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.

The complex and multi-scale nature of thin-films poses significant modelling challenges for many systems which occur in nature or industrial contexts ranging from foams, to engine lubricants in electric vehicles, from biomembranes to non-alcoholic beverages, from contact lenses to industrial coatings. The applications of the thin liquid films where the interface is contaminated either accidentally or on purpose, are endless. This naturally leads to considerable research and economic opportunities associated with the ability to understand and control the effect of additives and contaminants on the thin-film interface. The main difficulty here, after many years of intense research, remains with the fact that the role of a contaminant on the interface is generally not well understood. We are starting to understand the effect of surfactants, which is a subset of contaminants with surface-active agents, such as washing up liquid and detergents, but a generalised theory of contaminants remains elusive. This is due to not only the limited models of surface-altering agents upto dilute concentrations, which is not always the case in nature, but also the lack of an unifying framework upon which to study contaminants that are not surfactants. This project will provide such an unifying mathematical framework to study a generalised contaminant on a thin liquid film. By describing the inputs of the generalised contaminant into the system as contributing to an effective gradient in the surface tension, induced by whichever special property the contaminant possesses, our approach introduces new mechanisms into the continuum dynamics and allows comparisons to be made with experimental studies which often combines multiple effects of the contaminant. Disentangling the various nonlinear effects in the contaminant is a difficult problem which cannot be overlooked. The mathematical framework is a vital first step towards a complete categorisation of all the component in the multiphysics soup of a generalised contaminant solution. This categorisation not only allows us to tackle vastly more complex contaminants than previous possible, but also enables us to engineer thin liquid interfaces to an exacting specification or stability for a particular application, such as a non-alcoholic beer with the same foaming characteristics as an alcoholic version or a non-foaming engine lubricant for high-efficiency electric vehicles, both of which are examples of thin liquid interfaces which would benefit from a complete understanding of the role contaminants play on the surface.

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.