Efferon® devices are based on proprietary technology developed and disclosed in international patents [1]
How it used to be?
LPS-selective adsorbents don’t
have pores of the required diameter
and morphology for effective removal
of excess of cytokines and other
exo- and endogenous toxins.
The porous structure of non-selective adsorbents does not yield efficient removal of associates and micelles of lipopolysaccharides from the whole
blood.
What is the novelty of
Efferon LPS technology?
The first component
of adsorbent — is hypercrosslinked polystyrene matrix
Polymers of this structure were first obtained and described by Davankov and Tsyurupa [3-4]. Their distinctive features are the degree of porosity that is unattainable for other organic polymeric materials (specific surface area of 700-900 m2/g) and low thrombogenicity due to its structure. Large closed cavities in their volume can reach a diameter of up to 100 nm, and the channels penetrating the matrix are much smaller. This structure provides fast mass transfer of small and medium proteins (which include DAMP, IL-6, IL-1b and other cytokines) and prevents the loss of larger proteins such as albumin (66 kDa).
The adsorption of cytokines in the pores proceeds according to a nonspecific mechanism (hydrophobic and van der Waals interactions) and is a reversible equilibrium process. As a result, the degree of removal turns out to be higher for the protein initially present in a higher concentration [5]. Thus, in the course of hemoperfusion through such adsorbents, cytokine clearance decreases over time. Such a mechanism is appropriate to reduce the peak concentrations of these important inflammatory mediators while maintaining levels above zero.
SEM picture of polymeric adsorbent
The second component of adsorbent is a synthetic ligand to the lipid A moiety of lipopolysaccharide, covalently immobilized on the surface of a hypercrosslinked polystyrene matrix
The ligand binding to glucosamine phosphate residues and hydrophobic acyl substituents of the LPS molecule proceeds by a mechanism similar to the binding of the LPS molecule to Polymyxin B enriched with lysine residues [6].
The molecular weight of monomeric LPS varies from 2.5 to 70 kDa and usually in the 10-20 kDa range. The sizes of LPS compounds with blood plasma proteins and cations Ca2+ and Mg2+ reach orders of magnitude larger, up to 1,000,000 kDa [7].
Strategies for removing LPS from blood based on adsorption in pores of a certain diameter are unable to reduce its concentration below therapeutically significant levels. On the contrary, LPS binding to the affinity ligand is an irreversible process. Bench experiments demonstrate [8] that the residual concentration of LPS in bovine blood after perfusion through unmodified hypercrosslinked polystyrene decreases only to 0.3-0.5 EU/ml (such high levels are associated with severe endotoxemia), while sorbent modified with LPS-binding ligand reduces the concentration of LPS below critical values (less than 0.05 EU/ml).
What is the result?
1. Bessonov I.V., Morozov A.S., Kopitsyna M.N. // A polymeric sorbent, preparation and use thereof, patent No WO2018217137, 2018.
2. Magomedov M.A., Kim T.G., Masolitin S.V., Yaralian A.V., Kalinin E.Yu., Pisarev V.M. // Use of sorbent based on hypercrosslinked styrene-divinylbenzene copolymer with immobilized LPS-selective ligand In hemoperfusion for treatment of patients with septic shock. General Reanimatology. 2020;16(6):31-53.
3. Davankov V.A., Rogozhin S.V., Tsjurupa M.P. // Macronet polystyrene structures for ionites and method of producing same, patent No US3729457A, 1973.
4. Davankov V.A., Tsyurupa M.P. // Structure and properties of hypercrosslinked polystyrene — the first representative of a new class of polymer networks. Reactive Polymers. 1990;13(1-2):27-42.
5. Honore P.M. et al. // Cytokine removal in human septic shock: Where are we and where are we going? Annals of intensive care. 2019;9(1):56.
6. David S.A. // Towards a rational development of anti‐endotoxin agents: novel approaches to sequestration of bacterial endotoxins with small molecules. Journal of Molecular Recognition. 2001;14(6):370-387.
7. Caroff M., Karibian D. // Structure of bacterial lipopolysaccharides. Carbohydrate Research. 2003;338(23):2431-2447.
8. Morozov A.S. et al. // A selective sorbent for removing bacterial endotoxins from blood. Russian Journal of Physical Chemistry A, 2016;90(12):2465-2470.