title: A Biohybrid Device for the Systemic Control of Acute Inflammation.
abstract: Properly regulated inflammation facilitates recognition and reaction to injury or infection, but inadequate or overly robust inflammation can lead to disease. Sepsis is an inflammatory disease that accounts for nearly 10% of total U.S. deaths, costing more than $17 billion. Acute inflammation in sepsis may evolve too rapidly to be modulated appropriately, and we suggest that therapies should focus not on abolishing inflammation, but rather on attenuating the positive feedback cycle of inflammation/damage/inflammation. In Gram-negative sepsis, bacterial endotoxin causes inflammation and is driven and regulated by the cytokine tumor necrosis factor-α (TNF-α), which is, in turn, negatively regulated via its endogenous inhibitor, soluble TNF-α receptor (sTNFR). We generated stably gene-modified variants of human HepG2 hepatocytes, using lentiviral constructs coding for mouse sTNFR driven by the constitutive cytomegalovirus promoter, and seeded them in a scaled-down, experimental liver bioreactor. When connected to anesthetized, cannulated rats subjected to endotoxin infusion and maintained solely by the animals' circulation, this biohybrid device elevated circulating sTNFR, reduced the levels of TNF-α and other key inflammatory mediators, alleviated hypotension, and reduced circulating markers of organ damage. This novel class of biohybrid devices may bemodified for patient- and disease-specific application, and, thus, may represent a disruptive strategy that offers the potential for rational inflammation reprogramming.
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania. ; Center for Inflammation and Regenerative Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rami A
authors.initials: RA
authors.lastname: Namas
authors.forename: Maxim
authors.initials: M
authors.lastname: Mikheev
authors.forename: Jinling
authors.initials: J
authors.lastname: Yin
authors.forename: Patrick
authors.initials: P
authors.lastname: Over
authors.forename: Matthew
authors.initials: M
authors.lastname: Young
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Constantine
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.forename: Jörg
authors.initials: J
authors.lastname: Gerlach
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
keywords: biohybrid device; endotoxin; multiple organ dysfunction syndrome; sepsis; soluble tumor necrosis factor-alpha receptor 1; tumor necrosis factor alpha