VANCOMYCIN CATIONIC LIPOSOME COMBINED WITH NANO-HYDROXYAPATITE/CHITOSAN/KONJACGLUCOMANNAN SCAFFOLD FOR TREATMENT OF INFECTED BONE DEFECTS IN RABBITS_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

HUANG Jinliang , MA Tao , TANG Hui , FAN Xinyu , XU Yongqing.

Orthopedic Center, Kunming General Hospital of Chengdu Military Command,Kunming Yunnan, 650032, P.R.China.;

Corresponding author：

Keywords：

Nano-hydroxyapatite/chitosan/konjac glucomannan scaffold; Cationic l iposome; Vancomycin; Infected bone defect; Rabbit

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【Abstract】 Objective To investigate the anti-infection and bone repair effects of cationic l i posome-encapsulated
vancomycin combined with the nano-hydroxyapatite/chitosan/konjac glucomannan (n-HA/CS/KGM) composite scaffold in
vivo. Methods Fifty-one 6-month-old New Zealand white rabbits, weighing 1.5-3.0 kg, were selected to prepare chronic
infectious tibia bone defect model by using Staphylococcus aureus. After 4 weeks, 48 survival rabbits were randomly divided into 4 groups (n=12). After debridement, defect was treated with nothing in group A, with n-HA/CS/KGM composite scaffold in group B, with vancomycin and n-HA/CS/KGM composite scaffold in group C, and with cationic l i posome-encapsulated vancomycin and n-HA/CS/KGM composite scaffold in group D. After 8 weeks of treatment, general observation, X-ray, HE staining, the bacterial culture, and the measurement of the longest diameter of bone defect were done. Results At 4 weeks after modeling, 48 rabbits were diagnosed as having osteomyelitis, including periosteal new bone formation, destruction of bone, and soft tissue swell ing. The Norden score was 3.83 ± 0.52. At 8 weeks after treatment, sinus healed in groups C and D, but sinus was observed in groups A and B; the gross bone pathologieal scores of group D were significantly better than those of groups A and B (P lt; 0.05). Bone defects were repaired completely in group D, the results of the longest diameter of bone defects in group D was significantly better than those in the other 3 groups (P lt; 0.05). New bone formation was observed in groups C and D, but periosteal reaction
and marrow low-density shadow were observed in groups A and B; Norden score in group D was significantly better than those in groups A, B, and C (P lt; 0.05). HE staining showed that there were a large number of trabecular bone formation and fibrosis, with no obvious signs of infection in groups C and D, but neutrophil accumulation was observed in groups A and B; Smeltzer scores in groups C and D were significantly better than those in groups A and B (P lt; 0.05). Bacteriological results showed higher negative rate in groups C and D than in groups A and B (P lt; 0.05). Conclusion Cationic l iposome-encapsulated vancomycin and n-HA/CS/KGM composite scaffold can be a good treatment for infectious bone defects in rabbits, providing a new strategy for the therapy of bone defects in chronic infection.

Citation： HUANG Jinliang,MA Tao,TANG Hui,FAN Xinyu,XU Yongqing.. VANCOMYCIN CATIONIC LIPOSOME COMBINED WITH NANO-HYDROXYAPATITE/CHITOSAN/KONJACGLUCOMANNAN SCAFFOLD FOR TREATMENT OF INFECTED BONE DEFECTS IN RABBITS. Chinese Journal of Reparative and Reconstructive Surgery, 2012, 26(2): 190-195. doi: Copy

1.	Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg (Am), 1990, 72(2): 299-304.
2.	de Carvalho CC. Biofilms: recent developments on an old battle. Recent Pat Biotechnol, 2007, 1(1): 49-57.
3.	Widmer AF. New developments in diagnosis and treatment of infection in orthopedic implants. Clin Infect Dis, 2001, 33 Suppl 2: S94-106.
4.	Kim HJ, Jones MN. The delivery of benzyl penicillin to Staphylococcus aureus biofilms by use of liposomes. J Liposome Res, 2004, 14(3-4): 123-139.
5.	Ma T, Shang BC, Tang H, et al. Nano-hydroxyapatite/chitosan/konjac glucomannan scaffolds loaded with cationic liposomal vancomycin: preparation, in vitro release and activity against Staphylococcus aureus biofilms. J Biomater Sci Polym Ed, 2011, 22(12): 1669-1681.
6.	Norden CW, Myerowitz RL, Keleti E. Experimental osteomyelitis due to Staphylococcus aureus or Pseudomonas aeruginosa: a radiographic-pathological correlative analysis. Br J Exp Pathol, 1980, 61(4): 451-460.
7.	Rissing JP, Buxton TB, Weinstein RS, et al. Model of experimental chronic osteomyelitis in rats. Infect Immun, 1985, 47(3): 581-586.
8.	Smeltzer MS, Thomas JR, Hickmon SG, et al. Characterization of a rabbit model of staphylococcal osteomyelitis. J Orthop Res, 1997, 15(3): 414-421.
9.	Hatzenbuehler J, Pulling TJ. Diagnosis and management of osteomyelitis. Am Fam Physician, 2011, 84(9): 1027-1033.
10.	Popat KC, Eltgroth M, Latempa TJ, et al. Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nanotubes. Biomaterials, 2007, 28(32): 4880-4888.
11.	Ince A, Schutze N, Hendrich C, et al. Effect of polyhexanide and gentamycin on human osteoblasts and endothelial cells. Swiss Med Wkly, 2007, 137(9-10): 139-145.
12.	van de Belt H, Neut D, Uges DR, et al. Surface roughness, porosity and wettability of gentamicin-loaded bone cements and their antibiotic release. Biomaterials, 2000, 21(19): 1981-1987.
13.	Movassaghian S, Moghimi HR, Shirazi FH, et al. Dendrosome-dendriplex inside liposomes: as a gene delivery system. J Drug Target, 2011, 19(10): 925-932.
14.	Halwani M, Yebio B, Suntres ZE, et al. Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa. J Antimicrob Chemother, 2008, 62(6): 1291-1297.
15.	Moghimi SM, Porter CJ, Illum L, et al. The effect of poloxamer-407 on liposome stability and targeting to bone marrow:comparison with polystyrene microspheres. Int J Pharnm, 1991, 68(1-3): 121-126.
16.	Kadry AA, Al-Suwayeh SA, Abd-Allah AR, et al. Treatment of experimental osteomyelitis by liposomal antibiotics. J Antimicrob Chemother, 2004, 54(6): 1103-1108.
17.	Trafny EA, Stepinska M, Antos M, et al. Effects of free and liposome-encapsulated antibiotics on adherence of Pseudomonas aeruginosa to collagen type I. Antimicrob Agents Chemother, 1995, 39(12): 2645-2649.
18.	Datta N, Pham QP, Sharma U, et al. In vitro generated extracellular matrix and fluid shear stress synergistically enhance 3D osteoblastic differentiation. Proc Natl Acad Sci U S A, 2006, 103(8): 2488-2493.
19.	Kankilic B, Bayramli E, Kilic E, et al. Vancomycin containing PLLA/β-TCP controls MRSA in vitro. Clin Orthop Relat Res, 2011, 469(11): 3222-3228.
20.	Zhu CT, Xu YQ, Shi J, et al. Liposome combined porous beta-TCP scaffold: preparation, characterization, and anti-biofilm activity. Drug Deliv, 2010, 17(6): 391-398.
21.	Zhou G, Li Y, Zhang L, et al. Preparation and characterization of nano-hydroxyapatite/chitosan/konjac glucomannan composite. J Biomed Mater Res A, 2007, 83(4): 931-939.

1. Gustilo RB, Merkow RL, Templeman D. The management of open fractures. J Bone Joint Surg (Am), 1990, 72(2): 299-304.
2. de Carvalho CC. Biofilms: recent developments on an old battle. Recent Pat Biotechnol, 2007, 1(1): 49-57.
3. Widmer AF. New developments in diagnosis and treatment of infection in orthopedic implants. Clin Infect Dis, 2001, 33 Suppl 2: S94-106.
4. Kim HJ, Jones MN. The delivery of benzyl penicillin to Staphylococcus aureus biofilms by use of liposomes. J Liposome Res, 2004, 14(3-4): 123-139.
5. Ma T, Shang BC, Tang H, et al. Nano-hydroxyapatite/chitosan/konjac glucomannan scaffolds loaded with cationic liposomal vancomycin: preparation, in vitro release and activity against Staphylococcus aureus biofilms. J Biomater Sci Polym Ed, 2011, 22(12): 1669-1681.
6. Norden CW, Myerowitz RL, Keleti E. Experimental osteomyelitis due to Staphylococcus aureus or Pseudomonas aeruginosa: a radiographic-pathological correlative analysis. Br J Exp Pathol, 1980, 61(4): 451-460.
7. Rissing JP, Buxton TB, Weinstein RS, et al. Model of experimental chronic osteomyelitis in rats. Infect Immun, 1985, 47(3): 581-586.
8. Smeltzer MS, Thomas JR, Hickmon SG, et al. Characterization of a rabbit model of staphylococcal osteomyelitis. J Orthop Res, 1997, 15(3): 414-421.
9. Hatzenbuehler J, Pulling TJ. Diagnosis and management of osteomyelitis. Am Fam Physician, 2011, 84(9): 1027-1033.
10. Popat KC, Eltgroth M, Latempa TJ, et al. Decreased Staphylococcus epidermis adhesion and increased osteoblast functionality on antibiotic-loaded titania nanotubes. Biomaterials, 2007, 28(32): 4880-4888.
11. Ince A, Schutze N, Hendrich C, et al. Effect of polyhexanide and gentamycin on human osteoblasts and endothelial cells. Swiss Med Wkly, 2007, 137(9-10): 139-145.
12. van de Belt H, Neut D, Uges DR, et al. Surface roughness, porosity and wettability of gentamicin-loaded bone cements and their antibiotic release. Biomaterials, 2000, 21(19): 1981-1987.
13. Movassaghian S, Moghimi HR, Shirazi FH, et al. Dendrosome-dendriplex inside liposomes: as a gene delivery system. J Drug Target, 2011, 19(10): 925-932.
14. Halwani M, Yebio B, Suntres ZE, et al. Co-encapsulation of gallium with gentamicin in liposomes enhances antimicrobial activity of gentamicin against Pseudomonas aeruginosa. J Antimicrob Chemother, 2008, 62(6): 1291-1297.
15. Moghimi SM, Porter CJ, Illum L, et al. The effect of poloxamer-407 on liposome stability and targeting to bone marrow:comparison with polystyrene microspheres. Int J Pharnm, 1991, 68(1-3): 121-126.
16. Kadry AA, Al-Suwayeh SA, Abd-Allah AR, et al. Treatment of experimental osteomyelitis by liposomal antibiotics. J Antimicrob Chemother, 2004, 54(6): 1103-1108.
17. Trafny EA, Stepinska M, Antos M, et al. Effects of free and liposome-encapsulated antibiotics on adherence of Pseudomonas aeruginosa to collagen type I. Antimicrob Agents Chemother, 1995, 39(12): 2645-2649.
18. Datta N, Pham QP, Sharma U, et al. In vitro generated extracellular matrix and fluid shear stress synergistically enhance 3D osteoblastic differentiation. Proc Natl Acad Sci U S A, 2006, 103(8): 2488-2493.
19. Kankilic B, Bayramli E, Kilic E, et al. Vancomycin containing PLLA/β-TCP controls MRSA in vitro. Clin Orthop Relat Res, 2011, 469(11): 3222-3228.
20. Zhu CT, Xu YQ, Shi J, et al. Liposome combined porous beta-TCP scaffold: preparation, characterization, and anti-biofilm activity. Drug Deliv, 2010, 17(6): 391-398.
21. Zhou G, Li Y, Zhang L, et al. Preparation and characterization of nano-hydroxyapatite/chitosan/konjac glucomannan composite. J Biomed Mater Res A, 2007, 83(4): 931-939.

Chinese Journal of Reparative and Reconstructive Surgery

VANCOMYCIN CATIONIC LIPOSOME COMBINED WITH NANO-HYDROXYAPATITE/CHITOSAN/KONJACGLUCOMANNAN SCAFFOLD FOR TREATMENT OF INFECTED BONE DEFECTS IN RABBITS

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