Method 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-8758286-B2
Publication Date
2014-06-24
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 micro-porous 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 present invention is directed to a method for removing cytokines and/or pathogens from blood or blood serum by contacting the blood with a solid, essentially non-microporous substrate that has been surface treated with heparin, heparan sulfate, or other molecules or chemical groups having a binding affinity for the targeted cytokines or pathogens. The substrate’s interstitial channel size is balanced with the media’s surface area and the concentration of binding sites to provide both adequate adsorptive capacity and enable relatively high flow rates of blood through the adsorbent media. The process ensures that the transport of adsorbates to the media's binding sites occurs primarily through forced convection rather than the much slower process of molecular diffusion.
This invention contrasts with conventional porous adsorbent media, which require very slow flow rates to achieve significant separation due to reliance on diffusional transport of adsorbates into micropores. Instead, the use of substantially nonporous media with optimized interstitial channels allows for quick, high-throughput removal of cytokines and pathogens, providing clinically relevant adsorptive capacity under flow rates typical of clinical extracorporeal blood circuits used in treatments such as dialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation.
The problem being solved is the need for efficient removal of harmful blood-borne cytokines and pathogens—such as those present during sepsis or autoimmune disorders—without resorting to the systemic administration of free heparin, which has been associated with undesirable bleeding complications. The invention achieves efficacy without the use of systemic heparin by covalently binding heparin or similar adsorbents to a high-surface-area substrate, enabling high flow rates, reduced risk of clotting, and avoiding complications related to heparin leaching.
Additionally, the invention allows for the construction of devices that incorporate mixed adsorbent surfaces, such as combining heparinized and inherently thrombogenic but highly adsorptive surfaces, thereby extending removal capabilities to a broader spectrum of cytokines, pathogens, endotoxins, and bacteria, while maintaining blood compatibility during extracorporeal treatments.
Claims Coverage
The patent contains three independent claims, each defining inventive features related to devices for extracorporeal removal of cytokines, pathogens, and toxins from blood using solid substrates with surface-immobilized adsorbents and optimized convection-driven designs.
Device for removing cytokines, pathogens, and toxins from blood using a solid, non-microporous substrate with surface-immobilized polysaccharide adsorbent and convection transport
A container comprising a solid, high-surface-area substrate having at least one polysaccharide adsorbent immobilized on its surface, where: - The substrate is sufficiently solid to prevent passage of adsorbates through pores. - The interstitial channel spaces are large enough to permit transport of blood cells. - The amount of interstitial surface area enables contact between flowing blood and binding sites on the polysaccharide adsorbent, so the adsorbate (cytokine, pathogen, or toxin) binds and is separated from blood. - Transport of adsorbates from blood to adsorbent sites is primarily by convection, not Brownian diffusion into substrate pores.
Device with rigid polyethylene beads functionalized with covalently end-point attached heparin for adsorbate removal under convection conditions
A container containing a solid substrate of rigid polyethylene beads functionalized with heparin (with binding affinity for the adsorbate) on their surfaces, wherein: - The beads are sufficiently solid to prevent adsorbates from passing through pores. - Interstitial channel spaces allow blood cell transport and appropriate surface area for adsorbate binding during flow. - The heparin is covalently end-point attached in an amount of 0.5–10 mg heparin per gram of bead. - Adsorbate binding occurs by convection transport. - Configurations for flow rate, bead size, and specific cytokines are included.
Device comprising a solid substrate with two portions—one with polysaccharide adsorbent and one with more thrombogenic, cationic, positively charged adsorbent—for simultaneous removal of different blood components
A device containing a container with a high-surface-area solid substrate divided into: 1. A first portion with at least one polysaccharide adsorbent having binding sites for the adsorbate. 2. A second portion with a cationic, positively charged (more thrombogenic than heparin) molecule on its surface. - Both portions provide solid substrates allowing blood cell transport, proper interstitial channel access, and convection-driven adsorption of cytokines, pathogens, and toxins without Brownian diffusion into substrate pores.
The inventive features center on extracorporeal devices utilizing solid, essentially non-microporous substrates with immobilized polysaccharide adsorbents and/or cationic surfaces, optimized large interstitial channels, and convection-based transport, to effectively remove cytokines, pathogens, and toxins from blood.
Stated Advantages
Provides clinically relevant adsorptive capacity for cytokines and pathogens while allowing safe, high flow rates typically used in clinical extracorporeal blood circuits.
Eliminates the need for free, systemic heparin, thereby reducing the risk of bleeding complications associated with heparin administration.
Removes harmful cytokines and pathogens more rapidly than conventional microporous adsorbent media, due to convection-dominated transport rather than slow diffusion.
Reduces the risk of clot formation and minimises hemolysis by optimizing interstitial channel dimensions for blood cell passage while maintaining low pressure drop.
Enhances device safety by employing covalent end-point attachment of heparin to prevent leaching into the blood.
Allows for multifunctionality by incorporating different adsorbent chemistries to target a broader range of harmful substances in blood, while maintaining blood compatibility.
Documented Applications
Use in extracorporeal blood filtration and treatment devices, such as those used for dialysis, cardiopulmonary bypass, and extracorporeal membrane oxygenation.
Removal of cytokines and/or pathogens from blood or blood serum for the treatment of diseases characterized by elevated cytokine or pathogen levels, including sepsis.
Prevention and treatment of disease through removal of harmful substances from blood during collection, storage, and transfusion of blood or during direct transfusion between patients.
Selective removal of heparin-binding cytokines such as IL-6, VCAM, TNF-α, GRO-α, IL-8, and RANTES from blood.
Removal of specific pathogens including viruses (e.g., Adenovirus, Coronavirus, Dengue virus, Hepatitis B and C, HIV, HPV, Cytomegalovirus), bacteria (e.g., Bacillus anthracis, Chlamydia pneumoniae, Listeria monocytogenes, Pseudomonas aeruginosa, Staphylococcus aureus, MRSA, Streptococcus pyogenes, Yersinia enterocolitica), and parasites (e.g., Giardia lambitia, plasmodium spp.) from blood.
Combination with other blood filtration or separation methods, including operation in series with conventional extracorporeal circuits such as CPB, hemodialysis, and oxygenation.
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