BONE CEMENT WITH HYALURONIC ACID

Abstract

A bone cement composition including a powder component, a liquid component, and hyaluronic acid (HA) or a salt thereof in an amount ranging from 0.01% to 10% w/w in the powder component and/or in the liquid component. The powder component includes calcium phosphate compounds having at least alpha-tricalcium phosphate (α-TCP) and having at least calcium-deficient apatite (CDA). Also, a bone cement obtainable by a process including the following steps: (i) the preparation of a cement composition by mixing the powder component, and the liquid component and (ii) the setting of the cement composition. Further, the use in vitro or ex vivo of a bone cement composition or bone cement in the manufacture of a dental or bony implant.

Claims

1-21. (canceled)

22. A bone cement composition comprising: a powder component comprising: calcium phosphate compounds comprising at least alpha-tricalcium phosphate (α-TCP) and comprising at least calcium-deficient apatite (CDA), and optionally at least one calcium sulfate compound; a liquid component; and hyaluronic acid (HA) or a salt thereof; wherein: said hyaluronic acid (HA) or salt thereof is comprised in said powder component in an amount ranging from 0.01% to 10% w/w; and/or said hyaluronic acid (HA) or salt thereof is comprised in said liquid component in an amount ranging from 0.01% to 10% w/w.

23. The bone cement composition according to claim 22, wherein said liquid component is an aqueous solution or an aqueous suspension.

24. The bone cement composition according to claim 22, wherein said powder component comprises said α-TCP in an amount ranging from 60% to 95% w/w.

25. The bone cement composition according to claim 22, wherein said powder component comprises said CDA in an amount ranging from 2.5% to 20% w/w.

26. The bone cement composition according to claim 22, wherein said powder component comprises at least one further calcium phosphate compound selected from the group consisting of hydroxyapatite (HA.sub.p), amorphous calcium phosphate (ACP), monocalcium phosphate anhydrous (MCPA), monocalcium phosphate monohydrate (MCPM), dicalcium phosphate dihydrate (DCPD), dicalcium phosphate anhydrous (DCPA), β-tricalcium phosphate (β-TCP), octacalcium phosphate (OCP), tetracalcium phosphate (TTCP), and a mixture thereof; and/or at least one calcium sulfate compound selected from the group consisting of anhydrous calcium sulfate, calcium sulfate hemihydrate, calcium sulfate dihydrate, and a mixture thereof.

27. The bone cement composition according to claim 22, wherein said powder component consists of α-TCP, CDA and DCPA or consists of α-TCP, CDA, DCPD and MCPM.

28. The bone cement composition according to claim 22, wherein said liquid component further comprises at least one inorganic salt selected from the group consisting of sodium chloride (NaCl), trisodium phosphate (Na.sub.3PO.sub.4), disodium hydrogen phosphate (Na.sub.2HPO.sub.4), monosodium dihydrogen phosphate (NaH.sub.2PO.sub.4), and a mixture thereof; wherein said inorganic salt is in an amount ranging from 0.01% to 20% w/w.

29. The bone cement composition according to claim 22, wherein said liquid component further comprises at least one inorganic salt selected from the group consisting of Na.sub.2HPO.sub.4 and a Na.sub.2HPO.sub.4/NaH.sub.2PO.sub.4 mixture; wherein said inorganic salt is in an amount ranging from 0.1% to 1% w/w or from 2 to 8% w/w.

30. The bone cement composition according to claim 22, wherein said liquid component comprises at least one biological liquid selected from the group consisting of blood, plasma, platelets, platelets concentrate, bone marrow, bone marrow concentrate, and mixtures thereof.

31. The bone cement composition according to claim 22, wherein said liquid component consists of water, HA or salt thereof, optionally Na.sub.2HPO.sub.4, and optionally at least one biological liquid selected from the group consisting of blood, plasma, platelets, platelets concentrate, bone marrow, bone marrow concentrate, and mixtures thereof.

32. The bone cement composition according to claim 22, wherein said HA or salt thereof has a molecular weight ranging from 1 kDa to 5 000 kDa.

33. The bone cement composition according to claim 22, wherein said powder component comprises said HA or salt thereof in an amount ranging from 0.01% to 5% w/w.

34. The bone cement composition according to claim 33, wherein said powder component comprises said HA or salt thereof in an amount ranging from 0.1% to 1% w/w.

35. The bone cement composition according to claim 22, wherein said liquid component comprises said HA or salt thereof in an amount ranging from 0.01% to 5% w/w.

36. The bone cement composition according to claim 35, wherein said liquid component comprises said HA or salt thereof in an amount ranging from 0.1% to 1% w/w.

37. The bone cement composition according to claim 22, wherein the liquid component/powder component (L/S) ratio ranges from 0.3 to 0.7 ml/g.

38. The bone cement composition according to claim 22, wherein said bone cement composition is injectable.

39. The bone cement composition according to claim 22, further comprising at least one active ingredient selected from the group consisting of antibiotics, anti-inflammatory drugs, anti-cancer drugs, anti-osteoporosis drugs, bone anabolic drugs, growth factors, water-soluble radiopaque agents, contrast agents, and a mixture thereof.

40. A bone cement obtainable by a process comprising the following steps: the preparation of a bone cement composition according to claim 22, and the setting of said bone cement composition.

41. A kit-of-parts for manufacturing a bone cement composition according to claim 22, said kit-of-parts comprising: a first part being a powder component comprising: calcium phosphate compounds comprising at least alpha-tricalcium phosphate (α-TCP) and comprising at least calcium-deficient apatite (CDA), and optionally at least one calcium sulfate compound; a second part being a liquid component; and hyaluronic acid (HA) or a salt thereof; wherein: said hyaluronic acid (HA) or salt thereof is comprised in said powder component in an amount ranging from 0.01% to 10% w/w; and/or said hyaluronic acid (HA) or salt thereof is comprised in said liquid component in an amount ranging from 0.01% to 10% w/w.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0145] FIG. 1 is a series of photographs showing the aspect of cement compositions HBS, 3H and 31 after injection and after hardening, for qualitative evaluation of their cohesiveness as described in Example 3.

[0146] FIG. 2 is a series of photographs showing the aspect of cement compositions 3J, 4H and 5J after injection and after hardening, for qualitative evaluation of their cohesiveness as described in Example 3.

[0147] FIG. 3 is a series of photographs showing the microstructure characterization (SEM) of cement HBS, 3H and 3J as described in Example 3. The structure of the cements 3H and 3J have a lower mineral density than HBS cement, so that the cements according to the invention results have a higher porosity.

[0148] FIG. 4 is a series of photographs showing the aspect of cement compositions 3H and M after injection and after hardening, for qualitative evaluation of their cohesiveness as described in Example 4.

EXAMPLES

[0149] The present invention is further illustrated by the following examples.

Example 1

Bone Cement Compositions and Manufacture thereof

[0150] Materials and Methods

[0151] Materials

[0152] Sodium hyaluronate (NaHA) with molecular weight of about 800 kDa, hydroxypropylmethylcellulose (HPMC) and inorganic salts were purchased from commercial providers and used without further purification.

[0153] Methods

[0154] Liquid component preparation: Solid sodium hyaluronate (NaHA) was dissolved in a disodium hydrogen phosphate (Na.sub.2HPO.sub.4) aqueous solution so as to obtain the liquid component.

[0155] Powder component preparation: The solid substances were mechanically mixed together so as to obtain the powder component. The powder component has a main population of particle size (i.e., more than 50% of particles in the powder) ranging from 3 to 30 μm.

[0156] Bone cement preparation: The powder component was placed in a mortal and the liquid component was added thereto, then the mixture was mixed at room temperature with a metal spatula until a homogeneous paste was obtained (about 1 min). Reference time to is defined as the moment of the liquid-powder contact.

[0157] Results

[0158] The disclosed bone cement compositions have the following compositions:

TABLE-US-00001 TABLE 1 Composition Powder component (% w/w) A B C α-tricalcium phosphate 67.5 ± 2.5% 77.5 ± 2.5% 87.5 ± 2.5% (α-TCP) dicalcium phosphate 14.8 ± 0.3%  9.8 ± 0.3%  4.8 ± 0.3% anhydrous (DCPA) calcium-deficient 15.1 ± 0.3% 10.1 ± 0.3% 5.1 ± 0.3% hydroxyapatite (CDA) hydroxypropylmethylcellulose  2.9 ± 0.1%  1.9 ± 0.1%  0.9 ± 0.1% (HPMC) Liquid component (% w/w) A B C disodium hydrogen phosphate  0.50 ± 0.02%  0.50 ± 0.02%  0.50 ± 0.02% (Na.sub.2HPO.sub.4) water q.s. q.s. q.s. Liquid/powder ratio (L/S) 0.460 ± 0.015 0.460 ± 0.015 0.460 ± 0.015 (mL/g) Composition Powder component (% w/w) D E F G α-TCP 77.5 ± 2.5% 77.5 ± 2.5% 77.5 ± 2.5% 77.5 ± 2.5% DCPA  9.8 ± 0.3%  9.8 ± 0.3%  9.8 ± 0.3% — CDA 10.1 ± 0.3% 10.1 ± 0.3% 10.1 ± 0.3% 10.1 ± 0.3% dicalcium phosphate — — —  5.2 ± 0.2% dihydrate (DCPD) monocalcium — — —  4.9 ± 0.2% phosphate monohydrate (MCPM) Liquid component (% w/w) D E F G Na.sub.2HPO.sub.4  0.50 ± 0.02%  0.50 ± 0.02%  0.50 ± 0.02%  5.0 ± 0.3% water q.s. q.s. q.s. q.s. L/S (mL/g) 0.460 ± 0.015 0.510 ± 0.015 0.560 ± 0.015 0.510 ± 0.015

[0159] Sodium hyaluronate (NaHA) is further present in the liquid component in the following amounts:

TABLE-US-00002 TABLE 2 1 2 3 4 NaHA (% w/w) — 0.1% 0.5% 1%

[0160] The cement compositions have been successfully manufactured using the materials and methods as described hereinabove.

[0161] Composition 1 is the control cement without hyaluronic acid. Compositions 2-4 are compositions of the invention.

Example 2

Properties of the Compositions

[0162] Materials and Methods

[0163] Materials

[0164] The bone cement compositions were manufactured as described in Example 1 above.

[0165] Methods

[0166] Measurement of Injectability—Extrusion Method: After Mixing the Solid and Liquid components, the cement composition (2.5 mL) was introduced in a syringe (Terumo®) with a 1.5 mm diameter needle, then was extruded by applying a syringe plunger displacement at a speed of 15 mm min−1.

[0167] Measurement of setting time—Gillmore needle method (ASTM C266-2018): The principle of this method is visual examination of the surface of the cement composition, the setting time being the moment at which a needle (with a given diameter and a weight) leaves only a small footprint when it is placed on the surface of the cement composition. Gillmore needle system consists of two needles: the first needle has a large diameter and a small weight and it is used to measure the initial setting time, noted t, whereas the second needle has a smaller diameter and a larger weight and it is used to measure the final setting time, noted t.sub.f. The clinical meaning of t, and t.sub.f is that the cement can be implanted until t, and that the wound can be closed as from t.sub.f. Between t.sub.i and t.sub.f, the cement composition must not be touched nor deformed, as the hardening process is ongoing.

[0168] Measurement of Young's Modulus (YM) [as described in Kaplan et al., J. Biomech, 1985 and Zhang et al. Acta Biomater. 2014] and compressive strength (R.sub.s): After mixing the solid and liquid components, the cement composition was moulded before being placed in a NaCl aqueous solution at 37° C. (similar to in vivo conditions). The measurement of diametric tensile strength and compressive strength were carried out at different times in order to follow the evolution of the mechanical properties during the setting of the cement until the setting reaction is considered complete (generally from 24 to 72 hours).

[0169] Results

[0170] Injected volume (Inj.), applied force for injection (Inj, force), setting time (ST), Young's Modulus (YM) and compressive strength (R.sub.s) of compositions 1-4B are shown on

[0171] Table 3:

TABLE-US-00003 TABLE 3 Inj. Inj, force ST YM R.sub.S # (mL) (N) (min) (MPa) (MPa) 1B (0%) 2.5 5.23 ± 2.31 8.0 891 ± 47 23.1 ± 1.3 2B (0.1%) 2.5 5.88 ± 1.22 7.5 802 ± 66 22.5 ± 0.8 3B (0.5%) 2.5 5.12 ± 2.77 7.0 701 ± 90 21.6 ± 1.5 4B (1%) 2.5 8.11 ± 1.87 5.0 569 ± 54 18.1 ± 0.9

[0172] Applied force for injection tends to be similar—and within adequate working range—for all tested compositions 1-4B, although a limited increase is observed when high NaHA amounts are used (4B).

[0173] Gillmore setting time is significantly reduced in presence of NaHA in compositions 2-4B, depending of the amount of NaHA (from −6% to −38%).

[0174] Young's modulus is also significantly reduced in presence of NaHA in compositions 2-4B, depending of the amount of NaHA (from −10% to −36%). This reduced rigidity is interesting for bone filling applications.

[0175] Compressive strength tends to be similar—and within adequate working range—for all tested compositions 1-4B.

[0176] Therefore, the above results evidence that addition of hyaluronic acid or a salt thereof to the liquid component of a bone cement composition unexpectedly lead to significant improvement of physical and mechanical properties for both the cement composition (paste) and the bone cement (final material). Increasing amounts of HA ranging from 0.1 to 1% w/w in liquid component lead to increase of the properties relatively to the HA amount.

[0177] In order to study the effect of L/S ratio on the properties of the compositions, injectability (Inj.) and setting time (ST) of compositions 1D (control) and 3E-F (0.5% w/w NaHA, increasing L/S ratio from 0.45 to 0.55 mL/g) have been measured. The results are shown on Table 4:

TABLE-US-00004 TABLE 4 Inj. (Force (N), ST # % extrusion) (min) ID >25N 3.7 ± 0.3 min 41% 3E 59.4 ± 5.2N 7.0 ± 0.5 min 94% ± 1% 3F 28.7 ± 4.7N 7.7 ± 0.3 min 94% ± 3%

[0178] In the compositions of the invention 3E and 3F, injectability (filter pressing, 4 min, 4 measures) increases as L/S ratio increases, whereas applied force decreases.

[0179] As L/S ratio increases, setting time (ST) (3 measures) also increases in compositions 3E and 3F compared to control 1D, but however remains within adequate working range (7-8 min).

[0180] Therefore, increasing the L/S ratio in the bone cement compositions of the invention may be an interesting option when increase of injectability is desired.

Example 3

Comparative Experiments over Graftys® HBS

[0181] The properties of the compositions according to the invention were compared with the properties of Graftys® HBS bone cement composition.

[0182] Materials and Methods

[0183] Materials

[0184] Graftys® HBS bone cement composition (“HBS” composition in Table 5 below), sodium hyaluronate (NaHA) with molecular weight of about 800 kDa and inorganic salts were purchased from commercial providers and used without further purification.

[0185] Methods

[0186] Manufacturing methods: Liquid component preparation: NaHA was dissolved in a disodium hydrogen phosphate (Na.sub.2HPO.sub.4) aqueous solution to obtain the liquid component. Powder component preparation: The solid substances were mechanically mixed together to obtain the powder component. The powder component has a main population of particle size (i.e., more than 50% of particles in the powder) ranging from 2 to 100 μm. Cement preparation: The powder component was placed in a mortar and the liquid component was added to it, then the mixture was mixed at room temperature with a pestle until a homogeneous paste was obtained (about 1 min). Reference time to is defined as the moment of the liquid-powder contact.

[0187] Characterization methods: Measurement of injectability & cohesiveness—Extrusion method: After mixing the solid and liquid components, the cement composition (3.5 mL) was introduced in a syringe (Terumo®) with a 1.5 mm diameter needle. After 15 min, the paste was extruded by applying a syringe plunger displacement at a speed of 1 mm s.sup.−1.

[0188] The applied force for injection was measured. Cohesiveness was qualitatively evaluated by taken a picture just after injection in a physiological solution and after 24 h or 72 h of incubation at 37° C. in the same solution. Measurement of initial setting time—Gillmore needle method (ASTM C266-2018): The principle of this method is visual examination of the surface of the cement composition, the setting time being the moment at which a needle (with a given diameter and a weight) leaves only a small footprint when it is placed on the surface of the cement composition. Measurement of compressive strength (R.sub.s) and Young's Modulus (YM): After mixing the solid and liquid components, cement paste was molded in cylinders before being placed in a physiological solution at 37° C. (similar to in vivo conditions). After 72 h, at least 5 porous cylinders per condition were submitted to increasing compression load (compressive displacement of 1 mm s.sup.−1). From the obtained stress vs. strain curve, compressive strength of the material was evaluated. Young's Modulus (YM) was evaluated as the slope of the stress-strain curve in the elastic region (linear region) [as described in Kaplan et al., J. Biomech, 1985 and Zhang et al. Acta Biomater. 2014]. Microstructure characterization by SEM: The measurements were carried out on cylindrical cement blocks allowed to harden for 72h in 0.9 wt. % NaCl at 37° C. Then, a 1 mm.sup.2 polished cross-section of the samples was obtained using a JEOL cross section polisher SM09010, by applying an argon ion beam accelerated by a voltage from 4.5 to 6 kV perpendicular to the surface of each specimen for 4 to 8 hours. SEM observation of those samples was performed using a Field Emission Gun Scanning

[0189] Electron Microscope (Jeol 7600F). Images were acquired on a back scattered electron mode with an 8 pA beam current and a 8 kV accelerated voltage.

[0190] Results

[0191] The compared bone cements have the following compositions:

TABLE-US-00005 TABLE 5 Composition Powder component (% w/w) HBS H 1 J α-tricalcium phosphate 77.5 ± 2.5% 79.5 ± 2.5% 79.5 ± 2.5% 79.5 ± 2.5% (α-TCP) dicalcium phosphate  5.2 ± 0.2%  5.1 ± 0.2%  5.1 ± 0.2%  5.1 ± 0.2% dihydrate (DCPD) monocalcium phosphate  4.9 ± 0.2%  5.2 ± 0.2%  5.2 ± 0.2%  5.2 ± 0.2% monohydrate (MCPM) calcium-deficient 10.1 ± 0.3% 10.1 ± 0.3% 10.1 ± 0.3% 10.1 ± 0.3% hydroxyapatite (CDA) Hydroxy-propyl-methylcellulose  1.9 ± 0.1% — — — (HPMC) Liquid component (% w/w) HBS H 1 J disodium hydrogen  5.1 ± 0.2%  5.1 ± 0.2%  5.1 ± 0.2%  5.1 ± 0.2% phosphate (Na.sub.2HPO.sub.4) water q.s. q.s. q.s. q.s. Liquid/powder ratio (L/S) (mL/g)  0.59 ± 0.015  0.59 ± 0.015  0.50 ± 0.015  0.65 ± 0.015

[0192] Sodium hyaluronate (NaHA) is further present in the liquid component in the following amounts:

TABLE-US-00006 TABLE 6 3 4 5 NaHA (% w/w) 0.5 1 0.75

[0193] Composition HBS is the control cement. HBS comprises HPMC and does not comprise hyaluronic acid. Graftys® HBS is a state-of-the art commercial bone cement composition.

[0194] The interest of adding HPMC as organic component in the powder of Graftys® HBS is disclosed in WO 2008/023254 Al patent application (Khairoun, I. et al.). Compositions 3H, 4H, 3I, 3J and 5J are compositions according to the invention.

[0195] Measured applied force for injection (Inj, force), setting time (ST), compressive strength (R.sub.s) and Young's Modulus (YM) of the cement compositions are shown on

[0196] Table 7:

TABLE-US-00007 TABLE 7 Inj, force ST R.sub.s YM # (N) (min) (MPa) (MPa) HBS 12.67 ± 2.68  12.75 ± 0.25 8.43 ± 1.96 367 ± 81  3H 7.50 ± 1.43 11.06 ± 0.25 13.28 ± 0.85  836 ± 35  3I 6.16 ± 0.30 11.46 ± 0.39 15.63 ± 2.31  765 ± 92  3J 3.00 ± 1.10 14.64 ± 0.32 9.92 ± 1.33 671 ± 72  4H 9.50 ± 1.38 12.13 ± 0.18 14.51 ± 1.29  824 ± 37  5J 3.85 ± 0.54 13.67 ± 0.28 9.93 ± 2.08 598 ± 108

[0197] FIG. 1 and FIG. 2 show the cohesiveness of the cement compositions after injection and after hardening. FIG. 3 shows the microstructure comparison between HBS and 3H and 3J.

[0198] Injectability is significantly increased in the compositions according to the invention, as evidenced by the applied force for injection that is significantly reduced when the liquid component comprises NaHA (up to −76%).

[0199] Increasing the L/S ratio up to 0.65 significantly increases injectability in 3J, whereas the difference in L/S ratio between 3H and 3I (0.59 and 0.50 respectively) does not significantly impact the decrease in the force for injection. At L/S constant ratio, a significant increase in hyaluronic acid concentration come up with an increase in the viscosity of the liquid phase and therefore, the applied force for injection is increased in 4H in comparison with 3H. By contrast, a small difference in NaHA concentration (from 0.5 to 0.75 wt. %) does not significant affect the applied force for injection in 3J and 5J.

[0200] In any case, the injectability of all the compositions according to the invention (3H, 3I, 3J, 4H and 5J) is significantly improved compared to prior art composition (HBS).

[0201] Moreover, the cohesiveness is increased in the compositions according to the invention (3H, 3I, 3J, 4H and 5J) comprising NaHA compared to prior art composition (HBS) (FIG. 3): a higher shape retention of the cement filaments after injection into an aqueous solution is observed in 3H, 3I, 3J, 4H and 5J than in HBS. Especially, no disintegration is observed for 3H, 3I, 3J, 4H and 5J after injection.

[0202] Higher injectability and cohesiveness are very interesting properties for bone filling applications.

[0203] Gillmore setting time (ST) tends to be similar for all tested compositions.

[0204] Compressive strength (Rs) is increased (from +58% to +85%) in the cements 3H, 3I and 4H according to the invention, which have the same or lower L/S ratio as HBS.

[0205] Young's modulus is increased (up to +128%) in all the cements according to the invention (3H, 3I, 3J, 4H and 5J) compared to prior art composition (HBS).

[0206] In the microstructure analysis, different types of particles are observed for HBS and the cements according to the invention (3H and 3J). The size distribution ranges from 1.4 to 32 μm and the average size is 9 μμm. These particles correspond to (i) a dense small amount, either along their whole cross-section or in their inner part, and correspond to unreacted or partially hydrolyzed α-TCP or DCPD; (ii) a large amount of particles that have a geode-like morphology with a dense shell lined in its inner part with interdigitated platelet crystals, as a result of a full hydrolysis of α-TCP into CDA. The intergranular space (i.e., the area in between all these particles) is mostly occupied by CDA platelet crystals forming channels with a “sand rose” architecture. From FIG. 3 it is evidenced that the replacement of HPMC in the cement powder with NaHA in the liquid phase leads to a lower mineral density and higher particle size in the intergranular space.

[0207] As a consequence, the cements 3H and 3J according to the invention have a more open structure, of high porosity and with mechanical properties similar or superior to HBS, with less polymer added in the cement (about 85% less polymer in the cement). The latest characteristics would have a positive impact on cell colonization and the resorption of cement.

[0208] Therefore, the above results clearly evidence that the addition of hyaluronic acid or a salt thereof to the liquid component instead of HPMC in the powder component of a bone cement composition lead to significant improvement of physical and mechanical properties for both the cement paste and the bone cement (final material).

Example 4

Effect of Hyaluronic Acid in Liquid or Solid Component

[0209] The effect of adding hyaluronic acid either in the liquid component or in the solid component has been studied.

[0210] Materials and Methods

[0211] Materials

[0212] Sodium hyaluronate (NaHA) with molecular weight of about 800 kDa and inorganic salts were purchased from commercial providers and used without further purification.

[0213] Methods

[0214] Manufacturing methods: Liquid component preparation: NaHA was dissolved in a disodium hydrogen phosphate (Na.sub.2HPO.sub.4) aqueous solution to obtain the liquid component. Cement powder preparation: The solid substances were mechanically mixed together to obtain the powder component. NaHA-cement powder preparation: NaHA filaments were mixed with the cement powder overnight so as to obtain the powder component. The powder component has a main population of particle size (i. e., more than 50% of particles in the powder) ranging from 2 to 100 μm. Cement preparation: The powder component was placed in a mortar and the liquid component was added to it, then the mixture was mixed at room temperature with a pestle until a homogeneous paste was obtained (about 1 min). Reference time to is defined as the moment of the liquid-powder contact.

[0215] Characterization methods: Measurement of injectability & cohesiveness—Extrusion method: After mixing the solid and liquid components, the cement composition (3.5 mL) was introduced in a syringe (Terumo®) with a 1.5 mm diameter needle. After 15 min, the paste was extruded by applying a syringe plunger displacement at a speed of 1 mm s-1.

[0216] The applied force for injection was measured. Cohesiveness was qualitatively evaluated by taken a picture just after injection in a physiological solution and after 24h or 72h of incubation at 37° C. in the same solution. Measurement of initial setting time—Gillmore needle method (ASTM C266-2018): The principle of this method is visual examination of the surface of the cement composition, the setting time being the moment at which a needle (with a given diameter and a weight) leaves only a small footprint when it is placed on the surface of the cement composition.

[0217] Results

[0218] The compared bone cements have the following compositions:

TABLE-US-00008 TABLE 8 Composition Powder component (% w/w) 3H M α-tricalcium phosphate 79.5 ± 2.5% 79.5 ± 2.5% (α-TCP) dicalcium phosphate  5.1 ± 0.2%  5.1 ± 0.2% dihydrate (DCPD) monocalcium phosphate  5.2 ± 0.2%  5.2 ± 0.2% monohydrate (MCPM) calcium-deficient 10.1 ± 0.3% 10.1 ± 0.3% hydroxyapatite (CDA) Sodium hyaluronate —  0.28 ± 0.02% (NaHA) Liquid component (% w/w) 3H M Sodium hyaluronate  0.50 ± 0.02% — (NaHA) disodium hydrogen  5.1 ± 0.2%  5.1 ± 0.2% phosphate (Na.sub.2HPO.sub.4) water q.s. q.s. Liquid/powder ratio  0.59 ± 0.015  0.59 ± 0.015 (L/S) (mL/g)

[0219] 10

[0220] Compositions 3H and M are compositions according to the invention. 3H has the sodium hyaluronate in the liquid component, whereas M has the sodium hyaluronate in the powder component. This is the only difference between compositions 3H and M because, due to the L/S ratio of 0.59, the concentration of sodium hyaluronate after mixing the liquid and solid component is actually the same (about 0.2% w/w).

[0221] Measured applied force for injection (Inj, force) and setting time (ST) of the cement compositions are shown on Table 9:

TABLE-US-00009 TABLE 9 Inj, force ST # (N) (min) 3H 7.50 ± 1.43 11.06 ± 0.25 M 7.02 ± 1.72 12.88 ± 0.25

[0222] FIG. 4 shows the cohesiveness of the cement compositions after injection and after hardening.

[0223] The applied force for injection is low in presence of NaHA, whether it is in the liquid component (3H) or in the powder component (M). Additionally, cohesiveness is high and adequate (FIG. 4). The low applied forces for injection and the cohesiveness make those compositions fully injectable and easy-to-use, and thus of high interest for bone filling applications.

[0224] Gillmore setting time is in the adequate range of low viscosity bone cement paste for both compositions according to the invention (3H and M).

[0225] Therefore, the above results unambiguously evidence that the addition of hyaluronic acid or a salt thereof in a bone cement composition leads to similar properties, whether it is added in the liquid component and/or in the powder component.