Novel nano-hydroxyapatite/polyurethane composite scaffold in the treatment of chronic osteomyelitis_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

ZHANG Dongli , LIU Wen , WU Xiangdong , HE Xiaoqiang , LIN Xiao ,  HUANG Wei

Department of Orthopedics, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R.China;

Corresponding author：

HUANG Wei, Email: huangwei68@263.net

Keywords：

Chronic osteomyelitis; levofloxacin; biomaterial; bone repair; rabbit

DOI：

10.7507/1002-1892.201802049

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ObjectiveTo evaluate the bone repair efficacy of the new nano-hydroxyapatite (n-HA)/polyurethane (PU) composite scaffold in the treatment of chronic osteomyelitis in tibia.MethodsA novel levofloxacin@mesoporous silica microspheres (Lev@MSNs)/n-HA/PU was successfully synthesized. Its surface structure was observed by scanning electron microscopy (SEM). Fifty adult female New Zealand rabbits were randomly selected, and osteomyelitis was induced in the right tibia of the rabbit by injecting bacterial suspension (Staphylococcus aureus; 3×10⁷ CFU/mL), which of the method was described by Norden. A total of 45 animals with the evidence of osteomyelitis were randomly divided into 4 groups, and the right medullary cavity of each animal was exposed. Animals in the blank control group (group A, n=9) were treated with exhaustive debridement only. The remaining animals were first treated by exhaustive debridement, and received implantations of 5 mg Lev@PMMA (group B, n=12), 1 mg Lev@MSNs/n-HA/PU (group C, n=12), and 5 mg Lev@MSNs/n-HA/PU (group D, n=12), respectively. At 12 weeks postoperatively, the right tibia of rabbits were observed by X-ray film, and then gross observation, methylene blue/acid fuchsin staining, and SEM observation of implant-bone interface, as well as biomechanical test (measuring the maximal compression force) were performed.ResultsX-ray films showed that the infection were severer than those of preoperation in group A, while the control of inflammation and bone healing of rabbits in group D were obviously better than those at preoperation. The gross observation showed extensive bone destruction in group A, a significant gap between bone tissue and the material in groups B and C, and close combination between bone tissue and the material in group D. The histology of the resected specimens showed that there was no obvious new bone formation around the materials in groups B and C, and there was abundant new bone formation around the periphery and along the voids of the materials and active bone remodeling in group D. The SEM observation of the bone-implant interface demonstrated that no new bone formation was observed at the bone-implant interface in groups B and C. However, bony connections and blurred boundaries were observed between the material and host bone tissue in group D. The biomechanical test showed the maximal compression force of groups B and D were significantly higher than that of groups A and C (P<0.05), but there was no significant difference between groups B and D (P>0.05).ConclusionThe novel synthetic composite Lev@MSNs/n-HA/PU exhibit good antibacterial activities, osteoconductivity, and biomechanical properties, and show great potential in the treatment of chronic osteomyelitis of rabbits.

Citation： ZHANG Dongli, LIU Wen, WU Xiangdong, HE Xiaoqiang, LIN Xiao, HUANG Wei. Novel nano-hydroxyapatite/polyurethane composite scaffold in the treatment of chronic osteomyelitis. Chinese Journal of Reparative and Reconstructive Surgery, 2018, 32(7): 880-886. doi: 10.7507/1002-1892.201802049 Copy

1.	Salvana J, Rodner C, Browner BD, et al. Chronic osteomyelitis: results obtained by an integrated team approach to management. Conn Med, 2005, 69(4): 195-202.
2.	Romano CL, Romano D, Logoluso N, et al. Bone and joint infections in adults: a comprehensive classification proposal. Eur Orthop Traumatol, 2011, 1(6): 207-217.
3.	Smeltzer MS, Thomas JR, Hickmon SG, et al. Characterization of a rabbit model of Staphylococcal osteomyelitis. J Orthop Res, 1997, 15(3): 414-421.
4.	Mader JT, Landon GC, Calhoun J. Antimicrobial treatment of osteomyelitis. Clin Orthop Relat Res, 1993, (295): 87-95.
5.	Lew DP, Waldvogel FA. Osteomyelitis. Lancet, 2004, 364(9431): 369-379.
6.	Ellington JK, Harris M, Webb L, et al. Intracellular Staphylococcus aureus: A mechanism for the indolence of osteomyelitis. J Bone Joint Surg (Br), 2003, 85(6): 918-921.
7.	Krajewski J, Bode-Böger SM, Tröger U, et al. Successful treatment of extensively drug-resistant Pseudomonas aeruginosa osteomyelitis using a colistin- and tobramycin-impregnated PMMA spacer. Int J Antimicrob Agents, 2014, 44(4): 363-366.
8.	McKee MD, Li-Bland EA, Wild LM, et al. A prospective, randomized clinical trial comparing an antibiotic-impregnated bioabsorbable bone substitute with standard antibiotic-impregnated cement beads in the treatment of chronic osteomyelitis and infected nonunion. J Orthop Trauma, 2010, 24(8): 483-490.
9.	Lepretre S, Chai F, Hornez JC, et al. Prolonged local antibiotics delivery from hydroxyapatite functionalised with cyclodextrin polymers. Biomaterials, 2009, 30(30): 6086-6093.
10.	Wang Q, Chen C, Liu W, et al. Levofloxacin loaded mesoporous silica microspheres/nano-hydroxyapatite/polyurethane composite scaffold for the treatment of chronic osteomyelitis with bone defects. Sci Rep, 2017, 7: 41808.
11.	Wang Y, Ding X, Chen Y, et al. Antibiotic-loaded, silver core-embedded mesoporous silica nanovehicles as a synergistic antibacterial agent for the treatment of drug-resistant infections. Biomaterials, 2016, 101: 207-216.
12.	Lee JE, Lee N, Kim H, et al. Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery. J Am Chem Soc, 2010, 132(2): 552-557.
13.	Yubao L, Klein CP, Zhang X, et al. Formation of a bone apatite-like layer on the surface of porous hydroxyapatite ceramics. Biomaterials, 1994, 15(10): 835-841.
14.	Li L, Zuo Y, Zou Q, et al. Hierarchical structure and mechanical improvement of an n-HA/GCO-PU composite scaffold for bone regeneration. ACS Appl Mater Interfaces, 2015, 7(40): 22618-22629.
15.	Norden CW. Experimental osteomyelitis. Ⅰ. A description of the model. J Infect Dis, 1970, 122(5): 410-418.
16.	Pollak AN, Jones AL, Castillo RC, et al. The relationship between time to surgical débridement and incidence of infection after open high-energy lower extremity trauma. J Bone Joint Surg (Am), 2010, 92(1): 7-15.
17.	Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg (Am), 1990, 72(2): 299-304.
18.	Stanley CM, Rutherford GW, Morshed S, et al. Estimating the healthcare burden of osteomyelitis in Uganda. Trans R Soc Trop Med Hyg, 2010, 104(2): 139-142.
19.	Marais LC, Ferreira N. Bone transport through an induced membrane in the management of tibial bone defects resulting from chronic osteomyelitis. Strategies Trauma Limb Reconstr, 2015, 10(1): 27-33.
20.	la Société de Pathologie Infectieuse de Langue Française (SPILF)1, Collège des Universitaires de Maladies Infectieuses et Tropicales (CMIT), Groupe de Pathologie Infectieuse Pédiatrique (GPIP), et al. Clinical practice recommendations. Osteoarticular infections on materials (prosthesis, implants, osteosynthesis). Med Mal Infect, 2009, 39(11): 815-863.
21.	唐佳民, 张瑞涛. 介孔二氧化硅纳米粒的研究进展. 现代药物与临床, 2015, 30(11): 1422-1426.
22.	董志红, 李玉宝, 邹琴, 等. 羟基磷灰石/聚氨酯复合骨诱导再生膜的细胞相容性及自身降解性能. 中国组织工程研究与临床康复, 2008, 12(10): 1847-1850.
23.	Kendall RW, Duncan CP, Smith JA, et al. Persistence of bacteria on antibiotic loaded acrylic depots. A reason for caution. Clin Orthop Relat Res, 1996, (329): 273-280.
24.	Ensing GT, van Horn JR, van der Mei HC, et al. Copal bone cement is more effective in preventing biofilm formation than Palacos R-G. Clin Orthop Relat Res, 2008, 466(6): 1492-1498.
25.	Anagnostakos K, Kelm J. Enhancement of antibiotic elution from acrylic bone cement. J Biomed Mater Res B Appl Biomater, 2009, 90(1): 467-475.
26.	Neut D, van de Belt H, van Horn JR, et al. Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads after 5 years of implantation. Biomaterials, 2003, 24(10): 1829-1831.
27.	Mastrogiacomo M, Scaglione S, Martinetti R, et al. Role of scaffold internal structure on in vivo bone formation in macroporous calcium phosphate bioceramics. Biomaterials, 2006, 27(17): 3230-3237.
28.	Li S, Demirci E, Silberschmidt VV. Variability and anisotropy of mechanical behavior of cortical bone in tension and compression. J Mech Behav Biomed Mater, 2013, 21(1): 109-120.

1. Salvana J, Rodner C, Browner BD, et al. Chronic osteomyelitis: results obtained by an integrated team approach to management. Conn Med, 2005, 69(4): 195-202.
2. Romano CL, Romano D, Logoluso N, et al. Bone and joint infections in adults: a comprehensive classification proposal. Eur Orthop Traumatol, 2011, 1(6): 207-217.
3. Smeltzer MS, Thomas JR, Hickmon SG, et al. Characterization of a rabbit model of Staphylococcal osteomyelitis. J Orthop Res, 1997, 15(3): 414-421.
4. Mader JT, Landon GC, Calhoun J. Antimicrobial treatment of osteomyelitis. Clin Orthop Relat Res, 1993, (295): 87-95.
5. Lew DP, Waldvogel FA. Osteomyelitis. Lancet, 2004, 364(9431): 369-379.
6. Ellington JK, Harris M, Webb L, et al. Intracellular Staphylococcus aureus: A mechanism for the indolence of osteomyelitis. J Bone Joint Surg (Br), 2003, 85(6): 918-921.
7. Krajewski J, Bode-Böger SM, Tröger U, et al. Successful treatment of extensively drug-resistant Pseudomonas aeruginosa osteomyelitis using a colistin- and tobramycin-impregnated PMMA spacer. Int J Antimicrob Agents, 2014, 44(4): 363-366.
8. McKee MD, Li-Bland EA, Wild LM, et al. A prospective, randomized clinical trial comparing an antibiotic-impregnated bioabsorbable bone substitute with standard antibiotic-impregnated cement beads in the treatment of chronic osteomyelitis and infected nonunion. J Orthop Trauma, 2010, 24(8): 483-490.
9. Lepretre S, Chai F, Hornez JC, et al. Prolonged local antibiotics delivery from hydroxyapatite functionalised with cyclodextrin polymers. Biomaterials, 2009, 30(30): 6086-6093.
10. Wang Q, Chen C, Liu W, et al. Levofloxacin loaded mesoporous silica microspheres/nano-hydroxyapatite/polyurethane composite scaffold for the treatment of chronic osteomyelitis with bone defects. Sci Rep, 2017, 7: 41808.
11. Wang Y, Ding X, Chen Y, et al. Antibiotic-loaded, silver core-embedded mesoporous silica nanovehicles as a synergistic antibacterial agent for the treatment of drug-resistant infections. Biomaterials, 2016, 101: 207-216.
12. Lee JE, Lee N, Kim H, et al. Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery. J Am Chem Soc, 2010, 132(2): 552-557.
13. Yubao L, Klein CP, Zhang X, et al. Formation of a bone apatite-like layer on the surface of porous hydroxyapatite ceramics. Biomaterials, 1994, 15(10): 835-841.
14. Li L, Zuo Y, Zou Q, et al. Hierarchical structure and mechanical improvement of an n-HA/GCO-PU composite scaffold for bone regeneration. ACS Appl Mater Interfaces, 2015, 7(40): 22618-22629.
15. Norden CW. Experimental osteomyelitis. Ⅰ. A description of the model. J Infect Dis, 1970, 122(5): 410-418.
16. Pollak AN, Jones AL, Castillo RC, et al. The relationship between time to surgical débridement and incidence of infection after open high-energy lower extremity trauma. J Bone Joint Surg (Am), 2010, 92(1): 7-15.
17. Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg (Am), 1990, 72(2): 299-304.
18. Stanley CM, Rutherford GW, Morshed S, et al. Estimating the healthcare burden of osteomyelitis in Uganda. Trans R Soc Trop Med Hyg, 2010, 104(2): 139-142.
19. Marais LC, Ferreira N. Bone transport through an induced membrane in the management of tibial bone defects resulting from chronic osteomyelitis. Strategies Trauma Limb Reconstr, 2015, 10(1): 27-33.
20. la Société de Pathologie Infectieuse de Langue Française (SPILF)1, Collège des Universitaires de Maladies Infectieuses et Tropicales (CMIT), Groupe de Pathologie Infectieuse Pédiatrique (GPIP), et al. Clinical practice recommendations. Osteoarticular infections on materials (prosthesis, implants, osteosynthesis). Med Mal Infect, 2009, 39(11): 815-863.
21. 唐佳民, 张瑞涛. 介孔二氧化硅纳米粒的研究进展. 现代药物与临床, 2015, 30(11): 1422-1426.
22. 董志红, 李玉宝, 邹琴, 等. 羟基磷灰石/聚氨酯复合骨诱导再生膜的细胞相容性及自身降解性能. 中国组织工程研究与临床康复, 2008, 12(10): 1847-1850.
23. Kendall RW, Duncan CP, Smith JA, et al. Persistence of bacteria on antibiotic loaded acrylic depots. A reason for caution. Clin Orthop Relat Res, 1996, (329): 273-280.
24. Ensing GT, van Horn JR, van der Mei HC, et al. Copal bone cement is more effective in preventing biofilm formation than Palacos R-G. Clin Orthop Relat Res, 2008, 466(6): 1492-1498.
25. Anagnostakos K, Kelm J. Enhancement of antibiotic elution from acrylic bone cement. J Biomed Mater Res B Appl Biomater, 2009, 90(1): 467-475.
26. Neut D, van de Belt H, van Horn JR, et al. Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads after 5 years of implantation. Biomaterials, 2003, 24(10): 1829-1831.
27. Mastrogiacomo M, Scaglione S, Martinetti R, et al. Role of scaffold internal structure on in vivo bone formation in macroporous calcium phosphate bioceramics. Biomaterials, 2006, 27(17): 3230-3237.
28. Li S, Demirci E, Silberschmidt VV. Variability and anisotropy of mechanical behavior of cortical bone in tension and compression. J Mech Behav Biomed Mater, 2013, 21(1): 109-120.

Chinese Journal of Reparative and Reconstructive Surgery

Novel nano-hydroxyapatite/polyurethane composite scaffold in the treatment of chronic osteomyelitis

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