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

心脏是一个电控机械泵，其功能障碍与生命不相容。正常和紊乱的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，然后每一个纤维才会在规定的时间内缩短。类似地，单个细胞产生的力大部分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，通过非肌肉的“结缔”组织连接在一起，这种排列不仅使肌肉缩短，而且使肌肉收缩，以将血液从心腔中推出并进入供应身体所有器官的动脉。准确了解详细的心脏组织结构对于心脏疾病的诊断、预测其进展、确定治疗策略，甚至对于医生的教学和培训都非常重要（心脏是“错误学习”不可选择的器官之一！）。这种临床相关性与以下事实形成对比：至少在传统上，建立任何组织的结构意味着“将其切开”（也不是一种选择）。非侵入性技术的最新改进，如磁共振成像（MRI），已经开始提供对器官结构和功能越来越详细的了解。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，但很明显，这项技术正在朝着这个方向发展，重要的是，我们现在就开始开发处理大量数据所需的工具，医生将能够从高分辨率MRI或类似技术中提取这些数据。这是一个重大挑战。它需要技能和专业知识的结合，通常不存在于一个单一的实验室或诊所。其中包括：自动图像配准、分析和对齐;创建计算可用的三维（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“参考图谱”，随后可以从该参考图谱“形态化”个体解剖结构;将所有数据整合到跳动心脏的计算机模型中; 3D可视化;以及随后在具有“临床意义”的时间范围内（数小时，而不是数月）将上述所有内容应用于个人。该项目致力于开发这项技术，结合心脏MRI（牛津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（牛津大学计算实验室）的领先团队的专业知识。这些团队将共同实施和验证所需的整个工具范围，以完全非侵入性成像技术有效重建单个跳动的心脏，基于小型啮齿动物的原理证明，注意所有算法都是可扩展的，以便在未来适应临床应用所需的更大器官尺寸。长期的愿景是，在临床指示的心脏MRI之后，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（冠状动脉血管阻塞或组织受损部分），评估治疗方式，预测结果，和/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远未实现。尽管如此，该提案将通过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学详细的功能3D模型中，从而迈出重要的一步。

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.