Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR061988-01
Application #
8206400
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
2011-08-01
Budget End
2012-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$659,141
Indirect Cost

  Institution

Name
Tufts University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
073134835
City
Medford
State
MA
Country
United States
Zip Code
02155

  Publications

Levin, Michael; Pietak, Alexis M; Bischof, Johanna (2018) Planarian regeneration as a model of anatomical homeostasis: Recent progress in biophysical and computational approaches. Semin Cell Dev Biol :
Herrera-Rincon, Celia; Golding, Annie S; Moran, Kristine M et al. (2018) Brief Local Application of Progesterone via a Wearable Bioreactor Induces Long-Term Regenerative Response in Adult Xenopus Hindlimb. Cell Rep 25:1593-1609.e7
Ng, Johnathan; Wei, Yiyong; Zhou, Bin et al. (2018) Ectopic implantation of juvenile osteochondral tissues recapitulates endochondral ossification. J Tissue Eng Regen Med 12:468-478
Pai, Vaibhav P; Pietak, Alexis; Willocq, Valerie et al. (2018) HCN2 Rescues brain defects by enforcing endogenous voltage pre-patterns. Nat Commun 9:998
McLaughlin, Kelly A; Levin, Michael (2018) Bioelectric signaling in regeneration: Mechanisms of ionic controls of growth and form. Dev Biol 433:177-189
Estell, Eben G; Murphy, Lance A; Silverstein, Amy M et al. (2017) Fibroblast-like synoviocyte mechanosensitivity to fluid shear is modulated by interleukin-1?. J Biomech 60:91-99
Ng, Johnathan; Spiller, Kara; Bernhard, Jonathan et al. (2017) Biomimetic Approaches for Bone Tissue Engineering. Tissue Eng Part B Rev 23:480-493
O'Connell, Grace D; Tan, Andrea R; Cui, Victoria et al. (2017) Human chondrocyte migration behaviour to guide the development of engineered cartilage. J Tissue Eng Regen Med 11:877-886
Herrera-Rincon, Celia; Pai, Vaibhav P; Moran, Kristine M et al. (2017) The brain is required for normal muscle and nerve patterning during early Xenopus development. Nat Commun 8:587
Mathews, Juanita; Levin, Michael (2017) Gap junctional signaling in pattern regulation: Physiological network connectivity instructs growth and form. Dev Neurobiol 77:643-673

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