Surgical insert and bone cement

Abstract

The present invention relates to a surgical insert (1) comprising a first layer (11) and a second layer (12), wherein the first layer and the second layer comprise openings (111, 112) having a figure-of-eight shape. The invention also relates to a bone cement comprising a pulverulent solid phase that comprises natural polysaccharides and a ceramic filler, a liquid acrylate, and a polymerising agent.

Description

Description Title: Surgical insert and bone cement Technical field [1] The present disclosure relates to a surgical insert and a bone cement, in particular a surgical insert comprising a first layer and a second layer comprising octomorphic shaped orifices as well as a bone cement comprising a powdery solid phase comprising natural polysaccharides or polysaccharides derived from natural compounds and a ceramic filler and an acrylate in liquid phase. Prior art [2] Maxillofacial injuries are common injuries that mainly affect men and young people between 18 and 25 years old. They are mainly due to accidents on public roads, fights, accidents related to sports, and domestic accidents. [3] In maxillofacial trauma, the areas mainly affected are the teeth, the nasal bones and the orbital structure, which is affected in more than 40% of cases due to its exposed position and very thin bone thickness. A fracture of the orbital structure can have functional consequences. Thus, there may be incarceration of the muscle and / or fat surrounding the eye, causing a difference in elevation between the two eyes (diplody). It can cause compression of the infraorbital nerve (V2) which passes under the orbital structure. This compression is responsible for sensory disturbances in the areas around the eye such as the cheek, nose, teeth and upper lip. It can also lead, in the case of a significant fracture or collapse of the orbital structure, to enophthalmos, a dystropia of the eyeball.Finally, a fracture of the orbital structure can also have aesthetic repercussions when it is associated with a fracture of the orbital rim, the nose or the zygomatic body by modifying the bony reliefs of the face. [4] In cases where the fracture of the orbital frame is significant enough, it is necessary to reconstruct the orbital volume. This reconstruction must be strictly observed because complications, such as those mentioned above, may occur. In order for the eyeball to recover its normal function and positioning, the reconstruction must be precise and conform to the anatomy of the affected person's orbit, but it also requires repositioning of the intraorbital soft tissues. [5] The advent of computer-assisted surgery has enabled many advances in cases of fractures requiring complex reconstructions of bone volume. In particular, it makes it possible to generate a virtual three-dimensional patient file faithfully reproducing the patient's specific anatomical bone structure. It is thus possible to have a faithful basis for reconstruction. It is particularly suitable for reconstructions of the orbital structure, a particularly complex area of ​​the human body and very different depending on the individual. [6] The main objective of orbital structure reconstruction is to restore the shape and volume of the orbit specific to the anatomy of each patient. However, reduction of the thin bone fragments of the orbital floor is sometimes not sufficient or even impossible. It is therefore necessary to cover or fill the defect to avoid complications such as displacement of the tissues around the eye. Thus, the insertion of a biocompatible material, also called an orbital implant, is sometimes indicated depending on the size and location of the defect in order to support the tissues around the eye and to reshape the orbit. This orbital implant must, however, be adapted to the anatomy of each patient in order to function optimally. [7] Many materials with different characteristics can be used to make implants for the repair of orbital lesions. The specifications of a material used as a bone substitute include: its biocompatibility, chemical and mechanical, its osteoconductivity, the ability to allow the different cellular elements to reach the bone area to be repaired, its mechanical resistance which must be close to that of the bone and its macroporosity in order to allow the colonization of cells and the revascularization of the graft. [8] A first material used is autologous bone. Autologous bone is a bone material taken from another part of the body such as the calvarium, the cranial vault bone, the iliac crest, one of the coxal bones, or microvascularized bones in the case of extensive reconstructions. This material is useful for the reconstruction and augmentation of the contours of the orbit, in particular after the resection of a tumor by treatment with ionizing rays. However, the bone parts cannot be of real anatomical shape and there appears a reduction in bone volume by bone resorption. It is also possible to use chondrocostal cartilage. [9] A second material that can be used is based on resorbable polymer membranes. These are ideal for small defects, with a surface area of ​​less than 1 cm 2However, for larger defects, resorbable polymer membranes do not have sufficient mechanical characteristics to support and stabilize the orbital walls.

[0010] A third commonly used material is titanium and its alloys. It has been in use for about fifteen years and demonstrates excellent biocompatibility and excellent integration into the bone site. Titanium is a material with excellent corrosion resistance, a useful property given that the human body is particularly corrosive, as well as high mechanical strength. It is easily shaped, making it suitable for use in many types of implants.

[0011] Finally, a fourth material used is bioceramics. They come in the form of granules or macroporous cylinders. They adapt to the defect to be filled and offer good results in terms of bioactivity and osteoconduction. However, they have the disadvantage of having to be shaped before implantation.

[0012] A therapeutic alternative to bioceramics is bone substitutes in the form of cements. Cement is less invasive, easy to handle, and easily adapts to the volume to be treated. There are two main families of cements. The first family is phosphocalcic cements. They are mainly composed of calcium phosphate, which gives them many advantages such as biocompatibility, bioresorption properties, and bone regrowth. However, they have the disadvantage of being fragile and brittle. The second family of cements is represented by acrylic cements. They are mainly composed of polymethyl methacrylate, formed by polyaddition and used for fixing prostheses. They have good biocompatibility and excellent mechanical strength. However, they have the disadvantage of shrinkage behavior after in situ setting, resulting in a void between the implant and the bone.This behavior can cause serious problems such as the loosening of certain prostheses.

[0013] Furthermore, beyond the characteristics of the specifications of a material used as a bone substitute, it appears that none of the materials mentioned above exhibits excellent bioactivity with the environment in which it is implanted. Indeed, bioactivity as well as interaction of the material with the liquid media making up the implant area would allow it to be used as a matrix for the release of different substances, for example medications. It also appears that an implant with the capacity to expand in volume by absorbing fluids would be particularly suitable for use as a bone implant due to its ability to come into close contact with the recipient bone site.

[0014] The first type of implant is a flat implant with manual shaping. To create it, the surgeon uses sterilized ABS (acrylonitrile butadiene styrene) replicas of the patient's skull to place and shape the implant to adapt it to the patient's anatomy. This implant almost completely respects the patient's anatomy and thus improves the precision of surgical repairs. However, this solution requires prerequisites: being able to manufacture and sterilize the patient's skull in ABS, to desterilize and resterilize the implant, to have the time to carry out this operation and to be in a structure that has access to this technology.

[0015] A second solution is to design implants for most individuals by anatomically preforming an implant covering the orbital floor and medial wall. These implants have "average" dimensions, that is, their dimensions are not specific to an individual but are suitable for the different anatomical shapes of the orbit. These implants are available in two different sizes. They have allowed a significant improvement over standard implants. However, because the fractures are not constant in volume or location, and the anatomical shape of the orbital wall is very complex, they do not perfectly cover the orbital wall.

[0016] There is therefore still a need for the design of an anatomically shaped orbital implant covering the lesion site adapted to each patient produced by rapid prototyping. The use of rapid prototyping will thus allow the optimization of the implant shape as well as the optimization of its internal structure in order to allow better circulation of fluids, bone recolonization and sufficient mechanical support properties.

[0017] There is also a need to design a material that meets the specifications of a material used as a bone substitute but also those of a material capable of coming into close contact with the implant area and being used as a substance release matrix. Summary

[0018] This disclosure improves the situation.

[0019] According to a first aspect, a surgical insert is proposed comprising: - a first layer, and - a second layer, wherein the first layer and the second layer comprise orifices having an octomorphic shape.

[0020] The surgical insert according to the first aspect of the invention has an internal architecture optimized for better fluid circulation and bone regrowth. The first layer and the second layer allow the surgical insert to have sufficient mechanical support properties, in particular by a significant reduction in maximum stresses. This surgical insert can be used as a bone substitute, in particular for human or veterinary use. Its general shape can be adapted to result in an anatomically shaped bone implant. Thus, it can be used, for example, to replace a part of the skeleton such as the orbital floor, serve as an osteosynthesis plate or form a joint prosthesis.

[0021] This surgical insert, or surgical implant, can also be used for human or animal surgery, particularly on vertebrates. It can be implanted or replace all or part of the structures of the human or animal body, for example a limb, the skull, the trunk, etc. It can be used in particular in reconstructive surgery of the limbs (lower and upper), the face (including the jaws, the teeth) or the trunk (for example the spine). It can also be used in vascular, abdominal or digestive surgery.

[0022] According to a second aspect, there is provided a bone substitute in the form of bone cement (also called bone cement) comprising: - a powdery solid phase comprising natural polysaccharides or those derived from natural compounds and a ceramic filler, - a liquid phase acrylate, - a polymerizer, and / or - a radiopacifier, and / or - a swelling-limiting agent.

[0023] The bone cement according to the second aspect of the invention has advantageous properties, including excellent biocompatibility with the human body, excellent osteoconductivity and mechanical strength close to that of human bone. It also has a macroporosity property allowing cell colonization and revascularization of the graft. Brief description of the drawings

[0024] Other features, details and advantages will become apparent upon reading the detailed description below, and upon analyzing the attached drawings, in which:

[0025] [Fig. 1] shows schematically a top view of an octomorphic orifice;

[0026] [Fig. 2] schematically shows a top view of octomorphic shaped orifices arranged in a triangular pattern;

[0027] [Fig. 3] schematically shows a top view of octomorphic shaped orifices arranged in a square pattern;

[0028] [Fig. 4] schematically shows a top view of octomorphic shaped orifices arranged in a hexagonal pattern;

[0029] [Fig. 5] schematically shows a top view of octomorphic orifices arranged in a heterogeneous pattern;

[0030] [Fig. 6] schematically shows a top view of an example of a surgical insert according to the invention, of square shape having fixing tabs at one of its sides;

[0031] [Fig. 7] schematically shows a top view of an example of a surgical insert according to the invention, of round shape;

[0032] [Fig. 8] schematically shows a top view of an example of a surgical insert according to the invention, of triangular shape with two zones of different porosity;

[0033] [Fig. 9] shows the two faces of an example of a surgical insert according to the invention;

[0034] [Fig. 10a] schematically shows a top view of a first layer of a surgical insert according to the invention;

[0035] [Fig. 10b] schematically shows a top view of a second layer of the same surgical insert as Fig. 10a;

[0036] [Fig. 11] schematically shows an example of a surgical insert according to the invention, in three dimensions comprising two layers separated from each other by a plurality of separators;

[0037] [Fig. 12] shows schematically an example of a pillar with a straight longitudinal axis perpendicular to the mean plane of the first or second layer;

[0038] [Fig. 13] shows the evolution of the weighting coefficient C2 as a function of the torsion angle 0 of the pillars of the surgical insert according to the invention;

[0039] [Fig. 14] schematically shows an example of a pillar with a vertical longitudinal axis of helical shape with a torsion angle other than 0;

[0040] [Fig. 15] shows the evolution of the weighting coefficient C3 as a function of the angle of inclination Q of the straight pillars of the surgical insert according to the invention;

[0041] [Fig. 16] schematically shows an example of a pillar with a longitudinal axis having a non-zero inclination angle Q relative to the vertical;

[0042] [Fig. 17] shows schematically an example of a pillar with a curved axis;

[0043] [Fig. 18] schematically shows an example of a pillar with a straight longitudinal axis of helical shape having pores at its lateral surface;

[0044] [Fig. 19] schematically shows an example of a section of a layer of the surgical insert according to the invention and having an octomorphic-shaped orifice and transverse octomorphic-shaped orifices;

[0045] [Fig. 20] schematically shows an example of a surgical insert according to the invention, in three dimensions having three layers separated by a plurality of pillars with a vertical longitudinal axis of helical shape having pores at its lateral surface;

[0046] [Fig. 21] shows an example of a Bézier curve or function;

[0047] [Fig. 22] shows a distribution of octomorphic shaped orifices along a Bézier curve;

[0048] [Fig. 23] is an enlargement of a portion of the Bézier curve of Figure 22 at an extremum;

[0049] [Fig. 24] shows overlap sections induced by a homothetic duplication of the first layer leading to the second layer;

[0050] [Fig. 25] shows octomorphic orifices arranged in a partial rectangular pattern;

[0051] [Fig. 26] shows octomorphic orifices arranged partially along the contours of an octagon;

[0052] [Fig. 27] shows an example of a surgical insert according to the invention and its limit box;

[0053] [Fig. 28] shows the simulation results of two inserts both having octomorphic shaped holes, one having mechanical reinforcement, the other without;

[0054] [Fig. 29] shows the ternary diagram of variation of cellulose acetate, ceramic filler and starch included in the bone cement according to the invention;

[0055] [Fig. 30] shows the evolution of the Young's modulus in the field of study of bone cement according to the invention;

[0056] [Fig. 31] shows the evolution of the shear modulus in the field of study of the bone cement according to the invention;

[0057] [Fig. 32] shows the evolution of swelling in the study area of ​​the bone cement according to the invention;

[0058] [Fig. 33] shows the evolution of temperature as a function of time for the three formulations of bone cement according to the invention;

[0059] [Fig. 34] shows the evolution of the setting time of an acrylic cement as a function of the mass proportion of vitamin C in the bone cement according to the invention;

[0060] [Fig. 35] shows the evolution of the maximum temperature reached by an acrylic cement as a function of the mass proportion of vitamin C in the bone cement according to the invention;

[0061] [Fig. 36] shows the evolution of the swelling of example 2.1 of the bone cement according to the invention in different liquid media as a function of the number of days of immersion;

[0062] [Fig. 37] shows the evolution of the swelling of example 2.2 of the bone cement according to the invention in different liquid media as a function of the number of days of immersion;

[0063] [Fig. 38] shows the evolution of the swelling of example 2.3 of the bone cement according to the invention in different liquid media as a function of the number of days of immersion;

[0064] [Fig. 39] shows the evolution of the open porosity of examples 2.1, 2.2 and 2.3 of the bone cement according to the invention as a function of the number of days for immersion in distilled water;

[0065] [Fig. 40] shows the evolution of injectability strength for six botanical varieties of starch;

[0066] [Fig. 41] shows the cell survival rate as a function of each formulation of bone cement according to the invention and two controls, the first based on 100% alumina, and the second based on tissue culture polystyrene (TCPS), the material constituting the culture plates;

[0067] [Fig. 42] shows the total amounts of ciprofloxacin (CFX) present in the different formulations of bone cement according to the invention; and

[0068] [Fig. 43] shows the CFX release profile as a function of time for the three formulations of bone cement according to the invention. Detailed description

[0069] The present invention relates according to a first aspect to a surgical insert which will be described subsequently with reference to figures 1 to 28.

[0070] Surgical insert 1 includes: - a first layer 11, and - a second layer 12, in which the first layer 11 and the second layer 12 comprise orifices 111, 121 having an octomorphic shape.

[0071] The term "octomorphic" refers to orifices in the shape of the number 8, that is to say an elongated shape with two lobes at the ends and a narrow central part.

[0072] The octomorph shape can be described as consisting of two end parts, each formed by a circle of radius n. The two end parts are connected to each other by a central part formed by a circular fillet of radius r2 so that the width of the central part is less than the width of the end parts equal to 2xri. Thus, the radius is a first radius of curvature of the octomorph shape in the end parts and the radius r2 is a second radius of curvature of the octomorph shape in the central part.

[0073] The octomorph shape can also be described as a two-dimensional shape, oblong, tapered to half its length and comprising two end portions and a tapered central portion. The octomorph shape may have a curved contour, i.e., the contour has no angles. The two end portions may have a first radius of curvature n oriented towards the inside of the orifice. The tapered central portion may comprise a central area having a second radius r2 of curvature oriented towards the outside of the orifice.

[0074] When an orifice is referred to as having an octomorphic shape, this means that a section of the orifice has such a shape. The section generally considered is a section parallel to the mid-plane of the surface from which the orifice extends.

[0075] An "octomorphic orifice" will also be understood to mean an orifice that does not have an octomorphic shape due to the paving and sizing of the insert. That is to say, any orifice resulting from paving with octomorphic orifices followed by trimming to the desired shape of the insert is considered an octomorphic orifice.

[0076] The octomorph shape may include a center of symmetry in the constricted central part. The octomorph shape may have two axes of symmetry perpendicular to each other.

[0077] Several parameters can be defined to characterize the layers 11, 12 and the orifices 111, 121: - laughed the first ray of curvature, - r2 the second radius of curvature - L o the total length of the orifice 111, 121, - to the total width of the orifice 111, 121, - t c the central width of the central part of the orifice 111, 121, - h the thickness of the surgical insert 1, - L the length of the smallest side of the first and second layers 11, 12, - (p the porosity of a layer being the ratio between the surface occupied by the orifices 111, 121 of the layer and the total surface of the layer 11, 12, - e the minimum distance between two orifices 111, 121, and - Fia force applied to insert 1.

[0078] Figure 1 shows a top view diagram of an orifice 111, 121 of octomorphic shape. Thus, length is understood to be a dimension taken in a direction extending between the two lobes, the direction corresponding in particular to one of the axes of symmetry if present. Width is understood to be a dimension perpendicular to the length. The thickness of the surgical insert is understood to be a distance between the two end faces of the insert in the direction of superposition of the layers. Unless otherwise indicated, it is understood to be the average of the thickness on the insert. The distance between two orifices is taken between the centers of these orifices.

[0079] Total length, L o , can be between 200 pm and 50 mm. In some cases (e.g. for orbital floors), this length is preferably 200 pm to 2 mm. In other cases (e.g. for osteosynthesis plates), this length is preferably 10 to 50 mm.

[0080] The ratio of the total length, L o , over the total width, t o , can be understood between 1.8 and 2.2, preferably between 1.9 and 2.1, preferably between 1.95 and 2.05, for example 2.

[0081] The ratio between the first radius of curvature, n, and the second radius of curvature, r2, may be between 1.3 and 1.7, preferably between 1.4 and 1.6, preferably between 1.45 and 1.55, for example 1.5.

[0082] The ratio between the total width, t o , and the central width, t c , may be between 1.3 and 1.7, preferably between 1.4 and 1.6, preferably between 1.45 and 1.55, for example 1.5.

[0083] The preferred value of a parameter depends on the case studied and is generally a function of the maximum force which will be exerted on insert 1 once in place and also of the general shape of insert 1 which will condition the distribution of the stress resulting from the loading.

[0084] The octomorphic orifices 111, 121 may be arranged at the layer 11, 12 according to a particular pattern. The pattern may be locally partial, that is to say that octomorphic orifices 111, 121 are missing. This pattern may be chosen from a triangular pattern, a square pattern, a hexagonal pattern or a heterogeneous pattern. The pattern may also be chosen so that the octomorphic orifices 111, 121 draw the contours of a geometric shape, in particular a regular one, such as a triangle, a rectangle, a square, a pentagon, a hexagon, etc. A triangular pattern is a pattern in which the center of each orifice 111, 121 is located at a vertex of a triangle. A square pattern is a pattern in which the center of each hole 111, 121 is at a vertex of a square. A hexagonal pattern is a pattern in which the center of each hole 111, 121 is at a vertex of a hexagon.A heterogeneous pattern is a pattern in which the center of each orifice 111, 121 is arranged randomly. The distribution of the orifices according to a particular pattern does not predict the angular orientation of each of the orifices around its center. Thus, the orientation can be homogeneous (identical angular orientation for all the orifices), centrifugal (different angular orientations for the orifices so that their lengths are collinear with a line connecting the center of the orifice to the center of the pattern) or heterogeneous (at least two orifices having different angular orientations).

[0085] An example of a heterogeneous pattern can be described using a Bézier curve or function (see Figure 21) defined by a set of control points whose number is n and at least equal to 2, P o , Pi, ..., P n -i. The parametric representation is as follows: where the B's -1are Bernstein polynomials: In such a pattern, the center Q(t0), Q(ti), ... of circles of radius ri are arranged on the Bézier curve (see Figure 22). Preferably, between two consecutive extrema of the Bézier curve, a single octomorphic orifice is arranged.

[0086] Furthermore, the shortest measurable distance between the contours of two octomorphic orifices is greater than 0, preferably greater than 50 pm, still preferably greater than 100 pm, still preferably greater than 200 pm. Thus, the octomorphic orifices are disconnected.

[0087] Preferably, if n Q is the total number of centers Q(t0), Q(ti), ... of circle of radius and ti the parametric coefficient corresponding to the i ème center Q(tj), then for i from 2 to n Q , we define Qi, Q2 and Q3 as follows: Pj, or the (i— 1 ) ème center; , or the i ème center ; x p I, soit ' e P°' nt located between I e (i-1) ème center and the i ème center. We also define a point with coordinates (x c ; (c) as follows: (x k ; yk) being the coordinates of point Qk; then, the arrangement of the centers of the circles of radius is preferably chosen so that Rc yx (2 x ri + d); where y is a safety coefficient chosen between 4 and 8, preferably 6 (see figure 23). This condition ensures that the minimum distance condition between two octomorphic orifices is respected.

[0088] Figures 2, 3, 4 and 5 respectively show a top view diagram of octomorphic shaped orifices arranged in a triangular, square, hexagonal and heterogeneous pattern. In the case of the triangular pattern of Figure 2, the square pattern of Figure 4 and the hexagonal pattern of Figure 4, the orientation of the orifices is homogeneous. Figure 25 shows a top view diagram of octomorphic shaped orifices arranged in a partial rectangular pattern. It can be seen from Figure 25 that the octomorphic shaped orifices octomorphic holes are inserted into the MR1 nodes of a rectangular MR mesh but that other MR2 nodes of this mesh are not occupied by an octomorphic-shaped hole. Figure 26 shows a top view diagram of octomorphic-shaped holes arranged partially along the contours of a hexagon. Figure 22 shows a top view diagram of octomorphic-shaped holes arranged in a heterogeneous pattern described by a Bézier curve.

[0089] The porosity of the layers 11, 12 may be from 0.1 to 0.93, preferably from 0.4 to 0.8.

[0090] The two layers are preferably parallel to each other.

[0091] The porosity of a layer 11, 12 as well as the mechanical resistance of a layer 11, 12 are two quantities which evolve in opposite directions. When the porosity is included in the intervals defined above, the layer 11, 12 has an elastic limit stress lower than 830 MPa which is the conventional elastic limit (Rp0.2) of the TA6V titanium implant.

[0092] The greater the porosity, the lighter the structure will be. Furthermore, the more fluid circulation will be improved. The mechanical strength of insert 1 decreases with increasing porosity.

[0093] The octomorphic orifices 111, 121 may be arranged at the level of the layer 11, 12 and in at least one area in a parallel manner, that is to say that the 8 forming these orifices 111, 121 are all oriented in the same direction in this area. In certain cases, all the orifices 111, 121 of the layer 11, 12 are parallel to each other.

[0094] The surgical insert 1 may further comprise a fixing tab 14 extending from one of the layers. The fixing tab 14 may have an oblong-shaped fixing 141, in particular with an orifice 142 which is also oblong and connected to the first and / or second layers 11, 12 by a tab 143.

[0095] The surgical insert 1 may have different shapes, for example a square shape, a round shape or a triangular shape and more generally, any shape physiologically compatible with the reconstruction of a structure of the human body.

[0096] Figures 6, 7 and 8 schematically show a top view of a surgical insert 1 of square shape with fixing tabs on one of its sides, of round shape and of triangular shape respectively. The triangular shape insert 1 is shown with two zones of different porosity.

[0097] The surgical insert 1 may have a truncated circle cross-section shape on the apex side. Such a surgical insert is advantageous for orbital floor reconstruction.

[0098] The surgical insert 1 may be composed of a material chosen from a polymer, a metal, a ceramic or a composite; these materials being of medical grade.

[0099] When insert 1 is composed of a polymer, it may in particular be composed of polyetheretherketone, polylactic acid or their derivatives.

[0100] When the insert 1 is composed of a metal, it may in particular be composed of titanium, a titanium alloy, stainless steel, a cobalt alloy (such as cobalt chrome), or tantalum.

[0101] When the insert 1 is composed of a ceramic, this ceramic may be a bioglass or a bioceramic, in particular a phosphocalcic bioceramic, for example hydroxyapatite, tricalcium phosphate (TCP) and mixtures thereof.

[0102] When insert 1 is composed of a composite, it may in particular be composed of the bone cement described in more detail below.

[0103] Insert 1 may also be composed of bone cement, in particular that described below.

[0104] Generally speaking, the surgical insert 1 according to the invention can be made from a patient scan. For example, it can be composed of a polymer, metallic or bioceramic material before being covered with the bone cement described below or be made exclusively of bone cement by rapid prototyping. The insert 1 is then washed to remove all residual traces: it is washed with ether then with water before being left to dry in the oven at 37°C for 24 hours. If an active ingredient is to be added, the insert 1 can be brought into contact with a drug before implantation for its biofunctionalization.

[0105] According to one embodiment, the ratio Uh between the length L of the smallest side of the first 11 and second 12 layers and the thickness h of the surgical insert 1 is chosen to be greater than 20.

[0106] Also, the thickness h of each layer can verify the relationship: [Math. 1]

[0107] where I is the maximum width of the surgical insert and L is the maximum length of the surgical insert.

[0108] In the following, we will describe the values ​​of the parameters in the case where the L / h ratio is greater than 20.

[0109] The first radius of curvature can be greater than or equal to the first minimum radius of curvature r^ min of 345 pm and may be less than or equal to the first maximum radius of curvature i max defined by Math. 2.

[0110] [Math. 2] [mi where S is the total surface area of ​​insert 1, <p est la porosité totale de l’insert 1 , et N le nombre de pores octomorphes d'une couche.

[0112] When the first radius of curvature is within the limits defined above, it allows good osteogenesis, that is to say, it allows the formation and development of bone at the level where it is inserted. The lower limit was determined by fluid mechanics, it is in agreement with the orifices used classically in bioceramics. To determine the upper limit, a parametric study on 190 cases by varying the geometric dimensions and the loads applied to the unit cell was conducted.

[0113] The minimum distance between two orifices 111, 121 may be greater than or equal to 100 μm. The minimum distance between two orifices 111, 121 may be less than or equal to 4 times the first radius of curvature. If two orifices 111, 121 have a different size, then the minimum distance between two orifices 111, 121 may be less than or equal to 4 times the first radius of curvature of the larger orifice 111, 121. The lower limit determines the minimum load that the insert can support. The interval ensures the circulation of fluids.

[0114] The thickness h of insert 1 can be greater than or equal to the minimum thickness h m in 100 pm and may be less than or equal to the maximum thickness h max defined by Math. 3.

[0115] [Math. 3] ri + e I h L max < — — -

[0116] The only real maximum limit on the thickness of insert 1 is the biological limit, i.e. the size of insert 1 must be adapted to the area in which it is inserted and the trauma it is to repair. However, it may be advantageous for insert 1 to remain within the Kirch h off-Love assumptions. In which case, the maximum thickness must respect the relationship Math. 3.

[0117] The admissible load is then defined by the relation Math. 4 whose parameters are given in table 1.

[0118] [Math. 4]

[0119] The maximum permissible load supported by insert 1 can be determined using the Kirchoff-Love assumptions as well as the geometric parameters of insert 1 defined previously.

[0120] [Table 1]

[0121] The relationship between f(a) and a is shown in the following Table 2:

[0122] [Table 2]

[0123] These values ​​allow the best compromise between sizes and distributions of the orifices 111, 121. These values ​​allow for better circulation of fluids, better bone recolonization and sufficient mechanical support properties.

[0124] With regard to the non-uniform patterns of orifices 111, 121, those skilled in the art will be able to carry out a verification of the mechanical behavior of the insert 1 by a final numerical analysis in order to validate the size and distribution of the orifices 111, 121 proposed.

[0125] The first layer 11 may have a porosity greater than the porosity of the second layer 12. The ratio of the maximum length of the orifices 111 of the first layer 11 Li and the maximum length of the first orifices 121 of the second layer 12 L2 may be greater than 1.4, preferably it is greater than 1.4 and less than 3.2.

[0126] The first layer 11 has the objective of being in direct contact with the bone structure. Thus, preferably, the first layer 11 is made of a material biocompatible with osteoblasts to integrate with the bone tissue without risk of formation of fibrous tissue. The second layer 12 has the objective of supporting the tissues or organs. Thus, preferably, it has a smooth and low-porosity surface to avoid infections.

[0127] The second layer 12 may have a keying device.

[0128] The second layer 12 may have two zones, a first zone 122 with orifices 1221 having a first maximum length L2 and a second zone 123 with second orifices 1231 having a second maximum length. The ratio between the first maximum length l_3 and the second maximum length l_2 may be between 1.6 and 2, preferably between 1.7 and 1.9, preferably between 1.75 and 1.85, for example 1.8.

[0129] The ratio between the maximum length of the orifices 111 of the first layer Li and the first maximum length L2 may be between 1.4 and 1.8, preferably between 1.5 and 1.7, preferably between 1.55 and 1.65, for example 1.6.

[0130] The ratio between the maximum length of the orifices 111 of the first layer Li and the second maximum length l_3 may be between 2.8 and 3.2, preferably between 2.9 and 3.1, preferably between 2.95 and 3.05, for example 3.

[0131] The first zone 122 with lower porosity makes it possible to increase the stability of the insert 1. This denser zone 122 can also be useful for the surgeon when placing the insert 1 in the damaged area. Indeed, the octomorphic orifices 121 having a smaller size can serve as a foolproof device to know the positioning direction of the insert 1.

[0132] This bi-layer structure allows fluids to circulate easily through the insert 1 in order to avoid any stagnation and / or risk of infection.

[0133] Figure 9 shows the two faces of an example of such a bilayer structure. Figures 10a and 10b show respectively a top view of the first layer 11 and a top view of the second layer 12.

[0134] The total porosity of insert 1 is calculated using the following formula:

[0135] [Math. 5]

[0136] where (ptot is the total porosity of the surgical insert 1 , (pi is the porosity of the first layer 11 , <p2est la porosité de la deuxième couche 12, Si est la surface totale de la première couche 11 et S2est la surface totale de la deuxième couche 12. Pour une couche donnée, la porosité est le ratio entre la surface occupée par les orifices octomorphes et la surface totale de la couche.

[0137] Preferably, the insert 1 has a total porosity greater than or equal to 0.6 and less than or equal to 0.93. Preferably, the insert 1 has a ratio between the total surface area occupied by the orifices of a layer and the total surface area of ​​this layer greater than or equal to 0.09 and less than or equal to 0.92.

[0138] When the pattern of holes is a hexagonal pattern, the ratio of the total area occupied by the holes in a layer to the total area of ​​that layer is greater than or equal to 0.111 and less than or equal to 0.923.

[0139] According to another embodiment, the L / h ratio is less than 4. Subsequently, the characteristics will be described in the case of an L / h ratio less than 4. Furthermore, the fluid flows are then generally complex.

[0140] The second layer 12 may have two zones, a first zone 122 with orifices 1221 having a first maximum length l_2 and a second zone 123 with second orifices 1231 having a second maximum length. The ratio between the first maximum length l_3 and the second maximum length l_2 may be between 1.6 and 2, preferably between 1.7 and 1.9, preferably between 1.75 and 1.85, for example 1.8.

[0141] In the case of octomorphic orifices 111 distributed according to a heterogeneous pattern described by a Bézier curve on the first layer 11, the arrangement of the octomorphic orifices 121 on the second layer 12 may correspond to a homothetic duplication of the arrangement of the octomorphic orifices 111 of the first layer 11. That is to say that the orifices undergo a translation and a rotation (duplication) then a homogeneous scaling (homothetic). This homothetic duplication can be described by the following formulas: with : Mi(x,y,z), the coordinates of the centers of the octomorphic orifices of the first layer; M2(x,y,z), the coordinates of the centers of the octomorphic orifices of the second layer; X, the value of the translation along the main vector X; Y, the value of the translation along the main vector Y; Z, the value of the translation along the main vector Z; 0, the rotation angle along the main Z axis; and SE, the scaling coefficient.

[0142] There may be a single set of orifices 121 of the second layer 12 or several sets of orifices 121 of the second layer 12 differing from each other by the rotation angle θ and / or the scaling coefficient SE. Thus, from an orifice 111 of the first layer 11, there may be 1, 2, 3, 4 orifices 121 of the second layer 12, or more.

[0143] Preferably, the homothetic duplication induces a minimum overlap section SR of 0.2 mm 2 between the orifice 111 of the first layer 11 and the orifice 121 of the second layer 12 which results therefrom (see figure 24). Still preferably, the overlap is at most a quarter of the surface of the orifice 111 of the first layer 11.

[0144] A plurality of separators 15 may be disposed between the first layer 11 and the second layer 12.

[0145] Each separator 15 may be in the form of a pillar 15. Figure 11 shows a three-dimensional surgical insert comprising two layers separated from each other by a plurality of pillars of octomorphic section.

[0146] The pillar 15 may have a longitudinal axis. This longitudinal axis may be straight (Figures 12, 14 and 16) or curved (Figure 17). When the longitudinal axis is straight, it may extend perpendicularly from the mean plane formed by the first layer 11 or by the second layer 12. It may also be understood to form a non-right angle with this mean plane. When the longitudinal axis is curved, it follows the curve of a parametric equation between the first layer 11 and the second layer 12.

[0147] Each separator 15 of the plurality of separators 15 may have a cross-section that has an octomorphic shape as described above. Thus, the pillar 15 may be obtained by translating the octomorphic shape along the longitudinal axis (Figures 12, 16). Alternatively, the pillar 15 may be obtained by a combination of translating and rotating the octomorphic shape along the longitudinal axis so as to give the lateral surface of the pillar 15 a helical shape (Figure 14).

[0148] In the case of a pillar 15 with a helical-shaped lateral surface, preferably, the number of rotations of the octomorphic shape between the first layer 11 and the second layer 12 may be 1 / 4+k, 1 / 2+k, 3 / 4+k or 1 -ik, where k is a number greater than or equal to 0; for example 0, 1, 2, 3. In the case where the number of rotations is 1 / 4+k or 3 / 4+k, this means that the orientation of the octomorph at the second layer 12 is 90° (270°) from its orientation at the first layer 11. In the case where the number of rotations is 1 / 2+k or 1 -ik, this means that the orientation of the octomorph at the second layer 12 is 180° (360°) from its orientation at the first layer 11.

[0149] More generally, in the case where the pillar 15 is chosen as being a pillar 15 of helical shape with a torsion angle p, said angle p can be between 0 and 180°, preferably less than 90°.

[0150] The parametric equation for designing the helical-shaped pillar 15 is expressed below.

[0151] [Math. 6] 5.440 x(t) = rx cos(t),y(t) = rx sin(t),z(t) = — — — rxt

[0152] where t and P are expressed in radians.

[0153] The separators 15 are preferably sized to support the load and in particular to take up a normal compression force and resist buckling.

[0154] In order to study the influence of the different parameters of the pillars 15 on the admissible load, the following parameters are defined, the extreme values ​​of which will be determined by a parametric analysis: - H the height of the pillar 15 measured as the distance between the first layer 11 and the second layer 12, - P the torsion angle of pillar 15, this angle is non-zero when pillar 15 is helical, - Q the angle of inclination of pillar 15 for a straight pillar 15, and - C the curve of a parametric equation for a curved pillar 15.

[0155] Each pillar 15 among the plurality of pillars 15 may have a height greater than or equal to 3 mm. The height is considered perpendicular to the mean plane of the first or second layer. The maximum value H max the height of pillar 15 can respect the following formula:

[0156] [Math. 7] H max = 637,040 x Fp -0 ' 493 x rf

[0157] where Fp is the total force that pillar 15 can support for a straight pillar 15, and is the first radius of curvature.

[0158] The helical pillar 15 can support an admissible load increased by a factor C2 expressed by the formula Math. 8.

[0159] [Math. 8]

[0160] Figure 13 shows the evolution of the weighting coefficient as a function of the torsion angle 0. This weighting coefficient can be determined by parametric analysis. We can see that above 90°, the weighting coefficient C2 increases sharply.

[0161] In the case where the pillar 15 is chosen as a straight axis pillar 15 with an inclination angle Q, said angle Q can be between 0 and 85°, it is preferable to place a mirrored pillar 15 with an opposite angle so that the support is more effective. The inclination angle is measured relative to the normal to the mean plane formed by the first or second layer.

[0162] The straight axis pillar can support an admissible load increased by a factor C3 expressed by the formula Math. 9.

[0163] [Math. 9] F p m = C3F p , C3= O,OOOO680 3 +9.7110 2 - 0.03860 + 1.1782

[0164] Figure 15 shows the evolution of the weighting coefficient C3 as a function of the inclination angle Q. This weighting coefficient can be determined by analysis parametric. We see that the higher the angle of inclination, the more the weighted force increases.

[0165] Each pillar 15 may comprise through-orifices 151 at its lateral surface (figure 18). These through-orifices 151 make it possible to improve the circulation of fluids between the first 11 and the second layer 12. Indeed, the presence of the pillars 15 forces the fluids to bypass them, the orifices 151 thus allow a portion of the fluids to pass through the pillars 15, making the flow less complex.

[0166] The ratio between the surface area of ​​the transverse orifices 151 and the lateral surface area of ​​the pillar 15 can be between 0.25 and 0.3.

[0167] As illustrated in Figure 19, the orifices 111, 121 of the first layer and / or of the second layer may have a side wall formed in the thickness of the corresponding layer, and in which the first layer 11 and / or the second layer 12 comprises transverse orifices 112, 124 passing through with an octomorphic section as described previously and extending between the side wall of two orifices 111, 121 of the corresponding layer 11, 12. Alternatively, the transverse orifices 112, 124 may have a circular or oval section. These transverse orifices 112, 124 may be entirely within the thickness of the first layer 11 or the second layer 12 (e.g. the transverse orifices 112, 124 form channels) or on the surface thereof (e.g. these transverse orifices 112, 124 form free-surface channels). The two types of channels may coexist in the same insert 1.

[0168] The number of transverse orifices 112, 124 may be greater than or equal to 4 and less than or equal to 8, for example 4, 5, 6, 7 and 8.

[0169] In the case where, as in the three-dimensional insert 1, the thickness of the insert 1 is of the order of magnitude of the smallest length of the insert 1, it is possible to add a network of transverse orifices 112, 124 of octomorphic shape in order to assist the circulation of fluids. They are arranged so as to connect the orifices 111, 121 of the first layer 11 and of the second layer 12 to each other. The desired number of interconnections N is around 6 to 8 interconnections. The number of interconnections is defined as being the number of transverse orifices 112, 124 extending from a single octomorphic orifice 111, 121 of the corresponding layer 11, 12. Too small a number of interconnections can lead to a “clutter” creating excess pressure in the orifices 111, 121 of the first or second layer 11, 12 and too high a flow rate in the transverse orifices 112, 124. Too many transverse orifices 112, 124 can increase the risk of multiplication of “dead channels” by leaving the fluid the possibility of finding a clearly preferential path.

[0170] When the layers of the insert comprise transverse orifices 112, 124, the section of each orifice 111, 121 of each layer 11, 12 is preferably greater than or equal to 0.7 mm. 2 and less than or equal to 1.2 mm 2 .

[0171] The plurality of pillars preferably includes transverse holes at the side surface of the insert.

[0172] The surgical insert may further comprise a third layer 13 comprising orifices 131 of octomorphic shape as described previously and separated from the first layer 11 or the second layer 12 by a plurality of separators 15 as described previously (figure 20).

[0173] The number of layers is actually not limited and the surgical insert can include 4, 5, 6, 7, 8, 9, or even 10 layers and even more if necessary.

[0174] The surgical insert may also comprise a mechanical reinforcement 16 (see figure 27). The mechanical reinforcement 16 absorbs the bending, torsion and compression forces so that the layers 11, 12 of the insert 1 do not undergo deterioration. In addition, the mechanical reinforcement 16 must not hinder the fixing of the insert 1.

[0175] The mechanical reinforcement 16 may be continuous or discontinuous. In the latter case, the mechanical reinforcement 16 is composed of a plurality of reinforcement units.

[0176] Preferably, the mechanical reinforcement 16 or each of the reinforcement units is an excess thickness of the surgical insert 1, in particular on one of the layers 11, 12 of the insert 1. This excess thickness is advantageously at least 1 mm. In addition, the mechanical reinforcement 16 or each of the reinforcement units is free of octomorphic orifices.

[0177] In the case where an orifice 161 intended for the passage of fixing screws (in particular round or oblong) is provided through the mechanical reinforcement 16 or a reinforcement unit, a border 162 of at least 1 mm thickness is preferably provided around this orifice 161.

[0178] Such mechanical reinforcement 16 is advantageous when, the insert being inserted into a boundary box BB (in English bounding box) of dimensions a, b, c of which c is the smallest dimension, at least one of the following conditions is fulfilled: - > 10 OR - > 10. cc

[0179] A bounding box BB for a set of points in three dimensions is defined as the parallelepiped box with the smallest volume that can contain the set of points (see Figure 27).

[0180] The surgical insert 1 can be used as a carrier to add at least one of particular agents and active ingredients to avoid the risk of infection. Thus, the octomorphic orifices 111, 121 can contain at least one of particular agents and active ingredients.

[0181] Specific agents include bacteriophages and phage lysins. Bacteriophages have the ability to target bacteria embedded in a biofilm on the surface of the surgical insert. Phage lysins are hydrolytic enzymes.

[0182] The active ingredients can be in liquid, hydrogel, cement, powder or microbead form. These forms all allow for a prolonged release of the active ingredients, inhibiting bacterial adhesion, biofilm formation and bacterial proliferation.

[0183] Among the active ingredients, we can cite: anti-infectives, anti-oncotics and activators of adhesion and bone healing.

[0184] Among the anti-infectives, we can cite: antibiotics and antifungals.

[0185] Antibiotics include: gentamicin, rifampicin (eg Rifadine®), ceftriaxone, quinolones such as fluoroquinolones (eg Ciprofloxacin® and Moxifloxacin®), amoxicillin, tetracyclines (e.g. Doxycycline® and Minocycline®), mixtures of trimethoprim and sulfamethoxazole (e.g. Bactrim® and Eusaprim®), clindamycin, linezolid (e.g. Zyvoxyd®), fusidic acid, chlorhexidine and silver sulfadiazine. The use of surgical inserts impregnated with antibiotics allows the local release, e.g. at the site at risk of colonization, of a high concentration of antibacterial agents. Combinations of antibiotics can be advantageously used, such as: rifampicin / tetracycline (notably Minocycline®) and chlorhexidine / silver sulfadiazine.

[0186] Antifungals include terbinafine, ketoconazole, and amphotericin B.

[0187] Among the anti-oncotics, anti-osteosarcoma anti-oncotics can be mainly mentioned. Indeed, osteosarcoma is the most common malignant tumor originating in the bone. Examples of such anti-oncotics are: methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide and etoposide.

[0188] Among the activators of bone adhesion and healing, growth factors and collagen can be mentioned, but also mesenchymal stem cells.

[0189] Other biological materials may also be added to the surgical insert.

[0190] The present invention relates according to a second aspect to a bone cement comprising: - a powdery solid phase comprising natural polysaccharides or those derived from natural compounds and a ceramic filler, - a liquid phase acrylate, and - a polymerizer.

[0191] It may further include at least one of: - a radiopacifier, and - a swelling-limiting agent.

[0192] The natural polysaccharide or polysaccharide derived from natural compounds may be selected from a cellulose derivative (e.g., cellulose acetate) and a starch (e.g., wheat starch, potato starch, corn starch, and pea starch), as well as mixtures thereof. Preferably, the natural polysaccharide or polysaccharide derived from natural compounds may be a mixture of cellulose acetate and starch, including potato, pea, or corn starch. Potato starch also has the advantage of being easily metabolized by the human or animal body.

[0193] The powdered solid phase may further comprise alpha amylase, particularly when it comprises a starch other than potato starch.

[0194] Cellulose acetate is a derivative of cellulose. The latter is a carbohydrate consisting of a linear chain of D-glucose molecules. It is a biopolymer that makes up the wall of plant cells and represents 35 to 50% of plant biomass. Cellulose acetate thus differs from cellulose in that hydroxyl groups in the D-glucose molecule are replaced by acetate groups.

[0195] The mass proportion of cellulose acetate relative to the total mass of the bone substitute may be between 6% and 24%, preferably between 8% and 20%, always preferably between 10% and 17%, for example approximately 15%.

[0196] Starch is a reserve molecule of higher plants, that is, all plants excluding algae and mosses. Starch is mainly found in seeds, for example, cereal seeds such as corn, wheat, and rice. Starch can also be found in roots, tubers (for example, the potato tuber where it is commonly called starch), and fruits. Starch is a complex carbohydrate composed of D-glucose units. More specifically, starch is a mixture of two homopolymers composed of D-glucose units, amylose, and amylopectin, making it a member of the family of polysaccharides, more specifically natural polysaccharides, that is, those found directly available in nature.

[0197] The mass proportion of starch, in particular potato, pea or corn, relative to the total mass of the bone substitute may be between 5% and 30%, preferably between 5% and 20%, always preferably between 5% and 10%, for example approximately 7%.

[0198] The ceramic filler can be chosen from alumina, calcium sulfate hemihydrate, hydroxyapatite, tricalcium phosphate, bioglass and their mixtures. The use of ceramic filler is considered for economic reasons but also for the properties that this ceramic filler can bring to the bone cement, in particular mechanical properties of compressive strength and biological properties in order to improve bioactivity and bone regrowth.

[0199] The mass proportion of the ceramic filler can be between 18% and 45% relative to the total mass of the bone substitute.

[0200] The acrylate can be hydroxyethylmethacrylate (HEMA), methylmethacrylate (MMA), or a mixture thereof.

[0201] HEMA is a colorless liquid organic compound that has the property of rapid polymerization. It is a monomer used in the manufacture of many polymers, such as polyhydroxyethylmethacrylate (pHEMA). pHEMA is a hydrophobic polymer with hydrogel properties. It has the ability to swell in the presence of water due to the hydrophilic part of HEMA without leading to the dissolution of the polymer network. In the literature, cases of hydrogels whose mass is multiplied by a thousand by water absorption are reported.

[0202] The mass proportion of acrylate relative to the total mass of the bone substitute may be between 30% and 50%, preferably between 35% and 45%, preferably between 37.5% and 42.5%, for example 40%.

[0203] The polymerizer is a reagent that initiates the polymerization of monomers with each other in the reaction medium. The polymerizer may be a radical polymerizer. A radical polymerizer is a compound capable, under certain conditions, of generating free radicals that initiate the polymerization of acrylate monomers to form a polyacrylate such as polyhydroxyethylmethacrylate, polymethylmethacrylate, or a polymer obtained from HEMA and MMA.

[0204] This radical polymerizer can be a chemical initiator or a photochemical initiator.

[0205] A thermal initiator is a compound that generates free radicals through thermal decomposition. An example of a chemical initiator is benzoyl peroxide (BPO). In this case, a catalyst may be used, for example, dimethyl-p-toluidine (DMT).

[0206] A photochemical initiator is a compound that generates free radicals under the influence of radiation emitted by a radiation source. When exposed to radiation, they enter an excited state and release free radicals. Photopolymerization is particularly suitable for shaping cement by 3D printing. Radiation can include ultraviolet radiation. An example of a photochemical initiator is the riboflavin / triethanolamine system.

[0207] A radiopacifier is a compound that increases the radiopacity of a material. Radiopacity is defined as the opacity to X-rays and radiofrequency waves, i.e., the relative inability of these rays to pass through the material. Radiopacifiers are primarily used in the medical field, as they can be used, for example, as a contrast agent for radiography. Medical devices, such as implants, often contain them to improve visualization during the implantation of temporary devices such as catheters or the placement of permanent implants. Metallic implants generally have inherent radiopacity, while polymer-based implants require the addition of a radiopacifier to increase their contrast.

[0208] The radiopacifier can be chosen from zirconia (ZrO2), barium sulfate (BaSO4) and their mixtures.

[0209] Because bone cement is in constant contact with body fluids, it may be necessary to add an agent to limit the swelling of the pHEMA. If the pHEMA swells too much, the bone cement can put stress on the area where it is implanted and cause injury or pain. This swelling-limiting agent can be water or an aqueous solution containing a medication.

[0210] The bone cement may further comprise an activator and / or a setting retarder.

[0211] A setting activator and a setting retarder are adjuvants used to accelerate or delay the setting of bone cement. They thus allow respectively to reduce or increase the time during which the cement can be modeled. Depending on the use to which the bone cement will be put, it may sometimes be necessary to increase the setting time to give the practitioner more time to model it and give it the desired complex shape while in other uses, it may be necessary to decrease it. Thus, for example, if the clinical pathology is simple, a rapid setting allows to reduce the intraoperative time while on the contrary, for more complex procedures, the setting time can be increased. In another context, if the cement is used by 3D printing, the setting time must be long enough for the machine to be able to print the 3D part.

[0212] An example of a setting enhancer is hydroquinone. An example of a setting retarder is vitamin C. Furthermore, vitamin C can also act as a setting enhancer depending on the amount of the product added. More specifically, When the concentration of vitamin C is low, it has more of an activating effect. When the concentration of vitamin C is high, it has more of a delaying effect.

[0213] The bone substitute preferably has a Young's modulus of between 1 MPa and 32 MPa after 7 days of immersion in phosphate buffered saline, preferably greater than 5 MPa.

[0214] The bone substitute preferably has a shear modulus of between 100 Pa.s and 150,000 Pa.s, preferably between 2,000 Pa.s and 20,000 Pa.s. Examples

[0215] Example 1: Influence of the quantities of solid phase components on the properties of cement.

[0216] In this example, Young's modulus, complex shear modulus (G*) and swelling will be determined as a function of the proportion of the different components of the solid phase, ceramic filler, starch and cellulose acetate.

[0217] The mass proportion of HEMA was set at 40% by mass and the mass proportion of ceramic filler, cellulose acetate and starch relative to the total mass of bone cement varied according to the following intervals: - from 18% to 45% by mass of ceramic filler, - from 6 to 30% by mass of starch, and - from 6 to 24% by mass of cellulose acetate.

[0218] Cement preparation:

[0219] To prepare the cement, the liquid and solid phases are initially separated. They are then brought into contact and mixed to obtain a homogeneous paste. The paste is then shaped in different ways depending on the desired cement shape, for example by molding, casting, or 3D printing. Bringing the powder into contact with the liquid phase causes the HEMA to polymerize. This polymerization reaction is an exothermic reaction. Once the cement has hardened, it can be removed from the mold, for example, if the shaping was carried out by casting.

[0220] In order to study the variations in bone cement properties when the mass proportion of ceramic filler, cellulose acetate, and starch vary, Xi is defined as the ratio of the mass proportion of ceramic filler to the total mass of the solid phase, i.e., the mass ratio of ceramic filler in the solid phase, X2 as the ratio of the mass proportion of starch to the total mass of the solid phase, i.e., the mass ratio of starch in the solid phase, and X3 as the ratio of the mass proportion of cellulose acetate to the total mass of the solid phase, i.e., the mass ratio of cellulose acetate in the solid phase. The lower and upper limits of each mass ratio are shown in Table 3.

[0221] [Table 3]

[0222] Figure 29 thus shows the ternary variation diagram of Xi, X2 and X3. The circled area is the domain that will be studied.

[0223] Measurement of the Younq modulus

[0224] First, the Young's modulus of the cement after setting is measured in the study area. The Young's modulus is measured by a compression test according to ISO 5833:2002. The test sample is a cylindrical specimen with a diameter of 10 mm and a height of 15 mm. The sample was previously immersed for 7 days in a phosphate buffer saline (PBS) solution.

[0225] Figure 30 shows the evolution of the Young's modulus in the study area. It can be seen that the higher the cellulose acetate ratio, the more the Young's modulus increases. A minimum of the Young's modulus is measured at 1 MPa and a maximum of the Young's modulus at 32 MPa.

[0226] Thus, the Young's modulus varies greatly within the study area. The Young's modulus of the cement must be close to that of the bone into which the cement will be injected. This wide range thus makes it possible to adapt the Young's modulus of the cement to the cement injection zone.

[0227] Shear modulus measurement

[0228] In a second step, the shear modulus of the cement after setting is measured in the study area. The shear modulus is measured in a rheometer in speed-controlled mode. The measurement was carried out at 25 °C with a diameter of 40 mm and a cone angle of 2 ° in the shear rate range, with a reading every 10 seconds for 300 seconds.

[0229] Figure 31 shows the evolution of the shear modulus in the study area. It can be seen that, as with the Young's modulus, the shear modulus increases when the mass ratio of cellulose acetate increases. A minimum is measured at 100 Pa.s and a maximum at 150,000 Pa.s.

[0230] Thus, the shear modulus varies greatly in the field of study. The shear modulus of cement must be particularly controlled to allow easy injection but in such a way that the cement is not too liquid to avoid leaks or clinical complications. This wide range thus makes it possible to adapt the shear modulus of the cement to the cement injection zone and especially to the specificities required by the clinician (either in the form of a paste to be applied with a spatula, or in a more liquid form to be injected).

[0231] Swelling measurement

[0232] Thirdly, the swelling of the cement after setting is measured in the study area. The swelling is measured by calculating the ratio between the volume of a cylindrical sample with a diameter of 10 mm and a height of 15 mm before immersion and after 7 days of immersion in a PBS solution.

[0233] Figure 24 shows the evolution of swelling in the study area. It is noted that swelling decreases when the mass ratio of the ceramic filler increases. A minimum is measured at 21% and a maximum at 32%.

[0234] The swelling can thus be adapted to the cement injection area. The swelling must be large enough to completely cover the area to be protected, but not so large that the cement does not exert stress on the bones. Too much swelling can damage the bone and lead to complications.

[0235] Example 2: Influence of the type of ceramic filler on the properties of the cement

[0236] In this example, the nature of the ceramic filler in the solid phase of bone cement is modified in order to study the influence of the nature of the ceramic filler on the properties of the cement.

[0237] To evaluate the preparation of the cement, three formulations were produced according to the following table 4 showing the mass proportions:

[0238] [Table 4] - CSH: calcium sulfate hemihydrate - HA: hydroxyapatite - TCP: tricalcium phosphate

[0239] These three formulations were shaped using a cylindrical silicone mold 10 mm in diameter and 15 mm in height. They were removed from the mold after the cement had hardened.

[0240] Acrylic cements are characterized by the setting time and the maximum polymerization temperature. The setting time corresponds to the time required for the average setting temperature to be reached. The average temperature is represented by the average of the maximum polymerization temperature and the ambient temperature of the room.

[0241] Figure 33 shows the temperature evolution as a function of time for the three examples. The measurements were carried out with a type T thermocouple and are shown in Table 5.

[0242] [Table 5]

[0243] Thus, the setting temperature remains relatively constant depending on the ceramic used.

[0244] Depending on the ceramic filler, the setting time varies from 90 to 120 seconds. However, it is possible to increase it by keeping the product in a cold room, the setting time then increases to 300 seconds. The addition of a setting retarder can also be considered depending on the application and shaping of the cement.

[0245] Vitamin C is known for its properties as both a set retarder and a set activator in acrylic cements such as polymethyl methacrylate (PMMA). Thus, depending on the composition of the cement, it can have the property of a retarder, an activator, or both. The set retarder effect was tested in Example 2.1.

[0246] Figure 34 shows the evolution of the setting time as a function of the mass proportion of vitamin C and Figure 35 shows the evolution of the maximum temperature as a function of the mass proportion of vitamin C. We note that for a formulation without vitamin C, the setting time is 83 s and the maximum temperature is 86.7 °C. With a mass proportion of vitamin of 1.6%, maximum proportion tested, the setting time is 225 s and the maximum temperature is 48.9 °C.

[0247] The amount of BPO and DMT also influences the setting time of the cement. The greater the amount of BPO-DMT, the longer the setting time. Thus, a setting time of 5 min is observed for 0.3 mL of BPO-DMT and a setting time of 40 min for 0.7 mL of BPO-DMT. However, increasing the amount of BPO-DMT can lead to an increase in the cytotoxicity of the cement. The compromise between cytotoxicity, a subject that will be discussed below, and setting time is found for a quantity of 0.5 mL of BPO-DMT with a setting time of 12 min.

[0248] The Young's modulus and the breaking stress of the cement after setting were measured by a compression test for Example 2.3, loaded with HA / TCP. The cement has a cylindrical shape with a height of 15 mm and a diameter of 10 mm. The Young's modulus was measured before and after a 7-day immersion in PSB. The results are shown in Table 6.

[0249] [Table 6]

[0250] The sample after immersion shows a very ductile behavior, it is easily cut with a scalpel and has a pore volume of approximately 30%.

[0251] To evaluate the behavior of cement in a liquid medium, a hydrostatic weighing device is used. A hydrostatic weighing device is used to measure the weight of an object with an undeterminable apparent volume, such as powdered materials. The device thus makes it possible to measure the swelling as well as the open porosity of the cement. The measurement method consists of weighing dry cement pellets, cylindrical in shape with a diameter of 10 mm and a height of 2 mm, then immersing them in a liquid medium at a rate of 15 mL per pellet while stirring at 180 rpm and at room temperature. On each sampling day, the samples are weighed wet and in the hydrostatic balance basket, under water. Each weighing is repeated 3 times and on 5 identical pellets.

[0252] The swelling of the material is calculated by the formula math 10 and the porosity by the formula math 11.

[0253] [Math. 10] .100

[0254] [Math. 11] .100

[0255] where M s is the dry mass of the pellet, M h is the wet mass of the pellet, PO is the open porosity of the cement pellet and M e is the underwater mass of the pellet.

[0256] The swelling and open porosity of the three cement formulations were tested in different liquid media: - distilled water, - the PBS, - simulated body fluid (SBF), and - alcohol.

[0257] The swelling of the pellets is mainly due to pHEMA. This swelling is useful in the context of implantation in bone sites. It allows filling a bone gap, whereas the removal of PMMA-based cements, for example, promotes the harmful development of fibrous tissue at the cement-bone interface. It also makes it possible to deal with the possibility, from the first hours, of incomplete filling of the bone cavity during placement by the surgeon.

[0258] Figure 36, 37 and 38 show the evolution of the swelling of formulation 1, 2 and 3 respectively in the different liquid media as a function of the number of days of immersion. The swelling occurs very quickly, after one day and peaks around for aqueous media, i.e. water, PBS and SBF. It can be seen that the swelling in alcohol is significantly higher than in aqueous media, since the maximum swelling of the cement reaches 40% from the 3 e day. Despite the very significant swelling in alcohol, which can reach up to 60%, no degradation of the tablet took place.

[0259] Figure 39 shows the evolution of the open porosity of formulations 1, 2 and 3 as a function of the number of days for immersion in distilled water. Before immersion, the samples have an open porosity of 3%. A very rapid increase in open porosity is observed in one day before reaching a ceiling of 30% for formulations 1 and 2 and 33% for formulation 3. This difference in open porosity between the formulations is to be linked to the swelling of the formulations in water in Figures 16, 17 and 18. It can therefore be deduced that in the case of water, the swelling is due to the open porosity. In addition, after reaching the ceiling of the open porosity, it is observed that the swelling of the cement no longer increases. It can be assumed that water does not penetrate or penetrates very little into the cement or that the closed porosity of the cement is low or almost non-existent.

[0260] Swelling can be limited by pre-saturating the cement with an aqueous fluid. Indeed, achieving swelling of the cement through hydration is certainly very appreciable for the reasons mentioned above. However, in many pathologies concerned by bone filling, the bones may already be fragile (osteoporosis, osteosarcoma for example). Incorporating a cement that becomes too saturated with biological fluid could weaken the surrounding bones and induce other bone disorders.

[0261] Distilled water was added to the liquid phase before mixing the two phases. Tests on the mixability and setting of the cement led us to set the quantity at 0.28 g of water for 1.3 g of HEMA. Indeed, incorporating water into the cement does not improve mixability. The addition of 0.28 g makes it possible to move from a cement without water that swells by 34% after two days to cement that swells by 24% after two days.

[0262] The injectability criterion is important for the administration of cement, either by injection by the clinician into the bone, for example by vertebroplasty, kyphoplasty or by spatula deposition, or to deposit the cement on a support manually or better by rapid prototyping.

[0263] Rapid prototyping is a computer-controlled manufacturing method. It allows for the rapid creation of models that will be produced in order to reduce development time. The tooling required for implementing this method is inexpensive while ensuring excellent performance of the final product. Finally, through the use of machines such as 3D printers and milling machines, rapid prototyping is capable of producing extremely complex shapes, particularly suitable for bone implants, for example.

[0264] For the same amount of starch, the injectability force was measured for 6 botanical varieties of starch. The results are shown in Figure 40. The injectability test consists of placing 5 mL of cement in a sterile 10 mL syringe, then placing the syringe in a compression machine and measuring the force applied for a constant displacement of 1 mm per second.

[0265] It is important to assess the cytotoxicity of the cement, that is, its ability to attack or even destroy the body's cells. To do this, the pellets used to test the swelling and open porosity of the cement are rinsed and dried. They are then sterilized by UV radiation for 30 minutes per side.

[0266] Cement pellets were placed in a 24-well plate and covered with 1 mL of Eagle's Minimum Essential Medium culture medium containing bovine proteins. The plate was incubated at 37°C for 48 hours. After two days, the culture medium in contact with the pellets was removed and 100 μL was deposited on MC3T3-E1 osteoblasts at 60% confluence. The survival rate was determined by measuring cell activity using the Alamar blue method.

[0267] Figure 41 shows the cell survival rate based on each cement formulation and two controls, the first based on 100% alumina, and the second based on tissue culture polystyrene (TCPS), the material used in the culture plates. It can be seen that the alumina-based control induces the death of all cells, while the pellets of the three cement formulations have a cell survival rate with a minimum of 78% for formulation 3 and a maximum of 81% for formulations 1 and 2.

[0268] In order to reduce the cytotoxicity of cement formulations, it is necessary to divide the amount of BPO and DMT by three, that is, to 19 mL and follow the following protocol: - wash the cement with ether 3 times for 20 min, - wash the cement with ethanol for 30 min, - wash the cement with water for 48 hours, and - dry the cement in an oven.

[0269] An increase in cell survival rate was observed when the previous protocol was followed, with a cell survival rate of 92% for all three formulations.

[0270] Bone cement, due to its hydrogel properties, can be used as a release agent for substances in the body, including drugs. To study the amount of substance release in vitro, the pellets underwent a desorption test and an impregnation test with ciprofloxacin (CFX).

[0271] CFX belongs to the fluoroquinolone family. This active ingredient is used in the treatment of many infections, including skin and soft tissue infections, as well as osteoarticular infections. It is an antibiotic whose action inhibits topoisomerase I and topoisomerase IV, which are responsible for the replication, transcription, repair, and recombination of bacterial DNA.

[0272] The desorption test was carried out following the following protocol: - the cement pellets are left to soak for 24 hours in a CFX perfusion solution at a concentration of 2 g / L, stirring at 180 rpm and at room temperature, - the cement pellets are introduced into a volume of 20 mL of 0.1 mol / L sodium hydroxide placed under stirring at 80 rpm at 37°C for 12 h, and - the quantity of CFX released by the cement pellets is measured by UV / Visible spectrophotometry.

[0273] Figure 42 shows the total amounts of antibiotic present in the different cements. The cements absorbed similar amounts of CFX during impregnation, around 3.2 mg / g of cement, without likely demonstrating a significant difference depending on the load.

[0274] The impregnation test was carried out following the following protocol: - the cement pellets are left to soak for 24 hours in a ciprofloxacin perfusion solution at a concentration of 2 g / L, stirring at 180 rpm and at room temperature, - the cement pellets are dried for 24 hours at 37°C, - the pellets are placed in a release cell comprising a 5 mm diameter ruby ​​bead, more particularly on a bed of 1 mm diameter glass beads, - a flow of PBS from a 100 mL volume reservoir is sent via a pump into a UV / Visible spectrophotometer, then into the release cell, then back into the reservoir and back into the UV / Visible spectrophotometer.

[0275] The UV / Visible spectrophotometer measures absorbances at 270 nm every 5 minutes for the first 6 hours and then at 15-minute intervals for up to 24 hours.

[0276] Figure 43 shows the release profile of ciprofloxacin as a function of time for the three cement formulations. For the alumina-filled cement, formulation 1, the release profile appears prolonged. Although the release is faster in the first hours (0.50 mg / g of cement at 1 hour), the maximum concentration plateau does not appear to be fully reached at 24 hours: the quantity released is then 1.53 mg / g of cement and this represents 47% of the amount released by the desorption test. It can therefore be assumed that the release continues after 24 hours.

[0277] For CSH-loaded cement, formulation 2, the release of CFX occurs during the first hours, as the plateau is reached at 15 hours at 2.2 mg of CFX / g of cement, which represents 69% of its total quantity in CFX.

[0278] The biphasic cement loaded with HA / TCP, formulation 3, is the cement that releases the largest quantity of antibiotic and the fastest. The active ingredient is released gradually and reaches a quantity released at 24 hours of 3.1 mg of CFX / g of cement, or 86% of the total quantity present in the cement. It can be concluded that the biphasic cement presents good results for a massive release of CFX, since it releases a large quantity of the active ingredient and gives the best release rate. Knowing that the release by a cement is on a local scale, therefore in a restricted environment, the release of this antibiotic by such cements is conceivable in clinical practice.

[0279] In addition, it would also be possible to adjust the concentration of the impregnation solution to increase the amount absorbed by the cement. The form of the active ingredient can also vary its release profile.

[0280] For prophylactic antibiotic release, alumina-filled cement is an interesting solution, as is CSH. A prolonged release profile can be interesting for the release of drugs such as, as here, antibiotics but also anticancer drugs or analgesics, for example.

[0281] Example 3: Optimal composition of cement for deposition on a titanium insert

[0282] In this example, an optimal composition of bone cement will be presented. This optimal composition is the best compromise between the different properties of bone cement.

[0283] The optimal composition of cement includes: - a liquid phase composed of 1.8 g of HEMA and 0.0031 g of DMT, and - a solid phase composed of 1.733 g of HA / TCP, 0.675 g of cellulose acetate, 0.294 g of starch and 0.01 g of BPO.

[0284] The two phases are brought into contact to form a paste which is poured into a silicone mold. After the cement has set, it is removed from the mold. Four cement pellets are made.

[0285] The 4 cement pellets are characterized after 7 days of immersion in PBS. The characterization results are presented in the following table.

[0286] [Table 7]

[0287] This composition is the most optimized, that is to say it is the best compromise between mechanical properties, injectability and moderate swelling.

[0288] Example 4: Two-layer surgical insert without separators

[0289] In this example, a 1-layer surgical insert will be presented with two zones 122, 123 of different porosities in the second layer 12.

[0290] A surgical insert 1 was produced by rapid prototyping. Figure 9 shows the two faces of insert 1 and its properties are presented in the table below.

[0291] [Table 8]

[0292] The holes have the dimensions shown in the table below.

[0293] [Table 9]

[0294] A 4 mm deposit of the bone cement shown in Example 1 was made on surgical insert 1. The coated insert was immersed for 4 days in PBS. The properties of insert 1 with deposit after immersion are shown in the table below.

[0295] [Table 10]

[0296] Example 5: Surgical insert with mechanical reinforcement

[0297] Figure 28 shows the simulation results of two inserts both having octomorphic shaped holes. One 1a has no mechanical reinforcement (black bars) and the other 1a has mechanical reinforcement 16 (grey bars). The bars represent the simulated maximum displacement in the case where the insert is subjected to a bending force F, a tensile force Tr or a torsion force To. The values ​​are normalized by the values ​​obtained for insert 1a without mechanical reinforcement. It can be seen that the maximum displacement is lower when applying the three types of force for insert 1b with mechanical reinforcement compared to that without mechanical reinforcement. Digital references

[0298] 1: surgical insert, 11: first layer, 111: orifices of the first layer, 112: transverse orifices of the first layer, 12: second layer, 121: orifices of the second layer, 122: first zone of the second layer, 1221: orifices of the first zone of the second layer, 123: second zone of the second layer, 1231: orifices of the second zone of the second layer, 124: transverse orifices of the second layer, 13: third layer, 131: orifices of the third layer, 14: fixing lugs, 15: plurality of separators, and 151: orifices of the plurality of separators.

Claims

Claims

1. Bone cement comprising: - a powdery solid phase comprising natural polysaccharides or those derived from natural compounds and a ceramic filler, - a liquid phase acrylate, and - a polymerizer.

2. A bone cement according to claim 1 further comprising at least one of: - a radiopacifier, and - a swelling-limiting agent.

3. Bone cement in the form of cement according to claim 2, in which the natural polysaccharide or polysaccharide derived from natural compounds is selected from cellulose acetate and starch.

4. Bone cement according to claim 3, wherein the starch is selected from wheat starch, potato starch, corn starch, pea starch and mixtures thereof, preferably potato starch.

5. Bone cement according to any one of claims 1 to 4, further comprising a setting activator or retarder, in particular said setting activator or retarder being vitamin C.

6. Bone cement according to any one of claims 1 to 5, wherein the mass proportion of the acrylate relative to the total mass of the bone substitute is between 30% and 50%, preferably between 35% and 45%, preferably between 37.5% and 42.5%, for example 40%.

7. Bone cement according to any one of claims 1 to 6, having a Young's modulus of between 1 MPa and 32 MPa after 7 days of immersion in saline phosphate buffer, preferably greater than 5 MPa.

8. Bone cement according to any one of claims 1 to 7, having a shear modulus of between 100 Pa.s and 150,000 Pa.s, preferably between 2,000 Pa.s and 20,000 Pa.s.

9. Bone cement according to any one of claims 24 to 31, having a swelling ratio of between 21% and 32% after 7 days of immersion in phosphate buffered saline.

10. Surgical insert (1) made of bone cement and comprising: - a first layer (11), and - a second layer (12), wherein the first layer and the second layer comprise orifices (111, 121) having an octomorphic shape; wherein the bone cement is according to one of claims 1 to 9.

11. A surgical insert according to claim 10, wherein the octomorphic shape is a shape composed of two end portions, each formed by a circle of radius; the two end portions being connected to each other by a central portion formed by a circular fillet of radius r2 so that the width of the central portion is less than the width of the end portions.

12. A surgical insert according to claim 10 or claim 11, wherein the first radius of curvature of the orifices of a layer is greater than or equal to 345 pm and less than or equal to the following formula: [Math. r l,max where n.max is the first maximum radius of curvature of the holes in the first layer, S is the total surface area of ​​a layer, <p est le rapport entre la surface totale occupée par les orifices et la surface totale de la première couche et / Vest le nombre de orifices d’une couche.

13. A surgical insert according to any one of claims 10 to 12, wherein the ratio of the total surface area occupied by the orifices of a layer to the total surface area of ​​that layer is greater than or equal to 0.09 and less than or equal to 0.

92.

14. A surgical insert according to any one of claims 10 to 13, wherein the orifices are arranged in a pattern selected from a square pattern, a hexagonal pattern, and a heterogeneous pattern.

15. A surgical insert according to claim 14, wherein the orifices are arranged in a heterogeneous pattern defined by a Bézier curve.

16. Surgical insert according to one of claims 10 to 15, in which the arrangement of the octomorphic shaped orifices (121) of the second layer results from a homothetic duplication of the arrangement of the octomorphic shaped orifices (111) of the first layer.

17. Insert according to claim 16, in which the homothetic duplication induces a minimum overlap section of 0.2 mm. 2 between the octomorphic shaped orifice of the first layer and that of the second layer.

18. A surgical insert according to any one of claims 10 to 17, wherein the first layer has a porosity greater than that of the second layer.

19. Surgical insert according to one of claims 10 to 18, in which the orifices of the first layer have a total length and the orifices of the second layer have a total length; wherein the ratio of the total length of the orifices of the first layer and the total length of the first orifices of the second layer is greater than 1.

4.

20. Surgical insert according to one of claims 10 to 19, in which the second layer has a keying device (122).

21. A surgical insert according to claim 20 wherein the keying device is formed of two zones on the second layer, a first zone with orifices having a first total length and a second zone with second orifices having a second total length; wherein the ratio between the first total length and the second total length is between 1.6 and 2, preferably between 1.7 and 1.9, preferably between 1.75 and 1.85, for example 1.

8.

22. A surgical insert according to any one of claims 10 to 21, further comprising a plurality of separators (15) disposed between the first layer and the second layer.

23. Surgical insert according to claim 22, in which the thickness h of each layer satisfies the relationship: [Math. 1] where / is the maximum width of the surgical insert and L is the maximum length of the surgical insert.

24. A surgical insert according to claim 22 or claim 23, wherein each of the plurality of separators is a pillar having a cross-sectional shape as described in claims 1 to 3.

25. A surgical insert according to any one of claims 22 to 24, wherein each of the plurality of pillars has a longitudinal axis forming an angle with the midplane formed by the first layer and the second layer greater than or equal to 5° and less than or equal to 90°.

26. A surgical insert according to any one of claims 22 to 25, wherein each of the plurality of pillars is helical and has a twist angle greater than 0° and less than or equal to 180°, preferably less than or equal to 90°.

27. ​​A surgical insert according to any one of claims 22 to 26, wherein each of the plurality of pillars comprises transverse holes (151) at its lateral surface.

28. A surgical insert according to any one of claims 10 to 27, wherein the orifices of the first layer and / or the second layer have a side wall formed in the thickness of the corresponding layer, and wherein the first layer and / or the second layer comprises transverse orifices of octomorphic shape as described in claims 10 to 12 and extending between the side wall of two orifices of the corresponding layer.

29. Surgical insert according to claim 27 or claim 28, wherein each of the orifices of each layer has a section greater than or equal to 0.70 mm 2 .

30. A surgical insert according to any one of claims 10 to 29, being composed of a material selected from a polymer, a metal, a ceramic or a composite.

31. A surgical insert according to any one of claims 10 to 30, further comprising a securing tab (14) extending from one of the first layers.

32. A surgical insert according to any one of claims 10 to 31, further comprising a mechanical reinforcement (16).

Images