A platform for studying the role of haemodynamics in microvascular disease

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.

1) Clinicians and Patients
The data generated in this project aims to provide a foundation for a new avenue of research into microvascular diseases, focussing on the role of blood mechanical properties. The project will not explicitly address blood samples from patients with microvascular diseases, but will rather mimic generic changes observed in population studies of patients affected by these conditions. In doing so, the results will be broadly applicable to multiple diseases and will act as proof of concept that can be built upon in future studies. Evidence of how blood properties are related to microvascular dysfunction will directly impact both clinicians working with microvascular diseases, and their patients. As an example, the sight of almost 1% of the global adult population is threatened by diabetic retinopathy, which has no cure and limiting progression of sight loss is the best available treatment. Changes to the retinal vasculature, which may be a response to changes in the blood, precede vision loss in DR, so identifying early alterations to blood properties could provide a new method of early diagnosis and monitoring. In the long term, it is possible that interventional treatments could be developed that interact with the blood, for example by binding plasma fibrinogen to reduce RBC aggregation or encourage higher turnover of RBCs and thus increase deformability of RBCs in the cell population. Furthermore, improving healthcare has the potential to reduce costs to the NHS.
2) The Public
Through outreach activities such as talks to school students and annual demonstrations at the Great Exhibition Road Festival, this project will help to inform the public about novel approaches that are being proposed to deal with the individual and societal problems of diabetes, as well as other diseases. In particular, the role of bioengineers in this field is often surprising to the public, as the connections between engineering, physiology and medicine are not immediately obvious. It is particularly important to communicate with young people who might pursue engineering in the future: by informing them of the broad and fascinating range of bioengineering activities, we may capture the imagination of a wider range of talented students to the field of engineering.
3) Industry
Insight from the research on multiphase flows may be applicable to industry, in fields such as inkjet and 3D printing, in which multiphase fluids in microscale environments are prevalent. Additionally, understanding the interactions between flow and the behaviour of the endothelial cells that control growth of blood vessels may provide beneficial insight for tissue engineering, in which a major factor limiting scalability is vascularisation. The study could also benefit companies researching point-of-care microfluidic devices, for example in separating rare cancer cells from blood. Better understanding of how blood will behave in such devices will inform an improved design process and enable greater optimisation of such devices.
Networking events with healthcare professionals and companies, organised the departmental industrial liaison manager, Robert Fergusson, will provide the opportunity to increase awareness of this research across the sector.
4) Students
The results of the study will also benefit UG and MSc students in biomedical engineering. I regularly use my research to inspire students when teaching, which has been explicitly praised in annual feedback from the course. The research will also form a basis for related student research projects. The downstream effects of an enthusiastic and well trained group of UG students will benefit the British economy and increase the long term impact of the research.
Finally, while the project does not explicitly aim to develop technology, many of the applications would arise in the UK, and could hence benefit the UK economy.