Periodic Reporting for period 1 - devise (Engineered viscoelasticity in regenerative microenvironments)
Período documentado: 2023-09-01 hasta 2026-02-28
Tissues in our bodies consist of cells and a network of proteins and other molecules called the extracellular matrix (ECM). Cells are sensitive to the biochemical composition of the ECM but they can also feel its mechanical properties. The basic mechanical property is stiffness, how rigid or soft something is, cells can differentiate between stiff and soft matrices. This is important as depending on how rigid their environment is they perform different functions, and high stiffness – for example in fibrosis, that is a consequence of chronic inflammation – can lead to disease including cancer. Yet, this is not the whole story. Importantly the ECM is a viscoelastic material and this means that its properties evolve with time as force is applied. This is important as cells can feel this property too and determine their biochemistry and behaviour based on this. In this project, we will engineer biomaterials that will imitate the viscoelastic properties of the ECM, to understand how cells respond to this property and eventually design new biomaterials that can support regenerative medicine but also understand degenerative diseases and cancer.
We have worked hard to engineer biomaterials, hydrogels, with controlled viscoelasticity,which involves independent control of elasticity (rigidity) and viscosity. We have engineered materials to understand cell behaviour in 2D but also in 3D.
In 2D, we have demonstrated how stem cells (key cells in regenerative medicine) respond to viscoelasticity. Importantly, we have demonstrated that for cells to feel the dynamic, time dependent properties of viscoelastic substrates, not only cell adhesion receptors (i.e. integrins) are important, but also other ion channels such as piezo1 are essential. Piezo 1 is a well-known mechanoreceptor which was awarded the Nobel prize in 2020 – here we demonstrate that it is key to feel the dynamic properties of the matrix too.
In 3D, we have engineered hydrogels with controlled viscoelasticity and encapsulated stem cell spheroids. We have demonstrated that the spheroids are extremely sensitive to viscoelasticity. For example, in rigid matrices, regardless of the level of viscoelasticity, the spheroid remains as it was originally: spherical and unable to spread into the hydrogel. The situation changes for soft viscoelastic matrices, where spheroids, by taking advantage of the dynamic properties of the hydrogels, they reorganise the environment and invade it.
In 2D, we have demonstrated how stem cells (key cells in regenerative medicine) respond to viscoelasticity. Importantly, we have demonstrated that for cells to feel the dynamic, time dependent properties of viscoelastic substrates, not only cell adhesion receptors (i.e. integrins) are important, but also other ion channels such as piezo1 are essential. Piezo 1 is a well-known mechanoreceptor which was awarded the Nobel prize in 2020 – here we demonstrate that it is key to feel the dynamic properties of the matrix too.
In 3D, we have engineered hydrogels with controlled viscoelasticity and encapsulated stem cell spheroids. We have demonstrated that the spheroids are extremely sensitive to viscoelasticity. For example, in rigid matrices, regardless of the level of viscoelasticity, the spheroid remains as it was originally: spherical and unable to spread into the hydrogel. The situation changes for soft viscoelastic matrices, where spheroids, by taking advantage of the dynamic properties of the hydrogels, they reorganise the environment and invade it.
The project has the potential to impact in areas beyond the generation of new knowledge. There are two areas of potential impact: (i) the design and engineering of novel bioinks with controlled viscoelastic properties –there are no bioinks in the market with controlled elasticity and viscosity. This is important to develop physiologically relevant in vitro models and also to support models that can be used in the future for drug testing; (ii) the project aims to develop Brillouin microscopy as a tool to understand the evolution of the viscoelastic properties of 3D in vitro models and based on this knowledge, it has the ambition to develop a diagnostic tool based on the mechanical properties of cells and their environments.