Controlled release properties and final macroporosity of a pectin microspheres-calcium phosphate composite bone cement.

The use of calcium phosphate cements (CPC) is restricted by their lack of macroporosity and poor drug release properties. To overcome these two limitations, incorporating degradable polymer microparticles into CPC is an attractive option, as polymer microparticles could help to control drug release and induce macroporosity after degradation. Although few authors have yet tested synthetic polymers, the potentiality of polysaccharides' assuming this role has never been explored. Low-methoxy amidated pectins (LMAP) constitute valuable candidates because of their biocompatibility and ionic and pH sensitivity. In this study, the potentiality of a LMAP with a degree of esterification (DE) of 30 and a degree of amidation (DA) of 19 was explored. The aim of this study was to explore the influence of LMAP microspheres within the composite on the cement properties, drug release ability and final macroporosity after microspheres degradation. Three LMAP incorporation ratios, 2%, 4% and 6% w/w were tested, and ibuprofen was chosen as the model drug. In comparison with the CPC reference, the resulting composites presented reduced setting times and lowered the mechanical properties, which remained acceptable for an implantation in moderate-stress-bearing locations. Sustained release of ibuprofen was obtained on at least 45days, and release rates were found to be controlled by the LMAP ratio, which modulated drug diffusion. After 4months of degradation study, the resulting CPC appeared macroporous, with a maximum macroporosity of nearly 30% for the highest LMAP incorporation ratio, and interconnectivity between pores could be observed. In conclusion, LMAP appear as interesting candidates to generate macroporous bone cements with tailored release properties and macroporosity by adjusting the pectin content within the composites.

Behaviour of an injectable calcium phosphate cement with added tetracycline.

A calcium phosphate cement containing an antibiotic can be used for filling bone defects and to ensure local antibiotherapy. A calcium phosphate cement (already marketed under the name of Cementek can become injectable thanks to the addition of silicone. For dental applications, the behaviour of this injectable cement with added tetracycline was investigated. The tetracycline hydrochloride does not allow maturation of the cement: the tetracycline has to be treated with a calcium sulphate solution. The treated tetracycline (TTC) allowed maturation of the cement towards hydroxyapatite. But the setting time was longer and the mechanical properties decreased. Study in a continuous flow cell showed that the tetracycline is released in a continuous manner: thus, after 6 days, 60% of the antibiotic was released into the surrounding medium.

Setting characteristics and mechanical behaviour of a calcium phosphate bone cement containing tetracycline.

Calcium phosphate cements are used for bone defect filling and they may also be used as delivery systems for active agents. The physicochemical behaviour of an ionic cement, with a final composition of hydroxyapatite, containing tetracycline hydrochloride was investigated. Chemical characterisation, X-ray diffraction analysis, compressive strength and tensile strength were performed. It is known that the antibiotic can be adsorbed on calcium phosphate compounds and the presence of chloride ions can strongly influence the behaviour of the cement. Adding more than 1% (w/w) of 95% pure tetracycline hydrochloride in the solid phase led to a cement with poor mechanical properties, but which, in addition to hydroxyapatite, contained residual starting reagents. For this reason, experiments were also performed with tetracycline previously treated with a calcium sulphate solution. Using a treated tetracycline, it was possible to introduce at least 7% (w/w) of active ingredient whilst still allowing the reaction to proceed to completion i.e. the formation of hydroxyapatite with good mechanical properties. Therefore, treating the tetracycline HCI with calcium sulphate solution prior to reaction conserved the activity of the antibiotic, limited the influence of the antibiotic on the cement evolution and retained the physical properties of the cement.

Effects of various adjuvants (lactic acid, glycerol, and chitosan) on the injectability of a calcium phosphate cement.

Calcium phosphate cements are well-known orthopedic materials for filling bone. Various formulations are proposed. The current challenge is to place the material in the surgical site by methods as least invasive as possible. One approach consists of making the cement injectable by incorporation of various adjuvants. However, the requirement properties of the cement must be preserved: setting times suited to a convenient delay with surgical intervention, limited disintegration in aqueous medium, and sufficient mechanical resistance. Various additives were studied: in particular, lactic acid, glycerol, chitosan, and sodium glycerophosphate. Injectability, setting time, disintegration, and toughness after 10 days were followed in vitro. Glycerol greatly improved injectability and increased setting time, but decreased mechanical properties. Lactic acid reduced setting time, increased toughness of the material, but limited the dissolution rate. After injection, the cement did not present any disintegration. The effects lactic acid were correlated with the formation of calcium complex. Its association with sodium glycerophosphate is particularly interesting. Chitosan alone improved injectability, increased setting time, and limited the evolution of the cement by maintaining the OCP phase. Only slight disintegration was observed. These first results show that is possible to transform the cement into an injectable paste by addition of adjuvants without fundamentally modifying the chemical reactions occurring during setting and hardening.

Heterogeneous crystallization of dicalcium phosphate dihydrate on titanium surfaces.

The kinetics of nucleation and crystal growth of dicalcium phosphate dihydrate (DCPD, CaHPO4.2H2O) on titanium powders with different grain sizes have been investigated using the constant composition crystal growth method at 37 degrees C and pH = 5.50. Nucleation is independent of titanium powder size while crystal growth rate is strongly size-dependent. A minimum relative supersaturation ratio, sigma(min), required in the system for a detectable crystal growth rate to occur, taking into account the presence of the foreign substrate in the system, was determined. Based on the kinetic data and on the various characterizations by X-ray photoelectron spectroscopy and by scanning electron microscopy, we propose a crystal growth kinetic equation as a function of two parameters: the size of the substrate and the excess of supersaturation (sigma-sigma(min)) which is squared, indicating a spiral growth mechanism.

In vitro crystallization of octacalcium phosphate on type I collagen: influence of serum albumin.

The heterogeneous crystallization of octacalcium phosphate (OCP, Ca8H2(PO4)6.5H2O) on demineralized Type I collagen has been studied from metastable supersaturated solutions, at 37degreesC and pH=6.50, using the constant composition crystal growth technique. The induction period, before OCP crystal growth, varied markedly with the degree of supersaturation of the solution. The data obtained allowed us to determine the apparent order for the precipitation and the growth mechanism of OCP on Type I collagen. Infrared spectroscopy analyses indicated the progressive mineralization of collagen and observations by scanning electron microscopy confirmed the development of OCP crystals on the collagen surface. The influence of bovine serum albumin on both the kinetics of OCP nucleation and growth has also been investigated. Because this protein was adsorbed on calcium phosphate nuclei, it exhibited two distinct effects as a function of its concentration in solution. We proposed a mechanism explaining the interaction between albumin and calcium phosphate nuclei or crystals and its incidence on the OCP crystallization kinetics. Observations by scanning electron microscopy revealed a modification of the size and the appearance of crystals grown on collagen due to the adsorption of albumin on the crystal surface.