Department of Chemical Engineering, University of Utah, Salt Lake City, USA.
Department of Biomedical Engineering, University of Utah, Salt Lake City, USA.
Acta Biomater. 2019 Jun;91:135-143. doi: 10.1016/j.actbio.2019.04.028. Epub 2019 Apr 17.
Elevated shear force caused by an anastomotic stenosis is a common complication at the blood vessel-vascular implant interface. Although elevated shear forces were found to cause platelet aggregation around a stenotic region, transient platelet exposure to elevated shear forces and subsequent downstream events occurring under lower shear force were not extensively studied. We hypothesize that effects of elevated shear forces on pre-activation of platelets for downstream adhesion and activation are relevant in understanding the increased thrombotic risk associated with blood-contacting devices. We designed a microfluidic flow system to mimic the hemodynamic environment of vasculature with an upstream anastomotic stenosis with five wall shear strain rates ranging from 1620 s to 11560 s. Under shear flow conditions, transient exposure of whole blood to elevated shear forces resulted in higher downstream platelet adhesion onto three different immobilized platelet agonists: fibrinogen, collagen, or von Willebrand factor. Platelet expression of four activation markers (P-selectin, GPIIb/IIIa, lysosomal glycoprotein, and phosphatidylserine) significantly increased after transient exposure to higher upstream wall shear strain rates of 2975-11560 s. A significant lysis was observed when platelets were primed by upstream wall shear strain rate of 11560 s. These experimental results could be helpful to understand how altered hemodynamics around an anastomotic stenosis promotes thrombus formation downstream. STATEMENT OF SIGNIFICANCE: Studying the downstream response of platelets following transient exposure to an upstream agonist is important because of significant clinical implications to the implantation of vascular devices. Due to intimal fibrous hyperplasia, vascular biomaterials such as synthetic small-diameter vascular grafts sometimes become stenotic (narrow), leading to transient platelet exposure to elevated shear forces. In this study, a microfluidic flow system was developed to mimic a stenosed vascular graft and to investigate how highly elevated, transient upstream shear forces, typically found in severe stenosis, results in the pre-activation of platelets for downstream adhesion and activation. The findings of the present study have implications for optimizing the design of blood-contacting biomaterials in order to minimize thrombotic risk associated with transiently elevated shear forces. The findings also provide additional insights into the mechanisms of thrombus formation at the post-stenotic regions of vascular implants.
吻合口狭窄导致的切变力升高是血管-血管植入物界面的常见并发症。虽然已经发现升高的切变力会导致血小板在狭窄区域周围聚集，但血小板短暂暴露于升高的切变力以及随后在较低切变力下发生的下游事件并未得到广泛研究。我们假设升高的切变力对下游黏附激活的血小板预激活的影响对于理解与接触血液的器械相关的血栓形成风险增加是相关的。我们设计了一种微流控流动系统，以模拟具有上游吻合口狭窄的血管的血液动力学环境，上游狭窄处的壁切应变率范围为 1620s 至 11560s。在切变流条件下，全血短暂暴露于升高的切变力会导致更多的血小板下游黏附到三种不同的固定化血小板激动剂上：纤维蛋白原、胶原或血管性血友病因子。短暂暴露于上游壁切应变率为 2975-11560s 后，血小板上四种活化标志物（P-选择素、GPIIb/IIIa、溶酶体糖蛋白和磷脂酰丝氨酸）的表达显著增加。当血小板被上游壁切应变率为 11560s 预先激活时，观察到明显的溶解。这些实验结果有助于理解吻合口狭窄周围的血流动力学改变如何促进下游血栓形成。
研究血小板短暂暴露于上游激动剂后的下游反应很重要，因为这对血管器械的植入具有重要的临床意义。由于内膜纤维增生，血管生物材料（如合成小直径血管移植物）有时会变得狭窄，导致血小板短暂暴露于升高的切变力下。在这项研究中，开发了一种微流控流动系统来模拟狭窄的血管移植物，并研究了通常在严重狭窄中发现的高度升高的短暂上游切变力如何导致血小板的预激活，从而促进下游黏附激活。本研究的结果对于优化接触血液的生物材料的设计具有意义，以尽量降低与短暂升高的切变力相关的血栓形成风险。这些结果还为血管植入物的狭窄后区域血栓形成的机制提供了更多的见解。
