? ? Connective soft tissues, which include skin, fascia, ligament, tendon, blood vessel, etc, rely upon extracellular matrix to provide the bulk of their mechanical properties. In the body, soft connective tissues must withstand the physical forces that are created by physiological processes and by movement in every day life. Collagenous extracellular matrix provides tensile load bearing properties in all soft connective tissues. In some connective tissues, such as skin and blood vessel, extracellular elastin also contributes recoil in response to tensile strain. If we are to engineer functional connective tissues """"""""from scratch"""""""", then it is crucial to understand the deposition and remodeling of extracellular matrix proteins, particularly collagen and elastin. Only by fundamentally understanding the processes that govern matrix formation in regenerative medicine can we successfully design functional connective tissues. While multiple investigators have successfully engineered individual tissues with good mechanical properties, we currently possess no tools for a more global understanding of the process of matrix formation. Mathematical models for matrix synthesis and mechanics, and bioreactor systems that allow imaging of matrix deposition are not readily at hand. Indeed, the focus of the NIH PAR 06-504, """"""""Enabling Technologies for Tissue Engineering and Regenerative Medicine"""""""", is on the development of just such tools. In this application, we will exploit and develop novel mathematical models, bioreactors, and non- invasive imaging systems to predict, track and quantify the deposition of extracellular matrix in vitro. The goal of this work is to generate novel, yet translatable, tools for understanding extracellular matrix formation. These tools, in turn, will fundamentally advance our abilities to grow connective tissues for regenerative medicine. The imaging, bioreactor and modeling approaches developed in this application will be directly translatable to other laboratories that are working in these areas. In order to ensure broad applicability of the tools created herein, we will use mathematical models, novel bioreactors and imaging systems to study matrix deposition in two commonly used tissue engineering systems: planar hydrogel scaffolds, and tubular mesh scaffolds. Planar hydrogel scaffolds will be used as a model of sheet-like connective tissues, such as fascia and ligament. Tubular mesh scaffolds will be used as a model of tubular connective tissues, such as blood vessels. In both of these experimental systems, we will apply novel bioreactors and non-invasive microscopy techniques, and will couple experimental design and observations with computational models of extracellular matrix formation, in order to advance our understanding of the deposition and remodeling of matrix proteins. The purpose of these studies is to develop broad, generalizable tools for use in tissue engineering and regenerative medicine. While methods for growing tissues have advanced, our abilities to predict how tissues will develop, and our abilities to monitor tissue growth, remain very limited. In this application, we will develop sophisticated mathematical models, non-invasive imaging techniques, and novel bioreactors that will allow us to precisely control and predict how new tissues will grow. (End of Abstract) ? ? ?

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-N (O1))
Program Officer
Hunziker, Rosemarie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Schools of Medicine
New Haven
United States
Zip Code
Huang, Angela H; Niklason, Laura E (2014) Engineering of arteries in vitro. Cell Mol Life Sci 71:2103-18
Lee, P-F; Bai, Y; Smith, R L et al. (2013) Angiogenic responses are enhanced in mechanically and microscopically characterized, microbial transglutaminase crosslinked collagen matrices with increased stiffness. Acta Biomater 9:7178-90
Simon, D D; Horgan, C O; Humphrey, J D (2012) Mechanical restrictions on biological responses by adherent cells within collagen gels. J Mech Behav Biomed Mater 14:216-26
Zhou, Jing; Niklason, Laura E (2012) Microfluidic artificial ""vessels"" for dynamic mechanical stimulation of mesenchymal stem cells. Integr Biol (Camb) 4:1487-97
Simon, D D; Humphrey, J D (2012) On a Class of Admissible Constitutive Behaviors in Free-Floating Engineered Tissues. Int J Non Linear Mech 47:173-178
Quint, Clay; Arief, Melissa; Muto, Akihito et al. (2012) Allogeneic human tissue-engineered blood vessel. J Vasc Surg 55:790-8
Quint, Clay; Kondo, Yuka; Manson, Roberto J et al. (2011) Decellularized tissue-engineered blood vessel as an arterial conduit. Proc Natl Acad Sci U S A 108:9214-9
Huang, Angela H; Niklason, Laura E (2011) Engineering biological-based vascular grafts using a pulsatile bioreactor. J Vis Exp :
Gui, Liqiong; Zhao, Liping; Spencer, Randal W et al. (2011) Development of novel biodegradable polymer scaffolds for vascular tissue engineering. Tissue Eng Part A 17:1191-200
Lee, Eun Jung; Niklason, Laura E (2010) A novel flow bioreactor for in vitro microvascularization. Tissue Eng Part C Methods 16:1191-200

Showing the most recent 10 out of 15 publications