Periodic Reporting for period 1 - RE-ALIGN (Restoring anisotropy in living tissues 'in situ')
Periodo di rendicontazione: 2022-11-01 al 2025-04-30
Living tissues in our body comprise cells and a supporting structure called the extracellular matrix. These are naturally organised to perform specific functions. However, when regenerating tissues inside the body in the context of Regenerative Medicine, the focus is often on replacing cells but not on restoring the tissue's original organised structure. This is particularly problematic for tissues like the heart, where proper function depends on this well-organised structure. Indeed, two decades of research into the regeneration of the damaged heart have mainly focused on restoring tissue composition (e.g. by replenishing cells) with limited success.
The RE-ALIGN project aims to improve heart function after damage by restoring the organised tissue structure, which is crucial for the heart's performance and for reducing cardiac scarring and inflammation. The project explores using low-intensity ultrasound to non-invasively re-align heart tissue and regain the original structure-function properties of a healthy heart.
To get there, the project involves:
• Creating models: We create living models of heart tissue of different length scales (cell to organ), both healthy and damaged, to study how they function before and after re-alignment.
• Using ultrasound: We design new ultrasound workflows and test if ultrasound can be used to guide the organisation of cells and tissues.
• Computer simulations: We use computer models to predict how re-aligning the tissue will affect heart function.
The project aims to answer three main questions:
1. Can restoring the organised structure of damaged heart tissue improve heart function and reduce scarring and inflammation?
2. How do factors like scar tissue, heartbeats, and immune responses affect this restoration?
3. Can we use ultrasound to re-align heart tissue remotely?
By addressing these questions, the project hopes to provide new insights and tools for Regenerative Medicine, particularly for heart regeneration.
The RE-ALIGN project aims to improve heart function after damage by restoring the organised tissue structure, which is crucial for the heart's performance and for reducing cardiac scarring and inflammation. The project explores using low-intensity ultrasound to non-invasively re-align heart tissue and regain the original structure-function properties of a healthy heart.
To get there, the project involves:
• Creating models: We create living models of heart tissue of different length scales (cell to organ), both healthy and damaged, to study how they function before and after re-alignment.
• Using ultrasound: We design new ultrasound workflows and test if ultrasound can be used to guide the organisation of cells and tissues.
• Computer simulations: We use computer models to predict how re-aligning the tissue will affect heart function.
The project aims to answer three main questions:
1. Can restoring the organised structure of damaged heart tissue improve heart function and reduce scarring and inflammation?
2. How do factors like scar tissue, heartbeats, and immune responses affect this restoration?
3. Can we use ultrasound to re-align heart tissue remotely?
By addressing these questions, the project hopes to provide new insights and tools for Regenerative Medicine, particularly for heart regeneration.
To test our idea that we can re-align heart tissue non-invasively and remotely (which is crucial for future medical use), we started by creating living lab models of the heart at both the cell level and the tissue level. We also used computer models to predict how re-aligning the tissue would affect the heart's function. At the same time, we developed a system to study how we can use ultrasound to guide the organisation of cells and tissues.
At the cell level, we conducted experiments on heart cells (i.e. cardiac fibroblasts and/or cardiomyocytes) on different materials to mimic the conditions of a heart after a heart attack. We used advanced techniques, like live imaging and traction force microscopy, to study how these cells behave, collaborate, communicate, and function mechanically following a heart attack. Next, we developed new methods and protocols to use low-intensity ultrasound to move and manipulate the cells without harming them. Using these protocols, we could (re)arrange and pattern cells to designated locations as a first step in re-aligning heart tissue after a heart attack.
At the tissue level, we built three-dimensional miniature models of living heart tissue that can be adjusted regarding cell types, tissue structure, and tissue size. By locally damaging the tissues and adding inflammation agents, we simulated heart attacks in these models to study tissue response and healing. These models will be instrumental in investigating the effects of ultrasound-induced restoration of tissue organisation.
Advanced computer simulations were performed to predict how changes in heart tissue structure and organisation will affect heart function after a heart attack. From these simulations, it was concluded that improving tissue alignment during healing slightly enhances heart function in the early stages following the attack. The following steps will concentrate on the effect of long-term remodelling on heart function.
At the cell level, we conducted experiments on heart cells (i.e. cardiac fibroblasts and/or cardiomyocytes) on different materials to mimic the conditions of a heart after a heart attack. We used advanced techniques, like live imaging and traction force microscopy, to study how these cells behave, collaborate, communicate, and function mechanically following a heart attack. Next, we developed new methods and protocols to use low-intensity ultrasound to move and manipulate the cells without harming them. Using these protocols, we could (re)arrange and pattern cells to designated locations as a first step in re-aligning heart tissue after a heart attack.
At the tissue level, we built three-dimensional miniature models of living heart tissue that can be adjusted regarding cell types, tissue structure, and tissue size. By locally damaging the tissues and adding inflammation agents, we simulated heart attacks in these models to study tissue response and healing. These models will be instrumental in investigating the effects of ultrasound-induced restoration of tissue organisation.
Advanced computer simulations were performed to predict how changes in heart tissue structure and organisation will affect heart function after a heart attack. From these simulations, it was concluded that improving tissue alignment during healing slightly enhances heart function in the early stages following the attack. The following steps will concentrate on the effect of long-term remodelling on heart function.
We developed the RE-ALIGN PLATFORM, a unique setup combining microscopy, ultrasound, and laser ablation tools to manipulate and investigate cell and tissue mechanical functions ‘live’ for prolonged periods in the laboratory.
We created new laboratory and computer models to mimic heart tissue and changes in tissue structure and function after a heart attack. These models can find broader applications in studies on the mechanobiology of the heart and in cardiac disease management.
We created new laboratory and computer models to mimic heart tissue and changes in tissue structure and function after a heart attack. These models can find broader applications in studies on the mechanobiology of the heart and in cardiac disease management.