Resorbable composites with growth factors and antibiotics for dual drug release for the treatment of bone infections

• Applicant: Privatdozent Dr.-Ing. Michael Seidenstücker
• Subject Area: Biomaterials ; Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388988890

The aim of our application is to develop mechanical stable resorbable composites that release both growth factors and antibiotics while being released for at least four weeks. To guarantee rapid accessibility for clinical use, we are employing familiar materials that are already FDA-approved. Our composite is based on a microporous ß-TCP ceramic with interconnected pores. This porous ceramic wil be filled with hydrogels that largely consist of alginate. In creating this composite, we developed a new process that enables the porous ceramic to be filled completely. To achieve this, we must be able to determine the viscosity in relation to the hydrogel's composition. Alginate and alginate-di-aldehyde (ADA) hydrogels function as the reservoir for the active ingredients (antibiotics and growth factors) and regulate their release. Continuous, delayed release is achieved via the gelatinous nanoparticles introduced into the hydrogel (which are loaded with growth factors). They then diffuse out of the microparticles and into the hydrogel, and from thence into the surrounding tissue. This should enable a delayed release, whereby the antibiotic is released first to fight the infection and the growth factor is released at a later timepoint to stimulate growth. The antibiotics' presence will be proven via capillary-zone electrophoresis and a photodiode detector at 190-300nm. Such a (reproducible) method is already well established. The antibiotics' stability will be determined applying the same method, and that of the growth factors via fluorescence spectroscopy. To substitute for the growth factor, we will first use the model substance protein A + FITC. The growth factor's concentration will be assessed using an ELISA kit (and that of the model substance by measuring the fluorescence on a reader). Biocompatibility will be tested according to EN ISO 10993-5 in cell culture trials experiments with MG-63 cells as well as human osteoblasts. The microbiotic efficacy of the concentrations released from the composite will be investigated according to DIN 20776-1:2006 via microtiter experiments with Staphylococcus aureus. We will then test the minimal inhibitory concentration. The composite revealing the best biocompatibility, release charcteristics, and antimicrobial efficacy will then be subjected to testing on animals: a bone-infection model employing New Zealand rabbits will be applied. The composite will be implanted three weeks after the infection's induction. We will then investigate the concentration of antibiotics in the animals' blood and after the investigation period has ended, subject the tissue at and surrounding the implant site to microbial, histological and immunohistological testings. Furthermore, the surrounding tissue and implant will be subjected to Kirby-Bauer testing to identify any residual traces of antibiotic (in order to clarify any up-concentration effects by the antibiotic in the tissue surrounding the implant.

• DFG Programme: Research Grants