Neutral Styrene Divinylbenzene Copolymers for Adsorption of Toxins in Liver Failure

Abstract

In artificial extracorporeal liver support systems, albumin-bound toxins such as bilirubin, bile acids, or aromatic amino acids are removed by adsorption to polymer beads. To overcome the potential weaknesses of anion exchange polymers currently used in liver support, namely, binding of heparin and activation of coagulation, we prepared two series of neutral polystyrene divinylbenzene resins with average pore sizes of 5-6 and 8-9 nm, respectively. In in vitro experiments using human plasma spiked with bilirubin, cholic acid, tryptophan, and phenol, we found that only pores larger than 5-6 nm were accessible to strongly albumin-bound substances, such as bilirubin. On the other hand, less strongly albumin-bound substances, such as bile acids, were efficiently bound by polymers of the small pore size range due to a higher accessible surface area. None of the neutral resins bound significant amounts of heparin. To assess the influence of the polymers on activation of coagulation, generation of thrombin-antithrombin complexes (TAT) was measured at different citrate concentrations. While none of the neutral polymers induced TAT generation, TAT levels were significantly elevated after incubation of plasma with an anion exchange polymer that is in clinical use for extracorporeal liver support. Binding characteristics of the neutral resins for the natural anticoagulants protein C and antithrombin showed remarkable differences, with weak binding of antithrombin but strong removal of protein C, not only for the anion exchanger, but also for neutral polymers of the large pore size range. In conclusion, neutral polystyrene divinylbenzene polymers with a pore size larger than 5-6 nm are efficient adsorbents for albumin-bound toxins that do not induce generation of thrombin-antithrombin complexes.

Removal of Bilirubin with a New Adsorbent System: In Vitro Kinetics

“…In LF, various extracorporeal therapies have been tried to support hepatic detoxification function, removing potentially toxic molecules, especially bilirubin [2][3][4][5][6][7][8][9][10][11], and controlling the inflammatory response [4,5].…”

“…The most widely studied hepatic toxin is bilirubin that is differentiated into hydrophobic unconjugated bilirubin, strongly albumin-bound [2] (association constant: 9.5 × 10 -7 M -1…”

“…We hypothesized that, thanks to its hydrophobicity, the resin might be able to adsorb bilirubin irreversibly, breaking its strong bond with albumin [2].…”

Affinity binding of antibodies to supermacroporous cryogel adsorbents with immobilized protein A for removal of anthrax toxin protective antigen

“…An attractive feature of the cryogelation technique is the possibility of macropore formation in which large interconnected pores ensure a large surface area for bioligand attachment allowing the production of adsorptive materials with a high capacity towards a target compound. This has recently been demonstrated by the use of a polystyrene microparticle embedded composite cryogel to effectively adsorb liver toxins such as bilirubin, bile acid, and aromatic amino acids indicating a potential application for extracorporeal blood purification for the removal of liver toxins [16].…”

Liver dialysis in acute-on-chronic liver failure: current and future perspectives

“…To exclude the limitations of the anion exchange polymers that are used in the current systems, i.e., binding of heparin and activation of coagulation, Weber et al prepared two series of neutral polystyrene divinylbenzene resins with average pore sizes of 5-6 and 8-9 nm, respectively. In vitro experiments showed that neutral polystyrene divinylbenzene polymers with a pore size larger than 5-6 nm acted as efficient adsorbents for albumin-bound toxins without inducing generation of thrombin-antithrombin complexes [57]. In another in vitro study by Dominik et al [58], three novel membranes of different pore sizes were compared with the MARS Flux membrane for cytokine removal and detoxification qualities in vitro.…”