Approach to the treatment of osteomyelitis and fractures with critical bone loss using biocomposites containing nanoparticulate polymeric systems for intracellular delivery of BMP-encoding plasmids, tenoxicam, and vancomycin

BACKGROUND: Osteomyelitis remains a pressing problem due to its high recurrence rate and risk of serious complications. The situation is exacerbated by increasing antibiotic resistance, which reduces the effectiveness of conventional antibacterial therapy. In this context, the development of novel therapeutic strategies for osteomyelitis, especially in cases accompanied by critical bone loss, is of particular importance. AIM: The work aimed to test an approach to the treatment of purulent-septic inflammation complicated by bone tissue loss using biocomposite bone implants impregnated with a gel exhibiting multifunctional pharmacological activity, providing local antibacterial, anti-inflammatory, and osteogenic effects. The efficacy of the approach was evaluated in a rat model of experimental osteomyelitis. METHODS: The research methods included the development of polysaccharide gels with mechanical and rheological properties similar to those of soft tissues (G’ = 176–271 kPa, G’’ = 3.7–4.2 kPa), containing 250 mg/g of dry polymer of amikacin and vancomycin, 0.28 mg/mL of tenoxicam gel, and 12.83 ng/mL of a plasmid encoding bone morphogenetic protein (BMP), thereby ensuring the implants exert local antibacterial and targeted anti-inflammatory effects in combination with stimulation of bone tissue growth. Two types of nanoparticulate carriers of different diameters were introduced into the gel: hyaluronic gel nanoparticles with a bimodal size distribution (d = 100 and 3000 nm) for intracellular delivery of tenoxicam into phagocytic immunocompetent cells, and nanocapsules coated with a transfection agent (d = 50–100 nm) for transmembrane transport of the plasmid into non-phagocytic cells, whose ribosomes synthesize BMP-2, initiating differentiation via the osteogenic pathway. Antibiotics are released from the carrier only in response to bacterial attack on the implant via bacterial enzymes, ensuring a local concentration 200 times higher than the bactericidal threshold. Cytotoxicity, calculated per dry gel, was 1800 µg/mL. The minimum inhibitory concentration against Staphylococcus aureus 209P was 25 µg/mL, and the bactericidal concentration was 100 µg/mL. RESULTS: Biocomposites impregnated with a drug-containing gel were found to effectively inhibit local bacterial infection, reduce the overall level of local aseptic inflammation, and promote bone regeneration in osteomyelitis. CONCLUSION: The therapeutic approach to treating purulent-septic inflammation complicated by bone tissue loss using implants with multifunctional pharmacological activity should be regarded as promising.