Periodic Reporting for period 1 - MicroMechAthero (Identifying Atherosclerotic Plaques at Risk: A Microstructure-based Biomechanistic Approach)
Reporting period: 2023-03-01 to 2025-08-31
Atherosclerotic plaque rupture in arteries is the primary cause of cardiovascular events such as heart infarct and stroke, which are responsible for 45% of deaths in Europe. Plaque rupture is a mechanical event, where the collagenous plaque tissue fails to withstand blood pressure loading. Identifying plaques at high risk of rupture is the key to prevent these fatal events. However, the current risk assessment strategy fails to achieve this as it lacks mechanistic insights into tissue failure. To address this unmet, urgent clinical need, I propose a paradigm shift to a biomechanistic risk assessment concept. I will achieve this with the MicroMechAthero project by revealing plaque failure mechanisms and developing a clinically applicable computational risk assessment framework. MicroMechAthero will combine ex-vivo, in-silico, and in-vivo research. Ex-vivo mechanical failure tests on post-mortem human plaque samples will involve tissue's collagen architecture imaging with recently developed polarization-sensitive optical coherence tomography and full-field, local, 3D tissue deformation measurements with the digital volume correlation technique. This frontier opto-mechanical approach will revolutionize soft tissue testing and, coupled with the virtual fields method, will provide unprecedented data for local, heterogeneous (hyper)elastic and failure properties of fibrous plaque tissue, linked to the underlying collagen network. Furthermore, a microstructure-based, in-silico tissue failure framework will be developed, using eXtended Finite Element Modeling technique, for plaque-specific risk prediction. This computational framework will be validated and tested for its clinical potential in an in-vivo patient study.
The overarching aim of this project is to develop a clinically applicable, biomechanistic rupture risk assessment strategy for atherosclerotic plaques. To achieve this aim, several distinct gaps in our knowledge
and technical/theoretical advances will be addressed through the following specific objectives:
1. Reveal local elastic and failure properties of fibrous plaque tissue with respect to the collagen network,
2. Establish a microstructure-based computational framework for fibrous plaque tissue failure,
3. Validate the new biomechanistic rupture risk assessment approach and test its feasibility for clinical use.
Overall, MicroMechAthero will provide a ground-breaking advance in our understanding of plaque rupture and develop a biomechanistic in-silico framework for patient-specific in-vivo risk analysis, leading to revolutionary changes in cardiovascular medicine.
The overarching aim of this project is to develop a clinically applicable, biomechanistic rupture risk assessment strategy for atherosclerotic plaques. To achieve this aim, several distinct gaps in our knowledge
and technical/theoretical advances will be addressed through the following specific objectives:
1. Reveal local elastic and failure properties of fibrous plaque tissue with respect to the collagen network,
2. Establish a microstructure-based computational framework for fibrous plaque tissue failure,
3. Validate the new biomechanistic rupture risk assessment approach and test its feasibility for clinical use.
Overall, MicroMechAthero will provide a ground-breaking advance in our understanding of plaque rupture and develop a biomechanistic in-silico framework for patient-specific in-vivo risk analysis, leading to revolutionary changes in cardiovascular medicine.
The following technical achievements have been reached so far:
1. Coupling a mechanical test rig (Cellscale, Biotester 5000) with a digital image correlation system with two digital cameras (LaVision, StrainMaster Portable Stereo-DIC System). This allows us to control both systems with the same controller to overcome synchronization problems between the two components. This system allows us to collect scientific data on tissue failure properties to achieve Objective 1 & 2.
2. Design and creation of a rupture test rig: Inspired by the recent fracture testing setup design of Alloisio et al. (Acta Biomaterialia 167:147–157, 2023), we have designed and created a new fibrous tissue rupture test rig. This new design allows us to obtain well-controlled failure data of fibrous plaque tissue.
3. Vertical inflation test setup: We have designed and are now in the process of manufacturing a new vertical artery inflation test setup. This inflation setup will allow us to perform intraluminal pressurization of diseased arteries and collect data for Objective 3.
The following research achievements have been reached so far:
1. Extracellular matrix imaging and mechanical properties characterization of tissue-engineered atherosclerotic plaque cap analogs (Objective 1&2): Using a recently developed tissue engineering approach in my group (APL Bioeng 7: 036120, 2023), we have created tissue-engineered atherosclerotic plaque cap analogs and evaluated the structural and mechanical features of this tissue engineering model to understand plaque rupture mechanisms. The main scientific finding was that ruptures generally initiate within and expand toward high-strain regions, highlighting the potential utility of strain measurements as a tool for rupture risk assessment (Acta Biomaterialia 194: 185–193, 2025).
2. Extracellular matrix structure characterization of carotid atherosclerotic plaque fibrous tissue (Objective 1&2): This is still an ongoing study. So far, we have performed multiphoton microscopy imaging on multiple optically cleared atherosclerotic plaques to assess the collagen and elastin organization in plaques of different disease stages.
3. Impact of tissue storage conditions on arterial tissue behavior (Objective 1): As the immediate testing of the collected tissue samples is not practical, we evaluated six commonly used tissue storage protocols for arterial tissue characterization. Our preliminary results indicate that all protocols we tested, except one have a statistically significant impact on the tested mechanical properties.
1. Coupling a mechanical test rig (Cellscale, Biotester 5000) with a digital image correlation system with two digital cameras (LaVision, StrainMaster Portable Stereo-DIC System). This allows us to control both systems with the same controller to overcome synchronization problems between the two components. This system allows us to collect scientific data on tissue failure properties to achieve Objective 1 & 2.
2. Design and creation of a rupture test rig: Inspired by the recent fracture testing setup design of Alloisio et al. (Acta Biomaterialia 167:147–157, 2023), we have designed and created a new fibrous tissue rupture test rig. This new design allows us to obtain well-controlled failure data of fibrous plaque tissue.
3. Vertical inflation test setup: We have designed and are now in the process of manufacturing a new vertical artery inflation test setup. This inflation setup will allow us to perform intraluminal pressurization of diseased arteries and collect data for Objective 3.
The following research achievements have been reached so far:
1. Extracellular matrix imaging and mechanical properties characterization of tissue-engineered atherosclerotic plaque cap analogs (Objective 1&2): Using a recently developed tissue engineering approach in my group (APL Bioeng 7: 036120, 2023), we have created tissue-engineered atherosclerotic plaque cap analogs and evaluated the structural and mechanical features of this tissue engineering model to understand plaque rupture mechanisms. The main scientific finding was that ruptures generally initiate within and expand toward high-strain regions, highlighting the potential utility of strain measurements as a tool for rupture risk assessment (Acta Biomaterialia 194: 185–193, 2025).
2. Extracellular matrix structure characterization of carotid atherosclerotic plaque fibrous tissue (Objective 1&2): This is still an ongoing study. So far, we have performed multiphoton microscopy imaging on multiple optically cleared atherosclerotic plaques to assess the collagen and elastin organization in plaques of different disease stages.
3. Impact of tissue storage conditions on arterial tissue behavior (Objective 1): As the immediate testing of the collected tissue samples is not practical, we evaluated six commonly used tissue storage protocols for arterial tissue characterization. Our preliminary results indicate that all protocols we tested, except one have a statistically significant impact on the tested mechanical properties.
In this initial phase of the project, the main efforts were made in the kick-off of the work packages, designing, producing, and characterizing new technical systems, and obtaining preliminary scientific results. Although it requires further scientific confirmation, our finding on the strong association of the local high strain with fibrous plaque tissue failure location has the potential to advance the research field beyond the state-of-the-art and provide a clinically imageable marker for plaque rupture risk.