The control of porosity morphology and physico-chemical characteristics of calcium phosphate bone substitutes is a key-point to guaranty healing success. In this work, micro- and macroporosity of materials processed with 70% Hydroxyapatite (HAP) and 30% beta-tricalcium phosphate (beta-TCP) were controlled by sintering temperature and porogen addition, respectively. Porosity was quantified by scanning electron microscopy (pore size) and mercury intrusion porosimetry (interconnection between pores). The content of macrointerconnections and their size were dependent on porogen content, shape, and size. Mechanical properties (compressive strength) were strongly dependent on macroporosity size and content, on the basis of exponential laws, whereas microporosity ratio was less influent. Relying on those results, three types of materials with contrasting porous morphologies were processed and assessed in vitro, in primary culture of human osteoblasts and fibroblasts. With both types of cells, an exponential cellular growth was effective. Cells colonized the surface of the materials, bridging macroporosity, before colonizing the depth of the materials. Cell migration across and into macroporosity occurred via the emission by the cells of long cytoplasmic extensions that hanged on microporosity. Both macroporosity and macrointerconnectivity size influenced the penetration of cells. An interconnection size of 15 microm appeared to be effective to support this invasion without bringing down mechanical strength.

Decreasing the microscale morphology of synthetic bone substitutes is of primary importance in order to enhance the morphology of the surface of the material, which is directly in contact with osteoconductive cells when it is implanted in bone. The aim of this study was to investigate the influence of ball milling of slurries on the microscale morphology of hydroxyapatite and tricalcium phosphate bone substitutes and the influence on their processing. Ball milling appeared to be a successful method in order to raise the sintering reactivity of the powders, that is, to decrease the sintering temperature and microstructural morphology of the material. However, it was demonstrated that ball milling had a great influence on dispersion, which became very difficult under long milling times because of dissolution of the calcium phosphate powders. Due to dissolution, ionic species were generated in the slurry and interfered with the dispersing agent. Moreover a reprecipitation process occurred simultaneously, and large particles of the most stable phase (HAP) formed. The presence of such large particles generated stress gradients and cracks in the material during the sintering stage.

Infections and their consequences are a considerable problem in orthopaedic surgery. Despite intravenous prophylactic antibiotic administration, infection rates can reach in some occasions more than 1%. Indeed, the concentration in bone tissues is very low with the majority of antibiotics. Because high local dose can be obtained, the local release of gentamicin from acrylic bone cements has been shown to be efficient in preventing infections. However, for surgical procedures other than cemented prostheses no other local antibiotic releasing device is clinically available. The purpose of this study was to validate the concept of a gentamicin loaded bone substitute. About 125 mg of gentamicin were introduced into a HAP/TCP bone substitute for prophylactic purpose, to enhance the efficiency of systemic antibiotic treatments. The release rate of gentamicin from the bone substitute was investigated in vitro, in 0.9% sodium chloride solution. The rate appeared to be related to the bone substitute volume. All the gentamicin was released in less than 48 h. This release rate corresponds to the recommendations for the prophylactic use of antibiotics: the duration of the treatment should be less than 48 h, not to select antibiotic-resistant bacterial strains.

Despite systemic prophylaxis, infection rates after orthopedic surgery can reach more than 1%. A new HAP/TCP bone substitute loaded with 125 mg of gentamicin was designed for prophylactic use. Its aim was to enhance the efficacy of systemic prophylactic treatments by increasing the local antibiotic concentration. The release rate of gentamicin from the bone substitute was investigated after implantation in the femoral condyle of five sheep. In order to investigate the local and systemic gentamicin concentrations, synovial fluids and blood samples were assessed over a 5-day period. The mean gentamicin concentration peak in blood was 4.2 μg/ml and the mean local concentration in synovial fluids during the first 8 h was 305 μg/ml. After 48 h, the concentrations in blood and synovial fluids were less than 0.5 μg/ml. No remaining gentamicin was detected in bone substitutes explanted after 8 days of implantation. The gentamicin release rate from the bone substitutes assessed corresponds to the recommendations for the prophylactic use of antibiotics: high local concentration but limited in time (less than 48 h) not to select antibiotic-resistant bacterial strains. Our results indicated that this implant should be an effective prophylactic tool in orthopedic surgery in combination with systemic prophylaxis.

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