可塑性纳米-羟基磷灰石/聚β-羟基丁酸与戊酸酯-聚乙二醇-庆大霉素药物释放系统的生物相容性及安全性（英文）

Biocompatibility and security of the plastic nano-hydroxyapatite/poly(beta-hydroxybutyrateco-beta-hydroxyvalerate)-polyethylene glycolgentamicin drug delivery system

背景:庆大霉素珠链释药系统应用于临床以来,其被认为是治疗骨髓炎的有效方法;但其存在不能降解、需二次手术取出,滋生病原菌等缺点,故可生物降解的释药系统成为当前热点。以纳米技术构建的羟基磷灰石/聚β-羟基丁酸与戊酸酯-聚乙二醇-庆大霉素局部药物缓释系统可能解决当前应用的困境。目的:评价可塑性骨修复重建和释药材料纳米羟基磷灰石/聚β-羟基丁酸与戊酸酯-聚乙二醇-庆大霉素局部药物缓释系统植入动物体内后可能引发的急、慢性全身、局部组织、皮内刺激及其细胞毒性和溶血反应,为骨髓炎的治疗寻找一种新的材料。方法:以具良好可塑性能纤维蛋白胶为微球支架,纳米羟基磷灰石为载药核心,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可塑性纳米羟基磷灰石/聚β-羟基丁酸与戊酸酯-聚乙二醇-庆大霉素释药系统。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试验,对其进行急性全身毒性试验、植入试验、亚急性及慢性全身毒性试验、溶血试验、细胞毒性试验、皮内刺激试验。结果与结论:1可塑性纳米-羟基磷灰石/聚β-羟基丁酸与戊酸酯-聚乙二醇-庆大霉素药物释放系统无毒性,材料埋置动物体内后未引起明显血生化指标及肝肾功能变化,病理组织切片示材料周围的包裹组织,其炎性变化符合一般的炎症变化转归规律。2植入体内后材料发生降解并被骨组织取代。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材料与人体骨髓细胞体外培养见细胞形态良好,细胞增殖正常。5动物背部皮内注射材料浸提液后按标准刺激反应判为无刺激。6说明可塑性纳米-羟基磷灰石/聚β-羟基丁酸与戊酸酯-聚乙二醇-庆大霉素药物释放系统具有良好的生物相容性及生物安全性。

BACKGROUND： Gentamicin bead chain is an effective drug delivery system for treatment of osteomyelitis, but it cannot be degraded, need to be removed by second operation, and can breed pathogens. As a result, biodegradable drug delivery systems become a hotspot. Nanohydroxyapatite/poly（β-hydroxybutyrate-co-β-hydroxyvalerate）-polyethylene glycol-gentamicin（nano-HA/PHBV-PEG-GM-DDS） is considered to be a good choice for the current predicament. OBJECTIVE： To evaluate the acute or chronic toxic reactions of the whole body and local tissues, intracutaneous stimulation, cytotoxicity and hemolytic reactions after bone remodeling and implantation of nano-HA/PHBV-PEG-GM-DDS, thus providing a new kind of material for treating osteomyelitis. METHODS： Plastic nano-HA/PHBV-PEG-GM-DDS was prepared using plastic fibrin glue as microsphere scaffold and nano-HA as the core carrier of GM that was coated with PHBV and PEG. The acute, subacute/chronic toxicity, implantation, hemolysis, cytotoxicity and intracutaneous stimulation tests were performed according to the evaluated criteria of medical implanted materials as well as biological and animal trials recommended in GB/T16886.1-1997. RESULTS AND CONCLUSION： The plastic nano-HA/PHBV-PEG-GM-DDS was nontoxic and caused no apparent changes in liver and kidney function and serum biochemical indexes. Pathological examination showed that the implanted material was covered with tissues, and inflammation changes accorded with the general regularity of inflammatory outcomes. After implantation, the nano-HA/PHBV-PEG-GM-DDS was biodegraded and replaced by osseous tissues. The hemolytic rate of the material extract to the composite diffusion solution was 1.2%, which was below the standard criteria（5%）. Human bone marrow cells cultured in vitro with the plastic nano-HA/PHBV-PEG-GM-DDS grew normally with good morphology. There was no stimulation reaction according to the criteria after the diffusion solution was subcutaneously injected into the back of the animal. These findings indicate that the plastic nano-HA/PHBV-PEG-GM-DDS for treating osteomyelitis possesses excellent biocompatibility and security.