NEW SINGLE-STEP MANUFACTURING PROCESS FOR FOAMED BIOMATERIALS

Abstract

Processes for the preparation of biomaterials, in particular foams and solid structures, suitable for bone surgery and odontology, bone regeneration, bone defect fillings, stabilizing bone fractures, coating of prostheses or implants, fixing of prostheses or implants, drug delivery systems, and tissue engineering scaffolds, and to the biomaterials obtained thereby. Besides that, this invention, also relates to self-setting calcium phosphate foams which may be obtained by simultaneously mixing and foaming of a powder phase and a liquid phase.

Claims

1. A process for the preparation of a self-setting calcium phosphate foam, comprising a single step of simultaneous mixing and foaming a powder phase and a liquid phase, wherein the powder phase comprises at least one calcium source and at least one phosphate source, wherein the liquid phase is an aqueous solution, wherein the powder phase, the liquid phase or both contain at least one additive selected from the group consisting of surfactants and foaming agents, and wherein the mixing and simultaneous foaming are performed by back-and-forth movements of the material through a narrow connection between two containers, one of them containing the powder phase and the other one the liquid phase.

2. The process according to claim 1, wherein the simultaneous mixing and foaming are performed by mechanical whipping at a rotation speed between 1000 rpm and 15000 rpm.

3. (canceled)

4. (canceled)

5. The process according to claim 1, wherein the two containers are two syringes and the back-and-forth movements are performed through a tip-to-tip connection between the two syringes.

6. The process according to claim 1, wherein at least one of the additives is a non-ionic surfactant.

7. The process according to claim 6, wherein the non-ionic surfactant is polyoxyethylene sorbitan monooleate.

8. The process according to claim 7, wherein the polyoxyethylene sorbitan monooleate is added in the liquid phase at a weight % with respect to the liquid phase between 0.1 and 10%.

9. The process according to claim 1, wherein the ratio between mL of liquid phase and grams of powder phase is comprised between 0.35 mL/g and 0.90 mL/g.

10. The process according to claim 1, wherein: the at least one calcium source is selected from the group consisting of tetratracalcium phosphate, dicalcium phosphate anhydrous, dicalcium phosphate dihydrate, alpha-tricalcium phosphate, beta-tricalcium phosphate, monocalcium phosphate monohydrate, hydroxyapatite, calcium deficient hydroxyapatite, fluorapatite, amorphous calcium phosphate, calcium- sodium- and potassium-phosphate, calcium- and sodium-phosphate, calcium- and potassium-phosphate, calcium pyrophosphate, calcium carbonate, calcium sulphate, calcium sulfate hemihydrate, calcium oxide and calcium hydroxide; and the at least one phosphate source is selected from the group consisting of tetratracalcium phosphate, dicalcium phosphate anhydrous, dicalcium phosphate dihydrate, alpha-tricalcium phosphate, beta-tricalcium phosphate, monocalcium phosphate monohydrate, hydroxyapatite, calcium deficient hydroxyapatite, fluorapatite, amorphous calcium phosphate, calcium- sodium- and potassium-phosphate, calcium- and sodium-phosphate, calcium- and potassium-phosphate, calcium pyrophosphate, and phosphoric acid.

11. (canceled)

12. The process according to claim 1, wherein the liquid phase comprises between 0.1 and 5 weight % of one or more of Na.sub.2HPO.sub.4, NaH.sub.2PO.sub.4, KH.sub.2PO.sub.4 and K.sub.2HPO.sub.4.

13. The process according to claim 1, wherein at least one of the phases comprises between 1 and 20 weight % of at least one oligomeric compound or polymer.

14. The process according to claim 13, wherein the oligomeric compound or polymer is selected from the group consisting of poloxamer, sodium alginate, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl starch, soluble starch, cyclodextrin, dextran sulphate, polyvinylpyrrolidone, quitosan, and hyaluronic acid.

15. The process according to claim 1, wherein the powder phase comprises alpha tricalcium phosphate with a medium particle size inferior to 100 micrometers.

16. The process according to claim 15, wherein the medium particle size is inferior to 15 micrometers.

17. The process according to claim 1, wherein the powder phase comprises precipitated tricalcium phosphate or precipitated hydroxyapatite, in a quantity inferior to 10 weight % with regard to the total weight of the powder phase.

18. The process according to claim 1, wherein at least one of the phases further comprises one or more biologically active agents, and wherein the biologically active agent is selected from the group consisting of growth factors, anti-cancerogenic substances, antibiotics, and antioxidants.

19. (canceled)

20. A self setting calcium phosphate foam obtainable by the process of claim 1.

21. (canceled)

22. A process for the preparation of a solid structure suitable for use in bone regeneration or tissue engineering, comprising: a) obtaining a self setting calcium phosphate according to the process as defined in claim 1; and b) allowing the self setting calcium phosphate foam to set, either after injection into a mammal body or outside a mammal body.

23. A solid structure obtainable by the process as defined in claim 22.

24. (canceled)

25. The solid structure according to claim 23, wherein the solid structure has a total porosity comprised between 25 and 95 vol % and a macroporosity comprised between 2 and 80 vol %.

26. The solid structure according to claim 23, wherein the solid structure comprises macropores having a diameter comprised between 5 and 700 m.

Description

DESCRIPTION OF THE DRAWINGS

[0064] FIG. 1. As an illustrative example, a FESEM image of a section of the calcium phosphate foam is shown. The calcium phosphate foam is obtained by the addition of a 1 wt % of a biocompatible non-ionic surfactant to the liquid phase of an alpha-tricalcium phosphate cement, using a liquid to powder ratio of 0.55 ml/g and 10 wt % of Pluronic as additive in the powder phase. Mixing and foaming of the two phases was performed by mechanical whipping during 30 s at 6000 rpm.

[0065] In the following, the invention will be further illustrated with examples, although it must be understood that the examples should not be interpreted as restricting the invention to the compositions specified in the examples.

EXAMPLES

Examples 1-4

[0066] For the foam preparation, a liquid phase comprising 1 wt % of Tween80 (Polysorbate 80: polyoxyethylene (20) sorbitan monooleate or (x)-sorbitan mono-9-octadecenoate poly(oxy-1,2-ethanediyl) dissolved in distilled water was used. A powder phase comprising alpha-TCP particles including 2 wt % of precipitated hydroxyapatite as seed material was used. The liquid-to-powder ratio was chosen between 0.45 and 0.75 mL/g. The foams were prepared by simultaneously mixing and foaming the two phases, by mechanical whipping at 6000 rpm during 30 s, and were then moulded by injection into cylindrical moulds and allowed to set during approximately 24 hours, at 100% relative humidity and 37 C., followed by 6 days submerged in distilled water at 37 C. The compressive strength, mean interconnection diameter and total porosity were then evaluated for each of the foams. For all foams that were prepared, it was observed that an interconnected macroporous paste was obtained. Once submerged in distilled water, the calcium phosphate foams had cohesion, providing after setting solid foams of hydroxyapatite with different properties. The total porosity, interconnectivity and compressive strength are presented in Table 1.

TABLE-US-00001 TABLE 1 Composition, compressive strength, total porosity and mean diameter of interconnection of the different foams prepared. The standard deviation is given within brackets (n = 12). Compressive Total porosity Mean diameter of Example No. L/P ratio (mL/g) strength (MPa SD) (% SD) interconnections (m SD) 1 0.45 1.87 (0.34) 76.7 (1.1) 123 13 2 0.55 0.62 (0.06) 83.9 (0.3) 189 41 3 0.65 0.29 (0.03) 86.8 (0.6) 203 17 4 0.75 0.11 (0.02) 89.0 (0.4) 177 19 Comparative 0.55 71.98 (4.94) Example (EP1787626B1)

[0067] It was observed that, over the whole range of liquid to powder ratio studied, an effect on the macroporosity was obtained. In general, more porous foams were obtained when a higher liquid to powder ratio was used. The increase of the liquid to powder ratio reduced the compressive strength of the foams, and also produced a variation in the mean diameter of interconnection.

[0068] The coefficient of variation of foams with the same composition prepared via the protocol described in EP 1787626 B1 led to a variation of 6.86% while the protocol described herein led to a variation of 0.32% in the value of the total porosity, as measured by mercury immersion and helium pycnometry.

Examples 5-7

[0069] For the foam preparation, a liquid phase comprising 1 wt % of Tween80 dissolved in distilled water was used. A powder phase comprising alpha-TCP particles including 2 wt % of precipitated hydroxyapatite as seed material and a variable percentage of Pluronic F127 (Poloxamer 407), a polymeric surfactant based on ethylene oxidepropylene oxide block polymers was used. The liquid-to-powder ratio was fixed at 0.65 mL/g. The foam was prepared by simultaneously mixing and foaming the two phases, by mechanical whipping at 6000 rpm during 25 s and were then molded by injection into cylindrical moulds and allowed to set during approximately 24 hours at 100% relative humidity and 37 C., followed by 6 days submerged in distilled water at 37 C. The compressive strength, mean interconnection diameter and total porosity were then evaluated for each foam.

TABLE-US-00002 TABLE 2 Pluronic Compressive strength Total porosity Mean diameter of Example No. (weight %) (MPa SD) (% SD) interconnections (m SD) 3 0 0.29 0.03 86.8 0.6 203 17 5 5 0.22 0.02 88.9 1.1 143 13 6 10 0.76 0.12 83.7 0.2 124 21 7 15 0.86 0.07 84.72 1.25 97 27

[0070] The addition of Pluronic F127 allowed controlling the diameter of the interconnections between the macropores from 203 m down to 97 m. The total porosity being superior to 80%, this additive allows tuning the pore size and mechanical properties.

Example 8

[0071] For the foam preparation, a liquid phase comprising 1 wt % of Pluronic F-127 (Poloxamer 407) and 8 wt % of NaH.sub.2PO.sub.4 as accelerant dissolved in distilled water was used. A powder phase comprising alpha-TCP particles including 2 wt % of precipitated hydroxyapatite as seed material and 9 wt % of Pluronic F127 (Poloxamer 407) was used. The liquid-to-powder ratio was fixed at 0.55 mL/g.

[0072] The powder phase was placed in a 3 mL syringe while the liquid phase was placed in a 5 mL syringe. The two syringes were connected tip-to-tip using a double-female luer-lock connector. 10 back-and-forth movements were performed to simulatenously mix and foam the two phases, during 15 s. The foam was then moulded by injection into cylindrical molds and allowed to set during 7 d at 100% relative humidity and 37 C.

[0073] The entrance pore size distribution as measured by mercury intrusion porosimetry is reported in FIG. 2. The total porosity evaluated by mercury intrusion porosimetry is 74.0%, 55.5% of it being pores bigger than 10 m.