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，这是由于临床需要改善监测和预测治疗或疾病的异常凝血反应。在西方社会，血栓栓塞性疾病和相关的血液凝固异常导致了显著的发病率和死亡率，在英国，中风是第三大死亡原因。每年在英国医院内，凝血异常造成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，医疗保健效益不确定，临床效用有限。我们希望利用我们在纳米技术和血块检测方面的进步来克服这些缺点。它们为监测、评估和预测完全形成的血块的关键微观结构和力学特性提供了一种新方法的基础，这种方法基于在几分钟内对小样本血液进行近病人测试获得的信息。完全形成的凝块的微观结构决定了它的机械强度（因此有能力防止出血）以及它对身体分解和扩散的抵抗力。这些特性的异常与重大的健康风险有关。我们发现早期（“婴儿”）凝块的分形微观结构及其在模板化完全形成（“成熟”）凝块中的作用为我们的建议提供了基础。我们已经通过先进的成像和模型（纤维蛋白凝血酶）凝块分析确定了其可行性。我们现在需要在治疗和病理改变的血液中做这个。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。我们在纳米粒子荧光方面的工作已经建立了先进的识别/跟踪技术，我们已经将它们应用于研究生物细胞。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），由荧光纳米颗粒加载到血液样本中形成。一个令人兴奋的方面涉及分析血块在应力作用下的变形。光阵列提供了一个二元图的点划分凝块结构和报告变形。我们预计，这一概念将在相同的测量中提供“世界第一”，以产生不断变化的凝块的微观结构和机械特性。这项工作所产生的监测、评估和预测能力的改进将支持(i)对抗凝和/或抗血小板（如阿司匹林）治疗的凝血反应的改进监测；（ii）改善对治疗反应的血块破裂的预测；（iii）改进了这些治疗的剂量反应评估，（iv）为在服用华法林时复发性深静脉血栓形成或肺栓塞的患者提供了异常凝块筛查的基础，而根据目前的测试（INR），这些患者表现出充分的抗凝作用。我们的医疗影响伙伴关系将为以下方面的合作提供框架：(1)设备的纳米技术方面的专家，生物系统的成像和分析；（二）在医疗设备和微加工方面具有专业知识的工业伙伴；（iii）位于斯旺西莫里斯敦ABMU NHS信托医院的止血生物医学研究中心（HBRU）。HBRU拥有临床专家科学家和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支持医院护理环境内外近距离患者测试技术的发展。

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.