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

Mechanobiologic signals play critical roles in regulating cellular responses under both physiologic and pathologic conditions. Using a combination of synthetic biology and tissue engineering, we developed a mechanically-responsive bioartificial tissue that responds to mechanical loading to produce a pre-programmed 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. These cells were then engineered into living tissues constructs that respond to mechanical compression to drive the production of the anti-inflammatory biologic interleukin-1 receptor antagonist. Mechanical loading of these tissues constructs in the presence of the cytokine interleukin-1-alpha protected constructs from inflammatory degradation. This mechanogenetic approach enables long-term autonomous delivery of therapeutic compounds that are driven by physiologically-relevant mechanical loading with cell-scale mechanical force resolution. The development of synthetic mechanogenetic gene circuits provides a novel approach for the autonomous regulation of cell-based drug delivery systems.