The role that biophysical forces play in regenerative medicine is expanding, with increased interest in the use of intrinsic electrical forces (via regulation of cell membrane channels) and externally applied electric fields (via bioreactor environments) as important control points. Despite significant potential of electrical signals for regenerative medicine, they have not yet been integrated into the design of tissue engineering systems. We propose a radically new strategy to improve connective tissue regeneration by electrotherapeutic control of cell function, through the integrated use of molecular and electrical control of cell function and tissue formation. Our hypothesis is that the synergistic application of molecular control of transmembrane ion flux and externally applied electric fields will improve the quality of cartilage and bone regeneration and accelerate their integration in vivo. We will rigorously test this hypothesis by studying the regeneration of composite bone/cartilage grafts. The regulation of cell function and tissue regeneration will be first studied in vitro using controlled bioreactor environments, and then in vivo in an orthotropic animal model of cartilage and bone regeneration.
Three specific aims will be pursued: (a) Biophysical regulation of chondrogenesis and osteogenesis in adult human stem cells, (b) Electrotherapeutic bioreactor models for regeneration of cartilage/bone tissues, and (c) Animal studies of cartilage/bone regeneration. The anticipated scientific impact will be in significant new insights into the biophysical control of connective tissue repair by modulation of electrical regulatory signals. The main technological impact will be in improved regeneration of cartilage/bone tissues, and the new generation of electrotherapeutic medical devices termed BioDomes.

Public Health Relevance

Radically new approaches are necessary for advancing the integration and healing of musculoskeletal tissues. The proposed studies are designed to enable in-depth understanding of the effects and mechanisms of electrical cellular control on connective tissue healing and regeneration. The scientific findings will be translated into the development of novel electrotherapeutic devices, BioDomes, for potential application in a range of regenerative medicine scenarios.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR061988-03
Application #
8517587
Study Section
Special Emphasis Panel (ZRG1-BST-M (02))
Program Officer
Wang, Fei
Project Start
2011-08-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$609,262
Indirect Cost
$100,454
Name
Tufts University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155
Bernhard, Jonathan C; Vunjak-Novakovic, Gordana (2016) Should we use cells, biomaterials, or tissue engineering for cartilage regeneration? Stem Cell Res Ther 7:56
Çakmak, Anıl S; Çakmak, Soner; White, James D et al. (2016) Synergistic effect of exogeneous and endogeneous electrostimulation on osteogenic differentiation of human mesenchymal stem cells seeded on silk scaffolds. J Orthop Res 34:581-90
Pai, Vaibhav P; Martyniuk, Christopher J; Echeverri, Karen et al. (2016) Genome-wide analysis reveals conserved transcriptional responses downstream of resting potential change in Xenopus embryos, axolotl regeneration, and human mesenchymal cell differentiation. Regeneration (Oxf) 3:3-25
Ng, Johnathan; Wei, Yiyong; Zhou, Bin et al. (2016) Extracellular matrix components and culture regimen selectively regulate cartilage formation by self-assembling human mesenchymal stem cells in vitro and in vivo. Stem Cell Res Ther 7:183
Li, Chunmei; Levin, Michael; Kaplan, David L (2016) Bioelectric modulation of macrophage polarization. Sci Rep 6:21044
Wobma, Holly; Vunjak-Novakovic, Gordana (2016) Tissue Engineering and Regenerative Medicine 2015: A Year in Review. Tissue Eng Part B Rev 22:101-13
Lobikin, Maria; Paré, Jean-François; Kaplan, David L et al. (2015) Selective depolarization of transmembrane potential alters muscle patterning and muscle cell localization in Xenopus laevis embryos. Int J Dev Biol 59:303-11
White, James D; Wang, Siran; Weiss, Anthony S et al. (2015) Silk-tropoelastin protein films for nerve guidance. Acta Biomater 14:1-10
Spiller, Kara L; Freytes, Donald O; Vunjak-Novakovic, Gordana (2015) Macrophages modulate engineered human tissues for enhanced vascularization and healing. Ann Biomed Eng 43:616-27
Yodmuang, Supansa; McNamara, Stephanie L; Nover, Adam B et al. (2015) Silk microfiber-reinforced silk hydrogel composites for functional cartilage tissue repair. Acta Biomater 11:27-36

Showing the most recent 10 out of 69 publications