Periodic Reporting for period 3 - SimInSitu (In-silico Development- and Clinical-Trial-Platform for Testing in-situ Tissue Engineered Heart Valves)
Berichtszeitraum: 2024-01-01 bis 2024-12-31
SimInSitu aims to develop a sophisticated in-silico method to predict the short- and long-term behaviour of in-situ Tissue Engineered Heart Valves (TEHV) by combining advanced tissue remodelling algorithms with a personalized virtual heart modelling approach. The method will be specifically developed to predict the complex transformation process of biodegradable heart valves from the initially synthetic scaffold into a fully remodelled & functional valve. Though significant progress was made during the past years in developing TEHV based devices, it remains challenging, costly, time-consuming, and rich with obstacles. New knowledge can only be generated through a tedious trial & error process (requiring preclinical and clinical studies) since the restorative process cannot be replicated in an in-vitro environment.
SimInSitu’s main goals can be summarized as follows:
• To develop the first in-silico model able to predict the short and long-term behaviour of in-situ Tissue Engineered Heart Valves in a patient-specific environment while combining state-of-the-art Fluid-Structure-Interaction with Growth-Remodelling-Algorithms
• To generate virtual patient libraries that can be used to test virtually aortic medical devices.
• To implement thoroughly established Verification, Validation, and Uncertainty Quantification (VVUQ) standards / guidance in the computational modelling but also in the experimental assessments while following a hierarchical system approach
• To share and disseminate actively academic and practical findings & learnings with relevant stakeholders and the in-silico community.
SimInSitu’s main goals can be summarized as follows:
• To develop the first in-silico model able to predict the short and long-term behaviour of in-situ Tissue Engineered Heart Valves in a patient-specific environment while combining state-of-the-art Fluid-Structure-Interaction with Growth-Remodelling-Algorithms
• To generate virtual patient libraries that can be used to test virtually aortic medical devices.
• To implement thoroughly established Verification, Validation, and Uncertainty Quantification (VVUQ) standards / guidance in the computational modelling but also in the experimental assessments while following a hierarchical system approach
• To share and disseminate actively academic and practical findings & learnings with relevant stakeholders and the in-silico community.
The SimInSitu project has completed its fourth year, accomplishing most defined tasks, WPs, and milestones. For the hierarchical development and VVUQ approach for the in-silico platform (see image 1), complexity levels 1-6 from a total of 7 were developed and have undergone the planned credibility assessments. In its final year (2025), the SimInSitu project will focus on the completion of the last Complexity Level, which is equivalent to WP7 (in-silico ETR Platform). Below is a brief summary of achievements across Complexity Levels and corresponding Work Packages.
WP1 Scaffold Material Characterization (Complexity Level 1): All scaffold materials were fully characterized using a multitude of test modalities. Additionally, the epistemics uncertainty origination from the test methods and process implementation was evaluated via Round Robin test, while the aleatory uncertainty was evaluated by using a statistically adequate number of test samples. Furthermore, crack-growth was assessed experimentally.
WP2 Scaffold Material Modelling (Complexity Level 1): Relying on these experimental characterization data, complex anisotropic, hyperelastic material models were developed, implemented in commercial Finite Element Method (FEM) software, verified and validated. Using specifically developed Bayesian-statistic based calibration process, all needed material parameters and their distribution functions were evaluated. A separate validation, sensitivity analysis, and uncertainty quantification completed this work.
WP3 Device Modelling (Complexity Level 1 – 4): Within the Device-Modelling work package, all three device-models have been successfully developed and undergone the Model Verification, Validation, and Uncertainty Quantification process using various sources of in-vitro test data. For the Sapien-3 model, two FSI methods have been used – the initially anticipated FlowVision Solver and the alternative (backup) SPH solution. The extensive tiered validation approach using in-vitro structural and hemodynamic validation data was implemented while the uncertainty from pervious WPs was propagated in addition to device-modelling related factors.
WP4 Patient Specific Modelling (Complexity Level 1 – 5): Both development branches, the TAVI Patient-Specific Model, and the Right-Ventricle Outflow Track (RVOT) Patient-Specific Model, were fully developed and successfully verified, validated, and underwent extensive uncertainty quantification. Typical challenges of validating patient-specific / clinical models were overcome through harvesting and analysing extensive pre- and post-treatment data, and through combining cohort-based clinical data with in-vivo preclinical data, which is a further extension of the tiered validation approach.
WP5 ETR Modelling & WP6 Animal Trials (Complexity Level 1 – 6): The Endogenous Tissue Restauration (ETR) process has been developed and calibrated using several animal trials, which were not always fully successful. Additionally, historical data from a large collection of animal trial data was provided by Xeltis to support calibration process. The ETR model was implemented into a Sequential Simulation process. Due to the high complexity and numerical effort, surrogate models were needed and successfully developed using Artificial-Neural-Network models. Finally, the model was validated using available data from WP6 and historical data from preclinical data from Xeltis.
WP7 in-silico ETR Platform (Complexity Level 7): The convergence of all lower complexity levels into this final Complexity Level / work-package has not started yet, except for some strategic assessments of possible In-Silico Clinical Trial approaches. This will be the focus for the final year of the SimInSitu Project.
WP9 Dissemination and Exploitation Pathways: Dissemination and Exploitation is picking up momentum with continuous stream of social-media / web-based contributions, a second combined EU workshop (innovaHeart 2024), a collaboration with other related consortia in the EU funded Horizon Results Booster, and additional publications.
WP1 Scaffold Material Characterization (Complexity Level 1): All scaffold materials were fully characterized using a multitude of test modalities. Additionally, the epistemics uncertainty origination from the test methods and process implementation was evaluated via Round Robin test, while the aleatory uncertainty was evaluated by using a statistically adequate number of test samples. Furthermore, crack-growth was assessed experimentally.
WP2 Scaffold Material Modelling (Complexity Level 1): Relying on these experimental characterization data, complex anisotropic, hyperelastic material models were developed, implemented in commercial Finite Element Method (FEM) software, verified and validated. Using specifically developed Bayesian-statistic based calibration process, all needed material parameters and their distribution functions were evaluated. A separate validation, sensitivity analysis, and uncertainty quantification completed this work.
WP3 Device Modelling (Complexity Level 1 – 4): Within the Device-Modelling work package, all three device-models have been successfully developed and undergone the Model Verification, Validation, and Uncertainty Quantification process using various sources of in-vitro test data. For the Sapien-3 model, two FSI methods have been used – the initially anticipated FlowVision Solver and the alternative (backup) SPH solution. The extensive tiered validation approach using in-vitro structural and hemodynamic validation data was implemented while the uncertainty from pervious WPs was propagated in addition to device-modelling related factors.
WP4 Patient Specific Modelling (Complexity Level 1 – 5): Both development branches, the TAVI Patient-Specific Model, and the Right-Ventricle Outflow Track (RVOT) Patient-Specific Model, were fully developed and successfully verified, validated, and underwent extensive uncertainty quantification. Typical challenges of validating patient-specific / clinical models were overcome through harvesting and analysing extensive pre- and post-treatment data, and through combining cohort-based clinical data with in-vivo preclinical data, which is a further extension of the tiered validation approach.
WP5 ETR Modelling & WP6 Animal Trials (Complexity Level 1 – 6): The Endogenous Tissue Restauration (ETR) process has been developed and calibrated using several animal trials, which were not always fully successful. Additionally, historical data from a large collection of animal trial data was provided by Xeltis to support calibration process. The ETR model was implemented into a Sequential Simulation process. Due to the high complexity and numerical effort, surrogate models were needed and successfully developed using Artificial-Neural-Network models. Finally, the model was validated using available data from WP6 and historical data from preclinical data from Xeltis.
WP7 in-silico ETR Platform (Complexity Level 7): The convergence of all lower complexity levels into this final Complexity Level / work-package has not started yet, except for some strategic assessments of possible In-Silico Clinical Trial approaches. This will be the focus for the final year of the SimInSitu Project.
WP9 Dissemination and Exploitation Pathways: Dissemination and Exploitation is picking up momentum with continuous stream of social-media / web-based contributions, a second combined EU workshop (innovaHeart 2024), a collaboration with other related consortia in the EU funded Horizon Results Booster, and additional publications.
At project completion, it is expected that two in-silico models/platforms are developed, verified, and validated as much as possible given the available time, resources, and encountered complexity: a TAVI (left heart) patient-specific model and a RVOT (right heart) model. It is further expected that the models were fully assessed at the individual complexity levels and the overall uncertainty is evaluated using a propagation approach.
SimInSitu has a potential multi-level impact. At the technical modelling and simulation level, many advances in device modelling, FSI modelling, patient-specific, and ETR modelling can be expected. For the uncertainty quantification and propagation, many advanced with respect to implementation in complex models and usage of emulator can be expected. For credibility assessment, the hierarchical modelling and VVUQ could significantly influence regulatory frameworks for in-silico modelling.
SimInSitu has a potential multi-level impact. At the technical modelling and simulation level, many advances in device modelling, FSI modelling, patient-specific, and ETR modelling can be expected. For the uncertainty quantification and propagation, many advanced with respect to implementation in complex models and usage of emulator can be expected. For credibility assessment, the hierarchical modelling and VVUQ could significantly influence regulatory frameworks for in-silico modelling.