Periodic Reporting for period 4 - BIOLOCHANICS (Localization in biomechanics and mechanobiology of aneurysms: Towards personalized medicine) Reporting period: 2019-11-01 to 2020-12-31 Summary of the context and overall objectives of the project BIOLOCHANICS was a five-year and eight-month project aimed at achieving patient-specific predictions of aneurysm risk of rupture and of aneurysm reactions to biochemical treatments. Four work packages (WPs) were planned and all of them are conducted in parallel. Below we summarize the main achievements of the fourth period of the project:WP1. We were the first worldwide to achieve patient specific simulations with the homogenized constrained mixture model by coupling two commercial software: Ansys and Abaqus (combined efforts of 2 postdocs: Jamal Mousavi and Jayendiran Raja). Our PhD student Joan Laubrie, who had a scholarship from CONYCIT (Chilean government) implemented the model in an open source environment which is hosted in Github. At the end of the project, we had a postdoc (Ataollah Ghavamian) who refined the model with the contractile role of Smooth Muscle Cells (SMCs).WP2. We developed mechanobiological experiments of induced proteolytic remodelling on porcine aortas collected from a local abattoir. With that, we were able to identify material properties and damage mechanisms preceding rupture in porcine thoracic aortas. We also studied SMCs (thesis of Claudie Petit). We were able to obtain very interesting and original results, showing for instance that the basal tone of SMCs is larger in ATAAs and that this can be explained by the presence of hypertrophic cells. The hypertrophy and the larger basal tones are correlated with the need to maintain the extracellular matrix which is undergoing damage in aneurysms. We also involved Ali Karkhaneh (post-doc hired for WP4) to develop a finite-element model of SMCs in order to elucidate the links between the evolution of aortic tissue and the regulation of forces inside the cell.WP3. We were able to measure the 3D strain fields of thick aneurysmal wall under pressure and this permitted to understand how the wall remodels in aortic lesions. We recently published a major paper in Nature Scientific Reports. It summarizes more than 4 years of work in collaboration with Jay Humphrey’s group.WP4. We developed finite element models (fluid and solid) of the different patients involved in the study permitting to have for the first time the conceptual models of WP1 applied to predict aneurysm progression in real patients. The coupling between fluid analyses and structural analysis was established by assuming that regions of high wall shear stress are the ones where lesions start, and this is followed by remodeling. We have published a number of papers on these achievements and delivered numerous invited speeches and seminars. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far Rupture of Aortic Aneurysms (AA) kills more than 30000 persons every year in Europe and the USA. It is a complex phenomenon that occurs when the wall stress exceeds the local strength of the aorta due to degraded properties of the tissue. The state of the art in AA biomechanics and mechanobiology revealed in 2014 that major scientific challenges still had to be addressed to permit patient-specific computational predictions of AA rupture and enable localized repair of the structure with targeted pharmacologic treatment. A first challenge related to ensuring an objective prediction of localized mechanisms preceding rupture. A second challenge related to modelling the patient-specific evolutions of material properties leading to the localized mechanisms preceding rupture. We worked at addressing these challenges in BIOLOCHANICS. We developed digital twin framework for helping clinicians to establish prognosis for patients harbouring an AA. Thanks to Magnetic Resonance Imaging and computer fluid dynamics simulations, we estimate hemodynamics loads on the aortic wall. The impact of the hemodynamics loads on the mechanical properties aortic tissue and aortic smooth muscle cells has been extensively characterized throughout the project. Eventually we simulated the induced evolutions through finite element models to predict aneurysmal progression and potential risk of rupture. A first group of patients is currently evaluating this digital twin framework. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) For each of the four WPs of Biolochanics, the main achievements beyond the state of the art which can be highlighted:WP1. Implementation of the constrained mixture model to simulate growth and remodeling in patient-specific arterial geometries. Transfer to open source software. WP2. Use of optical coherence tomography (OCT) and digital volume correlation (DVC) for vascular biomechanics. It has permitted for the first time ever to measure strains in the wall of thick arteries. Potential transfer as a laboratory equipment enabling such mechanical characterizations of soft tissues with micrometric resolution. We also discovered that smooth muscle cells in aneurysms become stronger and hypertrophic, which is a step towards possible development of pharmaceutical treatments for aneurysmsWP3. Regional variations of material properties in thoracic aneurysms were never observed before and our original results on mice confirm the major importance of localized remodelling in the progression of aortic aneurysms.WP4. We showed for the first time the correlation between the risk of rupture of aneurysms, their stiffness (the stiffer = the more brittle) and hemodynamics. These results are very important for the management of ATAA by clinicians. biolochanics-summary-for-publication.png
