Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - BIOLOCHANICS (Localization in biomechanics and mechanobiology of aneurysms: Towards personalized medicine)

Teaser

BIOLOCHANICS is a-five year project aimed at achieving patient-specific predictions of aneurysm risk of rupture and of aneurysm reactions to biochemical treatments.Rupture of Aortic Aneurysms (AA) kills more than 30,000 persons every year in Europe and the USA, It is a complex...

Summary

BIOLOCHANICS is a-five year project aimed at achieving patient-specific predictions of aneurysm risk of rupture and of aneurysm reactions to biochemical treatments.
Rupture of Aortic Aneurysms (AA) kills more than 30,000 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 reveals that major scientific challenges still have 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 relates to ensuring an objective prediction of localized mechanisms preceding rupture. A second challenge relates to modelling the patient-specific evolutions of material properties leading to the localized mechanisms preceding rupture. Addressing these challenges is the aim of BIOLOCHANICS.
AAs are an important issue for our society in the context of population ageing and of recently established screening programs in different European countries. Their mortality rate is between 3% and 5%. Following surgical operations, a stay in the intensive care unit is usually required, followed by another five to seven days in the hospital. Therefore, there is a need for nonsurgical treatment options presenting minimized invasiveness and less cost for the community without lowering the quality of care. This promises to be achieved with localized repairs of the aneurysm structure using targeted pharmacologic treatments and novel region-specific cell-based regenerative therapies. Nevertheless research still needs to overcome a number of challenges to translate these localized repairs to clinical practice. Personalized models of localization in aneurysm mechanobiology developed in the BIOLOCHANICS project will be an essential contribution to the success of this venture.
To achieve this, the specific objectives of the project regarding biomechanics are:
1. developing constitutive models of AA damage and failure that consider lengthscale parameters which are intrinsic to soft tissues. This requires implementing a nonlocal continuum theory and its extension to mechanobiology with the concept of constrained mixture.
2. characterizing point-wisely the stress-strain response of the AA tissues at the appropriate spatial resolution and solving inverse problems related to the distribution of the material properties.
3. validating the concepts at different levels, from in vitro experiments to in vivo clinical studies, for a final transfer to the clinical world.

Work performed

BIOLOCHANICS has four work packages (WPs) which are conducted in parallel. Below we summarize the main achievements of the first 18 months of the project:
WP1 (Fundamental research on novel enriched computational models for blood vessels): We have implemented the novel finite-element approach of BIOLOCHANICS based on the constrained mixture approach (a paper was recently submitted to Biomechanics and Modelling in Mechanobiology Journal) and started to apply it to the prediction of damage progression in aneurysms. We also started the extension of our computational approach for the prediction of growth and remodelling in aneurysms.
WP2 (Experimental characterization of localization mechanisms preceding rupture in blood vessels):
We purchased an optical coherence tomography (OCT system and a software for digital volume correlation (DVC)) for quantitative assessments of local strain fields related to the localized mechanisms preceding rupture in aneurysms. We are about to submit the first paper about the proof of concept of the method, which is completely novel for vascular biomechanics and which will permit for the first time ever to measure strains in the wall of thick arteries. Meanwhile, we are also developing mechanobiological experiments of induced proteolytic remodelling on porcine aortas collected from a local abattoir, in order to identify material properties and damage mechanisms preceding rupture in porcine thoracic aortas.
WP3 (In vivo application to genetic and pharmacological models of mice and rat aneurysms): This WP is done in collaboration with Prof. Jay Humphrey from Yale University in the USA. A PhD student at Yale (Matt Bersi) has already collected data on different mice models of aneurysms. We developed the inverse method based on the virtual fields method for the identification of the distribution of material properties across mice aneurysms at different stages of aneurysm progression. We have already published the proof of concept in the Journal of Biomechanical Engineering and will submit soon the first publication about regional variations of material properties in thoracic aneurysms of mice based on two models (Fib4 KO and Marfan).
WP4 (In vivo application to personalized predictions of aneurysm risk of rupture in humans): We acquired data on 20 patients in the first year of the project with the Saint-Etienne University Hospital (Beneficiary SEUH). The data include a 4D MRI, a dynamic CT scan, bulge inflation tests on the collected samples of aneurysm and histological analyses. We started the development of a new inverse method that will permit to reconstruct local stiffness distributions from the pre-operative images. We have already obtained results on five patients. We also initiated discussions with other groups having similar data on aneurysms in order to extend our database for the clinical validation of our assumptions. We have also started to collect data on smaller growing aneurysms in order to calibrate the growth and remodeling computational models of WP1 on real human data. Ten patients have been recruited already and they will be followed up during two years with MRI exams every six months.

Final results

For each of the four WPs, we have made great progress for the past 18 months. Our main achievements beyond the state of the art are:
WP1. Implementation of the constrained mixture model in the Abaqus software has been done for the first time ever for patient-specific predictions of aneurysm damage or growth. Transfer to open source software is planned for the second stage of the project as the simulations could be used for diagnosis in hospitals when we have done enough validations.
WP2. The use of OCT & DVC is completely novel for vascular biomechanics and it will permit for the first time ever to measure strains in the wall of thick arteries. There is potential to transfer the technique in other laboratories of vascular biomechanics. Transfer to in vivo non-invasive measurements is also a possibility that will be investigated further during the project.
WP3. Regional variations of material properties in thoracic aneurysms were never observed before and our first results on mice confirm the major importance of localized remodeling in the progression of aortic aneurysms.
WP4. We showed for the first time the correlation between the risk of rupture of aneurysms and their stiffness (the stiffer = the more brittle). These results are very important because the dynamic data acquired before the surgery permit to estimate the stiffness of the artery. We have shown that if we use these data, the brittleness of 10 patients’ aneurysm could have been predicted retrospectively. The impact for the prediction of potential risk of rupture is huge. For the moment, we still need to include more patients in the study and to determine a threshold of stiffness that would separate patient with high risk to other patients before transferring it to clinicians.