Calcium phosphate bioceramics with controlled porosity as local drug delivery systems – BiocerPorDDS2

Inorganic materials, such as calcium phosphate ceramics, widely used as bone substitutes, are also good candidates as drug carriers. The drug substances, included in the micropores of the ceramics, are subsequently released in the surrounding tissues when the bone substitute is implanted. The kinetics of drug delivery is essentially modulated by the porous architecture (size, shape, tortuosity) of the ceramic material and the chemical affinity of the pore surfaces with drug substances. This targeted drug delivery is particularly interesting to treat diseases such as bone infections and tumors, as it allows lower drug concentrations to be used, in comparison with systemic administration, and consequently reduced side effects.

The objective of this project is to elaborate calcium phosphate ceramics with well-defined and controlled porous structure in order to guarantee a controlled antibiotic release over time. Moreover, the influence of the chemical nature of pore surface on its affinity with drug substances will be considered.

Most of the methods used to elaborate porous ceramic materials produce randomly arranged irregular pores of variable sizes and have limited flexibility to control pore volumes and porosity distribution in the final structure. Recently, we used a new colloidal process based on hetero-coagulation to elaborate a well-controlled microporous hydroxyapatite material. In this project, we will adapt the hetero-coagulation method to a range of calcium phosphate ceramics, in order to control both the porous structure and the chemical nature of the pore surface. In addition, pulsed plasma polymerisation process will be used to create a polymer layer on the drug-loaded calcium phosphate ceramics, as a second control of the drug release rate.

After the elaboration and characterization of such bioceramics, the loading and in vitro release of antibiotics will be studied. For the drug release study, a standardized flow-through dissolution apparatus will be used. This system presents the advantage of ensuring reproducible in vitro conditions and taking into account the effect of the medium flow rate on the drug delivery. To our knowledge, this has not yet been addressed in the literature.

In parallel, molecular model will be developed to understand the drug/bioceramic interactions. These numerical simulations, based on the kind and strength of interaction between the drug and bioceramic will help to select the right drug for the right calcium phosphate ceramics.

Then, in vitro cell/bioceramic interactions and protein adsorption will be studied. Since the ultimate objective of the project is to confer antibacterial properties to the elaborated materials, the inhibition of bacteria in the presence of such a drug delivery system will also be addressed. The originality of this work is to study cell/bioceramics and bacteria/bioceramics interactions under flow conditions mimicking drug release, protein adsorption and cell/bacteria adhesion under real hydrodynamic forces.

It is known that the sterilization of a medical device can modify some of the properties of the delivery system. Therefore, the sterilization process will be considered as soon as the most promising delivery systems will be identified. The method that will be applied is the irradiation, a “cold” process without release of any degradation residues and recognized by the European Pharmacopeia.

Finally, in vivo experiments of selected drug delivery systems will be carried on an infected rat model. The efficiency of the locally administered antibiotic vs. a systemic treatment will be investigated. The originality of this proposal is to follow the infection using imaging methods and to determine the in vivo drug release kinetics.