ES2697701B2 - ANDAMIO THREE-DIMENSIONAL DESIGN METHOD AND / OR IMPLANT WITH INTERCONNECTED MACROPOROSITY FOR OSEOS FABRIC ENGINEERING - Google Patents

Description

ANDAMIO THREE-DIMENSIONAL DESIGN METHOD AND / OR IMPLANTING WITH

INTERCONNECTED MACROPOROSITY FOR FABRIC ENGINEERING

BONES

DESCRIPTION

Object of the invention.

The present invention describes the method of computer-assisted three-dimensional design of a scaffold and / or implant for large-area bone engineering with interconnected and defined macroporosity from the creation of multiple cylinders of variable thickness (ie Trabecular Thickness; Tb.Th ) whose direction is defined from two random points selected on the internal surface of the volumetric shape of the bone defect to be replaced.

The preferred purpose of scaffolding and / or implant is its application as a bioimplant for bone stabilization and / or regeneration from its manufacture by three-dimensional (3D) printing with biocompatible materials prior to three-dimensional reconstruction of the defect.

Field of application of the invention.

This invention is applicable in the field dedicated to the manufacture of biocompatible and / or biodegradable and / or bioactive scaffolds and implants for the stabilization and regeneration of bone tissue. More specifically, the invention relates to the computer-assisted design (ie Computer Assisted Design; CAD) of a scaffolding and / or macroporous implant for printing with rapid prototyping techniques in applications that require high specific surface area and variable combination of porosity with the aim of improving cell penetration, adhesion and growth, nutrient flow and vascularization.

State of the art

Bone is the second most transplanted tissue in the world. Population aging, tumors, congenital or degenerative defects and osteoporosis are the first causes of fractures and bone defects. In the last decades Autografts (autotransplantation) and allografts (donor) have been used in bone repair. However, pain, infection, immune rejection and other associated pathologies cause an increasing interest in the development of artificial bone with mimetic microstructure to 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 scaffolding or support for its three-dimensional (3D) regeneration. Therefore, 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 your search you should select not only the most suitable biomaterial but also the architecture or structure of the scaffold that favor the requirements of support and mass transport The interest is remarkable as indicated by the exponential increase in the number of publications dedicated to the design and manufacture of bone scaffolding in Tissue Engineering in the last decade More than 5,000 publications and 100,000 citations in this area In the last 20 years, it justifies the importance of the issue (database website: Sc ience, 2012, Thomson Reuters).

Recent advances in the design and manufacture of scaffolds in Bone Tissue Engineering (ie Bone Tissue Engineering ; BTE) have tried to improve the mechanical properties and flow properties through it in order to completely mimic the 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 scaffolding in BTE. The ultimate goal is to develop bioactive and biomimetic artificial scaffolds that are not recognized as a foreign body, perform their initial lift function and are resorbed in a controlled manner facilitating osteogenic activity.

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 spongy trabecular bone, mass transport properties, mechanical properties and the biomaterial itself. In the three-dimensional design of the structure, the size and shape of the pores, interconnections, trabecular separation (Tb.Sp) and trabecular thickness must be taken into account (Tb.Th), not only because of the mechanical properties, but also to facilitate the penetration of the cells in the scaffold, their adhesion and the ease to the flow of nutrients through it, as well as neovascularization. The properties described for scaffolds must be maintained during the process of resorption or biodegradability of the same until its complete replacement by the new formation of bone tissue. Some of the properties required of porous scaffolds are:

Biocompatibility : Ability to perform its function in host tissue without causing any immune response.

Biodegradability : The rate of degradation of the scaffold must coincide with the growth of the new bone tissue during its replacement.

Mechanical properties : Mechanical strength sufficient to provide temporary support and resist load forces in vivo. Elastic modulus (300-500 MPa) and resistance (5-10 MPa) similar to trabecular bone.

Microarchitecture : Variable and interconnected porosity structures in order to distribute tensions evenly and facilitate the flow of cells and nutrients. Osteoinductivity : Promote the fixation of specific and forming cells of bone tissue.

Porosity : Volume and size of the pores to allow tissue growth, neovascularization, mass transport and osteogenesis. A porosity greater than 75% is desirable. The macroporosity of between 200 and 400 microns to facilitate the union of cells on the tissue. Open and interconnected porosity facilitates the colonization of scaffolding by cells, the diffusion of essential nutrients and oxygen for cell survival and waste products.

Surface properties: Appropriate topographic and chemical properties to promote cell adhesion, proliferation and differentiation.

All the properties described depend directly or indirectly on the three-dimensional design of the porous scaffold in relation to the porosity, specific surface area of the scaffold, shape and size of the pores, trabeculae and trabecular junctions, among others.

The technologies used to manufacture this type of scaffolding are multiple and varied. Solid Free Form (SFF) technology, also known as Rapid Prototyping (ie 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, scaffolding can be constructed from different additive manufacturing techniques with biocompatible and bioresorbable material. Scaffolds are printed layer by layer from the export of STL files ( STereoLitography files). Printing can be done by different procedures: thermal, chemical, mechanical or optical. Some of them are: Melt Extrusion or molten 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 have higher resolutions. Stereolithography is one of the oldest and most accurate technologies of additive manufacturing techniques (ie Additive Manufacturing; AM).

Currently, Computer Aided Design (CAD) programs have been used to model simple 3D scaffolding geometries from the combination of standard solids or primitives (cylinders, spheres, cubes, etc.) with Boolean joining, subtraction and intersection. Additionally, multiple copy operations have been used as 3D matrices in the three-dimensional definition of porous scaffolds for 3D printing.

Other three-dimensional structures or 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.

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.

Finally, the combination of the new CAD tools, Computed Tomography (CT) and micro-Tomography (pCT) can create biomimetic scaffolds with an irregular structure identical to trabecular bone tissue. However, such a microstructure requires expensive equipment and, in most of the cases, such detailed reproduction is not necessary.

At the patent level, US 2012/0321878 A1, describes a scaffold model with porous structure designed three-dimensionally following a different procedure to those described above. The scaffolding is designed from the creation of Voronoi regions in the form of polyhedra where the trabeculae, which can have different section and size, are generated from three-dimensional scanning operations with constant section along the edges that define the Voronoi polyhedra. The pore shape is obtained as the space not occupied by the trabeculae generated in the operation. This type of structural design does not finish mimicking the anisotropic architecture of the natural trabecular bone because of the way in which the trabeculae, trabecular junctions, pores and their connectivity are presented.

The proposed invention describes a new computer-aided design method 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 softened connectivities. The invention describes the methodology necessary to obtain models with variable and interconnected porosity from the parametric thickness modification (Tb.Th) and trabecular separation (Tb.Sp) in order to design porous models with a less dense core and a more compact exterior. Three-dimensional models of designed scaffolding are characterized by having a high relationship between their surface and total volume (BS / TV) and can be exported for manufacturing using additive techniques (AM) in various biomaterials.

Description of the invention

The present invention describes the computer-aided design method to obtain the three-dimensional (3D) model of a scaffold and / or implant that can be manufactured in any material with current rapid prototyping techniques. The scaffolding and / or implant, designed with variable and interconnected porosity where the trabeculae and trabecular separation vary according to their needs and Connectivities are rounded. The scaffolding and / or defined implant takes the form of the bone defect to be replaced, but it is not limited only to this type of adaptation, made evident to any person skilled in the art.

In more detail, the method of the present invention comprises the following steps:

1. Obtaining random points on the surface of the bone defect to be filled.

The definition of a volume by means of computer-aided design (CAD) techniques or the reconstruction of the defect to be replaced from medical micro-tomography (pCT), magnetic resonance imaging (MRI) or similar images, allows to randomly position a variable number of points on it (see Figure 1). The division of the points into two groups and the creation of random lines between the points of each of the groups defines a network of crossed lines.

2. Definition of trabecular width.

The definition of a solid cylinder of variable radius for each of the lines created allows defining the macroporous scaffold of high surface area 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.

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 extent, on the junction radius 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, an aspect that would facilitate cell adhesion.

The three-dimensional modeling procedure of scaffolds and / or implants described allows filling any type of 3D geometry or volume with different percentage of porosity with the macroporous pattern.

In the example of Figure 1 a volumetric model of a cylinder has been taken on which random points and connecting lines between them have been defined to create the trabeculae of Figure 2.

3. Scaffolding design with variable porosity.

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 tensions in that direction. The relative density of the bone and the porosity depend on the magnitude of the load distribution. The proposed design methodology allows defining a structure with variable porosity (1-BV / TV) in different volumetric regions, with its trabeculae being perfectly connected between the different regions. An example is shown in Figure 3 where two regions with different porosity are presented because they are defined by different number of trabeculae forming lines. To define 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.

Description of the figures.

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 is attached to the present specification in which, for illustrative and non-limiting purposes, the following has been represented:

- Figure 1.A shows a cylindrical volume on whose internal surface (1) a certain number of points (2) have been located randomly. The points, also randomly, are separated into two groups. In Figure 1.B. random junctions (3) formed from the union of said points are represented.

- Figure 2 shows a macroporous scaffolding after forming the cylinders (4) on each of the lines created above. The binding radius is observed at the intersections of the cylinders and the resulting interconnected macroporosity (5).

- Figure 3 is an example similar to that of Figure 1, but that would allow the construction of a scaffolding model with defined porosity defined in two or more different, contiguous and continuous volumes of interest (VOI).

- Figure 4 shows different macroporous scaffolds generated from a number of different surface points (25, 50, 75, 100 and 125) on a cylindrical volume.

- Figure 5 shows the variation of the radius of union between the generated trabeculae.

- Figure 6 shows the macroporous models encapsulated in a tube in order to improve their mechanical properties.

- Figure 7 shows scaffolding models made on a cylindrical volume of 10 mm diameter and 8 mm height with 200, 400, 600, 800 and 1000 0.2 mm radius generation lines. The accompanying Table shows the values of BS / BV, BS / TV, BV / TV and porosity (1-BV / TV) of each of them. The models present, from 800 lines, BS / BV and BS / TV values higher than those shown by other scaffolds used in bone tissue engineering: Schwarts Primitive, Schwarts W, Schoen's Gyroid and others.

- 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.

Preferred embodiment of the invention.

As can be seen in Figure 1, the macroporous scaffolding 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 scaffolding and / or implant.

The interior voids (5) presented by the macroporous structure obtained from the described methodology are interconnected to facilitate the penetration of the cells in the scaffolding and / or implant, their adhesion and the flow of nutrients through it. The number of trabeculae and their thickness (radius of the cylinders) can be regulated to achieve different volume fraction (BV / TV) or porosity for the volume of interest (ie Region-üf-interest; ROI) selected.

To create a macroporous scaffold and / or implant with variable porosity in different regions of the same, as illustrated in Figure 3, the described methodology allows to create different density of points on the inner surface limit 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 space interest.

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 pCT or other technologies.

Claims (6)

1. Three-dimensional design method of macroporous scaffolding and / or implant characterized in that the internal structure is generated from variable radius cylinders following the direction defined by lines established between two random points previously created randomly on the internal boundary surface and / or additionally on other internal surfaces defined by interest of the defect design to be filled in previously reconstructed in three dimensions (3D) from medical images or from its 3D design. 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 more or less random numbers created on the inner boundary surface of the form to be filled and / or on other internal surfaces defined by interest of the design 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. Three-dimensional design method 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 ratio BS / TV. 4. Three-dimensional design method of macroporous scaffolding and / or implant based on the preceding claims, characterized in that the scaffolding 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. Three-dimensional design method of macroporous scaffolding and / or implant based on the preceding claims, characterized in that the scaffolding and / or implant is confined in a geometric volume in any way, regardless 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. Three-dimensional design method of macroporous scaffolding and / or implant based on the preceding claims, characterized in that the scaffolding and / or implant is manufactured with 3D printing techniques in biocompatible polymeric, ceramic and / or metallic materials.