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Increases in reconstructive orthopaedic surgery, such as total hip replacement and spinal fusion, resulting from advances in surgical practice and the ageing population, have lead to a demand for bone graft that far exceeds supply. Consequently, a number of synthetic bone-graft substitutes (BGSs) have been developed with mixed success and surgical acceptance. Skeletal tissue regeneration requires the interaction of three basic elements: cells, growth factors (GFs) and a permissive scaffold. This can be achieved by pre-loading a synthetic scaffold with GFs or pre-expanded cells; however, a 'simpler' approach is to design intrinsic 'osteoinductivity' into your BGS, i.e. the capability to recruit and stimulate the patient's own GFs and stem cells. Through investigation of the mechanisms controlling bone repair in BGSs, linking interactions between the local chemical and physical environment, scientists are currently developing osteoinductive materials that can stimulate bone regeneration through control of the scaffold chemistry and structure. Moreover, this body of research is providing the foundations for future generations of BGSs and bone-repair therapies and may ultimately contribute towards improving the quality of life through maintenance of the skeleton and reversal of disease states, as opposed to the mending of broken bones that we currently practice. Will we be able to grow our own bones in a bioreactor for use as autologous graft materials in the future? Could surgery be limited to accidental trauma cases, with greater restoration of function through biochemical or gene therapies? The technology and research probes necessary to this task are currently being developed with the advent of nanotechnology, genomics and proteomics: are we about to embark on a chemical revolution in medicine? This paper aims to discuss some of the current thinking on the mechanisms behind bioactivity and biocompatibility in bone and how a fuller understanding of the interactions between cells and the materials used today could bring about completely new approaches for the treatment of bone fracture and disease tomorrow.

This paper describes an investigation into the influence of microporosity on early osseointegration and final bone volume within porous hydroxyapatite (HA) bone graft substitutes (BGS). Four paired grades of BGS were studied, two (HA70-1 and HA70-2) with a nominal total porosity of 70% and two (HA80-1 and HA80-2) with a total-porosity of 80%. Within each of the total-porosity paired grades the nominal volume fraction of microporosity within the HA struts was varied such that the strut porosity of HA70-1 and HA80-1 was 10% while the strut-porosity of HA70-2 and HA80-2 was 20%. Cylindrical specimens, 4.5 mm diameter x 6.5 mm length, were implanted in the femoral condyle of 6 month New Zealand White rabbits and retrieved for histological, histomorphometric, and mechanical analysis at 1, 3, 12 and 24 weeks. Histological observations demonstrated variation in the degree of capillary penetration at 1 week and bone morphology within scaffolds 3-24 weeks. Moreover, histomorphometry demonstrated a significant increase in bone volume within 20% strut-porosity scaffolds at 3 weeks and that the mineral apposition rate within these scaffolds over the 1-2 week period was significantly higher. However, an elevated level of bone volume was only maintained at 24 weeks in HA80-2 and there was no significant difference in bone volume at either 12 or 24 weeks for 70% total-porosity scaffolds. The results of mechanical testing suggested that this disparity in behaviour between 70 and 80% total-porosity scaffolds may have reflected variations in scaffold mechanics and the degree of reinforcement conferred to the bone-BGS composite once fully integrated. Together these results indicate that manipulation of the levels of microporosity within a BGS can be used to accelerate osseointegration and elevate the equilibrium volume of bone.

Bioceramics have been considered for use as synthetic bone graft substitutes (BGSs) for over 30 years, throughout which there have been two primary areas of research: (i) optimization of the physical pore structure and (ii) formulation of an appropriate bioceramic chemistry. While it is well recognized that both the rate of integration and the final volume of regenerated bone are primarily dependent on the macroporosity, there still seems to be some dispute regarding the optimum “type” of porosity. The rate and quality of bone integration have, in turn, been related to a dependence on pore size, porosity volume fraction, and interconnection size and interconnection density, both as a function of structural permeability and mechano‐transduction. Moreover, the role of strut microstructure and pore geometry have been considered with respect to their influence on entrapment and recruitment of growth factors (GFs) in addition to its influence on scaffold mechanics. Deconvoluting the relative affects of these parameters is complicated by the use of both resorbable and nonresorbable bioactive bioceramics, which are believed to mediate bioactivity in the osseous environment through two principal mechanisms: (i) directly through dissolution and release of ionic products in vivo, elevating local concentrations of soluble species that interact directly with local cells or influence cell behavior by their effect on local pH, (ii) indirectly through the influence that surface chemistry will have on protein adsorption, GF entrapment, and subsequent cell attachment and function. This article aims to review some of the recent developments in bioceramic BGSs, with a view to understanding how the various physiochemical parameters may be optimized to promote bone healing.

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Abstract:Previous investigations have shown that both the early biological response and the mechanical properties of a porous hydroxyapatite bone graft substitute are highly sensitive to its pore structure. The objective of this study was to evaluate whether the pore structure continued to influence bone integration in the medium to long term. Two screened batches of porous hydroxyapatite (PHA) designated as batch A and batch B, with porosities of ϳ60 and 80%, respectively, were selected for this study and implanted for periods of 5, 13, and 26 weeks into the lower femur of New Zealand White rabbits. Histomorphometric analysis of the absolute volume of bone ingrowth within batch A and B implants from 5 to 26 weeks showed that the absolute volume of bone ingrowth was consistently lower in batch A (10 -21%), compared to batch B implants (24 -31%). However, when the volume of bone ingrowth was normalised for the available pore space, this difference was reduced (23-47% and 32-42% for batches A and B, respectively). These observations suggest that differences in the volume of bone ingrowth initially depended on pore interconnectivity rather than pore size, whereas the volume or morphology of the PHA influenced the volume and morphology of bone ingrowth at later time points. Compression testing showed that bone ingrowth had a strong reinforcing effect on PHA bone graft substitutes, and a strong correlation was identified between mechanical properties and the absolute volume of ingrowth for both batches A and B. Furthermore, at 13 and 26 weeks, there was no significant variation in the ultimate compressive strength of integrated batch A and B implants. This similarity in ultimate mechanical properties indicated that the absolute volume of ingrowth may be mediated by the PHA structure through its impact on the dynamics of the local biomechanical environment. The results of push-out testing showed that fixation of PHA bone graft substitutes was independent of density within the range studied, with no significant difference in the interfacial shear stress between batches A and B at each time point throughout the study.

Phase pure hydroxyapatite (HA) and a 0.8 wt % silicon substituted hydroxyapatite (SiHA) were prepared by aqueous precipitation methods. Both HA and SiHA were processed into granules 0.5-1.0 mm in diameter and sintered at 1200 degrees C for 2 h. The sintered granules underwent full structural characterization, prior to implantation into the femoral condyle of New Zealand White rabbits for a period of 23 days. The results show that both the HA and SiHA granules were well accepted by the host tissue, with no presence of any inflammatory cells. New bone formation was observed directly on the surfaces and in the spaces between both HA and SiHA granular implants. The quantitative histomorphometry results indicate that the percentage of bone ingrowth for SiHA (37.5%+/-5.9) was significantly greater than that for phase pure HA (22.0%+/-6.5), in addition the percentage of bone/implant coverage was significantly greater for SiHA (59.8%+/-7.3) compared to HA (47.1%+/-3.6). These findings indicate that the early in vivo bioactivity of hydroxyapatite was significantly improved with the incorporation of silicate ions into the HA structure, making SiHA an attractive alternative to conventional HA materials for use as bone substitute ceramics.