Purpose. The aim of this study was to impregnate microporous β-TCP scaffolds with different antibiotic solutions and to determine their release behavior. Materials and Methods. We impregnated a β-TCP scaffold with antibiotics by using three methods: drop, dip, and stream coating with 120?mg/mL of antibiotic solution. After drying for 72?h at 37°C, 2 mL of distilled water was added to the antibiotic-coated plugs and incubated at 37°C. After defined time points (1, 2, 3, 6, 9, and 14 days), the liquid was completely replaced. The extracted liquid was analyzed by capillary zone electrophoresis and the Kirby Bauer disc diffusion test. For statistical analysis, we calculated a mean and standard deviation and carried out an analysis of variance using ANOVA. Results. The VAN and CLI release from the β-TCP scaffolds was rapid, occurring within 24?h with 89 ± 0.8% VAN and 90.4 ± 1.5% CLI regardless of the type of insulation. After six days, the VAN and CLI were completely released. All samples taken at later time points had a VAN or CLI concentration below the detection limit of 4?μg/mL. The released amounts of VAN and CLI within the first three days revealed antimicrobial activity. 1. Introduction Osteoinductive calcium phosphate ceramics are suitable materials for delivery systems [1–5]. This applies in particular to the release of drugs to prevent bone infection. Local drug delivery is especially valuable in association with bone infection since it spares patients the adverse effects of systematically administrated drugs, reduces the risks from resistant bacteria, and enables a high concentration of medication at the infection site [6]. A variety of materials have been used as carriers for the local delivery of antibiotics. These materials are classified as biodegradable or nondegradable. The most commonly used of the non-degradable material is PMMA, which is often impregnated with antibiotics such as gentamycin, clindamycin, or vancomycin. PMMA is not only used as a bone cement or with an antibiotic offset bone cement like PALACOS R+G, but also as antibiotic-impregnated PMMA beads such as SEPTOPAL chains which have been on the market for the last two decades. The major drawback associated with PMMA beads is that they must be surgically removed after exposure to antibiotic release, which usually takes place four weeks after their implantation [7]. The use of biodegradable materials could therefore be advantageous to eliminate the need for a second operation. The most widely used biodegradable materials are polyglycolide and polylactide (PLGA/PLLA). PLGA and
References
[1]
A. Aneja, J. Woodall, S. Wingerter, M. Tucci, and H. Benghuzzi, “Analysis of tobramycin release from beta tricalcium phosphate drug delivery system,” Biomedical Sciences Instrumentation, vol. 44, pp. 88–92, 2008.
[2]
S. Bose and S. Tarafder, “Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: a review,” Acta Biomaterialia, vol. 8, no. 4, pp. 1401–1421, 2012.
[3]
W. J. E. M. Habraken, J. G. C. Wolke, and J. A. Jansen, “Ceramic composites as matrices and scaffolds for drug delivery in tissue engineering,” Advanced Drug Delivery Reviews, vol. 59, no. 4-5, pp. 234–248, 2007.
[4]
E. Verron, I. Khairoun, J. Guicheux, and J.-M. Bouler, “Calcium phosphate biomaterials as bone drug delivery systems: a review,” Drug Discovery Today, vol. 15, no. 13-14, pp. 547–552, 2010.
[5]
O. Zamoume, S. Thibault, G. Regnié, M. O. Mecherri, M. Fiallo, and P. Sharrock, “Macroporous calcium phosphate ceramic implants for sustained drug delivery,” Materials Science and Engineering C, vol. 31, no. 7, pp. 1352–1356, 2011.
[6]
K. Kanellakopoulou and E. J. Giamarellos-Bourboulis, “Carrier systems for the local delivery of antibiotics in bone infections,” Drugs, vol. 59, no. 6, pp. 1223–1232, 2000.
[7]
M. J. Patzakis, K. Mazur, J. Wilkins, R. Sherman, and P. Holtom, “Septopal beads and autogenous bone grafting for bone defects in patients with chronic osteomyelitis,” Clinical Orthopaedics and Related Research, no. 295, pp. 112–118, 1993.
[8]
Z. Pan and J. Ding, “Poly(lactide-co-glycolide) porous scaffolds for tissue engineering and regenerative medicine,” Interface Focus, vol. 2, no. 3, pp. 366–377, 2012.
[9]
D. B. Thordarson and G. Hurvitz, “PLA screw fixation of lisfranc injuries,” Foot and Ankle International, vol. 23, no. 11, pp. 1003–1007, 2002.
[10]
T. M. O’Shea and X. Miao, “Preparation and characterisation of plga-coated porous bioactive glass-ceramic scaffolds for subchondral bone tissue engineering,” in Proceeding of the 9th International Symposium on Ceramic Materials and Components for Energy and Environmental Applications, Shanghai Institute of Ceramics, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, China, 2009.
[11]
W. Friess and M. Schlapp, “Sterilization of gentamicin containing collagen/PLGA microparticle composites,” European Journal of Pharmaceutics and Biopharmaceutics, vol. 63, no. 2, pp. 176–187, 2006.
[12]
M. Schlapp and W. Friess, “Collagen/PLGA microparticle composites for local controlled delivery of gentamicin,” Journal of Pharmaceutical Sciences, vol. 92, no. 11, pp. 2145–2151, 2003.
[13]
X. Li, X. Wang, L. Zhang, H. Chen, and J. Shi, “MBG/PLGA composite microspheres with prolonged drug release,” Journal of Biomedical Materials Research B, vol. 89, no. 1, pp. 148–154, 2009.
[14]
C. M. Agrawal and K. A. Athanasiou, “Technique to control pH in vicinity of biodegrading PLA-PGA implants,” Journal of Biomedical Materials Research, vol. 38, no. 2, pp. 105–114, 1997.
[15]
H. K. Koerten and J. Van Der Meulen, “Degradation of calcium phosphate ceramics,” Journal of Biomedical Materials Research, vol. 44, no. 1, pp. 78–86, 1999.
[16]
M. Epple, Biomaterialien und Biomineralisation, Teubner, Wiesbaden, Germany, 2003.
[17]
J. Eitenmuller, G. Peters, and W. Golsong, “Utilising absorbable coatings for inhibition of antibiotic release from biodegradable tricalciumphosphate-ceramic beads for local treatment of osteomyelitis,” Langenbecks Archiv fur Chirurgie, vol. 360, no. 3, pp. 193–206, 1983.
[18]
F. Laurent, A. Bignon, J. Goldnadel et al., “A new concept of gentamicin loaded HAP/TCP bone substitute for prophylactic action: in vitro release validation,” Journal of Materials Science, vol. 19, no. 2, pp. 947–951, 2008.
[19]
J. Zhang, C. Wang, J. Wang, Y. Qu, and G. Liu, “In vivo drug release and antibacterial properties of vancomycin loaded hydroxyapatite/chitosan composite,” Drug Delivery, vol. 19, no. 5, pp. 264–269, 2012.
[20]
H. O. Mayr, M. Dietrich, F. Fraedrich et al., “Microporous pure β-tricalcium phosphate implants for press-fit fixation of anterior cruciate ligament grafts: strength and healing in a sheep model,” Arthroscopy, vol. 25, no. 9, pp. 996–1005, 2009.
[21]
A. Bernstein, D. N?bel, H. O. Mayr, G. Berger, R. Gildenhaar, and J. Brandt, “Histological and histomorphometric investigations on bone integration of rapidly resorbable calcium phosphate ceramics,” Journal of Biomedical Materials Research B, vol. 84, no. 2, pp. 452–462, 2008.
[22]
H. O. Mayr, Mikropor?se Formk?rper aus phasenreinem beta-Tricalciumphosphat zur Fixierung der vorderen Kreuzbandplastik und als Knochenersatz—biomechanische, radiologische und histologische Untersuchungen zur Erforschung der Stabilit?t und des Einheilverhaltens, Medizinische Fakult?t, Martin Luther Universit?t, Halle, Germany, 2007.
[23]
V. Menkin, “The role of hydrogen ion concentration and the cytology of an exudate,” in In Biochemical Mechanisms in Inflammation, C. C. Thomas, Ed., pp. 66–103, Springfield, Ill, USA, 1956.
[24]
A. Lardner, “The effects of extracellular pH on immune function,” Journal of Leukocyte Biology, vol. 69, no. 4, pp. 522–530, 2001.
[25]
R. Friebe, K. Rauscher, J. Voigt, I. Wilke, and K. -Th. Wilke, Chemische Tabellen und Rechentafeln für Die Analytische Praxis, Harri Deutsch, Frankfurt, Germany, 2000.
[26]
M. Bohner and F. Baumgart, “Theoretical model to determine the effects of geometrical factors on the resorption of calcium phosphate bone substitutes,” Biomaterials, vol. 25, no. 17, pp. 3569–3582, 2004.
[27]
P. J. Jiang, S. Patel, U. Gbureck, et al., “Comparing the efficacy of three bioceramic matrices for the release of vancomycin hydrochloride,” Journal of Biomedical Materials Research Part B, vol. 93, no. 1, pp. 51–58, 2010.
[28]
G. Wang, J. F. Hindler, K. W. Ward, and D. A. Bruckner, “Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period,” Journal of Clinical Microbiology, vol. 44, no. 11, pp. 3883–3886, 2006.
[29]
M. Seidenstuecker, “Development of a quantitative method for determination of the released antibiotics concentration out of beta TCP scaffolds by using CZE and validation of the applicability of different coating methods,” in Centre for Engineering Sciences, Martin Luther University, Halle/S., Germany, 2010.
[30]
H. O. Mayr, R. Hube, A. Bernstein, A. B. Seibt, W. Hein, and R. V. Eisenhart-Rothe, “Beta-tricalcium phosphate plugs for press-fit fixation in ACL reconstruction—a mechanical analysis in bovine bone,” Knee, vol. 14, no. 3, pp. 239–244, 2007.
[31]
J. Zhou, T. Fang, Y. Wang, and J. Dong, “The controlled release of vancomycin in gelatin/beta-TCP composite scaffolds,” Journal of Biomedical Materials Research Part A, vol. 100, no. 9, pp. 2295–2301, 2012.
[32]
M. Bohner, J. Lema?tre, P. Van Landuyt, P.-Y. Zambelli, H. P. Merkle, and B. Gander, “Gentamicin-loaded hydraulic calcium phosphate bone cement as antibiotic delivery system,” Journal of Pharmaceutical Sciences, vol. 86, no. 5, pp. 565–572, 1997.
[33]
M. P. Hofmann, A. R. Mohammed, Y. Perrie, U. Gbureck, and J. E. Barralet, “High-strength resorbable brushite bone cement with controlled drug-releasing capabilities,” Acta Biomaterialia, vol. 5, no. 1, pp. 43–49, 2009.
[34]
Y. Zhang and M. Zhang, “Calcium phosphate/chitosan composite scaffolds for controlled in vitro antibiotic drug release,” Journal of Biomedical Materials Research, vol. 62, no. 3, pp. 378–386, 2002.
[35]
M. H. Alkhraisat, C. Rueda, J. Cabrejos-Azama et al., “Loading and release of doxycycline hyclate from strontium-substituted calcium phosphate cement,” Acta Biomaterialia, vol. 6, no. 4, pp. 1522–1528, 2010.
[36]
S. Hesaraki, F. Moztarzadeh, R. Nemati, and N. Nezafati, “Preparation and characterization of calcium sulfate-biomimetic apatite nanocomposites for controlled release of antibiotics,” Journal of Biomedical Materials Research B, vol. 91, no. 2, pp. 651–661, 2009.