摘要
目的:观察可塑性骨修复重建和释药材料纳米羟基磷灰灰石/羟基丁聚酸酯-羟基戊酸酯共聚物-聚乙二醇庆大霉素局部释药系统植入动物体内后可能引发的急、慢性全身毒性反应、对动物机体局部组织的影响、皮内刺激反应的程度及其细胞毒性和溶血反应,评价其生物安全性和生物相容性。方法:实验于2004-10/2005-04全部实验在南方医科大学珠江医院中心实验室完成。选取新西兰大白兔42只,KM小鼠20只,将可塑性纳米羟基磷灰灰石/聚羟基丁酸酯-羟基戊酸酯共聚物-聚乙二醇庆大霉素释药系统植入动物肌和骨内及动物腹腔注射材料浸提液。可塑性纳米羟基磷灰灰石/羟基丁酸酯-羟基戊酸酯共聚物-聚乙二醇庆大霉素聚释药系统以具良好可塑性能纤维蛋白胶为微球支架,纳米羟基磷灰灰石为载药核心,外包裹生物相容性好且降解可调控的聚羟基丁酸酯-羟基戊酸酯共聚物及聚乙二醇,承载硫酸庆大霉素制成。按照GB/T16886.1-1997医用植入材料评价标准和所推荐的生物学和动物实验,对其进行急性全身毒性实验、植入实验、亚急性及慢性全身毒性实验、溶血实验、细胞毒性实验、皮内刺激实验。结果:入选兔42只,鼠20只,全部进入结果分析。①注射可塑性纳米羟基磷灰灰石/羟基丁酸酯-羟基戊酸酯共聚物-聚乙二醇庆大霉素聚释药系统浸提液后,在规定的72h观察期内,小鼠实验与对照组体质量均呈上升趋势,且两组体质量增加各时间段比较差异无显著性意义(0.20±0.05,0.19±0.050.35±0.07,0.36±0.06;0.52±0.09,0.54±0.10t=0.46,;;0.23,0.54,P>0.05)②材料埋置动物体内后,植入局部皮肤未见过敏、。感染及液化坏死征象;未引起明显肝肾功能变化,丙氨酸氨基转移酶、天门冬氨酸氨基转移酶、尿素氮、肌酐含量实验组与对照组无显著性差异(丙氨酸氨基转移酶:t=0.775,1.230,0.169,0.650,P>0.05;天门冬氨酸氨基转移酶:t=0.081,0.316,0.104,0.326,P>0.05;尿素氮:t=0.617,0.840,1.517,0.341,P>0.05;肌酐:t=0.749,0.335,0.614,0.806,P>0.05),且实验组内各时相点两两比较差异无显著性(丙氨酸氨基转移酶:F=0.347,P>0.05;天门冬氨酸氨基转移酶:F=0.144,P>0.05尿素氮:;F=0.784,P>0.05;肌酐:F=0.467,P>0.05);病理组织切片示材料周围的组织,其炎性变化符合一般的炎症变化转归规律。③材料浸提液与血液混溶的溶血率为1.2%,低于标准规定的5%。④骨髓基质细胞与材料复合培养组体外培养见细胞形态良好,细胞增值率与对照组无显著性差异(t=1.584,0.540,0.529,P>0.05)⑤动物背部皮内注射材料浸提液后。均未出现红斑、水肿和坏死,皮肤反应程度得分为0分。结论:可塑性纳米羟基磷灰灰石/羟基丁酸酯-羟基戊酸酯共聚物-聚聚乙二醇庆大霉素释药系统具有良好的生物相容性及生物安全性。
AIM： To study the acute or chronic toxic reaction on the whole body induced by the plastic nano-HA/PHBV-PEG gentamicin drug delivery system （nano-HA/PHBV-PEG-GM-DDS） for bone reconstruction and drug delivery after implanting in vivo and its effect on partial constitution of animal organs, and investigate its degree of subcuticular stimulation reaction, cytotoxicity and hemolysis reaction, evaluating its biocompatibility and safety. METHODS： The experiment was performed in the Central Laboratory, Zhujiang Hospital affiliated to Southern Medical University from October 2004 to April 2005. Forty-two New Zealand white rabbits and 20 KM mice were included. Plastic nano-HA/PHBV-PEG-GM-DDS was implanted into the rabbits＇muscles and bones, and its leaching liquor was injected into KM mice abdominal cavity. Plastic nano-HA/PHBV-PEG-GM-DDS were prepared using nano-hydroxyapatite ＇（nano-HA） as the core cartier of gentamicin （GM）, then coating nano-HA with poly（3-hydroxybutyrate- hydroxyvalerate） （PHBV） and polyethylene glycol （PEG） and then using plastic fibrin glue （FG） as the microsphere scaffold. The experiments on acute toxicity, subacute and chronic toxicity, hemolysis, cytotoxic and intracutaneous stimulation were administered according to the evaluated criteria of medical implanted materials, biology and animal trial recommended in GB/T16886.1-1997. RESULTS： All the 42 rabbits and 20 KM mice entered the result analysis. ①Within 72 hours after injection with the leaching liquor, the body mass KM mice in the test group and the control group assumed rising tendency and body mass increasing in the test group was not significantly different from that in the control group （0.20±0.05, 0.19±0,05; 0.35±＋0.07, 0.36±0.06; 0.52±0.09, 0.54±0.10; t=0.46, 0.23, 0.54, P 〉 0.05）. ②The phenomena of the allergy, infection, liquefaction and necrosis were not discovered on local rabbits skin after the materials was implanted in vivo. There were no obvious changes in the function of liver and kidney. The contents of alanine transferase, aspartic acid transferase, blood uria nitrogen and creatinine had no significant differences between the test group and the control group （alanine transferase： t=0.775,1.230, 0.169, 0.650, P 〉 0.05; aspartic acid transferase： t=0.081, 0.316, 0.104, 0.326, P 〉0.05; blood urianitrogen： t=0.617, 0.840, 1.517, 0.341, P〉0.05; creatinine： t=0.749, 0.335, 0.614, 0.806, P 〉 0.05）, and there was no significant difference between each other group in the test group at different points （alanine transferase： F=0.347, P 〉 0.05; aspartic acid transferase： F=0.144, P 〉 0.05; blood uria nitrogen： F=0.784, P 〉 0.05; creatinine： F=0.467, P 〉 0.05）. Pathologic tissue section showed that the peripheral packed tissue of materials and inflammation change accorded with the general regularity of inflammatory outcome. ③The rate of haemolysis to the leaching liquor was 1.2%, which was lower than the standard criteria （5%）. ④ The morphological characters of the bone marrow stramal cell were very well cultured in the mixture of cells and the materials. The cell proliferation rate was not significantly different from that in the control group （t=1.584, 0.540, 0.529, P 〉 0.05）. ⑤There were no erythema, edema and necrosis after the leaching liquor was injected into the back of animal, and electrodermal response degree was 0 score. CONCLUSION： Plastic nano-HA/PHBV-PEG-GM-DDS possesses excellent biocompatibility and safety.
出处
《中国临床康复》
CAS
CSCD
北大核心
2006年第1期57-60,i0003,共5页
Chinese Journal of Clinical Rehabilitation
