美罗培南骨水泥体外生物力学及洗脱特性研究

doi:10.3877/cma.j.issn.1674-134X.2021.01.011

目的

研究不同含量的美罗培南骨水泥的体外生物力学特性和药物洗脱特性。

方法

40 g骨水泥(Palacos LV，40 g聚合物粉剂+20 ml单体液剂)中分别加入2、4、6 g注射用美罗培南和2、4 g注射用盐酸万古霉素复合，制备成A2、A4、A6、B2、B4和不含抗菌药物的对照组共6组样品。对6组样品分别进行能承受的最大压力和剪切力载荷测试，并计算耐压强度、压缩模量。采用高效液相色谱法(HPLC)对美罗培南标准品溶液和美罗培南骨水泥洗脱液进行检测，绘制美罗培南色谱图及标准线性回归方程；检测A4组美罗培南骨水泥在37 ℃恒温条件下浸渍24、48、72 h和6、12、24 d后洗脱液药物浓度，并绘制时间-药物浓度曲线。采用方差分析对样品最大压力载荷、最大剪切力载荷、耐压强度和压缩模量进行比较；采用线性相关与回归分析获得标准线性回归方程。

结果

和对照组比较，A2、A6组样品能承受的最大压力载荷和耐压强度相似(P> 0.05)；A4组能承受的最大压力载荷和耐压强度高于对照组(t ＝4.41、4.41，均为P< 0.01)；B2、B4组能承受的最大压力载荷(t ＝9.01、9.01，均为P <0.01)和耐压强度低于对照组(t ＝12.26、12.26，均为P <0.01)；且B4组低于B2组，差异均有统计学意义(t ＝4.01、4.01，均为P <0.01)。A2、A4、A6、对照组样品压缩模量和能承受的最大剪切载荷组间比较，差异无统计学意义(P > 0.05)。B2、B4组压缩模量低于对照组(t＝4.85、8.15，均为P<0.01)，且B4组低于B2组，差异有统计学意义(t＝4.73，P <0.05)。B2、B4组能承受的最大剪切载荷相似(P> 0.05)，但都低于对照组(t＝5.84、5.05，均为P< 0.01)。美罗培南标准品溶液的标准线性回归方程(y ＝15.0265x＋13.5218，R＝1.00)。A4组样品，在37 ℃恒温条件下浸渍24、48、72 h和6、12、24 d后，洗脱液中的美罗培南药物浓度分别为60.05、9.99、4.3、4.05、1.96、0.62 μg/ml。

结论

40 g Palacos LV骨水泥中加入最多6 g美罗培南时，不降低骨水泥的力学特性，同时优于相同含量万古霉素骨水泥的力学特性。10%含量的美罗培南骨水泥在37 ℃恒温条件下能持续释放美罗培南达24 d。

关键词: 美罗培南, 万古霉素, 骨粘合剂, 动力学, 生物力学现象

Objective

To summarize the biomechanical effects and elution of meropenem-loaded bone cement with the different contents.

Methods

Forty grams of Palacos LV bone cement was respectively added two, four, six grams meropenem, or two and four grams vancomycin or no antibiotic and prepared into a total of six groups cylindrical samples of A2, A4, A6, B2, B4 and control group (antibiotic-free). The maximum compression and shear tests were performed on each group of samples, and the compressive strength and compressive modulus were calculated. The standard curve of meropenem was draw and the regression equation was calculated. At a constant temperature of 37 ℃, meropenem-loaded bone cement cylinders (A4) were serially immersed in saline solution. The eluent was collected at predetermined time points of 24, 48, 72 h and six, 12, 24 d. The drug concentration of eluent was measured by high performance liquid chromatography and the elution kinetics was studied. The analysis of variance (ANOVA) method was used to compare the overall difference of the maximum compression loads, maximum shear loads, compressive strength and compressive modulus between groups. Linear correlation and regression analysis were used to obtain the standard regression equation of meropenem.

Results

Six groups of samples, A2, A4, A6, B2, B4 and the control group, were successfully made. The maximum compression loads and compressive strengths of group A2, A6 and the control group were similar (P>0.05). The maximum compression load and compressive strength of group A4 were higher than those of control group (t=4.41, 4.41, both P<0.01). The parameters of group B2 and B4 were lower than those of the control group(maximum compression load : t=9.01, 9.01, compressive strength: t=12.26, 12.26, all P<0.05), and those of B4 were lower than those of group B2 (t=4.01, 4.01, both P< 0.05). There were no significant differences in compressive modulus and maximum shear loads between groups A2, A4, A6 and the control group (P >0.05). The compressive modulus of group B2 and B4 were lower than that of control group (t=4.85, 8.15, both P <0.05), and that of B4 was lower than that of group B2(t=4.73, P <0.05). The maximum shear loads of B2 and B4 groups were similar, but lower than that of control group (t=5.84, 5.05, both P <0.05). The regression equation of meropenem was(y=15.0265x + 13.5218, R=1.00). At the time points of 24, 48, 72 h and six, 12, 24 d, the drug concentration of eluent were 60.05, 9.99, 4.3, 4.05, 1.96 μg/ml and 0.62 μg/ml respectively.

Conclusions

When 40 g Palacos LV bone cement is added no more than 6 g meropenem, the biomechanical effects will not be reduced, and they are superior to vancomycin-loaded bone cement with the same contents. At a constant temperature of 37 ℃, meropenem can be released from bone cement for up to 24 d.

Key words: Meropenem, Vancomycin, Bone cements, Kinetics, Biomechanical phenomena

图1 抗生素骨水泥样品的制备。图A为游标卡尺测量抗生素骨水泥样品的直径；图B为游标卡尺测量抗生素骨水泥样品的长度

图2 抗生素骨水泥样品的制备。图A为40 g骨水泥(Palacos LV 40 g聚合物粉剂＋20 ml单体液剂)中加入2 g美罗培南，复合物呈稀糊状；图B为40 g骨水泥(Palacos LV 40 g聚合物粉剂＋20 ml单体液剂)中加入6 g美罗培南，复合物呈面糊状；图C为40 g骨水泥(Palacos LV 40 g聚合物粉剂＋20 ml单体液剂)中加入4 g万古霉素，复合物呈湿粉状

表1 6组不同浓度样品的最大压力载荷和最大剪切力载荷比较(±s)

组别	样本数	最大压力载荷(KN)	耐压强度(MPa)	压缩模量(MPa)	最大剪切载荷(KN)
A2组	6	10.98±0.41^ab	97.05±3.62^ab	1415.21±125.03^ab	2.89±0.02^ab
A4组	6	11.41±0.08^cdef	100.86±0.67^cdef	1413.28±139.05^de	2.90±0.02^de
A6组	6	10.64±0.36^cgh	94.11±3.18^cgh	1416.15±137.65^gh	2.67±0.03^gh
B2组	6	7.78±0.55^adgij	68.78±4.89^adgij	1107.06±88.32^adgij	1.54±0.09^adgj
B4组	6	6.36±0.66^behik	56.26±5.88^behik	801.17±133.20^behik	1.64±0.11^behk
对照组	6	10.51±0.49^fjk	92.90±4.37^fjk	1402.74±122.37^jk	2.69±0.18^jk
F值		114.51	116.05	24.88	44.22
P值		<0.01	<0.01	<0.01	<0.01

表1 6组不同浓度样品的最大压力载荷和最大剪切力载荷比较(±s)

组别	样本数	最大压力载荷(KN)	耐压强度(MPa)	压缩模量(MPa)	最大剪切载荷(KN)
A2组	6	10.98±0.41^ab	97.05±3.62^ab	1415.21±125.03^ab	2.89±0.02^ab
A4组	6	11.41±0.08^cdef	100.86±0.67^cdef	1413.28±139.05^de	2.90±0.02^de
A6组	6	10.64±0.36^cgh	94.11±3.18^cgh	1416.15±137.65^gh	2.67±0.03^gh
B2组	6	7.78±0.55^adgij	68.78±4.89^adgij	1107.06±88.32^adgij	1.54±0.09^adgj
B4组	6	6.36±0.66^behik	56.26±5.88^behik	801.17±133.20^behik	1.64±0.11^behk
对照组	6	10.51±0.49^fjk	92.90±4.37^fjk	1402.74±122.37^jk	2.69±0.18^jk
F值		114.51	116.05	24.88	44.22
P值		<0.01	<0.01	<0.01	<0.01

图3 空白骨水泥洗脱液、美罗培南标准品储备液和美罗培南骨水泥洗脱液色谱图。图A为空白骨水泥对照组洗脱液；图B为874.7850 μg/ml浓度的美罗培南标准品储备液；图C为A4组美罗培南骨水泥样品37.0 ℃恒温条件下浸渍12 d洗脱液

图4 美罗培南骨水泥洗脱液的时间-药物浓度曲线

[1]	Mandell JB, Orr S, Koch J, et al. Large variations in clinical antibiotic activity against staphylococcus aureus biofilms of periprosthetic joint infection isolates[J]. J Orthop Res, 2019, 37(7): 1604-1609.
[2]	Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections[J]. Science, 1999, 284(5418): 1318-1322.
[3]	Konrads C, Franz A, Hoberg M, et al. Similar outcomes of two-stage revisions for infection and one-stage revisions for aseptic revisions of knee endoprostheses[J]. J Knee Surg, 2019, 32(9): 897-899.
[4]	Akhtar A, Mitchell C, Assis C, et al. Cement pedestal spacer technique for infected two-stage revision knee arthroplasty: description and comparison of complications[J]. Indian J Orthop, 2019, 53(6): 695-699.
[5]	Biring GS, Kostamo T, Garbuz DS, et al. Two-stage revision arthroplasty of the hip for infection using an interim articulated Prostalac hip spacer: a 10- to 15-year follow-up study[J]. J Bone Joint Surg Br, 2009, 91(11): 1431-1437.
[6]	Dufour S, Piroth L, Chirouze C, et al. Staphylococcus aureus bloodstream infection in patients with prosthetic joints in the prospective VIRSTA cohort study: frequency and time of occurrence of periprosthetic joint infection[J/OL]. Open Forum Infect Dis, 2019, 6(12): ofz515. doi: 10.1093/ofid/ofz515.
[7]	Fagotti L, Tatka J, Salles M, et al. Risk factors and treatment options for failure of a two-stage exchange[J]. Curr Rev Musculoskelet Med, 2018, 11(3): 420-427.
[8]	Fantoni M, Borrè S, Rostagno R, et al. Epidemiological and clinical features of prosthetic joint infections caused by gram-negative bacteria [J]. Eur Rev Med Pharmacol Sci, 2019, 23(2 Suppl): 187-194.
[9]	Kierzkowska M, Pedzisz P, Babiak I, et al. Orthopedic infections caused by obligatory anaerobic gram-negative rods: report of two cases[J]. Med Microbiol Immunol, 2017, 206(5): 363-366.
[10]	Zafar Y, Elkafrawy AA, Nahar J, et al. Acalculous cholecystitis presenting as a septic joint: a case report[J/OL]. Cureus, 2019, 11(7): e5193.doi: 10.7759/cureus.5193.
[11]	Boelch SP, Rueckl K, Fuchs C, et al. Comparison of elution characteristics and compressive strength of bi-antibiotic-loaded PMMA bone cement for spacers: copal® spacem with gentamicin and vancomycin versus palacos® R＋G with vancomycin[J/OL]. Biomed Res Int, 2018, 2018: 4323518. doi: 10.1155/2018/4323518.
[12]	Al-Tawfiq JA, Rabaan AA, Saunar JV, et al. Antimicrobial resistance of gram-negative bacteria: a six-year longitudinal study in a hospital in Saudi Arabia[J]. J Infect Public Health, 2020, 13(5): 737-745.
[13]	Chinowaita F, Chaka W, Nyazika TK, et al. Sepsis in cancer patients residing in Zimbabwe: spectrum of bacterial and fungal aetiologies and their antimicrobial susceptibility patterns[J/OL]. BMC Infect Dis, 2020, 20(1): 161. doi: 10.1186/s12879-020-4886-2.
[14]	Mendez AS, Dalomo J, Steppe M, et al. Stability and degradation kinetics of meropenem in powder for injection and reconstituted sample[J]. J Pharm Biomed Anal, 2006, 41(4): 1363-1366.
[15]	An, Ogbuagu VI, Ejikeugwu CP, et al. Multi-antibiotic resistance and factors affecting carriage of extended spectrum β-lactamase-producing enterobacteriaceae in pediatric population of Enugu Metropolis, Nigeria[J/OL]. Med Sci (Basel), 2019, 7(11): 104. doi: 10.3390/medsci7110104.
[16]	Baleani M, Persson C, Zolezzi C, et al. Biological and biomechanical effects of vancomycin and meropenem in acrylic bone cement[J]. J Arthroplasty, 2008, 23(8): 1232-1238.
[17]	Samuel S, Mathew BS, Veeraraghavan B, et al. In vitro study of elution kinetics and bio-activity of meropenem-loaded acrylic bone cement[J]. J Orthop Traumatol, 2012, 13(3): 131-136.
[18]	Andollina A, Bertoni G, Bertoni F, et al. Vancomycin and meropenem in acrylic cement: elution kinetics of in vitro bactericidal action[J]. Chir Organi Mov, 2008, 91(3): 153-158.
[19]	Chen AF, Parvizi J. Antibiotic-loaded bone cement and periprosthetic joint infection[J]. J Long Term Eff Med Implants, 2014, 24(2/3): 89-97.
[20]	Hinarejos P, Guirro P, Puig-Verdie L, et al. Use of antibiotic-loaded cement in total knee arthroplasty[J]. World J Orthop, 2015, 6(11): 877-885.
[21]	Sukur E, Akar A, Topcu HN, et al. The effect of N-acetylcysteine on mechanical fatigue resistance of antibiotic-loaded bone cement[J/OL]. J Orthop Surg Res, 2018, 13(1): 132. doi: 10.1186/s13018-018-0843-9.
[22]	Aimiya K, Mamiya T, Tabuchi K, et al. Comparison of twice a day and three times a day meropenem administration in elderly patients in a Japanese community hospital[J]. Nagoya J Med Sci, 2018, 80(3): 391-400.
[23]	Decousser JW, Woerther PL, Soussy CJ, et al. The tigecycline evaluation and surveillance trial; assessment of the activity of tigecycline and other selected antibiotics against gram-positive and gram-negative pathogens from France collected between 2004 and 2016[J/OL]. Antimicrob Resist Infect Control, 2018, 7: 68. doi: 10.1186/s13756-018-0360-y.
[24]	Jiménez A, Sánchez A, Rey A, et al. Recovery of aerobic and anaerobic bacteria from patients with acute appendicitis using blood culture bottles[J]. Biomedica, 2019, 39(4): 699-706.
[25]	Persson C, Baleani M, Guandalini L, et al. Mechanical effects of the use of vancomycin and meropenem in acrylic bone cement[J]. Acta Orthop, 2006, 77(4): 617-621.
[26]	Li T, Fu L, Wang J, et al. High dose of vancomycin plus gentamicin incorporated acrylic bone cement decreased the elution of vancomycin[J]. Infect Drug Resist, 2019, 12: 2191-2199.
[27]	Paz E, Sanz-Ruiz P, Abenojar J, et al. Evaluation of elution and mechanical properties of high-dose antibiotic-loaded bone cement: comparative " in vitro" study of the influence of vancomycin and cefazolin[J]. J Arthroplasty, 2015, 30(8): 1423-1429.
[28]	Bishop AR, Kim S, Squire MW, et al. Vancomycin elution, activity and impact on mechanical properties when added to orthopedic bone cement[J/OL]. J Mech Behav Biomed Mater, 2018, 87: 80-86. doi: 10.1016/j.jmbbm.2018.06.033.
[29]	Gálvez-López R, Peña-Monje A, Antelo-Lorenzo R, et al. Elution kinetics, antimicrobial activity, and mechanical properties of 11 different antibiotic loaded acrylic bone cement[J]. Diagn Microbiol Infect Dis, 2014, 78(1): 70-74.
[30]	Yang C, Wang J, Yin Z, et al. A sophisticated antibiotic-loading protocol in articulating cement spacers for the treatment of prosthetic joint infection: a retrospective cohort study[J]. Bone Joint Res, 2019, 8(11): 526-534.

[1]	高小康, 张净宇, 刘金伟, 田东牧, 胡永成, 徐卫国. 连接型人工膝关节假体运动和负重模式的演变和进展[J/OL]. 中华关节外科杂志(电子版), 2024, 18(04): 505-516.
[2]	蒋政, 郑楠, 毛彦杰, 何阿祥, 林蔚铭, 郭瀚, 刘语嫣, 臧慧, 王聪, 刘万军. 关于胫骨高位截骨术后髌股关节变化的研究进展[J/OL]. 中华关节外科杂志(电子版), 2024, 18(03): 398-404.
[3]	杜伟, 廖土明, 李雄才, 关刚强, 何燊, 吴佳桥, 朱和荣. 2%利多卡因凝胶和润滑剂凝胶在女性尿流动力学检查中应用的随机对照研究[J/OL]. 中华腔镜泌尿外科杂志(电子版), 2024, 18(06): 613-617.
[4]	丁荷蓓, 王珣, 陈为国. 七氟烷吸入麻醉与异丙酚静脉麻醉在儿童腹股沟斜疝手术中的应用比较[J/OL]. 中华疝和腹壁外科杂志(电子版), 2024, 18(05): 570-574.
[5]	李先锋, 何懿, 程贞永, 邓国魁, 胡波, 谢红, 王莉, 王小燕, 李晓明. 右美托咪定对腹腔镜腹股沟疝修补术患者血流动力学及麻醉复苏效果的影响[J/OL]. 中华疝和腹壁外科杂志(电子版), 2024, 18(04): 437-441.
[6]	彭敏敏, 杨晓斌, 芮亚楠. 羟考酮复合舒芬太尼在腹腔镜疝修补术中的应用[J/OL]. 中华疝和腹壁外科杂志(电子版), 2024, 18(02): 218-222.
[7]	郭建丽, 珠娜, 宋飞, 柴国东. 七氟烷吸入复合瑞芬太尼麻醉在小儿腹腔镜疝修补术中的效果[J/OL]. 中华疝和腹壁外科杂志(电子版), 2024, 18(02): 223-227.
[8]	罗霞, 王宝梅, 李淑景, 杨英. 特发性肺动脉高压血清PCSK9表达及预后意义[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(04): 585-589.
[9]	潘忠军, 戎国祥, 丁明, 殷优宏, 张双龙. 非气管插管麻醉下单孔胸腔镜手术对肺结节及血流动力学、炎性指标的影响[J/OL]. 中华肺部疾病杂志(电子版), 2024, 17(02): 272-275.
[10]	赵天瑶, 孙英娟, 江晓丹, 李学民. 重视聚维酮碘在白内障手术中的应用与研究[J/OL]. 中华眼科医学杂志(电子版), 2024, 14(02): 65-70.
[11]	王守森, 傅世龙, 鲜亮, 林珑. 深入理解控制性减压技术对创伤性颅脑损伤术中脑膨出的预防机制与效果[J/OL]. 中华神经创伤外科电子杂志, 2024, 10(05): 257-262.
[12]	谢浩文, 丁建英, 刘小霞, 冯毅, 姚婧. 椎旁神经阻滞对微创胃切除肥胖患者术中血流、术后应激及康复质量的影响[J/OL]. 中华消化病与影像杂志(电子版), 2024, 14(06): 569-573.
[13]	于伟伟, 张国高, 吴军, 胡俊, 黄一宁, 徐晶. 线粒体相关内质网膜相关线粒体功能障碍在阿尔茨海默病中的研究进展[J/OL]. 中华临床医师杂志(电子版), 2024, 18(02): 223-230.
[14]	刘聪辉, 何浩然, 黄一诺, 张凤, 王凡月, 郝翰. 膳食铜补充对大鼠心肌梗死后心肌基质金属蛋白酶2表达水平及血流动力学的影响[J/OL]. 中华诊断学电子杂志, 2024, 12(03): 166-172.
[15]	芦乙滨, 李梦蝶, 许明. PDCA（计划、执行、检查和处理）循环教学在内科住院医师重症超声指导血流动力学评估培训中的效果评价[J/OL]. 中华卫生应急电子杂志, 2024, 10(04): 224-228.

阅读次数

全文

摘要

选择文件类型/文献管理软件名称

选择包含的内容

In vitro biomechanical effects and elution of meropenem-loaded bone cement

模态框（Modal）标题

选择文件类型/文献管理软件名称

选择包含的内容

In vitro biomechanical effects and elution of meropenem-loaded bone cement