A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues.

Journal Article (Journal Article)

Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue loading is transduced into an osmotic signal that activates TRPV4. Either osmotic or mechanical loading of tissues transduced with TRPV4-responsive circuits protected constructs from inflammatory degradation by interleukin-1α. This synthetic mechanobiology approach was used to develop a mechanogenetic system to enable long-term, autonomously regulated drug delivery driven by physiologically relevant loading.

Full Text

Duke Authors

Cited Authors

  • Nims, RJ; Pferdehirt, L; Ho, NB; Savadipour, A; Lorentz, J; Sohi, S; Kassab, J; Ross, AK; O'Conor, CJ; Liedtke, WB; Zhang, B; McNulty, AL; Guilak, F

Published Date

  • January 2021

Published In

Volume / Issue

  • 7 / 5

PubMed ID

  • 33571125

Pubmed Central ID

  • PMC7840132

Electronic International Standard Serial Number (EISSN)

  • 2375-2548

Digital Object Identifier (DOI)

  • 10.1126/sciadv.abd9858


  • eng

Conference Location

  • United States