Jiang Ting, Xie Zhou, Wu Feng, Chen Jiang, Liao Yuzhen, Liu Luying, Zhao Ansha, Wu Jian, Yang Ping, Huang Nan
School of Life Science and Engineering, Southwest Jiaotong University, No. 111 of the North First Section of Second Ring Road, Chengdu 610031, PR China.
Institute of Biomaterials and Surface Engineering, Key Lab. for Advanced Technologies of Materials, Ministry of Education, Southwest Jiaotong University, No. 111 of the North First Section of Second Ring Road, Chengdu 610031, PR China.
ACS Biomater Sci Eng. 2019 Apr 8;5(4):1833-1848. doi: 10.1021/acsbiomaterials.9b00295. Epub 2019 Mar 25.
Vascular stent implantation is the primary treatment for coronary artery disease. Surface modification of coronary stents is a topic of interest to prevent thrombosis and restenosis and to promote endothelization. However, bioactive coatings on implants have not yet been fully developed for the time-ordered biological requirements of vascular stents. The first month after vascular stent implantation, the pathological changes in the injured vascular tissue are complex and time-ordered. Therefore, vascular stents possess time-dependent biofunctions with early phase anticoagulant and anti-inflammatory properties. In the later stage, inhibitory effects on smooth muscle cell proliferation and the promotion of endothelial cell adhesion might meet the requirements of vascular repair. We fabricated three types of hyaluronic acid nanoparticles (HA-NPs) by subjecting HA and poly(ether imide) to ethyl(dimethylaminopropyl) carbodiimide/-hydroxysuccinimide coupling reaction. The HA-NPs prepared by HA with a molecular weight of 100 kDa showed the best stability in a hyaluronidase environment. HA-NP composite films (HA-NCFs) were then fabricated by coimmobilizing selected HA-NPs (100 kDa) and HA molecules (100 kDa) through amide reaction on PDA/HD coated 316 L stainless steel surfaces. The detachment behavior of HA-NPs (100 kDa) in PBS for 20 days indicated that the HA-NPs (100 kDa) gradually detached from the surface. In vitro tests (anticoagulant and anti-inflammatory tests, endothelial cells, and smooth muscle cells seeding, and bacterial adhesion test) indicated that the newly fabricated HA-NCFs have inhibitory effects on the adhesion of fibrinogen, platelets, macrophages, bacteria, SMCs, and ECs. As the HA-NPs detached from the surface, the HA-NCFs showed excellent gradual comprehensive biocompatibility, which promoted adhesion and proliferation of ECs while still exerting inhibitory effects on the platelets, macrophages, and SMCs. Finally, in vivo SS wire implantation test (aortic implantation in healthy Sprague-Dawley rats) showed that HA-NCFs possessed anti-inflammatory properties, inhibited the proliferation of smooth muscle cells, and promoted re-endothelialization. In particular, HA-NCFs with time-dependent biofunctions showed better antirestenosis effects than those of surfaces modified with molecular HA, which exhibited constant biocompatibility. This study provides an important basis for the construction of HA-NP composite films with favorable time-dependent biofunctions for the time-ordered biological requirements of vascular stent.
血管支架植入是冠状动脉疾病的主要治疗方法。冠状动脉支架的表面改性是一个备受关注的课题，旨在预防血栓形成和再狭窄，并促进内皮化。然而，针对血管支架的时间顺序生物学需求，植入物上的生物活性涂层尚未得到充分开发。血管支架植入后的第一个月，受损血管组织的病理变化复杂且具有时间顺序性。因此，血管支架具有时间依赖性生物功能，早期具有抗凝和抗炎特性。在后期，对平滑肌细胞增殖的抑制作用以及对内皮细胞黏附的促进作用可能满足血管修复的需求。我们通过使透明质酸（HA）与聚（醚酰亚胺）进行N-乙基-N'-(3-二甲氨基丙基)碳二亚胺/ N-羟基琥珀酰亚胺偶联反应，制备了三种类型的透明质酸纳米颗粒（HA-NPs）。由分子量为100 kDa的HA制备的HA-NPs在透明质酸酶环境中表现出最佳稳定性。然后，通过酰胺反应将选定的HA-NPs（100 kDa）和HA分子（100 kDa）共固定在聚多巴胺/己二胺修饰的316L不锈钢表面上，制备了HA-NP复合膜（HA-NCFs）。HA-NPs（100 kDa）在PBS中20天的脱离行为表明，HA-NPs（100 kDa）逐渐从表面脱离。体外试验（抗凝和抗炎试验、内皮细胞和平滑肌细胞接种以及细菌黏附试验）表明，新制备的HA-NCFs对纤维蛋白原、血小板、巨噬细胞、细菌、平滑肌细胞和内皮细胞的黏附具有抑制作用。随着HA-NPs从表面脱离，HA-NCFs表现出优异的逐渐增强的综合生物相容性，促进了内皮细胞的黏附和增殖，同时对血小板、巨噬细胞和平滑肌细胞仍具有抑制作用。最后，体内SS丝植入试验（在健康的Sprague-Dawley大鼠主动脉中植入）表明，HA-NCFs具有抗炎特性，抑制平滑肌细胞增殖，并促进再内皮化。特别是，具有时间依赖性生物功能的HA-NCFs比用分子HA修饰的表面表现出更好的抗再狭窄效果，后者表现出恒定的生物相容性。本研究为构建具有良好时间依赖性生物功能的HA-NP复合膜以满足血管支架的时间顺序生物学需求提供了重要依据。
