Bai Long, Yang Ying, Mendhi Jayanti, Du Zeyu, Hao Rui, Hang Ruiqiang, Yao Xiaohong, Huang Nan, Tang Bin, Xiao Yin
Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane 4059, Australia.
J Mater Chem B. 2018 Oct 21;6(39):6322-6333. doi: 10.1039/c8tb01675e. Epub 2018 Sep 17.
Percutaneous coronary intervention with stenting is the most widely adopted surgical technique for the treatment of coronary disease. However, in-stent restenosis (ISR) continues to cause serious concern. Improving the functionality of endothelial cells (ECs) is of importance for dealing with ISR. However, limited successes in in vivo studies imply that the underlying mechanism relating to the process of intervention with a material has not been well understood to date. Another determining factor that has long been underestimated in the design of stents is immune response dominated by macrophages (MΦs). In the present study, TiO nanotube arrays (TNAs) with different diameters were fabricated by anodization. The diameter could be precisely adjusted from 15 nm (Nano-15) to 120 nm (Nano-120). The effect of distinct nanodimensions on the behavior of ECs/MΦs and their crosstalk was investigated. The results indicated that Nano-15 not only promoted the initial vitality of ECs and function-related gene expression but also enhanced the activation and spread of MΦs. In addition, Nano-15 downregulated the gene expression of inflammatory cytokines and pro-inflammatory M1 markers, while upregulating the gene expression of pro-healing M2 markers, autophagy markers, and growth factors of MΦs. A further investigation conducted using a specialized specimen-conditioned medium (SCM) from MΦs/ECs disclosed that the SCM derived from Nano-15 was able to manipulate a favorable microenvironment to facilitate MΦ-EC crosstalk via downregulation of inflammation-related gene expression and upregulation of function-related gene expression in ECs. Moreover, we further investigated the hemocompatibility of specimens in an ex vivo animal model. The results indicated that both pure Ti and Nano-15 possess satisfactory hemocompatibility, as manifested by the few thrombi that formed around the specimens. Additionally, in comparison with Nano-120, Nano-15 can significantly alleviate platelet activation and manipulate a loose structure of fibrin fibers in a dynamic situation. This study suggests that the application of Nano-15 as a surface coating for coronary stents may be a promising strategy for preventing ISR.
经皮冠状动脉介入治疗并植入支架是治疗冠心病应用最广泛的外科技术。然而，支架内再狭窄（ISR）仍然令人严重担忧。改善内皮细胞（ECs）的功能对于应对ISR至关重要。然而，体内研究取得的有限成功表明，与材料介入过程相关的潜在机制迄今尚未得到充分理解。在支架设计中，另一个长期被低估的决定性因素是以巨噬细胞（MΦs）为主导的免疫反应。在本研究中，通过阳极氧化制备了不同直径的TiO纳米管阵列（TNAs）。直径可精确从15nm（纳米-15）调整到120nm（纳米-120）。研究了不同纳米尺寸对ECs/MΦs行为及其相互作用的影响。结果表明，纳米-15不仅促进了ECs的初始活力和功能相关基因表达，还增强了MΦs的活化和扩散。此外，纳米-15下调了炎性细胞因子和促炎M1标志物的基因表达，同时上调了促愈合M2标志物、自噬标志物和MΦs生长因子的基因表达。使用来自MΦs/ECs的专用标本条件培养基（SCM）进行的进一步研究表明，纳米-15衍生的SCM能够通过下调ECs中炎症相关基因表达和上调功能相关基因表达来营造有利的微环境，以促进MΦ-EC相互作用。此外，我们在体外动物模型中进一步研究了标本的血液相容性。结果表明，纯钛和纳米-15都具有令人满意的血液相容性，表现为标本周围形成的血栓较少。此外，与纳米-120相比，纳米-15在动态情况下可显著减轻血小板活化并使纤维蛋白纤维结构疏松。本研究表明，将纳米-15用作冠状动脉支架的表面涂层可能是预防ISR的一种有前景的策略。
