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Title:
DOPED CALCIUM SILICATE-BASED CERAMIC MATERIALS AND THE USE THEREOF
Document Type and Number:
WIPO Patent Application WO/2021/113927
Kind Code:
A1
Abstract:
The present invention relates to doped calcium silicate-based ceramic materials, and in particular to bismuth doped baghdadite and the manufacture and use thereof. In one embodiment, the doped baghdadite has a formula Ca3-aBiaSi2ZrO9, wherein a >0 and <0.5. The present invention also relates to implantable medical devices comprising a material of the invention and methods for production thereof. The present invention further relates to methods for improving the long-term stability of an implantable medical device comprising a material of the invention. Further, the present invention relates to methods for regenerating or resurfacing of tissue using a material of the invention.

Inventors:
NO YOUNG JUNG (AU)
ZREIQAT HALA (AU)
NGUYEN TIEN (AU)
LU ZUFU (AU)
Application Number:
PCT/AU2020/051366
Publication Date:
June 17, 2021
Filing Date:
December 14, 2020
Export Citation:
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Assignee:
UNIV SYDNEY (AU)
International Classes:
A61L27/10; A61L27/28; A61L27/34; A61L27/54; A61L27/56; A61L27/58; B29C64/10; B29C64/118; C03C12/00
Foreign References:
US20140193499A12014-07-10
Other References:
ZHONG, J. ET AL.: "Synthesis, electronic structures, and photoluminescence properties of an efficient and thermally stable red-emitting phosphor Ca3ZrSi209:Eu3+,Bi3+ for deep UV-LEDs", vol. 8, no. 24, 2018, pages 13054 - 13060, XP055834823
MOHAMMADI H, HAFEZI M, NEZAFATI N, HEASARKI S, NADERNEZHAD A, GHAZANFARI S M H, SEPANTAFAR M: "Bioinorganics in Bioactive Calcium Silicate Ceramics for Bone Tissue Repair: Bioactivity and Biological Properties", J. CERAM. SCI. TECH, vol. 5, no. 1, 1 January 2014 (2014-01-01), pages 1 - 12, XP055833864, DOI: 10.4416/JCST2013-00027
Attorney, Agent or Firm:
FPA PATENT ATTORNEYS PTY LTD (AU)
Download PDF:
Claims:
Claims

1 . A ceramic material comprising bismuth doped Baghdadite.

2. A ceramic material of claim 1 , wherein the bismuth doped Baghdadite has a formula Ca3-aBiaSi2ZrO9, wherein a >0 and <0.5.

3. The ceramic material of claim 2, wherein a is 0.1 -0.4.

4. The ceramic material of claim 2, wherein a is 0.1 or 0.2.

5. The ceramic material of any one of claims 1 to 4 having a formula Ca2.6-2.9Bi0.1-0.4Si2ZrO9 .

6. The ceramic material of any one of claims 1 to 5 having a formula Ca2.9Bi0.1Si2ZrO9 or

Ca2.8Bi0.2Si2ZrO9.

7. The ceramic material of any one of claims 1 to 6 having the formula Ca2.9Bi0.1Si2ZrO9, wherein the material has an X-ray diffraction pattern comprising one or more diffraction angles 2θ selected from the group comprising: about 12.231 , about 27.711 , about 29.549, about 29.983, about 31 .191 , about 31 .493, about 36.049 and about 37.034.

8. The ceramic material of any one of claims 1 to 6 having the formula Ca2.8Bi0.2Si2ZrO9, wherein the material has an X-ray diffraction pattern comprising one or more diffraction angles 2θ selected from the group comprising: about 12.283, about 27.764, about 29.602, about 30.048, about 31 .243, about 31 .558, about 36.101 , and about 37.073.

9. The ceramic material of any one of claims 1 to 8 having an X-ray diffraction pattern having 2θ diffraction angles of undoped Baghdadite, wherein one or more of the 2θ diffraction angles are shifted at least minus 0.01 degrees 2θ.

10. The ceramic material of any one of claims 1 to 7 having an X-ray diffraction pattern having 2θ diffraction angles of undoped Baghdadite, wherein one or more of the 2θ diffraction angles are shifted at least minus 0.05 degrees 2θ.

11. The ceramic material of any one of claims 1 to 10, wherein the material does not comprise undoped Baghdadite.

12. The ceramic material of any one of claims 1 to 11 , wherein the material is monophasic.

13. A method of preparing the ceramic material of any of claims 1 to 12, comprising combining calcium carbonate, silicon dioxide, zirconium dioxide and bismuth carbonate to form a mixture, and subjecting the mixture to calcination.

14. The method of claim 13, wherein the calcium carbonate, silicon dioxide, zirconium dioxide and bismuth carbonate may be in the form of powders.

15. The method of claim 13 or 14, wherein the calcination involves heating at a temperature of about 1350 °C.

16. A bone substitute including a ceramic material of any of claims 1 to 12.

17. An implantable medical device including a ceramic material of any of claims 1 to 12.

18. A method for improving long-term stability of an implantable medical device comprising: applying to the implantable medical device to the ceramic material of any of claims 1 to 12.

19. A method for producing an implantable medical device, the method comprising: applying the ceramic material of any of claims 1 to 12 onto a substrate so as to form the implantable medical device.

20. A method of regenerating or resurfacing a tissue, the method comprising: applying the ceramic material of any of claims 1 to 12 to the tissue.

21 . The method of claim 20, wherein the tissue is bone.

22. A method for forming osseous tissue on an orthopaedic defect, the method comprising: contacting the defect with the ceramic material of any of claims 1 to 12.

Description:
DOPED CALCIUM SILICATE-BASED CERAMIC MATERIALS AND THE USE THEREOF

[0001] This application claims priority to Australian provisional patent application no. 2019904720 (filed on 13 December 2019), the entire contents of which is hereby incorporated by reference.

Field of the invention

[0002] The present invention relates to doped calcium silicate-based ceramic materials, and in particular to bismuth doped baghdadite and the manufacture and use thereof.

Background

[0003] Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0004] Bone is a dynamic tissue and its homeostasis represents a balance between bone formation and bone resorption. In bone formation, adult stem cells differentiate into bone progenitor cells (ie, osteoprogenitor cells) that have the ability to mature into osteoblasts, osteocytes, and form mature bone and mineralized matrix. In bone resorption, osteoclasts (cells that resorb bone tissue) dissolve the mineralized matrix and create cavities on the bone surface. The balance between bone formation and bone resorption is instrumental in the maintenance of healthy bones.

[0005] Despite the capacity for bone tissue to rejuvenate itself, repairing non-union bone fractures and regenerating bone defects remains a major challenge. Indeed, bone is now second only to blood as the most transplanted tissue.

[0006] Bone grafts, where bone is harvested from a patient (eg, from the hip, leg or calvarial bones) and re-applied to a bone defect, fracture or void, are commonly used to repair bone injuries that cannot be efficiently repaired through natural processes. Over 2.2 million bone graft procedures are performed annually worldwide for the repair of bone defects. However, successful reconstruction of large bone defects using conventional autograft and allograft transplantation has remained a clinical challenge.

[0007] Autografts, although considered the current gold standard of graft materials, suffer from significant limitations including the requirement for second surgery, donor site morbidity, limited available bone for resection and considerable graft resorption. Allografts are restricted by the risk of disease transmission, reliance on donors and reduced bioactivity of the graft due to the decellularisation procedures necessary to remove graft immunogenicity.

[0008] A number of commercial bone substitutes, such as those manufactured from calcium phosphate-based materials, are used to replace bone grafts in orthopaedic procedures but their wide spread use remains limited due to failure to satisfy many of the regenerative requirements of bone tissue, such as suboptimal strength and bioactivity and practical requirements relating to surgery and handling.

[0009] A clinical need exists for the development of purely synthetic, readily available and off-the-shelf bone substitutes with the same desirable characteristics as bone grafts, but without their associated limitations so as to provide an alternative treatment option that produces improved outcomes for bone repair.

[0010] Against this background, the present inventors have developed a doped calcium silicate-based compound that offers a number of advantages over known bone substitute materials.

Summary of the invention

[0011] In a first aspect the present invention provides a ceramic material which is baghdadite doped with bismuth.

[0012] The ceramic material may be a sintered ceramic material.

[0013] The ceramic material may be biocompatible and preferably demonstrating antimicrobial properties. In some embodiments, the antimicrobial properties may be effective against drug resistant microbes, such as multidrug resistant Staphyloccocus aureus (MRSA).

[0014] The ceramic material may have the formula Ca 3-a Bi a Si 2 ZrO 9 , wherein a >0 and <0.5. Preferably a is 0.1 , 0.2, 0.3, 0.4 or 0.5. More preferably, a is 0.1-0.4. Even more preferably, a is 0.1 or 0.2. [0015] The ceramic material may have the formula Ca 2.6-2.9 Bi 0.1-0.4 Si 2 ZrO 9 .

[0016] The ceramic material may have a formula selected from the group consisting of:

Ca 2.9 Bi 0.1 Si 2 ZrO 9 and Ca 2.8 Bi 0.2 Si 2 ZrO 9 .

[0017] In one embodiment, wherein the ceramic material has the formula Ca 2.9 Bi 0.1 Si 2 ZrO 9 , the material may have an X-ray diffraction pattern comprising the following diffraction angles 2Q selected from the group comprising: about 12.231 , about 27.711 , about 29.549, about 29.983, about 31.191 , about 31.493, about 36.049 and about 37.034, based on the International Centre for Diffraction Data powdered diffraction file for baghdadite (ICDD-PDF #54-0710). In some embodiments, the ceramic material may have an X-ray diffraction pattern including at least one diffraction angles 2Q selected from the group comprising: about 12.231 , about 27.711 , about 29.549, about 29.983, about 31.191 , about 31.493, about 36.049 and about 37.034. The X-ray diffraction pattern may include one, two, three, four, five, six, seven or eight of the diffraction angles 2Q. The diffraction angles 2Q may be plus or minus 0.01 - 0.2 degrees, including 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 and 0.20 degrees.

[0018] In one embodiment, wherein the ceramic material has the formula Ca 28 Bi 02 Si 2 ZrO g , the material may have an X-ray diffraction pattern comprising the following diffraction angles 2Q selected from the group comprising: about 12.283, about 27.764, about 29.602, about 30.048, about 31.243, about 31.558, about 36.101 , about 37.073, based on the International Centre for Diffraction Data powdered diffraction file for baghdadite (ICDD-PDF #54-0710). In some embodiments, the ceramic material may have an X-ray diffraction pattern including at least one diffraction angles 2Q selected from the group comprising: about 12.283, about 27.764, about 29.602, about 30.048, about 31 .243, about 31 .558, about 36.101 , about 37.073. The X- ray diffraction pattern may include one, two, three, four, five, six, seven or eight of the diffraction angles 2Q. The diffraction angles 2Q may be plus or minus 0.01 - 0.2 degrees, including 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11 , 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19 and 0.20 degrees.

[0019] In one embodiment, the ceramic material may have an X-ray diffraction pattern having 2Q diffraction angles of undoped Baghdadite, wherein at least one of the 2Q diffraction angles is shifted at least plus or minus 0.01 degrees 2Q, preferably 0.01 - 1 degrees. More preferably, at least one of the 2Q diffraction angles is shifted at least minus 0.01 degrees 2Q, preferably minus 0.01 - 1 degrees, including 0.01 , 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09 or 1 degrees. In one embodiment, whereinthe ceramic material has the formula Ca 2.9 Bi 0.1 Si 2 ZrO 9 , the material may have an X-ray diffraction pattern having 2Q diffraction angles of undoped Baghdadite, wherein at least one of the 2Q diffraction angles is shifted at least minus 0.05 degrees 2θ. Preferably, at least one, two, three, four, five, six, seven or eight of the 2θ diffraction angles of undoped Baghdadite are shifted at least minus 0.05 degrees 2θ in the X- ray diffraction pattern of the material. In one embodiment, wherein the ceramic material has the formula Ca 2.8 Bi 0.2 Si 2 ZrO 9 , the material may have an X-ray diffraction pattern having 2θ diffraction angles of undoped Baghdadite, wherein at least one of the 2θ diffraction angles is shifted at least minus 0.01 degrees 2θ. Preferably, at least one, two, three, four, five, six, seven or eight of the 2θ diffraction angles of undoped Baghdadite are shifted at least minus 0.01 degrees 2θ in the X-ray diffraction pattern of the material.

[0020] Preferably, the material does not include un-doped Baghdadite. More preferably, the material does not have a transmission X-ray diffraction pattern characteristic of un-doped Baghdadite. More preferably, the material is monophasic.

[0021] In a second aspect the present invention provides a method for preparing a ceramic material of the first aspect comprising combining calcium carbonate, silicon dioxide, zirconium dioxide and bismuth carbonate to form a mixture, and subjecting the mixture to calcination.

[0022] The calcium carbonate, silicon dioxide, zirconium dioxide and bismuth carbonate may be in the form of powders.

[0023] Calcination may involve heating at a temperature of about 1350 °C.

[0024] In a third aspect the present invention provides a ceramic material when prepared by the method of the second aspect.

[0025] In a fourth aspect the present invention provides use of a ceramic material of the first aspect as a bone substitute.

[0026] In a fifth aspect the present invention provides an implantable medical device comprising the ceramic material of the first aspect.

[0027] In a sixth aspect the present invention provides a method for improving long-term stability of an implantable medical device comprising the step of applying to the device the ceramic material of the first aspect.

[0028] In a seventh aspect the present invention provides a method for producing an implantable medical device comprising applying a ceramic material of the first aspect onto a substrate so as to form the implantable medical device.

[0029] In an eighth aspect the present invention provides use of a ceramic material of the first aspect in the regeneration or resurfacing of tissue.

[0030] The tissue may be bone.

[0031] In a ninth aspect the present invention provides a method for regeneration of, or resurfacing of tissue comprising contacting the tissue with an amount of ceramic material of the first aspect for a period of time sufficient to at least partially effect regeneration or resurfacing of the tissue.

[0032] The tissue may be bone.

[0033] In a tenth aspect the present invention provides a kit for regenerating or resurfacing tissue comprising the ceramic material of the first aspect and a therapeutic agent that stimulates and/or accelerates tissue regeneration.

[0034] The tissue may be bone.

[0035] In an eleventh aspect the present invention provides a method for forming osseous tissue on an orthopaedic defect comprising contacting the defect with a ceramic material of the first aspect.

[0036] In a twelfth aspect the present invention provides an implantable drug delivery device comprising the ceramic material of the first aspect.

Brief Description of the Drawings

[0037] Embodiments of the invention will now be described by way of example only with reference to the accompanying drawings, in which:

[0038] Figure 1 are radiographic cross sections measured using microCT at x-ray energy of 70 keV: (A) baghdadite; (B) 0.1 mol% bi-baghdadite; (C) 0.2 mol% bi-baghdadite.

[0039] Figure 2 is a linear correlation between increased concentration of Element X and Hounsfield unit (radiopaque capacity) at an x-ray energy of 70 keV. (*) indicates significant differences relative to corresponding 0 mol% baghdadite values (p < 0.05). (#) indicates significant differences relative to corresponding 0.1 mol% bismuth- baghdadite values (p< 0.05).

[0040] Figure 3 is an X-ray diffraction (XRD) analysis pattern of baghdadite and two bismuth doped baghdadites in accordance with embodiments of the invention.

[0041] Figure 4 shows compressive strength and compressive modulus of baghdadite and two bismuth doped baghdadites in accordance with embodiments of the invention.

[0042] Figure 5 shows (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4- sulfophenyl-2H-tetrazolium) (MTS) assay absorbance values measured at 490nm indicating primary human osteoblast proliferation activity in accordance with embodiments of the invention. Measurements were taken after culture for 1 day and 7 days.

[0043] Figure 6 shows confocal microscopy of ceramic material of (a) undoped bagdadite and (b) bismuth doped bagdadite ( Ca 2.9 Bi 0.1 Si 2 ZrO 9 ) following application of MRSA to the material (initial cell concentration: OD 600 nm = 0.1), incubation (37 °C, 18h, dark conditions) and staining with Syto ® 9 (green) and propidium iodide (PI; red) fluorescent dyes. Live MRSA are shown in green, and dead MRSA are shown in red.

Definitions

[0044] The term "about" is understood to refer to a range of numbers that a person of skill in the art would consider equivalent to the recited value in the context of achieving the same function or result.

[0045] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps. Thus, in the context of this specification, the term "comprising" means "including principally, but not necessarily solely."

[0046] In the context of this specification the terms "a" and "an" are used herein to refer to one or to more than one (i.e to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0047] As used herein the term "implant" refers to an article or device that is placed entirely or partially into an animal body, such as for example by a surgical procedure.

[0048] As used herein the term "biocompatible" means that the compound, material or item to which it refers does not produce a toxic or immunological response when exposed to the animal body or animal bodily fluids.

[0049] As used herein the terms "ceramic material", "baghdadite doped with bismuth" and "bismuth doped baghdadite" are synonymous.

[0050] As used herein the term "doped with bismuth" is understood to mean that the baghdadite comprises a small, minute, negligible or trace amount of bismuth. Doping as used herein refers to the incorporation of specific species of ions or atoms into a host lattice core structure to produce a hybrid material with new and useful properties. In the context of the invention described herein, the host lattice core structure is Baghdadite. As used herein, the dopant is bismuth. Doping can influence the size and shape of the lattice structure, which is reflected in the transmission X-ray diffraction (XRD) pattern and lattice parameters. The XRD pattern of bismuth-doped forms of Baghdadite exhibit shifted peak lines of intensity compared with undoped Baghdadite. Doping may also influence other properties including osteoblast biological activity.

Detailed Description of the Invention

[0051] Baghdadite is a calcium zirconium silicate ceramic mineral having the molecular formula Ca 3 ZrSi 2 0 9 . It occurs in melilite skarn in contact with a banded diorite in the Qala- Dizeh region of north east Iraq. [0052] In one aspect the present invention relates to a ceramic material which is baghdadite doped with bismuth.

[0053] In some embodiments, the ceramic material may have the formula Ca 3.a Bi a Si 2 ZrOg, wherein a >0 and <0.5.

[0054] In one embodiment, a is 0.1 -0.4.

[0055] In other embodiments, a is 0.1 or 0.2.

[0056] In one embodiment, the ceramic material as a formula Ca 2.6-2.9 Bi 0.1-0.4 Si 2 ZrO 9 .

[0057] In one embodiment the amount of bismuth present is an amount that does not induce a phase change or formation of a new phase in the baghdadite. Preferably, the ceramic material is monophasic. More preferably, the ceramic material does not comprise undoped Baghdadite.

[0058] In some embodiments the ceramic material includes a substitutional doping of calcium with bismuth in an amount of between about 0.01 mol and about 0.5 mol. In some embodiments, the substitutional doping can be about 0.01 mol, about 0.02 mol, about 0.03 mol, about 0.04 mol, about 0.05 mol, about 0.06 mol, about 0.07 mol, about 0.08 mol, about 0.09 mol, about 0.1 mol, about 0.11 mol, about 0.12 mol, about 0.13 mol, about 0.14 mol, about 0.15 mol, about 0.16 mol, about 0.17 mol, about 0.18 mol, about 0.19 mol, about 0.2 mol, about 0.21 mol, about 0.22 mol, about 0.23 mol, about 0.24 mol, about 0.25 mol, about 0.26 mol, about 0.27 mol, about 0.28 mol, about 0.29 mol, about 0.3 mol, about 0.31 mol, about 0.32 mol, about 0.33 mol, about 0.34 mol, about 0.35 mol, about 0.36 mol, about 0.37 mol, about 0.38 mol, about 0.39 mol, about 0.4 mol, about 0.41 mol, about 0.42 mol, about 0.43 mol, about 0.44 mol, about 0.45 mol, about 0.46 mol, about 0.47 mol, about 0.48 mol, about 0.49 mol, about 0.5 mol, between about 0.01 mol and about 0.1 mol, between about 0.1 mol and about 0.2 mol, between about 0.2 mol and about 0.3 mol, between about 0.3 mol and about 0.4 mol, between about 0.4 mol and about 0.5 mol, between about 0.01 mol and about 0.1 mol, between about 0.01 mol and about 0.2 mol, between about 0.01 mol and about 0.4 mol, between about 0.1 mol and about 0.3 mol, between about 0.1 mol and about 0.4 mol, between about 0.1 mol and about 0.5 mol, between about 0.2 mol and about 0.3 mol, between about 0.2 mol and about 0.4 mol, between about 0.2 mol and about 0.5 mol, between about 0.3 mol and about 0.4 mol, between about 0.3 mol and about 0.5 mol, between about 0.4 mol and about 0.5 mol, or any other range between any listed value. In some embodiments, the substitutional doping can be less than about 0.5 mol, less than about 0.4 mol, less than about 0.3 mol, less than about 0.2 mol. In some embodiments, the substitutional doping is greater than 0.

[0059] In some embodiments, the substitutional doping can be the highest concentration at which no further phases are observed and no melting occurs. In other embodiments, the substitutional doping can be at a concentration at which melting is observed, regardless of sintering temperature.

[0060] The inventors have found that bismuth can be doped into baghdadite without affecting baghdadite's mechanical properties. Surprisingly, it has also been found that the bismuth doped baghdadite retains cytocompatibility with primary human osteoblasts, and in addition enhances osteoblast biological activity.

[0061] In some embodiments, the bismuth doped baghdadite may also result in enhanced radioopacity (due to its atomic weight and high X-ray mass attenuation coefficient) and antibacterial activity as compared to baghdadite which is not doped. Figures 1 and 2 illustrate this by illustrating that with increasing amounts of bismuth doping, radiopacity increases in a linear manner.

[0062] The bismuth doped baghdadite may be prepared by sintering. For example, in one embodiment the bismuth doped baghdadite is prepared by calcination of a powdered mixture comprising calcium carbonate, silicon dioxide, zirconium dioxide and bismuth carbonate in a furnace at about 1350 °C. The temperature may be increased to 1350 °C gradually, for example at a rate of about 2 °C per minute.

[0063] The bismuth doped baghdadite is typically medical grade or implant grade. In one embodiment, the bismuth doped baghdadite has a purity of greater than about 95%. In some embodiments the purity is greater than about 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 99.5 or 99.9%.

[0064] In some embodiments the bismuth doped baghdadite is biocompatible when placed in physiological fluid. The bismuth doped baghdadite may form a hydroxyapatite layer upon exposure to bodily fluids. As will be apparent to those skilled in the art, the formation of hydroxyapatite is widely recognised as strong evidence that the body accepts the material as sui generis and is a requirement for the material to chemically bond with living bone and tissue.

[0065] In some embodiments the bismuth doped baghdadite may be used as a bone substitute. Bone substitutes find use in many surgical procedures, such as for example repairing of fractures, treatment of bone diseases (such as osteonecrosis), spinal fusion, dental implant surgery, filling of bone defects and sinus augmentation.

[0066] In some embodiments the bismuth doped baghdadite may be provided in crystalline form mixed with crystalline apatite or crystalline tricalcium phosphate.

[0067] The present invention also relates to an implantable medical device comprising the bismuth doped baghdadite. The bismuth doped baghdadite may be formed into a medical device or used as a coating on a medical device. The medical device may be, for example, a 3D implantable scaffold, an orthopaedic implant for reconstructive surgery, a dental implant/prosthesis, a spine implant, an implant for craniofacial reconstruction and/or alveolar ridge augmentation, an implant for cartilage regeneration, an osteochondral defect implant, a surgical fastener (such as a clamp, clip, sheath, or staple), a surgical fabric, an artificial heart valve (such as a sheath, flange, leaf or hinge), a strut, a stent or a stent-graft or a scaffold for bone tissue regeneration and maxillofacial reconstruction. As a result of its interconnected pores, the bismuth doped baghdadite serves as an ideal osteoconductive scaffold and supports the formation of new bone.

[0068] When used to coat implants the bismuth doped baghdadite may improve/enhance the long-term stability of the implant. This may be particularly useful in the case of orthopaedic implants, for example on areas that are subject to wear. In addition, it has been found that the bismuth doped bagdadite shows enhanced antimicrobial properties relative to undoped bagdadite. These antimicrobial properties may reduce the risk of post-implantation infection and may therefore make the bismuth doped bagdadite of the invention a superior material for any of the internal uses within the body of a subject described herein.

[0069] The bismuth doped baghdadite may be formed into a medical device in a similar manner to that described in Hench L. L. J. Am. Ceram. Soc. 1991 ; 74: 1487-1510 and Zhao J. et al. Biomed. Mater. 2006; 1 (4): 188-92. Accordingly, in some embodiments the invention also relates to a bone implant, a tooth filing implant, a biocement or a composite biocompatible material, each comprising the bismuth doped baghdadite.

[0070] In some embodiments, the medical device may be permanently implanted. In alternative embodiments the medical device is temporarily implanted. The medical device may be substantially biodegradable or resorbable. The medical device may be implanted into a body in different ways, including, but not limited to subcutaneous implantation, implantation at the skin surface and implantation in the oral cavity.

[0071] In some embodiments the device may be coated with one or more resorbable polymers, such as for example, polyglycolides, polydioxanones, polyhydroxyallcanoates, polylactides, alginates, collagens, chitosans, polyanhydrides and the like.

[0072] The coating material may further comprise healing promoters such as thrombosis inhibitors, fibrinolytic agents, vasodilator substances, anti-inflammatory agents, cell proliferation inhibitors, inhibitors of matrix elaboration or expression and promoters of osteogenesis and chrondogenesis. The present invention also contemplates using a polymer coating in conjunction with a healing promoter to coat the implantable medical device, for example as described in Wu C. Acta Biomateilia, 2008; 4: 343-353.

[0073] The porosity of the medical device comprising the bismuth doped baghdadite may be between about 20% and 80%. However, those skilled in the art will appreciate that the device may be formulated or produced to have a lower or higher porosity depending on the intended use. For example, the porosity of the medical device may be about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% or about 95%.

[0074] In some embodiments the pore size of the medical device is between about 20 pm and 500 pm. However, it will be appreciated that the device may be formulated or produced to have lower or higher pore sizes depending on the intended use. Typically, the pore size of the ceramic materials are measured using scanning electron microscopy (SEM) imaging, followed by image analysis, for example using any suitable image analysis software or algorithm.

[0075] Those skilled in the art will appreciate that the porosity of a ceramic may be adjusted by controlling the content and size of porogens. The compressive strength of the bismuth doped baghdadite may be between about 1.8 to 5.1 MPa with porosities in the range of 65% to 78%. This is ideal for scaffolds intended for use in load-bearing applications as the strength of the natural bone is within this range.

[0076] The present invention also relates to a method for producing an implantable medical device comprising applying the bismuth doped baghdadite onto a substrate thereby forming the implantable medical device.

[0077] Those skilled in the art will appreciate that there are a number of methods available for applying materials onto a substrate. Exemplary techniques include, but are not limited to, electrodeposition, electroless deposition, thermal spraying, slurry coating, wire deposition, chemical vapour deposition, physical vapour deposition and plasma vapour deposition. In one embodiment the bismuth doped baghdadite may be applied by plasma spraying. This method comprises spraying molten or heat-softened material onto a surface of the substrate. The material, in the form of powder, is injected into a high temperature plasma flame, where it is rapidly heated and accelerated to a high velocity. The hot material impacts the substrate surface and rapidly cools to form a coating (see for example Liu X. in Biomedicine & Pharmacotherapy 2008; 62(8):526-529). The coatings typically have a dense structure with a thickness of about 50 pm.

[0078] The bismuth doped baghdadite may also find use in resurfacing tissue, such as for example arthritic joints to promote the growth of articular cartilage. In other embodiments the bismuth doped baghdadite may be used in the development of 3D scaffolds which promote migration, proliferation and differentiation of bone and endothelial cells, for example in orthopaedic and maxillofacial surgeries, and yet also provide sufficient mechanical properties for load-bearing parts. The bismuth doped baghdadite may also support bone tissue regeneration/formation and vascularization whilst also providing minimal fibrotic reactions. The enhanced antimicrobial properties of the bismuth doped bagdadite also may assist with its use as a tissue resurfacing agent as the risk of microbial infection is reduced.

[0079] The present invention also relates to biphasic scaffolds for osteochondral defects. The defect could be contacted with, for example, a cementing paste comprising bismuth doped baghdadite and cured or allowed to set. The presence of bismuth doped baghdadite would act to stimulate the formation of the osseous tissue on the orthopaedic defect. The antimicrobial properties of the bismuth doped bagdadite may make it preferable for this use, relative to undoped bagdadite and similar ceramic materials. [0080] The present invention also relates to a kit for regenerating or resurfacing tissue comprising bismuth doped baghdadite and a therapeutic agent that stimulates and/or accelerates tissue regeneration. Therapeutic agents that stimulate and/or accelerate tissue regeneration will be known to those skilled in the art.

[0081] The present invention also relates to an implantable drug delivery device comprising bismuth doped baghdadite. The drug delivery device may deliver any drug and can be shaped to suit the particular application. See for example Krajewski et al. in J. Mater. Sci.: Mater. In Med. 12 (2006) 763-771 .

[0082] The invention is further described below by reference to the following non-limiting examples.

Examples

Synthesis of baghdadite and bismuth doped baghdadite powder

[0083] Ceramics were prepared using a solid-state sintering route as set out below.

1 . Powdered reagents were weighed according to the desired stoichiometric ratios to a total of 40 grams (see Table 1 below).

2. Powders were homogenised in a planetary ball mill for 3 hours at 150 rpm.

3. Mixed powdered reagents were transferred from the ball mill to a crucible.

4. Calcination of the powders was performed in a furnace at 1350 °C. A typical heating profile comprises: a) raising the temperature in the furnace at a rate of 2 °C per minute until a temperature of 600 °C is reached; b) holding for 1 hour at 600 °C; c) raising the temperature in the furnace at a rate of 2 °C per minute until a temperature of 1350 °C is reached; d) holding for 3 hours at 1350 °C; and e) cooling to ambient temperature, leaving the powered sample inside the closed furnace during the cooling step.

5. The calcinated powders were removed from the crucible and finely ground using a mortar and pestle.

6. The baghdadite and bismuth doped baghdadite were stored until sample preparation.

Table 1

[0084] About 1 gram of each ceramic powder was used for X-ray diffraction (XRD) analysis using an X-ray diffractometer (PANalytical X'Pert Powder, Malvern Analytical). All XRD analyses were carried out using XRD analysis software (Jade5.0).

[0085] 2Q angles ranged from 10 to 50 at 0.01 per step. Peaks in the XRD profiles were compared to the International Centre for Diffraction Data powdered diffraction file (ICDD- PDF) database. As shown in Figure 3, doping bismuth ions into baghdadite did not introduce new phases or changes in phase.

[0086] Undoped Baghdadite (Ca 3 ZrS i2 O9) is characterised by an XRD pattern obtained from a copper source having the following diffraction angles 2Q: about 12.283, about 27.777, about 29.641 , about 30.035, about 31 .256, about 31 .558, about 36.115, about 37.099.

[0087] Bismuth doped Baghdadite (Ca 3.a Bi a S i2 ZrO 9 , wherein a = 0.1) is characterised by an XRD pattern obtained from a copper source having the following diffraction angles 2Q: about 12.231 , about 27.711 , about 29.549, about 29.983, about 31.191 , about 31.493, about 36.049 and about 37.034.

[0088] Bismuth doped Baghdadite (Ca 3.a Bi a S i2 ZrO 9 , wherein a = 0.2) is characterised by an XRD pattern obtained from a copper source having the following diffraction angles 2Q: about 12.283, about 27.764, about 29.602, about 30.048, about 31.243, about 31.558, about 36.101 , about 37.073.

[0089] The phase peak positions of bismuth doped Baghdadite (Ca 3-a Bi a S i2 ZrO g , wherein a >0 and <0.5), shifted at least about minus 0.01- 0.07 degrees 2Q relative to undoped Baghdadite (Ca 3 ZrSi 2 O 9 ) with increasing bismuth concentration.

[0090] The inventors surprisingly found that the doping process results in the formation of monophasic doped-Baghdadite, without the formation of additional phases. The shifts in the 2- theta values in the XRD profiles of bismuth doped Bagdhadite relative to undoped Baghdadite, indicate slight changes in the dimensions of the crystal unit cell, but still retains the crystal structure that defines the material ‘Baghdadite’.

Synthesis of sintered baghdadite and bismuth doped baghdadite samples for testing

[0091] The diameter of the ceramic disk to be used for biological testing was measured to be about 15 millimetres, and the diameter of the ceramic disk to be used for mechanical testing was measured to be about 6 millimetres. The calcined ceramic powders were then transferred into a steel die having the corresponding diameter. The steel die, including the ceramic powder, was pressed at about 300 MPa using a hydraulic press.

[0092] The pressed samples were placed on a crucible and sintered in a furnace at about

1350 C. A typical heating profile comprises: a) raising the temperature in the furnace at a rate of 2 C per minute until a temperature of 600 C is reached; b) holding for 1 hour at 600 C; c) raising the temperature in the furnace at a rate of 2 C until a temperature of 1350 C is reached; d) holding for 3 hours at 1350 C; and e) cooling to ambient temperature, leaving the powered sample inside the closed furnace during the cooling step. The surface of the sintered ceramic was polished using grade 1000 sand paper for 10 minutes.

[0093] The synthesis method was modified to determine the effect of bismuth concentration and sintering temperature on the properties of the disks. As shown in Table 2, bismuth doping concentration and sintering temperature influenced the structure of sintered baghdadite and bismuth doped disks.

Table 2

Mechanical testing

[0094] For compressive testing, sintered baghdadite and bismuth doped baghdadite cylinders (about 5 mm diameter, about 8 mm length) were compressed to failure. Compressive strength and modulus of at least four specimens per ceramic group were measured and recorded using a universal testing machine (Instron, UK) and a load cell of 10 kN, at a compression rate of 0.5 mm/min. As shown in Figure 4, doping of bismuth ions into baghdadite did not significantly influence the compressive mechanical properties of baghdadite. Cytocompatibility testing

[0095] Baghdadite and bismuth doped baghdadite discs (diameter of about 12 mm after sintering due to densification) were sterilised before cell culturing using an autoclave (121 °C for 20 minutes).

[0096] Primary human osteoblast cells (HOBs) were isolated from normal human trabecular

3 bone. The bone was divided into 1 mm pieces, washed several times in phosphate- buffered saline (PBS), and digested for 90 minutes at 37 °C with 0.02% (w/v) trypsin (Sigma-Aldrich, USA) in PBS. The digested cells were cultured in complete medium containing cr-MEM supplemented with 10 vol% heat-inactivated fetal calf serum (FCS) (Gibco Laboratories, USA), 2 mM l-glutamine (Gibco Laboratories, USA), 25 mM Hepes buffer (Gibco Laboratories, USA), 2 mM sodium pyruvate, 100 U/ml penicillin, 100 /vg/ml streptomycin (Gibco Laboratories, USA) and 1 mM l-ascorbic acid phosphate magnesium salt (Wako Pure Chemicals, Japan). The cells were cultured at 37 °C with 5% C0 2 and complete medium changes were performed every 3 days. All HOBs used in the experiments were at passage three. After the cells reached 80%-90% confluence, they were trypsinized with TrypLE™ Express (Invitrogen) and subsequently suspended in complete medium.

[0097] For HOB proliferation studies, cells were seeded on the discs at initial cell densities of

4

5 x 10 cells per sample, in 90 m I of cell suspension. A suspension of HOBs was gently dropped onto the discs ( n = 4), placed into 24-well plates (untreated, NUNC) and incubated for 90 minutes at 37 °C to allow the cells to attach. Each disc was then transferred to a new well and 1.5 ml of culture medium was added for culturing. At the designated time points, HOBs on the discs were analysed for viability.

[0098] The CellTiter 96 Aqueous Assay (Promega, USA) was used to determine the number of viable cells on the cultured discs via a colorimetric method. The assay solution is a combination of tetrazolium compound (3-(4,5-dimethylthiazol-2-yl)-5-(3- carboxymethoxyphenyl)-2-(4-sulfophenyl-2H-tetrazolium), MTS) with an electron coupling reagent (phenazine methosulfate, PMS) at a volume ratio of 20:1. The former compound can be bio-reduced by viable cells into formazan, which is soluble in cell culture medium, and the absorbance of formazan at 490 nm is directly proportional to the number of viable cells present. The HOB proliferation was evaluated after 1- and 7-day culture. At each time point tested the culture medium was replaced with 1 .5 ml of the MTS working solution, which included the CellTiter 96 Aqueous Assay solution diluted in PBS at a volume ratio of 1 :5. After 4 hours of incubation at 37°C, 100 mI of the working solution was transferred to a 96-well cell culture plate and the absorbance at 490 nm was recorded using a microplate reader (PathTech, Australia) and the Accent software (Australia).

[0099] As shown in Figure 5, bismuth doping significantly enhances primary HOB proliferation on the baghdadite disks. Results taken at after 7-day culture were significant (p < 0.05) within each group (ie Ca 3 ZrSi 2 O 9 , Ca 2.9 Bi 0.1 Si 2 ZrO 9 and Ca 2.8 Bi 0.2 Si 2 ZrO 9 groups) and results for Ca 2.9 Bi 0.1 Si 2 ZrO 9 were found significant (p < 0.05) relative to corresponding time point against pure bagdadite (ie Ca3ZrSi 2 Og) at 1-day and 7-day culture periods.

Radiopacity

[0100] Dense, non-porous ceramic samples are prepared. The samples have a diameter of about 6 mm and a thickness of about 5 mm. One sample is baghdadite, one is 0.1 mol% bi- baghdadite and one is 0.2 mol% bi-baghdadite. Radiopacity of these samples is measured microCT (cone beam computed tomography) at x-ray energy of 70 keV. The Hounsfield Units generated is calculated after calibrating air (-1000 HU) and water (0 HU) standards on a grayscale value. Data is provided in Figures 1 and 2.

Antimicrobial properties

[0101] Ceramic materials of undoped bagdadite or bismuth doped bagdadite (Ca 2.9 Ba 0.1 Si 2 ZrO 9 ) were inoculated with multidrug resistant Staphylococcus aureus (MRSA) at an initial cell concentration of OD 600 nm = 0.1 . The materials were then incubated at 37 °C for 18 hours under light exclusion (dark conditions). The ceramic materials were then stained with Syto ® 9 (green) and propidium iodide (PI; red) fluorescent dyes, and subjected to confocal visualization according to the following protocol.

[0102] A confocal laser scanning microscope (CLSM), a ZEISS LSM 880 Airyscan upright microscope (Oberkochen, Germany), was used to evaluate the proportions of live and dead cells in each bacterial sample. Cells were dyed using a LIVE/DEAD ® BacLight™ Bacterial Viability Kit (including SYTO ® 9 and PI) (Molecular Probes™, Invitrogen, Grand Island, NY, USA). Specifically, SYTO ® 9 permeated both intact and damaged cell membranes, binding to nucleic acids and fluorescing green when excited by a 485 nm wavelength laser. PI dominantly enters cells that have undergone membrane damage, which are considered to be non-viable, and binds with higher affinity to nucleic acids than SYTO ® 9. Bacterial suspensions were stained according to the manufacturer’s protocol. Importantly, discrepancies in viability assessment were avoided by ensuring that no green (485 nm) and red (543 nm) fluorescence overlap was observed during image assessment. Furthermore, photobleaching of the SYTO ® 9 dye was avoided by limiting each surface location to a single confocal scan. Live and dead cell ratio was quantified using Cell-C (software originally published as a supplement in: Jyrki Selinummi, Jenni Seppala, Olli Yli-Harja, and Jaakko A. Puhakka, Software for quantification of labeled bacteria from digital microscope images by automated image analysis, BioTechniques, Volume 39, Number 6: pp 859-863) providing a meaningful assessment of the antibacterial activity of the surface.

[0103] The CLSM results are shown in figures 6a (undoped bagdadite) and 6b (bismuth doped bagdadite - Ca 2.9 Ba 0.1 Si 2 ZrO 9 ) and show clearly visible amounts of dead MRSA (shown in red) on the bismuth doped ceramic material compared to living MRSA (shown in green). These results suggest that the bismuth doped bagdadite is suitable for use in internal biological environments, as foreign surfaces often serve as substrates for microbial growth, and the increased antimicrobial properties demonstrated may serve to minimize the risk of post application/implantation infection .