Modeling of Intraluminal Thrombus Formation

A. Specific Aims Proper biomechanical modeling of the development of an intraluminal thrombus (ILT) has the potential to help us answer the question "Why do certain abdominal aortic aneurysms (AAAs) grow and eventually rupture?". The overall goal of this project, therefore, is to quantify the development of ILT from the initial blood clot to a mature formation, with special attention to axial changes in the clot structure. Our hypothesis is that AAA growth is a direct consequence of ILT development. Towards this end, we will combine and exploit three recent advances by our separate groups (Holzapfel at Graz, Karaj at Zagreb, and via continued collaboration Humphrey at New Haven): development of a new general theoretical framework for growth and remodeling (G&R) of ILT (radial changes), finite element simulations capable to address mass changes in living tissues, and a well-equipped laboratory with precisely defined experimental procedures for ILT specimens. Thus, the specific aims for this project are: Specific Aim 1: To develop a mathematical theory of growth and remodeling of an intraluminal thrombus considering its three main layers, i.e. luminal, medial, and abluminal. We will employ a rule-of-mixtures relation for the stress response and a full mixture theory for the turnover of constituents in a stressed configuration on axially symmetric geometry (axial and radial changes will be addressed). Specific Aim 2: To perform a set of experiments on samples harvested from open surgical aneurysm repair. Specimens will be submitted to mechanical testing (biaxial tensile and triaxial shear) and histological analysis (radial and axial changes of biomolecules, including proteases). Experimental results will be used to tune unknown parameters in the numerical model with mechanical data (macro-mechanics) and histological data (micro-mechanics). This will lead to more accurate ILT models capable of predicting the layered structure (luminal, medial, and abluminal), concentrations of elastases and collagenases diffusing into aortic wall, and eventually the rate of AAA enlargement. Specific Aim 3: To implement the developed mathematical model of ILT G&R in a finite element code capable of modeling evolving changes in structure and properties of complex living tissues such as AAAs. Results will be verified with available data from our experiments or with data available in the literature. Successful realization of these aims will advance the field of vascular mechanics by allowing, for the first time, quantification of the kinetics of an intraluminal thrombus within AAAs, and factors that significantly influence aneurysmal growth and risk of rupture.

Proper biomechanical modeling of the development of an intraluminal thrombus (ILT) has the potential to help us answer the question Why do certain abdominal aortic aneurysms (AAAs) grow and eventually rupture? The overall goal of this project, therefore, was to quantify the development of ILT from the initial blood clot to a mature formation, with special attention to axial changes in the clot structure. Our hypothesis is that AAA growth is a direct consequence of ILT development. Towards this end, we combined and exploit three recent advances: development of a new general theoretical framework for growth and remodeling (G&R) of ILT, finite element simulations capable to address mass changes in living tissues, and a well-equipped laboratory with precisely defined experimental procedures for ILT specimens. This project gave contribution in two very important aspects of our long-term goals: 1. We implemented a developed G&R theory within a finite element code. Results were verified with available data from our experiments and with data available in the literature mostly on the behavior of aortic walls. The developed mathematical G&R model is capable of modeling evolving changes in structure and properties of complex living tissues such as AAAs. 2. We performed a set of experiments to prove use of more accurate DIC (Digital Image Correlation) methods for the biaxial mechanical testing of soft tissue. Results were compared with traditionally used methods and showed certain improvements. This could lead to more accurate experiments, and accordingly to better tuning of material models.