RESORBABLE CERAMICS WITH CONTROLLED STRENGTH LOSS RATES

• US 20090276056A1
• Filed: 04/25/2007
• Published: 11/05/2009
• Est. Priority Date: 04/25/2006
• Status: Active Grant

• Current Assignee: Washington State University
• Original Assignee: Washington State University
• Inventors: Bose, Susmita, Bandyopadhyay, Amit
• Granted Patent: US 9,028,871 B2
• Time in Patent Office: Days
• US Class Current: 623/23.720
• CPC Class Codes: A61L 2400/12 Nanosized materials, e.g. nanofibres, nanoparticles, nanowires, nanotubes; Nanostructured surfaces
• CPC Class Codes: A61L 2420/06 Coatings containing a mixture of two or more compounds
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 2430/12 for dental implants or prostheses
• CPC Class Codes: A61L 27/10 Ceramics or glasses
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/306 Other specific inorganic materials not covered by A61L27/303 - A61L27/32
• CPC Class Codes: A61L 27/32 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/425 of phosphorus containing material, e.g. apatite
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: C04B 2235/3201 Alkali metal oxides or oxide-forming salts thereof
• CPC Class Codes: C04B 2235/3206 Magnesium oxides or oxide-forming salts thereof
• CPC Class Codes: C04B 2235/3208 Calcium oxide or oxide-forming salts thereof, e.g. lime
• CPC Class Codes: C04B 2235/3212 Calcium phosphates, e.g. hydroxyapatite
• CPC Class Codes: C04B 2235/3213 Strontium oxides or oxide-forming salts thereof
• CPC Class Codes: C04B 2235/3232 Titanium oxides or titanates, e.g. rutile or anatase
• CPC Class Codes: C04B 2235/3272 Iron oxides or oxide forming salts thereof, e.g. hematite, magnetite
• CPC Class Codes: C04B 2235/3281 Copper oxides, cuprates or oxide-forming salts thereof, e.g. CuO or Cu2O
• CPC Class Codes: C04B 2235/3284 : Zinc oxides, zincates, cadmium oxides, cadmiates, mercury oxides, mercurates or oxide forming salts thereof
• CPC Class Codes: C04B 2235/3291 : Silver oxides
• CPC Class Codes: C04B 2235/34 : Non-metal oxides, non-metal mixed oxides, or salts thereof that form the non-metal oxides upon heating, e.g. carbonates, nitrates, (oxy)hydroxides, chlorides
• CPC Class Codes: C04B 2235/3418 : Silicon oxide, silicic acids or oxide forming salts thereof, e.g. silica sol, fused silica, silica fume, cristobalite, quartz or flint
• CPC Class Codes: C04B 2235/442 : Carbonates
• CPC Class Codes: C04B 2235/445 : Fluoride containing anions, e.g. fluosilicate
• CPC Class Codes: C04B 2235/5445 : submicron sized, i.e. from 0,1 to 1 micron
• CPC Class Codes: C04B 2235/608 : Green bodies or pre-forms with well-defined density
• CPC Class Codes: C04B 2235/77 : Density
• CPC Class Codes: C04B 2235/786 : Micrometer sized grains, i.e. from 1 to 100 micron
• CPC Class Codes: C04B 2235/80 : Phases present in the sintered or melt-cast ceramic products other than the main phase
• CPC Class Codes: C04B 2235/96 : Properties of ceramic products, e.g. mechanical properties such as strength, toughness, wear resistance
• CPC Class Codes: C04B 35/447 : based on phosphates , e.g. hydroxyapatite
• CPC Class Codes: C04B 35/6261 : Milling

Abstract

Particular aspects provide bioresorbable and biocompatible compositions for bioengineering, restoring or regenerating tissue or bone, comprising a three-dimensional porous or non-porous scaffold material comprising a calcium phosphate-based ceramic having at least one dopant therein selected from metal ion or ion dopants and metal oxide dopants, wherein the composition is sufficiently biocompatible to provide for a cell or tissue scaffold, and resorbable at a controlled resorption rate for controlled stregthloss, depending on dopant composition, under body, body fluid or simulated body fluid conditions. Preferably, the at least one dopant is selected from the group consisting of Zn²⁺, Mg²⁺, Si²⁺, Na⁺, K⁺, Sr²⁺, Cu²⁺, Fe³⁺/Fe²⁺, Ag⁺, Ti⁴⁺, CO₃²⁻, F⁻, MgO, ZnO, NaF, KF, FeO/Fe₂O₃, SrO, CuO, SiO₂, TiO₂, Ag₂O and CaCO₃, present in an amount between 0 and about 10 w %, from about 0.5 to about 5 w %, or from about 1 to about 3 w %, and methods of using same.

Claims

1. A bioresorbable and biocompatible composition for bioengineering, restoring or regenerating tissue or musculoskeletal tissue, comprising:

a three-dimensional porous or non-porous scaffold material comprising a calcium phosphate-based ceramic, the ceramic having at least one dopant included therein selected from the group consisting of metal salts with metal ions and metal oxide dopants, wherein the composition is sufficiently biocompatible to provide for a cell or tissue scaffold, and resorbable at a controlled resorption rate, to control mechanical strength and strength degradation, dependent upon the dopant composition, under body, body fluid or simulated body fluid conditions.

2. The composition of claim 1, wherein the at least one dopant is selected from the group consisting of Zn²⁺, Mg²⁺, Si²⁺, Na⁺, K⁺, Sr²⁺, Cu²⁺, Fe³⁺/Fe²⁺, Ag⁺, Ti⁴⁺, CO₃²⁻

, F⁻

, MgO, ZnO, NaF, KF, FeO/Fe₂O₃, SrO, CuO, SiO₂, TiO₂, Ag₂O and CaCO₃, present in a single-element or multi-element amount between 0 and about 10 wt %, from about 0.5 to about 5 wt %, from about 1 to about 3 wt %, from about 2 to about 7 wt %, from about 3 to about 7 wt %, from about 4 to about 7 wt %.

3. The composition of claim 1, wherein biocompatibility comprises biocompatibility with respect to at least one cell or tissue type selected from the group consisting of eukaryotic cells, mammalian cells, bone forming or restructuring cells, osteoblastic or osteoblastic precursor cells, cartilage cells, muscle cells, stem cells, differentiated stem cells, bone marrow stem cells, and nerve cells.

4. The composition of claim 1, wherein the tissue comprises at least one selected from the group consisting of bone, cartilage, muscle and musculoskeletal tissue.

5. The composition of claim 2, wherein the at least one dopant is present in an amount sufficient to maintain the compressive strength of the material at about 30% of original or higher, 40% of original or higher, 50% of original or higher, 60% of original or higher, 70% of original or higher, 80% of original or higher, 90% of original or higher, in each case, for a period of at least 6, at least 7, least 8, at least 9, at least 10, at least 11 or at least 12 months under body, body fluid or simulated body fluid conditions, to provide for a slow-degrading composition.

6. The composition of claim 2, wherein the at least one dopant is present in an amount sufficient to reduce the compressive strength of the material to about 90%, or less than 90%, 80%, or less than 80%, 70%, or less than 70%, 60%, or less than 60% or 50%, or less than 50% of original, in each case, within a period of about 3 months, about 4 months, about 5 months or about 6 months under body, body fluid or simulated body fluid conditions, to provide for a fast-degrading composition.

7. The composition of claim 2, wherein the at least one dopant is selected from the group consisting of SrO, ZnO, TiO₂, MgO and SiO₂ dopants, present in a single-element or multi-element amount between 0 and about 10 wt %, from about 0.5 to about 5 wt %, from about 1 to about 3 wt %, from about 2 to about 7 wt %, from about 3 to about 7 wt %, from about 4 to about 7 wt %.

8. The composition of claim 1, wherein the ceramic comprises a multi-element dopant comprising at least two dopants selected from the group consisting of Zn²⁺, Mg²⁺, Si²⁺, Na⁺, K⁺, Sr²⁺, Cu²⁺, Fe³⁺/Fe²⁺, Ag⁺, Ti⁴⁺, CO₃²⁻

, F⁻

, MgO, ZnO, NaF, KF, FeO/Fe₂O₃, SrO, CuO, SiO₂, TiO₂, Ag₂O and CaCO₃, present in a single-element or multi-element amount between 0 and about 10 wt %, from about 0.5 to about 5 wt %, from about 1 to about 3 wt %, from about 2 to about 7 wt %, from about 3 to about 7 wt %, from about 4 to about 7 wt %.

9. The composition of claim 1, wherein the ceramic comprises at least one dopant ions and/or oxides present in a single-element or multi-element amount between 0 and about 10 wt %, from about 0.5 to about 5 wt %, from about 1 to about 3 wt %, from about 2 to about 7 wt %, from about 3 to about 7 wt %, from about 4 to about 7 wt %.

10. The composition of claim 1, wherein the calcium phosphate comprises at least one single or mixed phase calcium phosphate material having the formula (Ca_x(PO₄)_y, where x=1 or more, and y=1 or more), or hydroxylated variants thereof.

11. The composition of claim 1, wherein the calcium phosphate comprises at least one single or mixed phase calcium phosphate material having calcium to phosphate ratio (Ca/P) in a range from about 1.4:

1 to about 1.7;

1, or from about 1.0;

1 to about 2.0;

1.

12. The composition of claim 11, wherein the calcium to phosphate ratio is about 1.5:

1, or about 1.67;

1.

13. The composition of claim 1, wherein the calcium phosphate-based ceramic comprises at least one of tricalcium phosphate (TCP;

Ca₃(PO₄)₂) and Hydroxyapitite (HAp;

Ca₁₀(PO₄)₆(OH)₂).

14. The composition of claim 1, wherein the scaffold material comprises a plurality of ceramic particles, and further comprises an open and interconnected porous network.

15. The composition of claim 14, wherein the open and interconnected porous network is between and among said ceramic particles, and wherein the pore size of the open and connected porous network is within a restricted or controlled range established during formation of the scaffold material.

16. The composition of claim 15, wherein the restricted or controlled range of pore size comprises a microporous or macroporous pattern having pore sizes in the range of about 10 μ

m to about 5 mm, or comprises nanoscale or microscale pores ranging from about 10 nm to about 500 μ

m in diameter, or from about 1 nm to about 1 μ

m.

17. The composition of claim 1, wherein the scaffold material comprises dense to solid structures, or porous structures having internal cavities with sizes varying from nano-scale to larger sizes, or micro porous structures, wherein the core of the bulk scaffold material is comprised of a geometric pattern of material with voided areas or low density structures with a quasi-solid exterior.

18. The composition of claim 1, further comprising at least one chemical, drug, growth factor or biological agent deposited, incorporated into, or stored within and/or on a surface of the scaffold material or within one or more pores thereof to operatively provide for release, controlled release or burst release of the agent to facilitate bioengineering, restoring or regenerating bone or other tissue.

19. The composition of claim 18, wherein the at least one agent comprises at least one selected from the group consisting of antibiotics, antimicrobial agents, growth factors, osteoinductive growth factors, drugs, polypeptides and proteins.

20. The composition of claim 18, wherein the at least one agent can be selectively activated and/or released at set times by the application of at least one chemical, electrical, magnetic or photochemical triggering event.

21. The composition of claim 20, wherein the at least one chemical, electrical, magnetic or photochemical triggering event is at least one selected from the group consisting of chemical ingestion or infusions, exposure to UV light, ultrasound, magnetic fields, and electric current.

22. The composition of claim 1, wherein the composition is a coating material.

23. The composition of any one of claims 1 and 2, wherein the biocompatibility is sufficient to provide for bioengineering, restoring or regenerating bone or other tissue in the body of a human or other vertebrate or animal.

24. The composition of any one of claims 1 and 2, wherein the composition is useful for at least one of dental and orthopedic implants, craniomaxillofacial applications, and spinal grafting, and said composition is suitable to promote bone in-growth and repair.

25. The composition of any one of claims 1 and 2, comprising disks, solids, or porous scaffolds.

26. A method for making a bioresorbable and biocompatible composition for bioengineering, restoring or regenerating bone or other tissue according to any one of claims 1 and 2, comprising at least one of sintering of the calcium phosphate-based ceramic, and the use of synthesized nanopowders of the calcium phosphate-based ceramic.

27. The method of claim 26, wherein the material properties of the composition are selectively modulated by using at least one of sintering processes to reduce grain sizes, and synthesized nanopowders to further reduce grain size for increased strength and hardness and/or improved cell materials interactions.

28. The method of claim 26, further comprising depositing, incorporating into, or storing a chemical, drug, growth factor or biological agent within and/or on a surface of the scaffold material or within one or more pores thereof to operatively provide for release, controlled release or burst release of the agent to facilitate bioengineering, restoring or regenerating bone or other tissue.

29. The method of claim 28, wherein the at least one agent comprises at least one selected from the group consisting of antibiotics, antimicrobial agents, growth factors, osteoinductive growth factors, drugs, polypeptides and proteins.

30. The method of claim 28, wherein the at least one agent can be selectively activated and/or released at set times by the application of at least one chemical or photochemical triggering event.

31. The method of claim 30, wherein the at least one chemical or photochemical triggering event is at least one selected from the group consisting of chemical ingestion or infusions, exposure to UV light, ultrasound, magnetic fields, and electric current.

32. A method for tissue or musculoskeletal tissue engineering, comprising placement, under body, body fluid or simulated body fluid conditions, a bioresorbable and biocompatible composition for bioengineering, restoring or regenerating bone and/or other tissue according to any one of claims 1 and 2, wherein the bone and/or other tissue is, at least in part, bioengineered, restored or regenerated.

33. The method of claim 32, wherein bioengineering, restoring or regenerating bone or another tissue is in vitro or ex vivo, comprising placement under simulated body fluid conditions or body fluid conditions.

34. The method of claim 32, wherein bioengineering, restoring or regenerating bone and/or other tissue is in vivo, comprising placement under body fluid conditions or body conditions.

35. The method of claim 32, wherein the three-dimensional tissue scaffold comprises an open interconnected porous network to facilitate at least one of cell adhesion, growth, spreading, metabolism, proliferation and differentiation, with temporally controlled strength loss of the scaffold material such that the tissue being bioengineered, restored or regenerated is subjected to a range of mechanical forces normally associated with such tissues.

36. The method of claim 32, wherein the bone tissue or other tissue comprises at least one cell or tissue type selected from the group consisting of eukaryotic cells, mammalian cells, bone forming or restructuring cells, osteoblastic or osteoblastic precursor cells, cartilage cells, muscle cells, stem cells, differentiated stem cells, bone marrow stem cells, and nerve cells.

37. The method of any one of claims 32-35, wherein the composition is used for dental and orthopedic implants, craniomaxillofacial applications and spinal grafting, and said composition is suitable to promote bone in-growth and repair.

38. A method for providing a coated material for use in bioengineering, restoring or regenerating tissue or musculoskeletal tissue, comprising:

obtaining a substrate material and

coating the material with a composition according to any one of claims 1 and 2, to provide at material suitable for use in bioengineering, restoring or regenerating tissue or musculoskeletal tissue.

39. A method for tissue or musculoskeletal tissue engineering, comprising placement, under body fluid or simulated body fluid conditions, a bioresorbable and biocompatible composition for bioengineering, restoring or regenerating bone and/or other tissue according to any one of claims 1 and 2, wherein the bone and/or other tissue is, at least in part, bioengineered, restored or regenerated.