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Bio-Design and Manufacturing  2023 Vol.6 No.6 P.718-734

http://doi.org/10.1007/s42242-023-00250-6


Accelerated fracture healing by osteogenic Ti45Nb implants through the PI3K–Akt signaling pathway


Author(s):  Jia Tan, Jiaxin Li, Zhaoyang Ran, Junxiang Wu, Dinghao Luo, Bojun Cao, Liang Deng, Xiaoping Li, Wenbo Jiang, Kai Xie, Lei Wang & Yongqiang Hao

Affiliation(s):  Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; more

Corresponding email(s):   kai.xie@hotmail.com, wanglei12041985@163.com, hyq_9hospital@hotmail.com

Key Words:  Fracture healing, Ti45Nb alloy, PI3K–Akt pathway, Orthopedic implant


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Jia Tan, Jiaxin Li, Zhaoyang Ran, Junxiang Wu, Dinghao Luo, Bojun Cao, Liang Deng, Xiaoping Li, Wenbo Jiang, Kai Xie, Lei Wang & Yongqiang Hao. Accelerated fracture healing by osteogenic Ti45Nb implants through the PI3K–Akt signaling pathway[J]. Journal of Zhejiang University Science D, 2023, 6(6): 718-734.

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author="Jia Tan, Jiaxin Li, Zhaoyang Ran, Junxiang Wu, Dinghao Luo, Bojun Cao, Liang Deng, Xiaoping Li, Wenbo Jiang, Kai Xie, Lei Wang & Yongqiang Hao",
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%A Jia Tan
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A1 - Bojun Cao
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Abstract: 
The key to managing fracture is to achieve stable internal fixation, and currently, biologically and mechanically appropriate internal fixation devices are urgently needed. With excellent biocompatibility and corrosion resistance, titanium–niobium alloys have the potential to become a new generation of internal fixation materials for fractures. However, the role and mechanism of titanium–niobium alloys on promoting fracture healing are still undefined. Therefore, in this study, we systematically evaluated the bone-enabling properties of Ti45Nb via in vivo and in vitro experiments. In vitro, we found that Ti45Nb has an excellent ability to promote MC3T3-E1 cell adhesion and proliferation without obvious cytotoxicity. Alkaline phosphatase (ALP) activity and alizarin red staining and semiquantitative analysis showed that Ti45Nb enhanced the osteogenic differentiation of MC3T3-E1 cells compared to the Ti6Al4V control. In the polymerase chain reaction experiment, the expression of osteogenic genes in the Ti45Nb group, such as ALP, osteopontin (OPN), osteocalcin (OCN), type 1 collagen (Col-1) and runt-related transcription factor-2 (Runx2), was significantly higher than that in the control group. Meanwhile, in the western blot experiment, the expression of osteogenic-related proteins in the Ti45Nb group was significantly increased, and the expression of PI3K–Akt-related proteins was also higher, which indicated that Ti45Nb might promote fracture healing by activating the PI3K–Akt signaling pathway. In vivo, we found that Ti45Nb implants accelerated fracture healing compared to Ti6Al4V, and the biosafety of Ti45Nb was confirmed by histological evaluation. Furthermore, immunohistochemical staining confirmed that Ti45Nb may promote osteogenesis by upregulating the PI3K/Akt signaling pathway. Our study demonstrated that Ti45Nb exerts an excellent ability to promote fracture healing as well as enhance osteoblast differentiation by activating the PI3K/Akt signaling pathway, and its good biosafety has been confirmed, which indicates its clinical translation potential.

上海交通大学医学院附属九院郝永强教授团队 | 具有促成骨活性的Ti45Nb植入物通过影像PI3K-Akt信号通路来加速骨折愈合

本研究论文聚焦Ti45Nb植入物对骨愈合的积极作用。骨折治疗的关键是稳定的内固定,目前,我们亟需一个兼具生物学活性与适合机械强度的固定装置。钛铌合金因其出色的生物相容性和耐腐蚀性而受到关注,被视为新型骨折固定材料的有力候选者。不过,关于其在骨折愈合中的具体效应和作用机制,我们尚缺乏深入了解。为此,我们针对Ti45Nb进行了一系列的实验评估。在体外实验中,Ti45Nb展现了优越的细胞相容性,能够促进MC3T3-E1细胞的粘附和增殖,且不具细胞毒性。对比Ti6Al4V,它更能推动MC3T3-E1细胞向成骨细胞分化。此外,关键骨相关基因和蛋白在Ti45Nb的影响下表达增强,尤其是PI3K-Akt相关蛋白,暗示Ti45Nb通过调控该信号路径来促进骨愈合。在体内实验中,Ti45Nb组对比Ti6Al4V组显示出更快的骨折愈合速度,同时还证实了其良好的生物兼容性。免疫组化分析进一步证实了Ti45Nb通过调节PI3K-Akt信号来促进骨生成。总的来说,我们的发现证实了Ti45Nb在骨愈合中的积极作用,尤其是它激活的PI3K-Akt信号路径,有巨大的临床应用转化前景

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