Resorbable ceramics with controlled strength loss rates

• US 9,028,871 B2
• Filed: 04/25/2007
• Issued: 05/12/2015
• Est. Priority Date: 04/25/2006
• Status: Active Grant

• Current Assignee: Washington State University
• Original Assignee: Washington State University
• Inventors: Bose, Susmita, Bandyopadhyay, Amit
• Primary Examiner(s): Krass, Frederick
• Assistant Examiner(s): Liu, Tracy
• Application Number:
  US12/298,012
• Publication Number:
  US 20090276056A1
• Time in Patent Office: 2,939 Days
• Field of Search: None
• US Class Current: 424/484
• 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 glass constituents C04B2235/36
• 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 strength loss, 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 method of providing a biocompatible ceramic material for bioengineering, restoring, or regenerating a tissue, the method comprising:

determining an ex vivo degradation rate of a plurality of biocompatible ceramic materials each including a three-dimensional scaffold ceramic material composed of calcium phosphate ceramic sintered with a dopant uniformly distributed therein;

wherein determining the ex vivo degradation rate includes;

placing the plurality of biocompatible ceramic materials under body fluid or simulated body fluid conditions; and

measuring a loss of mechanical strength of the individual biocompatible ceramic materials after a period of time; and

selecting and providing one of the biocompatible ceramic materials for implantation in an environment associated with a tissue having a growth rate such that the ex vivo degradation rate of the one of the selected biocompatible ceramic materials correlates with the growth rate of the tissue, wherein the dopant is present in an amount sufficient to maintain the compressive strength of the biocompatible ceramic 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, or 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.

2. The method of claim 1 wherein determining the ex vivo degradation rate includes measuring a plurality of values of loss of mechanical strength of the individual biocompatible ceramic materials after multiple periods of time.

3. The method of claim 1 wherein:

the environment includes surrounding tissues proximate the tissue; and

providing one of the biocompatible ceramic materials includes avoiding formation of a gap at an interface between the surrounding tissues and the biocompatible ceramic material as the surrounding tissues grow.

4. The method of claim 1 wherein providing one of the biocompatible ceramic materials includes providing one of the biocompatible ceramic materials based on an expected growth rate of the tissue in vivo.

5. The method of claim 1 wherein the provided one of the biocompatible ceramic materials has a composition and a concentration of the dopant in the biocompatible ceramic material sufficient to render the biocompatible ceramic material resorbable at the ex vivo degradation rate.

6. The method of claim 1 wherein the provided one of the biocompatible ceramic materials has a composition and a concentration of the dopant in the biocompatible ceramic material to achieve a compressive strength of about 30% to about 90% of an initial compressive strength of the biocompatible ceramic material over a period of about 3 months to about 12 months.

7. The method of claim 1 wherein:

the environment includes surrounding tissues proximate the identified target tissue; and

providing one of the biocompatible ceramic materials also includes providing one of the biocompatible ceramic materials based on at least one characteristic of adhesion, growth, spreading, metabolism, proliferation, or differentiation of cells of the surrounding tissues in the environment.

8. A method for providing a biocompatible ceramic composition for bioengineering, restoring, or regenerating a tissue, the method comprising:

determining an ex vivo degradation rate of a biocompatible ceramic material by;

placing the biocompatible ceramic material under body fluid or simulated body fluid conditions; and

subsequently measuring a loss of mechanical strength of the biocompatible ceramic material after a period of time, the biocompatible ceramic material including a three-dimensional scaffold ceramic material comprising a calcium phosphate-based ceramic sintered with a dopant; and

selecting and providing the biocompatible ceramic material for implantation in an environment associated with a tissue having a growth rate that correlates with the determined ex vivo degradation rate of the selected biocompatible ceramic material, wherein the dopant is present in an amount sufficient to maintain the compressive strength of the biocompatible ceramic 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, or 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.

9. The method of claim 8 wherein the dopant is present in an 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 %, or from about 4 to about 7 wt %.

10. The method of claim 8 wherein the biocompatible ceramic material is biocompatible with respect to at least one cell 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.

11. The method of claim 8 wherein the tissue comprises at least one selected from the group consisting of bone, cartilage, and musculoskeletal tissue.

12. The method of claim 8 wherein the calcium phosphate-based 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⁺, F⁻

, MgO, ZnO, NaF, KF, FeO/Fe₂O₃, SrO, CuO, SiO₂, TiO₂, Ag₂O and CaCO₃, present in an 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 %.

13. The method of claim 8 wherein the calcium phosphate-based ceramic comprises a single dopant, or at least two dopants, in an 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 %.

14. The method of claim 8 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.

15. The method of claim 8 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.

16. The method of claim 15 wherein the calcium to phosphate ratio is about 1.5:

1, or about 1.67;

1.

17. The method of claim 8 wherein the calcium phosphate-based ceramic comprises at least one of Ca₃(P0₄)₂ and Ca₁₀(PO₄)₆(OH)₂.

18. The method of claim 8 wherein the scaffold ceramic material comprises a plurality of ceramic particles, and further comprises an open and interconnected porous network.

19. The method of claim 18 wherein the open and interconnected porous network is between and among the ceramic particles, and wherein the pore size of the open and connected porous network is within a range established during formation of the scaffold material.

20. The method of claim 19 wherein the range of pore size comprises a microporous or macroporous pattern having pore sizes in the range of about 10 nm 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.

21. The method of claim 8 wherein the scaffold ceramic 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.

22. The method of claim 8 wherein the scaffold ceramic material further includes 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.

23. The method of claim 22 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.

24. The method of claim 22 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.

25. The method of claim 24 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.

26. A method for providing a biocompatible ceramic composition for bioengineering, restoring, or regenerating a tissue, the method comprising:

selecting and providing a biocompatible ceramic material for implantation in an environment associated with a tissue having a growth rate that correlates with an ex vivo degradation rate of the selected biocompatible ceramic material, wherein the ex vivo degradation rate of the biocompatible ceramic material is determined by;

immersing the biocompatible ceramic material in a simulated body fluid; and

measuring a loss of mechanical strength of the biocompatible ceramic material after a period of time; and

wherein the biocompatible ceramic material includes a three-dimensional scaffold ceramic material comprising a calcium phosphate-based ceramic sintered with a dopant uniformly included therein, wherein the dopant is present in an amount sufficient to maintain the compressive strength of the biocompatible ceramic 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, or 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.

27. The method of claim 26 wherein the dopant is present in an 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 %, or from about 4 to about 7 wt %.

28. The method of claim 26 wherein the biocompatible ceramic material is biocompatible with respect to at least one cell 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.

29. The method of claim 26 wherein the calcium phosphate-based ceramic comprises 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 %.

30. The method of claim 26 wherein the calcium phosphate-based ceramic comprises a single dopant, or at least two dopants, in an 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 %.

31. The method of claim 26 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.

32. The method of claim 26 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.

33. The method of claim 32 wherein the calcium to phosphate ratio is about 1.5:

1, or about 1.67;

1.

34. The method of claim 26 wherein the calcium phosphate-based ceramic comprises at least one of Ca₃(P0₄)₂) and Ca₁₀(PO₄)₆(OH)₂.

35. The method of claim 26 wherein the scaffold ceramic material comprises a plurality of ceramic particles, and further comprises an open and interconnected porous network.