Filter Media

Abstract

The present disclosure provides a filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium. The present disclosure further provides a device comprising a filtration medium, the filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 171,476, filed April 6, 2021, the entire contents of which are incorporated herein by reference for all purposes. [Background technology]

[0002] ExThera Medical's Seraph® 100 is a CE marked device for reducing pathogens in bloodstream infections. Treatment with Seraph® 100 can remove greater than 34% and up to 99% of pathogens in the incoming patient's blood with each pass through the extracorporeal filter. At typical blood flow rates used in chronic dialysis and continuous renal replacement therapy, this treatment significantly reduces the patient's blood flow just a few hours after treatment begins.

[0003] More recently, Seraph® 100 has been shown to improve hemodynamic stability in cases requiring mechanical ventilation and vasopressor support in novel coronavirus disease (2019). In vasopressor treatment of COVID-19, body temperature, interleukin-6, and C-reactive protein levels were reduced after treatment with Seraph® 100. SARS-CoV-2 viremia was confirmed in tested patients and cleared by the completion of treatment (see Non-Patent Document 1). Because of the recommended treatment of COVID-19 patients, Seraph® 100 has been granted Emergency Use Authorization (EUA) by the FDA for the treatment of COVID-19 patients with respiratory involvement. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] SW Olson et al., Crit Care Explorer, August 2020, Issue 8 Summary of the Invention [Problem to be solved by the invention]

[0005] Despite the progress made to date, there remains a need for new filtration media for treating patients with acute kidney injury (AKI) or suffering from bloodstream infections or other inflammatory conditions. The present disclosure meets these needs while providing other advantages. [Means for solving the problem]

[0006] In certain embodiments, the present disclosure provides a filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium.

[0007] In another embodiment, the present disclosure provides a device, the device comprising a filtration medium, the filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium.

[0008] In some instances, the combination of (i) hollow fiber membrane and (ii) adsorption media described above reduces the total volume of the patient's blood passed through the extracorporeal device, thereby improving patient safety. Furthermore, by placing an adsorption media, such as a heparinized media, after or downstream of the hollow fiber membrane in the dialyzer, inflammation (e.g., cellular activation or release of inflammatory mediators) caused by the dialyzer is reduced or eliminated. Furthermore, by combining (i) hollow fiber membrane and (ii) adsorption media in a single housing or device, the total amount of housing surface area exposed to the patient's blood is reduced, potentially reducing foreign body immune responses. Furthermore, by combining the technologies in one device, less tubing is required, which further reduces the blood volume and surface area exposed to the tubing. Finally, by combining both technologies in one device, priming is simplified, and only one device needs to be degassed instead of two devices that need to be properly degassed. This simplifies the set-up and also reduces the risk of air embolism.

[0009] These and other aspects, objects and embodiments will become more apparent from a reading of the following detailed description and figures. [Brief description of the drawings]

[0010] [Figure 1] FIG. 1 shows an embodiment of the present invention. [Diagram 2] FIG. 2 shows an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] An extracorporeal blood circuit typically includes an arterial blood circuit with a dual or multi-lumen needle or arterial needle for withdrawing blood from the patient, a venous blood circuit with a venous needle at its tip for returning blood to the patient, and a filter between the arterial and venous blood circuits.

[0012] In an embodiment, the present disclosure provides a filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium. The filtration medium, method and device of the present disclosure are used in blood purification methods such as those used in hemodialysis and hemofiltration. For example, a subject's blood is circulated extracorporeally through a filtration medium as disclosed herein using a blood circuit consisting of flexible tubing and a filtration device.

[0013] A blood circuit having the filtration medium of the present disclosure can be used in hemodialysis, hemofiltration, or continuous or intermittent renal replacement therapy (RRT). The device can also be used in the context of a blood bank, where blood is stored and preserved.

[0014] In one aspect, the arterial blood circuit, the filtration medium, and the venous blood circuit are connected via flexible tubing, and blood drawn from the patient is brought into contact with the device and the filtration medium via the flexible tubing.

[0015] The subject's blood is withdrawn from the subject's body via an arterial blood circuit and introduced into the blood circuit, where it then flows through flexible tubing and into the device containing the separation medium.

[0016] In an embodiment, the disclosure provides a filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium, wherein blood that has passed through the filtration medium and then discharged therefrom is returned from the exterior to the interior of the subject's body, e.g., via a venous blood circuit, as blood with reduced concentrations of uremic substances, pathogens, inflammatory molecules, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), toxins, protein-bound uremic toxins, other septic mediators, and / or circulating tumor cells (CTCs).

[0017] The filtration media of the present disclosure are useful for reducing uremic substances, pathogens, and inflammatory molecules, and can be applied to patients with acute or chronic kidney injury (AKI), thereby reducing the concentration of uremic toxins and / or inflammatory molecules in the blood of patients with AKI or chronic kidney disease.

[0018] The filtration media of the present disclosure often comprises (i) a hollow fiber membrane and (ii) an adsorption media that allows blood to pass through but adsorbs toxins, pathogens, and other harmful substances. The hollow fiber membrane may be a plurality of hollow fiber membranes.

[0019] In one embodiment, the hollow fiber membrane is made of a polymer. Suitable polymers include, but are not limited to, polypropylene, polyethyleneimine-treated polyacrylonitrile (AN69), polymethyl methacrylate (PMMA), polysulfone (PSf), polyethersulfone (PES), polyvinylpyrrolidone (PVP), cellulose triacetate (CA), polyacrylonitrile (PAN), ethylene vinyl alcohol (EVOH), polyvinylidene fluoride (PVDF), and combinations thereof. The hollow fiber membrane is used in hemodialysis, hemofiltration, plasma separation, and the like.

[0020] The hollow fiber membranes can be hemocompatible. In some embodiments, the hollow fiber membranes comprise a polymer of polysulfone or a mixture of polysulfone and other polymers, such as polyvinylpyrrolidone, that can be spun together or used to coat the hollow fiber membranes.

[0021] In one embodiment, the thickness of the hollow fiber membrane is from about 0.01 mm to about 5 mm, e.g., about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 0.6 mm, 0.7 mm, 0.8 mm, 0.9 mm, 1 mm, 1.1 mm, 1.2 mm, 1.3 mm, 1.4 mm, 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 2.1 mm, 2.2 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 2.1 mm, 2.2 mm, 2.3 ...9 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2. 3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 0.8 mm, 0.9 mm, 3 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, and / or 5 mm. In one embodiment, the hollow fiber membrane is used as a hollow fiber membrane type module that is inserted into a housing, container, or device.

[0022] In one embodiment, the hollow fiber membranes are contained within a housing, for example, a bundle of multiple short or medium length hollow fiber membranes is inserted into a cylindrical housing as a hollow fiber membrane column.

[0023] In one aspect, the present disclosure provides a filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium, which is typically a coated substrate. Substrates suitable for adsorption media include, but are not limited to, non-porous rigid beads, including polymer beads, particles, or packings, reticulated foams, rigid monolithic layers (e.g., formed from sintered beads or particles), columns packed with woven or non-woven fabrics, columns packed with solid or hollow dense (non-microporous) monofilament fibers, spiral-wound cartridges formed from flat films or dense membranes, or combinations of media such as mixed bead / fiber cartridges. Substrates suitable for use in the present disclosure are those that are initially microporous, but become essentially non-porous when the surface is treated before, during, or after the formation of adsorption sites, for example, coated with end-point-attached polysaccharides such as heparin.

[0024] In some embodiments, the adsorption medium has a macroporous structure that provides a high surface area for blood or serum while preventing large pressure drops and high shear rates. High pressure drops should be avoided because they can damage the blood by hemolysis, as well as shut down extracorporeal circuits equipped with automatic shutoff functions in response to a pressure drop. The substrate can also take the form of a dense barrier membrane, for example in a spiral configuration. In some embodiments, the surface of the non-porous film is modified by a coating, for example, by binding heparin, heparan sulfate, or other adsorptive polysaccharides to the surface of the membrane, along with any adsorptive groups not derived from heparin, heparan sulfate, or adsorptive polysaccharides.

[0025] In one embodiment, the adsorption medium is a solid substrate with a surface coating. Suitable surface coatings include heparin, polyethyleneimine (PEI), sialic acid, hyaluronic acid, polyvinylpyrrolidone (PVP), and combinations thereof.

[0026] In certain other aspects, the surface coating includes, but is not limited to, monoclonal antibodies, proteins, carbohydrates, polysaccharides, and combinations thereof.

[0027] In one embodiment, the surface area of ​​the adsorption medium is about 5 m 2 and about 50m 2 For example, about 10 m 2 and about 20m 2 It is between.

[0028] In one embodiment, the filtration medium is provided packed inside a container or housing, such as a column, designed to hold the combination of hollow fiber membranes and adsorption medium without being carried away in the flowing blood ("preventing flow of the medium"), while allowing blood to flow across essentially all of the surfaces of the medium.

[0029] In one embodiment, the adsorption medium is a bead.

[0030] In some embodiments, the substrate of the adsorption medium is in the form of solid beads or particles. The "beads" can be made of a material (e.g., polymer beads) that is sufficiently rigid to resist deformation / compression under the flow rate or pressure encountered. Resistance to deformation is advantageous to maintain the interstitial dimensions and overall free volume of the packed bed contactor and to maintain a low subsequent pressure drop. Dimensional stability of the packed bed is also important to maintain sufficient separation between the beads to avoid blood cell filtration. The majority of the substrate is substantially free of accessible pores, eliminating the need for the adsorbate to diffuse into the pores prior to adsorption / binding. The adsorption sites of the present disclosure are primarily on the surface of the medium and therefore in accessible locations for adsorbates in the blood, many of which are carried to the surface by convective transport. A suitable substrate need not have a perfectly smooth surface, as roughness creates a desirable increase in surface area of ​​binding sites for ionic or preferably covalent attachment of, for example, heparin. On the other hand, accessible internal pores of molecular dimensions are largely avoided to eliminate the need for adsorbates to diffuse into the pores before attaching to the binding sites.

[0031] Various types of beads may be used in the present disclosure. Suitable beads are of sufficient size and rigidity to avoid deformation / compression during use in the present method, and have sufficient surface area to be coated with heparin and used in the present method.

[0032] Beads or other high surface area matrices may be made from a number of different biocompatible materials that are essentially free of leachable impurities, such as natural or synthetic polymers, or non-polymeric materials, including glass, ceramics, and metals. Some exemplary polymers include polyurethane, polymethylmethacrylate, copolymers of polyethylene or ethylene with other monomers, polyethyleneimine, polypropylene, and polyisobutylene. Examples of useful matrices include non-porous ultra-high molecular weight polyethylene (UHMWPE). Other suitable beads are optionally cross-linked polystyrene, high and low density polyethylene, silica, polyurea, and chitosan.

[0033] Methods for making such beads are known in the art. Polyethylene and other polyolefin beads can be produced directly during the polymer synthesis process and often can be used without further size reduction. Other polymers may need to be milled, or spray dried and classified, or otherwise processed to form beads of the desired size distribution and shape.

[0034] In some embodiments, the size of the flow passages or interstitial spaces between individual beads for extracorporeal hemofiltration reduces or eliminates high pressure drops between the inlet and outlet of the cartridge, allowing blood cells to safely pass between individual beads in high flow environments, and provides adequate interstitial surface area for binding polysaccharide adsorbents to toxins, cytokines, or pathogens in the blood. For a closely packed bed of 300 micron roughly spherical beads, a suitable interstitial pore size is about 68 microns in diameter. Useful beads have sizes ranging from about 100 microns to 500 microns or more in diameter, for example, 100 microns, 125 microns, 150 microns, 175 microns, 200 microns, 125 microns, 250 microns, 275 microns, 300 microns, 325 microns, 350 microns, 375 microns, 400 microns, 425 microns, 450 microns, 475 microns, and / or 500 microns. The average size of the beads may be 150 microns to 450 microns. For example, polyethylene beads from Polymer Technology Group, Berkeley, USA, having an average diameter of 0.3 mm are suitable. The interstitial porosity is a function of the size of the beads. In use, suitable beads are contained within a container such as a column.

[0035] In some embodiments, other suitable forms of the substrate include reticulated foam. Reticulated foam has open cells and is made, for example, from polyurethane and polyethylene. Control of pore size can be achieved by controlling the manufacturing process. Generally, reticulated foam can have 3-100 pores / inch and can be as small as 66 cm. 2 It can exhibit a larger surface area than

[0036] In one embodiment, the beads can be sintered into a monolithic porous structure through either chemical or physical means. Polyethylene beads can be sintered by heating the beads above their melting temperature in a cartridge and applying pressure. The resulting interstitial pore size is slightly reduced from the interstitial pore size of a packed bed of comparable sized unsintered beads. This reduction can be empirically determined and used to produce the desired final interstitial pore size.

[0037] In some aspects, the adsorptive polysaccharides of the adsorption media can be attached to the surface of a solid substrate (e.g., beads) in a variety of ways, including covalent or ionic attachment. The adsorption media can comprise heparin covalently attached to the surface of the solid substrate. In one embodiment, the heparin is attached to the solid substrate by covalent end-point attachment. This method improves the safety of the device by reducing or eliminating the release of heparin from the substrate surface that can enter the bloodstream. Elution of heparin into the bloodstream should be avoided, as it increases the risk of bleeding and heparin-induced thrombocytopenia. Covalent attachment of polysaccharides, e.g., heparin, to a solid substrate provides better control of parameters such as surface density and orientation of the immobilized molecules, as compared to non-covalent attachment. These parameters have been shown to be advantageous for providing optimal binding of antithrombin III, cytokines, or pathogens to the immobilized carbohydrate molecules. Surface densities of heparin on solid substrates are often 1-10 μg / cm. 2 Covalent end attachment means that the polysaccharide, e.g., heparin, is covalently attached to the solid substrate via the terminal residues of the heparin molecule. Heparin may also be attached to the surface at multiple points. However, end attachment is preferred.

[0038] In some embodiments, the heparin is full length heparin having an average molecular weight in the range of 15-25 kDa, for example an average molecular weight of about 21 kDa or greater.

[0039] In one embodiment, heparin is 1-20 μg / cm 2 of, for example, about 5-15 μg / cm 2 The surface density is

[0040] In one embodiment, the heparin is full-length heparin that is covalently attached to the solid substrate via a stable secondary amino group.

[0041] In one embodiment, the total surface area of ​​the solid substrate is between 0.5-3 m 2 The range is.

[0042] In some embodiments, the beads may be hydrophilized prior to attachment of a polysaccharide, such as heparin or other composition. Possible methods for preparing the beads include acid etching, plasma treatment, and exposure to strong oxidizing agents such as potassium permanganate.

[0043] In one embodiment, the adsorption medium is sized larger than the inner diameter of the hollow fiber membrane.

[0044] In another example, the adsorption medium includes a material similar to the filter or filtration device of the Seraph® Microbind® Affinity Blood Filter, which allows bodily fluids to pass through microbeads coated with molecular receptor sites that mimic the receptors on human cells that pathogens use to colonize the human body. The adsorption medium is a flexible platform that uses covalently immobilized heparin or heparan sulfate to exploit its unique binding capabilities. See, for example, U.S. Patent No. 8,663,148, U.S. Patent No. 8,758,286, or U.S. Patent No. 9,173,989, which disclose at least one polysaccharide adsorbent or immobilized heparin. Each of these patents is incorporated herein by reference.

[0045] In other examples, the adsorption medium can be a material similar to that of an extracorporeal hemosorption filter device for removing cytokines from the circulating blood, e.g., a biocompatible adsorption bead technology such as CytoSorb from CytoSorbent. CytoSorb hemosorption beads are polystyrene-divinylbenzene porous particles (average particle size 450 μm, pore size 0.8-5 nm, surface area 850 m) with a biocompatible polyvinyl-pyrrolidone coating. 2 See, for example, U.S. Patent No. 8,647,666, which claims a method of using a composition comprising a polystyrene-divinylbenzene copolymer and a polyvinyl-pyrrolidone polymer.

[0046] In one embodiment, the disclosure provides a device, the device comprising a filtration medium, the filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium.

[0047] Turning now to FIG. 1, one embodiment of the device 100 of the present disclosure is a column, housing, or vessel that contains or holds a filtration medium, the filtration medium including a combination of hollow fiber membranes and an adsorption medium. In this embodiment, the device 100 has a first end 101, a substantially cylindrical portion 102 that contains hollow fiber membranes 106, and a second end 108. During passage of blood through the device 100, the blood or bodily fluid enters the device 100 entirely through a connection device or adapter 110, such as a Luer connection device. The bodily fluid may pass through the device in a clockwise or counterclockwise direction. As shown in FIG. 1, the device has a first end cap 115a and a second end cap 115b. In this configuration, the adsorption medium 145a is contained within the portion 122a of the device between the first end cap 115a and the cylindrical portion 102. As shown, device 100 includes a first adsorption medium 145a, a hollow fiber membrane 106, and a second adsorption medium 145b, where hollow fiber membrane 106 is sandwiched between first adsorption medium 145a and second adsorption medium 145b. Adsorption media 145a and 145b may be the same or different.

[0048] The housing or device 100 has an inlet port 110 and an outlet port 152 for fluid to flow (e.g., blood or bodily fluid in its entirety) through the first adsorption medium 145a, the hollow fiber membrane 106, and the second adsorption medium 145b (in the direction of the arrows pointing from 101 to 108). In some embodiments, the first adsorption medium 145a, or alternatively the second adsorption medium 145b, may be optional. In this configuration, 122a or 122b are omitted and the device has only one adsorption medium portion.

[0049] In one embodiment, first adsorption medium 145a and second adsorption medium 145b are the same material, for example, heparin-coated beads.

[0050] In some embodiments, the first adsorption medium 145a and the second adsorption medium 145b are different materials, for example, the beads can have different polysaccharide coatings or different polysaccharide combinations.

[0051] In one embodiment, a screening or retention filter 158a is disposed between the hollow fibers 106 and the adsorption media 145a at the first end 101. Similarly, a screening or retention filter 158b is disposed between the hollow fibers 106 and the adsorption media 145b at the second end 108.

[0052] In one embodiment, the first end cap 115a and the second end cap 115b have attachments for the bodily fluid inlet 110 and / or bodily fluid outlet 152 of the device. In one embodiment, the attachments are luer fittings. Although the bodily fluid inlet 110 and bodily fluid outlet 152 of the device are illustrated, in alternative embodiments, bodily fluid may flow through the device in the opposite direction to the bodily fluid inlet 152 and bodily fluid outlet 110.

[0053] In one embodiment, the first sorption medium 145a is disposed between the pair of retention plates 158a, 160a. Similarly, in one embodiment, the second sorption medium 145b is disposed between the pair of retention plates 158b, 160b.

[0054] In one embodiment, the set of supporting plates is a screening substrate or a porous substrate.

[0055] In one embodiment, the first end cap 115a includes a hole 112a.

[0056] In one embodiment, the second end cap 115b includes a hole 112b.

[0057] In one aspect, the device has a first end cap 115a and a second end cap 115b with the filtration media disposed therebetween, 145a, 106, 145b. In alternative embodiments, either 145a or 145b are omitted.

[0058] In one embodiment, the device has gaps 170a and 170b between the retaining plate and the potting material.

[0059] In some embodiments, the device has a media fill port 182 .

[0060] Turning now to Figure 2, the present disclosure provides a device 200 that is attached directly to a dialyzer. In other words, in one embodiment, the device 200, when attached, allows a commercially available dialyzer to function similarly to the device 100 of Figure 1. For example, commercially available dialyzers typically include hollow fiber membranes made of polysulfone (PSf), modified cellulose, or ethylene-vinyl alcohol copolymer (EVAL), etc. The device 200 may be attached directly to either the top or bottom of the dialyzer, or even directly to both the top and bottom of the dialyzer with two devices.

[0061] 2 shows a device 200 of the present disclosure which is a column, housing or vessel containing an adsorption medium. In this embodiment, the device 200 has a first end 201, a portion 222 containing an adsorption medium 245, and a second end 208. During blood flow through the device 200, the entirety of the blood or bodily fluid enters the device 200 at the first end 201 through a connection device or adapter 210, such as a Luer connection device (e.g., a male adapter). As shown in FIG. 2, the device has a first end cap 215a and a second end cap 215b. In this configuration, the absorbent medium 245 is contained between the first end cap 215a and the cylindrical portion 222.

[0062] In one embodiment, screening or retention filter 258a is disposed between the adsorption media 245 at the first end 201. Similarly, screening or retention filter 258b is disposed between the adsorption media 245 at the second end 208.

[0063] In some embodiments, the first end cap 215a and the second end cap 215b have attachments for the bodily fluid inlet 210 and / or bodily fluid outlet 252 of the device. In some embodiments, the attachments are luer fittings. Although the bodily fluid inlet 210 and bodily fluid outlet 252 of the device are illustrated, in alternative embodiments, bodily fluid may flow through the device in the opposite direction to the bodily fluid inlet 252 and bodily fluid outlet 210.

[0064] In one embodiment, the adsorption medium 245 is disposed between a pair of retention plates 258a, 258b.

[0065] In one embodiment, the set of supporting plates is a screening substrate or a porous substrate.

[0066] In one embodiment, the first end cap 215a includes a hole 212a.

[0067] In one embodiment, the second end cap 215b includes a hole 212b.

[0068] In some embodiments, the device optionally includes a media fill port 282 .

[0069] In certain embodiments, the device is used for a therapy that is a member selected from the group consisting of hemodialysis, hemofiltration, renal replacement therapy (RRT), hemoperfusion, and / or glycocalyx replacement therapy.

[0070] In addition to dialysis machines, the devices and methods of the present disclosure may be used in combination with extracorporeal organ assist devices (ECOS), such as extracorporeal membrane oxygenators, extracorporeal CO2 removal (ECCO2R), and extracorporeal liver assist machines.

[0071] In some embodiments, the devices are used for acute kidney injury (AKI), or for patients suffering from a bloodstream infection or other inflammatory condition.

[0072] In one embodiment, the hollow fibers remove renal toxins, while the adsorption media removes pathogens, inflammatory molecules, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), toxins, circulating tumor cells (CTCs), protein-bound uremic toxins, and other sepsis mediators.

[0073] Comparative Example 1 A dialysis blood circuit is constructed using a commercially available dialyzer. Both the blood and the dialysate side of the dialyzer are primed with 500 ml of phosphate buffered saline (PBS) at a flow rate of 200 ml / min. Then, a test sample of mammalian blood containing urea and methicillin-resistant Staphylococcus aureus (MRSA) is passed through the system. A significant amount of urea is removed by the dialyzer, however, MRSA remains in the blood. After the blood sample passes through the blood circuit several times, inflammatory mediators such as IL-1β, TNF-α, IL-6, and IL-15, and chemokines such as IL-8 and GRO-α show increased concentrations in the blood sample.

[0074] Comparative Example 2 A dialysis blood circuit is constructed using a Seraph® Microbind® Affinity Blood Filter. Both the blood and dialysate sides of the hemofiltration device with Seraph® are primed with 500 ml of PBS at a flow rate of 200 ml / min. Then, a test sample of mammalian blood containing urea and methicillin-resistant Staphylococcus aureus (MRSA) is passed through the system. Only MRSA is removed from the sample, and urea remains in the blood sample.

[0075] (Experimental Example 1) The dialysis blood circuit is constructed using a commercially available dialyzer and a Seraph® Microbind® Affinity Blood Filter. Both the blood and the dialysate side of the dialyzer-filter combination are primed with 500 ml of PBS at a flow rate of 200 ml / min. A significant amount of urea is removed by the dialyzer and MRSA is removed by the Seraph® filter. After the blood sample passes through the blood circuit several times, no inflammatory mediators are present in the blood sample.

[0076] Comparative Example 3 In the first blood circuit, the blood circuit has two devices in series, (i) Seraph® Microbind® Affinity Blood Filter and (ii) a commercial dialyzer device, used in combination. In the second blood circuit, the device of the present invention is used as a single device, which is a combination of Seraph® Microbind® Affinity Blood Filter and dialyzer (hollow fiber membrane). By combining the two column technology (circuit 1) with the second blood circuit of the present invention (Seraph® Microbind® Affinity Blood Filter + dialyzer hollow fiber membrane) into a single column, several advantages are realized. The single column of the present invention reduces the blood volume by eliminating the need for two end caps of an additional column. Each column alone has two end caps, which takes up volume, and running in series in the first blood circuit means that there are four end caps. The hybrid device of the present invention requires only two end caps, and therefore the total blood volume is less.

[0077] For example, as an estimate, the total blood volume in blood circuit 1 (Seraph® Microbind® Affinity Blood Filter + dialyzer) is estimated to be about 250 mL. The blood volume of each of the Seraph® end caps is about 25 mL, and the dialyzer end cap is about 5 mL. Therefore, by combining all the end caps into blood circuit 1, it is estimated that about 60 mL of blood is required to fill its volume during use.

[0078] In contrast, the hybrid device of the present invention has two fewer end caps (one less from the Seraph® and one less from the dialyzer), estimated at 30 mL. This results in less blood being removed from the patient during treatment, resulting in a safer device. Hypotensive events, which often occur at the start of an extracorporeal session due to blood "losing" during the first few minutes of treatment, may also occur less frequently due to the smaller volume of blood.

[0079] Seraph® blood filters can be located either upstream or downstream of the dialyzer, but the Seraph® Microbind® Affinity Blood Filter can be used immediately upstream of the dialyzer to provide an antithrombogenic surface that can also function to prevent blood clotting within the dialyzer while acting as a depth filter to prevent microclots from entering and clogging the hollow fiber membranes of the dialyzer. This keeps the dialyzer running at peak efficiency and also prevents alarms that require the involvement of health care workers. Safety is improved through regular or intermittent prophylactic use of the small Seraph® cartridges to remove pathogens, thereby preventing serious bloodstream infections / sepsis, the second leading cause of death among chronic dialysis patients.

[0080] Those skilled in the art will readily appreciate that the above description is not exhaustive and that aspects of the disclosed subject matter may be practiced other than as specifically disclosed above. Indeed, embodiments of the disclosed subject matter may be implemented in hardware and / or software using any systems, structures, devices, and / or software known to, or later developed by, those skilled in the art that are applicable from the functional descriptions provided herein.

[0081] In this application, unless otherwise noted, the use of the singular includes the plural and the separate use of "or" and "and" includes the other, i.e., "and / or." Furthermore, the words "including" or "having," as well as other aspects such as "includes," "included," "has," or "had," are intended to have the same effect as "comprising," and therefore should not be understood as limiting.

[0082] Any range set forth herein should be understood to include the endpoints and all values ​​between those endpoints. Whenever the words "substantially," "approximately," "essentially," "near," or similar expressions are used in conjunction with a particular value, a variation of up to and including 10% of that value is contemplated, unless otherwise expressly stated.

[0083] It is therefore apparent that there has been provided, in accordance with the present disclosure, an extracorporeal blood treatment system and method for performing batch processing. This disclosure is susceptible to many alternatives, modifications, and variations. While specific examples have been shown and described in detail to illustrate the application of the principles of the invention, it should be understood that the invention may be embodied in other ways without departing from those principles. For example, the disclosed features may be combined, rearranged, omitted, etc. to provide additional embodiments. On the other hand, certain disclosed features may be used to advantage without the corresponding use of other features. Accordingly, the applicant intends to embrace all such alternatives, modifications, equivalents, and variations that are within the spirit and scope of the present invention. All documents mentioned throughout this disclosure are incorporated herein by reference.

Claims

1. A filtration medium comprising a combination of a hollow fiber membrane and an adsorption medium; The hollow fiber membrane is optionally a filtration medium made of a polymer.

2. (i) the polymer is a member selected from the group consisting of polypropylene, polyethyleneimine-treated polyacrylonitrile (AN69), polymethyl methacrylate (PMMA), polysulfone (PSf), polyethersulfone (PES), cellulose triacetate (CA), polyacrylonitrile (PAN), ethylene vinyl alcohol (EVOH), polyvinylidene fluoride (PVDF), and combinations thereof; or (ii) the adsorption medium is a surface-coated solid substrate, or (iii) the surface coating is optionally a member selected from the group consisting of heparin, polyethyleneimine (PEI), sialic acid, hyaluronic acid, polyvinylpyrrolidone (PVP), and combinations thereof; or 2. The filtration media of claim 1, wherein (iv) the surface coating is a member selected from the group consisting of monoclonal antibodies, proteins, carbohydrates, and combinations thereof.

3. The surface area of ​​the adsorption medium is about 5 m ２ and about 50m ２ or 3. The filtration medium of claim 1, wherein the surface area of ​​the adsorption medium is between about 10 m2 and about 20 m2.

4. 4. The filtration medium according to claim 1, wherein the adsorption medium has a size larger than an inner diameter of the hollow fiber membrane.

5. 5. The filtration medium of claim 1, wherein the adsorption medium is a bead.

6. A device, the device comprising a filtration medium, the filtration medium comprising a combination of (i) a hollow fiber membrane and (ii) an adsorption medium; Optionally, the filtration medium is a sandwich configuration of a first adsorption media portion, a hollow fiber membrane portion, and a second adsorption media portion, the hollow fiber membrane being sandwiched between the first adsorption media portion and the second adsorption media portion.

7. 7. The device of claim 6, wherein the hollow fiber membrane is made of a polymer, optionally selected from the group consisting of polypropylene, polyethyleneimine-treated polyacrylonitrile (AN69), polymethyl methacrylate (PMMA), polysulfone (PSf), polyethersulfone (PES), cellulose triacetate (CA), polyacrylonitrile (PAN), ethylene vinyl alcohol (EVOH), polyvinylidene fluoride (PVDF), and combinations thereof.

8. The adsorption medium is a solid substrate with a surface coating, The surface coating is optionally a member selected from the group consisting of heparin, polyethyleneimine (PEI), sialic acid, hyaluronic acid, polyvinylpyrrolidone (PVP), and combinations thereof; or 8. The device of claim 6, wherein the surface coating is a member selected from the group consisting of monoclonal antibodies, proteins, carbohydrates, and combinations thereof.

9. The surface area of ​​the adsorption medium is about 5 m ２ and about 50m ２ or 9. The device of claim 6, wherein the surface area of ​​the adsorption medium is between about 10 m2 and about 20 m2.

10. The adsorption medium is sized larger than the inner diameter of the hollow fiber membrane, or A screening or retention filter is placed between the hollow fibers and the adsorption medium, or 7. The device of claim 6, wherein the first and second end caps have attachments for a bodily fluid inlet and / or a bodily fluid outlet of the device.

11. 11. A device according to any one of claims 6 to 10, wherein the first adsorption medium portion is disposed between a pair of retaining plates.

12. The set of support plates is optionally a screening substrate or a porous substrate, or the second adsorption medium portion is disposed between the pair of retention plates; or The set of support plates is a screening substrate or a porous substrate; or The first end cap may include a hole or The device of claim 11 , wherein the second end cap comprises a hole.

13. Use of a filtration medium in the manufacture of a pharmaceutical product, said filtration medium comprising a combination of a hollow fiber membrane and an adsorption medium, said adsorption medium comprising a surface-coated solid substrate for reducing inflammation in a patient using a dialysis machine.

14. the surface coating is a member selected from the group consisting of heparin, polyethyleneimine (PEI), sialic acid, hyaluronic acid, polyvinylpyrrolidone (PVP), and combinations thereof; or 14. The use of claim 13, wherein the surface coating is a member selected from the group consisting of monoclonal antibodies, proteins, carbohydrates, and combinations thereof.

15. The surface area of ​​the adsorption medium is about 5 m ２ and about 50m ２ or The surface area of ​​the adsorption medium is between about 10 m2 and about 20 m2; or The adsorption medium is sized larger than the inner diameter of the upstream hollow fiber membrane, or 15. The use according to any one of claims 13 to 14, wherein the adsorption medium is a bead.

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