Characterizing accelerated capture of deoligomerized TNF within hemoadsorption beads used to treat sepsis

Abstract

Sepsis is a systemic inflammatory response to infection, characterized by overexpression of cytokines in the circulating blood. Removal of cytokines and other inflammatory mediators from the blood may help attenuate systemic inflammation during sepsis and improve patient outcomes. In this work, we examined the dynamics of TNF capture within porous, polymeric sorbent beads used in a cytokine adsorption device. We sought to quantify how perturbation of TNF oligomeric structure accelerates TNF removal within the device. TNF was incubated with 10% DMSO for 24 h, which promoted complete monomerization of trimeric TNF, and accelerated TNF capture within the sorbent device compared with native TNF; removal halftime = 13.3 ± 1.5 min versus 112.8 ± 13.3 min, respectively. Intramolecular crosslinking stabilized the trimeric TNF structure and prevented DMSO monomerization. Results demonstrate that TNF is an unstable oligomeric molecule that can be dissociated into its smaller monomeric constituents to facilitate faster capture by hemoadsorption beads. Strategies to promote localized TNF deoligomerization at the sorbent surface may significantly accelerate TNF capture rates from the circulating blood using hemoadsorption as a treatment for sepsis. This concept could be extended to improve removal of other oligomeric molecules using size exclusion filtration materials for a variety of disease states.