title: Recommendation for modifying current cytotoxicity testing standards for biodegradable magnesium-based materials.
abstract: As one of the most promising medical metal implants, magnesium (Mg) or its alloys have shown significant advantages over other candidates attributed to not only their excellent biodegradability and suitable mechanical properties but also their osteopromotive effects for bone applications. Prior to approval mandated by the governmental regulatory body, the access to the medical market for Mg-based implants requires a series of testing for assurance of their safety and efficacy via preclinical evaluations and clinical tests including phase 1 and 2 evaluations, and phase 3 of multi-center randomized double blind and placebo-controlled clinical trials. However, as the most widely used protocols for biosafety evaluation of medical devices, current ISO 10993 standards should be carefully reevaluated when directly applying them to predict potential health risks of degradable Mg based biomaterials via cytotoxicity tests due to the huge gap between in vitro and in vivo conditions. Therefore, instead of a direct adoption, modification of current ISO standards for in vitro cytotoxicity test is desirable and justified. The differences in sensitivities of cells to in vitro and in vivo Mg ions and the capability of in vivo circulation system to dilute local degradation products were fully considered to propose modification of current ISO standards. This paper recommended a minimal 6 times to a maximal 10 times dilution of extracts for in vitro cytotoxicity test specified in ISO 10993 part 5 for pure Mg developed as potential orthopedic implants based on literature review and our specifically designed in vitro and in vivo tests presented in the study. Our work may contribute to the progress of biodegradable metals involved translational work.
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Center for Translational Medicine Research and Development, Institute of Biomedical and Health Engineering, Chinese Academy of Sciences, Shenzhen 518055, China; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China; Shenzhen Bioactive Materials Engineering Lab for Medicine, Shenzhen 518055, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Wang
authors.affiliation: Julius Wolff Institute and Center for Musculoskeletal Surgery, Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Frank
authors.initials: F
authors.lastname: Witte
authors.affiliation: Center for Biomedical Materials and Tissue Engineering, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Tingfei
authors.initials: T
authors.lastname: Xi
authors.affiliation: State Key Laboratory for Turbulence and Complex System and Department of Materials Science and Engineering, College of Engineering, Peking University, Beijing 100871, China; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Institute of Metal Research, Chinese Academy of Sciences, 72 Wenhua Road, Shenyang 110016, China; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: Institute of Metal Research, Chinese Academy of Sciences, 72 Wenhua Road, Shenyang 110016, China; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Yuansheng
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Orthopedics, Affiliated Zhongshan Hospital of Dalian University, Dalian 116622, China.
authors.forename: Dewei
authors.initials: D
authors.lastname: Zhao
authors.affiliation: China Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Meng
authors.affiliation: Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Yangde
authors.initials: Y
authors.lastname: Li
authors.affiliation: Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China.
authors.forename: Weirong
authors.initials: W
authors.lastname: Li
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region.
authors.forename: Kaiming
authors.initials: K
authors.lastname: Chan
authors.affiliation: Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Center for Translational Medicine Research and Development, Institute of Biomedical and Health Engineering, Chinese Academy of Sciences, Shenzhen 518055, China; Guangdong Innovation Team for Biodegradable Magnesium and Medical Implants, Dongguan E-ande Co. Ltd, Dongguan, China. Electronic address: qin@ort.cuhk.edu.hk.
authors.forename: Ling
authors.initials: L
authors.lastname: Qin
mesh_terms: D000818:Animals; D001672:Biocompatible Materials; D002478:Cells, Cultured; D008274:Magnesium / Q000633:toxicity*; D008297:Male; D011817:Rabbits; D018675:Toxicity Tests
chemical_list: D001672:Biocompatible Materials; D008274:Magnesium
keywords: Biodegradability; Biometal; Cytotoxicity; ISO standards; Magnesium