AUTHOR=Namas Rami A. , Mikheev Maxim , Yin Jinling , Barclay Derek , Jefferson Bahiyyah , Mi Qi , Billiar Timothy R. , Zamora Ruben , Gerlach Jorg , Vodovotz Yoram 

TITLE=An adaptive, negative feedback circuit in a biohybrid device reprograms dynamic networks of systemic inflammation in vivo

JOURNAL=Frontiers in Systems Biology

VOLUME=2

YEAR=2023

URL=https://www.frontiersin.org/journals/systems-biology/articles/10.3389/fsysb.2022.926618

DOI=10.3389/fsysb.2022.926618

ISSN=2674-0702

ABSTRACT=<p><bold>Introduction:</bold> Systemic acute inflammation accompanies and underlies the pathobiology of sepsis but is also central to tissue healing. We demonstrated previously the <italic>in vivo</italic> feasibility of modulating the key inflammatory mediator tumor necrosis factor-alpha (TNF-α) through the constitutive production and systemic administration of soluble TNF-α receptor (sTNFR) via a biohybrid device.</p><p><bold>Methods:</bold> We have now created multiple, stably transfected human HepG2 cell line variants expressing the mouse NF-κB/sTNFR. In vitro, these cell lines vary with regard to baseline production of sTNFR, but all have ~3.5-fold elevations of sTNFR in response to TNF-α.</p><p><bold>Results:</bold> Both constitutive and TNF-α-inducible sTNFR constructs, seeded into multicompartment, capillary-membrane liver bioreactors could reprogram dynamic networks of systemic inflammation and modulate PaO<sub>2</sub>, a key physiological outcome, in both endotoxemic and septic rats.</p><p><bold>Discussion:</bold> Thus, Control of TNF-α may drive a new generation of tunable biohybrid devices for the rational reprogramming of acute inflammation.</p>