组织诱导性材料生物安全性评价研究策略与实践
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摘要
背景:组织诱导性生物材料种类复杂多样,评价标准缺乏及评价标准存在不足使得开展生物安全性评价是一个热点问题,也是一个难点问题。上述问题的存在导致生产商在开展组织诱导性医疗器械生物安全性试验研究时存在困惑。目的:在从事生物安全性实验评价的基础上,对研发阶段的材料样品应遵循的安全性评价策略,对拟上市注册的产品生物学实验项目的选择提供一些思路和借鉴。方法:对2016年度组织诱导性材料开展生物学实验项目进行了统计分析。统计结果表明,细胞毒性、刺激、致敏实验是开展最多的3大基本实验,同时仅选择刺激、致敏、细胞毒3个实验的样品有58种81批次。在文章中,其中17种材料开展了免疫毒性研究,部分样品还选择了生物降解实验。结果与结论:通过分析表明,在产品的研发及临床前评价阶段,可采取不同的实验方案或者评价策略。在研发初期,可用细胞毒性、刺激、致敏实验进行筛查;在研发后期,选择满足安全性评价要求的非常规实验,如亚慢性毒性、降解、免疫毒性等实验。
BACKGROUND: Due to the complexity of tissue induced biomaterials, the current biosafety evaluation standard is not available. For years, to choose an effective evaluation strategy and practice in tissue induced materials has been always a hot topic, but still with no conclusion. The existence of this problem results in numerous issues for manufactures when conducting the biosafety evaluation of tissue induced medical devices. OBJECTIVE: To formulate the biosafety evaluation strategy that should be followed by the material samples at the research and development stage and to provides some ideas and lessons for the selection of the product biology experimental items to be listed and registered. METHODS: In 2016, a statistical analysis was carried out for biological test items of tissue induced biomaterials. Cytotoxicity, irritation and sensitization tests were the most commonly used tests for biomaterials and medical devices. A biosafety evaluation only via the above three tests had been applied in 58 kinds of materials with 81 batches of samples. In this study, immune toxicity tests were performed in 17 kinds of materials and biodegradation tests were done in some samples. RESULTS AND CONCLUSION: It had been found that different test programs or evaluation strategies may be adopted in the product development or listing registration stage. At early stage of development, cytotoxicity, irritation and sensitization tests are suitable for sample screening. In the later stage of research and development, more in-depth tests, such as subchronic toxicity, degradation and immunity toxicity, should be employed to meet the safety evaluation requirements.
BACKGROUND: Due to the complexity of tissue induced biomaterials, the current biosafety evaluation standard is not available. For years, to choose an effective evaluation strategy and practice in tissue induced materials has been always a hot topic, but still with no conclusion. The existence of this problem results in numerous issues for manufactures when conducting the biosafety evaluation of tissue induced medical devices. OBJECTIVE: To formulate the biosafety evaluation strategy that should be followed by the material samples at the research and development stage and to provides some ideas and lessons for the selection of the product biology experimental items to be listed and registered. METHODS: In 2016, a statistical analysis was carried out for biological test items of tissue induced biomaterials. Cytotoxicity, irritation and sensitization tests were the most commonly used tests for biomaterials and medical devices. A biosafety evaluation only via the above three tests had been applied in 58 kinds of materials with 81 batches of samples. In this study, immune toxicity tests were performed in 17 kinds of materials and biodegradation tests were done in some samples. RESULTS AND CONCLUSION: It had been found that different test programs or evaluation strategies may be adopted in the product development or listing registration stage. At early stage of development, cytotoxicity, irritation and sensitization tests are suitable for sample screening. In the later stage of research and development, more in-depth tests, such as subchronic toxicity, degradation and immunity toxicity, should be employed to meet the safety evaluation requirements.
引文
[1]宋晓航.生物材料的研究[J].中国高新区,2018,8(3):48.
[2]奚廷斐.我国生物医用材料现状和发展趋势[J].中国医疗器械信息,2013,12(8):1-5.
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[4]段平国,郭润生,余兴元,等.单一生物材料聚乳酸/羟基乙酸共聚物构建组织工程骨软骨的可行性[J].中国组织工程研究,2017,21(34):5423-5429.
[5]熊天铖.生物材料在牙再生领域中的应用与未来[J].好家长,2017,17(63):171.
[6]李明政,肖宇,吴珍珍,等.巨噬细胞在材料诱导成骨中作用的研究进展[J].口腔医学研究,2017,33(10):1123-1126.
[7]蔡高锐,刘威,何勇,等.纳米生物材料在骨组织工程中的应用[J].国际骨科学杂志,2017,38(5):303-306.
[8]郑力恒,吴昊,尚玉攀,等.组织工程支架材料性质对干细胞分化的影响[J].中国组织工程研究,2017,21(14):2274-2279.
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[10]顾忠伟.生物医用材料组织诱导作用的分子机制与设计原理取得重大突破[J].近代技术与市场,2017,24(3):1.
[11]冯刚.生物材料和再生医学的进展[J].现代经济信息,2017,38(17):377-379.
[12]付裕.组织工程相关生物材料[J].农家参谋,2017,35(16):134.
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[14]戴建武.引导组织再生智能生物材料的转化研究[J].生命科学,2016,28(8):907-914.
[15]许文燕,马树宝,徐晶,等.北京地区生物材料进口审批监管现状及风险管理探讨[J].检验检疫学刊,2017,27(6):48-51.
[16]蒋菡.新一轮进境生物材料监管改革启动[N].工人日报,2017-11-01(004).
[17]国家食品药品监督管理总局.总局关于发布动物源性医疗器械注册技术审查指导原则(2017年修订版)的通告(2017年第224号)[EB/OL].http://www.sda.gov.cn/WS01/CL0050/221700.html.
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[19]GBT16886.10-2005医疗器械生物学评价,第10部分:刺激与迟发型超敏反应试验[S].
[20]丁婷婷,张平,孙皎.生物材料引起机体炎症反应的研究进展[J].国外医学生物医学工程分册,2005,28(1):23-26.
[21]GBT16886.4-2003医疗器械生物学评价,第4部分:与血液相互作用试验选择[S].
[22]10993-4:2002,Biological evaluation of medicaldevices-Part4:Selection of tests for interactions withblood AMENDMENT 1[S].
[23]张明华,郑海燕.抗凝血生物材料的血液相容性[J].中国组织工程研究,2013,17(8):1505-1512.
[24]GB/T 16886.20-2015医疗器械生物学评价,第20部分:医疗器械免疫毒理学试验原则和方法[S].
[25]ISO/TS 10993-20:2006,Biological evaluation of medical devices-Part20:Principles and methods for immunotoxicology testing of medical devices[S].
[26]张蔓,李文,贺学英,等.无源医疗器械材料生物相容性研究进展[J].医疗装备,2016,29(3):46-50.
[27]GB/T16886.1-2011医疗器械生物学评价,第1部分:风险管理过程中的评价与试验[S].
[28]ISO 10993-1:2009,Biological evaluation of medical devices-Part 1:Evaluation and testing within a risk management process[S].
[29]李薇.生物医用金属镁表面酒石酸涂层的构建及其腐蚀降解性能和生物相容性的研究[D].西南交通大学,2017.
[30]朱敏,黄婷,杜晓宇,等.生物材料的3D打印研究进展[J].上海理工大学学报,2017,39(5):473-489.
[31]金嘉长,王扬,马维虎,等.3D生物打印技术在组织工程支架构建与再生中的应用进展[J].航天医学与医学工程,2016,29(6):462-468.
[32]梅昕,马凤森,喻炎,等.高分子可降解生物材料的降解研究进展[J].材料导报,2016,30(S1):298-303.
[33]李君涛,陈周煜.可降解生物医用材料研究现状与展望[J].新材料产业,2016,18(1):32-35.
[34]杨道朋,夏旭.3D打印生物材料研究及其临床应用优势[J].中国组织工程研究,2017,21(18):2927-2933.
[35]管博文,李程程,孟爱民.实验动物替代研究进展[J].生命科学,2017,29(6):546-551.
[36]李云飞.医疗器械化学性能检测的重要性分析[J].化工设计通讯,2017,43(12):169-171.
[37]陈亮,奚廷斐,王春仁.组织工程医疗产品免疫学评价研究[J].组织工程与重建外科杂志,2009,5(1):56-58.
[2]奚廷斐.我国生物医用材料现状和发展趋势[J].中国医疗器械信息,2013,12(8):1-5.
[3]生物谷.生物医用材料国内外产业现状和发展趋势[EB/OL].http://news.bioon.com/article/6692245.html.
[4]段平国,郭润生,余兴元,等.单一生物材料聚乳酸/羟基乙酸共聚物构建组织工程骨软骨的可行性[J].中国组织工程研究,2017,21(34):5423-5429.
[5]熊天铖.生物材料在牙再生领域中的应用与未来[J].好家长,2017,17(63):171.
[6]李明政,肖宇,吴珍珍,等.巨噬细胞在材料诱导成骨中作用的研究进展[J].口腔医学研究,2017,33(10):1123-1126.
[7]蔡高锐,刘威,何勇,等.纳米生物材料在骨组织工程中的应用[J].国际骨科学杂志,2017,38(5):303-306.
[8]郑力恒,吴昊,尚玉攀,等.组织工程支架材料性质对干细胞分化的影响[J].中国组织工程研究,2017,21(14):2274-2279.
[9]王秀梅.生物材料[J].新型工业化,2015,5(12):37-68.
[10]顾忠伟.生物医用材料组织诱导作用的分子机制与设计原理取得重大突破[J].近代技术与市场,2017,24(3):1.
[11]冯刚.生物材料和再生医学的进展[J].现代经济信息,2017,38(17):377-379.
[12]付裕.组织工程相关生物材料[J].农家参谋,2017,35(16):134.
[13]生物医用材料组织诱导作用的分子机制与设计原理取得重大突破[J].技术与市场,2017,24(3):1.
[14]戴建武.引导组织再生智能生物材料的转化研究[J].生命科学,2016,28(8):907-914.
[15]许文燕,马树宝,徐晶,等.北京地区生物材料进口审批监管现状及风险管理探讨[J].检验检疫学刊,2017,27(6):48-51.
[16]蒋菡.新一轮进境生物材料监管改革启动[N].工人日报,2017-11-01(004).
[17]国家食品药品监督管理总局.总局关于发布动物源性医疗器械注册技术审查指导原则(2017年修订版)的通告(2017年第224号)[EB/OL].http://www.sda.gov.cn/WS01/CL0050/221700.html.
[18]GBT16886.5-2003-医疗器械生物学评价,第5部分:体外细胞毒性试验[S].
[19]GBT16886.10-2005医疗器械生物学评价,第10部分:刺激与迟发型超敏反应试验[S].
[20]丁婷婷,张平,孙皎.生物材料引起机体炎症反应的研究进展[J].国外医学生物医学工程分册,2005,28(1):23-26.
[21]GBT16886.4-2003医疗器械生物学评价,第4部分:与血液相互作用试验选择[S].
[22]10993-4:2002,Biological evaluation of medicaldevices-Part4:Selection of tests for interactions withblood AMENDMENT 1[S].
[23]张明华,郑海燕.抗凝血生物材料的血液相容性[J].中国组织工程研究,2013,17(8):1505-1512.
[24]GB/T 16886.20-2015医疗器械生物学评价,第20部分:医疗器械免疫毒理学试验原则和方法[S].
[25]ISO/TS 10993-20:2006,Biological evaluation of medical devices-Part20:Principles and methods for immunotoxicology testing of medical devices[S].
[26]张蔓,李文,贺学英,等.无源医疗器械材料生物相容性研究进展[J].医疗装备,2016,29(3):46-50.
[27]GB/T16886.1-2011医疗器械生物学评价,第1部分:风险管理过程中的评价与试验[S].
[28]ISO 10993-1:2009,Biological evaluation of medical devices-Part 1:Evaluation and testing within a risk management process[S].
[29]李薇.生物医用金属镁表面酒石酸涂层的构建及其腐蚀降解性能和生物相容性的研究[D].西南交通大学,2017.
[30]朱敏,黄婷,杜晓宇,等.生物材料的3D打印研究进展[J].上海理工大学学报,2017,39(5):473-489.
[31]金嘉长,王扬,马维虎,等.3D生物打印技术在组织工程支架构建与再生中的应用进展[J].航天医学与医学工程,2016,29(6):462-468.
[32]梅昕,马凤森,喻炎,等.高分子可降解生物材料的降解研究进展[J].材料导报,2016,30(S1):298-303.
[33]李君涛,陈周煜.可降解生物医用材料研究现状与展望[J].新材料产业,2016,18(1):32-35.
[34]杨道朋,夏旭.3D打印生物材料研究及其临床应用优势[J].中国组织工程研究,2017,21(18):2927-2933.
[35]管博文,李程程,孟爱民.实验动物替代研究进展[J].生命科学,2017,29(6):546-551.
[36]李云飞.医疗器械化学性能检测的重要性分析[J].化工设计通讯,2017,43(12):169-171.
[37]陈亮,奚廷斐,王春仁.组织工程医疗产品免疫学评价研究[J].组织工程与重建外科杂志,2009,5(1):56-58.