With the current development of non-invasive diagnostics to more accurately measure the level of cardiovascular diseases (CVDs) clinically, a significant """"""""platform science"""""""" component is better mechanistic understanding of underlying physics, such as structure-function mechanics of the arterial wall. Much of this fundamental understanding comes from the development and study of models for biomechanics, which will provide guidance for developing diagnostics, and implementation of these diagnostics to the clinical setting in turn provides data for refining the physics models. In this project, we seek to develop a multiscale predictive mechanobiology model of extracellular matrix (ECM) mechanics from a fundamental mechanics perspective coupled with critical biophysical input, and to provide a clinical relevant relationship between biomechanical integrity, biochemical composition stability, and microstructure of the ECM. Such model will enable researchers and clinicians to probe basic mechanisms, and to assist in rational design of new therapies for CVD.
Specific Aim 1 : Create a multiscale predictive mechanobiology model of ECM mechanics. Molecular - fiber level: a statistical mechanics based approach is adopted to determine the strain energy change accompanying deformation of a single fiber. A freely joined chain (FJC) model will be adopted to describe the possible configurations, thus entropy, of a fiber during stretching. Inter-molecular cross-linking density is a material parameter that determines the extensibility of a single fiber. Fiber - tissue level: advance the fiber-level model into a tissue-level model by incorporating fiber distribution function and adding fiber density as the next set of material parameter. A multiscale mechanobiological model that incorporates inter-molecular cross-linking, fiber distribution and fiber density will be achieved for the description of tissue-level function.
Specific Aim 2 : Validation of the model using an integrated experimental - modeling approach. Tissue-level ECM mechanics: the tissue-level behavior of ECM network will be fully characterized using biaxial-tensile test. Elastin and collagen network will be isolated from aortic tissue and tested individually. Fiber distribution function: the fiber orientation information of elastin and collagen will be obtained using confocal microscopy and directly incorporated into the model. Fiber density and cross-linking: the content and crosslinking density of elastin and collagen will be measured biochemically through biological assay. Corresponding material parameters in the model will be determined from fits to the biaxial-tensile testing data. 1

Public Health Relevance

In this project, we seek to develop a multiscale predictive mechanobiology model for the study of extracellular matrix mechanics from a fundamental mechanics perspective coupled with critical biophysical input. The proposed work will be accomplished through two specific aims that couple modeling and experimental work for a complete model development and validation. Results from this research will provide clinical relevant relationship between biomechanical integrity, biochemical composition stability, and microstructure of the ECM. 1

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL098028-02
Application #
8204481
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Larkin, Jennie E
Project Start
2010-12-15
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$286,271
Indirect Cost
$111,271
Name
Boston University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Wang, Yunjie; Zeinali-Davarani, Shahrokh; Zhang, Yanhang (2016) Arterial mechanics considering the structural and mechanical contributions of ECM constituents. J Biomech 49:2358-65
Mattson, Jeffrey M; Turcotte, Raphaël; Zhang, Yanhang (2016) Glycosaminoglycans contribute to extracellular matrix fiber recruitment and arterial wall mechanics. Biomech Model Mechanobiol :
Turcotte, Raphaël; Mattson, Jeffrey M; Wu, Juwell W et al. (2016) Molecular Order of Arterial Collagen Using Circular Polarization Second-Harmonic Generation Imaging. Biophys J 110:530-3
Zhang, Yanhang; Barocas, Victor H; Berceli, Scott A et al. (2016) Multi-scale Modeling of the Cardiovascular System: Disease Development, Progression, and Clinical Intervention. Ann Biomed Eng 44:2642-60
Fry, Jessica L; Shiraishi, Yasunaga; Turcotte, Raphaël et al. (2015) Vascular Smooth Muscle Sirtuin-1 Protects Against Aortic Dissection During Angiotensin II-Induced Hypertension. J Am Heart Assoc 4:e002384
Silverstein, Moshe C; Bilici, Kübra; Morgan, Steven W et al. (2015) 13C, 2h NMR studies of structural and dynamical modifications of glucose-exposed porcine aortic elastin. Biophys J 108:1758-72
Wang, Yunjie; Zeinali-Davarani, Shahrokh; Davis, Elaine C et al. (2015) Effect of glucose on the biomechanical function of arterial elastin. J Mech Behav Biomed Mater 49:244-54
Zeinali-Davarani, Shahrokh; Wang, Yunjie; Chow, Ming-Jay et al. (2015) Contribution of collagen fiber undulation to regional biomechanical properties along porcine thoracic aorta. J Biomech Eng 137:051001
Chow, Ming-Jay; Turcotte, Raphaël; Lin, Charles P et al. (2014) Arterial extracellular matrix: a mechanobiological study of the contributions and interactions of elastin and collagen. Biophys J 106:2684-92
Liu, Yuanming; Cai, Hong-Ling; Zelisko, Matthew et al. (2014) Ferroelectric switching of elastin. Proc Natl Acad Sci U S A 111:E2780-6

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