EPSRC Healthcare Impact Partnership for new blood clotting diagnostics and management

我们建议建立一个医疗保健影响伙伴关系的研究，这是由一个未满足的临床需要，以改善监测和预测异常凝血反应的治疗或疾病的刺激。血栓栓塞性疾病和相关的凝血异常在西方社会引起显著的发病率和死亡率，其中中风是英国的第三大死亡原因。凝血异常每年导致英国医院内数千例可预防的死亡，越来越多的NHS门诊患者需要监测口服抗凝治疗（例如华法林）。但标准凝血试验与临床结果的相关性并不令人满意，在告知对正在进行的治疗或疾病进展的反应方面，医疗保健益处不确定，临床实用性有限。我们希望通过利用我们在纳米技术和凝块检测方面的进步来克服这些缺点。它们提供了一种新的方法来监测，评估和预测完全形成的凝块的关键微观结构和机械特性的基础，这些方法基于在对小样本血液进行近患者测试中在几分钟内获得的信息。完全形成的凝块的微观结构决定了其机械强度（因此能够防止出血）及其对身体分解和分散的抵抗力。这些财产的滥用与重大的健康风险有关。我们发现的分形微结构的早期（“婴儿”）凝块和它的作用，模板完全形成（“成熟”）凝块提供了我们的建议的基础。我们已经通过先进的成像和模型（纤维蛋白-凝血酶）凝块的分析确定了其可行性。我们现在需要在治疗和病理修饰的血液中做这件事。但是我们以前的成像技术不适合血液，我们计划一种新的方法。我们在纳米颗粒荧光方面的工作已经建立了先进的识别/跟踪技术，我们已经将其用于研究生物细胞。我们计划将这些方法转化为分析血凝块中异常微观结构的发展。这个概念是基于询问纳米级移动光显示（光簇），由荧光纳米粒子加载到血液样本中形成。一个令人兴奋的方面涉及分析凝块变形响应于应力。光阵列提供界定凝块结构和报告变形的点的二进制图。我们预计，这一概念将提供一个“世界第一”，在产生相关的微观结构和机械性能的发展凝块，在相同的测量。这项工作所产生的监测、评估和预测能力的改进将支持（i）对抗凝剂和/或抗血小板剂的凝血反应的改进监测（ii）改善对响应于治疗的凝块分解的预测;（iii）改善这些治疗的剂量反应评估，和（iv）在服用华法林的患者中筛查异常凝块的基础，患有复发性深静脉血栓形成或肺栓塞，同时根据目前的测试（INR）表现出充分的抗凝作用。我们的医疗保健影响合作伙伴关系将提供（i）设备，成像和生物系统分析纳米技术方面的专家之间的合作框架;（ii）具有医疗设备和微制造专业知识的工业合作伙伴;和（iii）ABMU NHS信托医院Morriston Swansea的止血生物医学研究单位（HBRU）。HBRU拥有专业的临床科学家和NHS顾问同事，为我们的研究及其翻译提供了面向临床的重点。我们的工业合作伙伴带来了专业知识，我们预计这些专业知识将为医院内外的近患者测试技术的发展提供支持。

We propose to establish a Healthcare Impact Partnership for research which is stimulated by an unmet clinical need for improved monitoring and prediction of abnormal clotting responses to therapy or disease. Thromboembolic disease and associated blood clotting abnormalities cause significant morbidity and mortality in Western society, with stroke being the third-leading cause of death in the UK. Clotting abnormalities are responsible for thousands of preventable deaths annually inside UK hospitals and increasing numbers of NHS outpatients require monitoring of oral anticoagulant therapy (e.g. warfarin). But correlation of standard clotting tests to clinical outcome has been unsatisfactory, with uncertain healthcare benefits and limited clinical utility in terms of informing responses to ongoing treatment or disease progression. We wish to overcome these shortcomings by exploiting our advances in nanotechnology and clot detection. They provide the basis of a new way of monitoring, assessing and predicting the key microstructural and mechanical properties of fully-formed clots, based on information acquired within a few minutes in near-patient tests on small samples of blood. The fully-formed clot's microstructure determines its mechanical strength (hence ability to prevent bleeding) and its resistance to breakdown and dispersal by the body. Abnormalities in these properties are linked to significant health risks. Our discovery of the fractal microstructure of incipient ('infant') clots and its role in templating fully-formed ('mature') clots provides the basis of our proposal. We have established its feasibility through advanced imaging and analysis of model (fibrin-thrombin) clots. We now need to do this in therapeutically and pathologically modified blood. But our previous imaging techniques are not suitable for blood and we plan a new approach. Our work on nanoparticle fluorescence has established advanced identification/tracking techniques and we have implemented them to study biological cells. We plan to translate these approaches to analyse abnormal microstructure development in blood clots. The concept is based on interrogating nanoscale moving light displays (clusters of light), formed by fluorescent nanoparticles loaded into blood samples. An exciting aspect involves analysing clot deformation in response to stress. The light arrays provide a binary map of points delimiting clot structure and reporting deformation. We anticipate that this concept will provide a 'world-first' in yielding linked microstructural and mechanical properties of evolving clots, in the same measurement. The improved monitoring, assessment and prediction capabilities arising from this work will underpin (i) improved monitoring of clotting responses to anticoagulant and/or antiplatelet (e.g. aspirin) therapies; (ii) improved predictions of clot breakdown in response to therapy; (iii) improved dose response assessments of these treatments, and (iv) a basis for abnormal clot screening in patients who, while taking warfarin, suffer recurrent deep vein thrombosis or pulmonary embolism while appearing adequately anticoagulated in terms of present tests (INR). Our Healthcare Impact Partnership will provide the framework for collaboration between (i) experts in nanotechnological aspects of devices, imaging and analysis of biosystems; (ii) industrial partners with expertise in medical devices and microfabrication; and (iii) the Haemostasis Biomedical Research Unit (HBRU) at ABMU NHS Trust Hospital Morriston Swansea. The HBRU, with its expert clinical scientists and NHS Consultant colleagues, provides the clinically-facing focus for our studies, and their translation. Our industrial partners bring expertise which we foresee will underpin the development of technologies for near-patient tests both inside and outside hospital care settings.