Technologies for 3D histologically-detailed reconstruction of individual whole hearts

心脏是一个电子控制的机械泵，它的功能与生命是不相容的。无论是正常活动还是异常活动，都与构成心脏的组织的精细结构细节密切相关。因此，收缩的电信号必须首先沿着心脏中数百万个肌肉细胞中的每一个传递，然后每个单独的纤维才会在规定的时间缩短。类似地，单个细胞产生的力主要沿着肌肉纤维的方向传递。此外，肌肉纤维以复杂的单位排列，由非肌肉的结缔组织连接在一起，这种排列不仅允许肌肉缩短，还允许肌肉增厚，以便将血液从心腔排出，进入供应身体所有器官的动脉。对详细的心脏组织结构的准确了解对于心脏病的诊断、病情进展的预测、治疗策略的确定，甚至对于医生的教学和培训都是非常重要的(心脏是器官之一，在这种情况下，错误学习不是一种选择！)这种临床相关性与这样一个事实形成鲜明对比，即至少在传统上，建立任何组织的架构意味着将其切开(也不是一种选择)。最近在非侵入性技术方面的改进，如磁共振成像(MRI)，已经开始提供对器官结构和功能的越来越详细的洞察。尽管这些记录中包含的细节还不足以可靠地识别患者心脏中的纤维方向，但显然这项技术正在朝着这个方向发展，我们现在开始开发所需的工具来处理医生将能够从高分辨率MRI或类似技术中提取的海量数据，这一点很重要。这是一个重大挑战。它需要通常不存在于单一实验室或诊所的技能和专业知识的组合。这些措施包括：自动图像配准、分析和配准；创建计算机可用的三维(3D)数据集；使用组织学进行全面验证，以获得整个器官的非常高分辨率的细节；建立个人解剖图，随后可以根据该图集对单个解剖结构进行“变形”；将所有数据整合到心脏跳动的计算机模型中；3D可视化；以及在具有“临床意义”的时间框架(数小时，而不是数月)内将所有上述操作应用于个人。该项目致力于开发这项技术，结合心脏核磁共振(牛津大学约翰·拉德克利夫医院心血管医学)、生物医学研究(牛津大学生理学、解剖学和遗传学系)和计算机(牛津大学计算实验室)等领域的领先团队的专业知识。这些团队将联合实施和验证从完全非侵入性成像技术中高效重建个体跳动心脏所需的一整套工具，这些工具基于对小型啮齿动物的原则证明，并注意所有算法都是可扩展的，以适应未来临床应用所需的显著更大的器官尺寸。更长远的愿景是，在进行了临床显示的心脏核磁共振检查后，医生将能够查看患者心脏的3D全息投影，放大任何相关细节(冠状动脉阻塞或组织受损部分)，评估治疗方式，预测结果，和/或使用先进的力反馈仪器/在患者进入手术室之前对心脏进行模拟手术。这一愿景的大部分仍遥遥无期。尽管如此，这项提案将迈出重要的一步，开发将非侵入性心脏成像与数据提取相联系的技术，并将其集成到个体心脏的解剖细节和功能3D模型中。

The heart is an electrically controlled mechanical pump, whose dysfunction is incompatible with life. Both normal and disturbed activity are closely associated with the fine architectural detail of the tissue that makes up the heart. Thus, electrical signals for contraction must first travel along every single of the millions of muscle cells in the heart, before each individual fibre will shorten at its prescribed timing. Similarly, the forces produced by individual cells are largely transmitted in the direction of muscle fibres. Furthermore, muscle fibres are ordered in complex units, joined together by non-muscle 'connective' tissue, and this arrangement allows the muscle not only to shorten, but also to thicken, in order to push blood out of the cardiac chambers and into the arteries that supply all organs of the body. A precise understanding of detailed cardiac tissue architecture would be of great importance for the diagnosis of cardiac diseases, prediction of their progression, identification of treatment strategies, and even for doctors' teaching and training (the heart is one of the organs where 'learning by mistake' is not an option!). This clinical relevance is contrasted by the fact that, traditionally at least, establishing architecture of any tissue meant 'cutting it open' (not an option either). Recent improvements in non-invasive techniques, such as Magnetic Resonance Imaging (MRI), have started to provide increasingly detailed insight into organ structure and function. Even though the detail contained in these recordings is not yet sufficient to reliably identify fibre orientation in a patient's heart, clearly the technology is moving in that direction, and it is important that we start now to develop the tools required to handle the vast amount of data that doctors will be able to extract from high resolution MRI or similar techniques. This is a major challenge. It requires a combination of skills and expertise not usually present in a single lab or clinic. These include: automated image registration, analysis, and alignment; creation of computationally usable three-dimensional (3D) data sets; comprehensive validation using histology to obtain very high resolution detail for the whole organ; establishment of a 'reference atlas' from which individual anatomies can subsequently be 'morphed'; integration of all data into computer models of the beating heart; 3D visualisation; and the subsequent application of all the above to an individual within a time-frame that makes 'clinical sense' (hours, not months). This project undertakes to develop exactly this technology, combining the expertise of leading teams in cardiac MRI (Cardiovascular Medicine at the John Radcliffe Hospital Oxford), bio-medical studies (Oxford University Department of Physiology, Anatomy & Genetics), and computing (Oxford University Computing Laboratory). These teams will jointly implement and validate the whole range of tools required to efficiently reconstruct individual beating hearts from entirely non-invasive imaging techniques, based on proof-of-principle in small rodents, taking care that all algorithms are scalable to be adapted, in future, to the significantly larger organ sizes required for clinical application. The longer-term vision is that after a clinically-indicated cardiac MRI, doctors will be able to look at a 3D holographic projection of the patient's heart, zoom-in on any relevant detail (a coronary vessel blockage or a damaged part of tissue), assess treatment modalities, predict outcomes, and / using advanced force-feedback instruments / conduct 'mock surgery' on that heart before the patient even enters the theatre. Much of this vision is still far ahead. Nonetheless, this proposal will make an important step by developing the technology to link non-invasive cardiac imaging to data extraction and integration into anatomically-detailed, functional 3D models of individual hearts.