Mechanobiology-based medicine / Mechanomeds

基于机械生物学的医学/机械医学

• 批准号: EP/X033554/1
• 负责人: Manuel Salmeron-Sanchez
• 金额: $ 453.72万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FX033554%2F1
• 关键词: Mechanobiology; based; medicine; Mechanomeds

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.

如今，由于鉴定与病理状态的发作相关的分子标记，诊断在很大程度上可以实现。然而，许多疾病逃脱了这种范式，因为异常细胞的生化指纹与健康患者没有显着差异，阻碍了早期诊断并减少治疗的影响。一个典型的例子是白血病，一种癌症，每年可杀死世界上30万人。随着年龄的增长，这种疾病的演变发生了，但是现在有证据表明，我们体内的细胞在使用当前的诊断技术识别出多年之前朝着恶性表型发展。该建议将利用机械生物学，这是一个在过去10年中发展的研究领域，作为一种新的方法，是一种质疑细胞状态的早期变化的新方法，通过结合先进的生物材料，新颖的显微镜技术和机器人技术，使其更接近医学使用。机械生物学告诉我们，细胞可以感觉到并对它们的机械环境做出反应。例如，癌细胞比正常细胞柔软。但是，其利基的重组会导致组织刚度增加。在这里，我们将使用机械刺激来询问细胞可能成为癌细胞的潜力。细胞对这些外部机械刺激的反应将揭示其从健康发展到疾病的潜力。我们将重点放在白血病上，这是一种起源于骨髓的癌症，如正常的造血干细胞，起着我们的血液的重要作用，起步，开始恶性转化导致白血病干细胞。我们已经证明，健康细胞和恶性/恶性细胞对机械刺激的反应不同。该项目将使用具有定义的机械和生化特性的软水凝胶开发出骨髓的体外模型，该特性构成了间充质干细胞和造血（或白血病）干细胞，如骨髓中所发现的那样。我们将使用受控频率的纳米级振动对模型进行外部机械刺激，并在健康与患病系统之间区分振幅。为了监视体外模型中的这些机械变化，我们将在生物学环境中使用布里鲁因显微镜。该技术基于系统中声波的传播，以表征机械性能，并将允许将骨髓模型的刚度详细绘制为时间的函数 - 重要的是以非侵入性的方式进行绘制。此外，机械刺激的水平将取决于布里鲁因显微镜提供的读数，该读数将进食控制系统以改变骨髓模型上施加的机械振动刺激水平。我们将开发该技术，以具有包括骨髓模型在内的强大片上系统并整合了机械刺激。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可以将其引起的白血病实体瘤的治疗（化学疗法/放射疗法）的脱靶作用，以及（2）评估该技术是否可以预测随着年龄的增长而兴起的血肿干细胞中的恶性转化，最终导致白血病。