Upon damage to blood vessels, platelets undergo a variety of functional changes to coordinate the clotting of the blood at the site of injury. This helps to repair the puncture in the blood vessel and prevent excessive blood loss. However, when platelets become activated inappropriately inside undamaged blood vessels, they can block blood supply to the heart and brain, triggering life-threatening heart attacks and strokes. As these acute cardiovascular events are amongst the leading causes of premature death in the UK, scientists are keen to understand the processes of both normal and abnormal blood clotting to help them develop new treatments that could save lives. Scientists have therefore developed a technique to watch blood clotting when blood vessels of anaesthetised mice are artificially damaged. This technique when used with drugs that target platelet proteins or genetically modified mice lacking specific proteins, can provide valuable insight into the molecular events underlying blood clotting. This has led to widescale adoption of this technique across the world, leading to large use of mice in basic platelet research. However this technique gives variable responses, and is difficult to standardise between groups, and the use of anaesthetics to reduce the pain and suffering of the mouse during the procedure are likely to affect the clotting responses observed. In addition, there are known differences in the physiology of mice and humans that might limit how useful they are at predicting the events occurring in our bodies. In this project we aim to create an alternative to the use of mice in these arterial thrombosis models that should both help reduce and replace the number of mice used in these types of experiments.
Previously we have managed to grow artificial human blood vessels that are able to replicate the ability to activate platelets. These blood vessels could be used to recreate the conditions within the human body, and therefore provide an alternative to studying blood clotting in live mice. To do this we will develop our prototype blood vessels further to ensure they can trigger the blood to form blood clots when exposed to blood samples from healthy human volunteers. Once this is achieved we will then develop a flow chamber in which we can recreate the blood flow conditions found in the human body using only a tiny blood volume. This will therefore provide us with an adequate replica of the human blood vessel which we can use to recreate the experimental procedures currently performed in mice. To validate this methodology we will perform a direct comparison of the clotting responses observed in our artificial blood vessels when perfused with human blood samples against the responses observed in live mice. We will also analyse the difficulty, cost and time taken to perform these two methods to assess whether our artificial blood vessels could provide a feasible alternative to mouse studies. By doing this we expect to create a new model system which will reduce and replace the use of mice in platelet research.
Harper A, Musa F, Hernandez AH and Yang Y (2018). Reducing and replacing the use of in vivo thrombosis models in rodents using human tissue-engineered arterial constructs. Poster presented at the NC3Rs Cardiovascular Showcase, March 2018.
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Principal investigatorDr Alan Harper
Co-InvestigatorProfessor Ying Yang
Dr Paul Roach
Professor Jon Gibbins