Point of care nanotechnology for early blood clot detection and characterisation in disease screening, theranostic and self monitoring applications

在西方社会，血栓栓塞性疾病和相关的凝血异常会导致显著的发病率和死亡率，其中中风是英国的第三大死因。中风的发病率随着年龄的增长而显著增加，在社会贫困地区往往更高。在卒中中，血管内皮细胞和血管的损伤、凝血级联的激活和纤溶作用的减少导致异常凝块，通常伴随着过度的交联性纤维蛋白网络。这方面工作的一个不令人满意的方面是，这种凝块的微观结构通常只用形容词来报道(例如，致密或致密)-通常基于对干燥的凝块碎片在扫描电子显微镜照片中的目视检查。及早发现血栓是至关重要的。早期的凝血事件可能会导致血栓前状态，这会加剧疾病状态，而血栓状态之后，由于血栓结构的不利变化，可能会迅速出现出血状态。通过早期检测和特征分析获得的现有治疗选择得到了极大的加强。新技术对于解决这一领域的不足至关重要。该项目将利用我们在血液凝块检测和用于设备应用的超敏感纳米材料开发方面的最新进展来克服这些缺点。在皇家学会Brian Mercer奖和EPSRC投资组合合作伙伴奖下，我们与NHS合作开发了一种新的血液流变学技术，用于早期检测和表征血栓。这导致发现，早期血栓的分形微结构是血栓形成条件的生物标记物，包括治疗干预。这一发现的意义源于早期血块作为后续血块发展的微观结构模板的作用。在平行的工作中，我们展示了垂直排列的氧化锌纳米线的可控可重复生长，并证实了它们的电流产生能力。我们的Grand Challenges计划涉及将这种纳米技术与我们的血液流变学工作相结合，以开发第一个能够早期发现和表征异常凝块的护理点(POC)设备。我们所说的护理设备指的是适合在医院外(即，在药房和外科手术内)广泛使用的技术，并且最终将被开发为供在家的患者使用。这将利用氧化锌纳米线阵列的压电特性作为换能器来检测凝血中的剪切波传播。我们的目标是大幅提高早期血栓检测的敏感性，以便更准确地评估(I)凝血异常和(Ii)在发育的最早阶段对异常血栓的治疗靶向。该项目涉及伦敦大学的体内和体外疾病模型(中风)工作，以及旨在使我们的设备执行治疗功能的工作。通过这种方式，我们建议为抗凝剂应用中的患者自我评估和患者自我管理的POC系统奠定基础，同时也为血栓栓塞性疾病筛查奠定新的技术基础。该项目还包括莫里斯顿NHS医院的抗凝中风患者志愿者。我们拥有一支高度多学科的团队，在流变学和血液流变学；纳米技术、纳米材料和纳米制造；纳米医学和药物输送；以及医疗器械设计的人机交互方面拥有国际领先的专业知识。我们有两个合伙人。第一个是NHS，他们将提供临床设施和管理临床研究。我们的第二个合作伙伴是博姿创新中心(BCI)，它的参与预计将在下一代药店提供涉及POC应用的医疗保健。BCI的角色是为与客户需求/体验、PoC市场和环境相关的设计提供信息。

Thromboembolic disease and associated blood coagulation abnormalities cause significant morbidity and mortality in Western society, with stroke being the third leading cause of death in the UK. The incidence of stroke increases markedly with age and is often higher in socially deprived areas. In stroke, the processes of endothelial and vascular damage, activation of the coagulation cascade and decreased fibrinolysis result in abnormal clots, often with excessively cross-linked fibrin networks. An unsatisfactory aspect of work in this area is that the microstructures of such clots are usually reported in only adjectival terms (e.g., dense or tight ) - usually on the basis of a visual inspection of fragments of dessicated clots in SEM micrographs. Early detection of clots is vital. Early clotting events may contribute to a pro-thrombotic state which exacerbates the disease state and thrombotic states can be followed rapidly by haemorrhagic states due to adverse changes in clot structure. The available therapeutic options informed by early detection and characterisation are greatly enhanced.New technology is essential to address shortcomings in this area. This project will exploit our recent advances in blood clot detection and ultra-sensitive nanomaterials development for device applications to overcome these shortcomings. Under a Royal Society Brian Mercer Award and an EPSRC Portfolio Partnership Award, in collaboration with the NHS, we have developed a new haemorheological technique for the early detection and characterisation of blood clots. This has led to the discovery that the incipient clot's fractal microstructure is a biomarker for the conditions of clot formation, including therapeutic intervention. The significance of this discovery stems from the incipient clot's role as the microstructural template for ensuing clot development. In parallel work we have demonstrated the controlled reproducible growth of vertical arrays of ZnO nanowires and have confirmed their electrical current generation capabilities. Our Grand Challenge proposal involves combining this nanotechnology with our haemorheological work to develop the first point of care (POC) device capable of the early detection and characterisation of abnormal clots. By a point of care device we refer to technology suitable for widespread use outside hospitals (i.e., within pharmacies and surgeries) and which will ultimately be developed for use by patients at home. This will exploit the piezoelectric properties of ZnO nanowire arrays as a transducer to detect shear wave propagation within coagulating blood. Our aim is to drastically improve the sensitivity of early clot detection for more accurate assessments of (i) coagulation abnormalities and (ii) therapeutic targeting of abnormal clots at the earliest stage of development. The project involves in vivo and in vitro disease model (Stroke) work at University of London, and work intended to enable our device to perform a therapeutic function. In this way we propose to lay the foundations for a POC system for Patient Self Assessment and Patient Self Management in anticoagulant applications, in addition to a new technological basis for thromboembolic disease screening. The project also includes anticoagulated Stroke patient volunteers at Morriston NHS Hospital.We have a highly multidisciplinary Team with internationally leading expertise in rheometry and haemorheology; nanotechnology, nanomaterials and nanofabrication; nanomedicine and drug delivery; and human-device interaction aspects of medical instrument design. We have two partners. The first is the NHS who will provide clinical facilities and governance of clinical research. Our second partner is Boots Centre for Innovation (BCI) whose involvement anticipates healthcare provision involving POC applications in next-generation pharmacies. BCI's role is to inform design relating to customer needs/experience, the POC market and environment.