• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Three-dimensional design method of scaffolding and / or implant with interconnected macroporosity for bone tissue engineering. Design of an interconnected and variable scaffold and / or implant of macroporosity defined by the creation of multiple cylinders of variable thickness (ie Trabecular Thickness; Tb.Th) whose direction is defined from two selected random points on the internal surface of the form volume of the bone defect to be replaced obtained previously from the three-dimensional reconstruction of its medical images or from its CAD design. This invention is applicable in the field dedicated to the manufacture of scaffolds and / or biocompatible and / or biodegradable and / or bioactive implants for the stabilization and / or regeneration of bone tissue with rapid prototyping techniques in applications that require the variable combination of porosity , resistance and permeability in different regions of the same in order to optimize the stability and mechanical strength of the scaffolding and / or implant, in the short and long term, as well as its flow properties or mass transport. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2697701A1
    申请号:ES201730970
    申请日:2017-07-26
    公开日:2019-01-28
    发明作者:Aguado Enrique Fernández；González Sergio Gómez
    申请人:Universitat Politecnica de Catalunya UPC；
    IPC主号:
    专利说明:

    [0001]
    [0002]
    [0003]
    [0004] Object of the invention.
    [0005]
    [0006] The present invention describes the computer-aided three-dimensional design method of a scaffold and / or implant for bone engineering of large specific surface area with interconnected macroporosity and defined from the creation of multiple cylinders of variable thickness (ie Trabecular Thickness; Tb.Th ) whose direction is defined from two selected random points on the internal surface of the volumetric form of the bone defect to be replaced.
    [0007]
    [0008] The preferred purpose of the scaffold and / or implant is its application as a bioimplant for the stabilization and / or bone regeneration from its manufacture by three-dimensional printing (3D) with biocompatible materials after three-dimensional reconstruction of the defect.
    [0009]
    [0010] Field of application of the invention.
    [0011]
    [0012] This invention is applicable in the field dedicated to the manufacture of scaffolds and / or biocompatible and / or biodegradable and / or bioactive implants for the stabilization and regeneration of bone tissue. More specifically, the invention relates to computer-aided design (ie Computer Assisted Design; CAD) of a scaffold and / or macroporous implant for printing with rapid prototyping techniques in applications requiring high surface area and the variable combination of porosity with the aim of improving the penetration, adhesion and cell growth, the flow of nutrients and vascularization.
    [0013]
    [0014] State of the art
    [0015]
    [0016] Bone is the second most transplanted tissue in the world. Population aging, tumors, congenital or degenerative defects and osteoporosis are the leading causes of bone fractures and defects. In the last decades autografts (autotransplant) and allografts (donor) have been used in bone repair. However, pain, infection, immune rejection and other associated pathologies cause a growing interest in the development of artificial bone with mimetic microstructure to the natural bone. The "scaffolding" or artificial structure used as a substitute for autografts and allografts must be able to support the growth of living tissue and act as a scaffold or support for its three-dimensional (3D) regeneration, which is why it is necessary to design and manufacture porous bone scaffolds that behave like natural bone, and are easy to produce, sterilize and store for later use as substitutes for damaged tissue In their search, not only the most suitable biomaterial must be selected, but also the architecture or structure of the scaffolding that favors the support and mass transport requirements, interest is remarkable as indicated by the exponential increase in the number of publications devoted to the design and manufacture of bone scaffolds in tissue engineering in the last decade More than 5,000 publications and 100,000 citations in this area in the last 20 years justifies the importance of the question (web of the database: Sc ience, 2012, Thomson Reuters).
    [0017]
    [0018] Recent advances in the design and manufacture of scaffolds in Bone Tissue Engineering (ie Bone Tissue Engineering , BTE) have sought to improve the mechanical properties and flow properties through them in order to completely mimic bone and copy its properties . High specific resistance, high permeability and an irregular porous arrangement with a high ratio of "bone surface" to "total volume" (ie Bone Surface to Total Volume ratio; BS / TV) are the desired properties in the design of the next generation of scaffolds in BTE. The ultimate goal is to develop bioactive and biomimetic artificial scaffolds that are not recognized as a foreign body, perform their initial support function and be resorbed in a controlled manner facilitating osteogenic activity.
    [0019]
    [0020] The main limitations in the designs of the current scaffolds are the low mechanical resistance and the lack of sufficient vascularization. For this reason, the general criteria for designing scaffolds must include an internal geometry similar to the microstructure of cancellous trabecular bone, the properties of mass transport, mechanical properties and the biomaterial itself. In the three-dimensional design of the structure, the size and shape of the pores, the interconnections, the trabecular separation (Tb.Sp) and the trabecular thickness should be taken into account. (Tb.Th), not only for the mechanical properties, but also to facilitate the penetration of the cells in the scaffolding, its adhesion and the ease of the flow of nutrients through it, as well as neovascularization. The properties described for the scaffolds must be maintained during the process of resorption or biodegradability of it until its complete replacement by the new formation of the bone tissue. Some of the properties required for porous scaffolds are:
    [0021]
    [0022] Biocompatibility : Ability to perform its function in the host tissue without causing any immune response.
    [0023] Biodegradability : The degradation rate of the scaffold must coincide with the growth of the new bone tissue during its replacement.
    [0024] Mechanical properties : Sufficient mechanical strength to provide temporary support and resist in-loading forces . Elastic module (300-500 MPa) and resistance (5-10 MPa) similar to trabecular bone.
    [0025] Microarchitecture : Structures of variable porosity and interconnected in order to distribute stresses uniformly and facilitate the flow of cells and nutrients. Osteoinductivity : Promote the fixation of specific cells and bone tissue formers.
    [0026] Porosity : Volume and size of the pores to allow tissue growth, neovascularization, mass transport and osteogenesis. Porosity greater than 75% is desirable. The macroporosity of between 200 and 400 microns to facilitate the union of cells on the tissue. The open and interconnected porosity facilitates the colonization of scaffolding by cells, the diffusion of essential nutrients and oxygen for cell survival and waste products.
    [0027] Surface properties: Appropriate topographic and chemical properties to promote cell adhesion, proliferation and differentiation.
    [0028]
    [0029] All the properties described depend directly or indirectly on the three-dimensional design of the porous scaffold in relation to the porosity, specific surface of the scaffolding, shape and size of the pores, trabeculae and trabecular junctions, among others.
    [0030]
    [0031] The technologies used to manufacture this type of scaffolding are multiple and varied. Solid Free Form (SFF) technology, also known as Rapid Prototyping ( RP), is a set of new techniques of additive manufacturing that allow to obtain irregular and interconnected 3D porous structures from three-dimensional CAD models. With these techniques, the scaffolds can be constructed from different additive manufacturing techniques with biocompatible and bioresorbable material. The scaffolds are printed layer by layer from the export of STL files ( STereoLitography files). The printing can be done by different procedures: thermal, chemical, mechanical or optical. Some of them are: Melt Extrusion or molded deposition modeling (ie Fused Deposition Modeling, FDM), stereolithography (SLA) and selective laser sintering (ie Selective Laser Sintering; SLS). In general, techniques that use optical procedures present higher resolutions. Stereolithography is one of the oldest and most accurate technologies of additive manufacturing techniques (ie Additive Manufacturing, AM).
    [0032]
    [0033] Currently, Computer Aided Design (CAD) programs have been used to model simple geometries of 3D scaffolds from the combination of solids or standard primitives (cylinders, spheres, cubes, etc.) with Boolean operations of union, subtraction and intersection. Additionally, multiple copying operations have been used as 3D arrays in the three-dimensional definition of porous scaffolds for 3D printing.
    [0034]
    [0035] Other structures or three-dimensional patterns printed in 3D and used as scaffolds in the replacement of bone defects are defined with periodic triple equations from implicit trigonometric functions ( Implicit Surface Modeling, ISM). In this way porous patterns are generated such as: Schwar's Diamond, Schoen's Gyroid and others, characterized by having a positive effect on cell migration and tissue growth.
    [0036]
    [0037] The Space Filling Curves (SFC) technology is a recent design methodology used in the construction of porous scaffolds with repetitive structure from the micro extrusion of a small diameter polymer filament. These methods allow manufacturing a repetitive pattern with different porosity in different regions.
    [0038]
    [0039] Finally, the combination of the new CAD tools, the Computed Tomography (CT) and the micro-Tomography (pCT) can create biomimetic scaffolds with an irregular structure identical to the trabecular bone tissue. However, such a microstructure requires expensive equipment and, in most cases, such detailed reproduction is not necessary.
    [0040]
    [0041] At the patent level, US 2012/0321878 A1 describes a scaffold model with a porous structure designed three-dimensionally following a procedure different from those previously described. The scaffolding is designed from the creation of Voronoi regions in the form of polyhedra where the trabeculae, which may have different section and size, are generated from three-dimensional scanning operations with constant section along the edges that define the Voronoi polyhedrons. The shape of the pore is obtained as the space not occupied by the trabeculae generated in the operation. This type of structural design does not stop mimicking the anisotropic architecture of natural trabecular bone because of the way in which the trabeculae, trabecular junctions, pores and their connectivity are presented.
    [0042]
    [0043] The proposed invention describes a new method of computer-aided design of porous scaffolds and / or implants to mimic the trabecular structure of natural bone in as much detail as possible. The macroporous scaffolds of the present invention are designed to maintain the external shape of the bone defect, adapted to the specific needs of the patient, with an anisotropic macrostructure where the trabeculae have a variable section with rounded and smoothed connectivities. The invention describes the methodology necessary to obtain models with variable and interconnected porosity from the parametric modification of the thickness (Tb.Th) and the trabecular separation (Tb.Sp) in order to design porous models with a less dense core and a more compact exterior. The three-dimensional models of designed scaffolds are characterized by having a high ratio between their surface and total volume (BS / TV) and can be exported for their manufacture by additive (AM) techniques in various biomaterials.
    [0044]
    [0045] Description of the invention.
    [0046]
    [0047] The present invention describes the method of computer-aided design to obtain the three-dimensional (3D) model of a scaffold and / or implant that can be manufactured in any material with the current techniques of rapid prototyping. The scaffold and / or implant, designed with variable and interconnected porosity where trabeculae and trabecular separation vary according to their needs and Connections are presented rounded. The scaffold and / or implant defined takes the form of the bone defect to be replaced, but is not limited to this type of adaptation, which is evident for any expert in the field.
    [0048]
    [0049] In more detail, the method of the present invention comprises the following steps:
    [0050]
    [0051] 1. Obtaining random points on the surface of the bone defect to be filled.
    [0052]
    [0053] The definition of a volume by means of computer aided design (CAD) techniques or the reconstruction of the defect to be replaced by medical images of micro-tomography (pCT), magnetic resonance (MR) or similar, allows to place at random, a variable number of points on it (see Figure 1). The division of the points in two groups and the creation of lines of random form between the points of each one of the groups defines a network of crossed lines.
    [0054]
    [0055] 2. Definition of the trabecular width.
    [0056]
    [0057] The definition of a solid cylinder of variable radius for each of the lines created allows defining the macroporous scaffold of high surface and interconnected macroporosity. To facilitate cell adhesion and improve permeability, the intersection of the cylinders is rounded in order to create a transition surface between the cylinders.
    [0058]
    [0059] The porosity depends on the number of lines defined in stage 1 and the radius of the cylinder established in stage 2 and, to a lesser degree, on the radius of union at the intersection of the cylinders. In this way, scaffolds created with a greater number of points and defined with small radio values have a higher BS / TV ratio, which would facilitate cell adhesion.
    [0060]
    [0061] The three-dimensional modeling procedure of described scaffolds and / or implants allows to fill with the macroporous pattern any type of 3D geometry or volume with different percentage of porosity.
    [0062] In the example of Figure 1 we have taken a volumetric model of a cylinder on which random points and lines of union have been defined between them to create the trabeculae of Figure 2.
    [0063]
    [0064] 3. Design of scaffolds with variable porosity.
    [0065]
    [0066] The density and shape of the trabecular bone structure depends on the tension to which the bone tissue is subjected (Wolf's Law, 1869). When the charges are equal in the three main directions, the bone tissue tends to have an equiaxial and isotropic microstructure. When the main load is defined in one of the directions, the bone structure is adapted in order to minimize stress in that direction. The relative density of the bone and the porosity depend on the magnitude of the distribution of loads. The proposed design methodology allows to define a structure with variable porosity (1-BV / TV) in different volumetric regions, with its trabeculae perfectly connected between the different regions. Figure 3 illustrates an example where two regions with different porosity are presented because they are defined by a different number of trabecular forming lines. To define the models with variable porosity it is necessary to create different volumes of interest (VOI) with different number of points on the surface and follow the procedure described in the previous section.
    [0067]
    [0068] Description of the figures.
    [0069]
    [0070] To complement the description that is being made and in order to facilitate the understanding of the characteristics of the invention, a set of drawings in which, with an illustrative and non-limiting character, the following has been represented is attached to the present specification:
    [0071]
    [0072] - Figure 1.A shows a cylindrical volume on whose internal surface (1) a determined number of points (2) have been located randomly. The points, also randomly, are separated into two groups. In Figure 1.B. the random junctions (3) formed from the junction of said points are represented.
    [0073]
    [0074] - Figure 2 shows a macroporous scaffolding after forming the cylinders (4) on each of the lines created previously. The bond radius at the intersections of the cylinders and the resulting interconnected macroporosity (5) is observed.
    [0075] - Figure 3 is an example similar to that of Figure 1, but that would allow the construction of a scaffold model with variable porosity defined in two or more volumes of interest (VOI) different, contiguous and continuous.
    [0076]
    [0077] - Figure 4 shows different macroporous scaffolds generated from a number of different points on the surface (25, 50, 75, 100 and 125) on a cylindrical volume.
    [0078]
    [0079] - Figure 5 shows the variation of the bond radius between the generated trabeculae.
    [0080]
    [0081] - Figure 6 shows the macroporous models encapsulated in a tube in order to improve their mechanical properties.
    [0082]
    [0083] - Figure 7 shows models of scaffolds made on a cylindrical volume of diameter 10 millimeters and height 8 millimeters with 200, 400, 600, 800 and 1000 radio generation lines 0.2 millimeters. In the Table, which is attached, the values of BS / BV, BS / TV, BV / TV and porosity (1-BV / TV) of each of them are shown. The models show, from 800 lines, values of BS / BV and BS / TV higher than those shown by other scaffolds used in bone tissue engineering: Schwarts Primitive, Schwarts W, Schoen's Gyroid and others.
    [0084]
    [0085] - Figure 8 shows scaffolds generated from different geometric volumes: cone (Fig. 8.A), truncated pyramid (Fig. 8.B) and sphere (Fig. 8.C). The porous model adapts to any external geometry that must be filled in being useful with biological models obtained from the reconstruction of medical images.
    [0086]
    [0087] Preferred embodiment of the invention.
    [0088]
    [0089] As can be seen in Figure 1, the macroporous scaffold and / or implant obtained by the described methodology is defined from a set of points (2), located on the inner surface of the volume to be filled (1), which are divided randomly in two groups and connected, also randomly, to create lines of union between them (3). The creation of cylinders (4) in each of the lines and the smoothing of the junction radius at the intersections defines the final structure of the macroporous scaffold and / or implant.
    [0090]
    [0091] The internal voids (5) presented by the macroporous structure obtained from the described methodology are interconnected to facilitate the penetration of the cells in the scaffold and / or implant, their adhesion and the flow of nutrients therethrough. The number of trabeculae and their thickness (radius of the cylinders) can be regulated to achieve a different volume fraction (BV / TV) or porosity for the volume of interest (ie Region-üf-interest; ROI) selected.
    [0092]
    [0093] To create a macroporous scaffold and / or implant with variable porosity in different regions thereof, as illustrated in Figure 3, the described methodology allows to create different density of points on the inner limit surface of the volume to be filled and / or on any additional internal surface defined by design interest. In this way, macroporous CAD models with variable porosity are generated between different regions that can be modulated in any direction of interest in the space.
    [0094]
    [0095] The described methodology allows to create a scaffold and / or implant adapted to the bone defect to be filled from the definition of the points on the surface of the volume designed by computer or reconstructed from medical images such as the pCT or other technologies.
    权利要求:
    Claims (6)
    [1]
    1. Three-dimensional design method of macroporous scaffolding and / or implant characterized in that the internal structure is generated from cylinders of variable radius following the direction defined by lines established between two random points previously created randomly on the internal surface limit and / or of additional form on other internal surfaces defined by interest of the design of the defect to fill previously reconstructed in three dimensions (3D) from medical images or from its 3D design.
    [2]
    2. Three-dimensional design method of macroporous scaffolding and / or implant according to claim 1, characterized in that the greater or lesser interconnected porosity is generated from the definition of greater or lesser number of random points created on the internal boundary surface of the form to be filled and / or on other internal surfaces defined by the design interest and / or the radius of the generated cylinder, thus defining the basic histomorphometric relationships (BS / BV, BS / TV, BV / TV, etc.) and, consequently, all the properties of interest (mechanical, fluidic and biological).
    [3]
    Method of three-dimensional design of macroporous scaffolding and / or implant based on claims 1 and 2, characterized in that the lines defining the intersection between the cylinders are rounded with a different type of radius in order to smooth the transitions between the surfaces and improve cell adhesion by increasing the histomorphometric relationship BS / TV.
    [4]
    4. Three-dimensional design method of macroporous scaffold and / or implant based on the previous claims, characterized in that the scaffold and / or implant is confined in a geometric volume of any form with the volume of the bone defect to be filled obtained by reconstruction of medical images or other procedures.
    [5]
    Method of three-dimensional design of macroporous scaffolding and / or implant based on the previous claims, characterized in that the scaffold and / or implant is confined in a geometric volume of any form, independently of the existence or not of any bone defect to be filled, that allows, therefore, to define all types of implants and / or support structures such as nails, screws, plates, fillings, etc.
    [6]
    6. Three-dimensional design method of macroporous scaffolding and / or implant based on the previous claims, characterized in that the scaffold and / or implant is manufactured with 3D printing techniques in biocompatible polymeric, ceramic and / or metallic materials.
    类似技术:
    公开号 | 公开日 | 专利标题
    Ma et al.2018|3D-printed bioceramic scaffolds: From bone tissue engineering to tumor therapy
    ES2578705B1|2017-08-04|Macroporous scaffolding for bone tissue engineering, three-dimensional design method and applications
    Jariwala et al.2015|3D printing of personalized artificial bone scaffolds
    Giannitelli et al.2014|Current trends in the design of scaffolds for computer-aided tissue engineering
    Cheah et al.2003|Development of a tissue engineering scaffold structure library for rapid prototyping. Part 1: investigation and classification
    Kim et al.2010|Stereolithographic bone scaffold design parameters: osteogenic differentiation and signal expression
    US7174282B2|2007-02-06|Design methodology for tissue engineering scaffolds and biomaterial implants
    Duan et al.2011|Selective laser sintering and its application in biomedical engineering
    Yang et al.2015|Novel real function based method to construct heterogeneous porous scaffolds and additive manufacturing for use in medical engineering
    CN207590799U|2018-07-10|Nose filler
    CN102143721A|2011-08-03|Customized implants for bone replacement
    Armillotta et al.2008|Modeling of porous structures for rapid prototyping of tissue engineering scaffolds
    Kwon et al.2013|Biological advantages of porous hydroxyapatite scaffold made by solid freeform fabrication for bone tissue regeneration
    Li et al.2015|Current status of additive manufacturing for tissue engineering scaffold
    Vasireddi et al.2015|Conceptual design of three-dimensional scaffolds of powder-based materials for bone tissue engineering applications
    Bahraminasab2020|Challenges on optimization of 3D-printed bone scaffolds
    De Wild et al.2019|Osteoconductive lattice microarchitecture for optimized bone regeneration
    Jiankang et al.2006|Custom fabrication of composite tibial hemi-knee joint combining CAD/CAE/CAM techniques
    ES2697701B2|2019-10-28|ANDAMIO THREE-DIMENSIONAL DESIGN METHOD AND / OR IMPLANT WITH INTERCONNECTED MACROPOROSITY FOR OSEOS FABRIC ENGINEERING
    Richard et al.2014|Direct-write assembly of 3D scaffolds using colloidal calcium phosphates inks
    Yadegari et al.2017|Specific considerations in scaffold design for oral tissue engineering
    Montero et al.2021|Main 3D manufacturing techniques for customized bone substitutes. A systematic review
    CA2916586A1|2014-12-31|Bone replacement material and method for producing bone replacement material
    CN105147423B|2017-03-22|Preparation method of tissue engineering scaffold with three-dimensional composite porous structure
    CN108420573A|2018-08-21|A kind of artificial vertebral implant of biomedical ceramics
    同族专利:
    公开号 | 公开日
    ES2697701B2|2019-10-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2011060312A2|2009-11-12|2011-05-19|Smith & Nephew, Inc.|Controlled randomized porous structures and methods for making same|
    CN102087676A|2010-12-13|2011-06-08|上海大学|Pore network model -based bionic bone scaffold designing method|
    ES2578705A1|2015-01-28|2016-07-29|Universitat Politècnica De Catalunya|Macroporous scaffold for bone tissue engineering, three-dimensional design method and applications |
    法律状态:
    2019-01-28| BA2A| Patent application published|Ref document number: 2697701 Country of ref document: ES Kind code of ref document: A1 Effective date: 20190128 |
    2019-10-28| FG2A| Definitive protection|Ref document number: 2697701 Country of ref document: ES Kind code of ref document: B2 Effective date: 20191028 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201730970A|ES2697701B2|2017-07-26|2017-07-26|ANDAMIO THREE-DIMENSIONAL DESIGN METHOD AND / OR IMPLANT WITH INTERCONNECTED MACROPOROSITY FOR OSEOS FABRIC ENGINEERING|ES201730970A| ES2697701B2|2017-07-26|2017-07-26|ANDAMIO THREE-DIMENSIONAL DESIGN METHOD AND / OR IMPLANT WITH INTERCONNECTED MACROPOROSITY FOR OSEOS FABRIC ENGINEERING|
    [返回顶部]