorbable synthetic bone graft for use in the reconstruction and / or induced regeneration of bone defects. The macrostructure, microstructure, surface area, and chemical composition impart effective osteoconductivity, high hydrophilic properties, and controlled absorption / dissolution of the crystalline phase components of this bone graft, which is gradually resorbed by the body and replaced by newly formed bone tissue during the process of bone tissue repair or regeneration.

[0039] The present invention is a technology applicable to pre-defined medical devices and patient-specific medical devices having custom dimensions, the latter being manufactured by an additive manufacturing process (3D printing). This medical device is classified as a bone graft consisting of a porous structure based on bioceramics, preferably β-tricalcium phosphate (β-TCP).

[0040] In a preferred embodiment of the present invention, the structure of the medical device is as follows.

[0041]

Table 1

[0042] The examples of the devices shown in FIGS. 1 and 2 are classified as medical devices for patients only. These devices are virtually designed and manufactured (built) based on data obtained by computed tomography or magnetic resonance imaging using virtual 3D models and CAD / CAM technologies. Then, using this file generated by the plan, a customized product is obtained by additive manufacturing technology.

[0043] The virtual / digital planning and design of the device are obtained from a plan via software that processes images in DICOM (Digital Imaging and Communications in Medicine) format obtained from an imaging examination (computed tomography). In this plan, the device has a complex shape and is designed faithfully to the anatomical structure of the bone tissue to be reconstructed. In this process of planning the device of the present invention, an STL (Standard Triangle Language) file is obtained. This file is associated with additive manufacturing technology and generates complex-shaped parts that support individualized medical devices sub-classified as "for patients only".

[0044] A medical device for patients only is "a medical device that conforms to (or is adapted to) the anatomical structure of a patient using scaling technology based on anatomical references or using anatomical features obtained from an imaging examination". Usually, this medical device for patients only is batch-produced through a process that can be verified and reproduced under the responsibility of the manufacturer, even when the project is carried out with a qualified medical professional.

[0045] More specifically, the virtual planning of the model of the medical device according to the present invention includes the following steps. That is, - A step of examining a patient's image (e.g., computed tomography, DICOM file) using CAD software; - A step in which the plan is implemented, a plan report is created, and the report is sent for approval by the client (dentist); - After approval, a file in STL format (binary encoding) is imported into the printing preparation software, parameters related to the raw material are added, and it is sent to the printer via wireless or cable connection; and It is as follows.

[0046] The device according to the present invention is used to fill and / or reconstruct bone defects in the craniofacial region or other regions. Further, the device according to the present invention can also be used for alveolar bone ridge augmentation / reconstruction, or other craniofacial defects (related to resorbable or non-resorbable membranes, meshes or fabrics for tissue regeneration induction).

[0047] The device according to the present invention functions as a bone substitute, promotes three-dimensional reconstruction or spatial maintenance of bone defects, and provides defect regeneration. The device according to the present invention is slowly resorbed by the body, thereby promoting replacement of the graft by newly formed bone tissue during the tissue repair or regeneration process.

[0048] A preferred embodiment of the device according to the present invention includes an internal filler as shown in FIG. 4. The internal filler preferably has a gyroide form.

[0049] In this embodiment, the filling pattern of the customized block is composed of a cell structure for the purpose of mimicking bone tissue. The cell structure is preferably created elaborately with CAD. The gyroide structure model is a good example of a pattern that is well applied to 3D printing because it has both high strength and lightness.

[0050] Regarding that the embodiment of the present invention has a predefined shape as shown in FIG. 12, some of the shape and dimensions are described below. Model / Size (A) Length (C) × Width (W) × Height (H) Block - 01 10 x 10 x 03 mm Block - 02 10 x 15 x 03 mm Block - 03 10 x 10 x 05 mm Block - 04 20 x 20 x 08 mm Block - 05 20 x 20 x 10 mm Block - 06 20 x 30 x 08 mm Block - 07 20 x 30 x 10 mm (B) Length (C) × Width (W) × Height (H) - Angle Wedge - 01 20 x 15 x 6 mm - 9° Wedge - 02 20 x 15 x 8 mm - 14° Wedge - 03 20 x 15 x 10 mm - 19° Wedge - 04 20 x 15 x 12 mm - 24° Wedge - 05 20 x 15 x 14 mm - 29° (C) Diameter (φ) × Height (A) Cylinder - 01 08 x 10 mm Cylinder - 02 10 x 10 mm Cylinder - 03 12 x 10 mm Cylinder - 04 14 x 10 mm Cylinder - 05 08 x 20 mm Cylinder - 06 10 x 20 mm Cylinder - 07 12 x 20 mm Cylinder - 08 14 x 20 mm

[0051] In a preferred embodiment of the present invention, the medical device may include a carbon nanostructure (such as graphene, graphene oxide, reduced graphene oxide, carbon nanotube, etc.). The medical device preferably contains graphene at a concentration of 0.001% to 0.01%.

[0052] In a preferred embodiment of the present invention, the medical device may include a PDO membrane (polydioxanone membrane). Also, in a preferred embodiment of the present invention, the medical device may have a PDO membrane and stem cells. This composition has excellent potential for improving and promoting guided bone regeneration. Furthermore, the use of stem cells in the present invention optimizes the bioceramic by increasing the osteoinductive ability and osteogenic ability even in the presence of bone resorption of the present invention.

[0053] Application of the Device According to the Present Invention The present invention is a single-use invasive and implantable product that comes into contact with bone tissue, soft tissue in the craniofacial region, and body fluids for a long period (> 30 days). Its application can be carried out by a surgeon (dentist or physician) qualified to perform surgical procedures for bone reconstruction / regeneration in the craniofacial region, either in an outpatient-based or operating room environment (hospital). The techniques regarding the use and application of the device according to the present invention vary depending on the preferences and techniques recommended by the surgeon. The choice of treatment approach, prior virtual approval of the patient-specific medical device (shape, dimensions, and positioning of the product relative to the recipient bed), and approval by the surgeon are up to the surgeon.

[0054] Therefore, not all general surgical techniques are recommended for all patients. The surgical protocol must be carried out according to the surgeon's references and previous experience, and must always consider the optimal selection of bone grafts, techniques, grafting order, the use of membranes, meshes or fabrics if necessary, and must always be based on the conventional and established treatment techniques for tissue regeneration induction and bone grafting.

[0055] Prior to use, it is necessary to pre-analyze the amount and quality of the soft tissue at the implantation site. Regarding whether the adjacent soft tissue is sufficient to cover the device of the present invention without applying tension to the flap, in addition to the selection or plan wrongly approved by the client for the device used, errors in utilization, operation, preparation of bone tissue or soft tissue, and installation of the product can cause damage and contamination to the physical structure of the product and may contribute to product failure.

[0056] Proper preparation of the site (recipient bed) to which the device of the present invention is applied is very important. To promote angiogenesis in the recipient bed, the entire site to be treated must be prepared. If necessary, decortication of the recipient bed is advanced or perforations up to 2 mm in diameter are made with a drill to promote angiogenesis and nutrient supply to the device while suppressing bleeding, so that the bone graft fits perfectly into the recipient bed and the expected results are obtained.

[0057] Insertion of the device according to the present invention Insertion of the device of the present invention into the indicated position shown in FIG. 3 includes the following steps. That is, a. Initial site evaluation (clinical defect) and b. Step of peeling the tissue to expose the surgical field, c. Step of pre-using a polymer guide (bone graft analog, also manufactured by additive manufacturing) to confirm the compatibility of the device of the present invention, d. Step of perforating the surgical field to enable blood perfusion and nutrition supply of the device, e. Step of fitting the device of the present invention to the surgical field and stabilizing it with screws and

[0058] It is important to emphasize that the device of the present invention must be used by a qualified expert under aseptic surgical field conditions using appropriate preoperative disinfection to avoid the risk of contamination of sterile products.

[0059] The device of the present invention is used for the following applications. - Implantology: Bone reconstruction for horizontal and / or vertical reinforcement - Periodontology: Filling of intrabony defects - Craniomaxillofacial: Traumatology, bone reconstruction for horizontal and / or vertical enhancement (facial bones and neurocranium) - General clinical: Filling of intrabony defects, or bone reconstruction of long bones or the spine

[0060] The present invention presents a number of technical and economic advantages when compared to the prior art, some of which are listed below. - The device of the present invention is used for the inductive tissue regeneration, enhancement / reconstruction and filling of atrophic bone or bone defects, facial bones, neurocranium, spine, long bones, or bone defects caused by congenital, post-traumatic, or post-surgical problems, and is not essentially involved in the stability of the bone structure. - The device of the present invention is designed and manufactured to ensure safety and effectiveness regarding toxicity. - The device of the present invention is designed and manufactured to ensure safety and effectiveness regarding biocompatibility. Physicochemical analysis and preclinical tests guarantee the characteristics for performance for the intended purpose of use. - The device of the present invention is an absorbable product, and according to the identification test of trace elements and systemic toxicity, there is no risk derived from the substances released therefrom. - The device of the present invention is a product without the risk of injury related to its physical and ergonomic characteristics. It is also a patient-specific product and must perfectly adapt to the bone defect / patient bed according to each clinical case. - This product not only significantly improves the agility of surgery but also improves the quality of life of the patient. This is because the need to remove bone tissue from other parts of the patient's body or use grafts from other sources such as human or animal sources in a non-personalized manner is eliminated by reconstructing the lost tissue with a customized synthetic material. Therefore, this product enables accuracy, predictability, a significant reduction in surgery, and a reduction in complications such as infection and rejection in patients. - The three-dimensional macro and microstructures standardized by the additive manufacturing of the present invention impart effective osteoconductivity, high hydrophilicity characteristics, and controlled absorption / dissolution of the crystalline phase components of this bone graft, and are gradually absorbed into the body and replaced by newly formed bone tissue during the process of bone tissue repair or regeneration. - The compressive strength characteristics of these bone grafts ensure a mode of use that enables drilling and screw fixation. The contact of the present invention adjacent to the receptor bed increases the contact area between the two, promotes reperfusion, and provides for the movement of osteoblasts into the bone graft. Generally, resorbable synthetic materials are the materials of choice for bone regeneration because they are free of contaminants and organic moles from homogeneous and heterologous grafts that can induce an immunological response. Thus, synthetic materials can minimize the risk of postoperative infection, inflammation, and other complications. - Also, according to the histological analysis of the biocompatibility tests conducted on the present invention, it has been demonstrated that the projected external porosity design imparts to the product the properties of osteoconduction and integration into adjacent bone tissue. This was observed in transplantation tests using newly formed healthy bone tissue within the macropores. - The essential performance requirements related to the present invention include the following. a) Filling and / or reconstructing bone defects in the craniofacial region b) Acting as a bone substitute, promoting the maintenance of the space in the bone defect, and resulting in the repair of the defect or an increase in bone mass c) Being resorbed in the body and replaced by newly formed tissue during the process of bone tissue repair or regeneration - The essential safety requirements related to the present invention include the following. (a) Chemical composition (raw materials) (b) Sterilization (c) Mechanical strength (d) Biocompatibility (e) Clinical safety - side effects - In clinical studies, the augmentation of the atrophic maxilla is being carried out. - The present invention acts as a bone substitute, promotes the maintenance of the space in the bone defect, and results in the repair of the defect or an increase in bone mass. - The present invention provides for an increase in the maxilla and the maintenance of this increase / volume. - The present invention is resorbed in the body and replaced by newly formed tissue during the process of bone tissue repair or regeneration. - Also, new tissue was observed inside and adjacent to the present invention 8 months after the operation.

[0061] Test A. The following tests were conducted on embodiments of the present invention, which are medical devices dedicated to patients. Test 01. Mechanical test The mechanical test was based on evaluating the compressive strength provided by the product when a force was applied. The characteristics of the compressive strength ensure that the product can be drilled and fixed with screws without causing unintentional breakage (failure mode). The better the fixation near the recipient bed, the larger the contact area for angiogenesis and osteoconduction.

[0062] In the composition of β-tricalcium phosphate, as a result of the test, the average value of the maximum force reached was 508.42 ± 72.84 N. The average compressive strength was 25.89 ± 3.71 MPa, which was higher than that of the porous ceramic blocks (ChronOSTM (Depuy Synthes) and Adbone (Medbone)), similar products that have already been commercialized. In the case of hydroxyapatite, the average maximum force reached was 81.83 ± 23.09 N, and the compressive strength was 4.17 ± 1.18 MPa.

[0063] Test 02. Chemical / material properties The raw materials used in the manufacture of the device of the present invention are composite resins based on calcium phosphate-based bioceramics (β-tricalcium phosphate, β-TCP, or hydroxyapatite, HA in the crystalline phase). After the sintering process, only the inorganic phase (bioceramics) was obtained.

[0064] The tests carried out to ensure the quality of the raw materials used in the manufacturing process and the composition of the final product are as follows.

[0065] Trace elements: For the selected quantitative analysis, a highly sensitive and indicated method was adopted to determine the limit values of specific trace elements, namely arsenic (As), cadmium (Cd), mercury (Hg), lead (Pb) and the total of heavy metals. In the analyzed samples, all of the quantified analytes showed results lower than the LQ (Limit of Quantification) in both the composition of β-tricalcium phosphate and hydroxyapatite. Thus, it was concluded that the ceramic prototype in question is safe to use as a bone graft in terms of the residual quantification of trace elements (toxicity to heavy metals).

[0066] Qualitative and quantitative determination of the crystal phase: The mass fraction of the β-tricalcium phosphate phase was quantified by the Rietveld method. The three batches analyzed for the composition certified as β-tricalcium phosphate showed a composition of β-TCP > 95%. In addition, the purity of the crystal phase was evaluated by spectroscopy (FTIR) in the infrared region. On the other hand, the three batches certified as hydroxyapatite had a composition of HA > 95% and calcium oxide < 1%.

[0067] Chemical analysis and characterization of crystallinity and phase purity: In the FTIR analysis, since the identified bands were consistent with the spectra in the literature for this compound, it was confirmed that the analyzed sample was composed of β-tricalcium phosphate (β-TCP). Also, the purity of β-TCP was concluded to be appropriate because the spectra proved the absence of characteristic bands of α-type and β-type calcium pyrophosphate (i.e., 434 cm -1 , 757 cm -1 , 1210 cm -1 , 1185 cm -1 , 723 cm -1 , 454 cm -1 ).

[0068] Shape and Dimensions: In any composition, the analyzed samples showed dimensions suitable for the shape proposed in the project as samples for additive manufacturing. During the sintering process of the green pieces, combustion of the organic matter and rearrangement of the ceramic powder particles occur, and strong bonds or necks are formed at the contact points of the particles. As the contact increases, the porosity decreases significantly, and the particles approach each other, leading to shrinkage of the part. By analyzing the microscopic images of the sintered parts, it is possible to estimate the sintering stage, relative density, and grain formation profile of the parts. The analyzed samples appear 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.

[0069] Porosity: The theoretical density of β-TCP is 3.14 g / cm 3 However, the three batches of β-TCP composition had an average density of 3.61 ± 0.09 g / cm 3 and an average surface area of 0.23 ± 0.09 m 2 / g, indicating that the sintering process used in the process increases the relative density value. In addition, since mercury penetration is impossible under compression of 0 - 5000 PSI, pores smaller than 51 μm cannot be measured, and it was demonstrated that this block does not have a significant number of intrinsic pores between 51 μm and 0.02 μm. The average density of the three-layer samples printed with the hydroxyapatite composition was 3.3745 ± 0.03037 g / cm 3 and the average surface area was 0.1345 ± 0.0820 m 2 / g. The average porosity by mercury intrusion was 11.06 ± 2.58% and the average diameter was 0.56 μm. These data demonstrate the reproducibility and reliability of the manufacturing process in the post-treatment stage.

[0070] Properties of the graft structure such as porosity, interconnectivity, pore diameter, permeability, and pore shape are widely known to affect bone formation in vivo. In the analyzed specimens, the porosity and the diameter of the interconnectivity were estimated by mercury intrusion. The calculated value of the total porosity (micropores) was 28.66% and the permeability was 0.026 (cm 3 / g), the measured values of 80% of the interconnected pores were 5.47 - 0.39 μm (porosity), and the average pore diameter was 0.70 μm. To calculate the porosity, the actual density (3.213 ± 0.022 g / cm 3 ) was measured by helium gas pycnometry. Furthermore, the average surface area (0.243 ± 0.2 m 2 / g) was measured using the BET method (the initials of researchers Brunauer, Emmett, and Teller).

[0071] The porosity of 28.66% is similar to the porosity reported in other studies using printed β-TCP specimens with 400-μm pores in the filling structure. However, changing the filling shape and the size of the unit cell may cause significant variations in the porosity. Therefore, the complex shapes of these samples (gyroid with macropores: theoretical value φ400 μm, measured value 404 ± 0.0238 μm) add characteristics of the microstructure determined by these analyses and exhibit an essential porosity with interconnected micropores that promote fluid adsorption, adhesion, and cell growth, and it was concluded that this microstructure makes an excellent factor for the cytoskeleton.

[0072] Dissolution and pH change: For both compositions, the pH of the TRIS-HCl buffer did not change by more than 0.2 from the initial value during the assay. As a result of analyzing the calcium content in the solution by ICP-OES, the calcium ion concentration gradually increased during the analysis period. The mass loss was not large enough to be quantified (<LQ 0.1%) (LQ: Limit of Quantification).

[0073] In this way, these assays ensure the compatibility of the product regarding pH changes during implantation. This is because if the pH changes significantly after implantation, the inflammatory reaction may worsen, and the regeneration process and tissue formation may be inhibited. In addition, a biomaterial for bone filling / implantation is preferably decomposed at a rate close to the formation of new bone tissue. The degradation of the material is mainly governed by its chemical composition and physical properties, and the higher the Ca / P molar ratio, the lower the solubility of the material.

[0074] Test 03. Cytotoxicity Assay The cytotoxicity of the test substance is determined by the proportion of cells that continue to survive after exposing a given cell population to the concentration of the test substance extract.

[0075] Under the test conditions, the device of the present invention did not promote a significant decrease (>30%) in cell viability in any of the test groups and showed a cell viability of 96%. Therefore, the test article (β-TCP, ≥95%) has no cytotoxicity. Under the same test conditions, the test article (HA ≥95%) did not reduce the cell viability.

[0076] Test 04. Genotoxicity Test The micronucleus test aims to detect chromosomal changes during cell division and evaluate the genotoxic potential of substances. Under the test conditions, the device samples of the present invention did not show genotoxic (mutagenic) effects in short-term treatment and continuous treatment, regardless of the presence or absence of metabolic activation. Therefore, under the described conditions, both compositions (hydroxyapatite and β-TCP) were considered non-mutagenic.

[0077] Test 05. Maximal Percutaneous Sensitization The maximization percutaneous sensitization assay consists of analyzing the ability of a substance to cause an immunologically mediated skin reaction (characterized by the appearance of edema and erythema). The maximization method uses an adjuvant (Freund's complete adjuvant - FCA) that can stimulate the immune response to increase the sensitivity of the method. The LLNA (Local Lymph Node Assay) method evaluates the potential for skin sensitization in rodents.

[0078] Under the test conditions, the test articles of both compositions (hydroxyapatite and β-TCP) were classified as non-sensitizing.

[0079] Test 06. Intracutaneous Reactivity The intradermal reactivity test consists of the evaluation of local adverse effects that occur after percutaneous inoculation of a substance in a single dose. Under the test conditions, the test articles of both compositions (hydroxyapatite and β-TCP) did not induce intradermal reactivity in rabbits.

[0080] Test 07. Acute systemic toxicity The acute systemic toxicity test is an evaluation of the potential health risks and adverse effects that may be caused by a single exposure to a substance. These tests provide information on systemic toxic effects and form the basis for estimating the safety of a substance. Under the conditions of this test, the test articles of both compositions (hydroxyapatite and β-TCP) meet the requirement of having no acute systemic toxicity.

[0081] Test 08. Subchronic toxicity The subchronic toxicity test evaluates the potential toxicity and systemic effects that may result from the implantation (transplantation) of a material in an animal species. In this sense, this test aimed to evaluate the potential toxicity and systemic effects that may occur as a result of exposing rabbits to the bone implants of the test articles for 90 days. Under the conditions of this test, for both compositions (hydroxyapatite and β-TCP), no systemic or toxic signs were confirmed in daily clinical evaluations, body weight changes, weekly feed consumption, ophthalmological examinations, and biochemical, hematological, and anatomopathological measurements related to the subchronic (90-day) systemic exposure of the test articles to the implants. Thus, the test articles can be classified as non-toxic.

[0082] Test 09. Chronic toxicity The chronic systemic toxicity test evaluates the potential toxicity and systemic effects resulting from the implantation of materials in animal species. In this sense, this test aimed to evaluate the potential toxicity and systemic effects that could result from exposing rabbits to the bone implant of the test article for 180 days. Under the conditions of this test, no systemic or toxic signs were confirmed in daily clinical evaluations, weight changes, weekly feed consumption, ophthalmological examinations, and biochemical, hematological, and anatomopathological measurements related to the chronic systemic exposure (180 days) of the test article to the implant. Thus, the test article (both composed of hydroxyapatite and β-TCP) can be classified as non-toxic.

[0083] Test 10. Tests in Animal Models The bone implant assay evaluates the local effects after the implantation of materials in animal species. In this sense, this test aimed to characterize the history and evolution of the tissue reaction after the implantation of the medical device and to evaluate its biological safety and clinical performance similar to the intended use. Under the conditions of this test, no local or toxic signs were confirmed in the anatomopathological evaluation related to the chronic systemic exposure (26 weeks) due to the implantation of the test article. Summarizing the results obtained in this test, it is suggested that the test article (both composed of hydroxyapatite and β-TCP) has non-irritating properties.

[0084] Test 11. Tests of Embodiments of the Invention Containing Mesenchymal Stem Cells The integration of mesenchymal stem cells (MSCs) in the ceramic block was analyzed by electron microscopy together with the osteogenic differentiation ability. For this purpose, the cells were plated in duplicate at a density of 106 cells on the scaffold, and one of the samples was induced for osteogenic differentiation.

[0085] The structure of the ceramic block showed a strong tropism towards the cells such that the cells substantially covered the entire structure, and morphological changes suggesting calcification points were observed in the samples exposed to the osteogenic differentiation medium (Figs. 5 and 6).

[0086] Test 12. Clinical Research Block Bone Graft Title: Use of the Invention Compared to Autologous Block Grafting to Increase the Thickness of Atrophic Maxilla. Randomized Incision Clinical Research

[0087] Objective: The objective of this study is to evaluate the safety and efficacy of bone neoformation in the maxillary anterior region by comparing the use of the Invention with the use of autologous block grafting.

[0088] Methods - All participants underwent cone beam computed tomography (CT) (CBCT) before surgery. - The computed tomography files were sent together with information on which side of the maxilla to use the personalized block graft. From this file, a drawing of the customized block for the test group (virtual planning) was created with specific software, and then the customized block was created by additive manufacturing with a 3D printer suitable for ceramic printing. The customized piece (the Invention) was manufactured using lithography-based ceramic manufacturing (LCM) technology. In this process, a virtual piece of resin containing the desired bioceramic (slurry), in this case β-tricalcium phosphate (β-TCP), is printed. - Preparation and placement of autologous grafts - Placement of the Invention - Postoperatively - Biopsy: Eight months after bone grafting, the participants underwent new examinations. - Analysis: Bone resorption was calculated by subtracting the results eight months later from the immediate results. The resorption rate (% resorption) was calculated using the amount of resorption relative to the initial volume. - The CT scan images were compared immediately after placement of the graft (immediate) and eight months after the repair / regeneration period.

[0089] Results For 15 patients, the bone mass at the time of insertion (immediately after surgery) and 8 months after surgery (8 months postoperatively) was evaluated for autologous bone and the present invention. The results are shown in the following table.

[0090] Table 1 Results of bone mass and absorption of autologous bone and the present invention at the time of insertion (postoperative immediately, PO) and 8 months after surgery (8 months postoperatively)

[0091] Explanation The results of statistical analysis are shown in Tables 1 and 2. According to the results, there is no difference in the immediate volume and the volume after 8 months, but it was shown that the absorption rate after 8 months is 8.8 points lower for the present invention than for autologous bone. Therefore, from the perspective of volume maintenance, the present invention is superior to autologous bone (p < 0.05). Table 1 Comparison results of bone mass using ANOVA test by repeated measurement

[0092]

Table 2

[0093]

Table 3

[0094] Result: From the perspective of volume maintenance, it was shown that the present invention is superior to autologous bone.

[0095] Test 13. Macropore - Scanning Electron Microscopy The diameters of micropores and macropores are specified by measurement from a micrograph of a cross - section of the material obtained by SEM (scanning electron microscope). At the places where the pores are in contact with each other, a virtual boundary must be set between the pores.

[0096] Due to the technology of the manufacturing process, it is possible to manufacture a complex porous structure, so the same filling structure was applied to the samples used in the present invention. This sample is a gyroid with a unit cell of 2.4 mm, and as a result, macropores with a theoretical diameter of 400 μm were formed.

[0097] Figure 9 is a microscopic photograph of the sample body taken at a magnification of 25 times. From this figure, the average diameter of the macropores was determined using the software ImageJ (Wayne Rasband and the provider National Institutes of Health, USA).

[0098] The calculated average diameter of 404 ± 0.0238 μm is consistent with the theoretical diameter of 400 μm of the pores existing in the gyroide structure (Figure 4). The size of the macropores of the gyroide was designed for bone conduction. This is because in order to increase bone formation, the pores of the structure of the 3D printed ceramic implant must be larger than 300 μm, and the upper limit is 500 μm as shown by the results.

[0099] It was possible to measure the diameter of the macropores existing in the complex structure (having a gyroide structure) from the images generated by the scanning electron microscope (SEM) technique. As a result, the average macropore diameter of the sample (φ8 mm × 2.3 mm) was 404 ± 0.0238 μm, which was a value supporting the theoretical diameter of 400 μm predicted by CAD.

[0100] Test 14. Micropores - Scanning Electron Microscope (SEM) Figure 10 shows images of the sample body at different magnifications.

[0101] The micropores (fine pores) were measured on the surface of the sample body, and the average value was 0.69 μm, and were measured in the cross section (inside the sample), and the average value was 0.61 μm. In the mercury intrusion porosimetry test, the average pore diameter of the whole piece was 0.70 μm, which supported the results obtained by SEM.

[0102] The printed and sintered sample to be analyzed showed a shape according to the design (STL) submitted for additive manufacturing. Surface cracks were confirmed in the image. The cracks did not divide or completely cross the piece, but the interior was also observed in the image of the cross-section that cut the piece. In addition to the analysis of the surface and obvious pores (macropores), measuring the average diameter of the micropores was also one of the assay objectives. For this purpose, the pores on the surface and cross-section (interior) of the sample were measurable, and the average values were 0.69 μm and 0.61 μm, respectively.

[0103] B. The following tests referred to embodiments of the present invention that are pre-set shapes. Test 01. Mechanical properties Tests were conducted to confirm the effectiveness and safety of the product considering mechanical stress. The compressive strength property ensures that the product can be drilled and fixed with screws without causing unintended failure (failure mode). The compressive strength calculated considering the area of the gyroide structure in the cross-section was 18.83 ± 1.51 MPa, and this value is higher than the mechanical strength values of equivalent ceramic blocks that have already been commercialized.

[0104] Test 02. Chemical property evaluation of materials (raw materials) The raw material used in the production of the present invention is a resin based on calcium phosphate-based bioceramics (crystalline phase β-tricalcium phosphate), and only the inorganic phase β-tricalcium phosphate (β-TCP) is obtained after the sintering process. The tests conducted to ensure the quality of the raw material are as follows. Trace elements: All the quantified elements showed results below the specified limit values. Qualitative and quantitative determination of the crystal phase: It was concluded that the mass fraction of the quantified β-tricalcium phosphate phase conforms to the specified limit values. Porosity: The gyro structure with complex shapes and macro pores of φ404 ± 0.0238 μm shows essential porosity due to the presence of interconnected micropores that promote liquid adsorption, adhesion, and cell growth in addition to the characteristics of the microstructures determined by these analyses. The combination of this macrostructure and microstructure (fine structure) was concluded to be an excellent factor for the cell framework. Dissolution and pH change: According to the results, it was shown that the concentration of calcium ions gradually increased during the analysis period. Thus, these tests ensure the compatibility of the product regarding pH changes during transplantation. This is because if the pH changes significantly after transplantation, the inflammatory reaction may worsen, and the regeneration process and tissue formation may be inhibited. Biological compatibility: As a result of the characteristic tests, the present invention was shown to be safe without direct and indirect harmful effects related to comparable products in terms of raw material / chemical composition. Dissolution and pH change: Within specifications Cytotoxicity: Non-cytotoxic product Genotoxicity: Non-genotoxic product Skin sensitization - LLNA: Sensitizing product Intracutaneous reactivity: Non-irritating product Acute systemic toxicity: The product does not induce acute toxicity. Bioburden: The average microbial burden detected in three different batches was less than 1 CFU / unit, indicating a low possibility of a fever reaction due to substances of Gram-positive bacteria and fungi. Bacterial endotoxin (clot gel): Within the limits set by the FDA for medical devices Subchronic systemic toxicity: Non-toxic product Chronic systemic toxicity: Non-toxic product Transplantation (90 days): Non-irritating product Transplantation (180 days in rabbits): Non-irritating product

[0105] C. Tests of the embodiments of the present invention containing graphene The compositions of the present invention containing graphene in amounts of 0.01% and 0.005% were tested from the viewpoint of verifying the properties as viscosity and shear rate. Several samples were prepared from the compositions as shown in FIG. 7. The compositions tested were as follows.

[0106]

Table 4

[0107] As can be seen from FIG. 8, the viscosity × shear rate curves of the resin with graphene added and the resin without graphene added have the same profile and very close values, indicating that graphene does not cause a significant change in this property.

[0108] By adding graphene or other carbon structures to the composition of the medical device of the present invention, the mechanical properties of the device are improved. Also, the radiopacity of the device is increased, which is useful for visualizing the graft in imaging examinations, as can be confirmed from FIG. 13.

[0109] Test on the embodiment of the present invention including D.PDO film Evaluation of the bioactivity of the medical device of the present invention having a PDO film using cell-based tissue engineering for bone regeneration induction in severe cervical bone defects in rats Method: Male rats were divided into the following 3 groups: (1) Medical device (β-tricalcium phosphate) + PDO film, (2) Medical device + PDO film containing stem cells (β-tricalcium phosphate + adipose-derived stem cells (ASCs)), (3) Medical device + PDO film equipped with stem cells (β-tricalcium phosphate + adipose-derived stem cells (ASCs)) (including stem cells).

[0110] A surgical defect was created in the right parietal bone and the defect was filled with the above grafts. The animals were euthanized 7, 14, and 30 days after the surgical procedure for histomorphometric and immunolabeling analysis.

[0111] Results Cell-based treatment promoted bone area formation at the defect border and in the defect center, especially in group 3.

[0112] Conclusion: The combination of a medical device and a PDO membrane and the combined use of cell-based therapy have excellent potential to improve and promote bone regeneration induction. Furthermore, by using ASCs, even when the printed scaffold is absorbed, the bone induction ability and bone formation ability are improved, and the bioceramic is optimized.

[0113] At the end of the experiment, 30 days after the surgical procedure, in Group 1, bone tissue formation is present in the defect boundary region, but there is still significantly present connective tissue, which migrates into the defect where the biomaterial has been widely absorbed. In Group 2, the scaffold is substantially absorbed, and its interior is filled with highly vascularized connective tissue. Large bone tissue is formed at the defect boundary and also migrates to the central part of the defect. In Group 3, large bone tissue is formed at the defect boundary, migrates to the central part, and there are voids filled with osteocytes characterizing the organization and maturation of bone. The presence of highly organized connective tissue containing bone formation progenitor cells spreads to the central region replacing the highly absorbed scaffold.

[0114] Table 3 Proportion of areas of bone, connective tissue, and biomaterial in Group 1 at 7, 14, and 30 days

[0115]

Table 5

[0116] Table 4 Proportion of areas of bone, connective tissue, and biomaterial in Group 2 at 7, 14, and 30 days

[0117]

Table 6

[0118] Table 5 Proportion of areas of bone, connective tissue, and biomaterial in Group 3 at 7, 14, and 30 days

[0119]

Table 7

[0120] Table 6 Scores of immunolabeling analysis of TCP / PG (Group 1), TCPasc / PG (Group 2), and TCPasc / PGasc (Group 3). Antibodies against IL-6, OPN, and OCN

[0121]

Table 8

[0122] Manufacturing method of the present invention The process of manufacturing (preparing) the present invention generally includes the following steps. A. Patient-specific medical device a) The customer requests a customized product, a patient-specific model. b) Transmission of image examination (.DICOM) c) Processing of DICOM d) Planning and virtual modeling of patient-specific bone grafts e) Approval of the planned / modeled product by the customer (physician or dentist) f) Generation of.STL for printing

[0123] B. Medical device with a predefined shape a) Technical drawings of standard models (blocks, wedges, and cylinders) b) STL is prepared and already approved by the project team and the technical responsible person in an archive c) Customization of the graft (device with a fixed shape) and application to the recipient bed · Use drills for straight pieces and sterilized surgical / orthopedic disks to customize the graft according to the anatomical structure of the receiving bed (e.g., 702 drill, maxicut line model, diamond blade) · To avoid perforating the flap, leave no sharp edges or corners and apply appropriate finishing · Level all sides of the graft with respect to the bone defect and fit the block into the receiving bed without leaving a step

[0124] Furthermore, after the above steps, the following are performed - Primary and secondary assembly - Gamma ray irradiation sterilization - Inspection - Outer packaging assembly - Labeling and storage (inventory management)

[0125] Brief description of the steps of the manufacturing method The manufacturing method of the present invention is shown in FIG. 11 and will be described below

[0126] Virtual planning: Virtual planning (virtual plan) of the model of the patient-specific medical device is carried out by the project's technical team for the modeling of the planning proposed and approved by the client. From the examination of the patient's images (e.g., computed tomography, DICOM file), planning and modeling of the patient-specific product are performed using CAD software. When the planning is completed, a planning report is sent for the approval of the client (dentist or doctor). After approval, a file in STL format (binary encoding) is imported by the printing manufacturing software, where the parameters related to the raw material are added and sent to the printer via wireless connection or cable

[0127] The automatic dispenser serves to supply the raw material (a ceramic-based resin having a β-TCP crystal phase) to the tank during printing and maintains the required thickness for each layer to be photocured (printed) without intervening during the printing process. In this way, the manufacturing processes of both families are the same by additive manufacturing using the same raw material as in the lithography-based ceramic manufacturing (LCM) technology.

[0128] Post-treatment: After printing is completed, the parts are removed from the printing table and washed with an organic solvent to remove excess uncured resin from the surface. Then, to ensure the cleanliness of the internal porous structure, the parts are immersed in a solvent and subjected to a heated ultrasonic bath. After the external and internal cleaning processes, the excess solvent is removed with compressed air and the parts are stored in a drying oven for 24 hours. After the drying process, the employee places the manufactured parts (which are specified as special or standard according to the manufacturing order) on an alumina plate and selects a sintering program in an automatic muffle furnace equipped with an exhaust device and a catalyst. By heat treatment (sintering), the combustion of organic substances and the sintering of ceramic particles are reliably carried out at 1200°C.

[0129] Although examples of preferred embodiments of the present invention have been described, the scope of the present invention is limited only by the content of the appended claims and is understood to include other possible variations of the described inventive concept, including equivalents that may be included therein.

Claims

1. In particular, it is a medical device used as a synthetic bone graft, The aforementioned medical device is - Contains a synthetic bioceramic consisting of β-tricalcium phosphate or hydroxyapatite, - Manufactured using additive manufacturing, - It is porous, and its porosity is planned and distributed as needed. - Personalized shape or predefined shape A medical device characterized by the following features.

2. In the medical device described in claim 1, The medical device includes carbon nanostructures (graphene, graphene oxide, reduced graphene oxide, carbon nanotubes, etc.). A medical device characterized by the following features.

3. In the medical device according to claim 2, The medical device contains graphene at a concentration of 0.001% to 0.01%. A medical device characterized by the following features.

4. In the medical device described in claim 1, The medical device has the following structure Table 1 A medical device characterized by the following features.

5. In the medical device described in claim 1, The medical device has stem cells A medical device characterized by the following features.

6. In the medical device according to claim 5, The aforementioned stem cells are autologous adult mesenchymal stem cells obtained from a patient's skin punch. A medical device characterized by the following features.

7. In the medical device described in claim 1, The synthetic bioceramic consists of β-tricalcium phosphate (more than 95% of β-TCP) or hydroxyapatite (more than 95% of HA). A medical device characterized by the following features.

8. In the medical device described in claim 1, The medical device is a patient-specific medical device virtually planned and constructed based on data acquired by computed tomography or magnetic resonance imaging using a virtual 3D model and CAD / CAM technology. A medical device characterized by the following features.

9. In the medical device described in claim 1, The aforementioned medical device is a medical device with a predefined shape that is to be subsequently customized by a surgeon. A medical device characterized by the following features.

10. In the medical device described in claim 1, The medical device includes an internal filler. A medical device characterized by the following features.

11. In the medical device according to claim 10, The internal filler has a gyroid shape. A medical device characterized by the following features.

12. In the medical device described in claim 1, The medical device includes a polydioxanone polymer film. A medical device characterized by the following features.

13. A method for manufacturing a medical device according to claim 1, - The process of examining patient images (e.g., computed tomography, DICOM files) using CAD software, - The process involves the plan being executed, a plan report being created, and the report being sent for approval by the client (dental surgeon). - After approval, the STL format (binary encoding) file is imported into the printing and manufacturing software, parameters related to the raw materials are added, and the data is sent to the printer via wireless or cable connection. - The process by which the medical device is manufactured by additive manufacturing and A manufacturing method characterized by including the following.

14. A method for manufacturing a medical device according to claim 1, The aforementioned manufacturing method is a. Technical drawings of the standard model (block, wedge, and cylinder), b. Archives that are ready for STL and have already been approved by the project team and technical lead, c. The process of customizing the graft to match the anatomical structure of the receiving bed using a straight piece drill and a sterile surgical / prosthetic disc, d. A process to properly finish the flap, ensuring that no sharp edges or corners are left, in order to avoid perforation. e. The process of making all sides of the graft horizontal to the bone defect and fitting the block to the receiving bed without leaving any steps. A manufacturing method characterized by including the following.

15. A method for inserting a medical device according to any one of claims 1 to 12, The aforementioned insertion method is, a. Initial site evaluation (clinical defect), b. The process of removing tissue to expose the surgical bed, c. A step of confirming the suitability of the device of the present invention by using a polymer guide (bone graft analog, which is also manufactured by additive manufacturing) in advance, d. A step of perforating the operating bed in order to enable blood perfusion and nutrient supply to the device, e. The step of fitting the device according to any one of claims 1 to 5 to a surgical bed and stabilizing it with screws. An insertion method characterized by comprising the following:

16. In a method of using a medical device according to any one of claims 1 to 12, The medical device functions as a bone graft for both volume augmentation / reconstruction and space maintenance of defects in the craniofacial region, neurocranium, long bones, and spine, and is gradually replaced by newly formed bone. A method for using a medical device characterized by the following features.

17. In the method of use described in claim 16, The medical device is used for bone reconstruction for horizontal and / or vertical augmentation, filling of intraosseous defects; traumatology and bone reconstruction for horizontal and / or vertical augmentation; filling of intraosseous defects. A method of use characterized by the above.

18. In the method of use described in claim 13 or 14, The medical device functions as a bone graft for both volume augmentation / reconstruction and space maintenance of defects in the craniofacial region, neurocranium, long bones, and spine, and is gradually replaced by newly formed bone. A method of use characterized by the above.

19. In the method of use described in claim 18, The medical device is used for bone reconstruction for horizontal and / or vertical augmentation, filling of intraosseous defects; traumatology and bone reconstruction for horizontal and / or vertical augmentation; filling of intraosseous defects. A method of use characterized by the above.

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