Disposable oxygen reduction kits, devices, and methods for using them.

Abstract

To provide an oxygen reduction method for improving the preservation of whole blood and blood components. [Solution] The present invention provides a method for collecting blood and blood components that yields whole blood and blood components with reduced oxygen levels. The present invention provides a method for rapidly preparing deoxygenated blood and blood components for storage, which improves the overall quality of transfused blood and improves patient health outcomes.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 131,130, filed Mar. 10, 2015, which is hereby incorporated by reference in its entirety.

[0002] The present disclosure relates to a disposable oxygen reduction kit (ORDKit), apparatus, and method for improving the preservation of whole blood and blood components. More particularly, the present disclosure relates to improved apparatus and methods for collecting blood and blood components to result in whole blood and blood components with reduced oxygen levels. The methods, apparatus, and kits of the present disclosure improve the quality of blood and blood components for transfusion and improve patient safety and outcomes.

Background Art

[0003] Currently, the supply of blood and blood components is limited by the storage systems used in conventional blood storage operations. Using the current system, the stored blood, as a concentrated blood cell preparation, is refrigerated at a temperature above the freezing temperature (i.e., 4°C) for a period of about 42 days, after which the storage period ends. For example, the World Health Organization (WHO) estimates that more than 100 million units of blood are collected and stored annually worldwide. According to the American Association of Blood Bankers, in the United States alone, 13.6 million units of red blood cells (RBCs) were collected in 2013. During refrigerated storage, RBCs are gradually damaged by storage injury. When transfused within the current six-week limit, the stored RBCs are of reduced quality and may be toxic, and these can manifest as side effects of transfusion therapy. Observed storage injuries include changes in biochemical and physical parameters associated with the stored red blood cells. Examples of these changes include parameters measured in vitro such as decreased metabolite levels (adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG)), increased cell-free iron levels, hemolysis, increased microparticle levels, reduced surface area, acanthocytosis, phosphatidylserine exposure, and decreased deformability. Blood at the end of the storage period cannot be used and must be discarded as it may harm the ultimate recipient. For these and other reasons, the amount of readily available high-quality blood required for transfusion is limited.

[0004] When stored using conventional methods, stored blood undergoes steady deterioration associated with hemolysis, hemoglobin breakdown, decreased ATP, and reduced 2,3-DPG concentration. When transfused to a patient, the effects of this steady deterioration during storage manifest, for example, as reduced in vivo recovery within 24 hours. Red blood cells stored under conventional conditions for extended periods deteriorate, and up to 25% may be removed by the recipient's body immediately after transfusion. In patients receiving long-term transfusions, iron overload can occur due to non-surviving RBCs. The loss of 2,3-DPG means that hemoglobin in RBCs does not efficiently release oxygen in tissues. Due to loss of deformability, RBCs cannot enter and perfuse the capillary bed. Storage damage to transfused blood can lead to major organ failure in the lungs, heart, kidneys, liver, and central nervous system, among others. Storage damage to transfused blood may also be associated with increased morbidity.

[0005] Under conventional conditions, transfusing long-stored red blood cells (RBCs) can lead to higher morbidity and longer hospital stays compared to transfusing "fresh" red blood cells. This higher morbidity and longer hospital stay are due to RBCs being stored for more than three weeks. For example, using "old" blood results in poorer clinical outcomes in cardiac surgery, and multiple organ failure in postoperative patients is related to the time elapsed since the collection of transfused red blood cells. There is a correlation between old units and increased mortality in severe sepsis, and the reason why improvements in O2 consumption are not achieved is due to a decrease in 2,3-DPG. The decrease in cardiac index is related to increased blood viscosity.

[0006] The effects of RBC preservation damage include, in addition to the immediate removal of specific RBCs by the recipient, (i) ATP depletion (loss of the ability of RBCs to dilate precapillary arterioles), (ii) 2,3-DPG depletion, (iii) accumulation of oxidative damage caused by reactive oxygen species (ROS) formed by the reaction of denatured hemoglobin with O2, and (iv) decreased RBC deformability and increased RBC viscosity, partly due to oxidative damage to the membrane and cytoskeleton. RBCs with reduced deformability are expelled from the capillary pathway, resulting in lower capillary occupancy and reduced tissue perfusion. Furthermore, transfusing large amounts of cells with reduced deformability can contribute to multiple organ failure by clogging the capillary bed of organs. After transfusion, 2,3-DPG is synthesized relatively rapidly in vivo, reaching about 50% of normal levels in just 7 hours and about 95% of normal levels in 2-3 days. However, 2,3-DPG-depleted cells do not immediately recover 2,3-DPG levels, and their oxygen-carrying capacity is impaired to such an extent that it harms critically ill patients who require rapid oxygen supply and tissue perfusion. Numerous reports highlight the importance of highly oxygen-carrying RBCs in such clinical situations.

[0007] Red blood cell (RBC) transfusion is a life-saving treatment aimed at improving oxygen supply to tissues and vital organs in patients with severe anemia. Most RBC units used for transfusion are stored in oxygen-permeable polyvinyl chloride blood bags containing additive / preservation solutions at 1-6°C for up to 42 days.

[0008] The preservation of frozen blood is known in the art, but such frozen blood has limitations. For many years, blood banks and the military have used frozen blood for certain high-demand and rare blood types. However, frozen blood is difficult to handle. It needs to be thawed, and the cryoprotectant must be gradually washed away, making it impractical in emergency situations. Once thawed, the blood must be used within 48 hours. U.S. Patent No. 6,413,713 by Serebrennikov concerns a method for preserving blood at temperatures below 0°C.

[0009] U.S. Patent No. 4,769,318 by Hamasaki et al. and U.S. Patent No. 4,880,786 by Sasakawa et al. concern additives for blood preservation and activation. U.S. Patents No. 5,624,794 by Bitensky et al., U.S. Patent No. 6,162,396 by Bitensky et al., and U.S. Patent No. 5,476,764 by Bitensky et al. concern the preservation of red blood cells under oxygen-depleted conditions. U.S. Patent No. 5,789,151 by Bitensky et al. concerns blood preservation additives. For example, Rejuvesol (available from Citra Lab LLC in Braintree, Massachusetts) is added to blood after refrigeration (i.e., 4°C), immediately before transfusion, or before freezing for long-term storage (i.e., freezing with glycerol at -80°C). U.S. Patent No. 6,447,987 by Hess et al. concerns additives for refrigerated preservation of human red blood cells.

[0010] U.S. Patent No. 4,837,047 by Sato et al. relates to a container for long-term storage of blood in order to maintain good blood quality.

[0011] Conventional manual blood collection is performed by a skilled phrebotomist using a blood collection kit that includes at least a blood collection bag, a venous needle, and enough tubing to connect the needle to the blood collection bag containing an anticoagulant. Typically, the blood collection bag also contains an anticoagulant, but instead, the anticoagulant may be in a separate bag or container connected to the blood collection bag by suitable tubing. None of the components of currently available systems result in or contain oxygen reduction.

[0012] At the time of blood collection, before storage, it is necessary to begin reducing the oxygen content of the blood. In order to achieve blood reduction within the timeframe limited by existing infrastructure and current regulatory regimes, it is desirable to begin reducing the oxygen content as early as possible, preferably at the time of collection, before the temperature of the collected blood drops significantly. [Overview of the project] [Means for solving the problem]

[0013] This disclosure provides, and includes, an oxygen depletion device for depleting oxygen from blood before anaerobic storage, comprising a substantially oxygen-impermeable outer container, a foldable inner blood container having one or more oxygen-permeable chambers, and an oxygen absorbent placed inside the outer container.

[0014] This disclosure provides, and includes, an oxygen depletion device for depleting oxygen from whole blood before anaerobic storage, comprising a substantially oxygen-impermeable outer container, a foldable inner blood container having one or more oxygen-permeable chambers, and an oxygen absorbent placed inside the outer container.

[0015] This disclosure provides, and includes, an oxygen depletion device for depleting oxygen from packed red blood cells before anaerobic storage, comprising a substantially oxygen-impermeable outer container, a foldable inner blood container having one or more oxygen-permeable chambers, and an oxygen absorbent placed inside the outer container.

[0016] This disclosure provides, and includes, a method for preparing blood for storage, comprising: preparing an oxygen depletion device comprising a substantially oxygen-impermeable outer container, a foldable inner blood container sealed in the outer container, and an oxygen absorber placed between the outer container and the blood-compatible inner blood container; introducing blood into the foldable inner blood container of the oxygen depletion device; and producing oxygen-reduced blood having an oxygen saturation of less than 20%.

[0017] This disclosure provides and includes a method for preparing blood for storage, comprising: preparing an oxygen depletion device comprising a substantially oxygen-impermeable outer container, a foldable inner blood container sealed in the outer container, and an oxygen absorber placed between the outer container and the blood-compatible inner blood container; introducing blood into the foldable inner blood container of the oxygen depletion device; and producing oxygen-reduced blood with an oxygen saturation of less than 10%.

[0018] This disclosure provides and includes a blood preservation device for storing oxygen-depleted blood, comprising: an outer container that is substantially oxygen-impermeable; a foldable inner blood container having a positioning mechanism adapted to adjust the position of a foldable blood container within the shape of the outer container; and at least one inlet having a tube connecting the foldable blood container to a joint to the outer container, wherein the joint to the outer container comprises a substantially oxygen-impermeable inlet and an oxygen absorbent placed inside the outer container.

[0019] This disclosure provides and includes an oxygen depletion device 10 for depleting oxygen from blood before anaerobic storage, comprising a substantially oxygen-impermeable outer container 101, an oxygen indicator 206, a spacer material 110, and approximately 80 grams of oxygen absorbent 103 between the outer container 101 and a foldable silicone blood container 102 having a thickness of 15 μm to 200 μm.

[0020] This disclosure provides and includes an oxygen depletion device 10 for depleting oxygen from blood before anaerobic storage, comprising a substantially oxygen-impermeable outer container 101, an oxygen indicator 206, a spacer material 110, and approximately 80 grams of oxygen absorbent 103 between the outer container 101 and a foldable blood container 102 made of PVDF with a pore size of 0.2 μm. This disclosure also provides a method for preparing blood for storage, comprising preparing the oxygen depletion device 10, introducing blood into a foldable inner blood container 102, shaking the oxygen depletion device 10 for up to 3 hours, producing oxygen-depleted blood with an oxygen saturation of less than 20%, and transferring the oxygen-depleted blood to a blood storage device 20. This method further provides producing oxygen-depleted blood with an oxygen saturation of less than 20% less than 8 hours after blood collection from a donor. In further embodiments, the shaking is nutation.

[0021] This disclosure relates to a method for reducing oxygen from whole blood or its components, wherein the absorption rate is at least 1.86 cubic centimeters (cc·g) per hour per gram of absorbent. -1 · hr -1 The present invention provides a method comprising: placing whole blood or a component thereof into an instrument 20 containing an absorbent 207; incubating the blood-filled instrument 20 at ambient temperature for up to 4 hours while shaking it at least once per second by translating it at least 3 cm; and transferring the blood-filled instrument 20 to a storage chamber at 4-6°C. In a further embodiment, the blood-filled instrument 20 is stored at 4-6°C for up to 42 days.

[0022] As just one example, several aspects of this disclosure will be described herein with reference to the accompanying drawings. While detailed drawings are specifically referenced below, it should be emphasized that the details shown are illustrative and intended to illustrate embodiments of this disclosure. In this regard, how aspects of this disclosure can be carried out will be apparent to those skilled in the art through the description with reference to the drawings. [Brief explanation of the drawing]

[0023] [Figure 1A] An exemplary embodiment of the oxygen depletion apparatus according to this disclosure, having two parallel compartments, is shown. [Figure 1B] An exemplary embodiment of the oxygen depletion apparatus according to this disclosure, having two parallel compartments, is shown. [Figure 1C] An exemplary embodiment of the oxygen depletion apparatus according to this disclosure, having two parallel compartments, is shown. [Figure 2A] An exemplary embodiment of the oxygen depletion apparatus according to this disclosure, having three parallel compartments, is shown. [Figure 2B] An exemplary embodiment of the oxygen depletion apparatus according to this disclosure, having three parallel compartments, is shown. [Figure 3A] Exemplary embodiments of the anaerobic storage bag described herein are shown. [Figure 3B] Exemplary embodiments of the anaerobic storage bag described herein are shown. [Figure 4A] In accordance with this disclosure, an exemplary embodiment of a disposable oxygen-reduced storage system having a blood depletion device having two compartments and an anaerobic storage bag is shown. [Figure 4B] In accordance with this disclosure, an exemplary embodiment of a disposable oxygen-reduced storage system having a blood depletion device having three compartments and an anaerobic storage bag is shown. [Figure 5] This graph shows the decrease in sO2 in an exemplary oxygen-depleting device according to the method disclosed herein. [Figure 6A] Exemplary embodiments of the anaerobic storage bag described herein are shown. [Figure 6B] Exemplary embodiments of the anaerobic storage bag described herein are shown. [Figure 7] In accordance with this disclosure, an exemplary embodiment of a bonding layer 105 that joins films 113 and 114 in a two-step process is shown. [Figure 8A] In accordance with this disclosure, an exemplary embodiment of a spacer 110 having an inner mesh 117 co-extruded with a binder mesh 118, and being bonded to a film 113 (114), is shown. [Figure 8B] In accordance with this disclosure, an exemplary embodiment of a spacer 110 having an inner mesh 117 co-extruded with a binder mesh 118, and being bonded to a film 113 (114), is shown. [Figure 9A] Exemplary embodiments of an anaerobic storage bag having a bonding layer 105 that joins membranes 113 and 114 are shown in accordance with this disclosure. [Figure 9B] An exemplary embodiment of an anaerobic storage bag is shown, having a binding layer 105 attached to membranes 113 and 114, which provides a seal 108, wherein the binding layer 105 extends beyond the seal 108 by a distance 109. [Figure 10A] This disclosure shows an exemplary embodiment of a bonding layer 105 having a geometric feature portion 121. [Figure 10B]This disclosure shows an exemplary embodiment of a bonding layer 105 having a geometric feature portion 121. [Figure 10C] This disclosure shows an exemplary embodiment of a bonding layer 105 having a geometric feature portion 121 and further comprising a mixed structure 109. [Figure 10D] This disclosure shows an exemplary embodiment of a bonding layer 105 having a geometric feature portion 121 and further comprising a mixed structure 109. [Figure 11] In accordance with this disclosure, exemplary embodiments of a foldable blood container having a spacer 110, a bonding layer 105, and a geometric feature portion 121 are shown. [Figure 12] This graph shows the decrease in sO2 in an exemplary oxygen-depleting device according to the method disclosed herein. [Figure 13] This graph shows the decrease in sO2 in exemplary foldable inner blood containers 102 having varying blood volumes, according to the method of the present disclosure. [Figure 14] This graph shows the decrease in sO2 in an exemplary oxygen-depleting device according to the method disclosed herein. [Figure 15] This graph shows the decrease in sO2 in exemplary oxygen-depleting devices with different surface areas, according to the method of this disclosure. [Figure 16] This graph shows the effect of spacer 110 on the reduction of sO2 in an exemplary oxygen depletion device according to the present disclosure.

[0024] In some of the drawings, corresponding reference numerals indicate corresponding parts. The examples shown herein illustrate some embodiments of the invention and should not be construed as limiting the scope of the invention in any way.

[0025] Given current technology, there is a need to improve the quality of stored blood and blood components such as red blood cells, extend the shelf life of such blood and blood components before transfusion, and minimize transfusion-related morbidity. To meet regulatory requirements and ensure reliability, the preparation and processing of red blood cells must be completed within a limited timeframe. Furthermore, the preparation process for oxygen-reduced blood and blood components must not cause damage (including, but not limited to, hemolysis of blood). And to produce improved quality blood and blood components, there is a need for methods and equipment compatible with existing anticoagulants and additives. [Modes for carrying out the invention]

[0026] To address the above and other needs, this disclosure provides instruments and measures for preserving blood and blood components, including instruments and measures for initiating the preparation of oxygen-reduced blood and blood components at the stage of blood collection from a donor.

[0027] Before describing at least one aspect of this disclosure in detail, it should be understood that this disclosure is not necessarily limited in its intended use to the details shown in the following description or illustrated by the examples. This disclosure may also be in other aspects and may be implemented or performed in various ways.

[0028] As used herein, the term “bag” refers to a collapsible container made from a flexible material, including pouches, tubes, and gusset bags. As used herein and as included in this disclosure, the term “bag” includes collapsible bags having one, two, three or more folds and having one, two, three or more edges sealed or joined. Bags may be made using a variety of techniques known in the art, including joining sheets of one or more materials. Methods of joining materials to form bags are known in the art. This disclosure also includes and provides containers made by injection molding and blow molding. Methods of making blow-molded and injection-molded containers are known in the art. A preferred type of blow-molded or injection-molded container is a flexible container that can be reduced in size for efficient packaging and transport and can be expanded when containing blood or blood components to reduce oxygen. These containers may be designed to conform to the volume of blood until fully expanded. As used throughout this disclosure, "bag" refers to a foldable container, and these two terms are used synonymously throughout this disclosure.

[0029] As used herein, the term “foldable container” includes bags, containers, sealing bags, outer bags, pouches, pockets, casings and other devices capable of containing and holding liquids or fluids. In certain embodiments, foldable containers may be manufactured by conventional means such as injection molding or insert molding. In other embodiments, foldable containers may be manufactured from sheets of polymer material joined together using methods known in the art to produce a container capable of holding volume. Such foldable containers are well known in the art. See, for example, U.S. Patent No. 3,942,529 issued to Waage, U.S. Patent No. 4,131,200 issued to Rinfret and U.S. Patent No. 5,382,526 issued to Gajewski et al. Preferred methods for joining polymer materials to produce foldable containers according to this disclosure include thermal welding, ultrasonic welding, radio frequency (RF) welding and solvent welding. In certain embodiments, a number of joining methods may be used to construct the foldable containers according to the Disclosure. The foldable containers according to the Disclosure include sealed bags having one or more pleats, folds, diaphragms, bubbles, and gussets. Methods for constructing foldable containers are known in the Art. See, for example, U.S. Patent No. 3,361,041 issued to Grob, U.S. Patent No. 4,731,978 issued to Martensson, U.S. Patent No. 4,998,990 issued to Richter et al., and U.S. Patent No. 4,262,581 issued to Ferrell. The Disclosure also includes and provides a container that combines both flexible and inflexible portions, wherein the flexible portion allows for volume expansion, for example, through pleats, folds, or gussets and other similar geometric features in the package shape, while the inflexible portion provides rigidity and geometric definition to the container. Methods and designs for producing foldable containers having both flexible and inflexible portions are known in the art, as described in U.S. Patent No. 6,164,821 by Randall and U.S. Patent No. 5,328,268 by LaFleur.

[0030] As used herein, the term "about" refers to a range of ±10%.

[0031] The words "comprises," "comprising," "includes," "including," and "having," along with their cognates, all mean "to include, but not limited to, ~."

[0032] The phrase "consisting of" means "including and limited to".

[0033] The phrase "consisting essentially of" means that the composition, method, or structure may include additional components, steps, and / or parts, provided that such additional components, steps, and / or parts do not materially alter the basic and novel features of the claimed composition, method, or structure.

[0034] As used herein, unless otherwise clearly indicated by the context, the singular forms "a," "an," and "the" include multiple references. For example, the terms "compound" or "at least one compound" may include multiple compounds, including mixtures thereof.

[0035] Throughout this application, various embodiments of the disclosure may be described in the form of scope. It should be understood that scope descriptions are for convenience and conciseness only and should not be interpreted as strictly limiting the scope of the disclosure. Therefore, scope descriptions should be considered to include all conceivable sub-ranges specifically disclosed and the individual numbers within those ranges. For example, a scope description such as "1-6" should be considered to include specifically disclosed sub-ranges such as "1-3," "1-4," "1-5," "2-4," "2-6," and "3-6," and the individual numbers within those ranges, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the scope.

[0036] Whenever a numerical range is given herein, it is intended to include all the numbers (fractions or integers) mentioned within that range. The phrases "a range between / and" the first number and the second number and "a range / and" from the first number to the second number are used synonymously herein and mean including the first number, the second number, and all fractions and numbers between them.

[0037] As used herein, the term “method” means a scheme, means, technique and procedure for accomplishing a given task, and includes, but is not limited to, schemes, means, techniques and procedures that are known to experts in the fields of chemistry, pharmacology, biology, biochemistry and medicine, or that can be readily devised by experts in the fields of chemistry, pharmacology, biology, biochemistry and medicine from known schemes, means, techniques and procedures.

[0038] This disclosure provides and includes an oxygen depletion device 10 for depleting oxygen from blood, comprising a substantially oxygen-impermeable outer container 101, an oxygen-permeable, foldable inner blood container 102, and an oxygen absorbent 103 placed inside the outer container 101.

[0039] This disclosure also provides, and includes, an oxygen depletion device 10 configured to be a blood collection and oxygen depletion device 10. The oxygen depletion device 10 as described herein differs from an oxygen depletion device configured to collect and reduce blood oxygen, in that the blood collection and oxygen depletion device 10 further contains an anticoagulant to prevent whole blood from clotting during the blood collection process. In certain embodiments, the anticoagulant of the blood collection and oxygen depletion device 10 is provided within the blood collection and oxygen depletion device 10. Therefore, the contained anticoagulant is also an oxygen depleted anticoagulant. In alternative embodiments, the anticoagulant may be contained separately as either an oxygen depleted solution or an oxygen-containing solution. The blood collection and oxygen depletion device 10 is intended to be used with whole blood collected from a donor. As used throughout this disclosure, the oxygen depletion device 10 includes, and provides, the blood collection and oxygen depletion device 10. These two terms can and are used synonymously.

[0040] As used herein, the outer container is made of a material that is substantially oxygen-impermeable and optionally carbon dioxide-impermeable. In certain embodiments, the outer container 101 is made of a flexible film material. In other embodiments, the outer container 101 is made of a rigid or non-flexible film material.

[0041] This disclosure provides and includes a substantially oxygen-impermeable outer container 101. As used herein, the substantially oxygen-impermeable outer container 101 is sufficiently oxygen-impermeable to the extent that the oxygen level in the container is 10 cc or less for three months, and more preferably 5 cc or less for six months. As used herein, the term substantially oxygen-impermeable (SiO) refers to a material or composition that provides a barrier against the movement of oxygen from one side of the barrier to the other, and that is sufficient to prevent a significant increase in the partial pressure of oxygen.

[0042] It is worth noting that few materials provide complete impermeability, and even highly impermeable materials can be compromised when joining, welding, folding, and assembling the outer container 101 in other ways. As discussed below, the oxygen depletion device 10 may further include one or more inlet / outlet ports 30 comprising a tube 301 and a joint 302 to the outer container 101 (or outer container 201 below). The outer container 101 must also be designed to accommodate changes in the volume of the foldable inner blood container 102. Therefore, special design elements and manufacturing methods should be incorporated with particular care to ensure the integrity of the impermeability barrier.

[0043] The disclosure also provides and includes an outer container 101 which is substantially oxygen-impermeable and has an oxygen permeability of less than about 1.0 cc per square meter per day. In certain embodiments, a film suitable for use in the manufacture of the outer container and other elements of the disclosure is a material characterized by a Valor value of less than about 0.140 Valor.

[0044] Materials and methods for fabricating the outer container 101 are known in the art. See, for example, U.S. Patent No. 7,041,800 issued to Gawryl et al., U.S. Patent No. 6,007,529 issued to Gustafsson et al., and U.S. Patent Application Publication No. 2013 / 0327677 by McDorman, which are incorporated herein by reference in their entirety. Impermeable materials are commonly used in the art, and any suitable material can be used. In the case of molded polymers, additives are usually added to enhance the oxygen (and CO2) barrier properties. See, for example, U.S. Patent No. 4,837,047 issued to Sato et al. For example, U.S. Patent No. 7,431,995 issued to Smith et al. describes an oxygen and carbon dioxide impermeable container composed of layers of ethylene vinyl alcohol copolymer and modified ethylene vinyl acetate copolymer that are impermeable to oxygen and carbon dioxide. In another embodiment, the outer container 101 is oxygen and carbon dioxide impermeable.

[0045] In certain embodiments, a substantially oxygen-impermeable film may be a laminate film. In one embodiment, a substantially oxygen-impermeable laminate film is a laminate foil film. The film material may be a polymer, a foil material, or a multilayer construction material combining foil and polymer. In one embodiment, the laminate film may be a polyester film laminated with aluminum. Examples of suitable substantially oxygen-impermeable aluminum laminate films (also known as laminate foils) are known in the art. For example, U.S. Patent No. 4,798,728 to Sugisawa discloses aluminum laminate foils of nylon, polyethylene, polyester, polypropylene and vinylidene chloride. Other laminate films are known in the art. For example, U.S. Patent No. 7,713,614 to Chow et al. discloses a multilayer container containing a substantially oxygen-impermeable ethylene-vinyl alcohol copolymer (EVOH) resin. In one embodiment, the outer container 101 may be a barrier bag constructed by sealing three or four edges by heat sealing. The bag is constructed of a multilayer construction material containing materials that enhance O2 and CO2 barrier properties. Examples of such materials include Rollprint Clearfoil® V2 film with an oxygen permeability rate of 0.01 cc / 100 square inch / 24 hours, Rollprint Clearfoil® X film with an oxygen permeability rate of 0.004 cc / 100 square inch / 24 hours, and Clearfoil® Z film (Rollprint Packaging Products, Addison, Illinois) with an oxygen permeability rate of 0.0008 cc / 100 square inch / 24 hours. Other manufacturers also produce similar products with similar oxygen permeability rates, such as Renolit Solmed Wrapflex® film (American Renolit Corp., Commerce, California).Examples of suitable aluminum laminate films (also known as laminate foils) that are substantially oxygen-impermeable are available from Protective Packaging Corp. (Carrollton, Texas).

[0046] Another approach applicable to the fabrication of SiO materials is the production of multilayer graphite films by the slow chemical reduction of graphene oxide laminates with hydroiodic acid and ascorbic acid. See Su et al., “Impermeable barrier films and protective coatings based on reduced graphene oxide,” Nature Communications 5, Article number: 4843 (2014), which is incorporated herein by reference in its entirety. Nanoparticles that enhance oxygen barrier properties are also known in the art, such as the multilayer barrier stack film supplied by Tera-Barrier (Tera-Barrier Films Pte, Ltd, The Aries, Singapore) and described by Rick Lingle in the August 12, 2014 issue of Packaging Digest Magazine.

[0047] In embodiments of this disclosure, the outer container 101 may be made of a gas-impermeable plastic. In one embodiment, the gas-impermeable plastic may be a laminate. In a particular embodiment, the laminate may be a transparent barrier film, such as a nylon polymer. In an embodiment, the laminate may be a polyester film. In one embodiment, the laminate may be Mylar®. In a particular embodiment, the laminate may be a metallized film. In one embodiment, the metallized film may be coated with aluminum. In another embodiment, the coating may be aluminum oxide. In another embodiment, the coating may be an ethylene vinyl alcohol copolymer (EVOH) laminated between layers of low-density polyethylene (LDPE).

[0048] The outer container 101 of this disclosure may be formed of one or more parts made from a gas-impermeable material including plastic or other strong, lightweight material. In some embodiments, the sealing bag may be formed from two or more materials. In one embodiment, the outer container 101 may be formed from a material coated with a gas-impermeable material to produce a gas-impermeable sealing bag. In one embodiment, the rigid or flexible outer container 101 may be made from an injection-molded plastic. In embodiments of this disclosure, this plastic may be selected from polystyrene, polyvinyl chloride or nylon. In one embodiment, the material of the outer container 101 may be selected from the group consisting of polyester (PES), polyethylene terephthalate (PET), polyethylene (PE), high-density polyethylene (HDPE), polyvinyl chloride (PVC), polyvinylidene chloride (PVDC), low-density polyethylene (LDPE), polypropylene (PP), polystyrene (PS), high-impact polystyrene (HIPS), polyamide (PA) (e.g., nylon), acrylonitrile butadiene styrene (ABS), polycarbonate (PC), polycarbonate / acrylonitrile butadiene styrene (PC / ABS), polyurethane (PU), melamine formaldehyde (MF), plaster, phenols (PF), polyether ether ketone (PEEK), polyetherimide (PEI) (Ultem), polylactic acid (PLA), polymethyl methacrylate (PMMA), polytetrafluoroethylene (PTFE), urea-formaldehyde, and ethylene vinyl alcohol copolymer (EVOH). In certain embodiments, the outer container 101 may be made of polyethylene. In some embodiments, the polyethylene outer container 101 may include one or more polyethylene components that are welded together. In certain embodiments, the outer container is made of a multilayer film having a polyethylene outer layer, a polyester inner layer, and an aluminum oxide barrier layer placed between the inner and outer layers, for example, Clearfoil® Z film (Rollprint Packaging Products, Addison, Illinois) with an oxygen permeability rate of 0.0008 cc / 100 square inches / 24 hours.

[0049] This disclosure provides, and includes, the fabrication of an outer container 101 from a film and a foldable inner blood container 102 from a membrane. As used herein, membrane generally refers to the material used to fabricate the foldable inner blood container 102, and film refers to the material used to fabricate the outer container 101. For clarity, unless otherwise indicated that film is substantially impermeable, it can be seen that certain materials may be referred to as “membrane” by a manufacturer, or certain materials may be commonly known as “membrane.” A membrane comprises one or more layers of material in the shape of a sheet that allows one or more substances to pass from one side of the sheet to the other side of the sheet. As used herein, a membrane may be fabricated as a tube suitable for connecting the components of an oxygen depletion device 10, a blood collection kit, or for connecting the components of a blood collection device, an additive bag, a leukocyte reduction filter, and an anaerobic storage bag. As used herein, it can be seen that, depending on the application, the membranes of this disclosure may be formed as sheets or tubes. Furthermore, as shown above, the film for making the outer container 101 is substantially oxygen-impermeable, while the foldable inner blood container 102 is oxygen-permeable. As used herein, the film may be made as a tube suitable for connecting the components of the oxygen depletion device 10 and the blood collection kit, or for connecting the components of the blood collection device, additive bag, leukocyte reduction filter and anaerobic storage bag. As used herein, the outer container 101 includes all embodiments of 102 as further described in paragraph

[0172] [Translator's note: in PCT / US2016 / 021794, pages 45, line 27 to 46, line 10, corresponding to

[0157] herein] and paragraph

[0175] [Translator's note: in PCT / US2016 / 021794, pages 46, line 24 to 47, line 3, corresponding to

[0160] herein].

[0050] As used herein, the foldable inner blood container 102 is oxygen-permeable. In certain embodiments, the foldable inner blood container 102 is oxygen-permeable and carbon dioxide-permeable. In other embodiments, the foldable inner blood container 102 is oxygen-impermeable and carbon dioxide-permeable.

[0051] This disclosure provides, and includes, methods for producing an outer container 101 using heat sealing, blow molding, and injection molding. Suitable materials for producing the outer container 101 using heat sealing, blow molding, and injection molding include PET, standard and multilayer polypropylene, polyethylene, polycarbonate, ABS, and other polymers known to those skilled in the art. Methods for producing a blow-molded and injection-molded outer container 101, for example, a multilayer structure consisting of a barrier layer of ethyl vinyl alcohol (EVOH) or ethyl vinyl acetate (EVA) placed between two layers of polypropylene (PP), and supplied by Kortec (Kortec, Inc., Raleigh, Massachusetts), are known in the art and described in U.S. Patent No. 5,906,285 issued to Slat. Additives that enhance oxygen barrier properties and CO2 barrier properties before molding, or during polymer compounding or curing, are known in the art. One example is co-injection of multilayer polymers, which results in multilayer PET. Such barrier resins are typically incorporated during the preform stage as an inner layer with PET on both sides, so that the PET forms the liquid contact layer and the outer layer. A suitable outer container 101, blow-molded or injection-molded as shown below, is oxygen-impermeable. In certain embodiments, a suitable outer container 101, heat-sealed, blow-molded or injection-molded, is substantially both oxygen-impermeable and carbon dioxide-impermeable.

[0052] This disclosure provides, and includes, two types of materials for making either a permeable membrane or a substantially impermeable film. In one embodiment, a permeable membrane according to this disclosure allows substances, specifically, but not limited to, oxygen, to pass through the material. In certain embodiments, the membrane is selected to allow oxygen and carbon dioxide to pass through, while not allowing water, proteins, salts (e.g., plasma components), and cells (e.g., red blood cells, white blood cells, and platelets). The rate at which substances pass through the material depends on one or more properties, including particle size, phase of the substance (liquid versus gas), hydrophilicity, hydrophobicity, or solubility. The rate or flux through the material also depends on the presence or absence of driving forces, such as a pressure difference (or partial pressure), temperature difference, or concentration difference between one side of the membrane and the other. The flux through a membrane is known as the membrane permeation flux. The membrane permeation flux of a substance passing through a membrane is inversely proportional to the thickness of the membrane.

[0053] Membrane permeation flux is defined as the volume flowing through a membrane per unit area per unit time for gases. The SI unit used is m. 3 / m 2 ·s. For gases and vapors, this volume is highly dependent on pressure and temperature. Therefore, the permeation flux of a gas is often determined in terms of standard temperature and pressure (STP), defined as 0°C and 1 atmosphere (1.0013 bar) (e.g., 273°K and 760 Torre). As mentioned above, the passage velocity depends on the driving force or the difference on both sides of the membrane, and this dependence is incorporated into the permeation coefficient P, i.e., simply permeability.

[0054] Permeability (P) is defined as the permeation flux per unit driving force per unit thickness. The SI units of the permeability coefficient P are shown in Table 1. As in this disclosure, the common unit for gas separation is the valor, which is also shown in Table 1. Gas cm 3 (STP) / cm 2 The term 's' refers to the intermembrane volume flux of a diffusive species under standard conditions of 0°C and 1 atmosphere, the term 'cm' refers to the film thickness, and 'cm-Hg' refers to the intermembrane partial pressure driving force of a diffusive species. Permeability must be determined experimentally. JPEG2026082938000002.jpg45155

[0055] Suitable membranes for the methods and apparatus of this disclosure include dense membranes, porous membranes, asymmetric membranes, and composite membranes. In certain embodiments, suitable membranes may be multilayer membranes. In other embodiments, suitable membranes are made from inorganic materials. A dense membrane is a membrane made from a solid material that has no pores or voids. Substances permeate through a dense membrane by processes of dissolution and diffusion. An example of a dense membrane is a silicone membrane (polydimethylsiloxane, i.e., PDMS). This disclosure also includes and provides porous membranes having pores in a specific size range, which perform separation based on size exclusion. Examples of porous membranes suitable for use in accordance with this disclosure include PVDF membranes and polysulfone membranes.

[0056] This disclosure includes and provides composite membranes made of two or more materials, often as laminates, in which a dense material is attached to a porous support layer. An example of a composite membrane suitable for use in accordance with this disclosure is EMD Millipore GVHP hydrophobic PVDF with a pore size of 1.0 μm or 0.22 μm. Table 2: Permeability of fluoropolymers (thickness 100 μm, 23°C) JPEG2026082938000003.jpg81160

[0057] The present disclosure provides, and includes, a foldable inner blood container 102 made from a membrane 113 that is primarily characterized by oxygen permeability. Unless otherwise defined, a "substantially impermeable membrane" refers to a membrane that is substantially oxygen-impermeable. However, in certain devices and methods, the membrane may be further characterized by carbon dioxide permeability or impermeability. In certain applications, the membrane material is substantially oxygen-impermeable and serves as a barrier against the ingress of oxygen into blood, blood components, or a blood collection kit composed of multiple components. Such a substantially impermeable membrane is generally used to fabricate the outer container of the present disclosure. A suitable substantially impermeable membrane may also be used to fabricate tubes for connecting components of the device and kit. The substantially impermeable membrane may include a single layer or may be a laminated sheet or tube having two or more layers.

[0058] The present disclosure also provides, and includes, a membrane 113 that is substantially oxygen-permeable. The substantially oxygen-permeable membrane 113 is used in the present disclosure to fabricate the foldable inner blood container 102. In certain embodiments, the oxygen-permeable membrane 113 is approved for long-term contact with blood transfused to a patient and is also a biocompatible membrane suitable therefor. Similar to the substantially impermeable membrane, the substantially permeable membrane 113 may include a single layer or may include a laminated structure having two or more layers.

[0059] In one aspect, for fabricating the foldable blood container 102, an oxygen-permeable membrane 113 having an oxygen permeability greater than about 2.5×10 -9 cm 3 O2(STP) / ((cm 2 s)*(cmHgcm -1 )) is used. In another aspect, for fabricating the foldable blood container 102, an oxygen-permeable membrane 113 having an oxygen permeability greater than about 5.0×10 -9 cm 3 O2(STP) / ((cm 2 s)*(cmHgcm -1 )) is used. In yet another aspect, the oxygen permeability of the oxygen-permeable membrane 113 is about 1.0×10-8 cm 3 O2(STP) / ((cm 2 s)*(cmHgcm -1 )) exceeds. In certain embodiments, an oxygen-permeable membrane 113 suitable for use in the fabrication of a foldable blood container 102 is characterized by a Valor value exceeding approximately 25. In other embodiments, an oxygen-permeable membrane 113 suitable for use in the fabrication of a foldable blood container 102 is characterized by a Valor value exceeding approximately 50. In certain other embodiments, an oxygen-permeable membrane 113 suitable for use in the fabrication of a foldable blood container 102 is characterized by a Valor value exceeding approximately 100.

[0060] In one embodiment, the substantially oxygen-permeable membrane 113 can be a dense membrane made from a non-porous material. Examples of suitable materials that can achieve a high oxygen permeability rate include silicone, polyolefin, epoxy, and polyester. In another embodiment, the substantially oxygen-permeable membrane can be a porous membrane made from an organic polymer. The substantially oxygen-permeable membrane 113 may be made from a material selected from the group consisting of hydrophobized PVDF, nylon, cellulose ester, polysulfone, polyethersulfone, hydrophobized polypropylene, and polyacrylonitrile.

[0061] This disclosure provides, and includes, a method for producing a substantially oxygen-permeable membrane 113 not only by selecting materials but also by selecting and controlling the thickness. As shown above, permeability is proportional to the thickness of the membrane. Therefore, improvement in permeability can be achieved by reducing the thickness of the membrane. In certain embodiments, the minimum thickness is determined by the strength and resistance to puncture and tearing.

[0062] This disclosure also provides, and includes, a substantially oxygen-permeable membrane 113, including membranes 113 manufactured using blow molding and injection molding methods. Suitable materials for manufacturing a foldable inner blood container 102 using blow molding and injection molding include silicone materials such as 50 durometer Bluestar 4350, Silbione grade liquid silicone rubber, and Shin-Etsu KEG-2000-40A / B liquid silicone. The selection of the silicone durometer should be carefully chosen for its foldability and permeability, and then the wall thickness should be adequately controlled. Thinner materials result in higher permeability. Methods for manufacturing blow-molded and injection-molded foldable blood containers 102 are known in the art, for example, in U.S. Patent No. 4,398,642 issued by Okudaira et al., U.S. Patent No. 7,666,486 issued by Sato et al., U.S. Patent No. 8,864,735 issued by Sano et al., and U.S. Patent Application Publication No. 2012 / 0146266 by Oda et al. In one embodiment, a blow-molded foldable blood container 102 can be manufactured using LDPE used in the manufacture of foldable water containers. The oxygen permeability of a suitable blow-molded or injection-molded foldable blood container 102 is at least about 25 bars, as set forth below.

[0063] In aspects of this disclosure, a foldable blood container 102 can be manufactured from a microporous membrane 113 by various sealing methods such as heat sealing, heat crimping, and adhesive bonding. In one aspect of this disclosure, a pair of PVDF microporous membranes are joined at the periphery using an adhesive such as Loctite 4011 together with an adhesive primer such as Loctite 770, with a PVC injection tube portion appropriately positioned at the seam. In another aspect of this disclosure, a foldable blood container can be manufactured from a pair of microporous membranes by heat sealing the four edges of the pair of membranes together, with a multilayer tube portion sealed at the seam to provide fluid communication.

[0064] This disclosure provides, and includes, a foldable blood container 102 made from two or more types of membranes 113. In one embodiment, the foldable blood container 102 comprises a first membrane 113 and a second membrane 114 suitably joined together to form the container. As used herein, membrane 114 generally refers to a membrane identical to membrane 113. That is, the foldable blood container 102 is generally made from two joined membranes 113. This disclosure provides, and includes, a foldable blood container 102 made from membranes 113 and membrane 114 containing different materials. As shown in Figure 1C, the foldable blood container 102 is shown to be made from membranes 113 and membrane 114. Unless otherwise specified, membranes 113 and membrane 114 may be interchangeable. In another embodiment, the foldable blood container 102 comprises a membrane 113 combined with a second membrane 114 whose permeability is less than 30% of that of the first membrane 113. In certain embodiments, the second membrane 114 may include a relatively impermeable or low-permeability membrane to perform sufficient deoxygenation on its own, but may be combined with a suitable membrane 113. In certain embodiments, the second membrane 114 is relatively impermeable. In further embodiments, the second membrane 114 includes a molded membrane incorporating ridges, baffles or other structures to facilitate mixing. In one embodiment, the second membrane 114 may include a rigid structure bonded to the oxygen-permeable membrane 113. In embodiments according to this disclosure, the second membrane 114 is heat-sealed to the membrane 113.

[0065] In certain embodiments, the collapsible inner blood container 102 includes flow baffles positioned inside or outside the blood contact area, which, when shaken, increase turbulence within the collapsible blood container 102. In one embodiment, the baffles are positioned at a distance of 1 to 2 inches from each other and occupy 10 to 45% of the area of ​​the collapsible inner blood container 102.

[0066] This disclosure provides and includes a foldable blood container 102 which is substantially oxygen-permeable and is a microporous membrane made from polyvinylidene fluoride or polyvinylidene difluoride (PVDF). In certain embodiments, the PVDF membrane is a substantially oxygen-permeable hydrophobic microporous membrane.

[0067] In aspects of this disclosure, the microporous PVDF film contains pores ranging from 0.01 μm to 2.0 μm. In other aspects, the microporous PVDF film 113 contains pores ranging from 0.01 μm to 1.0 μm. In some aspects, the pore size of the microporous PVDF film 113 is 0.03 μm to 1.0 μm in diameter. In other aspects, the pore size of the microporous PVDF film 113 is 0.03 μm to 0.45 μm in diameter.

[0068] In an embodiment of this disclosure, the void ratio of the PVDF membrane 113 used to produce the foldable blood container 102 is 20-80%. In another embodiment, the void ratio of the PVDF membrane 113 used to produce the foldable blood container 102 is 35-50%.

[0069] In certain embodiments, the permeability of PVDF films with pores larger than approximately 1.0 μm may allow fluids to pass through the film, impairing both the fluid containment ability and the oxygen and carbon dioxide permeability. To address this permeability at larger pore sizes, so-called "superhydrophobic" films with contact angles greater than 150° can be employed. As used herein and as known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of non-hydrophobic PVDF materials is not recommended because the surface tension of the material is lower, and even within the above range, fluids may seep out of the pores.

[0070] In certain embodiments of this disclosure, the foldable blood container 102 is made from a PVDF permeable membrane 113 with a pore size of 0.1 to 0.8 μm in diameter. In another embodiment, the micropores of the porous PVDF membrane may be 0.22 to 0.8 μm in diameter. In one embodiment, the micropores of the porous PVDF membrane are 0.2 to 1.0 μm. In another embodiment, the micropores of the porous PVDF membrane may be greater than 0.1 μm and less than 1.0 μm. In yet another embodiment, the micropores of the porous PVDF membrane are in the range of about 0.05 to about 1.0 μm. In some embodiments, the micropores of the porous PVDF membrane are greater than 0.3 or 0.4 μm. In another embodiment, the micropores of the porous PVDF membrane are greater than 0.5 or 0.6 μm.

[0071] In an aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of less than 1.0 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of less than 0.8 μm. In a particular aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of less than 0.65 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of less than 0.45 μm.

[0072] In an embodiment of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of 0.1 μm. In another embodiment, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of 0.22 μm. In yet another embodiment, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of 0.20 μm. In a further embodiment of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of 0.45 μm. In a further embodiment, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of 0.65 μm. In another aspect of the present disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PVDF membrane 113 with a micropore size of 0.8 μm.

[0073] In some embodiments of this disclosure, the PVDF membrane may be less than 250 μm thick. In certain embodiments, the membrane is more than 10 μm thick. In some embodiments, the PVDF membrane may be 10 to 250 μm thick. In other embodiments, the PVDF membrane may be 10 to 125 μm thick or 25 to 150 μm thick. In one embodiment, the PVDF membrane may be 50 to 125 μm thick, 75 to 125 μm thick, 50 to 150 μm thick, 75 to 150 μm thick, 100 to 125 μm thick, 150 to 250 μm thick or 25 to 150 μm thick. In one embodiment, the membrane 113 of the foldable inner blood container 102 is about 20 μm thick. In another embodiment, the membrane 113 of the foldable inner blood container 102 is about 30 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is about 50 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is about 76 μm thick. In one embodiment, the membrane 113 of the foldable inner blood container 102 is about 120 μm thick.

[0074] In certain embodiments of this disclosure, the foldable blood container 102 is made from a PVDF permeable membrane 113 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a PVDF permeable membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a PVDF permeable membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 50 to 150 μm.

[0075] Examples of PVDF membranes suitable for fabricating oxygen-permeable, foldable inner blood containers in accordance with this disclosure include VVSP (115 μm thickness / 0.1 μm pores), GVSP (115 μm thickness / 0.22 μm pores), HVSP (115 μm thickness / 0.45 μm pores), DVSP (115 μm thickness / 0.65 μm pores), BVSP (115 μm thickness / 1.0 μm pores), VVHP (107 μm thickness / 0.1 μm pores), GVHP (125 μm thickness / 0.22 μm pores), HVHP (115 μm thickness / 0.45 μm pores), or DVHP (115 μm thickness / 0.65 μm pores).

[0076] Suitable PVDF membranes include commercially available membranes. Non-limiting examples of PVDF membranes are available from Millipore Corporation in Bedford, Massachusetts. In one embodiment, the PVDF membrane may be obtained from Millipore Corporation in Bedford, Massachusetts. Examples of such PVDF membranes include VVSP, GVSP, HVSP, DVSP, BVSP, VVHP, GVHP, HVHP, or DVHP.

[0077] This disclosure provides and includes a foldable blood container 102 which is a substantially oxygen-permeable microporous membrane made from polysulfone. In certain embodiments, the polysulfone membrane is a substantially oxygen-permeable hydrophobic microporous membrane.

[0078] In aspects of this disclosure, the microporous polysulfone membrane has pores ranging from 0.01 μm to 2.0 μm. In another aspect, the microporous polysulfone membrane 113 has pores ranging from 0.01 μm to 1.0 μm. In some aspects, the pore size of the microporous polysulfone membrane 113 is 0.03 μm to 1.0 μm in diameter. In another aspect, the pore size of the microporous polysulfone membrane 113 is 0.03 μm to 0.45 μm in diameter.

[0079] In an embodiment of this disclosure, the void ratio of the polysulfone membrane 113 used to produce the foldable blood container 102 is 20 to 80%. In another embodiment, the void ratio of the polysulfone membrane 113 used to produce the foldable blood container 102 is 35 to 50%.

[0080] In certain embodiments, permeable polysulfone films with pores larger than approximately 0.2 μm may allow fluids to pass through the film, impairing both fluid containment and oxygen and carbon dioxide permeability. To address this permeability at larger pore sizes, so-called "superhydrophobic" films with contact angles greater than 150° can be employed. As used herein and as known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of non-hydrophobic polysulfone materials is not recommended because the surface tension of the material is lower and fluids may seep out of the pores even within the above range.

[0081] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polysulfone membrane 113 having a pore size of 0.3 μm to 0.8 μm in diameter. In another embodiment, the micropores of the porous polysulfone membrane may be 0.22 μm to 0.8 μm in diameter. In one embodiment, the micropores of the porous polysulfone membrane are 0.2 μm to 1.0 μm. In another embodiment, the micropores of the porous polysulfone membrane may be greater than 0.1 μm and less than 1.0 μm. In yet another embodiment, the micropores of the porous polysulfone membrane are in the range of about 0.05 μm to about 1.0 μm. In some embodiments, the micropores of the porous polysulfone membrane may be greater than 0.3 μm or 0.4 μm. In another embodiment, the micropores of the porous polysulfone membrane may be greater than 0.5 μm or 0.6 μm.

[0082] In an aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of less than 1.0 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of less than 0.8 μm. In a particular aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of less than 0.65 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of less than 0.45 μm.

[0083] In an embodiment of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.1 μm. In another embodiment, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.22 μm. In yet another embodiment, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.20 μm. In a further embodiment of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.45 μm. In a further embodiment, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.65 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.8 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.03 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 0.05 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polysulfone membrane 113 with a micropore size of 1.2 μm.

[0084] In embodiments of this disclosure, the polysulfone membrane may be less than 250 μm thick. In certain embodiments, the membrane is more than 10 μm thick. In some embodiments, the polysulfone membrane may be 10 to 250 μm thick. In other embodiments, the polysulfone membrane may be 10 to 125 μm thick or 25 to 150 μm thick. In one embodiment, the polysulfone membrane may be 50 to 125 μm thick, 75 to 125 μm thick, 50 to 150 μm thick, 75 to 150 μm thick, 100 to 125 μm thick, 150 to 250 μm thick or 25 to 150 μm thick. In one embodiment, the membrane 113 of the foldable inner blood container 102 is about 20 μm thick. In another embodiment, the membrane 113 of the foldable inner blood container 102 is about 30 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is about 50 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is about 76 μm thick. In one embodiment, the membrane 113 of the foldable inner blood container 102 is about 120 μm thick.

[0085] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polysulfone membrane 113 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polysulfone membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polysulfone membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 50 to 150 μm.

[0086] Polysulfone membranes suitable for the fabrication of foldable inner blood containers, and examples of polysulfone membranes that are oxygen permeable according to this disclosure include SS003AH (thickness 10-250 μm / pore size 0.03 μm), SS005AH (thickness 10-250 μm / pore size 0.05 μm), SS010AH (thickness 10-250 μm / pore size 0.1 μm), SS Examples include 020AH (thickness 10-250 μm / pore size 0.2 μm), SS045AH (thickness 10-250 μm / pore size 0.45 μm), SS065AH (thickness 10-250 μm / pore size 0.65 μm), SS080AH (thickness 10-250 μm / pore size 0.8 μm), or SS120AH (thickness 10-250 μm / pore size 1.2 μm).

[0087] Suitable polysulfone membranes include commercially available membranes. Non-limiting examples of polysulfone membranes are available from Pacific Membranes. In one embodiment, the polysulfone membrane may be SS120AH, SS080AH, SS065AH, SS045AH, SS020AH, SS010AH, SS005AH, or SS003AH.

[0088] This disclosure provides and includes a foldable blood container 102 which is a substantially oxygen-permeable microporous membrane made from a polyolefin. In certain embodiments, the polyolefin membrane is a substantially oxygen-permeable hydrophobic microporous membrane.

[0089] In some embodiments of this disclosure, the microporous polyolefin film has pores ranging from 0.01 μm to 2.0 μm. In other embodiments, the microporous polyolefin film 113 has pores ranging from 0.01 μm to 1.0 μm. In some embodiments, the pore size of the microporous polyolefin film 113 is 0.03 μm to 1.0 μm in diameter. In other embodiments, the pore size of the microporous polyolefin film 113 is 0.03 μm to 0.45 μm in diameter.

[0090] In an embodiment of this disclosure, the void ratio of the polyolefin membrane 113 used to produce the foldable blood container 102 is 20 to 80%. In another embodiment, the void ratio of the polyolefin membrane 113 used to produce the foldable blood container 102 is 35 to 50%.

[0091] In certain embodiments, the permeability of polyolefin films with pores larger than approximately 1.0 μm may allow fluids to pass through the film, impairing both fluid containment and oxygen and carbon dioxide permeability. To address this permeability at larger pore sizes, so-called "superhydrophobic" films with contact angles greater than 150° can be employed. As used herein and as known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of non-hydrophobic polyolefin materials is not recommended because the surface tension of the material is lower, and even within the above range, fluids may seep out of the pores.

[0092] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polyolefin membrane 113 with a pore size of 0.1 μm to 0.8 μm in diameter. In another embodiment, the micropores of the porous polyolefin membrane may be 0.22 μm to 0.8 μm in diameter. In one embodiment, the micropores of the porous polyolefin membrane are 0.2 μm to 1.0 μm. In another embodiment, the micropores of the porous polyolefin membrane may be greater than 0.1 μm and less than 1.0 μm. In yet another embodiment, the micropores of the porous polyolefin membrane are in the range of about 0.05 μm to about 1.0 μm. In some embodiments, the micropores of the porous polyolefin membrane may be greater than 0.3 or 0.4 μm. In another embodiment, the micropores of the porous polyolefin membrane may be greater than 0.5 or 0.6 μm.

[0093] In an aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of less than 1.0 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of less than 0.8 μm. In a particular aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of less than 0.65 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of less than 0.45 μm.

[0094] In one aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of 0.1 μm. In another aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of 0.22 μm. In yet another aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of 0.20 μm. In a further aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of 0.45 μm. In a further aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of 0.65 μm. In another aspect of the present disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a polyolefin membrane 113 with a micropore size of 0.8 μm.

[0095] In some embodiments of this disclosure, the polyolefin film may be less than 250 μm thick. In certain embodiments, the film is more than 10 μm thick. In some embodiments, the polyolefin film may be 10 to 250 μm thick. In other embodiments, the polyolefin film may be 10 to 125 μm thick or 25 to 150 μm thick. In one embodiment, the polyolefin film may be 50 to 125 μm thick, 75 to 125 μm thick, 50 to 150 μm thick, 75 to 150 μm thick, 100 to 125 μm thick, 150 to 250 μm thick, or 25 to 150 μm thick. In one embodiment, the film 113 of the foldable inner blood container 102 is about 20 μm thick. In another embodiment, the film 113 of the foldable inner blood container 102 is about 30 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is about 50 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is about 76 μm thick. In one embodiment, the membrane 113 of the foldable inner blood container 102 is about 120 μm thick.

[0096] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polyolefin membrane 113 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polyolefin membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 100 μm to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable polyolefin membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 50 μm to 150 μm.

[0097] An example of a polyolefin membrane suitable for fabricating an oxygen-permeable, foldable inner blood container in accordance with this disclosure is described in U.S. Patent No. 4,440,815 issued to Zomorodi et al.

[0098] This disclosure provides and includes a foldable blood container 102 which is a substantially oxygen-permeable microporous membrane made from polytetrafluoroethylene (PTFE). In certain embodiments, the PTFE membrane is a substantially oxygen-permeable hydrophobic microporous membrane.

[0099] In some embodiments of this disclosure, the microporous PTFE film has pores ranging from 0.01 μm to 2.0 μm. In other embodiments, the microporous PTFE film 113 has pores ranging from 0.01 μm to 1.0 μm. In some embodiments, the pore size of the microporous PTFE film 113 is 0.03 μm to 1.0 μm in diameter. In other embodiments, the pore size of the microporous PTFE film 113 is 0.03 μm to 0.45 μm in diameter.

[0100] In an embodiment of this disclosure, the void ratio of the PTFE membrane 113 used to manufacture the foldable blood container 102 is 20-80%. In another embodiment, the void ratio of the PTFE membrane 113 used to manufacture the foldable blood container 102 is 35-50%.

[0101] In certain embodiments, the permeability of PTFE films with pores larger than approximately 1.0 μm may allow fluids to pass through the film, impairing both fluid containment and oxygen and carbon dioxide permeability. To address this permeability at larger pore sizes, so-called "superhydrophobic" films with contact angles greater than 150° can be employed. As used herein and as known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of non-hydrophobic PTFE materials is not recommended because the surface tension of the material is lower, and fluids may seep out of the pores even within the above range.

[0102] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable PTFE membrane 113 with a pore size of 0.1 μm to 0.8 μm in diameter. In another embodiment, the micropores of the porous PTFE membrane may be 0.22 μm to 0.8 μm in diameter. In one embodiment, the micropores of the porous PTFE membrane are 0.2 μm to 1.0 μm. In another embodiment, the micropores of the porous PTFE membrane may be greater than 0.1 μm and less than 1.0 μm. In yet another embodiment, the micropores of the porous PTFE membrane are in the range of about 0.05 μm to about 1.0 μm. In some embodiments, the micropores of the porous PTFE membrane may be greater than 0.3 or 0.4 μm. In another embodiment, the micropores of the porous PTFE membrane may be greater than 0.5 or 0.6 μm.

[0103] In an aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of less than 1.0 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of less than 0.8 μm. In a particular aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of less than 0.65 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of less than 0.45 μm.

[0104] In one aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of 0.1 μm. In another aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of 0.22 μm. In yet another aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of 0.20 μm. In a further aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of 0.45 μm. In a further aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of 0.65 μm. In another aspect of the present disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a PTFE membrane 113 with a micropore size of 0.8 μm.

[0105] In some embodiments of this disclosure, the PTFE membrane 113 may be less than 250 μm thick. In certain embodiments, the membrane is more than 10 μm thick. In some embodiments, the PTFE membrane 113 may be 10 to 250 μm thick. In other embodiments, the PTFE membrane 113 may be 10 to 125 or 25 to 150 μm thick. In one embodiment, the PTFE membrane 113 may be 50 to 125 μm thick, 75 to 125 μm thick, 50 to 150 μm thick, 75 to 150 μm thick, 100 to 125 μm thick, 150 to 250 μm thick, or 25 to 150 μm thick. In another embodiment, the membrane 113 of the foldable inner blood container 102 is about 30 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is about 50 μm thick. In a further embodiment, the membrane 113 of the foldable inner blood container 102 is approximately 76 μm thick. In one embodiment, the membrane 113 of the foldable inner blood container 102 is approximately 120 μm thick, 100-125 μm thick, 150-250 μm thick, or 25-150 μm thick.

[0106] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable PTFE membrane 113 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable PTFE membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable PTFE membrane 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 50 to 150 μm.

[0107] Examples of PTFE membranes suitable for fabricating oxygen-permeable, foldable inner blood containers in accordance with this disclosure include the Poreflon® FP, WP, and HP series PTFE membranes from Sumitomo Electric Interconnect Products in San Marcos, California, and Tetratex® 2 from Donaldson Membranes in Ivyland, Pennsylvania.

[0108] Suitable PTFE films include commercially available films. Non-limiting examples of PTFE films are available from Sumitomo Electric Interconnect Products in San Marcos, California, and Donaldson Membranes in Ivyland, Pennsylvania. In one embodiment, the PTFE film may be FP-010 from Sumitomo Electric Interconnect Products in San Marcos, California.

[0109] In certain embodiments, a suitable film that is substantially oxygen-permeable may be a multilayer film. In certain embodiments, this multilayer film is a substantially oxygen-permeable hydrophobic microporous film. Suitable multilayer films include those having two or more materials selected from the group consisting of hydrophobized PVDF, nylon, cellulose ester, polysulfone, polyethersulfone, hydrophobized polypropylene, and polyacrylonitrile.

[0110] This disclosure provides and includes a foldable blood container 102 which is substantially oxygen-permeable and is a microporous membrane made from an extruded monolayer, woven monolayer, nonwoven monolayer, extruded multilayer, woven multilayer, or nonwoven multilayer. In certain embodiments, the multilayer is a substantially oxygen-permeable hydrophobic microporous membrane.

[0111] In aspects of this disclosure, the microporous multilayer film has pores ranging from 0.01 micrometers (μm) to 2.0 μm. In another aspect, the microporous multilayer film 113 has pores ranging from 0.01 μm to 1.0 μm. In some aspects, the pore size of the microporous multilayer film 113 is 0.03 μm to 1.0 μm in diameter. In another aspect, the pore size of the microporous multilayer film 113 is 0.03 μm to 0.45 μm in diameter.

[0112] In an embodiment of this disclosure, the void ratio of the multilayer film 113 used to produce the foldable blood container 102 is 20 to 80%. In another embodiment, the void ratio of the multilayer film 113 used to produce the foldable blood container 102 is 35 to 50%.

[0113] In certain embodiments, the permeability of multilayer films with pores larger than approximately 1.0 μm may allow fluids to pass through the film, impairing both fluid containment and oxygen and carbon dioxide permeability. To address this permeability at larger pore sizes, so-called "superhydrophobic" films with contact angles greater than 150° can be employed. As used herein and as known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of non-hydrophobic multilayer materials is not recommended because the surface tension of the material is lower, and even within the above range, fluids may seep out of the pores.

[0114] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable multilayer film 113 with pore sizes of 0.1 μm to 0.8 μm in diameter. In another embodiment, the micropores of the porous multilayer film may be 0.22 μm to 0.8 μm in diameter. In one embodiment, the micropores of the porous multilayer film are 0.2 to 1.0 μm. In another embodiment, the micropores of the porous multilayer film may be greater than 0.1 μm and less than 1.0 μm. In yet another embodiment, the micropores of the porous multilayer film are in the range of about 0.05 μm to about 1.0 μm. In some embodiments, the micropores of the porous multilayer film may be greater than 0.3 or 0.4 μm. In another embodiment, the micropores of the porous multilayer film may be greater than 0.5 or 0.6 μm.

[0115] In an aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer membrane 113 with a micropore size of less than 1.0 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer membrane 113 with a micropore size of less than 0.8 μm. In a particular aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer membrane 113 with a micropore size of less than 0.65 μm. In another aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer membrane 113 with a micropore size of less than 0.45 μm.

[0116] In one aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer film 113 with a micropore size of 0.1 μm. In another aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer film 113 with a micropore size of 0.22 μm. In yet another aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer film 113 with a micropore size of 0.20 μm. In a further aspect of this disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer film 113 with a micropore size of 0.45 μm. In a further aspect, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer film 113 with a micropore size of 0.65 μm. In another aspect of the present disclosure, the oxygen depletion device 10 comprises a foldable inner blood container 102 having a multilayer membrane 113 with a micropore size of 0.8 μm.

[0117] In aspects of this disclosure, the multilayer film 113 may be less than 250 μm thick. In certain aspects, the film is more than 10 μm thick. In some aspects, the multilayer film 113 may be 10 to 250 μm thick. In other aspects, the multilayer film may be 10 to 125 μm thick or 25 to 150 μm thick. In one aspect, the multilayer film 113 may be 50 to 125 μm thick, 75 to 125 μm thick, 50 to 150 μm thick, 75 to 150 μm thick, 100 to 125 μm thick, 150 to 250 μm thick or 25 to 150 μm thick, 100 to 125 μm thick, 150 to 250 μm thick or 25 to 150 μm thick. In another aspect, the film 113 of the foldable inner blood container 102 is about 30 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is approximately 50 μm thick. In yet another embodiment, the membrane 113 of the foldable inner blood container 102 is approximately 76 μm thick. In one embodiment, the membrane 113 of the foldable inner blood container 102 is approximately 120 μm thick.

[0118] In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable multilayer film 113 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable multilayer film 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 100 μm to 125 μm. In certain embodiments of this disclosure, the foldable blood container 102 is made from a permeable multilayer film 113 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 50 μm to 150 μm.

[0119] This disclosure provides and includes a foldable blood container 102 which is substantially oxygen-permeable and is a membrane made of polyvinyl chloride (PVC). In embodiments of this disclosure, the foldable blood container 102 can be made from a PVC membrane with a thickness of 5 μm to 250 μm, more preferably about 10 μm to about 100 μm.

[0120] The use of PVC in the manufacture of foldable blood containers is well known in the art. The use of various plasticizers in various PVC formulations is also well known in the art, including the use of diethylhexyl phthalate (DEHP) for the long-term storage of red blood cells. When manufacturing foldable blood containers from PVC-DEHP, a bag structure is conventionally created by high-frequency (RF) welding of a pair of films, with the thickness of each film being approximately 350 μm to 400 μm. An example of a PVC-DEHP film is Renolit ES-3000 (American Renolit Corp., Commerce, California).

[0121] Because such films have relatively low oxygen permeability, and platelet storage requires high oxygen permeability, other plasticizers for PVC have been found to be useful in the manufacture of foldable blood containers, such as citrates (see, for example, “The Role of Poly(Vinyl Chloride) in Healthcare” by Colin R. Blass, copyright 2001 Rapra Technology, Ltd., ISBN: 1-85957-258-8). A suitable example of a PVC-citrate film is Renolit ES-4000 (American Renolit Corp., Commerce, California).

[0122] This disclosure provides a PVC material suitable for use in a foldable blood container 102 that is substantially oxygen-permeable. To provide a foldable blood container having the desired characteristics of high oxygen permeability, RF welding and joining, and high tensile strength, it is preferable to use a PVC-citrate film such as Renolit ES-4000 with a thickness of about 5 μm to about 250 μm, more preferably about 10 μm to about 100 μm.

[0123] This disclosure provides and includes a foldable blood container 102 which is substantially oxygen-permeable and is made of a silicone film. In an embodiment of this disclosure, the foldable blood container 102 can be made from a silicone film with a thickness of 15 μm to 100 μm. In an embodiment of this disclosure, the foldable blood container 102 can be made from a silicone film with a thickness of 5 μm to 500 μm. In another embodiment, the thickness of the foldable blood container 102 can be 5 μm to 200 μm. In another embodiment, the thickness of the foldable blood container 102 can be 20 μm to 120 μm. In another embodiment, the thickness of the foldable blood container 102 is 30 μm to 120 μm. In yet another embodiment, the thickness of the foldable blood container 102 is 50 μm to 120 μm. In a further embodiment, the thickness of the foldable blood container 102 can be 76 μm to 120 μm. In another embodiment, the thickness of the foldable blood container 102 can be 20 μm to 50 μm. This disclosure provides and includes a foldable blood container 102 having a thickness of 20 μm. In another embodiment, the foldable blood container 102 has a thickness of 15 μm. In yet another embodiment, the foldable blood container 102 has a thickness of 30 μm. In yet another embodiment, the foldable blood container 102 has a thickness of 50 μm. In an additional embodiment, the foldable blood container 102 has a thickness of 120 μm.

[0124] In aspects of this disclosure, the foldable blood container 102 can be made from a silicone film having a thickness of 20 μm to 400 μm. In another aspect, the thickness of the foldable blood container 102 can be 20 μm to 200 μm. In another aspect, the thickness of the foldable blood container 102 can be 40 μm to 300 μm. In another aspect, the foldable blood container 102 has a thickness of 40 μm to 400 μm. In yet another aspect, the foldable blood container 102 has a thickness of 300 μm to 450 μm. In yet another aspect, the thickness of the foldable blood container 102 can be 350 μm to 450 μm. This disclosure provides and includes a foldable blood container 102 having a thickness of approximately 450 μm. In another aspect, the foldable blood container 102 has a thickness of 425 μm. In yet another embodiment, the foldable blood container 102 has a thickness of 400 μm. In an additional embodiment, the foldable blood container 102 has a thickness of 350 μm.

[0125] Suitable silicone membranes include commercially available membranes. Non-limiting examples of silicone membranes are available from Wacker Silicones, such as the Silpuran® brand of medical-grade silicone sheet membranes (Wacker Silicones, Adrian, Michigan) and Polymer Sciences PS-1033 P-Derm® silicone elastomer membranes (Polymer Sciences, Inc., Monticello, Indiana). In one embodiment, the silicone membrane may be Polymer Sciences PS-1033 or Wacker Silpuran® 6000 silicone. Silicone membranes can be made from a variety of liquid silicone rubber (LSR) materials available from many silicone suppliers, including, to name a few, Wacker Silicones (Adrian, Michigan), Shin-Etsu Silicones of America (Akron, Ohio), NuSil Technology (Carpinteria, California), and Blue Star Silicones (East Brunswick, New Jersey).

[0126] In one aspect of this disclosure, a foldable blood container 102 can be manufactured from silicone by various molding methods such as compression molding, injection molding and insert molding, and by adhesive bonding of silicone sheets using a silicone adhesive. In one aspect of this disclosure, a pair of silicone sheets are joined at their edges using a silicone adhesive, with a silicone injection tube portion provided at the appropriate position at the seam. In another aspect of this disclosure, a three-sided shape is formed by injection molding of liquid silicone rubber onto a mold, and then further bonded to the remaining fourth side closure using a silicone adhesive, surrounding the silicone injection tube. In yet another aspect of this disclosure, a three-sided shape is formed by injection molding of liquid silicone rubber onto a mold, and then insert-molded to the remaining fourth side closure shape, into which the injection tube is incorporated.

[0127] This disclosure provides, and includes, a foldable blood container 102 having tear resistance. As used herein, “tear resistance” or “tear strength” is measured in kN / m. In embodiments of this disclosure, the foldable blood container 102 must be made from an oxygen-permeable material that also has tear resistance. Measurement of tear resistance is known in the art, e.g., ASTM D-412, and this method can also be used to measure tensile strength, modulus, and elongation. In certain embodiments, the foldable blood container 102 must be made from an oxygen-permeable material that is resistant to tear formation (e.g., tear initiation). Methods for measuring tear initiation and tear propagation are known in the art, e.g., ASTM D-624. Other methods include measuring tensile strength and elongation at break according to DIN 53 504-S1.

[0128] In one aspect of this disclosure, the foldable blood container 102 has a tensile strength of at least 2.4 N / mm 2 It must be made from an oxygen-permeable material.

[0129] This disclosure provides, and includes, an absorbent capable of binding to oxygen and removing oxygen from its surroundings. Unless otherwise specified, the term “absorbent” refers to oxygen absorbents and deoxidizers. As used herein, “deoxidizer” or “oxygen absorbent” is a substance that irreversibly binds or combines with O2 under the conditions of use. The term “oxygen absorbent” may be used herein as synonymous with “deoxidizer.” In certain embodiments of this disclosure, a substance can irreversibly bind to or combine with oxygen. In other embodiments, oxygen binds to the absorbent substance and releases at a rate k off This is extremely slow. In one embodiment, oxygen can chemically react with some component of the absorbent substance to be converted into another compound. Any substance whose rate of dissociation of bound oxygen is significantly slower than the residence time of blood can function as an oxygen scavenger.

[0130] When used herein, the amount of absorbent is given by volume (e.g., cubic centimeters (cc) or milliliters (ml)) and standard temperature and pressure (e.g., 0°C (273.15 Kelvin) and 1.01 × 10⁻¹⁰). 5 It is indicated as having a specific oxygen-binding capacity when measured at a pressure of Pa (100 kPa, 1 bar, 0.986 atmospheres, 760 mmHg). In another embodiment, oxygen absorbers and deoxidizers can further bind to carbon dioxide to remove it from the surroundings. In a particular embodiment, the absorbent 103 may be a mixture of a non-toxic inorganic salt and / or organic salt with oxygen, carbon dioxide, or a highly reactive divalent iron or other material for oxygen and carbon dioxide. In a particular embodiment, the oxygen absorber or deoxidizer is combined with a carbon dioxide absorbent. In another embodiment, the presence or absence of carbon dioxide-binding capacity of the oxygen absorber is not essential.

[0131] Suitable oxygen absorbers or deoxidizers are known in the art. The minimum oxygen absorption rate of a suitable oxygen absorber according to this disclosure is 0.44 ml / min. An absorber having a suitable absorption profile binds at least 45 ml of O2 within 60 minutes, 70 ml of O2 within 120 minutes, and 80 ml of O2 within 180 minutes. A suitable absorber may have both higher binding capacity and binding rate.

[0132] Non-limiting examples of oxygen absorbers or deoxidants include iron powder and organic compounds. Examples of O2 absorbents include cobalt chelates, iron, and Schiff bases. Further non-limiting examples of O2 absorbents can be found in U.S. Patent No. 7,347,887 issued to Bulow et al., U.S. Patent No. 5,208,335 issued to Ramprasad et al., and U.S. Patent No. 4,654,053 issued to Sievers et al., which are each incorporated herein by reference in their entirety. Oxygen absorbent materials may be formed or incorporated within fibers, microfibers, microspheres, fine particles, and foams.

[0133] In certain embodiments, suitable absorbents include those obtained from Multisorb Technologies (Buffalo, New York), Sorbent Systems / Impak Corporation (Los Angeles, California), or Mitsubishi Gas Chemical America (MGC) (New York, New York). Exemplary oxygen absorbents include Multisorb Technologies StabilOx® packaging, Sorbent Systems P / N SF100PK100 100cc oxygen absorbent, and Mitsubishi Gas Chemical America Ageless® SS-200 oxygen absorbent. MGC also supplies absorbents suitable for the methods and apparatus of this disclosure. Such suitable oxygen absorbents include MGC Ageless® and SS-200 oxygen absorbent.

[0134] In aspects of this disclosure, the absorbent may be an oxidizing organic polymer having a polymer backbone and a plurality of pendant groups. An example of an absorbent having a polymer backbone is a saturated hydrocarbon (<0.01% carbon-carbon double bond). In some aspects, this backbone may contain ethylene or styrene monomers. In one aspect, the polymer backbone may be ethylenically active. In another aspect, the oxidizing organic compound may be an ethylene / vinylcyclohexene copolymer (EVCH). Further examples of substituted moieties and catalysts are shown in U.S. Patent Application Publication 2003 / 0183801 by Yang et al., which is incorporated herein by reference in its entirety. In further aspects, the oxidizing organic polymer may also include substituted hydrocarbon moieties. An example of a deoxygenating polymer is described in International Publication W099 / 48963 by Ching et al., which is incorporated herein by reference in its entirety. Examples of oxygen absorbers include those described in U.S. Patent No. 7,754,798, U.S. Patent No. 7,452,601, or U.S. Patent No. 6,387,461 issued to Ebner et al., each of which is incorporated herein by reference in its entirety.

[0135] When used herein, the absorbent materials of this disclosure may or may not be contained in permeable sealing bags, containers, outer coverings, etc. In certain embodiments, the absorbent material is contained in one or more pouches made of a material that has high porosity and is essentially inresistant to gas transport. Examples of such materials include spun polyester films, perforated metal foils, and combinations thereof.

[0136] The disclosure further includes and provides absorbents incorporated as one or more laminate layers of an outer article that is substantially oxygen-impermeable. The above-described polymer absorbents may be laminated to a sheet used to manufacture the outer container using methods known in the art, including soft-contact lamination, heat lamination or solvent lamination.

[0137] This disclosure further includes and provides absorbents formed inside the pores of porous microglass fibers or encapsulated in other inert materials. Encapsulation of transition metal complexes in the pores of porous materials may be carried out by using ship-in-a-bottle synthesis, which involves reacting the final molecule with a smaller precursor inside the pore. Examples of such encapsulated absorbents are known in the art, for example, as described in Kuraoka, et al., “Ship-in-a-bottle synthesis of a cobalt phthalocyanine / porous glass composite membrane for oxygen separation,” Journal of Membrane Science, 286(1-2):12-14 (2006), which is incorporated herein by reference in its entirety. In some embodiments, porous glass fibers may be manufactured as shown in U.S. Patent No. 4,748,121 issued to Beaver et al., which is incorporated herein by reference in its entirety. In other embodiments, the absorbent can be formed as a porous sheet product using a papermaking / wet nonwoven fabric manufacturing apparatus. The sheet containing the oxygen absorber may be such as that described in U.S. Patent No. 4,769,175 issued to Inoue (which is incorporated herein by reference in its entirety), and the sheet may be coated with a silicone film after it has been formed.

[0138] As used herein, “decarbonizing agent” is a substance that binds to or combines with carbon dioxide under the conditions of use. The term “carbon dioxide absorbent” may be used herein synonymously with “decarbonizing agent.” In certain embodiments, the carbon dioxide absorbent may not be reactive with oxygen, or may have minimal reactivity with oxygen. In other embodiments, the oxygen absorbent may exhibit a secondary decarbonizing function. Examples of decarbonizing agents include metal oxides and metal hydroxides. Metal oxides react with water to produce metal hydroxides. Metal hydroxides react with carbon dioxide to produce water and metal carbonates. In certain embodiments of this disclosure, a substance may irreversibly bind to or combine with CO2. In embodiments of this disclosure, a substance may bind to CO2 with a higher affinity than hemoglobin. In other embodiments, the absorbent substance may bind to CO2 with high affinity so that carbon dioxide present in the blood or RBC cytoplasm is released and absorbed by the absorbent. In other embodiments, CO2 binds to the absorbent substance, and the release rate k off This process is extremely slow. In one embodiment, carbon dioxide can be chemically reacted with some components of the absorbent substance to be converted into another compound.

[0139] Carbon dioxide decontamination agents are known in the art. In certain embodiments of this disclosure, the carbon dioxide decontamination agent may be calcium oxide. When calcium oxide reacts with water, calcium hydroxide is produced, which can react with carbon dioxide to form calcium carbonate and water. In certain embodiments of this disclosure, water for producing calcium hydroxide is obtained by the diffusion of water vapor from blood through an inner oxygen-permeable container. In another embodiment, this water may be supplied from the surroundings through an outer container that is substantially oxygen-impermeable. In yet another embodiment, the water may be included together with the outer container of the oxygen depletion device.

[0140] Examples of non-limiting decarbonation agents include oxygen absorbers and decarbonation agents supplied by Multisorb Technologies (Buffalo, New York). Oxygen absorbers may also exhibit a secondary function of decarbonization.

[0141] In embodiments of this disclosure, the O2 depletion medium and the CO2 depletion medium may be blended in a desired ratio to obtain the desired results.

[0142] This disclosure further includes and provides absorbents in pouches. As used herein, “pouch” is any encapsulation bag for encapsulating and containing an oxygen absorbent, a carbon dioxide absorbent, or a combination of oxygen absorbents and carbon dioxide absorbents. The pouches according to this disclosure are contained in an outer packaging material that is both oxygen-permeable and carbon dioxide-permeable. In particular embodiments, this outer packaging material may be a combination of two or more materials, at least one of which is both oxygen-permeable and carbon dioxide-permeable. Preferred outer packaging materials have a known biocompatibility profile or conform to ISO 10993.

[0143] The pouches are sealed so that the absorbent contents are completely contained within the outer packaging and so that the absorbent does not leak or otherwise escape from the outer packaging. The pouches may be of any shape, but are typically rectangular or square. In one embodiment, the pouches are approximately 50 x 60 mm. In one embodiment, the oxygen absorbent 103 binds with 30 cc of oxygen per pouch in the STP. In one embodiment, the oxygen absorbent 103 binds with 60 cc of oxygen per pouch in the STP. In one embodiment, the oxygen absorbent 103 binds with 120 cc of oxygen per pouch in the STP. In one embodiment, the oxygen absorbent 103 binds with 30 to 120 cc of oxygen per pouch in the STP. In one embodiment, the oxygen absorbent 103 binds with 30 to 120 cc of oxygen per pouch in the STP. In one embodiment, the oxygen absorber 103 binds to 50 to 200 cc of oxygen per pouch in the STP. In a particular embodiment of this disclosure, the total oxygen adsorption capacity of the pouch is 100 cc of O2 in the STP. In a particular other embodiment of this disclosure, the total oxygen absorption capacity of the pouch is at least 200 cc of O2 in the STP.

[0144] In embodiments of this disclosure, the oxygen absorber 103 may be contained in one or more pouches. In another embodiment, the oxygen absorber 103 is contained in one large pouch. In yet another embodiment, the oxygen absorber 103 is contained in two pouches distributed in the headspace between the foldable inner container 102 and the outer container 101. In yet another embodiment, the oxygen absorber 103 is contained in four pouches distributed in the headspace between the foldable inner container 102 and the outer container 101. In embodiments of this disclosure, the oxygen depletion device 10 may contain 2 to 20 absorber packages.

[0145] In embodiments of this disclosure, the oxygen depletion device 10 contains 1 to 50 grams of absorbent material 103 in one or more pouches. In one embodiment, the oxygen depletion device 10 contains 1 to 100 grams of absorbent material 103 in one or more pouches. In one embodiment, the oxygen depletion device 10 contains 25 to 75 grams of absorbent material 103 in one or more pouches. In a further embodiment, the oxygen depletion device 10 contains approximately 25 grams of absorbent material 103. In yet another embodiment, the oxygen depletion device 10 contains approximately 50 grams of absorbent material 103. In one embodiment, the oxygen depletion device 10 contains approximately 35 or 45 grams of absorbent material 103 in one or more pouches. In one embodiment, the oxygen depletion device 10 contains approximately 10 or 15 grams of absorbent material 103 in one or more pouches. The pouches can be square, rectangular, circular, or oval in shape and have a circumference of 40 to 150 mm.

[0146] The pouch according to this disclosure may further contain a carbon dioxide absorbent. In one embodiment, the oxygen absorbent 103 also adsorbs carbon dioxide. In one embodiment, the oxygen absorbent 103 combines with 30 cc of carbon dioxide in STP. In one embodiment, the oxygen absorbent 103 combines with at least 170 cc of oxygen and at least 30 cc of carbon dioxide, in which case both of these gases are measured in STP.

[0147] This disclosure provides and includes an outer container 101 that is substantially oxygen-impermeable. As discussed above, the integrity of the oxygen barrier must be maintained when joining, welding, folding, or otherwise assembling the outer container 101. Poor assembly of the outer container 101 may impair the storage life of the oxygen depletion device 10 or prevent it from achieving its intended purpose of depleting oxygen from blood. Importantly, blood that is not adequately oxygen-depleted may not provide the benefits of depletion during storage and may have a considerably worse effect when transfused to a patient. In addition to meeting the requirements for blood collection and depletion, it is common to take a blood sample through a standard port 303 and to introduce various additives into the collected blood. More specifically, anticoagulants are added to almost all of the collected blood at the time of collection or during collection.

[0148] To address the need to add substances to collected blood and transfer the oxygen-depleted blood to a suitable anaerobic storage bag, the oxygen depletion device 10 may be further provided with one or more inlet / outlet ports 30. Special care must be taken in the assembly of the outer container 101 (and outer container 201) so that the inlet / outlet ports 30 do not become undesirable sources of oxygen intrusion when the oxygen-impermeable outer container 101 (and outer container 201) is moved laterally, as shown herein.

[0149] In embodiments of this disclosure, the outer container 101 comprises one or more inlet / outlet ports 30. In certain embodiments, one or more inlet / outlet ports 30 further comprises spike ports 303.

[0150] It is worth noting that few materials provide complete impermeability, and even highly impermeable materials can be compromised when the outer container 101 is joined, welded, folded, or assembled in any other way. As will be discussed below, the oxygen depletion device 10 may further incorporate optional spike ports 303 and inlet / outlet ports 30, and must be designed to accommodate changes in the volume of the foldable inner blood container 102. Therefore, special consideration is given to incorporating special design elements and manufacturing methods to ensure the integrity of the impermeability barrier.

[0151] Spike ports 303 used in blood collection kits and systems are widely known in the art, including products such as Vitalmed #20391 (Vitalmed, Inc., Lakeville, Massachusetts) and Qosina 65842 (Qosina Corp., Edgewood, New York). These ports are typically molded from PVC and have a removable cap that provides a sterile barrier before use, and also provide some degree of oxygen impermeability to the contents. In some embodiments, the spike port 303 is covered by an easily breakable seal portion of the outer container film, thereby providing a sterile barrier and further increasing the degree of oxygen impermeability. Improved oxygen impermeability is desirable because it extends the shelf life of kits and systems having oxygen depletion devices 10.

[0152] As is evident, conventional ports, inlets, and outlets can be undesirable sources of oxygen intrusion, which depends on the choice of both material and method used to join the port, inlet, or outlet to the outer container 101. Methods of joining materials are well known in the art. As shown herein, the inlet / outlet 30 comprises a tube 301 joined to the outer container 101 (or outer container 201) using a joint 302 that creates an oxygen-impermeable seal to the outer container 101 (or outer container 201). In one embodiment, the joint 302 is obtained by using a constant heat seal die heated to about 210°F and held at this temperature. In one embodiment, a film is placed between the heated dies and clamped to obtain a heat-sealed seam. In a particular embodiment, the heat seal is made in about 5 seconds. In a particular embodiment, the seal die has a grooved portion that is machined to accommodate an intermediate component. In some embodiments, the tube 301 includes an intermediate component which may be a multilayer tube or a small block of machined polymer or molded article of a certain length, as discussed below. In certain embodiments, the molded article is made from a polyolefin such as polyethylene. In embodiments according to this disclosure, the dimensions of the groove are about 10% smaller than the shape of the component, thereby allowing compression during sealing.

[0153] In some embodiments, the oxygen-impermeable joint consists of a multilayer tube portion heat-sealed to the seam of the outer container 101. In certain embodiments, this multilayer tube consists of a polyethylene outer layer, a PVC (polyvinyl chloride) inner layer, and an EVA (ethyl vinyl alcohol) intermediate layer (Pexco, Inc., Athol, Massachusetts). In some embodiments, additional portions of the PVC tube are solvent-bonded into the multilayer tube, for example, using cyclohexanone.

[0154] In some embodiments, the inlet / outlet 30 consists of a tube 301 made from a small diamond-shaped block of polyethylene with a central hole, the diamond-shaped block being heat-sealed to the seam of the outer container to provide an oxygen-impermeable joint 302, and the central through-hole providing fluid communication with the contents. In one embodiment, a portion of the PVC tube is bonded into the central hole of the diamond-shaped block using an oxygen-impermeable adhesive that can bond to polyethylene, such as Loctite 4310, Masterbond X17, or 3M Scothweld 4693, thereby providing fluid communication with the contents through the oxygen-impermeable outer container. In another embodiment, a multilayer tube can be bonded to the central hole of the diamond-shaped block using methods known in the art. In yet another embodiment, a multilayer tube can be used instead of a standard PVC drip tube to enhance oxygen barrier properties.

[0155] Users of collapsible containers need to be able to conveniently fill and remove the contents, and according to the ISO 3826 standard for blood containers, the contents must be able to be completely removed within two minutes. The outer container can shorten the filling time by restraining the collapsible container and preventing it from expanding. Therefore, in some embodiments, the blood storage device further comprises an expansion mechanism that allows for unlimited filling of the collapsible container. In some embodiments, this expansion mechanism consists of gusseted folds along one or more edges of the outer container. Typically, a fold of about a quarter inch is sufficient to expand the inner container, and the folds of this fold are sealed in a seam at the end. In some embodiments, the expansion mechanism consists of a third panel of barrier film sealed along the bottom of the outer container, which provides a three-dimensional bag.

[0156] During the development of the oxygen depletion device 10, it was discovered that controlling the size, shape, and number of chambers in the foldable inner blood container 102 was necessary to obtain suitable depletion dynamics. More specifically, it was found that using a standard blood bag configuration was insufficient, even with highly permeable materials, and the reaction dynamics were considerably slower. Although not limited by theory, deoxygenation is assumed to be a multi-step process involving the release of dissolved oxygen from hemoglobin, diffusion of dissolved oxygen into the cytoplasm of red blood cells, and diffusion of dissolved oxygen through the red blood cell membrane. Also, although not limited by theory, it is assumed that high concentrations of hemoglobin, which have a very high affinity for oxygen, significantly reduce the diffusion rate of dissolved oxygen into the cytoplasm. Similarly, once dissolved oxygen reaches the plasma through the plasma membrane, its diffusion is further restricted by absorption and binding to other red blood cells. Also, although not limited by theory, it is assumed that a gas-permeable membrane creates an additional diffusion barrier for dissolved oxygen, and in this membrane, dissolved oxygen not only needs to pass through the membrane but also changes its state from the soluble phase to the gaseous phase. The subsequent diffusion and adsorption by the absorbent occur in a gaseous state and are maximized by incorporating and maintaining a headspace within the outer container 101. Therefore, it is thought that the diffusion of gaseous oxygen is maximized by maintaining a concentration gradient in the headspace from the surface of the foldable inner blood container 102 to the oxygen absorbent 103. Furthermore, although not limited by theory, it is thought that by selecting an absorbent that has both rapid absorption kinetics and high binding capacity, a suitable diffusion gradient of gaseous oxygen can be maintained, thereby promoting rapid oxygen depletion in the oxygen depletion device 10.

[0157] This disclosure relates to an oxygen depletion device 10 for depleting oxygen from blood, wherein the surface area ratio to volume is 4.75 square centimeters / milliliter (cm²). 2 / ml)~6.9cm 2The present invention provides and includes an oxygen depletion device 10 comprising a foldable inner blood container 102 sealed in an outer container 101, and having a volume of / ml. In a particular embodiment, the oxygen depletion device 10 for depleting oxygen from blood has a surface-to-volume ratio of 4.84 cm² when filled with blood for oxygen depletion. 2 / ml~6.9cm 2 It has a volume of / ml and includes a foldable inner blood container 102 sealed in an outer container 101. In certain embodiments, the oxygen depletion device 10 for depleting oxygen from blood has a surface-to-volume ratio of 5.0 cm when filled with blood for oxygen depletion. 2 / ml~6.9cm 2 It has a volume of / ml and includes a foldable inner blood container 102 sealed in an outer container 101. In some embodiments, the oxygen depletion device 10 for depleting oxygen from blood has a surface-to-volume ratio of 5.0 cm when filled with blood for oxygen depletion. 2 / ml~6.5cm 2 It has a volume of / ml and includes a foldable inner blood container 102 sealed in an outer container 101. In some embodiments, the oxygen depletion device 10 for depleting oxygen from blood has a surface-to-volume ratio of 5.5 cm when filled with blood for oxygen depletion. 2 / ml~6.5cm 2 It has a volume of / ml and includes a foldable inner blood container 102 sealed inside the outer container 101.

[0158] As used herein, surface to volume and surface area to volume are used synonymously throughout this disclosure. As used herein, the surface to volume ratio is defined for a standard unit of whole blood of approximately 1 pint or 450–500 ml. As will be apparent to those skilled in the art, when less than one unit of blood is collected, the surface to volume ratio is considerably high, and the oxygen depletion device 10 is suitable for collecting fractions of a unit of blood without modification. When collecting more than one unit of blood, it will be necessary to adjust the size of the collapsible blood container 102 to obtain the desired rapid blood depletion dynamics. The type of modification required to adapt the oxygen depletion device 10 to collect more than one unit of blood is within the realm of ordinary knowledge in the art.

[0159] This disclosure further includes and provides an oxygen depletion device 10 for the collection and depletion of packed red blood cells. The full unit of packed red blood cells in the additive solution contains approximately 280 ± 60 ml.

[0160] In one aspect of the present disclosure, the surface area ratio of the foldable blood container 102 to its volume is at least 4.84 square centimeters / milliliter (cm²) when filled with blood to deplete oxygen. 2 ( / ml). Although not limited by theory, it is thought that by improving the surface-to-volume ratio, the diffusion distance of dissolved oxygen within the foldable inner blood container 102 can be shortened, thereby overcoming the diffusion limitations caused by the blood itself, particularly by red blood cells and hemoglobin. In one embodiment, the surface-to-volume ratio of the blood container 102 is at least 5.0 cm when filled with blood to deplete the oxygen. 2 The ratio of surface area to volume of the collapsible blood container 102 is at least 5.5 cm when filled with blood to deplete oxygen. 2 The ratio of surface area to volume of the collapsible blood container 102 is at least 6.0 cm when filled with blood to deplete oxygen. 2The ratio of surface area to volume of the collapsible blood container 102 is at least 6.5 cm when filled with blood to deplete oxygen. 2 It is / ml.

[0161] This disclosure also includes and provides improvements to the deoxygenation dynamics of blood by modifying the dimensions of a foldable inner blood container 102. While not limited by theory, reducing the height minimizes the average diffusion distance of red blood cells in the blood, leading to improved deoxygenation dynamics. In a particular aspect of this disclosure, the foldable blood container 102 measures 25.4 cm × 30.5 cm × 0.02 cm before filling with blood, and has a height of approximately 1.5 cm after filling with blood. In another aspect of this disclosure, the foldable blood container 102 measures 17.5 cm × 28.0 cm (7 × 11 inches) × 0.04 cm before filling with blood, and has a height of approximately 2.0 cm after filling with blood. In another aspect of this disclosure, the foldable blood container 102 measures 25.0 cm × 60.0 (10 × 23 inches) cm × 0.04 cm before being filled with blood, and has a height of approximately 0.3 cm after being filled with blood.

[0162] In certain embodiments, the height of the foldable blood container 102 is 0.005 cm or less when empty. In one embodiment, the height of the foldable blood container 102 is 0.1 cm or less. In certain embodiments, the height of the foldable blood container 102 is 0.002 to 0.1 cm. When filled with blood, the height of the foldable blood container 102 is 0.3 cm or less. In one embodiment, when filled with blood, the height of the foldable blood container 102 is 1.5 cm or less. In certain embodiments, when filled with blood, the height of the foldable blood container 102 is 0.2 cm to 2.5 cm.

[0163] This disclosure also provides an oxygen depletion device 10, which is sized to be suitable for implementing existing blood collection protocols using existing equipment. Designing the oxygen depletion device 10 with reference to existing technology reduces equipment costs at centralized processing centers and further improves consistency and reliability. As used herein, the dimensions of the oxygen depletion device 10 are primarily limited by the length and width of the outer container 101, where the height of the bag is determined by the requirements of a collapsible blood container 102 that holds approximately 1 pint or 450-500 ml of whole blood (corresponding to "1 unit of blood"). In another embodiment, the dimensions of the collapsible blood container 102 are determined to hold approximately 220-380 ml of packed red blood cells (corresponding to 1 unit of packed red blood cells). Furthermore, the height of the oxygen depletion device 10 is constrained by the presence of one or more absorbent packaging and equipment included for the purpose of maintaining adequate headspace. These considerations reveal that constraints on the dimensions of the outer container 101 of the oxygen depletion device 10 inevitably limit the dimensions of the foldable blood container 102. Therefore, the foldable blood container 102 may be divided into one or more fluid-communicating chambers.

[0164] In aspects of this disclosure, the oxygen depletion device 10 is designed to fit into an existing blood agitator. In certain embodiments, the oxygen depletion device 10 is sized to efficiently utilize the available space within the agitator and mixing table. In one embodiment, the oxygen depletion device 10 is sized to maximize the use of space within a platelet agitator, such as the Helmer Labs Platelet Agitator, Model PF96. Preferred dimensions of the oxygen depletion device 10 include dimensions that allow one, two, four, six, eight, ten, or more bags to be placed on the surface of the horizontal agitator or mixer.

[0165] The area of ​​the foldable blood container 102 inside the oxygen depletion device 10 is approximately 900-1800 cm². 2Therefore, in the oxygen depletion device 10 further equipped with spacer 110, the surface area available for gas exchange is effectively doubled. In the absence of spacer 110, the exchange rate of the membrane 113 of the foldable blood container 102 on the underside is greatly reduced, and the permeable membrane comes into contact with the impermeable film.

[0166] This disclosure provides, and includes, a foldable blood container 102 further comprising a bonding layer 105, as shown, for example, in Figures 1A, 1C, 6, 7, 9A, 9B, 10, and 11. As used herein, the bonding layer 105 comprises an intermediate material that bonds (joins) the membranes 113 (114) together. In certain embodiments, the bonding layer 105 comprises a solid material of a predetermined shape. As discussed below, the bonded bonding layer of a predetermined shape allows for the incorporation of geometrically characterized portions 121, including rounded corners and other mixing-promoting shapes. In certain embodiments, the bonding layer 105 comprises a liquid or gel that, upon drying or curing, adhesively bonds the membranes 113 together. Thus, a foldable blood container 102 comprising silicone membranes 113 can be bonded by a liquid silicone bonding layer 105. In certain embodiments, the silicone rubber bonding layer 116 may be liquid silicone rubber (LSR).

[0167] This disclosure provides, and includes, a foldable blood container 102 further comprising a binding layer 105 made from a solid material with a lower melting point than the membrane 113. By providing a binding layer 105 with a lower melting point, the membrane 113 can be thermally bonded via the binding layer 105 without damaging the structure of the microporous membrane (including melting and / or crystallization). In one embodiment, the binding layer 105 is selected such that its melting point is at least 3°C ​​lower than the melting point of the microporous membrane 113. In another embodiment, the melting point of the binding layer 105 is at least 10°C lower than the melting point of the microporous membrane 113. In yet another embodiment, a suitable binding layer 105 is selected such that the temperature difference between the binding layer and the microporous membrane 113 (114) to be bonded is maximized.

[0168] In embodiments of this disclosure, the binding layer 105 is selected from LDPE, and the microporous membrane 113 is selected from the group consisting of polysulfone, hydrophobic polyvinylidene fluoride (PVDF), cellulose ester, mixed cellulose ester (MCE), polyethersulfone (PES), hydrophobic polypropylene, and polyacrylonitrile. In one embodiment, the binding layer 105 is LDPE, and the microporous membrane 113 is polysulfone or hydrophobic polyvinylidene fluoride (PVDF). This disclosure provides, and includes, a selection of a suitable microporous film, as detailed in paragraphs

[0081] to

[0123] [Translator's note: located on pages 22, line 8 to page 32, line 21 in PCT / US2016 / 021794, corresponding to paragraphs

[0066] to

[0108] herein], and further includes a multilayer film 113 as shown in paragraphs

[0124] to

[0133] [Translator's note: located on pages 32, line 22 to page 35, line 1 in PCT / US2016 / 021794, corresponding to paragraphs

[0109] to

[0118] herein].

[0169] This disclosure provides, and includes, constructing a foldable blood container 102 having a binding layer, wherein the binding layer extends beyond a seal indicated as a gap 109, as shown, for example, in Figure 9B.

[0170] This disclosure provides and includes a gap 109 in space between the end of the seal and the end of the bonding layer. In certain embodiments, the gap 109 is 0.05 to 2.5 cm. In other embodiments, the gap 109 is at least 0.1 cm wide. In other embodiments, the gap 109 is at least 0.5 cm wide. In other embodiments, the gap 109 is at least 1 cm wide. In other embodiments, the gap 109 is at least 1.5 cm wide. In some embodiments, the gap 109 is 0.5 to 1.5 cm wide. In other embodiments, the gap 109 is at least 2 cm wide. In other embodiments, the gap 109 is 2 to 2.5 cm wide. In other embodiments, the gap 109 is at least 2.5 cm wide.

[0171] As shown in Figure 9B, seal 107 is laminated to film 113, and then the two are laminated together as seal 108. As shown in Figure 7, lamination of the bonding layer 105 can be done in two steps: first, it is laminated to a separate film 113, and then in the second step, the pre-laminated films 113 are joined together. Alternatively, the lamination process can be combined into a single step, in which case one bonding layer 105 is used to join the films together.

[0172] As shown in Figure 9B, the seal 107 may extend beyond the width of the seal 108. By extending the seal 107 beyond the width of the seal 108, the seal 107 reinforces the bending point 115, as shown in Figure 9A. Although not limited to a specific mechanism, the bonding layer 105 is thought to function as a strain reliever for reinforcement inside the seal, allowing the bag to bend in the seal when filling or removing blood products from the bag.

[0173] This disclosure provides, and includes, a foldable blood container 102 having geometric features that enhance blood mixing during the deoxygenation process. The shape improvements of this disclosure further include shapes that facilitate filling and emptying of the foldable blood container 102. The shape improvements reduce or eliminate "dead" spots in the bag. Dead spots occur at the corners of the bag due to the square shape, although this is not limited to theory. Prior to this disclosure, methods and blood depletion devices were able to achieve sufficient mixing with gas displacement methods that were not time-limited and were typically used. Therefore, the shortcomings of previous designs were not exposed.

[0174] In aspects of this disclosure, the foldable blood container 102 comprises one or more geometric feature portions 121. In one aspect, the geometric feature portion comprises rounded corners within the foldable blood container 102 to eliminate "dead" spots during mixing. This disclosure provides geometric feature portions 121 that are directly incorporated into the binding layer 105. In another aspect, the geometric feature portion 121 can be incorporated into the foldable blood container 102 using an external die or plate. In yet another aspect, the geometric feature portion of the foldable blood container 102 can be provided by a suitable mold having the shape of the geometric feature portion 121. In certain aspects, the geometric feature portion 121 brings a round or elliptical shape to the foldable blood container 102, for example, as shown in Figure 10.

[0175] In certain embodiments, the geometric feature portion 121 can be an ellipse with a first radius of approximately 0.1 cm to approximately 7.6 cm and a second radius of approximately 1 cm to approximately 7.6 cm. In one embodiment, the geometric feature portion 121 can be an ellipse with a first radius of approximately 2.5 cm and a second radius of approximately 5 cm. In one embodiment, the geometric feature portion 121 can be an ellipse with a first radius of approximately 5 cm and a second radius of approximately 7.6 cm. In one embodiment, the geometric feature portion 121 can be a circle with a diameter of approximately 5 cm. In one embodiment, the geometric feature portion 121 can be a circle with a diameter of approximately 7.6 cm.

[0176] As is evident, a predetermined size oxygen depletion device 10 necessarily limits the dimensions of the collapsible blood container 102 according to this disclosure. In certain embodiments, the collapsible blood container 102 is further limited by a predetermined ratio of surface area to volume. In accordance with these limitations, this disclosure provides, and includes, a collapsible blood container 102 having two or more fluid-communicating chambers.

[0177] The oxygen depletion device can be constructed in such a way that the blood volume relative to the bag area can be optimized relative to the overall size of the oxygen depletion device, while exposing a larger blood volume to an oxygen-permeable material within the space being used. The blood volume can be contained in a collapsible blood container 102 having two or more chambers that allow for specific arrangements within the outer container 101. In certain embodiments, the height of the oxygen depletion device 10 does not occupy impractical space in the intended mixing device when placed on a surface. The chambers can be arranged in parallel, stacked on top of each other, partially stacked, arranged in a staggered line, or stacked in a saddle-like manner with one or more heights. The absorbent material 103 can be placed to cover the chambers or between the chambers, as needed. The chambers may be filled and emptied individually or together when the chambers are connected via tubes or fluid channels that allow for easy filling and emptying. Those skilled in the art will see that the arrangement and interconnection of collapsible blood containers 102 having two or more chambers can be made.

[0178] In certain embodiments, the collapsible blood container 102 comprises two or more chambers. In one embodiment, the collapsible blood container 102 may have two chambers arranged side by side or end-to-end, depending on the dimensions. In another embodiment, the collapsible blood container 102 may have three chambers arranged side by side or end-to-end, depending on the dimensions. In yet another embodiment, the collapsible blood container 102 may have three chambers arranged side by side or end-to-end, depending on the dimensions. Those skilled in the art will be able to manufacture the collapsible blood container 102 in additional configurations having a number of chambers arranged in adjacent positions and orientations to maximize space utilization.

[0179] In other embodiments provided and included in this disclosure, the collapsible blood container 102 may comprise two or more stacked chambers. In the stacked configuration, spacers 110 or mesh 110 are included to separate adjacent chambers in order to maintain an optimal gas diffusion rate. In certain embodiments, one or more absorbent pouches are further included in the space between the stacked chambers in order to maintain an optimal gas diffusion rate. In certain embodiments, two chambers may be stacked. In other embodiments, three chambers may be stacked. In yet another embodiment, four chambers may be stacked.

[0180] This disclosure provides and includes a collapsible blood container 102 comprising a combination of stacked adjacent chambers. As shown herein, the number and stacking of chambers of the collapsible blood container 102 further includes a surface area ratio to volume of the combined chambers of at least 0.4 cm². 2 It is / ml. Those skilled in the art can create additional variations consistent with the present disclosure.

[0181] This disclosure provides, and includes, an oxygen depletion device 10 for depleting oxygen from blood, comprising a substantially oxygen-impermeable outer container 101, an oxygen-permeable foldable inner blood container 102, and an oxygen absorber placed inside the outer container, wherein the foldable blood container 102 further comprises one or more mixing structures 119 that enhance blood mixing during oxygen depletion. In certain embodiments, the mixing structures 119 are incorporated into the structure of the foldable blood container 102. In other embodiments, the mixing structures 119 are added to the inside of the foldable blood container 102 but are not physically attached to the foldable blood container 102. In yet another embodiment, the mixing structures 119 are an external structure of the foldable blood container 102 that restricts or modifies the shape of the container 102 to reduce or disrupt laminar flow. The mixing structure 119 according to this disclosure is designed to increase blood movement in the collapsible blood container 102, increase turbulence within the collapsible blood container 102, or a combination of both. Importantly, the mixing structure and mixing operation should not significantly increase the lysis or damage of red blood cells.

[0182] In aspects of this disclosure, the membrane 113 includes a mixed structure 119. In certain aspects, the mixed structure 119 within the membrane 113 comprises ridges, bumps or projections on the inside of the foldable blood container 102 that come into contact with the blood. In one aspect, the mixed structure 119 within the membrane 113 comprises one or more ridges. In one aspect, the mixed structure 119 includes the joining of an upper membrane and a lower membrane 113 (114), as shown, for example, in Figures 10C and 10D. In one aspect, one or more ridges extend across the entire width or length of the inner surface of the foldable blood container 102. In another aspect, the ridges may be arranged alternately or in a staggered arrangement. In certain aspects, the mixed structure 119 within the membrane 113 comprises bumps or other projections designed to disrupt laminar flow and induce turbulence. Similarly, in certain embodiments, the mixing structure 119 within the membrane 113 comprises recesses designed to disturb laminar flow and induce turbulence. In certain embodiments, the mixing structure 119 is a baffle incorporated into the membrane 113. The baffle is a vane or panel that guides the flow. In some embodiments, a mixing structure 119 comprising one or more baffles may be incorporated into a second membrane 114.

[0183] In certain embodiments, the mixing structure 119 is contained within the collapsible blood container 102. In one embodiment, the mixing structure 119 within the collapsible blood container 102 includes one or more beads or balls that help mix when the collapsible blood container 102 is shaken. In another embodiment, the mixing structure 119 within the collapsible blood container 102 includes one or more strings or elongated structures that help mix when the collapsible blood container 102 is shaken. In yet another embodiment, the mixing structure 119 within the collapsible blood container 102 includes a mesh that helps mix when the collapsible blood container 102 is shaken.

[0184] This disclosure provides and includes an oxygen depletion device 10 having a substantially oxygen-impermeable outer container 101 that encloses a foldable inner blood container 102 and provides a headspace. In one embodiment, an oxygen absorber 103 is placed in the headspace to create an oxygen-depleted state within the headspace. In one embodiment, the oxygen absorber 103 placed in the headspace further maintains the headspace in an oxygen-depleted state by removing oxygen that may enter through the outer container 101 or through one or more inlet / outlet ports 30.

[0185] Maintaining the headspace in an oxygen-depleted state improves the shelf life of the oxygen depletion device 10. In one embodiment, the shelf life of the assembled oxygen depletion device 10 is at least 24 months. In another embodiment, the shelf life of the oxygen depletion device 10 is at least 12 months from the time the components are assembled. In one embodiment of this disclosure, the assembled oxygen depletion device 10 meets the ISTA-2A standard.

[0186] In certain embodiments of this disclosure, headspace improves processing time. In the oxygen depletion device 10, removing the ambient air or flowed inert gas from the assembled device before sealing the outer container 101 reduces the headspace volume. Depressurizing the outer container 101 before sealing reduces the headspace volume and thus the total volume of the assembled oxygen depletion device. A reduction in the overall headspace volume reduces the transport volume, but may increase the filling time by constraining the collapsible blood container 102. In certain embodiments, nitrogen gas may be flowed into the headspace and then sealed at a pressure slightly lower than the ambient pressure to reduce the headspace volume in the oxygen depletion device 10 without significantly increasing the filling time and processing time.

[0187] In certain embodiments, oxygen may be depleted from the headspace by first flowing nitrogen into the headspace. In one embodiment, nitrogen gas is flowed into the headspace of the oxygen depletion device 10 before sealing the outer container 101. In one embodiment, the gas flowed is nitrogen gas with a concentration of ≥99.9%.

[0188] This disclosure includes and provides an oxygen depletion device 10 having a foldable inner blood container 102 divided into two or more compartments. In certain embodiments, the oxygen depletion device 10 having a foldable blood container 102 divided into multiple compartments has a headspace of 10 to 500 ml per compartment. In one embodiment, the headspace is 20 to 400 ml per compartment. In another embodiment, the headspace volume is 60 to 300 ml per compartment. In yet another embodiment, the headspace volume is 100 to 200 ml per compartment of the foldable blood container. In one embodiment, the oxygen depletion device 10 having a foldable inner blood container 102 divided into compartments has a headspace of about 10 ml per compartment. In another embodiment, the headspace is about 100 ml to about 200 ml per compartment. In another embodiment, the headspace is about 300 ml to about 500 ml per compartment.

[0189] This disclosure includes and provides an oxygen depletion device 10 having a foldable inner blood container 102 divided into two or more compartments. In certain embodiments, the oxygen depletion device 10 having a foldable blood container 102 divided into two compartments has a headspace of 20 to 1000 ml. In one embodiment, the headspace is 100 to 800 ml. In another embodiment, the headspace volume is 200 to 700 ml. In a further embodiment, the headspace volume is 300 to 500 ml with respect to the foldable blood container of two compartments. In one embodiment, the oxygen depletion device 10 having a foldable inner blood container 102 divided into two compartments has a headspace of about 700 ml. In another embodiment, the headspace is about 200 ml to about 700 ml. In another embodiment, the headspace is about 300 ml to about 500 ml.

[0190] This disclosure includes and provides an oxygen depletion device 10 having a foldable inner blood container 102 divided into two or more compartments. In certain embodiments, an oxygen depletion device 10 having a foldable blood container 102 divided into three compartments has a headspace of 20 to 1000 ml. In one embodiment, the headspace is 100 to 800 ml. In another embodiment, the headspace volume is 200 to 700 ml. In a further embodiment, the headspace volume is 400 to 600 ml with respect to a foldable blood container with three compartments. In one embodiment, an oxygen depletion device 10 having a foldable inner blood container 102 divided into three compartments has a headspace of about 800 ml. In another embodiment, the headspace is about 200 ml to about 700 ml. In another embodiment, the headspace is about 400 ml to about 600 ml. In one embodiment, the headspace is approximately 7000 ml due to the complete expansion of the headspace area. In another embodiment, the headspace is 700 to 7000 ml. In yet another embodiment, the headspace is 800 to 6000 ml. In yet another embodiment, the headspace is 1000 to 5000 ml. In yet another embodiment, the headspace is 2000 to 4000 ml.

[0191] This disclosure includes and provides an oxygen depletion device 10 having a foldable inner blood container 102 and further comprising one or more spacers 110 that separate the outer container 101 from the foldable inner blood container 102. The spacers 110 maintain headspace within the oxygen depletion device so that oxygen can efficiently diffuse from the surface of the membrane 113 to the absorbent 103. The spacers 110 can be made from one or more materials selected from the group consisting of mesh, molded mats, woven mats, nonwoven mats, strand bales and strand mats. In certain embodiments, the spacers 110 can be directly integrated into the foldable blood container 102 as ribs, dimples or other raised mechanisms that keep the outer container 101 and the foldable inner blood container 102 separated. This specification also includes and provides a spacer 110 integrated with the outer container 101, which serves as a rib, dimple or other preferred raised mechanism that can keep the outer container 101 and the foldable inner blood container 102 separate. Mixing is an important aspect of this disclosure. In one aspect of this disclosure, the spacer 110 is selected to be flexible so as not to impede the flow of the blood product.

[0192] This disclosure includes and provides a spacer 110 having an opening area to allow a gas to freely diffuse from the surfaces of permeable membranes 113 and 114. In one embodiment, the spacer 110 is provided as a mesh 110 having an opening space 111. As used herein, the opening area 111 is also referred to as a void 111. As shown herein, the void 111 can be provided by a regularly woven mesh 110, resulting in the void 111 being regular and repeating within the spacer 110. In another embodiment, the void 111 may include an irregular opening area, such as one provided by a spacer 110 constructed from a nonwoven mesh. In one embodiment, the area of ​​the void 111 is about 0.5 square millimeters (mm²). 2 ) ~ approximately 100mm 2 In a further embodiment, the area of ​​the void 111 is 1 mm 2 ~10mm 2In another embodiment, the gap 111 is 0.75 mm per opening. 2 It has a large opening. In one embodiment, the opening area or void space of the mesh occupies 30% to 90% of the total area of ​​the spacer 110. In another embodiment, the opening area or void space of the mesh occupies 50% to 80% of the total area of ​​the spacer 110. In yet another embodiment, the opening area occupies approximately 60%. In yet another embodiment, the opening area occupies up to 75% of the total area.

[0193] This disclosure provides, and includes, a foldable inner blood container 102 having a spacer 110 incorporated in a membrane 113, a membrane 114, or both. In embodiments of this disclosure, the spacer 110 not only separates the outer container 101 from the foldable inner blood container 102 but also reinforces the permeable membrane. In embodiments of this disclosure, the spacer 110 prevents the foldable inner blood container 102 from tearing, puncturing, or rupturing when filled with blood or used in the depletion method of this disclosure. In some embodiments, the spacer 110 is provided as a mesh 110 integrated into the silicone membrane during the manufacturing process. In other embodiments, the spacer 110 is attached to or bonded to the finished silicone membrane. In other embodiments, the spacer 110 is provided as an integrated mesh of the porous membrane.

[0194] In one embodiment, a membrane 113 or 114 having an integrated spacer 110 is prepared from a suspension of liquid silicone rubber (LSR). In one embodiment, the LSR is suspended in xylene, hexane, tert-butyl acetate, heptane, acetone, or naphtha. In embodiments of this disclosure, the suspension contains 10-30% LSR. As shown herein, a membrane 113 or 114 having an integrated spacer 110 is prepared by supplying a 20-750 μm LSR suspension layer, partially curing the LSR layer to provide the spacer 110 as shown herein, and then performing a second curing step to obtain a cured silicone membrane 113 with an integrated spacer 110 and a thickness of 10-100 μm.

[0195] This disclosure also includes and provides a mesh 110 comprising co-extruded fibers having an inner material 117 and a binder 118. In embodiments of this disclosure, the binder 118 integrates with the pores of the membrane 113 (114) when the mesh 110 is attached to the membrane. In one embodiment, the binder 118 integrates with the pores of the porous membrane 113 by heating. In embodiments of this disclosure, the binder 118 may be selected from the group consisting of ethyl vinyl alcohol (EVOH), ethyl vinyl acetate (EVA), or acrylate. In embodiments of this disclosure, the co-extruded fibers having an inner material 117 and a binder 118 are mesh 110 comprising the DuPont Bynel® series of modified ethyl vinyl acetate and modified ethyl vinyl acrylate.

[0196] This disclosure also includes and provides a foldable inner blood container 102 further comprising a window 112. As used herein, the window 112 is made of a transparent material and is bonded to or otherwise incorporated into the foldable inner blood container 102. According to this disclosure, a suitable material for the window 112 is blood-compatible. In certain embodiments, a suitable material for the window 112 is oxygen-impermeable. In other embodiments, a suitable material for the window 112 is oxygen-impermeable. The size of the window 112 may be large enough to observe the blood.

[0197] This disclosure also includes and provides a foldable blood container having bis(2-ethylhexyl) phthalate (DEHP). DEHP is included as a plasticizer in most PVC-based blood storage bags, in which case it has been observed to provide protection to the stored red blood cells. See U.S. Patent No. 4,386,069 issued to Estep. In certain embodiments, the oxygen depletion device 10 further includes DEHP incorporated into a foldable inner blood container 102. In other embodiments, the DEHP may be supplied separately within the foldable inner blood container 102.

[0198] This disclosure provides, and includes, an oxygen depletion device 10 that does not contain DEHP. DEHP is assumed to function as an endocrine disruptor, and certain regulatory authorities are considering instructing the removal of DEHP from blood bags. It has been observed that DEHP may be unnecessary when red blood cells are stored anaerobically. Refer to International Publication WO2014 / 134503, which is incorporated herein by reference in its entirety. Thus, in certain embodiments, DEHP is completely eliminated from all blood contact surfaces in the oxygen depletion device 10. In other embodiments, in the oxygen depletion device 10, DEHP contact surfaces are limited to tubes, ports, and inlets, as shown in the figures, for example, 106 and 205. In one embodiment, the oxygen depletion device 10 eliminates a collapsible blood container 102 that comes into contact with DEHP.

[0199] This disclosure provides, and includes, an oxygen depletion device 10 having an oxygen indicator 104. Similarly, this disclosure provides, and includes, a blood storage device 20 having an oxygen indicator 206. In one embodiment, the oxygen indicator 206 detects oxygen and indicates that the oxygen depletion device 10 has deteriorated and is no longer suitable for its intended purpose. In one embodiment, the oxygen indicator 206 visually indicates the presence of oxygen. In certain embodiments, the oxygen indicator 206 indicates the amount of oxygen.

[0200] In aspects of this disclosure, the outer container may be equipped with an oxygen indicator that notifies the user if the oxygen absorber is no longer active for any reason, such as aging, or if the outer container deteriorates and excess oxygen from the ambient air can enter. Such an oxygen indicator is readily available and is based on a methylene blue indicator dye that turns blue in the presence of approximately 0.5% or more oxygen and turns pink when the oxygen level falls below approximately 0.1%. Examples of such oxygen indicators are the Tell-Tab oxygen indicator tablet from Sorbent Systems, Inc. (Impak Corp., Los Angeles, California) and the Oxygen Indicator tablet from Mitsubishi Gas Chemical America (MGCA, New York, New York).

[0201] This disclosure provides, and includes, a method for preparing blood for storage under oxygen-depleted conditions, comprising supplying blood having red blood cells with oxygen to be removed to an oxygen-depleted device 10, incubating the blood for a period of time, and transferring the deoxygenated blood to an anaerobic storage bag. In embodiments of this disclosure, the method further includes shaking the oxygen-depleted device 10 to mix the blood to be deoxygenated. In other embodiments, shaking is not required depending on the configuration of the oxygen-depleted device 10.

[0202] For safety reasons, blood collection and processing are regulated by national or local government agencies. In the United States, the Food and Drug Administration (FDA) sets guidelines for the proper handling of blood and blood products. Similarly, in Europe, the European Union empowers regulatory authorities that are binding on member states and generally adhere to guidelines set by the Council of Europe. For example, key requirements for blood operations and hospital blood banks in the United Kingdom are defined in the Blood Safety and Quality Regulations (Statutory Instrument 2005 No. 50) and enforced by the Drugs and Medical Products Regulatory Agency, whose authority lies in UK law aimed at maintaining the safety and quality of blood and blood products for transfusion within the UK.

[0203] Generally, guidelines established by various organizations fall into two main groups. The first group, as exemplified by the United States, considers the acceptable timeframe from donor blood collection to platelet processing (i.e., the process of making RBCs storable at 2–6°C) to be 8 hours. Therefore, to maintain platelet viability, various processing steps (currently including plasma separation and recovery, leukocyte removal, platelet separation and recovery, and packed red blood cell preparation) must be completed within 8 hours to preserve the various components (see Moroff & Holme, “Concepts about current conditions for the preparation and storage of platelets” in Transfus Med Rev 1991;5:48–59). In Europe, the processing timeframe is 24 hours. Therefore, the methods and processes provided in this disclosure are designed to enable a beneficial level of deoxygenation, reducing storage damage, within approximately 8 hours of venous puncture, in preparation for blood storage.

[0204] According to the method of this disclosure, blood may be collected from a donor and processed to an oxygen saturation of less than 20% within 12 hours of collection. Starting the depletion process at the time of collection or immediately after collection increases the efficiency of the process by promoting an improvement in the reaction rate through a rise in temperature. In one embodiment, blood is collected from a donor at approximately 37°C and collected in an oxygen depletion device 10 having a suitable amount of anticoagulant. When blood is collected from a patient by venous puncture, in addition to the rise in temperature, the whole blood typically has an oxygen saturation of approximately 35-65%. In one embodiment of this disclosure, when blood is collected from a patient by venous puncture, the whole blood has an oxygen saturation of 35-65%. In another embodiment, when blood is collected from a patient by venous puncture, the whole blood has an oxygen saturation of 40-60%. In yet another embodiment, when blood is collected from a patient by venous puncture, the whole blood has an oxygen saturation of 45-55%. In another aspect, when whole blood is collected from a patient by venipuncture, the oxygen saturation is 50-65%. Conventional methods do not provide blood collection kits and bags that prevent oxygen intrusion. Therefore, the time required to prepare blood with reduced oxygen saturation of less than 20% can be significantly longer due to the delayed initiation of the oxygen reduction process.

[0205] The methods and apparatus of this disclosure further provide for preparing blood with reduced oxygen, specifically blood with an oxygen saturation of less than 10%. In one embodiment, this 10% level is achieved within 8 hours of blood collection from a donor. In another embodiment, the blood is reduced to an oxygen saturation of less than 10% within 6 hours. In yet another embodiment, the blood is reduced to an oxygen saturation of less than 10% within 4 hours.

[0206] As used herein, the term “blood” refers to whole blood, reduced white blood cell counts (RBCs), reduced platelet counts (RBCs), and reduced white blood cell and platelet counts (RBCs). The term “blood” further includes packed red blood cells, reduced platelet counts (RBCs), reduced white blood cell counts (LRpRBCs), and reduced white blood cell and platelet counts (RBCs). The temperature of blood can vary depending on the stage of the blood collection process; initially, it is 37°C, the normal body temperature at the time of collection, but immediately after the blood is taken from the patient’s body, it rapidly drops to about 30°C, and if left untreated, it further drops to room temperature over about 6 hours, and finally, it is refrigerated to about 2°C to 6°C.

[0207] As used herein, the term "whole blood" refers to a suspension of blood cells, including red blood cells (RBCs), white blood cells (WBCs), and platelets, suspended in plasma, and includes electrolytes, hormones, vitamins, antibodies, etc. In whole blood, white blood cells are typically 4.5–11.0 × 10⁴ 9 They are present in the range of cells / L, and the normal RBC range at sea level (0m) is 4.6–6.2 × 10⁻⁶ in males. 12 / L, for women: 4.2~5.4×10 12 The value is / L. Normal hematocrit levels, i.e., the percentage of packed cell volume, are approximately 40-54% in men and 38-47% in women. Platelet counts are typically 150-450 × 10⁶ in both men and women. 9 The volume is / L. Whole blood is collected from a blood donor and is usually mixed with an anticoagulant. Whole blood is initially collected at approximately 37°C and rapidly cooled to approximately 30°C during or immediately after collection, but is slowly cooled to ambient temperature over approximately 6 hours. Whole blood may be processed at the time of collection according to the method of this disclosure, which is started at 30–37°C or room temperature (typically about 25°C). As used herein, "1 unit" of blood, including anticoagulant, is approximately 450–500 ml.

[0208] As used herein, “blood donor” refers to a healthy person from whom whole blood is typically collected by venotomy or venipuncture, in which case the donated blood is processed and held in a blood bank for later use by a recipient other than the donor. A blood donor may be a person scheduled for surgery or other treatment who is able to provide blood for themselves in a process known as autologous blood transfusion. Alternatively, and most commonly, blood is provided by another person in a process known as xenotransfusion. The collection of whole blood samples from a donor, or from the patient in the case of autologous blood transfusion, may be done by techniques known in the art, such as by transfusion or apheresis. The oxygen saturation of whole blood obtained from a donor by venipuncture is in the range of approximately 30% to approximately 70% oxygen saturation (sO2).

[0209] As used herein, “red blood cells” (RBCs) include whole blood, RBCs with reduced white blood cell count, RBCs with reduced platelet count, and RBCs present in RBCs with reduced white blood cell and platelet count. In vivo, human red blood cells are in a dynamic state. Red blood cells carry oxygen throughout the body and contain hemoglobin, an iron-containing protein that makes red blood cells red. The percentage of blood volume composed of red blood cells is called the hematocrit. As used herein, unless otherwise specified, RBCs also include packed red blood cells (pRBCs). Packed red blood cells are prepared from whole blood using centrifugation methods widely known in the art. As used herein, the hematocrit value of pRBCs is approximately 50%, unless otherwise specified.

[0210] Platelets are small blood cell components that facilitate the coagulation process by adhering to the vascular intima and, when activated, promote healing by releasing growth factors. Like red blood cells, platelets are produced in the bone marrow and survive in the circulatory system for 9-10 days before being removed by the spleen. Platelets are typically prepared using a centrifuge, which separates them from a buffy coat sandwiched between a plasma layer and a pellet of red blood cells.

[0211] Plasma is the liquid portion of blood, a protein-salt solution in which red blood cells, white blood cells, and platelets are suspended. Plasma is 90% water and makes up about 55 percent of the blood volume. One of the main functions of plasma is to aid in blood clotting and immunity. Plasma is obtained by separating the liquid portion of blood from the blood cells. Typically, plasma is separated from blood cells by centrifugation. Centrifugation is a process used to separate the components of whole blood into plasma, white blood cells, platelets, and packed red blood cells. During centrifugation, the plasma first moves to the top of the container while it is gently swirling. Then, the plasma is removed from the container. White blood cells and platelets are removed during a second centrifugation cycle to make packed red blood cells.

[0212] This disclosure includes and provides a method for preparing oxygen-depleted blood for storage. Oxygen-depleted blood or blood components that are suitable for storage, benefit from reduced damage due to storage damage, have reduced toxicity, and importantly, reduce morbidity, are blood or blood components with an oxygen saturation of less than about 20%. In certain embodiments, the oxygen level of the blood or blood component is reduced to a level of less than 15%. In another embodiment, the oxygen saturation of the blood is reduced to 10% or less before storage. In yet another embodiment, the oxygen saturation of the blood is reduced to less than 5% or less than 3% before storage.

[0213] According to the method of this disclosure, blood or blood components are deoxygenated and stored within 4 to 24 hours of collection. In another embodiment, according to the method of this disclosure, blood is deoxygenated and stored within 8 hours of collection. In yet another embodiment, blood or blood components are deoxygenated and stored less than 6 hours after collection. In yet another embodiment, blood is deoxygenated and stored less than 4 hours after collection.

[0214] This disclosure provides, and includes, a method for preparing blood for storage under oxygen-depleting conditions, comprising supplying blood having red blood cells with oxygen to be removed to an oxygen-depleting device 10, and incubating the blood for a period of time. In certain embodiments, the blood is mixed by shaking. In other embodiments, the oxygen-depleting device performs sufficient deoxygenation with little or no mixing.

[0215] As can be seen, the oxygen saturation of the blood to be depleted can initially be at various levels. In certain embodiments, the blood is whole blood collected with a saturation of approximately 70% and a hematocrit of approximately 40%–45%. The method of this disclosure also performs rapid deoxygenation of LRpRBCs, which typically have a hematocrit of approximately 50% and a saturation level of up to 90% or more.

[0216] The apparatus and methods of this disclosure are intended to produce oxygen-depleted blood for storage in 24 hours or less. In certain embodiments, oxygen is removed by incubation with shaking over a period of time using the oxygen-depleting apparatus 10. In other embodiments, oxygen is removed using the oxygen-depleting apparatus 10 during the incubation period without shaking or otherwise mixing the depleting apparatus. As those skilled in the art will see, including a shaking or mixing step in this process can reduce the surface-to-volume ratio of the oxygen-depleting apparatus 10. Shaking can also reduce the permeability required to achieve the desired level of deoxygenation. To achieve the fastest depletion dynamics, a highly permeable oxygen-depleting apparatus 10 with a large surface-to-volume ratio is combined with shaking during the depletion period. Depending on the application and the processing protocol used, the time required to complete the process can vary from 4 to 24 hours. Therefore, the apparatus and methods of this disclosure can be incorporated into existing blood processing center protocols by modifying them as shown in this disclosure, and can comply with applicable regulations in each region.

[0217] In embodiments of this disclosure, the blood may be shaken or mixed during the depletion period to reduce the processing time required to achieve a blood saturation of less than 20%. In most embodiments, the blood is shaken or mixed for less than 24 hours. Since mixing and shaking the blood during processing can cause dissolution and degradation, the depletion period accompanied by shaking should be kept to a minimum.

[0218] In certain embodiments, the blood is incubated with shaking for less than 12 hours. In other embodiments, the incubation and shaking time is less than 8 hours. A method is also provided in which oxygen is reduced to less than 20% by using the oxygen depletion device 10 and incubating with shaking for less than 6 hours or less than 4 hours. In yet another embodiment, the incubation time with shaking is 3.5 hours or 3.0 hours. In certain embodiments, the blood can be reduced to less than 20% by incubating with shaking for 4 hours in the oxygen depletion device 10. In further embodiments, this method results in an incubation time of 0.5 or 1.0 hours. In another embodiment, the blood is incubated with oxygen depletion device 10 for 1.5 hours or 2.0 hours.

[0219] It is quite clear that the reaction rate is temperature-dependent, and that the reaction rate increases with increasing temperature. The rate constant k changes exponentially with temperature, and k = Ae -Ea / RT(Arrhenius equation). Notably, the temperature dependence is independent of the concentration of the reaction substrate and does not depend on whether the order of the reaction rate is constant (e.g., first-order versus second-order). Typically, a 10°C increase in temperature can double the reaction rate. Thus, those skilled in the art will recognize that the release of oxygen from hemoglobin and the other steps of the deoxygenation process are temperature-dependent. Importantly, the deoxygenation rate decreases significantly when the blood temperature drops to the standard storage temperature of 2°C to 6°C. Furthermore, currently accepted protocols for the collection, processing, and storage of blood for transfusion purposes do not mix the stored blood (which further reduces the rate at which oxygen can be removed). Therefore, the methods and apparatus of this disclosure are designed to remove most of the oxygen before storage, within the period specified by the applicable regulatory authority. As shown herein, oxygen depletion is intended to begin as soon as possible after blood collection from the donor and to be largely completed before the blood is cooled for storage.

[0220] As described herein, the method of this disclosure can be performed using blood collected from a donor at approximately 37°C shortly after collection. In another embodiment, the blood may be processed before depletion, including the removal of leukocytes, plasma, and platelets. Alternatively, the blood may be further processed after oxygen reduction.

[0221] This disclosure provides, and includes, processed blood cooled from body temperature to ambient temperature, typically about 25°C. Using the methods and apparatus disclosed herein, oxygen-reduced blood with an oxygen saturation of less than 20% can be prepared at ambient temperature (e.g., about 25°C). The ability to reduce oxygen to a desired and beneficial level at ambient temperature makes the systems and methods of this disclosure integrable into existing blood collection protocols and blood collection centers.

[0222] This disclosure provides and includes a method for preparing blood for storage under oxygen-depleting conditions, comprising supplying blood having red blood cells with oxygen to be removed to an oxygen-depleting device 10, incubating the blood for a period of time, and further comprising shaking or mixing during the incubation period. As used herein, the terms “agitating” and “mixing” are used synonymously and include, but are not limited to, a variety of mixing methods, including, rocking, nutating, rotating, stirring, massaging, swinging, linearly-oscillating and compressing of the oxygen-depleting device.

[0223] In the method of this disclosure, the incubation period with shaking can be as short as 30 minutes or as long as 24 hours. In certain embodiments, the method of this disclosure includes an incubation period of 1 to 3 hours in the oxygen depletion apparatus 10 with shaking. In other embodiments, the incubation period is 1 to 4 hours or 1 to 6 hours. In other embodiments, the incubation period is approximately 2 hours or approximately 4 hours.

[0224] In one aspect of this disclosure, a method for reducing oxygen from red blood cells includes placing red blood cells in the apparatus of this disclosure and placing the apparatus in a shaker to facilitate the removal of oxygen from the red blood cells through mixing. The use of a shaker during blood transfusion is well known in terms of preventing blood clot formation, as is the case with the use of a vibrating table and blood collection scale mixer that are tilted at approximately 7 degrees and vibrated gently at 1 to approximately 15 vibrations per minute. Proper mixing can be ensured using similar apparatus that is already available in oxygen depletion centers and is well known to the staff.

[0225] To maximize the dynamics of the oxygen depletion process, both physical and methodological approaches can be employed. As discussed above, the physical approach to reducing the diffusion resistance of the blood-compatible inner bag can be achieved by selecting a highly permeable material and reducing the material thickness to lower the Valar value. For microporous materials, the apparent Valar value can be reduced by reducing the size of the micropores and increasing their number. The size of the micropores is necessarily limited by the need to prevent water from penetrating through the barrier, and this penetration is found to occur in certain microporous materials with a size of approximately 1 μm. Also, as shown above, the surface-to-volume ratio should be selected to shorten the diffusion distance of dissolved oxygen, as dissolved oxygen moves towards the permeable surface. The material and design limitations and requirements for effective and rapid reduction of blood oxygen are discussed above.

[0226] In addition to minimizing the diffusion barrier and diffusion distance through design and appropriate material selection, the effective diffusion distance can be further shortened by proper mixing. As can be seen, oxygen-containing red blood cells enter an anaerobic environment close to the permeable membrane, so complete and efficient mixing effectively eliminates the effect of diffusion distance on the blood reduction process. Similarly, diffusion distance can also be eliminated by spreading the blood into an impractically thin volume. This disclosure provides methods and apparatus that optimize apparatus and methods to achieve high depletion rates.

[0227] This disclosure relates to a method for mixing blood in an oxygen depletion device 10, which provides a rapid deoxygenation rate and approximately 0.5 × 10 -2 min -1 ~Approx. 5.0×10 -2 min -1 The present disclosure provides, and includes, a method for obtaining a rate constant of at least -1.28 × 10⁻⁶. -2 min -1 In another embodiment, deoxygenation is carried out with a rate constant of at least -0.5 × 10 -2In another embodiment, deoxygenation is carried out at a rate constant of at least -0.9 × 10 -2 In another embodiment, deoxygenation is carried out at a rate constant of at least -1.0 × 10⁻⁶. -2 In another embodiment, deoxygenation is carried out at a rate constant of at least -1.5 × 10⁻⁶. -2 The deoxygenation is carried out at a rate of -1.0 × 10⁻¹⁰. In a further embodiment, deoxygenation is carried out with a rate constant of -1.0 × 10⁻¹⁰. -2 min -1 ~-3.0 × 10 -2 min -1 The deoxygenation is carried out at a rate of -1.0 × 10⁻¹⁰. In a further embodiment, deoxygenation is carried out with a rate constant of -1.0 × 10⁻¹⁰. -2 min -1 ~-2.0 × 10 -2 min -1 The deoxygenation is carried out at a rate of -1.0 × 10⁻¹⁰. In a further embodiment, deoxygenation is carried out with a rate constant of -1.0 × 10⁻¹⁰. -2 min -1 ~-4.0 × 10 -2 min -1 It is done at this speed.

[0228] In aspects of this disclosure, a suitable mixture is defined as having a surface-to-volume ratio of at least 5.0 cm². 2 This is achieved with oxygen depletion device 10 at a rate of / ml. Although not limited by theory, it is assumed that the smaller the surface-to-volume ratio, the less capable the collapsible blood container is of moving blood, and mixing will not occur. Like a greatly inflated mite, it will be obvious that a bag filled to its maximum capacity is inherently difficult to mix and cannot easily induce convection or other flow. In other words, in a collapsible inner container 102 filled to its maximum capacity where the flexibility of the bag material decreases beyond what can be achieved during shaking, mixing will essentially not occur. Therefore, at least 4.85 cm 2By selecting a surface-to-volume ratio of / ml, the blood can "move around," thus enabling mixing. If mixing is inadequate, it can undesirably lead to hemolysis of red blood cells. Therefore, there are practical limitations to mixing. This disclosure provides a device and method for achieving sufficient mixing while reducing the possibility of hemolysis.

[0229] In one aspect of the present disclosure, a method for reducing oxygen from red blood cells includes placing red blood cells in the apparatus of the present disclosure and placing the apparatus in a shaker to facilitate the removal of oxygen from the red blood cells. The use of shakers during blood transfusion is well known for preventing blood clot formation, such as in the use of vibrating tables and blood collection scale mixers when used with whole blood and red blood cell suspensions, and for platelet preservation (in which case platelets require oxygen for survival and shaking to prevent platelet aggregation and activation).

[0230] Whether whole blood or other red blood cell suspensions, currently available devices for shaking red blood cells typically have a platform that rotates a few degrees around a central axis to produce gentle vibrations, and there are many commercially available options. For example, the Bellco Glass Model #7740-10000 (Bellco Glass, Inc., Vineland, New Jersey) provides a 7-degree tilt and vibrations of 1 to approximately 12 times per minute. The Medicus Health Model 5277M5 tautation mixer (Medicus Health, Kentwood, Michigan) provides a 20-degree tilt at 24 rpm for red blood cell sample suspensions, while another style of device used during blood collection to prevent whole blood clotting is the Genesis blood collection mixer Model CM735A (Genesis BPS, Ramsey, New Jersey), which provides a tilt of approximately 20 degrees, performs 3 cycles in approximately 3 seconds, then pauses for approximately 2 seconds to weigh the sample, and repeats until the desired weight is reached. The Benchmark Scientific model B3D2300 (Benchmark Scientific, Inc., Edison, New Jersey) allows the tilt angle to be varied from 0 to 30 degrees, and provides 2 to 30 vibrations per minute.

[0231] The disclosure further provides, including other available means for shaking blood samples, such as the Model LOS-101 from Labocon Systems, Ltd. (Hampshire, UK) with a displacement of 20 mm and an vibration velocity of 20 to 240 rpm, or the Model EW-51820-40 from Cole-Parmer, Inc. (Vernon Hills, Illinois) with a displacement of 20 mm and an vibration velocity of 50 to 250 rpm.

[0232] Instruments for shaking platelets are also well known in the art, and various models are available, such as the Helmer Scientific PF96h (Helmer Scientific, Nobleville, Indiana), which provides linear vibration at approximately 70 cycles per minute and displacement of approximately 38 mm (1.5 inches), and the Terumo Penpol Model PAI200 (Terumo Penpol Ltd., Thiruvananthapuram, India), which provides vibration at approximately 60 cycles per minute and displacement of approximately 36 mm (1.4 inches).

[0233] The apparatus of this disclosure promotes the deoxygenation of red blood cells, but with modified operation, further oxygen is removed from the red blood cells. Since platelets can be activated by mechanical shaking such as shear force, it is well known that there are limitations regarding the degree of physical shaking that can be tolerated before platelet activation occurs. Approximately 6000 dynes / cm 2 It is estimated that hemolysis of red blood cells occurs at shear stress levels exceeding a certain threshold (Grigioni et al., J. Biomech., 32:1107-1112 (1999), Sutera et al., Biophys. J., 15:1-10 (1975)), which is an order of magnitude greater than the level required for platelet activation (Ramstack et al., J. Biomech., 12:113-125 (1979)). In certain embodiments, currently available platelet shakers operating with a displacement of approximately 36 mm and at approximately 65 cycles per minute (cpm) result in deoxygenation of red blood cells, as disclosed herein. In other embodiments, linear vibrations with displacements of 30 mm to approximately 125 mm are used to improve the rate and degree of deoxygenation without hemolysis. In yet another embodiment, the shaking is a linear vibration of approximately 50 mm to approximately 90 mm.

[0234] This disclosure also provides, and includes, the ability to adjust the vibration frequency to ensure efficient mixing. In addition to a platelet shaker with a displacement of about 36 mm and a frequency of about 65 cpm, in certain embodiments, the frequency is about 60 to about 150 cycles per minute (cpm). In certain embodiments, the shaking frequency is about 80 to about 120 cpm.

[0235] In certain embodiments of this disclosure, various chamber configurations are provided for a blood collection device 10 having two or more chambers when using a shaker or mixer. In a shaker operating in horizontal motion, in one embodiment, 2 to 8 horizontal (horizontal on the surface) chambers are arranged in parallel, with their ends touching, stacked on top of each other, or with one or more chambers partially covering the lower chamber(s). In another embodiment, in a shaker operating in vertical motion, 2 to 8 vertical (perpendicular to the surface) chambers are arranged in parallel, with their ends touching, stacked on top of each other, or with one or more chambers partially covering the lower chamber(s). In another embodiment, a vibrator that moves up and down while rotating at an angle greater than 0 degrees and less than 90 degrees with respect to the horizontal direction may be arranged with 2 to 8 vertically positioned chambers (greater than 0 degrees and less than 90 degrees with respect to the horizontal direction) in parallel, with their ends touching, stacked on top of each other, or with one or more chambers partially covering the lower chamber(s) on top of each other.

[0236] A further advantage of shaking and mixing the oxygen depletion device 10 is that the blood or blood components move as they are moved by the shaker, causing the absorbent pouch placed at the top or bottom of the oxygen depletion device 10 to move as well. When the absorbent pouch is placed at the top, the pouch moves up and down, so that the active ingredients that absorb oxygen in the headspace remain constantly present. This constant movement of the active ingredients moves the iron oxide particles so as not to interfere with the non-iron oxide particles, thereby accelerating the potential oxygen absorption capacity of the absorbent.

[0237] This disclosure provides, and includes, a method for mixing an oxygen depletion device 10 by compressing a collapsible blood container 102. The compression of the collapsible container 102 is performed by applying pressure at 30 cm / second over 1 to 3 seconds to generate a hydrostatic pressure of 100 to 300 mmHg inside the collapsible container, and then applying pressure at 10 to 30 cm / second over 1 to 3 seconds to generate a hydrostatic pressure of 100 to 300 mmHg inside the collapsible container. This process is carried out over 2 to 4 hours.

[0238] This disclosure provides, and includes, a method for mixing an oxygen depletion device 10 by kneading a collapsible blood container 102. The kneading of the collapsible container 102 is performed by displacing a roller-type device along one of the surfaces of the collapsible container, completing the maximum translation in 1 to 3 seconds, thereby crushing the collapsible container and shaking its contents. This process is performed for 1 to 2 hours. In another embodiment, the roller is moved along another surface of the collapsible container, completing the maximum translation in 1 to 3 seconds, thereby crushing the collapsible container and shaking its contents. This process is performed for 1 to 2 hours.

[0239] This disclosure provides and includes a blood storage device 20 for storing oxygen-depleted blood and keeping the blood deoxygenated during storage. Certain anaerobic blood storage devices (ASBs) are known in the art, including, for example, U.S. Patent No. 6,162,396 to Bitensky et al. Prior art anaerobic blood storage devices did not have ports and inlets designed to be substantially oxygen-impermeable. Therefore, prior art anaerobic storage devices had poor pre-use storage life and were considerably susceptible to oxygen intrusion. As shown in this disclosure, the improved blood storage device 20 incorporates a mechanism aimed at maintaining the integrity of the device while allowing blood sampling during storage and blood retention. The improved ASB also improves oxygen diffusion, and additional depletion occurs during storage.

[0240] The blood storage device 20 comprises an outer container 201 which is substantially oxygen-impermeable; a foldable blood container 202 which has a positioning mechanism 203 adapted to adjust the position of the foldable blood container 202 within the shape of the outer container 201; at least one inlet / outlet 30 which is connected to the foldable blood container 202 and has a joint 302 to the outer container 201, wherein the joint 302 to the outer container 201 is substantially oxygen-impermeable; and an oxygen absorbent 207 placed inside the outer container 201.

[0241] As used herein, the outer container 201 is at least equivalent to the outer container 101. Also as used herein, the foldable inner blood container 202 includes a blood container as shown above for the foldable inner blood container 102, but also provides a foldable blood container 202 made of a material with poor oxygen permeability, such as PVC. Also, as shown herein, the oxygen absorber 207 is at least equivalent to the absorber 103 and may be placed in a pouch as discussed above.

[0242] This disclosure includes and provides a blood collection kit. In aspects of this disclosure, an oxygen depletion device for depleting oxygen from the blood is included in the blood collection kit for reducing or eliminating oxygen intrusion during the blood collection process. Blood collection kits in the art do not include any mechanism or element to prevent oxygen intrusion during the blood collection process. Thus, kits in the art having multiple containers allow for further intrusion from materials and accessories, in addition to about 3 cc of residual oxygen per container, thereby raising the oxygen saturation (sO2) from about 40-60% venous oxygen saturation (SvO2) to a maximum of full saturation. In one aspect of this disclosure, the entire blood collection kit is housed in an oxygen-free or oxygen-reduced atmosphere. In one aspect, the blood collection kit is housed in a substantially oxygen-impermeable kit encapsulation bag containing a certain amount of oxygen-absorbing material. The amount of absorbent for the blood collection kit described herein is separate from, or in addition to, the amount of absorbent that may be included in the blood collection bag or anaerobic storage bag.

[0243] In certain embodiments of this disclosure, the amount of oxygen absorber contained in the blood collection kit is sufficient to remove oxygen that enters the kit during manufacturing. In one embodiment, the blood collection kit contains enough oxygen absorber to absorb 10 cc of oxygen. In another embodiment, the blood collection kit contains enough oxygen absorber to absorb 60 cc of oxygen. In another embodiment, the blood collection kit contains enough oxygen absorber to absorb 100 cc of oxygen. In another embodiment, the blood collection kit contains enough oxygen absorber to absorb 200 cc of oxygen. In another embodiment, the blood collection kit contains enough oxygen absorber to absorb 500 cc of oxygen. In another embodiment, the blood collection kit contains enough oxygen absorber to absorb 10 to 500 cc of oxygen. In another embodiment, the blood collection kit contains enough oxygen absorber to absorb up to 24,000 cc to allow for control of the storage life of the device. In certain embodiments of this disclosure, the oxygen absorber is contained in one or more pouches.

[0244] In one embodiment, the amount of oxygen absorber is sufficient to maintain an oxygen-depleted atmosphere for the blood collection kit during storage. In certain embodiments, oxygen is released from the blood collection kit during manufacturing. Therefore, the amount of oxygen absorber may be reduced to account for leakage and residual permeation of the substantially impermeable kit sealing bag.

[0245] This disclosure also includes and provides an additive solution bag that is substantially oxygen-impermeable. In embodiments of this disclosure, the substantially oxygen-impermeable additive solution bag prevents oxygen from re-entering the oxygen-reduced blood after it has been oxygen-reduced in an oxygen-reduced blood collection bag.

[0246] In aspects of this disclosure, the method of this disclosure may further include adding an additive to concentrated RBCs to form a suspension. In certain aspects, the additive may be selected individually or in combination from the group consisting of AS-1, AS-3 (Nutricel®), AS-5, SAGM, PAGG-SM, PAGG-GM, MAP, SOLX, ESOL, EAS61, OFAS1, and OFAS3. Additive AS-1 is disclosed in Heaton et al., “Use of Adsol preservation solution for prolonged storage of low viscosity AS-1 red blood cells,” Br J Haematol., 57(3):467-78 (1984). In further aspects, the pH of the additive may be 5.0 to 9.0. In other aspects, the additive may contain an antioxidant. In some aspects of this disclosure, the antioxidant may be quercetin, α-tocopherol, ascorbic acid, or an oxidase enzyme inhibitor. [Examples]

[0247] Example 1: Fabrication of outer container 101 A barrier bag is created by heat-sealing one edge by placing a pair of RollPrint Clearfoil® Z film #37-1275 (Rollprint Packaging Products, Inc., Addison, Illinois) sheets, approximately 23 x 30.5 cm (9 x 12 inches), in a heat sealer along the shorter 23 cm length. A multilayer tube (Pexco, Inc., Athol, Massachusetts, or Extrusion Alternatives, Inc., Portsmouth, New Hampshire) with an inner diameter of 0.4 cm, an outer diameter of 0.55 cm, and a length of approximately 2.6 cm, having a polyethylene outer layer, a PVC inner layer, and an EVA intermediate bonding layer, is placed in a solid brass mandrel approximately 0.4 cm in diameter and 2.5 cm in length, then placed between the above films and positioned in the transverse groove of a heat seal die heated to approximately 130°C. The press is activated, and 21 x 10 4Set to a length of about 4 seconds in Pascals (Pa), and with the above short multi-layer tube sealed in place, create a continuous welded seal along the length of the die. This short multi-layer tube provides an oxygen-impermeable seal across the outer diameter of the tube, while also providing fluid connectivity through the seal. Using cyclohexanone, solvent bond one PVC tube (Pexco, Inc. of Athol, Massachusetts or Extrusion Alternatives, Inc. of Portsmouth, New Hampshire) with an inner diameter of 0.3 cm, an outer diameter of 0.41 cm, and a length of about 30.5 cm from the outside of the bag to the multi-layer tube.

[0248] Seal the two long edges of the barrier film using an impulse heat sealer (McMaster Carr #2054T35, McMaster Carr, Inc. of Robbinsville, New Jersey). Leave the short edge remaining at the end of the barrier bag unsealed to place the blood container 102 inside.

[0249] Example 2: Preparation of a silicone sheet Liquid silicone rubber (LSR) A silicone sheet with a thickness of about 25 μm is fabricated by equally mixing a two-component silicone elastomer dispersion (e.g., NuSil MED10-6640) dispersed in a suitable solvent such as xylene. MED10-6640 is supplied as a two-component resin system. As the first step, liquid A and liquid B are mixed in equal measured amounts to make a dispersion. Next, air is removed under vacuum. The vacuum time was selected so that no air bubbles remained in the dispersion. Next, this dispersion is spread and passed under a precision knife edge on a custom-made knife coating tray. By heating, the sheet is partially cured, and then a sheet of polyester mesh fabric (Surgical Mesh, Inc. of Brookfield, CT#PETKM3002) is placed on the partially cured silicone sheet. By applying a load on this laminate, the polyester mesh fabric is pressed into the partially cured sheet. Using stepwise curing with a sequence of times and temperatures combined as 30 minutes at ambient temperature and humidity, 45 minutes at 75 °C (167 °F), and 135 minutes at 150 °C (302 °F), this laminate is cured to obtain a silicone membrane 113 with a thickness of about 25 μm and having an integrated spacer 110 (the thickness of the integrated spacer 110 is not included in the obtained silicone membrane). The polyester mesh fabric is adhered to the cured silicone membrane 113 but is not completely encapsulated in the silicone membrane 113. One surface of the membrane 113 has a matte finish suitable for contacting blood or blood products.

[0250] Using the silicone dispersion method, additional integrated silicone membranes with thicknesses of about 13 μm and about 50 μm are fabricated.

[0251] Example 3: Fabrication of a foldable inner blood container 102 A silicone blood bag is fabricated from a pair of silicone sheets by joining the edges of a pair of silicone sheets together using Smooth-On Sil-Poxy RTV adhesive (Smooth-On, Inc., Easton, Pennsylvania), and then placing the joined sheets between a pair of aluminum plates to obtain a silicone blood bag. To provide a fluid passage, a silicone injection tube (McMaster Carr #5236K83, McMaster Carr, Inc., Robbinsville, New Jersey) is joined into the seam and placed in a groove in the aluminum plate. The aluminum plate is then joined and secured with a large binder clamp, and the adhesive is allowed to cure overnight. The next day, the silicone blood bag is removed from the aluminum plate, and before use, a leak test is performed by blowing compressed air into it, immersing it in water, and observing for bubbles. Subsequently, the silicone blood bag is placed in an outer barrier bag fabricated as described in Example 1.

[0252] A silicone blood bag is placed inside a barrier bag as disclosed in Example 1, and the silicone infusion tube of the silicone blood bag is connected to the multilayer tube using a plastic barb fitting (McMaster Carr #5116K18, McMaster Carr, Inc., Robbinsville, NJ), and an oxygen sensor tab (Mocon #050-979, Mocon, Inc., Minneapolis, Minnesota) is attached to the inside of the barrier bag. A pair of plastic mesh spacers (McMaster Carr #9314T29, NJ McMaster Carr, Inc., Robbinsville, NJ) are cut to approximately 12.7 × 17.8 cm (5 × 7 inches), and the plastic mesh spacers are placed between the blood bag and the barrier bag. Just before sealing the last edge of the barrier bag with an impulse sealer, one or more pouches of oxygen absorber (Mitsubishi Gas Chemical America, New York, NY) are attached near the center of each plastic mesh piece. The resulting oxygen depletion device 10 will be used in a later test.

[0253] Example 4: Blood preparation Whole blood and blood products, including whole blood with reduced leukocyte count and red blood cells with reduced leukocyte count, are prepared using techniques known in the art. As shown, samples are analyzed using a Radiometer ABL-90 blood analyzer (Radiometer America, Blair, California) according to the manufacturer's instructions, including pH, blood gases, electrolytes, metabolites, oxygen saturation measurement, and baseline sO2 and pO2 levels. Free hemoglobin is measured using a Hemocue® Plasma Low Hb Photometer according to the manufacturer's instructions.

[0254] The blood's sO2 level is increased to a level typical for collected whole blood (65-90%) by passing blood or blood components through an artificial lung (Arvada,CO) called Sorin D100, which contains oxygen as an exchange gas, as needed. All experiments begin with an sO2 level of ≥50% before transferring the blood for testing to the oxygen-depleted device.

[0255] Example 5: Deoxygenation Test Blood is placed in the oxygen depletion apparatus of Example 2 and tested as follows. Whole blood (124 grams) is obtained, saturated with oxygen by injecting several cc of pure oxygen gas, and transferred aseptically using a Terumo Sterile Connection Device (SCD) to the silicone blood bag of Example 2, and the bag is weighed during transfer. The oxygen level in the headspace of the outer container 101 is measured using a Mocon OpTech Platinum oxygen analyzer and it is found to be 1.60 Torr at the start of the experiment. An initial sample of blood is taken and measured with a Radiometer ABL-90 blood analyzer (Radiometer America, Blair, California) and it is found that the saturated oxygen (sO2) is 98.7%. The barrier bag containing the blood is placed on a workbench at room temperature (21.0°C) and left to stand for 1 hour without shaking. After 1 hour, the sO2 is 93.5% sO2 and the oxygen in the headspace of the barrier bag is 0.70 Torr. A barrier bag containing blood was incubated at room temperature (21.0°C) for approximately 14 hours without shaking. After 14 hours of incubation, the sO2 was found to be 66.7%, and the final measured sO2 after a further 7 hours of incubation at 21°C without shaking was 51.2%. The deoxygenation rate followed a first-order rate equation, and the rate constant was calculated to be approximately min -1 It is to that extent.

[0256] Example 6: Oxygen depletion device for meandering urethane flow Water vapor permeability rate is 1800 gr / m 2A foldable blood bag is fabricated from a breathable polyurethane film (American Polyfilm, Branford, Connecticut) with a reported 24-hour permeability, and a meandering channel is created using a custom heat-seal die to weld a pair of films together to form the shape. The foldable bag with the meandering channel consists of a series of 12 channels, each approximately 5 mm wide and 220 mm long, resulting in an overall channel length of approximately 2640 mm. The foldable bag is sealed within an outer barrier according to Example 1. The resulting depletion device further comprises two multilayer tubes sealed inside one of the ends, as already described in this disclosure, with the inlet and outlet ports of the meandering channel being in fluid communication with the components of the multilayer tubes.

[0257] Cut two pieces of plastic spacer mesh (McMaster Carr #9314T29, McMaster Carr, Inc., Robbinsville, New Jersey) to approximately 125 x 180 mm (5 x 7 inches) and place them on either side of the collapsible blood container inside the outer barrier container. Place two pouches of oxygen absorber (SS-200, Mitsubishi Gas Chemical America, New York) between each plastic mesh spacer and the outer barrier container, and attach the oxygen sensor tab (Mocon #050-979, Mocon, Inc., Minneapolis, Minnesota) before sealing the last edge of the outer barrier container. Solvent-bond lengths of 914 mm (36 inch) standard IV tubing (Qosina T4306, Qosina, Corp., Edgewood, New York) to each multilayer tubing using cyclohexanone. A ratchet clamp (Qosina #140072, Qosina, Corp., Edgewood, New York) is placed above the discharge tube to control the flow.

[0258] Using a Terumo tube sterilization and joining device (Model TSCD-II, Terumo BCT, Inc., Lakewood, Colorado), a standard 500 mL blood bag (Model KS-500, KS Mfg., Avon, Massachusetts) was connected to the length of the discharge tube. 325 grams of blood were filled into a second standard 500 mL blood bag (Model KS-500, KS Mfg., Avon, Massachusetts) at 20.8°C, and the sample was measured using a Radiometer ABL-90 blood analyzer (Radiometer America, Blair, California), revealing an sO2 of 83.0% and a pO2 of 70.1 mmHg. A ratchet clamp (Qosina #140072, Qosina, Corp., Edgewood, New York) is placed over the infusion tube to control the flow, and then the filled blood bag is connected to the infusion tube using a Terumo tube sterilization and joining device (Model TSCD-II, Terumo BCT, Inc., Lakewood, Colorado). The ratchet clamp is closed to prevent inflow, the filled blood bag is suspended from an IV stand so that the infusion tube is fully extended, and the foldable blood bag is placed on the lab bench. The weight of the discharge bag is measured on a scale, and then it is placed on the floor with the discharge tube fully extended. The oxygen level in the headspace of the outer container is measured using a Mocon Op-Tech platinum oxygen analyzer, which shows an initial oxygen level of 0.05 Torr. The clamp is opened, a stopwatch timer is started to measure the inflow period, and after 3 minutes and 25 seconds, the infusion blood bag is emptied and the ratchet clamp is closed. Blood samples were taken and measured, revealing an sO2 of 84.1% and a pO2 of 71.6 mmHg. This elevation is presumed to be due to residual oxygen in an empty circuit. Headspace measurements showed 0.00 Torr oxygen, and the drained blood bag contained 277 grams of blood.

[0259] The empty infusion blood bag was removed from the IV stand and placed on the floor, while the drainage blood bag containing 277 grams of blood was suspended from the IV stand, and the flow was repeated. The IV stand was lowered to 457 mm (18 inches) to reduce the flow rate, the clamp was opened, and the cycle was repeated. This process was repeated five times, after which the blood was filled into a collapsible blood bag and left to stand on the lab bench for 80 minutes, and an end-level blood sample was taken for measurement with a hemoanalyte. The table below summarizes the results, which show that oxygen levels gradually increased slightly during flow and then slightly decreased after standing. These results indicate that the system described above does not cause apparent deoxygenation of the blood during the study, but oxygen is absorbed from the permeable standard PVC blood bag. This highlights the importance of taking additional measurements to prevent oxygen intrusion at the inlet, outlet, ports, and tubing. Table 3: Deoxygenation using urethane bags JPEG2026082938000004.jpg55154* The head height is 914mm. All other inflow operations have a height of 457mm.

[0260] Example 7: Testing of the configuration of a foldable inner blood container 102 A series of foldable inner blood containers 102 were prepared according to Table 4 below and sealed inside an outer container 101 as shown in Example 1. Reduction in leukocytes (LRpRBCs) were placed in container 102. The resulting oxygen depletion device 10 was further equipped with a Mocon Optech-O2 sensor. The assembled blood containers were placed on a Helmer Labs Platelet Shaker, Model PF96 according to Table 4, and blood and headspace samples were obtained and analyzed at time points 0 to 300 minutes. Table 4: Test configuration of foldable inner blood container 102 JPEG2026082938000005.jpg141164

[0261] As shown in Figure 5, oxygen depletion follows a first-order rate equation. The rate constants are shown in Table 5. Table 5: Rate constants JPEG2026082938000006.jpg84154

[0262] Example 8: Silicone bag with a thickness of 30.5 x 30.5 cm (12 x 12 inches) A foldable blood container 102 is fabricated from a pair of silicone sheets (McMaster Carr #87315K71, McMaster Carr, Inc., Robbinsville, New Jersey) with thicknesses of 152 μm and 228 μm respectively, joined at the edges and bonded with a silicone adhesive called Sil-Poxy (Smooth-On, Inc., Easton, Pennsylvania). A silicone tube (McMaster Carr #9628T42, McMaster Carr, Inc., Robbinsville, New Jersey) is then bonded to serve as an injection tube for fluid communication. The bonded sheets are then cured for two days between clamped aluminum plates.

[0263] The multilayer tubing of the outer container barrier bag 101 according to Example 1 and the injection tubing of the foldable blood bag are connected with a plastic barb fitting (McMaster Carr #5116K18, McMaster Carr, Inc., Robbinsville, New Jersey). Leak testing of the resulting outer container bag 101 is performed by blowing and immersion, as described in Example 1.

[0264] Assemble device 10 with two 330 x 330 mm mesh spacers (McMaster Carr #9314T29, McMaster Carr, Inc., Robbinsville, New Jersey) inserted. Attach four oxygen absorbers to each mesh spacer with tape (SS-200, Mitsubishi Gas Chemical America, New York). Insert a foldable blood container and an oxygen sensor tab (Mocon #050-979, Mocon, Inc., Minneapolis, Minnesota) and heat-seal the barrier bag 101. Solvent-bond the infusion tube, which consists of standard IV tubing (200 mm Qosina T4306, Qosina, Corp., Edgewood, New York), to the multilayer tubing of barrier bag 101 using cyclohexanone. Control the flow using a ratchet clamp (Qosina #140072, Qosina, Corp., Edgewood, New York).

[0265] After centrifugation, a pair of matched blood units were prepared for the study by adjusting the hematocrit to 50% and then recombining the red blood cells with the desired amount of plasma to obtain the target hematocrit level. Initial blood sO2 was measured using a Radiometer ABL-90 blood analyzer (Radiometer America, Blair, California), which showed an sO2 level of 39.0%. Three syringes containing 30cc of 100% oxygen were added to the blood to obtain an sO2 level of 85.6%, after which the study began. A portion of the blood was transferred to a pre-weighed standard 500mL blood bag (Model KS-500, KS Mfg., Avon, Massachusetts) and filled with 532 grams of blood to create a typical 500mL donated blood unit with high hematocrit and saturated oxygen levels. Using Terumo's tube sterilization and joining device (Model TSCD-II, Terumo BCT, Inc., Lakewood, Colorado), a standard 500 mL blood bag (Model KS-500, KS Mfg., Avon, Massachusetts) is attached to the length of the infusion tube, and the contents are transferred to the foldable blood bag of the test subject.

[0266] Place this foldable blood bag on top of the Helmer model PF96 of the platelet shaker (Helmer Scientific, Noblesville, Indiana), take a blood sample, measure it with the Radiometer ABL-90 of the blood analyzer (Radiometer America, Brea, California), and measure the oxygen level in the headspace with the Mocon Op-Tech platinum of the oxygen analyzer (Mocon, Inc., Minneapolis, Minnesota). At the start, it is found that the sO2 of the blood is 84.5%, and the oxygen partial pressure in the headspace is 2.48 torr. Shake the sample on the platelet shaker and take and measure the sample every 30 minutes for a period of 150 minutes. The results are summarized in Table 6 below. Table 6: Deoxygenation using a 30.5×30.5 cm silicone bag JPEG2026*********The calculated deoxygenation rate constant is -0.34×10 -2 min -1 is.

[0267] Example 9: Effect of mixing on oxygen depletion Four oxygen reduction bags (ORBs) having a foldable inner silicone blood container 102 are fabricated according to Example 3. The ratio of surface area to volume (SAV) is about 6 cm 2Fill the collapsible inner blood container 102 with leukocyte-reduced erythrocyte-pigmented red blood cells (LRPRBCs), prepared according to Example 4, to a volume of 1 / ml. Place the three LRPRBC-filled ORBs flat on a Helmer PF-96 Platelet Agitator (Nobleville, Indiana) or a PF-8 shaker and oscillate linearly at a standard cycle rate of 72 cpm or a modified cpm lower than the standard cpm (42 cpm). Place the third set of filled ORBs on a Benchmark 3D 5RVH6 shaker (Searville, New Jersey). Collect the samples and analyze them at 0, 60, 120, and 180 minutes for various ABL-90 output values ​​as outlined in Example 4.

[0268] As shown in Figure 12, when mixing in 3D, the oxygen depletion rate is fastest compared to the linear oscillatory mixing method, T 180 The proportion of sO2 is lowest at this point. Furthermore, in a comparison with linear oscillations (R-SLO) at a lower cpm than the standard cpm, the improvement in oxygen depletion rate is obtained by linear oscillations (SLO) at the standard cpm.

[0269] Example 10: Effect of surface area ratio to volume on oxygen depletion In another example, six oxygen-reducing bags (ORBs) with foldable inner blood containers 102 are fabricated from Bentec silicone. LRPRBCs are collected and fabricated according to Example 4. 176 mL, 220 mL, 250 mL, 270 mL, 300 mL, and 350 mL of LRPRBCs are filled into the foldable inner silicone blood containers 102, with a surface-to-volume ratio of 3.41–6.8 cm² as shown in Table 7. 2 Adjust to / ml. In an ORB containing various volumes of LRPRBC, measure the sO2 value at 0, 30, 60, 120, and 180 minutes, as described in Example 4. Table 7: Ratio of surface area to volume JPEG2026082938000008.jpg23154

[0270] As shown in Figure 13, the ratio of SAV is 5.45 cm 2 When the value falls below / ml, the surface area dynamics rate decreases.

[0271] In another example, five oxygen-reducing bags (ORBs) with foldable inner blood containers 102 are fabricated from PVDF instead of silicone. LRPRBCs are collected and fabricated according to Example 4. The foldable inner PVDF blood containers 102 are filled with blood volumes of 95 ml, 110 ml, 220 ml, 300 ml, or 360 ml so that the volume-to-surface area ratio is as shown in Table 8. In the ORBs containing the various volumes of LRPRBCs, the sO2 value is measured at 0, 30, 60, 120, and 180 minutes, as shown in Example 4.

[0272] As shown in Figure 14, the sO2 value after 180 minutes is lowest when the SAV ratio exceeds 5. Table 8: Ratio of surface area to volume JPEG2026082938000009.jpg26154

[0273] In another example, four oxygen reduction bags (ORBs) with single-sided or double-sided membranes (PSU or PVDF) are prepared. LRPRBCs are collected and prepared according to Example 4. 112–118 ml of LRPRBCs are filled into a foldable inner blood container 102 to reduce the surface area volume by 50% in the double-sided membranes. The sO2 value is measured in the ORBs containing single-sided or double-sided membranes as shown in Example 4. As shown in Figure 15, a 50% reduction in surface area results in a 50–60% reduction in overall kinetic velocity.

[0274] Example 11: Fabrication of a foldable blood container from microporous polysulfone or PVDF A heat-sealed, foldable, oxygen-permeable polysulfone and PVDF blood container 102 is prepared. The sealing process disrupts the microporous structure of the film, creating crystalline regions that are susceptible to bending stresses associated with fluid movement within the resulting container 102. The container 102 is prone to leaking and tearing, making it unsuitable for ORBs intended for use outside of experimental settings.

[0275] To address the inability to heat-seal polysulfone or PVDF membranes in a manner suitable for use in blood transfusion medicine, a heat-laminateable "binding" layer 105 is included in the container 102 structure made from a microporous membrane 113. As shown in Figure 9B, the sealing area is reinforced by pre-laminating low-density polyethylene (LDPE) pieces to the inner surfaces of the upper and lower membranes and aligning them with the bag sealing area. Pre-lamination yields a pre-laminated seal 107, as shown in Figure 9B. Subsequently, the two pre-laminated membranes 113 (114) are heat-sealed to form a seal 108, as shown in Figure 9B. Also, as shown in Figure 9B, the binding layer extends beyond the width of the seal by a certain amount.

[0276] LDPE melts at approximately 105°C, which is considerably lower than the melting temperatures of polysulfone (187°C) or PVDF (177°C). The bag is completed by aligning the sealing areas and heat-sealing the upper and lower membranes together to form the bag. Although not limited to a specific mechanism, it is thought that the LDPE flows into the membrane pores and acts as a stress reliever for reinforcement inside the seal and as a low-temperature "bonding" layer for the seal.

[0277] In addition to reinforcing the seal between the microporous membranes 113, the binding layer also functions as a geometric feature 121. That is, the overall internal shape can be easily adjusted by selecting the shape of the binding layer 105. An example of an exemplary shape is shown in Figure 10. As illustrated, the geometric feature 121 avoids the reduction of mixing forces associated with corners by resulting in a rounded internal shape. As shown in Figure 10, the resulting container 102 can be elliptical or circular and may further include a mixing mechanism 119 that induces a swirling flow of the blood product to facilitate mixing.

[0278] First, a foldable inner blood bag is fabricated from a pair of Millipore PVDF membranes, each having a pore size of 0.22 μm and measuring 177 × 177 mm square, by heat-bonding a low-density polyethylene (LDPE) binding layer frame to each membrane. The LDPE binding layer frame has a thickness of approximately 0.02 to 0.10 mm and an outer dimension of approximately 177 × 177 mm square. To be used with a 15 mm wide seal, the inner dimension is approximately 160 × 160 mm square, which provides an overlap of approximately 4 mm between the edge of the seal and the end of the binding layer, thereby relieving stress at the seal edge. The binding layer frame is heat-bonded to the PVDF membrane using an impulse heat sealer. Subsequently, as described above, a pair of custom-made constant-temperature aluminum dies with tube seal grooves are used to heat-seal the pair of binding layers bonded to the membranes at their periphery, thereby obtaining a foldable inner blood container. Cut a pair of Conwed Thermanet part #R03470 polymer integrated mesh sheets approximately 10 mm larger than the perimeter of the foldable inner blood bag. Place the integrated mesh on both sides of the foldable inner blood bag with the adhesive side of the polymer integrated mesh in contact with the foldable inner blood bag. Place this assembly between a pair of aluminum plates and heat to approximately 93-110°C (maximum 120°C) for approximately 3-15 minutes to melt the adhesive, allowing it to flow into the pores of the PVDF membrane directly beneath the integrated polymer mesh and at the perimeter of the foldable inner blood bag (at these pores, the polymer integrated meshes come into contact with each other, thereby creating a strong mechanical bond). Allow this assembly to cool to below approximately 50°C before removing the plates.

[0279] Example 12: Effect of spacer 110 on the deoxygenation rate The foldable inner blood bag and oxygen depletion device follow the above embodiments, with or without the spacer 110 according to the present disclosure. As shown in Figure 16, incorporating the spacer 110 significantly increases the oxygen depletion rate.

[0280] While the present invention has been described with reference to specific embodiments, those skilled in the art will see that various modifications can be made without departing from the scope of the invention, and elements of the invention can be replaced with equivalents. In addition, many modifications can be made without departing from the scope of the invention to adapt the teachings of the invention to specific situations or materials.

[0281] Therefore, the present invention is not limited to any particular embodiment such as the best mode disclosed for carrying out the invention, and is intended to include all embodiments that fall within the scope and spirit of the appended claims.

Claims

1. An oxygen depletion device 10 for depleting oxygen from the blood before anaerobic storage, The outer container 101 is substantially oxygen-impermeable, A foldable inner blood container 102 having one or more oxygen-permeable chambers, The oxygen absorber 103 placed inside the outer container 101, The oxygen depletion device 10 comprises the above-mentioned oxygen depletion device.

2. The oxygen-containing blood collected in the oxygen depletion device 10 is at least -1.28 × 10 -2 min -1 The oxygen depletion device 10 according to claim 1, which is depleted at the rate of [a certain speed].

3. When blood for depletion is filled and sealed in the outer container 101, the ratio of the surface area to the volume of the blood-compatible inner bag 102 is at least 4.48 square centimeters / milliliter (cm²). 2 The oxygen depletion device 10 according to claim 1, wherein the oxygen level is ( / ml).

4. The oxygen depletion device 10 according to claim 1, wherein the blood-compatible bag 102 contains a material with an oxygen permeability of at least about 25 bars.

5. The oxygen depletion device according to claim 1, wherein the oxygen depletion device 10 further comprises a headspace defined by the blood-compatible bag 102 and the substantially oxygen-impermeable outer container 101, and the oxygen absorbent 103 is disposed therein.

6. The oxygen depletion device according to claim 1, wherein the thickness of the foldable blood container 102 is selected from the group consisting of 20 micrometers (μm), 30 μm, 50 μm, 76 μm, and 120 μm.

7. The oxygen depletion device according to claim 1, wherein the foldable blood container 102 includes a polyvinylidene fluoride (PVDF) microporous membrane having a pore size in the range of approximately 0.05 micrometers (μm) to approximately 1.5 μm.

8. The oxygen depletion device according to claim 1, wherein the foldable blood container 102 is made by blow molding or insert molding.

9. The oxygen depletion device according to claim 1, further comprising an oxygen indicator 206 between the outer container 101 and the foldable inner blood container 102.

10. The oxygen depletion device according to claim 1, further comprising a headspace of 10 to 1000 ml in volume.

11. At least one inlet / outlet 30 penetrating the outer container 101, comprising a tube 301 and a joint 302, wherein the tube 301 and the joint 302 are substantially oxygen-impermeable, and the inlet / outlet 30 is in fluid communication with the foldable container 102. The oxygen depletion device according to claim 1, further comprising the features described above.

12. The oxygen depletion device according to claim 11, wherein the inlet / outlet 30 further comprises a port 303.

13. The ratio of surface area to volume is at least 4.48 cm². 2 / ml, 5cm 2 / ml or at least 5.5cm 2 The oxygen depletion device according to claim 2, wherein the oxygen level is / ml.

14. The oxygen depletion device according to claim 1, wherein the foldable inner blood container 102 is configured to form a layer less than 1 cm thick with the blood contained in the container.

15. The oxygen depletion device according to claim 1, wherein the foldable inner blood container 102 contains silicon having a thickness in the range of approximately 15 μm to approximately 200 μm.

16. The oxygen depletion device according to claim 15, wherein the thickness is selected from the group consisting of 20 μm (μm), 30 μm, 50 μm, 76 μm, and 120 μm.

17. The oxygen depletion device according to claim 1, wherein the foldable inner blood container 102 is cylindrical in shape.

18. The oxygen depletion device according to claim 1, further comprising a spacer material 110 sealed in the outer container 101.

19. The oxygen depletion device according to claim 18, wherein the spacer material 110 is a mesh.

20. The oxygen depletion device according to claim 19, wherein the mesh 110 is selected from the group consisting of molded mats, woven mats, nonwoven mats, strand bales, and strand mats.

21. Area is 0.75 mm 2 The oxygen depletion device according to claim 19, wherein the mesh 110 includes at least one void 111.

22. The oxygen depletion device according to claim 21, wherein the void space occupies at least 30% of the area of ​​the mesh 110.

23. The oxygen depletion device according to claim 1, wherein the foldable inner blood container 102 comprises one or more baffles.

24. The oxygen depletion device according to claim 1, wherein the foldable inner blood container includes a hydrophobic material having a contact angle greater than 150° or a hydrophobic material having a contact angle greater than 90°.

25. The oxygen depletion device according to claim 1, wherein the foldable inner blood container 102 includes a material with an oxygen permeability of at least about 25 bars.

26. The oxygen depletion device according to claim 1, wherein the foldable inner blood container 102 includes a polyvinylidene difluoride (PVDF) microporous membrane having a pore size of approximately 0.05 μm to approximately 1.5 μm.

27. The oxygen depletion device according to claim 26, wherein the foldable inner blood container 102 further comprises a transparent window 112 on its surface.

28. The oxygen depletion device according to claim 26, wherein the pore size of the PVDF microporous membrane is selected from the group consisting of 0.1 μm, 0.22 μm, and 1.0 μm.

29. The oxygen depletion device according to claim 1, wherein the total mass of the oxygen absorber 103 is at least 1 gram.

30. The oxygen depletion device according to claim 1, wherein the oxygen absorbent 103 further comprises a carbon dioxide absorbent.

31. The oxygen depletion device according to claim 1, wherein the oxygen absorber 103 is positioned on the outside of the foldable inner blood container 102.

32. The oxygen depletion device according to claim 1, wherein the oxygen absorber 103 is placed inside the foldable inner blood container 102.

33. The oxygen depletion device according to claim 1, wherein the foldable inner blood container 102 comprises at least two oxygen-permeable chambers, the chambers being in fluid communication.

34. The oxygen depletion device according to claim 33, wherein at least two oxygen-permeable chambers are stacked inside the outer container 101.

35. The oxygen depletion device according to claim 33, wherein at least two oxygen-permeable chambers are arranged in parallel within the outer container 101.

36. The oxygen depletion device according to claim 33, wherein the foldable inner blood container 102 comprises 2 to 8 oxygen-permeable chambers, the chambers being in fluid communication.

37. The oxygen depletion device according to claim 36, wherein the two to eight chambers are arranged in parallel within the outer container.

38. The oxygen depletion device according to claim 34, wherein the at least one absorbent 103 is placed between the stacked chambers of the foldable inner blood container 102.

39. The outer container 101 is substantially oxygen-impermeable, The foldable inner blood container 102 is sealed inside the outer container, An oxygen absorber 103 is placed between the outer container 101 and the blood-compatible inner blood container 102, Prepare an oxygen depletion device 10 equipped with the following: The blood is to flow into the foldable inner blood container 102 of the oxygen depletion device 10, To produce oxygen-reduced blood with an oxygen saturation of less than 20%, A method for preparing blood for storage, including [the specified element].

40. The method according to claim 39, wherein the blood is selected from the group consisting of whole blood, packed red blood cells (pRBCs), packed red blood cells with reduced white blood cell count (LRpRBCs), packed red blood cells with reduced platelet count, plasma, and platelets.

41. The method according to claim 40, wherein the oxygen saturation of the oxygen-reduced blood is less than 10%.

42. The method according to claim 40, wherein the oxygen saturation of the oxygen-reduced blood is less than 5%.

43. The method according to claim 40, wherein the oxygen saturation of the oxygen-reduced blood is less than 3%.

44. The method according to claim 40, wherein the blood is whole blood and the foldable inner blood container 102 further contains an anticoagulant.

45. The method according to claim 44, wherein the temperature of the whole blood is approximately 37°C.

46. The method according to claim 44, wherein the temperature of the whole blood is approximately 25°C.

47. The method according to claim 40, wherein the blood comprises red blood cells (LRpRBCs) with reduced white blood cell content.

48. The method according to claim 47, wherein the temperature of the leukocyte-reduced packed red blood cells (LRpRBCs) is approximately 25°C.

49. The method according to claim 44, further comprising removing platelets, plasma, and leukocytes from the oxygen-depleted whole blood to prepare leukocyte-reduced packed red blood cells.

50. The method according to claim 40, further comprising transferring the oxygen-reduced blood having an oxygen saturation of less than 20% to a blood storage device 20.

51. The method according to claim 39, further comprising shaking the blood in the foldable inner blood container 102 for a period of 30 minutes to 24 hours.

52. The method according to claim 39, wherein the shaking is selected from the group consisting of vibrating, nutating, rotating, stirring, kneading, oscillating, linearly oscillating and compressing the oxygen depletion device.

53. The method according to claim 40, wherein the procedure is performed at ambient temperature or approximately 25°C.

54. The method according to claim 39, further comprising flowing nitrogen into the outer container of the apparatus and removing the nitrogen from the apparatus before the inflow operation.

55. The method according to claim 39, wherein the initial oxygen saturation of the whole blood is at least 55%.

56. The method according to claim 55, wherein oxygen-reduced blood with an oxygen saturation of less than 20% is produced less than 12 hours after blood is collected from a donor.

57. The method according to claim 55, wherein oxygen-reduced blood with an oxygen saturation of less than 20% is produced less than eight hours after blood is collected from a donor.

58. The method according to claim 55, wherein oxygen-reduced blood with an oxygen saturation of less than 20% is produced less than six hours after blood is collected from a donor.

59. The method according to claim 55, wherein oxygen-reduced blood with an oxygen saturation of less than 20% is produced less than four hours after blood is collected from a donor.

60. A blood preservation device 20 for preserving oxygen-depleted blood, The outer container 201 is practically oxygen-impermeable, The foldable blood container 202 includes a positioning mechanism 203 adapted to adjust the position of the foldable blood container within the shape of the outer container 201, A foldable blood container 202 and a joint 302 to the outer container 201 comprising at least one inlet / outlet 30 having a tube 106 connecting the inlet / outlet 30, wherein the joint 302 to the outer container 201 is substantially oxygen-impermeable, and an oxygen absorbent 103 placed inside the outer container 201, The blood storage device 20 comprises the above-mentioned features.

61. The blood storage device according to claim 60, wherein the tube 106 is a multilayer tube that is substantially oxygen-impermeable.

62. The blood storage device according to claim 61, wherein the inlet / outlet 30 is a tube 205 connected to the tube 301, and the tube 205 is substantially oxygen-impermeable.

63. The blood storage device according to claim 61, wherein the inlet / outlet 30 is a tube 106 connected to the tube 301, and the tube 106 includes polyvinyl chloride (PVC).

64. The outer container 201 and the tube 205 are substantially oxygen-impermeable, and the oxygen partial pressure (PO) of the blood in the collapsible blood container remains constant for a maximum storage period of 64 days. 2 The blood storage device according to claim 61, wherein the blood pressure is maintained at less than 15 mmHg.

65. The blood storage device according to claim 60, wherein the oxygen absorber has an oxygen capacity of at least 60 cubic centimeters (c.c.) of oxygen.

66. The blood storage device according to claim 60, wherein the joint 302, which is substantially oxygen-impermeable, is solvent-sealed, heat-sealed, adhesive-bonded, ultrasonically welded, or high-frequency welded.

67. The blood storage device according to claim 60, wherein the positioning mechanism 203 is selected from the group consisting of a geometric cutout, a tactile surface mark, a die-cut reference mark, a spacer, a fitted cutout, and a printed mark.

68. The blood storage device according to claim 60, wherein the foldable blood container 202 is made by blow molding or insert molding.

69. The blood storage device according to claim 60, wherein the foldable blood container 202 further comprises one or more inlet / outlet ports 30 each comprising a tube 301 and a joint 302, and the tube 301 and the joint 302 are substantially oxygen-impermeable.

70. The blood storage device according to claim 69, wherein the foldable blood container 202 further comprises two inlet / outlet ports 30.

71. The blood storage device according to claim 70, wherein the foldable blood container further comprises a third inlet / outlet 30.

72. A method for reducing oxygen from whole blood or its components, The process involves placing the whole blood or its components into the device 20 over a certain period of time. The aforementioned device, The outer container 201 is practically oxygen-impermeable, The foldable blood container 202 has high oxygen permeability and is equipped with a positioning mechanism 203 adapted to adjust the position of the foldable blood container 201 within the shape of the outer container 201, The inlet / outlet 30 comprises a tube 301 and a joint 302, and is connected to the inner bag 202, wherein the joint 302 to the outer container 201 is substantially oxygen-impermeable. An oxygen absorber 207 is placed inside the outer container 201 and outside the inner blood bag 202, It is equipped with, The apparatus 20 containing the whole blood or its components is incubated for a certain period of time. The method comprising the above.

73. The method according to claim 72, further comprising shaking the whole blood or components thereof stored in the aforementioned apparatus.

74. The method according to claim 72, wherein the incubation is at ambient temperature.

75. The method according to claim 72, wherein the incubation temperature is 4 to 6°C.

76. The method according to claim 72, wherein the incubation is performed for a period of up to 64 days.

77. The method according to claim 72, wherein the whole blood or a component thereof is whole blood.

78. The method according to claim 72, wherein the component is selected from the group consisting of packed red blood cells, packed red blood cells with reduced white blood cell content, platelets, and plasma.

79. The method according to claim 78, wherein the component is concentrated red blood cells.

80. The method according to claim 72, wherein the period is selected from the group consisting of a maximum of 15 minutes, a maximum of 30 minutes, 2 to 3 hours, 2 to 4 hours, a maximum of 6 hours, a maximum of 8 hours, and a maximum of 24 hours.

81. The method according to claim 73, wherein the shaking is performed as a lateral shaking with translation of at least 3 cm at a rate of at least once per second.

82. The method according to claim 73, wherein the shaking is reversed at a rate of at least once every 5 seconds.

83. The method according to claim 82, wherein the inversion is a partial inversion of the device.

84. The method according to claim 82, wherein the inversion is a complete inversion of the apparatus.

85. The method according to claim 73, wherein the shaking comprises kneading or compressing one or more locations on the foldable blood container at a rate of at least five times per second.

86. The method according to claim 73, wherein the shaking is selected from the group consisting of vibrating, nutating, rotating, stirring, kneading, oscillating and compressing the foldable blood container.

87. The absorption rate of the oxygen absorbent 207 is at least 10 cubic centimeters (cc·g -1 hr -1 per hour per gram of the absorbent), and the method according to claim 72.

88. The absorption rate of the oxygen absorbent 207 is at least 5 cubic centimeters (cc·g) per hour per gram of absorbent. -1 hr -1 The method according to claim 87.

89. The method according to claim 72, wherein the outer container further comprises a gas port, and the method further comprises removing gas from the headspace between the outer container and the inner blood bag by depressurization.

90. An oxygen depletion device 10 for depleting oxygen from blood before anaerobic storage, The outer container 101 is substantially oxygen-impermeable, A foldable inner blood container 102 is made from an integrated silicone membrane 113 and has one or more oxygen-permeable chambers, Spacer 110 and, The oxygen absorber 103 placed inside the outer container 101, The apparatus 10 comprises the above.

91. The foldable oxygen-permeable blood container 102 according to claim 90, wherein the integrated silicone film 113 has a thickness of about 15 μm to about 200 μm.

92. The foldable oxygen-permeable blood container 102 according to claim 91, wherein the integrated silicone film 113 has a thickness of 76 μm or less.

93. A foldable oxygen-permeable blood container 102 according to claim 91, further comprising at least one binding layer 105.

94. The collapsible oxygen-permeable blood container 102 according to claim 93, wherein the collapsible blood container 102 comprises two binding layers 105.

95. The foldable oxygen-permeable blood container 102 according to claim 93, wherein the binding layer 105 contains silicone.

96. The foldable oxygen-permeable blood container 102 according to claim 95, wherein the binding layer 105 includes liquid silicone rubber (LSR).

97. When the blood for depletion is filled and sealed in the outer container 101, the ratio of the surface area to the volume of the blood-compatible inner bag 102 is at least 4.85 square centimeters / milliliter (cm²). 2 A foldable oxygen-permeable blood container 102 according to claim 90, wherein the volume is ( / ml).

98. An oxygen depletion device 10 for depleting oxygen from blood before anaerobic storage, The outer container 101 is substantially oxygen-impermeable, A foldable inner blood container 102 is made from a microporous membrane 113 and has one or more oxygen-permeable chambers, Spacer 111 and, The oxygen absorber 103 placed inside the outer container 101, The apparatus 10 comprises the above.

99. A foldable, oxygen-permeable blood container 102 comprising a first microporous membrane 113 and a second microporous membrane 113 joined by a surrounding binding layer 105, wherein the binding layer 105 comprises a material having a melting temperature at least 3°C ​​lower than the melting temperature of the microporous membrane 113.

100. The foldable oxygen-permeable blood container 102 according to claim 100, wherein the melting temperature of the binding layer 105 is at least 10°C lower than the melting temperature of the microporous membrane 113.

101. The foldable oxygen-permeable blood container 102 according to claim 98, wherein the microporous membrane 113 is composed of a microporous membrane selected from the group consisting of polysulfone, hydrophobic polyvinylidene fluoride (PVDF), cellulose ester, mixed cellulose ester (MCE), polyethersulfone (PES), hydrophobic polypropylene, and polyacrylonitrile.

102. The foldable oxygen-permeable blood container 102 according to claim 101, wherein the microporous membrane 113 is composed of polysulfone or hydrophobic polyvinylidene fluoride (PVDF).

103. The foldable oxygen-permeable blood container 102 according to claim 98, wherein the surrounding binding layer 105 is made of low-density polyethylene (LDPE).

104. A method for manufacturing a foldable inner blood container 102 having an integrated spacer 110, The process involves applying a 20-750 μm layer of liquid silicone rubber (LSR) suspension to the surface, curing the LSR layer in a first curing step to produce a partially cured layer, and attaching a spacer 110 containing a mesh to the partially cured layer. A second curing step is performed to produce a cured silicone film 113 with a thickness of 10 to 100 μm having an integrated spacer 110, The method comprising the above.

105. The method according to claim 104, wherein the LSR is suspended in xylene, hexane, tert-butyl acetate, heptane, acetone, or naphtha.

106. The method according to claim 104, wherein the LSR is suspended in xylene.

107. The method according to claim 104, wherein the LSR is a 10-30% suspension.

108. The method according to claim 104, further comprising assembling the silicone membrane 113 having an integrated spacer 110 to form a foldable inner blood container 102.

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