New multifunctional, degradable, polymeric biomaterial systems are needed that can be tailored to specific cell and tissue needs in vitro and in vivo. While protein-protein composites dominate tissue structure and function in our bodies, we have been unable to recapitulate the complexity and control of such systems in vitro for new biomaterials in order to direct cell and tissue functions. For example, material systems that can form mechanically robust and durable biomaterials to give highly flexible and dynamic biomaterials, remains a challenge. Our goal is to construct a panel of composite protein biomaterials that can cover a range of physical properties, to mimic the elasticity of diverse tissue structures and the consequential ability to control biological function - such as to direct stem cell responses. The hypothesis is that combinations of a highly elastic and dynamic structural protein (tropoelastin) with tough, durable proteins (silk) will generate new multifunctional protein composite systems that can offer a broad platform of utility to the biomaterials field. We propose to generate a new family of highly controllable composite fibrous protein systems, based on combinations of these two well-established structural proteins, tropoelastin and silk, both biodegradable protein polymers with good biocompatibility. These proteins encompass a range of biomaterial needs;tropoelastin provides highly flexible and dynamic structural features, silk provides mechanical toughness and slow degradation. Our findings of molecular-scale interactions between these two structural proteins, forms the basis of the present proposal. The experimental plans are focused on: (a) further elucidation of the mechanistic interactions between tropoelastin and silk to optimize control of material structure and function, (b) assessment of cell interactions for the range of materials generated to understand relationships between the protein composites, material compliance and cell outcomes, using hMSCs and cortical neurons, and in vivo screens of material degradation profiles and inflammatory responses, and (c) exploitation of the dynamic material properties achievable with these systems towards support of cell functions in vitro. The experimental plans are supported by extensive preliminary data that demonstrate our ability to generate the required materials (tropoelastin, silks), to functionalize the materials (e.g., surface chemistry),to probe the interactions among the two components with mechanistic insight, to process the proteins into new material formats, and to direct cell outcomes on these materials with outcomes dependent on the composition. The overall outcome from the plans would be a new protein composite biomaterials platform that would fill an important need in the field of biomaterials, with direct relevance to tough but flexible systems and strong, durable systems.

Public Health Relevance

There is a need for new biomaterials that are biocompatible, mechanically robust, can be formed into a wide range of biomaterials with different properties, and that can be use to control stem cell fate and function, which would provide a major advance to address biomedical demands and clinical needs. The goal of this study is to achieve such an outcome, by optimizing the molecular interface between tropoelastin and silk, making new composite materials and exploiting these new composite materials in a range of biomedical material applications. This impact is specifically highlighted in the revision with respect to cortical neuron growth and control in 2D and 3D systems. Further impact will be realized due to the range of mechanical properties achievable with this protein system, providing a biomaterials platform with a broad base of utility in the field of regenerative medicine when considered in combination with the diverse morphologies that can be formed (fibers, films, porous matrices for 1D, 2D and 3D, respectively), and the biocompatibility and degradability. !

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB014283-02
Application #
8518096
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Hunziker, Rosemarie
Project Start
2012-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$277,360
Indirect Cost
$60,578
Name
Tufts University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155
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Wise, Steven G; Yeo, Giselle C; Hiob, Matti A et al. (2014) Tropoelastin: a versatile, bioactive assembly module. Acta Biomater 10:1532-41
Lee, Pearl; Bax, Daniel V; Bilek, Marcela M M et al. (2014) A novel cell adhesion region in tropoelastin mediates attachment to integrin *V*5. J Biol Chem 289:1467-77
Fathi, Ali; Mithieux, Suzanne M; Wei, Hua et al. (2014) Elastin based cell-laden injectable hydrogels with tunable gelation, mechanical and biodegradation properties. Biomaterials 35:5425-35
Liu, Hongjuan; Wise, Steven G; Rnjak-Kovacina, Jelena et al. (2014) Biocompatibility of silk-tropoelastin protein polymers. Biomaterials 35:5138-47

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