Calcific aortic valve disease (CAVD) is the most common heart valve disorder worldwide. In its severe form — known as symptomatic aortic stenosis — it carries a 50% mortality rate within two years if left untreated. Despite its growing burden, there are currently no approved pharmacological treatments for CAVD. Surgical or transcatheter valve replacement (TAVI) remains the only available option. However, even after intervention, disease progression and poor outcomes remain a major clinical challenge.
One of the key barriers to developing effective therapies is our limited understanding of the mechanisms driving CAVD progression. Current animal models do not accurately reflect the complexity of human disease, and tissue-based studies provide only static snapshots, missing the dynamic interplay of mechanical forces, immune responses, and cell behaviour that shape disease over time.
To address this gap, our lab has developed a bioengineered, human-based organ-on-a-chip model that replicates the structural, mechanical, and cellular environment of the human aortic valve. This microphysiological system integrates:
- Human-derived valve endothelial and interstitial cells (VECs and VICs).
- Controlled hemodynamic and mechanical forces (e.g. shear stress, stretch).
- Tunable extracellular matrix (ECM) composition and stiffness.
This platform enables live-cell imaging, molecular profiling, and functional testing under disease-relevant conditions. Our model captures key features of CAVD, including:
- Endothelial inflammation and endothelial-to-mesenchymal transition (EndMT).
- ECM remodeling and stiffening.
- Immune cell recruitment.
- VIC activation and calcification.
Crucially, we have access to matched human valve tissue and blood samples from patients undergoing valve replacement at various stages of disease, as well as healthy controls.
These clinical samples allow us to refine and validate our in vitro models to ensure they accurately reflect human pathophysiology.
With this approach, we aim to:
- Understand how mechanical and immune cues drive CAVD progression.
- Identify early disease biomarkers and novel drug targets.
- Enable precision testing of candidate therapies in a clinically relevant system.
Our long-term vision is to use this model to shift CAVD management away from late-stage surgical intervention toward earlier, non-invasive, and personalised treatments. The adaptable design of our platform also makes it suitable for studying other mechanically active organs and diseases, such as vascular ageing and arrhythmia.
Key publications
- A disease-inspired in vitro model of aortic valve stenosis to investigate the drivers of endothelial–mesenchymal transition
Lab on a Chip 2025 - Piezo1 expression in neutrophils regulates shear-induced NETosis
Nature Communications 2024 15, Article number:7023 - Shear-sensing by C-reactive protein: linking aortic stenosis and inflammation
Circulation Research 2024 Volume 135, Number 11 - Transcatheter aortic valve implantation represents an anti-inflammatory therapy via reduction of shear stress–induced, Piezo-1–mediated monocyte activation
Circulation 2020 Volume 142, Number 11