Relevance of microstructure for the early antibiotic release of fresh and pre-set calcium phosphate cements

Calcium phosphate cements (CPCs) have great potential as carriers for controlled release and vectoring of drugs in the skeletal system. However, a lot of work still has to be done in order to obtain reproducible and predictable release kinetics. A particular aspect that adds complexity to these materials is that they cannot be considered as stable matrices, since their microstructure evolves during the setting reaction. The aims of the present work were to analyze the effect of the microstructural evolution of the CPC during the setting reaction on the release kinetics of the antibiotic doxycycline hyclate and to assess the effect of the antibiotic on the microstructural development of the CPC. The incorporation of the drug in the CPC modified the textural and microstructural properties of the cements by acting as a nucleating agent for the heterogeneous precipitation of hydroxyapatite crystals, but did not affect its antibacterial activity. In vitro release experiments were carried out on readily prepared cements (fresh CPCs), and compared to those of pre-set CPCs. No burst release was found in any formulation. A marked difference in release kinetics was found at the initial stages; the evolving microstructure of fresh CPCs led to a two-step release. Initially, when the carrier was merely a suspension of α-TCP particles in water, a faster release was recorded, which rapidly evolved to a zero-order release. In contrast, pre-set CPCs released doxycycline following non-Fickian diffusion. The final release percentage was related to the total porosity and entrance pore size of each biomaterial.