New promising technologies and treatment methods using antibacterial bio-active glass for bone infection and bone reconstruction.
Antibiotic overuse has led to increased antimicrobial resistance worldwide. In 2011, the World Health Organization estimated that antibacterial resistance in the EU may account for 25,000 deaths per year and costs of approximately €1.5 bn annually. In addition to restricting antibiotic use, new innovations to combat infection are also needed. Infected bone (osteomyelitis) is one of the most challenging conditions to treat. Bone infections may be caused by many pathogens, including multi-drug resistant bacteria.
Osteomyelitis is a destructive infection of the bone structure that eventually leads to bone necrosis. The infection may follow trauma caused by traffic or sport accidents, surgical procedures, or spreading of bacteria carried in the blood. The annual incidence of bone and joint infections in Europe is estimated to range from 30 to 60 per 100 000 habitants, with a prevalence of several tens of thousands of patients. These infections are most often associated with numerous surgical procedures resulting in an increased risk for complications and subsequently prolonged hospitalisation and long-term antimicrobial treatment. Co-morbidities such as diabetes, impaired peripheral vascular function, renal failure or lifestyle factors such as smoking, or drug or alcohol abuse are associated with a higher risk for bone and joint infection and poor prognosis. These factors are also associated with recurrence or chronic persistence and with subsequently high social and economic costs.
Despite advances in antibiotic therapies and surgical techniques, the treatment of bone infections remains challenging. The infected bone tissue must be removed, which often results in large bony defects. Such defects must be restored, which also often requires soft-tissue reconstruction. As part of standard care, surgical treatment commonly involves antibiotic-loaded polymethylmethacrylate bone cements. However, inadequate release of antibiotics can lead to the development of multi-drug resistant bacteria. Thus, the development of alternatives to antibiotic-loaded cements or bone substitutes is desirable in the fight against drug resistance. In such complex situations, bio-active glasses (BAGs) offer attractive solutions and advantages over existing technologies.
Why is BAG used in the treatment of bone defects?
BAG was developed by Professor Larry Hench in 1967, sparked by interest from the US Army Medical Research and Development Command. The aim was to develop a material with direct chemical bone-binding ability for the treatment of wounded soldiers. Since then, there has been worldwide interest in BAGs and their applications; this interest is reflected in the almost 1000 scientific publications per year.
What happens when the BAG is implanted in the body?
The behaviour and reactions of BAGs are composition dependent. BAGs contain mainly of oxides such as SiO2, Na2O, CaO, and P2O5. After implantation, a rapid exchange of alkaline ions in the glass with H+ and H3O+ ions from the solution occurs, resulting in a silica rich layer on the glass surface. On top of this surface another surface consisting of hydroxyapatite (i.e. the mineral in bone) will appear. This layer has been shown to chemically bind to bone. The reactions of the implanted glass also give rise to a bone stimulative effect, which promotes bone formation.
The antibacterial effect of BAGs—an unexpected useful bonus effect
The antibacterial effect observed for BAGs is based on the chemical reaction on the glass surface that occurs after the glass is implanted in the body. The dissolution of ions from the glass can initially raise the local pH of bodily fluids. The elevation of pH and the increased osmotic pressure subsequently disturbs the bacterial structure, which causes significant changes in morphology (i.e. cell shrinkage and damage to the bacterial membrane). BAGs have shown efficacy against approximately 50 clinically important bacterial strains, including both Gram-positive and Gram-negative species and aerobic and anaerobic bacteria.
Bacteria that colonise the body also produce bio-films on the surface of tissues and implants. Bio-films can be up to 1000-fold more resistant to antibiotic treatment than the same organism growing in a planktonic phase. Although administration of antimicrobial agents has been a useful approach for eliminating bio-films, not many antibiotics are effective on bio-films. Eradication of bacteria also requires high concentrations of antibiotics, causing toxicity toward non-target organisms and to the body. This has encouraged researchers to develop better compounds for infection treatment. Recent studies have revealed that BAGs are active also in destroying and inhibiting bio-films, making them ideal bone substitutes in bio-film related infections.
Antibiotic overuse is a serious global problem and is one of the main drivers of natural selection among microorganisms to develop antibiotic resistance, which seriously hampers the efficacy of antibiotics on bone infections. Laboratory observations suggest that multi-drug resistant bacteria are unable to adapt to the hostile environment created by BAG. As the antimicrobial mechanism of action of BAGs differs entirely from that of antibiotics, BAGs are expected to be extremely useful in infection treatment as resistance is unlikely to occur.
From laboratory to patient
Since the 1980s, extensive research on BAGs has been performed at the Johan Gadolin Process Chemistry Centre at the Åbo Akademi (ÅA) University in Finland. This research has yielded a commercially available BAG for treatment of bone defects. This BAG, named BAG-S53P4 (53% SiO2, 23% Na2O, 20% CaO, 4% P2O5) (BonAlive Biomaterials®), received EU approval for orthopaedic use in 2006 and approval for treatment of osteomyelitis in 2011. BAG-S53P4 is currently the most well documented bone substitute in clinical use on the market. However, new materials with increased bio-mechanical and surface reactive properties and a better understanding of BAGs and their clinical use are needed. At the Helsinki University Hospital (HUS) and the University of Helsinki (HU) in collaboration with ÅA, pre-clinical and clinical research on BAGs has been conducted for almost two decades to increase the knowledge of BAGs and to improve and develop new methods for bone reconstruction and infection treatment.
How is BAG used clinically in infection treatment?
The use of BAGs in bone infection treatment began in the 1990s with BAG-S53P4 in the treatment of frontal sinusitis. Long-term success rates of 90% were observed. BAG-S53P4 is also beneficial in the treatment of chronic infection in the mastoid of the ear to achieve a dry ear. The first patient with osteomyelitis in the distal tibia was treated with BAG-S53P4 in 2007 in Finland. In a multinational and multicentre cohort study, including The Netherlands, Italy, Germany, Azerbaijan, Poland and Finland, 116 patients with verified chronic osteomyelitis achieved an overall success rate of 90%. Most of the patients were treated in a one stage procedure, thus reducing treatment costs and patient recovery time and morbidity.
Current and future research
Research on BAGs at the HUS/UH/ÅA are focused on bone healing and bone promoting processes and the antibacterial properties of BAGs. For example, research to better understand how the mechanical environment of the scaffold, osteogenic cells, and the vascular, inflammatory, and growth factors involved in bone healing can be affected to achieve better antibacterial bone substitutes for bone reconstruction and infection treatment is ongoing. Active bone formation within new and more mechanically stable BAG scaffolds and expression of bone morphogen protein and vascular endothelial growth factors have been observed; these encouraging results make BAGs a promising device for single-stage treatment of bone defects.
In conclusion, the use and development of BAGs in bone infection treatment and bone reconstruction provides opportunities to improve patient care and to reduce antibiotic overuse and associated antibiotic resistance.
Nina Lindfors Assoc. prof, MD, PhD, MScEng
Director of Division of Teaching and Research
Musculoskeletal and Plastic Surgery
Helsinki University Hospital
University of Helsinki
+358 50 4270845
Please note, this article will appear in issue 32 of SciTech Europa Quarterly, which is available to read now.