Teicoplanin-loaded borate bioactive glass implants for treating chronic bone infection in a rabbit tibia osteomyelitis model
Introduction
Despite advances made in medical and surgical therapies [1], [2], the treatment of chronic osteomyelitis (bone infection) remains a clinical challenge. The development of new therapeutic methods for treating chronic osteomyelitis is therefore important for future advances. Currently, carrier systems that deliver drugs or antibiotics locally are widely-used experimentally and clinically to treat osteomyelitis because they can provide higher concentrations of drugs at the infected site. These systems avoid potential systemic adverse effects, and they enhance the efficiency of the drug at the infected site [3].
A large number of biomaterials, bioinert or biodegradable, are employed as carriers for local drug delivery. Commercial poly(methyl methacrylate), PMMA, has been used as a drug carrier for curing many types of bone or soft tissue infection for several decades. However, PMMA is bioinert, so an additional operation is needed for its removal, which is costly and painful. Poly(lactic-co-glycolic acid), PLGA, is a widely-used carrier material for controlled drug release. PLGA is biodegradable, but the acidic environment resulting from its degradation can be harmful to healthy tissue. A disadvantage of biodegradable polymers used as drug carriers in the treatment of chronic bone infection is that they do not form a firm bond with bone [3], [4].
Certain inorganic materials, referred to bioactive materials, such as tricalcium phosphate, (TCP) and bioactive glass, convert to a hydroxyapatite (HA)-type material, the main mineral constituent of bone, and bond strongly with bone and soft tissue in vivo [5], [6], [7]. However, TCP degrades too slowly to match the bone regeneration rate, so a biological augmentation is needed to improve its degradation rate and osteoinductive properties in vivo [8]. Since the discovery of 45S5 glass by Hench et al. [9], silicate bioactive glasses with compositions in the system SiO2–CaO or SiO2–P2O3–CaO have been fabricated by sol–gel methods and used as carrier materials for drugs [6], [10], [11]. However, the high SiO2 content of these glasses limits their degradation rate.
More recently, borate glasses with special compositions have been developed and evaluated for biomedical applications [12], [13], [14], [15]. The replacement of larger amounts of SiO2 in 45S5 bioactive glass with B2O3 was found to increase the degradation of 45S5 glass and its conversion to HA [13]. Particles (150–300 μm) of a borate equivalent of silicate 45S5 glass, designated 45S5B3, obtained by replacing all the SiO2 in 45S5 glass with B2O3, converted completely in an aqueous phosphate solution to HA within 3 days. In comparison, particles of 45S5 glass were only partially converted even after 70 days [13]. Partial replacement of B2O3 in a borate bioactive glass with Al2O3 was shown to reduce the degradation rate of the glass in an aqueous phosphate solution, and to enhance the compressive strength of the converted glass [16]. The addition of SrO to a borosilicate bioactive glass was shown to enhance its osteoinductive property [17]. By controlling the glass composition, it should be possible to match the degradation rate of borate or borosilicate bioactive glasses with the bone regeneration rate. In this way, as the glass degrades and converts to HA, it is replaced by new bone ingrowth.
Our previous work showed that pellets composed of borate bioactive glass particles bonded with an ammonium phosphate cement, used as a carrier for the drug Vancomycin, were effective for treating chronic bone infection in a rabbit model [18]. However, the drug loading in this system was limited to only 60 mg of Vancomycin per gram of glass particles, because higher amounts of the drug resulted in fracturing of the pellets after immersion for several days in a simulated body fluid (SBF). The objective of this work was to evaluate an improved carrier system for treating chronic bone infection in a rabbit tibia osteomyelitis model. Pellets composed of a chitosan-bonded mixture of borate bioactive glass particles (<50 μm) and teicoplanin powder (antibiotic) were used in an attempt to increase the drug loading and to avoid fracture of the pellets when immersed in an aqueous phosphate solution (such as the body fluid). Both the drug release behavior and the bioactivity of the pellets were evaluated in vitro and in vivo in order to compare the in vitro versus the in vivo behavior. The ability of the pellets to serve as a local drug delivery system and as a bone grafting material was assessed. Structural and microchemical changes in the pellets resulting from in vitro immersion and in vivo implantation were examined, and histological evaluation of the implant and tibia defect was performed.
Section snippets
Fabrication of teicoplanin-loaded borate bioactive glass (TBDC) pellets
Borate bioactive glass with the composition (mol%): 6Na2O, 8K2O, 8MgO, 22CaO, 54B2O3, 2P2O5 was prepared by mixing the required amounts of Na2CO3, K2CO3, MgCO3, CaCO3, H3BO3 NaH2PO4, (analytical grade, Sinopharm Chemical Reagent Co., Ltd. China) and melting the mixture in a platinum crucible for ∼1 h at 1100 °C. After the melt was quenched between cold steel plates, the glass was crushed, ground, and sieved to give particles of size <50 μm.
For the preparation of drug-loaded pellets, a mixture
Bioactivity of TBDC pellets in vitro and in vivo
Fig. 1 shows XRD patterns of the as-prepared TBDC pellets (a), and the TBDC pellets after immersion for 120 days in the PBS (b), and after implantation for 12 weeks in the rabbit tibiae (c). For comparison, the pattern of cortical bone in the region surrounding the implant (d), as well as the spectrum of a reference HA, Ca10(PO4)6(OH)2 (JCPDS 72–1243) are also shown. The XRD pattern of the as-prepared pellets showed broad bands typical of an amorphous glass. On the other hand, the patterns of
Discussion
Drug carriers capable of providing local delivery of antibiotics form an effective method to treat chronic bone infection. In this study, pellets composed of a chitosan-bonded mixture of borate bioactive glass particles and teicoplanin powder showed promising results for curing chronic bone infection in a rabbit tibia osteomyelitis model. Teicoplanin was selected as the antibiotic because it has a long serum half-life and a broad-spectrum antibacterial activity against most Gram-positive
Conclusions
Pellets consisting of a chitosan-bonded mixture of teicoplanin powder and borate bioactive glass particles cured chronic bone infection within 12 weeks of implantation in a rabbit tibia osteomyelitis model. The pellets provided a sustained release of teicoplanin over ∼9 days in vivo. Concurrently, the bioactive glass particles degraded in the body fluid and converted to a porous hydroxyapatite (HA)-type graft which supported new bone growth and bonded to firmly with the new bone, thereby
Acknowledgements
This work was supported by the Shanghai Committee of Science and Technology through the major project (Grant No. 084411900500), and the nano-technology promotion project (Grant No. 0952nm03400).
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