Mechanobiology-based medicine

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 to make our blood, start a malignant transformation giving rise to leukaemic stem cells. When this happens, we propose MSCs proliferate and produce new extracellular matrix, leading to a stiffer environment. It is believed that these changes in the environment trigger further expansion of leukaemic cells and vice versa. 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 leukaemic) stem cells. We will investigate how external mechanical stimulation of the model using nanoscale vibration of controlled frequency and amplitude can stimulate both cell populations to identify and maximise changes triggered by the presence of leukaemic cells. To monitor these mechanical changes in the bone marrow model we will develop Brillouin microscopy for use 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 first investigate the sensitivity of our technology to detect the presence of a single leukaemic cell in our bone marrow model and then, we will establish a proof of concept experiment with patient cells, through our clinical collaborators, that either have early signs of potential leukemic transformation or remain healthy as they age.