Patent Application
20140120149
The present invention relates to calcium sulphate based composites. More specifically, the present invention is concerned with such composites for use as bone graft substitutes.
Trauma to the skeleton can often necessitate the use of grafts to fill volumes of missing bone or to enhance healing of severe fractures. For example, revision arthroplasty surgery often involves loss of bone stock and cavity defects that result in suboptimal implant fit, reduced initial stability, and reduced potential for biologic fixation of porous implants. Currently the materials most commonly used to in bone grafting are morcelized autograft, allograft and industrially processed demineralized human bone. Such porous grafts are commonly used with segmental defects of long and flat bone fractures. Several types of biomaterials have been proposed for defect filling as substitutes for autogenous bone graft; these include calcium phosphate and calcium sulphate based materials. While there have been attempts to use such synthetic materials, they have normally been combined with autograft to act as ‘expanders’ to make less autograft go further. In a recent review of human studies the authors conclude: “Whilst current bone graft substitute materials provide some degree of osseoconduction, osseoinduction and substitution, this is generally less than that observed with autograft or allograft.” [Beswick and Blom, Injury, 2011, S40-S46].
In addition to replacing missing bone, it is sometimes necessary to induce bone to form within pores of a material providing mechanical interlocking and fixation. Known as osseointegration Clearly the requirements of grafts for the purposes of replacing deficient bone stock and induding osseointegration are different, yet the same graft materials are often used for both applications.
In the appended drawings:
In accordance with the present invention, there is provided:
The inventors have previously developed an assay to quantify bone ingrowth into porous model implants and have now gathered data (shown below) indicating that the new synthetic bone graft of the invention exceeded the performance of an industry leading allograft material in a large animal model.
Monetite is a known mineral (CaHPO4) consisting of an acid calcium hydrogen phosphate. It occurs in small quantities in many phosphate deposits, particularly as an incrustation on ancient bones and as a decomposition product of guano (seafowl excrement). It can be obtained from the thermal decomposition of brushite.
Calcium sulphate hemihydrate (CaSO4.½H2O), commonly known as “plaster of Paris”, can be produced by heating gypsum (CaSO4.2H2O). Crystacal Alpha K is a fine plaster (calcium sulphate hemihydrate) made by British Gypsum.
It is understood that in the above described methods, the wound of the patient should be closed and the bone should be given sufficient time to grow in the composite.
The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”) unless otherwise noted.
Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All subsets of values within the ranges are also incorporated into the specification as if they were individually recited herein.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context.
The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.
No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
Herein, the term “about” has its ordinary meaning. In embodiments, it may mean plus or minus 10% of the numerical value qualified.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Other objects, advantages and features of the present invention will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.
The present invention is illustrated in further details by the following non-limiting examples.
Prior to the implantation study, considerable work was performed to optimize handling and setting behaviour of the composite of the invention and a set of properties were derived that were optimal compared with others trialed and were sufficient for surgery. The composite satisfied the surgical requirements of a moderately strong osteoconductive material that is easily handled and sets within a clinically acceptable time frame to allow the surgeon to apply the material without compromising strength or prolonging surgery. As shown below, electron microscopy of the composite fracture surface clearly showed granules within the cement matrix, forming an extremely porous solid, ideal for bone ingrowth. When the new composite was compared with a leading commercial synthetic bone graft substitute it was apparent that there was much more remaining graft AROUND the model porous implant coated with the positive control. Closer evaluation revealed that the extent of bone growth INTO the porous metal rod was much higher. This last capacity for bone growth into the rod is believed to be important to rapid implant stability. When these data were quantified, it was apparent that bone in-growth was nearly double for the new composite. Similar results were obtained with demineralized human bone allografts. These are quite extraordinary results indicative of a truly unique product of substantial benefit to significant numbers of future patients.
Crystacal Alpha K plaster (calcium sulphate hemihydrate—CaSO4.½H2O) was obtained from BPB (Valley Forge, Pa., USA) and monocalcium phosphate monohydrate (MCPM) was obtained from ACBR GmbH (Karlsruhe, Germany). Beta tricalcium phosphate (β-TCP) was synthesized from a stoichiometric mixture of calcium carbonate and dicalcium phosphate dihydrate obtained from Merck KGaA (Darmstadt, Germany) heated to 1400° C. for 14 h followed by 1000° C. for 6 h. The resulting material was ground until <160 μm in size.
Brushite powder was made from β-TCP and MCPM mixed in a weight ratio of 1.5:1 β-TCP:MCPM mixed in a mortar and pestle. The powder mixture was mixed with de-ionized water at a powder-to-liquid ratio (P:L) of 3.0 g/ml and left to set overnight. After curing, the brushite was autoclaved at 121° C. for 20 minutes to induce the phase transformation to monetite. The monetite was characterized using X-ray diffractometry (XRD; Philips model PW1710, Bedrijven b. v. S&I, The Netherlands)
After autoclaving, the monetite was crushed into granules using a mortar and pestle and stratified using ASTM standard sieves (ASTM E-11 Specification No. 18, 35, 70) to create granules ranging in size from 212 to 500 μm and from 500 to 1000 μm.
Monetite granules were mixed in with Crystacal Alpha K to determine the optimal mixture for handling. The effects of granule size, weight percentage granules, powder-to-liquid ratio (P:L) and weight percentage calcium sulphate cement seeds on the setting time and compressive strength were measured to determine the optimal mixture. Qualitative results were also obtained for the ease of handling of the mixtures.
The composites were mixed and placed in cylindrical PTFE mould forms (6 mm ø×12 mm) and the setting time of the mixtures was determined using Gilmore needles (ASTM C266-08). The mechanical strength of the set composites was tested 24 h after mixing using a universal testing machine (Instron 5569, Norwood, Mass., USA).
Surface morphology of the cement granules and set composite were examined using SEM (Hitachi S-4700 Field Emission STEM, Schaumburg, Ill., USA)
XRD analysis, shown in
SEM imaging of the monetite granules showed a distribution of sizes within each range (
The various parameters of the composites were adjusted to measure their effects on both the qualitative and quantitative properties of the material. The properties tested are shown in Table 1.
SEM imaging of the composite fracture surface clearly showed monetite granules within the calcium sulphate matrix, forming an extremely porous solid (
The effect of granule size on the properties of the composites was mixed. Upon mixing, it was qualitatively observed that the 212-500 μm granules allowed for a more mixable paste that was easier to form into the mould. The ease of handling of the composite had little effect on the setting time with both mixtures setting. The 212-500 μm mixture was however slightly slower (
The effect of the weight percentage granules showed a mixed relationship for the initial (I) and final (F) setting times, with a large amount of fluctuation and no clear trend (
Powder-to-liquid ratio had far clearer results than the previous mixtures. Increases in P:L had a negative correlation with the setting times of the mixtures, most notably the final setting time, decreasing the time to setting by 50% between 2.0 and 4.0 g/ml (
Though the previous formulations showed excellent properties in strength and ease of handling, their setting times could, in some circumstances, be deemed less appropriate for the clinical setting. In an effort to decrease setting times, cured Crystacal Alpha K was ground up into powder seeds, which provided nucleation sites for the growth of the set material.
Increasing weight percentage of the seeds reduced the setting times of the material by over 15 minutes, keeping an even amount of time between initial and final setting (
The optimal composition is presented in Table 2.
The healing potential of two different Ca-based materials in a canine implant model using porous titanium implants is reported below.
Gap-type intramedullary implants were fabricated from commercially pure titanium with a 5 mm diameter central porous rod and 11 mm diameter solid end and central spacers to create two separate 3 mm gap regions between host bone and porous metal implant (
MicroCT quantified both native bone and residual CaS or CaP within the gaps, without discriminating one material from the other. Compared with time zero, the total material within CaP-filled gaps diminished by a mean volume of 25%±13% (
When these data were quantified (
BSEM images more clearly showed that CaP-filled gaps remained predominantly filled by the material, with some new bone formation in and around the material pores (
Previous studies have shown that a 3 mm gap around a porous implant in the proximal humerus does not spontaneously heal with bone after 12 weeks. At time zero, both Ca-based materials filled almost the entire gap. By 12 weeks, both materials resorbed and new bond was evident within the gap, on and within the porous implant and in continuity with surrounding host bone. The CaS resorbed to a much greater extent, facilitating more gap filling with new bone.
The scope of the claims should not be limited by the preferred embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety. These documents include, but are not limited to, the following:
This application claims benefit, under 35 U.S.C. §119(e), of U.S. provisional application Ser. No. 61/719,997, filed on Oct. 30, 2012.
| Number | Date | Country | |
|---|---|---|---|
| 61719997 | Oct 2012 | US |
