• 1 上海交通大學(xué)附屬第六人民醫(yī)院骨科（上海，200233）;;
  • 2 同濟(jì)大學(xué)材料科學(xué)與工程學(xué)院生物工程與信息技術(shù)材料研究所;

目的 評(píng)價(jià)載萬古霉素的注射型硼酸鹽殼聚糖復(fù)合物（vancomycin-loaded borate glass/chitosan composite，VBC）的體內(nèi)、外生物活性及治療骨髓炎效果，探討其生物降解及抗生素緩釋規(guī)律，為臨床應(yīng)用奠定基礎(chǔ)。 方法 VBC 固相由硼酸鹽玻璃及萬古霉素粉劑組成，液相由殼聚糖、檸檬酸和葡萄糖按照質(zhì)量比 1 ∶ 10 ∶ 20 比例混勻制成，固相及液相按質(zhì)量比2 ∶ 1 比例混合凝固獲得VBC。硫酸鈣粉劑代替硼酸鹽玻璃，無菌生理鹽水代替殼聚糖溶液，同法制備載藥硫酸鈣（vancomycin-loaded calcium sulfate，VCS），作為對(duì)照。采用高效液相色譜法檢測(cè)VBC 及VCS 抗生素釋放率，抗生素雙重管稀釋法測(cè)定釋放抗生素的最低抑菌濃度（minimum inhibitory concentration，MIC）；掃描電鏡觀察浸泡前及D-Hank’s 溶液中浸泡2、4、8、16、40 d 的VBC、VCS 降解情況，X 射線衍射儀分析VBC 浸泡后40 d 物相組成。取33 只成年健康新西蘭大白兔，雌雄不限，體重2.25 ～ 3.10 kg；采用Norden 方法制備右脛骨近端骨髓炎模型。4 周后將28 只骨髓炎模型制備成功的大白兔隨機(jī)分成4 組：A 組（n=8）單純清創(chuàng)，B、C 組（n=8）清創(chuàng)后注入VCS 及VBC 至缺損處，D 組（n=4）不作任何處理。術(shù)后2 個(gè)月攝X 線片并行Norden 評(píng)分，取缺損處標(biāo)本行組織學(xué)觀察。 結(jié)果 VBC 釋藥過程持續(xù)30 d，藥物緩釋前8 d 釋放率達(dá)75%，最終釋放率達(dá)90% 以上；VCS 釋藥過程僅持續(xù)16 d。VBC、VCS 的MIC 均為2 μg/mL。掃描電鏡觀察，VCS 浸泡前為光滑玻璃晶體表面，4 d 后已大部分降解；VBC 浸泡前具有典型光滑玻璃表面，8 d 后結(jié)合相的玻璃部分溶化，40 d 后材料表面幾乎完全被生成的白色顆粒狀沉淀物覆蓋，材料結(jié)合疏松。VBC 浸泡40 dX 線衍射分析反應(yīng)生成物主要物相為羥基磷灰石。術(shù)后2 個(gè)月X 線片及組織學(xué)觀察示C 組骨髓炎癥狀均消失，優(yōu)于其余各組。A、B、C、D 組X 線片評(píng)分分別為（3.50 ± 0.63）、（2.29 ± 0.39）、（2.00 ± 0.41）、（4.25 ± 0.64）分，Smeltzer 評(píng)分分別為（6.00 ± 0.89）、（4.00 ± 0.82）、（3.57 ± 0.98）、（7.25 ± 0.50）分。其中D 組評(píng)分顯著高于A、B、C 組，A 組顯著高于B、C 組，比較差異均有統(tǒng)計(jì)學(xué)意義（P  lt; 0.05）；B 組評(píng)分高于C 組，但差異無統(tǒng)計(jì)學(xué)意義（P  gt; 0.05）。 結(jié)論 VBC 具有藥物緩釋性及成骨性能，有望成為治療骨髓炎的理想材料。

引用本文： 趙存舉,王信富,張長青,崔旭,賈偉濤,黃文旵. 注射型硼酸鹽殼聚糖復(fù)合物作為藥物載體治療骨髓炎的實(shí)驗(yàn)研究. 中國修復(fù)重建外科雜志, 2012, 26(6): 641-646. doi: 復(fù)制

1. Shuford JA, Steckelberg JM. Role of oral antimicrobial therapy in the management of osteomyelitis. Curr Opin Infect Dis, 2003, 16(6): 515-519.
2. Hanssen AD. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop Relat Res, 2005, (437): 91-96.
3. Kanellakopoulou K, Giamarellos-Bourboulis EJ. Carrier systems for the local delivery of antibiotics in bone infections. Drugs, 2000, 59(6): 1223-1232.
4. Beardmore AA, Brooks DE, Wenke JC, et al. Effectiveness of local antibiotic delivery with an osteoinductive and osteoconductive bone-graft substitute. J Bone Joint Surg (Am), 2005, 87(1): 107-112.
5. McLaren AC. Alternative materials to acrylic bone cement for delivery of depot antibiotics in orthopaedic infections. Clin Orthop Relat Res, 2004, (427): 101-106.
6. Hench LL. Bioactive materials: the potential for tissue regeneration. J Biomed Mater Res, 1998, 41(4): 511-518.
7. Wilson J, Clark AE, Hall M, et al. Tissue response to Bioglass endosseous ridge maintenance implants. J Oral Implantol, 1993, 19(4): 295-302.
8. Yao AH, Wang DP, Huang WH. In vitro bioactive characteristics of borate-based glasses with controllable degradation behavior. J Am Ceram Soc, 2007, 90(1): 303-306.
9. 鐘炳南. 硼在生命科學(xué)中的作用及對(duì)人體健康的影響. 世界元素醫(yī)學(xué), 2005, 12(1): 49-50 .
10. Prabaharan M. Review paper: chitosan derivatives as promising materials for controlled drug delivery. J Biomater Appl, 2008, 23(1): 5-36.
11. Liu X, Xie Z, Zhang C, et al. Bioactive borate glass scaffolds: in vitro and in vivo evaluation for use as a drug delivery system in the treatment of bone infection. J Mater Sci Mater Med, 2010, 21(2): 575-582.
12. Zhang X, Jia W, Gu Y, et al. Teicoplanin-loaded borate bioactive glass implants for treating chronic bone infection in a rabbit tibia osteomyelitis model. Biomaterials, 2010, 31(22): 5865-5874.
13. Ning J, Yao AH, Wang DP, et al. Synthesis and in vitro bioactivity of a borate-based bioglass. Materials Letters, 2007, 61(30): 5223-5226.
14. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically-5thed. Approved Standard M7-A5. USA: NCCLS 2000.
15. 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.
16. Smeltzer MS, Thomas JR, Hickmon SG, et al. Characterization of a rabbit model of staphylococcal osteomyelitis. J Orthop Res, 1997, 15(3): 414-421.
17. Xie Z, Liu X, Jia W, et al. Treatment of osteomyelitis and repair of bone defect by degradable bioactive borate glass releasing vancomycin. J Control Release, 2009, 139(2): 118-126.
18. 張欣, 賈偉濤, 顧刈非, 等. 載替考拉寧治療骨髓炎癥的硼酸鹽生物玻璃藥物載體的研究. 無機(jī)材料學(xué)報(bào), 2010, 25(3): 1303-1309.
19. Lee SH, Lee JE, Baek WY, et al. Regional delivery of vancomycin using pluronic F-127 to inhibit methicillin resisitant Staphylococcus aureus (MRSA) growth in chronic otitis media in vitro and in vivo. J Control Release, 2004, 96(1): 1-7.
20. Edin ML, Miclau T, Lester GE, et al. Effect of cefazolinand vancomycin on osteoblasts in vitro. Clin Orthop Relat Res, 1996, (333): 245-251.
21. Antoci V Jr, Adams CS, Hickok NJ, et al. Antibiotics for local delivery systems cause skeletal cell toxicity in vitro. Clin Orthop Relat Res, 2007, (462): 200-206.
22. Ducheyne P. Bioceramics: material characteristics versus in vivo behavior. J Biomed Mater Res, 1987, 21(A2 Suppl): 219-236.
23. Clark AE, Hench LL, Paschall HA. The influence of surface chemistry on implant interface histology: a theoretical basis for implant materials selection. J Biomed Mater Res, 1976, 10(2): 161-174.
24. 刑小茹, 魏復(fù)盛, 吳國平. 人體硼暴露及其代謝的研究進(jìn)展. 安全與環(huán)境學(xué)報(bào), 2006, 6 (1): 131-135.
  1. 1. Shuford JA, Steckelberg JM. Role of oral antimicrobial therapy in the management of osteomyelitis. Curr Opin Infect Dis, 2003, 16(6): 515-519.
  2. 2. Hanssen AD. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop Relat Res, 2005, (437): 91-96.
  3. 3. Kanellakopoulou K, Giamarellos-Bourboulis EJ. Carrier systems for the local delivery of antibiotics in bone infections. Drugs, 2000, 59(6): 1223-1232.
  4. 4. Beardmore AA, Brooks DE, Wenke JC, et al. Effectiveness of local antibiotic delivery with an osteoinductive and osteoconductive bone-graft substitute. J Bone Joint Surg (Am), 2005, 87(1): 107-112.
  5. 5. McLaren AC. Alternative materials to acrylic bone cement for delivery of depot antibiotics in orthopaedic infections. Clin Orthop Relat Res, 2004, (427): 101-106.
  6. 6. Hench LL. Bioactive materials: the potential for tissue regeneration. J Biomed Mater Res, 1998, 41(4): 511-518.
  7. 7. Wilson J, Clark AE, Hall M, et al. Tissue response to Bioglass endosseous ridge maintenance implants. J Oral Implantol, 1993, 19(4): 295-302.
  8. 8. Yao AH, Wang DP, Huang WH. In vitro bioactive characteristics of borate-based glasses with controllable degradation behavior. J Am Ceram Soc, 2007, 90(1): 303-306.
  9. 9. 鐘炳南. 硼在生命科學(xué)中的作用及對(duì)人體健康的影響. 世界元素醫(yī)學(xué), 2005, 12(1): 49-50 .
  10. 10. Prabaharan M. Review paper: chitosan derivatives as promising materials for controlled drug delivery. J Biomater Appl, 2008, 23(1): 5-36.
  11. 11. Liu X, Xie Z, Zhang C, et al. Bioactive borate glass scaffolds: in vitro and in vivo evaluation for use as a drug delivery system in the treatment of bone infection. J Mater Sci Mater Med, 2010, 21(2): 575-582.
  12. 12. Zhang X, Jia W, Gu Y, et al. Teicoplanin-loaded borate bioactive glass implants for treating chronic bone infection in a rabbit tibia osteomyelitis model. Biomaterials, 2010, 31(22): 5865-5874.
  13. 13. Ning J, Yao AH, Wang DP, et al. Synthesis and in vitro bioactivity of a borate-based bioglass. Materials Letters, 2007, 61(30): 5223-5226.
  14. 14. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically-5thed. Approved Standard M7-A5. USA: NCCLS 2000.
  15. 15. 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.
  16. 16. Smeltzer MS, Thomas JR, Hickmon SG, et al. Characterization of a rabbit model of staphylococcal osteomyelitis. J Orthop Res, 1997, 15(3): 414-421.
  17. 17. Xie Z, Liu X, Jia W, et al. Treatment of osteomyelitis and repair of bone defect by degradable bioactive borate glass releasing vancomycin. J Control Release, 2009, 139(2): 118-126.
  18. 18. 張欣, 賈偉濤, 顧刈非, 等. 載替考拉寧治療骨髓炎癥的硼酸鹽生物玻璃藥物載體的研究. 無機(jī)材料學(xué)報(bào), 2010, 25(3): 1303-1309.
  19. 19. Lee SH, Lee JE, Baek WY, et al. Regional delivery of vancomycin using pluronic F-127 to inhibit methicillin resisitant Staphylococcus aureus (MRSA) growth in chronic otitis media in vitro and in vivo. J Control Release, 2004, 96(1): 1-7.
  20. 20. Edin ML, Miclau T, Lester GE, et al. Effect of cefazolinand vancomycin on osteoblasts in vitro. Clin Orthop Relat Res, 1996, (333): 245-251.
  21. 21. Antoci V Jr, Adams CS, Hickok NJ, et al. Antibiotics for local delivery systems cause skeletal cell toxicity in vitro. Clin Orthop Relat Res, 2007, (462): 200-206.
  22. 22. Ducheyne P. Bioceramics: material characteristics versus in vivo behavior. J Biomed Mater Res, 1987, 21(A2 Suppl): 219-236.
  23. 23. Clark AE, Hench LL, Paschall HA. The influence of surface chemistry on implant interface histology: a theoretical basis for implant materials selection. J Biomed Mater Res, 1976, 10(2): 161-174.
  24. 24. 刑小茹, 魏復(fù)盛, 吳國平. 人體硼暴露及其代謝的研究進(jìn)展. 安全與環(huán)境學(xué)報(bào), 2006, 6 (1): 131-135.