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Elution of amikacin and vancomycin from a calcium sulfate/chitosan bone scaffold
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 Title & Authors
Elution of amikacin and vancomycin from a calcium sulfate/chitosan bone scaffold
Doty, Heather A.; Courtney, Harry S.; Jennings, Jessica A.; Haggard, Warren O.; Bumgardner, Joel D.;
Treatment of polymicrobial infected musculoskeletal defects continues to be a challenge in orthopaedics. This research investigated single and dual-delivery of two antibiotics, vancomycin and amikacin, targeting different classes of microorganism from a biodegradable calcium sulfate-chitosan-nHA microsphere composite scaffold. The addition of chitosan-nHA was included to provide additional structure for cellular attachment and as a secondary drug-loading device. All scaffolds exhibited an initial burst of antibiotics, but groups containing chitosan reduced the burst for amikacin at 1hr by 50%, and vancomycin by 14-25% over the first 2 days. Extended elution was present in groups containing chitosan; amikacin was above MIC (, Pseudomonas aeruginosa) for 7-42 days and vancomycin was above MIC ( Staphylococcus aureus) for 42 days. The antibiotic activity of the eluates was tested against S. aureus and P. aeruginosa. The elution from the dual-loaded scaffold was most effective against S. aureus (bacteriostatic 34 days and bactericidal 27 days), compared to vancomycin-loaded scaffolds (bacteriostatic and bactericidal 14 days). The dual- and amikacin-loaded scaffolds were effective against P. aeruginosa, but eluates exhibited very short antibacterial properties; only 24 hours bacteriostatic and 1-5 hours bactericidal activity. For all groups, vancomycin recovery was near 100% whereas the amikacin recovery was 41%. In conclusion, in the presence of chitosan-nHA microspheres, the dual-antibiotic loaded scaffold was able to sustain an extended vancomycin elution longer than individually loaded scaffolds. The composite scaffold shows promise as a dual-drug delivery system for infected orthopaedic wounds and overcomes some deficits of other dual-delivery systems by extending the antibiotic release.
drug delivery;biodegradable scaffolds;chitosan;calcium sulfate;bone regeneration;
 Cited by
Anderson, A., Miller, A.D. and Bookstaver, B. (2011), "Antimicrobial prophylaxis in open lower extremity fractures", Open Access Emergency Med., 3, 7-11.

Aranaz, I., Mengibar, M., Harris, R., Panos, I., Miralles, B., Acosta, N., Galed, G. and Heras, A. (2009), "Functional characterization of chitin and chitosan", Curr. Chem. Biol., 3(2), 203-230.

Atilla, A., Boothe, H.W., Tollett, M., Duran, S., Diaz, D.C., Sofge, J. and Boothe, D.M. (2010). "In vitro elution of amikacin and vancomycin from impregnated plaster of Paris beads", Vet. Surg., 39(6), 715-721.

Brady, R.A., Leid, J.G., Costerton, J.W. and Shirtliff, M.E. (2006), "Osteomyelitis: Clinical overview and mechanisms of infection persistence", Clin. Microbiol. Newsl., 28(9), 65-72. crossref(new window)

Bucholz, R.W. (2002), "Nonallograft osteoconductive bone graft substitutes", Clin. Orthop. Relat. Res., 395, 44-52. crossref(new window)

Chesnutt, B.M., Viano, A.M., Yuan, Y., Yang, Y., Guda, T., Appleford, M.R., Ong, J.L., Haggard, W.O. and Bumgardner, J.D. (2009), "Design and characterization of a novel chitosan/nanocrystalline calcium phosphate composite scaffold for bone regeneration", J. Biomed. Mater. Res. Part A, 88(2), 491-502.

CLSI. (2012), Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard-Ninth Edition, CLSI document M07-A9, Wayne, PA: Clinical and Laboratory Standards Institute.

Clyburn, T.A. and Cui, Q. (2007), "Antibiotic laden cement: current state of the art", AAOS Now, 1, Available at:

Dash, M., Chiellini, F., Ottenbrite, R.M. and Chiellini, E. (2011), "Chitosan-A versatile semi-synthetic polymer in biomedical applications", Prog. Polym. Sci., 36(8), 981-1014. crossref(new window)

Doty, H.A., Leedy, M.R., Courtney, H.S., Haggard, W.O. and Bumgardner, J.D. (2014), "Composite chitosan and calcium sulfate scaffold for dual delivery of vancomycin and recombinant human bone morphogenetic protein-2", J. Mater. Sci. Mater. Med., 25(6), 1449-1459. crossref(new window)

Edin, M.L., Miclau, T., Lester, G.E., Lindsey, R.W. and Dahners, L.E. (1996). "Effect of cefazolin and vancomycin on osteoblasts in vitro", Clin. Orthop. Relat. Res., 333, 245-251.

Gentry, L.O. (1997), "Management of osteomyelitis", Int. J. Antimicrob. Agents, 9(1), 37-42. crossref(new window)

Gitelis, S. and Brebach, G.T. (2002), "The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant", J. Orthop. Surg. (Hong Kong), 10(1), 53-60. crossref(new window)

Gogia, J.S., Meehan, J.P., Di Cesare, P.E. and Jamali, A. (2009), "Local antibiotic therapy in osteomyelitis", Seminar. Plast. Surg., 23(2), 100-107. crossref(new window)

Hatzenbuehler, J. and Pulling, T.J. (2011), "Diagnosis and management of osteomyelitis", Am. Family Phys., 84(9), 1027-1033.

Hogan, A., Heppert, V.G. and Suda, A.J. (2013), "Osteomyelitis", Arch. Orthop. Trauma Surg., 133(9), 1183-1196. crossref(new window)

Howlin, R.P., Brayford, M.J., Webb, J.S., Cooper, J.J., Aiken, S.S. and Stoodley, P. (2015), "Antibiotic-loaded synthetic calcium sulfate beads for prevention of bacterial colonization and biofilm formation in periprosthetic infections", Antimicrob. Agents Chemother., 59(1), 111-120. crossref(new window)

Jackson, S.R., Richelsoph, K.C., Courtney, H.S., Wenke, J.C., Branstetter, J.G., Bumgardner, J.D. and Haggard, W.O. (2009), "Preliminary in vitro evaluation of an adjunctive therapy for extremity wound infection reduction: rapidly resorbing local antibiotic delivery", J. Orthop. Res., 27(7), 903-908. crossref(new window)

Jain, A.K. and Panchagnula, R. (2000), "Skeletal drug delivery systems", Int. J. Pharm., 206(1-2), 1-12. crossref(new window)

Kobayashi, N., Procop, G.W., Krebs, V., Kobayashi, H. and Bauer, T.W. (2008), "Molecular identification of bacteria from aseptically loose implants", Clin. Orthop. Relat. Res., 466(7), 1716-1725. crossref(new window)

Lazzarini, L., Mader, J.T. and Calhoun, J.H. (2004), "Osteomyelitis in long bones", J. Bone Joint Surg. Am., 86-A(10), 2305-2318.

Lew, D.P. and Waldvogel, F.A. (1997), "Osteomyelitis", New England J. Med., 336(14), 999-1007. crossref(new window)

Lodenkamper, H., Lodenkamper, U. and Trompa, K. (1982), "Elimination of antibiotics from Palacos bone cement (personal experience from a bacteriological viewpoint after 10-year application in joint replacement surgery", Zeitschrift fur Orthopadie und ihre Grenzgebiete, 120(6), 801-805. crossref(new window)

Masri, B.A., Duncan, C.P., Beauchamp, C.P., Paris, N.J. and Arntorp, J. (1995), "Effect of varying surface patterns on antibiotic elution from antibiotic-loaded bone cement", J. Arthroplasty, 10(4), 453-459. crossref(new window)

McConoughey, S.J., Howlin, R.P., Wiseman, J., Stoodley, P. and Calhoun, J.H. (2015), "Comparing PMMA and calcium sulfate as carriers for the local delivery of antibiotics to infected surgical sites", J. Biomed. Mater. Res. Part B Appl. Biomater., 103(4), 870-877. crossref(new window)

McLaren, A.C. (2004), "Alternative materials to acrylic bone cement for delivery of depot antibiotics in orthopaedic infections", Clin. Orthop. Relat. Res., 427, 101-106. crossref(new window)

McPherson, E.J., Dipane, M. V. and Sherif, S.M. (2013), "Dissolvable antibiotic beads in treatment of periprosthetic joint infection and revision arthroplasty - The use of synthetic pure calcium sulfate ($Stimulan^{(R)}$) impregnated with vancomycin & tobramycin", Reconstr. Rev., 3(1), 32-43.

Mousset, B., Benoit, M.A., Delloye, C., Bouillet, R. and Gillard, J. (1995), "Biodegradable implants for potential use in bone infection. An in vitro study of antibiotic-loaded calcium sulphate", Int. Orthop., 19(3), 157-161.

Nair, M.B., Kretlow, J.D., Mikos, A.G. and Kasper, F.K. (2011), "Infection and tissue engineering in segmental bone defects--a mini review", Curr. Opinion Biotechnol., 22(5), 721-725. crossref(new window)

Noel, S.P., Courtney, H.S., Bumgardner, J.D. and Haggard, W.O. (2010), "Chitosan sponges to locally deliver amikacin and vancomycin: a pilot in vitro evaluation", Clin. Orthop. Relat. Res., 468(8), 2074-2080. crossref(new window)

Parker, A.C., Smith, J.K., Courtney, H.S. and Haggard, W.O. (2011), "Evaluation of two sources of calcium sulfate for a local drug delivery system: a pilot study", Clin. Orthop. Relat. Res., 469(11), 3008-3015. crossref(new window)

Parvizi, J., Erkocak, O.F. and Della Valle, C.J. (2014), "Culture-negative periprosthetic joint infection", J. Bone Joint Surg. Am., 96(5), 430-436. crossref(new window)

Patzakis, M.J. and Wilkins, J. (1989), "Factors influencing infection rate in open fracture wounds", Clin. Orthop. Relat. Res., 243, 36-40.

Pecora, G., Andreana, S., Margarone, J.E., Covani, U. and Sottosanti, J.S. (1997), "Bone regeneration with a calcium sulfate barrier", Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol., 84(4), 424-429. crossref(new window)

Penner, M.J., Masri, B. and Duncan, C.P. (1996), "Elution characteristics of vancomycin and tobramycin combined in acrylic bone-cement", J. Arthroplasty, 11(8), 939-944. crossref(new window)

Petersen, K., Riddle, M.S., Danko, J.R., Blazes, D.L., Hayden, R., Tasker, S. a and Dunne, J.R. (2007), "Trauma-related infections in battlefield casualties from Iraq", Ann. Surg., 245(5), 803-811. crossref(new window)

Phillips, H., Boothe, D.M., Shofer, F., Davidson, J.S. and Bennett, R.A. (2007), "In vitro elution studies of amikacin and cefazolin from polymethylmethacrylate", Vet. Surg., 36(3), 272-278. crossref(new window)

Rathbone, C.R., Cross, J.D., Brown, K. V, Murray, C.K. and Wenke, J.C. (2011), "Effect of various concentrations of antibiotics on osteogenic cell viability and activity", J. Orthop. Res., 29(7), 1070-1074. crossref(new window)

Rauschmann, M.A., Wichelhaus, T.A., Stirnal, V., Dingeldein, E., Zichner, L., Schnettler, R. and Alt, V. (2005), "Nanocrystalline hydroxyapatite and calcium sulphate as biodegradable composite carrier material for local delivery of antibiotics in bone infections", Biomater., 26(15), 2677-2684. crossref(new window)

Reves, B.T., Bumgardner, J.D., Cole, J.A., Yang, Y. and Haggard, W.O. (2009), "Lyophilization to improve drug delivery for chitosan-calcium phosphate bone scaffold construct: a preliminary investigation", J. Biomed. Mater. Res. B. Appl. Biomater., 90(1), 1-10.

Reves, B.T., Jennings, J., Bumgardner, J.D. and Haggard, W.O. (2012), "Preparation and functional assessment of composite Chitosan-Nano-Hydroxyapatite scaffolds for bone regeneration", J. Func. Biomater., 3(1), 114-130. crossref(new window)

Richelsoph, K.C., Webb, N.D. and Haggard, W.O. (2007), "Elution behavior of daptomycin-loaded calcium sulfate pellets: a preliminary study", Clin. Orthop. Relat. Res., 461, 68-73.

Romainor, A.N.B., Chin, S.F., Pang, S.C. and Bilung, L.M. (2014), "Preparation and characterization of chitosan Nanoparticles-Doped cellulose films with antimicrobial property", J. Nanomater., 2014, 1-10.

Sakamoto, Y., Ochiai, H., Ohsugi, I., Inoue, Y., Yoshimura, Y. and Kishi, K. (2013), "Mechanical strength and in vitro antibiotic release profile of antibiotic-loaded calcium phosphate bone cement", J. Craniofac. Surg., 24(4), 1447-1450. crossref(new window)

Schlickewei, C.W., Yarar, S. and Rueger, J.M. (2014), "Eluting antibiotic bone graft substitutes for the treatment of osteomyelitis in long bones. A review: evidence for their use?", Orthop. Res. Rev., 6, 71-79.

Sinha, V.R., Singla, A.K., Wadhawan, S., Kaushik, R., Kumria, R., Bansal, K. and Dhawan, S. (2004), "Chitosan microspheres as a potential carrier for drugs", Int. J. Pharm., 274(1-2), 1-33. crossref(new window)

Thomas, L.A., Bizikova, T. and Minihan, A.C. (2011), "In vitro elution and antibacterial activity of clindamycin, amikacin, and vancomycin from R-gel polymer", Vet. Surg., 40(6), 774-780. crossref(new window)

Thomas, M. V and Puleo, D.A. (2009), "Calcium sulfate: Properties and clinical applications", J. Biomed. Mater. Res. B. Appl. Biomater., 88(2), 597-610.

Thomas, D.B., Brooks, D.E., Bice, T.G., DeJong, E.S., Lonergan, K.T. and Wenke, J.C. (2005), "Tobramycin-impregnated calcium sulfate prevents infection in contaminated wounds", Clin. Orthop. Relat. Res., 441, 366-371. crossref(new window)

Walsh, W.R., Morberg, P., Yu, Y., Yang, J.L., Haggard, W., Sheath, P.C., Svehla, M. and Bruce, W.J.M. (2003), "Response of a calcium sulfate bone graft substitute in a confined cancellous defect", Clin. Orthop. Relat. Res., 406, 228-236. crossref(new window)

Wenke, J.C., Owens, B.D., Svoboda, S.J. and Brooks, D.E. (2006), "Effectiveness of commercially-available antibiotic-impregnated implants", J. Bone Joint Surg. Br., 88(8), 1102-1104.

Wenke, J.C. and Guelcher, S.A. (2011), "Dual delivery of an antibiotic and a growth factor addresses both the microbiological and biological challenges of contaminated bone fractures", Expert Opinion Drug Deliv., 8(12), 1555-1569. crossref(new window)

Wichelhaus, T.A., Dingeldein, E., Rauschmann, M., Kluge, S., Dieterich, R., Schafer, V. and Brade, V. (2001), "Elution characteristics of vancomycin, teicoplanin, gentamicin and clindamycin from calcium sulphate beads", J. Antimicrob. Chemother., 48(1), 117-119. crossref(new window)

Zalavras, C.G., Patzakis, M.J., Holtom, P.D. and Sherman, R. (2005), "Management of open fractures", Infect. Dis. Clin. North Am., 19(4), 915-929. crossref(new window)

Zilberman, M. and Elsner, J.J. (2008), "Antibiotic-eluting medical devices for various applications," J. Control. Release, 130(3), 202-215. crossref(new window)