Methods for removing cytokines from blood with surface immobilized polysaccharides
Inventors
Ward, Robert S. • McCrea, Keith R. • Larm, Olle • Adolfsson, Lars
Assignees
EXTHERA MEDICAL LLC • Exthera Medical Corp
Publication Number
US-9408962-B2
Publication Date
2016-08-09
Expiration Date
2030-12-01
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Abstract
The present invention is directed to a method for removing cytokines and/or pathogens from blood or blood serum (blood) by contacting the blood with a solid, essentially non microporous substrate which has been surface treated with heparin, heparan sulfate and/or other molecules or chemical groups (the adsorbent media or media) having a binding affinity for the cytokine or pathogen(s) to be removed (the adsorbates), and wherein the size of the interstitial channels within said media is balanced with the amount of media surface area and the surface concentration of binding sites on the media in order to provide adequate adsorptive capacity while also allowing relatively high flow rates of blood through the adsorbent media.
Core Innovation
The invention provides a method for removing cytokines and/or pathogens from blood or blood serum by contacting the blood with a solid, essentially non-microporous substrate surface-treated with heparin, heparan sulfate, or other molecules with binding affinity for the target cytokines or pathogens. The substrate is designed with interstitial channels large enough to allow the transport of blood cells and promote high blood flow rates while maintaining significant surface area for adsorption.
This method addresses the problem of safely and effectively removing harmful substances such as cytokines and pathogens from blood, which is a challenge in conditions where elevated concentrations of these substances are linked to disease. Prior approaches using free heparin or porous adsorbents suffered from bleeding risks or inefficient adsorption at clinically relevant flow rates due to reliance on slow diffusion kinetics. The present invention achieves efficient removal by using convective transport to deliver adsorbates rapidly to binding sites on the substrate's surface.
The substrate may take the form of rigid beads, fibers, foams, or films, which are coated with polysaccharides through covalent or ionic attachment, with heparin frequently used to provide both selective adsorption and blood compatibility. By balancing interstitial channel size and surface area, the method enables clinically relevant adsorptive capacity during high-flow extracorporeal blood treatment procedures, offering an alternative to less effective or riskier blood purification techniques.
Claims Coverage
There are three independent claims, each defining a method for removing adsorbates from blood using specific characteristics pertaining to adsorbent substrate, transport mechanism, and functionalities.
Removal of adsorbates using convection on non-microporous polysaccharide-coated substrates
A method where a device comprises a container with a solid substrate of high surface area, the surface having at least one polysaccharide adsorbent with binding affinity for the target adsorbate (cytokine, pathogen, or toxin). The substrate is sufficiently solid to prevent passage of adsorbate through internal pores. Interstitial channel size is large enough to permit blood cell transport, with surface area sufficient for effective adsorption. When blood flows through the device, adsorbates are delivered to binding sites primarily by convection transport, and binding does not rely on Brownian diffusion into pores. The method requires that blood is flowed through the device for adsorbate removal.
Removal of adsorbates using rigid polyethylene beads with covalently attached heparin
A method involving a container with a solid substrate made up of rigid polyethylene beads that have heparin on their surface, with binding affinity for the adsorbate. The beads are sufficiently solid, interstitial channel spaces allow transport of blood cells, and the interstitial surface area supports interaction with flowing blood. Adsorbates are removed mainly via convection to the bead surface. Heparin is attached by covalent end-point attachment, in an amount of 0.5-10 mg per gram of bead. The method involves flowing blood through the device to remove the adsorbate.
Removal of adsorbates using a substrate with segregated portions for different binding functionalities
A method providing a device with a container containing a solid substrate of high surface area, where: - A first portion of the substrate includes surface-bound polysaccharide adsorbent(s) (such as heparin, heparan sulfate, hyaluronic acid, sialic acid, carbohydrates with mannose sequences, or chitosan) with binding sites for the adsorbate. - A second portion includes a solid substrate with a cationic, positively charged molecule (like chitosan or polyethylene imine), which is more thrombogenic than heparin. The substrate is non-microporous, with interstitial channel size enabling blood cell transport. Adsorbate removal occurs as flowing blood interacts with the substrate, with convection transport dominating and no requirement for Brownian diffusion into substrate pores.
The inventive features focus on methods of extracorporeal blood treatment, centering around non-microporous, polysaccharide-coated substrates configured for convective adsorption, with specific embodiments utilizing rigid polyethylene beads with covalently attached heparin and cartridges mixing various binding functionalities to enhance removal of cytokines, pathogens, and toxins.
Stated Advantages
Provides clinically-relevant adsorptive capacity at high, safe blood flow rates typical of extracorporeal circuits, enabling effective removal of cytokines and pathogens without requiring low flow rates.
Eliminates the need for systemic administration of free heparin, thereby reducing or eliminating bleeding complications associated with free heparin use.
Enables rapid removal of large molecular weight proteins and particles because forced convection, rather than slow molecular diffusion, transports adsorbates to the adsorbent sites.
Allows safe operation by designing the adsorption bed with large interstitial channels, preventing high pressure drops and minimizing risk of blood clotting or hemolysis.
Supports use of a mixture of different adsorbent media (e.g., heparinized and cationic/thrombogenic surfaces), allowing removal of a broader range of pathogens and toxins while maintaining blood compatibility.
Documented Applications
Used in extracorporeal blood treatments (e.g., dialysis, cardiopulmonary bypass, extracorporeal membrane oxygenation) to remove cytokines and/or pathogens with high-flow blood circuits.
Therapy for treating diseases characterized by elevated cytokines or pathogens, such as sepsis, by contact with the described adsorbent substrate and returning blood to the patient.
Prophylactic use during blood collection, transfusion of banked blood, or patient-to-patient transfusion to lessen or eliminate disease spread.
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