Vancomycin-Loaded, Nanohydroxyapatite-Based Scaffold for Osteomyelitis Treatment: In Vivo Rabbit Toxicological Tests and In Vivo Efficacy Tests in a Sheep Model.

The treatment for osteomyelitis consists of surgical debridement, filling of the dead space, soft tissue coverage, and intravenous administration of antimicrobial (AM) agents for long periods. Biomaterials for local delivery of AM agents, while providing controllable antibiotic release rates and simultaneously acting as a bone scaffold, may be a valuable alternative; thus, avoiding systemic AM side effects. V-HEPHAPC is a heparinized nanohydroxyapatite (nHA)/collagen biocomposite loaded with vancomycin that has been previously studied and tested in vitro. It enables a vancomycin-releasing profile with an intense initial burst, followed by a sustained release with concentrations above the Minimum Inhibitory Concentration (MIC) for MRSA. In vitro results have also shown that cellular viability is not compromised, suggesting that V-HEPHAPC granules may be a promising alternative device for the treatment of osteomyelitis. In the present study, V-HEPHAPC (HEPHAPC with vancomycin) granules were used as a vancomycin carrier to treat MRSA osteomyelitis. First, in vivo Good Laboratory Practice (GLP) toxicological tests were performed in a rabbit model, assuring that HEPHAPC and V-HEPHAPC have no relevant side effects. Second, V-HEPHAPC proved to be an efficient drug carrier and bone substitute to control MRSA infection and simultaneously reconstruct the bone cavity in a sheep model.

Combining local antibiotic delivery with heparinized nanohydroxyapatite/collagen bone substitute: A novel strategy for osteomyelitis treatment.

Osteomyelitis is a major challenge in bone surgery and conventional treatment is frequently ineffective to control the infection, with an alternative approach being required. In the present work, a heparinized nanohydroxyapatite/collagen biocomposite was produced in granular form, and loaded with vancomycin, to work as a local drug delivery system for osteomyelitis and as a bone substitute. This strategy involves the local delivery of high concentrations of vancomycin, to eradicate the infection. Additionally, these granules work as a scaffold with regenerative properties, to induce bone regeneration after antibiotic release. The heparinized nanohydroxyapatite/collagen granular bone substitute was produced using two different sintering temperatures to study their effect on granules properties and on vancomycin release profile. Morphological, topographic, chemical and mechanical characterization were carried out for granules sintered at both temperatures and some relevant differences were found. The mechanical strength was increased by several orders of magnitude with increasing sintering temperature, being able to maintain their porous macrostructure and withstand important processes for their commercialization such as packaging, shipping and surgical manipulation. The nanohydroxyapatite/collagen granules were able to release high concentrations of vancomycin, always above MIC, for 19 days. The released antibiotic was able to eradicate both planktonic and sessile methicillin-resistant Staphylococcus aureus. The cytotoxicity was assessed according to ISO 10993-5:2009 and the granules sintered at higher temperature showed no cytotoxic effect. Considering these results nanohydroxyapatite/collagen biocomposite loaded with vancomycin is a promising solution for osteomyelitis treatment.

The antibacterial and angiogenic effect of magnesium oxide in a hydroxyapatite bone substitute.

Bone graft infections are serious complications in orthopaedics and the growing resistance to antibiotics is increasing the need for antibacterial strategies. The use of magnesium oxide (MgO) is an interesting alternative since it possesses broad-spectrum antibacterial activity. Additionally, magnesium ions also play a role in bone regeneration, which makes MgO more appealing than other metal oxides. Therefore, a bone substitute composed of hydroxyapatite and MgO (HAp/MgO) spherical granules was developed using different sintering heat-treatment cycles to optimize its features. Depending on the sintering temperature, HAp/MgO spherical granules exhibited distinct surface topographies, mechanical strength and degradation profiles, that influenced the in vitro antibacterial activity and cytocompatibility. A proper balance between antibacterial activity and cytocompatibility was achieved with HAp/MgO spherical granules sintered at 1100 ºC. The presence of MgO in these granules was able to significantly reduce bacterial proliferation and simultaneously provide a suitable environment for osteoblasts growth. The angiogenic and inflammation potentials were also assessed using the in vivo chicken embryo chorioallantoic membrane (CAM) model and the spherical granules containing MgO stimulated angiogenesis without increasing inflammation. The outcomes of this study evidence a dual effect of MgO for bone regenerative applications making this material a promising antibacterial bone substitute.