Buscema Marzia, Deyhle Hans, Pfohl Thomas, Zumbuehl Andreas, Müller Bert
Biomaterials Science Center, Department of Biomedical Engineering, University of Basel, Gewerbestrasse 14, CH-4123 Basel, Switzerland.
Institute of Physics, University of Freiburg, Freiburg, Germany.
Mater Today Bio. 2019 Apr 2;1:100003. doi: 10.1016/j.mtbio.2019.100003. eCollection 2019 Jan.
Atherosclerosis gives rise to blood vessel occlusion associated with blood flow alteration and substantial increase of average wall shear stress. This modification was proved acting as a purely physical trigger for targeted vasodilator release from a particular type of liposomes composed of 1,3-diaminophospholipids (Pad-PC-Pad). The flow-induced structural changes of these faceted liposomes, however, are completely unknown. Therefore, spatially resolved small-angle X-ray scattering was combined with microfluidics to uniquely study the purely physical mechanisms, which give rise to the highly efficient drug release from mechanoresponsive liposomes of nanometer size. The microfluidic device, designed to mimic a stenotic blood vessel, consisted of a 1-mm-wide channel with a constriction, 125 μm in diameter. Here, the changes of the average bilayer thickness and the mean size of the mechanoresponsive liposomes have been locally detected under flow conditions. Overall shape and bilayer thickness do change already near the constriction inlet, but the alteration is dominant near the outlet. At a flow rate of 0.2 μL/s, the liposome's bilayer thickness increased by 30 compared to the situation well before the constriction and under static condition. The detected bilayer thickness increase of the faceted liposomes is in line with the mechanically induced loss of interdigitation between the phospholipid amide chains. These results imply that rather the gradient force than the wall shear stress provokes structural changes of Pad-PC-Pad liposomes and the related drug release at stenoses. The approach, i.e. the combination of microfluidics and spatially resolved small-angle X-ray scattering, paves the way to design highly efficient and specific systems for the targeted drug delivery at constrictions with predefined morphology.
动脉粥样硬化会导致血管闭塞，并伴有血流改变以及平均壁面剪应力大幅增加。已证实这种改变可作为一种纯粹的物理触发因素，促使由1,3 - 二氨基磷脂（Pad - PC - Pad）组成的特定类型脂质体释放靶向血管扩张剂。然而，这些多面脂质体的流动诱导结构变化完全未知。因此，将空间分辨小角X射线散射与微流体技术相结合，以独特地研究导致纳米尺寸机械响应脂质体高效药物释放的纯粹物理机制。设计用于模拟狭窄血管的微流体装置由一个带有直径为125μm缩窄部分的1mm宽通道组成。在此，已在流动条件下局部检测到机械响应脂质体的平均双层厚度和平均尺寸的变化。总体形状和双层厚度在缩窄入口附近就已发生变化，但在出口附近变化更为显著。在流速为0.2μL/s时，与缩窄之前及静态条件下相比，脂质体的双层厚度增加了30 。检测到的多面脂质体双层厚度增加与磷脂酰胺链之间机械诱导的叉指化丧失一致。这些结果表明，在狭窄处引发Pad - PC - Pad脂质体结构变化及相关药物释放的是梯度力而非壁面剪应力。微流体技术与空间分辨小角X射线散射相结合的方法，为设计具有预定义形态的狭窄处高效且特异性的靶向药物递送系统铺平了道路。
