A platform for studying the role of haemodynamics in microvascular disease

研究血流动力学在微血管疾病中的作用的平台

基本信息

批准号：
EP/T023155/1
负责人：
Joseph Sherwood
金额：
$ 39.91万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FT023155%2F1
关键词：
platform studying role haemodynamics microvascular

项目摘要

In order to function, all cells in the body require a regular supply of oxygen and continuous removal of waste products. Both are provided by blood delivered through the microvasculature, which comprises vessels smaller than 0.1 mm in diameter. In order to fulfil its function, the flow of blood must be tightly regulated. A key component of this regulation are the specialist 'endothelial cells' that line all microvessels. These cells sense frictional forces arising from the flowing blood and in response release chemical substances that can increase or decrease the size of the vessels to help regulate the flow. When this regulation fails, the results can be devastating. For example, dysregulation of blood flow is one of the first stages in diabetic retinopathy, a condition that threatens the sight of 1% of the world's adult population. It is therefore important to understand the details of how blood flows in microvessels. A major factor that influences microvascular blood flow is the mechanical properties of red blood cells (RBCs). RBCs are highly deformable, which allows them to deform while flowing in larger vessels and even fit through capillaries much smaller than their diameter. RBCs also have a propensity to stick together, in a process called aggregation that is dependent on local flow characteristics. As a result of these RBC behaviours, the flow of blood in microvessels is complex and poorly understood. This is particularly important, because in numerous microvascular diseases, including diabetes, the RBCs become less deformable and aggregate more than in healthy individuals. These changes have been shown to correlate with disease progression, but it has not yet been established exactly how changes to blood properties affect microvascular function. We hypothesise that the changes in RBC properties alter blood flow and hence the frictional forces experienced by the endothelial cells, which in turn leads to dysregulation of flow and ultimately damage to the microvasculature. In this project, we will use state-of-the-art experimental technology to directly evaluate how changes to RBC properties affect microscale blood flow. A key challenge is the complicated branching patterns of the microvessel network. These networks consist of vessels of different sizes, structure and functions, throughout which both RBC flow and concentration change significantly. In order to improve our knowledge of how blood flows in microvessels, we need to be able to measure both the velocity of the RBCs and their local concentration in a given blood vessel or section of a microvascular network. We will achieve this using recently developed optical techniques, combining measurements of light passing through a blood sample with fluorescence measurements of microparticles added to the plasma. Acquiring both of these parameters allows calculation of the frictional forces on the vessel wall, which will be compared to results generated with numerical models. It is not currently possible to make these measurements in humans or living animals, hence we will build realistic models of microvessels using a new technique where laser energy is used to degrade a hydrogel, leaving behind a vessel structure that can be precisely controlled. We will flow blood from healthy volunteers through these models and measure the flow and wall friction under various conditions. We will then chemically treat the blood samples to mimic changes that occur in diabetes and measure the corresponding changes in flow. In addition to providing new insight into blood flow, the evidence generated in this study will reveal how changes to blood mechanical properties might affect diseases such as diabetes. In the long term, this insight is expected to lead to new approaches for diagnosing and treating microvascular diseases.

为了发挥作用，体内的所有细胞都需要定期供应氧气并连续去除废物。两者都是通过微脉管系统输送的血液提供的，该血管包括直径小于0.1 mm的血管。为了履行其功能，必须严格调节血液的流动。该调节的关键组成部分是所有微血管的专家“内皮细胞”。这些细胞感觉到流动的血液引起的摩擦力，并释放可以增加或减少血管大小以帮助调节流动的化学物质。当该法规失败时，结果可能是毁灭性的。例如，血流失调是糖尿病性视网膜病的第一阶段之一，这种病威胁着世界成年人口的1％。因此，重要的是要了解微血管中的血液流动方式的细节。影响微血管血流的主要因素是红细胞（RBC）的机械特性。 RBC是高度可变形的，它使它们可以在较大的容器中流动时变形，甚至可以穿过毛细血管的直径小得多。 RBC在一个称为聚合的过程中也有倾向于将其粘在一起，该过程取决于局部流动特征。由于这些RBC行为，微血管中的血液流动很复杂且理解不佳。这尤其重要，因为在包括糖尿病在内的许多微血管疾病中，RBC的变形和骨料比健康个体的变形较低。这些变化已显示与疾病进展相关，但尚未确切确定血液特性的变化如何影响微血管功能。我们假设RBC特性的变化会改变血液流动，从而改变内皮细胞所经历的摩擦力，进而导致流动失调，最终导致微脉管系统损害。在这个项目中，我们将使用最先进的实验技术直接评估RBC特性的变化如何影响微观的血流。一个关键的挑战是微血管网络的复杂分支模式。这些网络由不同尺寸，结构和功能的血管组成，在RBC流量和浓度都显着变化。为了提高我们对微血管中血流的了解，我们需要能够测量RBC的速度及其在给定的血管或微血管网络中的局部浓度。我们将使用最近开发的光学技术实现这一目标，将通过血液样品的光与添加到血浆中添加的微粒的荧光测量结合在一起。获取这两个参数允许计算容器壁上的摩擦力，这将与数值模型产生的结果进行比较。目前不可能在人类或活动物中进行这些测量，因此我们将使用一种新技术来建立逼真的微血管模型，该技术使用激光能量来降解水凝胶，留下可以精确控制的容器结构。我们将通过这些模型从健康的志愿者流动血液，并在各种条件下测量流量和壁摩擦。然后，我们将化学治疗血液样本以模仿糖尿病中发生的变化，并测量相应的流量变化。除了提供有关血流的新见解外，本研究产生的证据还将揭示血液机械性能的变化如何影响诸如糖尿病之类的疾病。从长远来看，这种见解有望导致诊断和治疗微血管疾病的新方法。