Nandan Swati, Schiavi-Tritz Jessica, Hellmuth Rudolf, Dunlop Craig, Vaughan Ted J, Dolan Eimear B
Biomedical Engineering and Biomechanics Research Centre (BioMEC), School of Engineering, College of Science and Engineering, National University of Ireland Galway, Galway, Ireland.
Vascular Flow Technology, Dundee, United Kingdom.
Front Med Technol. 2022 Jun 21;4:886458. doi: 10.3389/fmedt.2022.886458. eCollection 2022.
Endovascular stenting presents a promising approach to treat peripheral artery stenosis. However, a significant proportion of patients require secondary interventions due to complications such as in-stent restenosis and late stent thrombosis. Clinical failure of stents is not only attributed to patient factors but also on endothelial cell (EC) injury response, stent deployment techniques, and stent design. Three-dimensional bioreactor systems provide a valuable testbed for endovascular device assessment in a controlled environment replicating hemodynamic flow conditions found . To date, very few studies have verified the design of bioreactors based on applied flow conditions and their impact on wall shear stress, which plays a key role in the development of vascular pathologies. In this study, we develop a computationally informed bioreactor capable of capturing responses of human umbilical vein endothelial cells seeded on silicone tubes subjected to hemodynamic flow conditions and deployment of a self-expanding nitinol stents. Verification of bioreactor design through computational fluid dynamics analysis confirmed the application of pulsatile flow with minimum oscillations. EC responses based on morphology, nitric oxide (NO) release, metabolic activity, and cell count on day 1 and day 4 verified the presence of hemodynamic flow conditions. For the first time, it is also demonstrated that the designed bioreactor is capable of capturing EC responses to stent deployment beyond a 24-hour period with this testbed. A temporal investigation of EC responses to stent implantation from day 1 to day 4 showed significantly lower metabolic activity, EC proliferation, no significant changes to NO levels and EC's aligning locally to edges of stent struts, and random orientation in between the struts. These EC responses were indicative of stent-induced disturbances to local hemodynamics and sustained EC injury response contributing to neointimal growth and development of in-stent restenosis. This study presents a novel computationally informed 3D testbed to evaluate stent performance in presence of hemodynamic flow conditions found in native peripheral arteries and could help to bridge the gap between the current capabilities of 2D cell culture models and expensive pre-clinical models.
血管内支架置入术是治疗外周动脉狭窄的一种很有前景的方法。然而，相当一部分患者由于支架内再狭窄和晚期支架血栓形成等并发症而需要二次干预。支架的临床失败不仅归因于患者因素，还与内皮细胞（EC）损伤反应、支架置入技术和支架设计有关。三维生物反应器系统为在模拟血流动力学条件的受控环境中评估血管内装置提供了一个有价值的试验平台。迄今为止，很少有研究根据应用的血流条件及其对壁面剪应力的影响来验证生物反应器的设计，而壁面剪应力在血管病变的发展中起着关键作用。在本研究中，我们开发了一种基于计算的生物反应器，能够捕捉接种在硅胶管上的人脐静脉内皮细胞在血流动力学条件下以及自膨胀镍钛诺支架置入时的反应。通过计算流体动力学分析对生物反应器设计进行验证，证实了具有最小振荡的脉动流的应用。基于第1天和第4天的形态、一氧化氮（NO）释放、代谢活性和细胞计数的内皮细胞反应证实了血流动力学条件的存在。首次证明，利用该试验平台，所设计的生物反应器能够捕捉内皮细胞对支架置入超过24小时的反应。对第1天至第4天内皮细胞对支架植入反应的时间研究表明，代谢活性显著降低，内皮细胞增殖减少，NO水平无显著变化，内皮细胞在支架支柱边缘局部排列，支柱之间随机取向。这些内皮细胞反应表明支架引起局部血流动力学紊乱和持续的内皮细胞损伤反应，导致新生内膜生长和支架内再狭窄的发展。本研究提出了一种新型的基于计算的三维试验平台，用于评估在天然外周动脉中存在的血流动力学条件下支架的性能，并有助于弥合当前二维细胞培养模型和昂贵的临床前模型之间的差距。
