Mechanobiology-based medicine / Mechanomeds

如今，诊断在很大程度上是通过识别与病理状态发生相关的分子标记来实现的。然而，许多疾病逃脱了这一范式，因为变异细胞的生化指纹与健康细胞没有显著差异，阻碍了早期诊断，并降低了治疗的影响。一个典型的例子是白血病，这是一种每年导致世界上30多万人死亡的癌症。这种疾病的演变是随着我们年龄的增长而发生的，但现在有证据表明，我们体内的细胞在用目前的诊断技术识别之前多年就向恶性表型进化。这项提议将利用机械生物学这一在过去10年中取得进展的研究领域，作为一种新的方法来询问细胞状态的非常早期的变化，通过将先进的生物材料、新的显微技术和机器人技术相结合，使其更接近医疗用途。机械生物学告诉我们，细胞可以感觉到机械环境并对其做出反应。例如，癌细胞比正常细胞柔软。然而，它们生态位的重组会导致组织硬度的增加。在这里，我们将使用机械刺激来询问细胞是否有可能成为癌细胞。细胞对这些外部机械刺激的反应将揭示它们从健康演变为疾病的可能性。我们将专注于白血病，一种起源于骨髓的癌症，因为正常的造血干细胞对制造我们的血液起着至关重要的作用，开始恶性转化，产生白血病干细胞。我们已经证明，健康细胞和癌前/恶性细胞对机械刺激的反应是不同的。该项目将使用具有明确机械和生化特性的软水凝胶开发骨髓的体外模型，这些水凝胶承载骨髓中共同发现的间充质干细胞和造血(或白血病)干细胞。我们将研究如何使用控制频率和幅度的纳米级振动对模型进行外部机械刺激，以区分健康和患病的系统。为了在体外模型中监测这些机械变化，我们将在生物学背景下使用布里渊显微镜。这项技术基于声波在系统中的传播，以表征机械特性，并将允许以非侵入性方式详细映射骨髓模型的硬度随时间的函数--重要的是以非侵入性方式。此外，机械刺激的水平将取决于布里渊显微镜提供的读数，该读数将输入控制系统以改变施加在骨髓模型上的机械振动刺激的水平。我们将开发这项技术，以拥有一个强大的芯片系统，其中包括骨髓模型和集成机械刺激。我们将在两个临床应用中使用该技术：(1)评估该技术是否可以预测作为实体肿瘤治疗(化疗/放射)的非靶点效应而诱发的白血病；(2)评估该技术是否可以预测随着年龄增长而发生的造血干细胞的恶性转化，最终导致白血病。

Nowadays diagnosis is largely enabled by the identification of molecular markers associated with the onset of a pathological state. Nevertheless, many diseases escape this paradigm, as the biochemical fingerprint of the aberrant cells do not differ significantly from healthy ones, hindering early diagnosis and reducing the impact of treatments. One prototypical example is Leukaemia, a type of cancer that kills more than 300,000 people in the world every year. The evolution of the disease happens as we get older, but there is now evidence that cells in our body progress towards a malignant phenotype many years before they can be identified with current diagnostic techniques. This proposal will exploit mechanobiology, a field of research that has progressed in the last 10 years, as a novel method to interrogate very early changes in cellular state, bringing it closer to medical use by combining advanced biomaterials, novel microscopy techniques and robotics. Mechanobiology has taught us that cells can feel and react to their mechanical environment. For example, cancer cells are softer than normal cells. However, reorganisation of their niche causes increased tissue stiffness. Here, we will use mechanical stimulation to interrogate cells potential to become cancer cells. Cell response to these external mechanical stimuli will reveal their potential to evolve from health to disease.We will focus on leukaemia, a cancer that originates in the bone marrow, as normal haematopoietic stem cells, which play the essential role of making our blood, start a malignant transformation giving rise to leukemic stem cells. We have demonstrated that healthy cells and pre-malignant/malignant cells respond differently to mechanical stimulation. This project will develop an in vitro model of the bone marrow using soft hydrogels with defined mechanical and biochemical properties that host mesenchymal stem cells and hematopoietic (or leukemic) stem cells, as are found together in the marrow. We will investigate how external mechanical stimulation of the model using nanoscale vibration of controlled frequency and amplitude discriminate between healthy vs diseased systems. To monitor these mechanical changes in the in vitro model we will use Brillouin microscopy in a biological context. This technique is based on the propagation of acoustic waves in the system to characterise mechanical properties and will allow detailed mapping of stiffness of the bone marrow model as a function of time - importantly in a non-invasive way. Moreover, the level of mechanical stimulation will be dependent on the readout provided by Brillouin microscopy that will feed into a control system to alter the level of the mechanical vibrational stimulation imposed on the bone marrow model. We will develop the technology to have a robust on-chip system that includes the bone marrow model and integrates mechanical stimulation.We will use the technology in two clinical applications: (1) to assess whether the technology can predict leukaemia which can be induced as an off-target effect of the treatment (chemotherapy/radiotherapy) of solid tumours and (2) to assess whether the technology can predict malignant transformations in heaematopoeitic stem cells that happes with age, eventally leading to leukaemia.