Vancomycin containing PLLA/β-TCP controls experimental osteomyelitis in vivo

Journal of Orthopaedic Surgery and Research

Feza Korkusuz²  Petek Korkusuz³  Elif Bilgic³  Berna Kankilic¹ 

[1] Department of Biotechnology, Institute of Applied Sciences, Middle East Technical University, Çankaya 06800, Ankara, Turkey;Department of Sports Medicine, Hacettepe University Faculty of Medicine, Sihhiye, Ankara 06100, Turkey;Department of Histology and Embryology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara 06100, Turkey

关键词: Infection;    MRSA;    ?-TCP;    PLLA;    Vancomycin;    Rat;    Drug delivery;    Osteomyelitis;    Bone;   

Others  :  1144397
DOI  :  10.1186/s13018-014-0114-3

 received in 2014-08-26, accepted in 2014-10-31,  发布年份 2014

【 摘 要 】

Background

Implant-related osteomyelitis (IRO) is recently controlled with local antibiotic delivery systems to overcome conventional therapy disadvantages. In vivo evaluation of such systems is however too little.

Questions/purposes

We asked whether vancomycin (V)-containing poly-l-lactic acid/?-tricalcium phosphate (PLLA/?-TCP) composites control experimental IRO and promote bone healing in vivo.

Methods

Fifty-six rats were distributed to five groups in this longitudinal controlled study. Experimental IRO was established at tibiae by injecting methicillin-resistant Staphylococcus aureus (MRSA) suspensions with titanium particles in 32 rats. Vancomycin-free PLLA/?-TCP composites were implanted into the normal and infected tibiae, whereas V-PLLA/?-TCP composites and coated (C)-V-PLLA/?-TCP composites were implanted into IRO sites. Sham-operated tibiae established the control group. Radiological and histological scores were quantified with microbiological findings on weeks 1 and 6.

Results

IRO is resolved in the CV- and the V-PLLA/?-TCP groups but not in the PLLA/?-TCP group. MRSA was not isolated in the CV- and the V-PLLA/?-TCP groups at all times whereas the bacteria were present in the PLLA/?-TCP group. Radiological signs secondary to infection are improved from 10.9?±?0.9 to 3.0?±?0.3 in the V-PLLA/?-TCP group but remained constant in the PLLA/?-TCP group. Histology scores are improved from 24.7?±?6.5 to 17.6?±?4.8 and from 27.6?±?7.9 to 32.4?±?8.9 in the CV-PLLA/?-TCP and the V-PLLA/?-TCP groups, respectively. New bone was formed in all the PLLA/?-TCP group at weeks 1 and 6.

Conclusions

CV- and V-PLLA/?-TCP composites controlled experimental IRO and promoted bone healing.

Clinical relevance

CV- and V-PLLA/?-TCP composites have the potential of controlling experimental IRO and promoting bone healing.

【 授权许可】

   
2014 Kankilic et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Ozturan KE, Yucel I, Kocoglu E, Cakici H, Guven M: Efficacy of moxifloxacin compared to teicoplanin in the treatment of implant-related chronic osteomyelitis in rats. J Orthop Res 2010, 28(10):1368-1372.
• [2]Zimmerli W: Infection and musculoskeletal conditions: prosthetic-joint-associated infections. Best Pract Res Clin Rheumatol 2006, 20(6):1045-1063.
• [3]Orhan Z, Cevher E, Y?ld?z A, Ah?skal? R, Sensoy D, Mülaz?mo?lu L: Biodegradable microspherical implants containing teicoplanin for the treatment of methicillin-resistant Staphylococcus aureus osteomyelitis. Arch Orthop Trauma Surg 2010, 130:135-142.
• [4]Jiang JL, Li YF, Fang TL, Zhou J, Li XL, Wang YC, Dong J: Vancomycin-loaded nano-hydroxyapatite pellets to treat MRSA-induced chronic osteomyelitis with bone defect in rabbits. Inflamm Res 2012, 61(3):207-215.
• [5]Li D, Gromov K, Søballe K, Puzas JE, O¿Keefe RJ, Awad H, Drissi H, Schwarz EM: Quantitative mouse model of implant-associated osteomyelitis and the kinetics of microbial growth, osteolysis, and humoral immunity. J Orthop Res 2008, 26(1):96-105.
• [6]Lew DP, Waldvogel FA: Osteomyelitis. Lancet 2004, 364:369-379.
• [7]Yin LY, Calhoun JH, Thomas JK, Shapiro S, Schmitt-Hoffmann A: Efficacies of ceftobiprole medocaril and comparators in a rabbit model of osteomyelitis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2008, 52(5):1618-1622.
• [8]Fang T, Wen J, Zhou J, Shao Z, Dong J: Poly (?-caprolactone) coating delays vancomycin delivery from porous chitosan/?-tricalcium phosphate composites. J Biomed Mater Res B Appl Biomater 2012, 100(7):1803-1811.
• [9]Makarov C, Berdicevsky I, Raz-Pasteur A, Gotman I: In vitro antimicrobial activity of vancomycin-eluting bioresorbable ?-TCP-polylactic acid nanocomposite material for load-bearing bone repair. J Mater Sci Mater Med 2013, 24(3):679-687.
• [10]Park PI, Makoid M, Jonnalagadda S: The design of flexible ciprofloxacin-loaded PLGA implants using a reversed phase separation/coacervation method. Eur J Pharm Biopharm 2011, 77(2):233-239.
• [11]Petrone C, Hall G, Langman M, Filiaggi MJ: Compaction strategies for modifying the drug delivery capabilities of gelled calcium polyphosphate matrices. Acta Biomater 2008, 4(2):403-413.
• [12]Ahola N, Männistö N, Veiranto M, Karp M, Rich J, Efimov A, Seppälä J, Kellomäki M: An in vitro study of composites of poly (L-lactide-co-?-caprolactone), ?-tricalcium phosphate and ciprofloxacin intended for local treatment of osteomyelitis. Biomatter 2013, 3(2):1-13.
• [13]Korkusuz F, Korkusuz P, Ek?io?lu F, Gürsel ?, Has?rc? V: In vivo response to biodegradable controlled antibiotic release systems. J Biomed Mater Res 2001, 55:217-228.
• [14]Gbureck U, Vorndran E, Barralet JE: Modeling vancomycin release kinetics from microporous calcium phosphate ceramics comparing static and dynamic immersion conditions. Acta Biomater 2008, 4:1480-1486.
• [15]Miyai T, Ito A, Tamazawa G, Matsuno T, Sogo Y, Nakamura C, Yamazaki A, Satoh T: Antibiotic-loaded poly-?-caprolactone and porous ?-tricalcium phosphate composite for treating osteomyelitis. Biomaterials 2008, 29:350-358.
• [16]Luginbuehl V, Ruffieux K, Hess C, Reichardt D, von Rechenberg B, Nuss K: Controlled release of tetracycline from biodegradable ?-tricalcium phosphate composites. J Biomed Mater Res B Appl Biomater 2010, 92B:341-352.
• [17]Kankilic B, Bayramli E, Kilic E, Da?deviren S, Korkusuz F: Vancomycin containing PLLA/?-TCP controls MRSA in vitro. Clin Ortop Relat Res 2011, 469:3222-3228.
• [18]Korkusuz F, Uchida A, Shinto Y, Inoue K, Ono K: Biomaterial centered chronic osteomyelitis. Turk J Med Res 1992, 10:268-292.
• [19]Aktekin CN, Ozturk AM, Tabak AY, Altay M, Korkusuz F: A different perspective for radiological evaluation of experimental osteomyelitis. Skeletal Radiol 2007, 36:945-950.
• [20]Petty W, Spanier S, Shuster JJ, Silverthorne C: The influence of skeletal implants on incidence of infection: experiment in a canine model. J Bone Joint Surg Am 1985, 67:1236-1244.
• [21]Lawson MC, Hoth KC, Deforest CA, Bowman CN, Anseth KS: Inhibition of Staphylococcus epidermidis biofilms using polymerizable vancomycin derivatives. Clin Orthop Relat Res 2010, 468(8):2081-2091.
• [22]Klemm K: The use of antibiotic-containing bead chains in the treatment of chronic bone infections. Clin Microbiol Infect 2001, 7:28-31.
• [23]Ozturk AM, Tabak AY, Aktekin CN, Altay M, Erdemli E, Karahuseyinoglu S, Korkusuz F: Alendronate enhances antibiotic-impregnated bone grafts in the treatment of osteomyelitis. Int Orthop 2008, 32:821-827.
• [24]Lucke M, Schmidmaier G, Sadoni S, Wildemann B, Schiller R, Haas NP: Gentamicin coating of metallic implants reduces implant-related osteomyelitis in rats. Bone 2003, 32(5):521-531.
• [25]Pihlajamäki H, Böstman O, Tynninen O, Laitinen O: Long-term tissue response to bioabsorbable poly-l-lactide and metallic screws: an experimental study. Bone 2006, 39:932-937.
• [26]Cao L, Duan PG, Wang HR, Li XL, Yuan FL, Fan ZY, Li SM, Dong J: Degradation and osteogenic potential of a novel poly (lactic acid)/nano-sized ?-tricalcium phosphate scaffold. Int J Nanomedicine 2012, 7:5881-5888.
• [27]Soundrapandian C, Sa B, Datta S: Organic¿inorganic composites for bone drug delivery. AAPS PharmSciTech 2009, 10(4):1158-1171.
• [28]Baro M, Sanchez E, Delgado A, Perera A, Evora C: In vitro-in vivo characterization of gentamicin bone implants. J Control Release 2002, 83:353-364.