Three-dimensional radioconjugate bone model production using hydroxyapatite

Abstract

The present invention relates to a method for the production of bone models (1) that are radioconjugates with bone, in particular a method for simulating the radiological properties of the trabecular structure. The invention provides a method for adding powdered hydroxyapatite (Ca10(PO4)6(OH)2) to the cavities of a bone model (1) corresponding to the internal volume of the bone. The radiopacity of a bone model (1) obtained according to the invention can be controlled by means of the amount of hydroxyapatite per unit area. Thanks to the inventive method, the radiopacity properties of the bone model (1) can be adjusted according to the radiological properties of the bone (anatomical or pathological) to be simulated. The production of an exemplary mandible (lower jaw bone) phantom according to the invention is also described.

Description

[0001] THREE-DIMENSIONAL RADIOCONJUGATE BONE MODEL PRODUCTION USING HYDROXYAPATITE

[0002] Technical Field

[0003] The present invention relates to a method for the production of three-dimensional phantom bone models that are radioconjugate with bone.

[0004] Prior Art

[0005] Organ and tissue phantoms are used for purposes such as testing and calibration of imaging techniques and equipment and training of healthcare personnel. A phantom of a particular tissue or organ exhibits similar characteristics to that tissue or organ under the relevant imaging technique. Phantoms can be compatible with more than one imaging and examination technique.

[0006] For bone tissue phantoms for radiologic imaging techniques, it is necessary to create a radioconjugates of the trabecular structure. For this, both cortical and spongious (trabecular) bone tissue needs to be simulated. Trabecular bone is composed of thin radiopaque plates and rods (trabeculae) surrounding numerous small pockets of radiolucent bone marrow between the layers of cortical bone. Physicians should examine the distribution, size and density of trabeculae to assess the trabecular pattern in a given area. Since changes in the density of trabeculae can be one of the early signs of pathologies, changes in radiopacity are very important in obtaining 3D phantoms.

[0007] However, difficulties are encountered in mimicking the geometry and distribution of the trabecular structure, and structures with a simplified geometry and homogeneous distribution can be obtained. Pathologic features cannot be mimicked with these structures.

[0008] Bone phantoms produced by 3D printing are usually limited by simplified geometry and homogeneous nature. Such phantoms are limited in that they represent only the average human body, not only in terms of proportion and radiation properties, but also in that they do not contain pathological features. Commercially available phantoms typically represent healthy "standard" persons. Such phantoms are composed of homogeneous materials that simulate certain tissue forms such as bone, muscle and lung. This homogeneity does not mimic the non-homogeneity of human tissues.

[0009] In addition to the homogeneity of 3D printing, another important problem is radiopacity. Polymers used as printing materials in 3D printers generally contain elements with low atomic numbers such as carbon and hydrogen. They are also radiolucent due to their low electron cloud density. For this reason, the fact that most 3D printing materials are not visible under x-rays brings with it an important limitation of use. In studies to overcome these limitations, heavy metal compounds such as barium sulfate, bismuth, etc. are generally used. Since the radiopacity of these compounds is quite high, it is also difficult to adjust the appropriate opacity.

[0010] In document US11426223B2, implants manufactured at least in part by deposition techniques are described. It is also stated that the implants may contain honeycomb, trabecular or porous parts. However, details on how to obtain a synthetic trabecular structure are not presented. It is also mentioned that radiolucency requirements can be considered during material selection and the use of a mixture of hydroxyapatite and tri-calcium phosphate.

[0011] In document WO2019094617A1, a bone tissue growing scaffold produced by deposition techniques is described. The scaffold can be produced from a mixture of hydroxyapatite, tricalcium phosphate and a light-curable polymer. The scaffold has a porous structure and its "mesh", "micro-lattice" and "biomimic" forms are exemplified in Figure-19. It is stated that the porous structure provides support to the cells and allows nutrient transfer.

[0012] In the document entitled "Stereolithographic models simulating trabecular bone and their characterization by thin-slice- and micro-CT" (Engelke K, Suss C, Kalender WA. Eur Radiol. 2001;l l(10):2026-40. doi: 10.1007 / s003300100927.), a method for the production of trabecular bone phantoms by stereolithography is described. The method utilizes hydroxyapatite doped resin. In this study, the aim was to replicate the trabecular structure instead of directly simulating the radiopacity caused by the trabecular structure, but only a structure magnified 2.5 times of the trabecular structure could be obtained. Objectives of the Invention

[0013] The purpose of the present invention is to develop a method for the production of radioconjugate phantom bone models with radiopacity heterogeneity and radiographic features that show high compatibility with bone structures.

[0014] Detailed Description of the Invention

[0015] The bone radioconjugate phantom realized to achieve the objects of the present invention is described in the attached figures.

[0016] Figure 1 The outer face of a bone model according to the invention comprising a cortex. Figure 2 The inner face of a bone model according to the invention comprising a cortex. Figure 3 The inner face of a bone model according to the invention comprising a cortex and dividers.

[0017] The parts in the figures are individually numbered and the corresponding numbers are given below.

[0018] 1. Bone model

[0019] 2. Tooth socket

[0020] 3. Divider

[0021] The inventive method, which enables the creation of a bone phantom that is a radioconjugate of bone tissue, in particular the trabecular structure, comprises the steps

[0022] - virtual creation of a bone model (1) corresponding to the bone cortex, production of the bone model (1) from a resin doped with hydroxyapatite (Caio(P04)e(OH)2) by an additive manufacturing technique, curing of the resulting structure, addition of powdered hydroxyapatite to the cavities in the inner part of the produced bone model (1) corresponding to the internal volume of the bone.

[0023] The bone model is produced in multiple parts, each corresponding to a part of the bone cortex and fitting together to form the cortex, preferably in two parts: a base part filled with powdered hydroxyapatite and a cover part covering it after the hydroxyapatite is filled. After the hydroxyapatite doped resin was obtained, the bone model (1) was produced and then cured. Hydroxyapatite powder was added to the cavities inside the cured bone model (1). Powdered hydroxyapatite does not require any further treatment after addition to the bone model (1).

[0024] Bone anatomy has diversity, variations and a wide range of radiopacities. Accordingly, the amount of hydroxyapatite per unit area is increased in direct proportion to the radiopacity and the radiopacity properties of the bone model (1) are adjusted according to the radiological properties of the bone (anatomical or pathological) to be simulated.

[0025] Hydroxyapatite is suitable for the creation of bone phantoms and implants due to its high biocompatibility, low degradation rate and chemical structure close to bone mineral. The hydroxyapatite additive ratio in the resin is selected according to the targeted radiopacity value of the inventive phantom. The hydroxyapatite content in the resin is preferably between 1 and 10% by volume. By varying this ratio, phantoms corresponding to different healthy or pathological bone samples can be obtained. As for the amount of powdered hydroxyapatite per unit area, increasing the proportion of hydroxyapatite in the resin increases the radiopacity.

[0026] With the use of hydroxyapatite as a powder, the heterogeneity of the bone tissue is ensured and its radiopacity can be changed by providing a cumulative effect by increasing or decreasing its amount. The heterogeneity of bone tissue and the random distribution of trabeculae are achieved by determining the amount and distribution of hydroxyapatite in powder form according to the properties of the tissue to be simulated.

[0027] In one embodiment of the invention, after the creation of the virtual bone model (1) and prior to the production of the bone model (1) by deposition manufacturing techniques, the step of forming dividers (3) on the bone model (1) corresponding to the inner part of the bone is also performed. In this case, the powdered hydroxyapatite added after curing settles in the spaces between the dividers (3).

[0028] The dividers (3) form abutments that prevent the powdered hydroxyapatite from collapsing. They also allow the powdered hydroxyapatite to be randomly distributed and natural gaps to form between them, effectively simulating the heterogeneity of bone tissue. The number and frequency of the dividers (3) can also be determined according to the characteristics of the tissue to be simulated. In one embodiment of the invention, a stereolithography machine and a resin curable by ultraviolet radiation are used to produce the bone model (1) by a deposition production technique. However, since the use of hydroxyapatite as a powder in the cavities of the bone model (1) can also be realized on bone models (1) produced by other three-dimensional printing techniques, the invention can also be applied with other three-dimensional printers and printing techniques (DLP, CDLP, FDM, MJ, MP J, SLS, SLM, etc...). After obtaining the hydroxyapatite doped resin, the bone model (1) was produced and then cured. Hydroxyapatite was added as powder to the cavities inside the cured bone model (1) and was not subjected to any further processing.

[0029] When hydroxyapatite is added to the resin used in bone model (1) production, it provides an increase in radi opacity in direct proportion to the amount of hydroxyapatite used. However, this increase in radiopacity has a homogeneous distribution and is limited in quantity. However, the hydroxyapatite obtained from hydroxyapatite doped resin and added in powder form to the cavities in the bone model (1) after curing allows both a higher increase in radiopacity and heterogeneous radiopacity to be obtained. Furthermore, the method of the invention is suitable for use in all three-dimensional bone models (1) obtained from three- dimensional printers as hollow.

[0030] A mandible (lower jaw bone) phantom was produced to evaluate the effectiveness of the inventive method. In the anterior region of the mandible, the trabeculae are thicker, less numerous and have a coarse-grained pattern compared to the anterior region of the maxilla. Accordingly, the bone marrow spaces are wider. In the mandibular posterior region, the trabeculae and bone marrow spaces between the roots are wider than in the mandibular anterior region. These different trabecular patterns, which vary according to the regions, lead to different radiopacities. Therefore, the mandibular bone is a suitable example for demonstrating the effectiveness of a three-dimensional phantom with a wide range of radiopacities in different regions. In this example, the heterogeneity of the trabeculae can be ensured by the method of the invention. The production of a mandibular bone phantom according to the invention is described below.

[0031] In order to ensure an exact match of the extracted teeth with the tooth sockets (2) in the bone model (1) and to visualize the periodontal ligament space (PDL), which is a radiolucent space between the tooth root and the lamina dura, a wax layer was covered around the extracted tooth roots. The tooth roots covered with a wax layer were scanned with a cone beam computed tomography (CBCT) device and 3D images were obtained in dicom format. The obtained data were uploaded to the CT AN software and a three-dimensional bone model (1) was designed that is exactly compatible with the tooth roots. A thin cortical bone model (1) was created by continuing the outer contour continuity of the bone model (1) in the tooth socket (2) to provide the appearance of the lamina dura surrounding the tooth socket (2). In order to mimic the septations in the trabecular bone, multiple dividers (3) were added on the bone model (1). The resulting bone model (1) was exported in STL file format and loaded into the 3D printer software. The SLA Formlabs 3 bone model (1) was printed with Formalabs White resin with 1-10% hydroxyapatite additive. Powdered hydroxyapatite was added between the compartments inside the bone model (1). Thus, a three-dimensional phantom jaw bone model (1) with controllable radi opacity was produced using a hydroxyapatite-doped, ultraviolet radiation-curable 3D printing resin.

[0032] The phantom obtained according to the invention is compatible for imaging with 2D (periapical radiography, panoramic radiography, etc.) and 3D imaging (computed tomography, cone beam computed tomography, magnetic resonance imaging, ultrasound, etc.).

Claims

CLAIMS1. A method for creating a bone phantom which is a radioconjugate of bone tissue comprising the steps of- virtually creating a bone model (1) corresponding to the bone cortex, - producing the bone model (1) from a resin doped with hydroxyapatite(Caio(P04)e(OH)2) by an additive manufacturing technique, curing the resulting structure characterized by further comprising the step of adding powdered hydroxyapatite to the cavities in the inner part of the produced bone model (1) corresponding to the inner volume of the bone.

2. A method according to claim 1, characterized in that it comprises the step of forming dividers (3) on the bone model (1) corresponding to the inner part of the bone, after generating the virtual bone model (1) and before producing the bone model (1) by additive manufacturing techniques.

3. A method according to claim 1 , characterized in that the proportion of hydroxyapatite in the resin is between 1 and 10% by volume.

4. A method according to claim 1, characterized in that a resin curable by ultraviolet radiation is used and the structure is cured by ultraviolet radiation.

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