Interactions with bone
Bioceramics have been the cornerstone of strategies for bone repair and uncemented implant fixation for more than 20 years. An important feature of these materials is that they form a carbonate apatite layer on their surface following implantation. This surface deposit has a similar composition to the mineral component of bone. This allows bone bonding and appropriate interactions with bone cells and the organic matrix they produce, which is a major factor in the successful use of these materials. This ability to interact in a beneficial way with bone is why these materials are termed bioactive. Although there is a wide range of glass and glass ceramic compositions that have found successful clinical application, this article will concentrate on the development and application of bioceramics based on calcium phosphates.
The use of bioceramics in human surgery began in the 1980s with hydroxyapatite coated hip replacements being used to provide a form of fixation, rather than bone cement, and the first human implantations for bone repair. A large research and development industry subsequently grew up and a variety of materials is now available. Calcium phosphates have been mainly used in orthopaedics; these materials range from naturally derived coralline material to porous synthetic hydroxyapatite and the more soluble tricalcium phosphate.1 These bone graft substitute materials have acceptable compressive strength, but are brittle and therefore not suitable for excessive load bearing in critical areas of the skeleton. Solubility and the ability to be actively resorbed during bone formation and remodelling are important features for nonmajor load bearing applications such as the repair of stabilised defects and fractures. Increased solubility increases resorption and there is some evidence to suggest it also enhances osteoconduction. Hydroxyapatite in sintered, bulk form is virtually insoluble, whereas the more soluble b-tricalcium phosphate is more readily resorbed.2 Bioactive ceramic cements are a more recent development. These can be based on calcium phosphate or the glass ionmer equivalents used in dentistry. These materials benefit from being injectable and space filling; calcium phosphate cements are also biodegradable.
The success of bioceramic implants and coatings is evident from their increasing use. There have been many clinical studies of, for example, hydroxyapatite-coated joint prostheses and the use of bioceramic bone substitutes in applications such as fracture healing, impaction grafting and the replacement of surgically removed bone. These have shown the powerful ability of these materials to bond to bone and provide a substrate for, and in some cases stimulate, bone formation. They are also relatively easy to synthesise from simple chemicals, they are stable and can be prepared in a number of formats. Hydroxyapatite-coated joint replacements perform well compared with the cemented alternatives; the latest follow up times of 15 years and more continue to show good performance.3,4 The development and use of these materials is a success story and the large product base includes the Furlong H-A.C. total hip replacement (www.jri-ltd.co.uk) and press fit prostheses from Stryker Orthopaedics (www.stryker.com). In addition, in the modern age of developments in tissue engineering and molecular approaches to the promotion of tissue repair, research using these materials continues apace. There is now a new range of bioceramic-based materials and material coatings, as discussed below, that are available or in development, which will improve the efficacy and extend the application range of bioceramics in bone.
Benefits of silicon substitution
An important development in the ability to manipulate calcium phosphate ceramics was the synthesis of phase-pure hydroxyapatite by carefully controlling the reaction conditions. Prior to this, the hydroxyapatite-based ceramics, both natural and synthetic, could be characterised, but were often a mixture of phases, for example, hydroxyapatite, b-tricalcium phosphate and calcium oxide are three separate phases that could be present in a preparation; substitution of phosphate and hydroxyl residues could also be present. This nonuniformity meant that the beneficial properties of a particular implant material could not be definitely ascribed to any particular component. Phase purity has allowed controlled substitution of ions into the hydroxyapatite lattice and their effect can therefore be carefully assessed. It is known that the main ion-substitution in bone mineral is carbonate and this increases its solubility. However the most useful substitution determined so far is silicon. Silicon substitution produced improved osteoconductivity following implantation5 and has led to the development of macroporous silicon-substituted hydroxyapatite implants (Figure 1). This material (Actifuse, Apatech Ltd, www.apatech.com) is being used successfully in spinal fusion procedures. New substitutions with, for example carbonate or yttrium ions, and different levels of substitution may lead to further improvements in the bioactivity of hydroxyapatite.
The application of hydroxyapatite to the surface of an implant component is important in determining its properties. Plasma spraying was found to be necessary for coating joint replacement prostheses to provide a good bond between the ceramic and the underlying substrate and prevent delamination. A conducting substrate, for example, implant grade alloys, is required and the process takes place at high temperature, which alters the material properties of the starting material and produces a mixture of phases. This, in turn, can increase the solubility and loss of the coated material over time by resorption during bone remodelling. A range of new techniques have been developed to apply bioceramics to implant surfaces in a more controlled way, while retaining the chemical nature of the coating material. These are described below. These methods have the additional benefit of being able to produce coatings of less than 1 μm thick and the coating can be performed at low temperatures, thus preventing phase-change. Incorporation of other bioactive molecules into these coatings is possible and may enable enhanced function.
Figure 2: Scanning electron micrograph of nano-sized hydroxyapatite ceramic particles.
Precipitation from simulated body fluid. Kokubo proposed that the bonelike apatite layer that forms on bioceramics in vivo and promotes bone bonding could also be formed in vitro in a mixture of salts at ionic concentrations equivalent to those in blood plasma, which he called simulated body fluid.6 This led to the development of biomimetic approaches to coating materials where a suitable substrate can be coated in simulated body fluid with a biomimetic apatite coating. This method is now being considered as a suitable approach for implant coating with the advantages that, as it forms at physiological temperatures, it can be applied to heat sensitive and nonconducting materials and growth factors and other bioactive agents can be incorporated into the coating.7 It can also be applied to
materials with complex geometries.
Magnetron sputtering. Other approaches for producing thin coatings of bioceramics on materials at room temp-erature include magnetron sputtering,8 which has been successfully used to apply silicon hydroxyapatite without altering the chemical nature of the ceramic.9
Electrostatic atomisation spraying.10 This is another technique for applying hydroxyapatite. Electrostatic atomisation spraying requires a ceramic material of a suitable size to produce a suspension that is capable of being sprayed with a fine jet. This involved the synthesis of nano-sized bioceramic materials. The development of successful methods for producing this material has opened up the way for nanoscale fabrication of implant materials and coatings.11 The mineral crystals in bone are plate-like with dimensions of 25350 nm and a thickness of 4 nm. Wet synthesis of polycrystalline nano-sized ceramic can produce a material whose smallest particles approach these dimensions (Figure 2). The application of these materials using electrospraying allows the deposition of complex patterns, which may help to promote controlled and guided tissue regeneration. Ink-jet printing is another technique for applying these nanoceramic particles.12 Both these techniques have the potential to produce surface patterning of applied bioceramic and the preparation of controlled three-dimensional structures.13,14
Degradable and nondegradable composites
Nano-sized bioceramics have also suggested routes for producing composite materials by mimicking the structure of bone with the hope of achieving equivalent material properties. Composite materials containing bioceramics have been developed and used successfully as prosthetic materials. For example Hapex (Gyrus ENT LLC, www.gyrus-ent.com), which combines hydroxyapatite with high-density polyethylene, has been successfully used for middle ear implants; the material provides the increased stiffness and bioactivity of hydroxyapatite with the toughness of polyethylene. Many composite materials have been developed and perhaps the most promising for bone repair are those where collagen has been mineralised to produce a biomimetic material resembling bone (www.orthomimetics.com) and the possibilities of using nano-sized bioceramic in biodegradable polymers.15 These approaches will provide the bene-fits of a polymer and the bioactivity of the bioceramic. Both components in these composites are potentially biodegradable and if the proportions and their combination can be carefully managed, there is the possibility of having a fully replaceable material for bone repair that allows the regeneration of normal bone without residual implant material.
The examples described above indicate that the bioceramics have a bright future. This is not only in the devices currently used, which will continue to perform well in bone. The promise lies in new formulations with innovative methods of application. In particular, composite materials will extend the range of applications by producing materials that can mimic the ability of bone to stimulate repair and
improve the mechanical performance of the individual components, and thus be used for load-bearing applications.
The author would like to thank Meera Arumugam for Figure 1; Zhijie Yang for Figure 2; and Dr Serena Best, Cambridge Centre for Medical Materials for helpful suggestions.