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 #
3R01HL098028-06S1
Application #
9718504
Study Section
Modeling and Analysis of Biological Systems Study Section (MABS)
Program Officer
Lee, Albert
Project Start
2010-12-15
Project End
2021-08-31
Budget Start
2018-09-15
Budget End
2019-08-31
Support Year
6
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Boston University
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
Yu, Xunjie; Wang, Yunjie; Zhang, Yanhang (2018) Transmural variation in elastin fiber orientation distribution in the arterial wall. J Mech Behav Biomed Mater 77:745-753
Wang, Yunjie; Hahn, Jacob; Zhang, Yanhang (2018) Mechanical Properties of Arterial Elastin With Water Loss. J Biomech Eng 140:
Zhang, Yanhang; Li, Jiangyu; Boutis, Gregory S (2017) The Coupled Bio-Chemo-Electro-Mechanical Behavior of Glucose Exposed Arterial Elastin. J Phys D Appl Phys 50:
Mattson, Jeffrey M; Turcotte, Raphaël; Zhang, Yanhang (2017) Glycosaminoglycans contribute to extracellular matrix fiber recruitment and arterial wall mechanics. Biomech Model Mechanobiol 16:213-225
Mattson, Jeffrey M; Zhang, Yanhang (2017) Structural and Functional Differences Between Porcine Aorta and Vena Cava. J Biomech Eng 139:
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
Wang, Yunjie; Zeinali-Davarani, Shahrokh; Zhang, Yanhang (2016) Arterial mechanics considering the structural and mechanical contributions of ECM constituents. J Biomech 49:2358-65
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 110:530-533
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
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 108:1758-1772

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