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.

Dynamic mechanical properties of a biomimetic hydroxyapatite/polyamide 6,9 nanocomposite.

A biomimetic composite of nanohydroxyapatite (nHap) and semicrystalline polyamide 6,9 (PA 6,9) was synthesized by thermally induced phase separation. The nHap powder was dispersed in a polymer matrix with a low ratio ranging 1-10 wt %. The mean size of the nHap, determined by scanning electron microscopy (SEM) was approximately 100-200 nm (length), 40-60 nm (width). Physicochemical analyses were performed in order to characterize the PA 6,9 and nHap separately on the one hand, and the PA 6,9/nHap composites on the other hand. Differential scanning calorimetry (DSC) and dynamic mechanical analyses (DMA) have pointed out an optimization of the composite physical properties as a function of nHap content till a limit value of 5 wt %. Above this value, the mechanical properties decreased. Four main parameters have been found to influence the composite physical properties improvement: the fillers content, the physical structure of the polymeric matrix, the particles dispersion and the physical interaction strength between organic and inorganic phases. The dynamic mechanical properties of this biomimetic nanocomposite were compared with human cortical bone.

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.

[Histological comparison of the effect of different implanted hydroxyapatites in the animal periodontium]. / Comparaison histologique de l'effet de diverses hydroxyapatites implantées dans le parodonte chez l'animal.

The effect of various types of synthetic hydroxyapatites (HA), coated or not with collagen or human plasmatic fibrin, has been studied after 3 month implantation either in freshly extracted alveoli in miniature pigs or in experimentally induced periodontal lesions in beagle dogs. The best histological results were observed in HA without organic coating. The Bioapatite consisting in crystals with a mean size of 146 nm +/- 47 nm were well integrated in the alveolar bone. Similar results were obtained with micro-sized hydroxyapatite, with a mean crystal size of 38 nm +/- 16 nm. But at 3 months, this HA type was still actively integrated in bone with osteogenesis. When these 2 types of HA were coated with collagen or plasmatic fibrin, they were less well incorporated in alveolar bone and were even able to develop localized and moderate inflammatory reactions. The main purpose of synthetic HA is to promote alveolar bone formation in periodontal lesions. For an improved tissular regeneration, it is recommended to use simultaneously in the future synthetic HA together with resorbable biocompatible synthetic membranes.

Apatitic calcium orthophosphates and related compounds for biomaterials preparation.

The authors show that to obtain well chemically defined apatitic bioceramics and to know the possible transformations of this material during sintering, it is necessary to prepare a good starting material. Moreover, they show that it is possible to prepare a new organic-inorganic phosphate compound. The precipitation of apatite in an aqueous medium at boiling temperature was studied using the methodology of experimental design. Independent variables were the volume of NH4OH in phosphate solution, the volume of NH4OH in calcium solution, and the time of precipitation; the response was the atomic Ca/P ratio of the obtained precipitate. A continuous variation of this ratio from 1.63 to 1.73 is observed. Implications of this result to the preparation of pure HA: Ca10(PO4)6(OH)2 is given. Moreover, when Ca/P greater than 1.67, HA reacts with Ca(OH)2 (after heating at 1000 degrees C in air for some days) to give rise to a single phase described as a modified HA (MHA), a Ca/P ratio of 1.75, an a value of 9.373 +/- 0.002 A, and a c value of 6.884 +/- 0.002 A. The reactivity (time versus temperature) of the MHA is described. If the precipitation of the calcium phosphate is realized at 37 degrees C in a water-ethanol medium in the presence of A2EP, a new apatite, chemically bonded to the organic molecule by pooling phosphate groups, is obtained.