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Chemical stability of a novel injectable bioceramic for stabilisation of vertebral compression fractures.

At present, the biomaterials used to stabilise fractured vertebrae are resin-based materials, composed principally of polymethylmetacrylate (PMMA). Although successful, the PMMA materials have some shortcomings with regard to handling properties and biocompatibility. Attempts are made to also use injectable ceramic materials. This paper describes the chemistry and mechanical properties of a ceramic material designed for stabilisation of collapsed vertebrae. The material is based on calcium-aluminate cement (CAC) as the reactive phase, and Zr[O.sub.2] as an inert filler added for extra radio-opacity. The material is non-resorbable after setting. The CAC based material was compared to a PMMA-based material intended for the vertebroplasty indication, regarding compressive strength development due to aging for a time period of 6 months. In addition the porosity and weight change over time were measured for the CAC material. The microstructure after hardening was studied using scanning electron microscopy and X-ray diffraction. The CAC material showed about similar compressive strength characteristics as the PMMA material throughout the test period. The spread in data was larger for CAC than for PMMA. The porosity of the material reached about 10-15% after 3 days and then stayed constant over the test period. The hardened bioceramic material's microstructure was homogenous with an even distribution of filler-particles and CAC. The crystalline phase composition increased in hydrates over time and decreased in calcium aluminate.


Over the past decade, vertebroplasty, treatment involving injecting cement into vertebra compression fractures (VCF) by means of a thin needle, has been developed into an established method of treatment. The procedure provides a favourable pain relief and improved mobility [1, 2]. So far, the cements used have generally been variations of conventional bone cement based on PMMA with extra radio-opacity due to the addition of e.g. barium sulphate [3, 4]. Recently also calcium phosphate cements have started to be used in the procedure [5].

Cements aimed for vertebroplasty should display a different property profile compared to conventional bone cements. Since the cement is injected under fluoroscopic guidance--to avoid cement leakage into the spinal column or veins--high radio-opacity is needed. Moreover, handling properties (rheology) during injection are important just as are well-defined working and setting times. Injectable resin cements set in situ and their setting-reactions are normally exothermic generating excess heat into the surrounding tissue, which is speculated to cause tissue damage. The excess heat is also speculated to be the reason for the rapid pain relief. Since the vertebra is mainly subjected to compressive stress, the strength level must be high enough to avoid fractures of the hardened cement and to ensure a rapid mobilisation of the patient. In addition, the material should be biocompatible and preferably also osteoconductive. Except from the exothermic setting reaction, PMMA normally not be injected directly after mixing due to a too liquid consistency and also has a strong smell. Thus the drawbacks with the current standard treatment are mainly during the handling and setting of the material. There are several attempts to develop new material systems to overcome the drawbacks with the PMMA handling as well as increasing the biological reactions to the set material.

All available material systems for injectable biomaterials originate from two major material classes: resins and ceramics. Injectable ceramics originate from the subclass chemically bonded ceramics (CBC), i.e. ceramics that form a solid body via chemical reactions as distinct from sintered ceramics, which are formed via a high temperature process. These materials are delivered as a powder and a liquid, which on mixing, form a paste that subsequently can be injected. Within the chemically bonded ceramics class of materials the calcium-phosphates and calcium-sulfates have been extensively explored, principally as so-called bone void fillers [6]. When compared with resin-based materials these materials display superior biocompatibility, no or limited, heat development during setting, resorption over time (the resins are inert), relatively low strength--especially in bending--and lower radio-opacity. Nevertheless, given the success of PMMA cements in vertebroplasty, attempts to use calcium-phosphate and/or calcium sulphate in vertebroplasty are investigated [5]. This is motivated chiefly by their better biocompatibility profile but also by their possible resorption. The use of CPC is mainly directed towards young patients with high bone turn-over. Within the chemically bonded ceramics system there are also other materials, e.g. the calcium-silicate cements (CSC) and calcium-aluminate cements (CAC), however not yet investigated to the same extent as biomaterials. Both systems have been proposed as dental materials [7-10]. The use of CAC as biomaterial for stabilisation of vertebrae compression fractures can be motivated via the following inherent features: high viscosity, direct injection after mixing, no toxic fumes, low exothermic reaction and high biocompatibility. Compared to CPC the material also has high strength and is inert in body fluids. This means that the strength is not reduced over time and thus the material could possibly also be used for older patients.

This investigation has the objective of reviewing the chemical rationale for using CAC as injectable biomaterial. And to follow the compressive strength, porosity and microstructure development due to aging in phosphate buffer solution for a CAC based material in comparison with a PMMA material. The aging was performed for up to 6 months. The CAC material has been specially developed for the stabilisation of vertebral compression fractures.

Review of the chemistry of CACs

Compared with calcium-phosphates (CPC) and calcium-sulfates, CAC's show many similarities (no smell, similar mixing procedure, ceramic) but also some differences, where two of these are of major importance when used as biomaterials, namely high strength and inertness. The chemical background to the similarities and differences will be reviewed in this section.

CAC can be found as double-oxides between CaO and [Al.sub.2][O.sub.3]. Crystalline phases with the composition CaO: [Al.sub.2][O.sub.3] with ratio 3:1, 12:7, 1:1, 1:2 and 1:6 can be synthesised [11]. The 1:1 oxide is the most commonly used. This is mainly based on its optimal reaction-rate compared with the other phases, where the calcium-richer phases react faster and the alumina-rich slower. The 1:1 oxide is isostructural to a mineral called Marokite. The hardened CAC-based material is formed through an acid-base reaction where water acts as a weak acid and the calcium-aluminate powder as a base. As the powder contacts the water, the dissolution process starts in which the CAC powder dissolves in the surrounding liquid phase, forming the ions [Ca.sup.2+], O[H.sup.-] and Al[(OH).sub.4.sup.-]. This reaction leads to a rise in pH of the solution due to the formation of O[H.sup.-].

Saturation of the metastable Al[(OH).sub.3]--gel is reached. This, in turn, allows for the precipitation of calcium-aluminate hydrates to take place, when their saturation limit has been reached. The on-going precipitation of hydrates and the reduction of the amount of liquid phase result in the formation of a skeleton, and hardness develop. This repeating reaction is fast at the beginning, resulting in setting within 15-20 minutes, but the final strength is first reached after a couple of days maturing. The reaction rate is mainly controlled via the lime (CaO) to alumina ratio of the starting powder. By adding salts that can complex with Al[(OH).sub.4.sup.-] the reaction can be accelerated since the lime/alumina ratio then increases. The chemical reaction at temperatures exceeding 30[degrees]C can be summarized according to:

3 (Ca[Al.sub.2][O.sub.4]) + 12 [H.sub.2]O [right arrow] [Ca.sub.3][(Al[(OH).sub.4]).sub.2][(OH).sub.4] + 4 Al[(OH).sub.3] (1)

The reaction can also be expressed in mineral form

Calcium aluminate + Water [right arrow] Katoite + Gibbsite (2)

As can be seen in Eq. (1) and (2) three Ca[Al.sub.2][O.sub.4] units consume twelve water molecules during hardening. This can be compared with the hardening of CPC where normally no extra water is consumed [12]. In the case of CPC, the reaction liquid is used as a vehicle for the reaction to take place. In both cases the hardening and formation of a solid body are driven by the precipitation of small hydrates with a suitable surface energy, Katoite and Gibbsite for CAC and Apatite or Brushite for CPC. The high water consumption feature for CAC's is very important for the strength, formulation and handling properties of the CAC material. For injectable ceramic materials the strength of the final hardened body is principally controlled by the porosity. The porosity originates from two sources, air bubbles from non-optimal mixing and injection procedure, and from the space occupied by the liquid. The first part is a technical issue and is not primarily controlled by the material formulation. To obtain an injectable paste, a certain powder/liquid ratio is needed. However, the space occupied by the liquid should, in the hardening process, be filled (replaced by hydrates to a great extent) to obtain a high-strength body. Studying the CAC-reaction formulation with volume units added according to

Ca[Al.sub.2][O.sub.4.sup.+] Water [right arrow] Katoite +Gibbsite (3)

it can be seen that the hydrates occupy a larger volume than the anhydrous Ca[Al.sub.2][O.sub.4] phase though this is a smaller volume than the sum of Ca[Al.sub.2][O.sub.4] and water. A net increase in solid volume occurs as the material hardens and the porosity initially filled with water is gradually filled. As can be seen in (3) the volume of the hydrates formed is not greater than the volume of the water and Ca[Al.sub.2][O.sub.4] together and in reality the total dimensional change is however close to zero. These features give several formulation possibilities. If the volume of water added to the powder for mixing is lower than the threshold for complete reaction of the powder the strength increases further, a reactive powder/liquid ratio of [greater than or equal to] 2.2 is optimal. This can be used to add filler particles without reducing the final strength of the hardened body. The filler particles do not participate in the hardening reaction but the ratio between available reactive powder and liquid increases with the addition of fillers. For CPC material the volume increase is, conditional upon reaction chemistry, zero or very low. From a strength point of view this results in difficulties when adding fillers. It should be noted that for CBC materials, irrespective of chemistry (CPC or CAC), the final porosity cannot be zero. When the hydrates precipitate as new grains, some space between the grains is not filled. This porosity is in the nanometer range and its exact amount is very difficult to determine, but 10-20% of the filled space (the original liquid-phase volume) is estimated to be pores [13]. This porosity lowers the mechanical strength (although being in the nanometer range) but also enables liquids to diffuse into, or even through, the hardened CBC materials.

The chemical stability of an injectable ceramic material is important since it determines whether or not the material can be viewed as inert or resorbable in situ. For CAC, the solubility products for the hydrates Katoite and Gibbsite are low. Katoite has pKs=22.3 and Gibbsite pKs=32.3 resulting in 3mM in solution and 10 nM in solution, respectively [14]. The values should be compared with Apatite that has pKs=58 and 300 nM in solution. Thus, it is Gibbsite that conveys the inertness to the material. This is also important because it explains why aluminate ions have very limited leakage from the hardened material.

Materials and Methods

A material formulation based on CAC, developed especially for the treatment of vertebrae compression fractures, was compared to a PMMA-based product for the same indication, Vertebroplastic (Depuy Acromed). CaO[Al.sub.2][O.sub.4] was chosen as the reactive phase and with zirconium dioxide (Zr[O.sub.2]) powder added as a radio-opacity source. The Zr[O.sub.2] can be considered as inert filler and does not participate in the reaction and is added in an amount of above 30 wt.%. The mixing liquid is based on water with minute amount of additives; LiCl <0.05 wt.%, (for control of setting time), methylcellulose < 1 wt.% and polycarboxylacid < 1 wt.% (for control of rheology). The powder/liquid ratio was about 4.4, thus well above the limit for total hydration of the CaO[Al.sub.2][O.sub.4] powder (including the filler) as described in the chemistry section above. The powder and liquid were machined mixed using a capsule system, the formed paste was extruded from the capsule using a hand gun into 1 ml syringes. The powder was preloaded into capsules, 30 grams in each capsule, and sterilised using radiation. Before mixing the appropriate amount of liquid was added to the powder. Mixing of the material was performed using a rotation/vibration. The PMMA material had barium-sulphate as a radio-opacity source and was hand-mixed according to the manufactures instructions. The PMMA paste was applied in sample moulds using 1 ml syringes.

Compressive strength was measured following the ISO 5833:2 (2002) [15] geometry, with n=20 / time period for CAC and n=8 / time period for PMMA. Before measuring the strength, the samples were aged in phosphate-buffered saline (PBS, Dulbecco's from Sigma Aldrich) for 1 day, 3 days, 7 days, 2 weeks, 3 months and 6 months at 37[degrees]C. The storage solution was exchanged once every week.

The porosity was measured (n=3 / time period) on cylindrical samples following:

1. Weigh the sample wet with no water on the surface. ([M.sub.wet])

2. Dry the sample in an oven at 105[degrees]C for 24 h.

3. Weigh the sample.([M.sub.dry])

4. Measure the sample dimensions and calculate the volume.([V.sub.tot])

5. The porosity is calculated according to:

[V.sub.Por] [congruent to] ([M.sub.Wet] - [M.sub.Dry]/([V.sub.Tot]) x 100. [%, Density of water = 1 g/[mm.sup.3]]

The microstructure of the aged CAC samples was studied using scanning electron microscopy (SEM) in backscattered mode at 20 kV. Stored samples were polished down to the bulk material with 2000 grit silicon carbide paper in water, dried at 37[degrees]C, gold sputtered and then examined in the SEM. At each time period low magnification images of the structure were taken to study the possible macro pore structure, high magnification images were taken to study the microstructure. The XRD was done on aged samples (the samples were crushed into powder before the measurements) in T-2T geometry (CuK[??]) using a Siemens diffractometer.





The compressive strength increased during the first weeks of hardening to reach a maximum and then have a constant value throughout the test period, see Fig. 1. The standard deviation of the CAC samples was higher than that of the PMMA. The mean strength was slightly higher for CAC than for PMMA.

After 24 hours the porosity of the samples was about 18 %, see Fig. 2. With time the porosity was lowered further to about 10-12 % after 3 days until 70 days. After 70 days the porosity was constant at about 15%. Low magnification SEM images showed round voids in the microstructure see Fig. 3. The voids were probably connected to the mixing procedure where air bubbles were entrained into the paste.

The microstructure of the CAC material consisted of evenly distributed grains of Zr[O.sub.2] in a matrix of CAC, see Fig. 4a. The Zr[O.sub.2] was present as the bright grains found mainly in small aggregates, the sizes of which were below 10 [??] m. The darker grains represented parts of the anhydrous grain structure. The hydrate grains formed were too fine to be imaged using SEM. Other studies indicate the hydrates to be in the nano-size range 10-50 nm Hermansson et al. (2006). The microstructure of Xeraspine did not change during the storage time, see Fig. 4a-f. The original CaO[Al.sub.2][O.sub.4] grains were transformed to hydrates over time, as could be distinguished comparing for example a) with f). In the PMMA-based material, the barium-sulphate filler grains were of a coarser grain size than that of the Zr[O.sub.2] added to the CAC material, see Fig. 4g. The distribution of the filler was also less uniform with larger domains of PMMA in between. The difference in magnification of the CAC and PMMA is selected to better reveal the differences in the materials structure and homogeneity.

Xeraspine is composed of mainly Ca[Al.sub.2][O.sub.4] and zirconiumdioxide before being mixed with the mixing liquid (mainly water). The crystalline phase development versus aging in PBS can be followed in Fig. 5. After 1 and 3 days the samples contained: Ca[Al.sub.2][O.sub.4], small amounts of Mayenite and possibly also Grossite and Katoite. With time (until 3 months) the amount of Katoite increased and the amount of Ca[Al.sub.2][O.sub.4] decreases. Amorphous peaks at 17-21[degrees] appear, probably belonging to Gibbsite. After 6 months there are some small amounts of Ca[Al.sub.2][O.sub.4] left in the samples, and Katoite and Gibbsite have increased even further. The zirconium dioxide peak was strong at all time observations.




For the chemically bonded ceramics, the ability to bond water is very important for achieving a material of high strength. The added water should be consumed during setting in order to achieve a low-porosity end product. The calcium-aluminate material bonds much more water than conventional CPC does. This is reflected in the strength values obtained, which were comparable with those of the PMMA-based material. Also the strength was rather constant over time with a peak value after 3 days. The microstructural development followed the theories for CAC materials as described in the chemistry section. It is important that the filler particles show a rather even distribution in the structure. Large aggregates may have negative influence on the strength acting as defects in the structure. The fillers in the CAC material were evenly distributed but with some aggregates in the size range of 10 micrometer.

The, in comparison with PMMA, high standard deviation of the CAC strength values can be coupled to the porosity of the material. Porosity of CBC materials is generally connected to either to the chemically formed pores due to the setting and hardening chemistry or to the mixing and ejection of the material. In the case of the CAC material the porosity due to the chemistry is in the size range of nanometres and is called gel-porosity, this type of pores are normally not visible in SEM images. The porosity visible in Fig. 4 originates from the mixing and ejection of the paste with entrapped air inside. These pores are of a larger size than that of the gel pores and contribute to the spread in the strength data. In tests more close to the clinical application the difference in the spread of the data compared to PMMA were not present [16]. These tests were conducted using extracted human vertebras. In geometries more textured than the simple geometry of the compressive strength samples, e.g. the vertebrae, the presence of larger voids compared to PMMA seems to be limited. The microstructure and phase composition of the CAC-material follow described reaction path going from anhydrous phase to hydrates, which bonds the material together and supplies the structure with its strength. It is important to study the fatigue properties of the material; this was not included in this study but is addressed in a separate study.

CAC is a new material concept and scientific questions regarding its biocompatibility and the possible leakage of Al are valid. Both in vitro and in vivo (preclinical and clinical) studies of its biological performance have been conducted. In a sheep vertebrae study comparing CAC-based material with a PMMA-based material, serum samples as well as tissue samples were found to contain low quantities of aluminium (serum: <0.22 [micro]mol/l, tissues: <0.8 mg/kg). The highest concentration of aluminium was found in lung samples. Histologically, aluminium was only detected in a kidney, confined probably in macrophages. Less inflammation and improved bone adaptation were observed for the CAC-based material when compared with the reference material based on PMMA. As mentioned in the introduction a number of physical parameters are important for successful surgical performance, some of the most important properties are presented in [17]. The data show, together with the data in this paper, that the in vitro physical properties are in comparison to PMMA. But since the setting chemistry is very different there are some fundamental differences, e.g. hydrophilic, no monomers, no toxic fumes, easy handling and possibility of precipitation of hydrates on tissue and in small voids.


* The CAC material showed similar compressive strength levels as the PMMA material but with a larger spread in data.

* The strength was stable over the 6 months aging period and the porosity was about 10-15%.

* Initially the hardened material contained unreacted cores of CAC, the amount of unreacted cores diminished over time and the amount of hydrates increased.

* Zirconium dioxide fillers were evenly distributed in the structure with some minor areas of aggregates.


The financial support from the Goran Gustafsson foundation for academic research is acknowledged.

Received 29 August 2007; published online 18 December 2007


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H. Engqvist (1) *, T. Persson T. (2), J. Loof (2), A. Faris (2), L. Hermansson (1)

(1) Uppsala University, The Angstrom Laboratory, Department of Materials Science, Box 534, SE-751 21 Uppsala, Sweden

(2) Doxa AB, Axel Johanssonsgata 4-6, SE-754 51 Uppsala, Sweden

* Corresponding author e-mail:
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Author:Engqvist, H.; Persson, T.T.; Loof, J.; Faris, A.; Hermansson, L.
Publication:Trends in Biomaterials and Artificial Organs
Geographic Code:4EUSW
Date:Jan 1, 2008
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