DEHP-free blood preservation and its use

Abstract

To provide a carbon dioxide permeable container for storing blood, and a method for improved storage of whole blood and blood components. [Solution] The present invention provides an improved device and method for collecting blood and blood components, which offers whole blood and blood components with reduced carbon dioxide levels, as well as the removal of the plasticizer DEHP. The device and method provides the preparation of carbon dioxide-depleted blood and blood components for storage, which improves the overall quality of transfused blood, improves patient health outcomes, and reduces the risks associated with DEHP. The device and method also provides the maintenance of a low oxygen content in the blood and blood components during storage.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the interests of U.S. Provisional Application No. 63 / 024,190, filed on 13 May 2020, and is incorporated herein by reference.

[0002] This disclosure relates to containers for the storage and carbon dioxide reduction of blood and blood products. This disclosure also relates to methods for managing carbon dioxide during storage for improved storage of blood and blood components. This disclosure further relates to methods and devices for the preparation of di-2-ethylhexylphthalate (DEHP)-free (DEHP-free) stored blood. [Background technology]

[0003] The supply of blood and blood components is currently limited by the available storage systems used in conventional blood preservation practices. Conventional storage practices include blood collection into anticoagulant solutions, preparation of red blood cell concentrates by plasma removal, leukocyte removal, and storage of red blood cell concentrates in additive solutions. Red blood cell preparations packaged using conventional storage systems expire after a refrigerated storage period of approximately 42 days at approximately 4°C.

[0004] Currently, red blood cells are the most widely transfused blood component in the world. Therefore, the development of preservation procedures that increase blood storage time while minimizing storage-related complications is essential.

[0005] During storage, the accumulation of biochemical and biophysical changes (collectively referred to as storage lesions, or "lesions") gradually reduces the quality of stored red blood cells (RBCs). See Yoshida T., et al., “Red blood cell storage lesion: causes and potential clinical consequences,” Blood Transfus. 27(17):27-52 (2019), Zimring JC., “Established and theoretical factors to consider in assessing the red cell storage lesion,” Blood 125(4):2185-2189 (2015), and Donadee C, et al., “Nitric oxide scavenging by red blood cell microparticles and cell-free hemoglobin as a mechanism for the red cell storage lesion,” Circulation. 124(4):465-476 (2011). Changes in parameters measured in vitro, such as reduced levels of metabolites (e.g., adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG)), and increased levels of exposure to free hemoglobin, hemolysis, non-transferrin-bound iron, particulate matter, and phosphatidylserine, are part of the biochemical preservation pathology. Physiologically, red blood cells experience reduced deformability during preservation.

[0006] Conservative lesions are associated with reduced in vivo recovery and blood quality. Clinical studies suggest that conservation-induced changes may adversely affect clinical outcomes in different patient populations when these cells are transfused. See Triulzi DJ, et al. “Clinical studies of the effects of blood storage on patient outcomes.” Transfus Apher Sci. 43(1):95-106 (2010), Voorhuis FT, et al. “Storage time of red blood cell concentrates and adverse outcomes after cardiac surgery: a cohort study.” Ann Hematol. 92(12):1701-1706 (2013), and Spinella PC, et al. “Duration of red blood cell storage is associated with increased incidence of deep vein thrombosis and in hospital mortality in patients with traumatic injuries”. Crit Care. 13(5):R151 (2009).

[0007] Over the years, several strategies have been explored to reduce storage lesions in red blood cells (RBCs) during refrigeration. See Lagerberg JW, et al., “Prevention of red cell storage lesion: a comparison of five different additive solutions.” Blood Transfus. 15(5):456-462 (2017), D'Alessandro A, et al., “Metabolic effect of alkaline additives and guanosine / gluconate in storage solutions for red blood cells.” Transfusion. 58(8):1992-2002 (2018), and Stowell SR, et al., “Addition of ascorbic acid solution to stored murine red blood cells increases posttransfusion recovery and decreases microparticles and alloimmunization,” Transfusion. 53(10):2248-57 (2013).

[0008] One contributing factor to storage lesions in red blood cells for transfusion is oxidative damage to lipids and proteins by reactive oxygen species (ROS), including hydroxyl, peroxyl, and alkoxy radicals, which are formed from oxygen present in the blood during storage. See Yoshida T, et al. "Extended storage of red blood cells under anaerobic conditions." Vox Sang. 92:22-31 (2007) and Yoshida T, et al. "Anaerobic storage of red blood cells." Blood Transfus. 8(4):220-36 (2010). Therefore, one approach shown to improve the quality of stored RBCs and in vivo recovery is the removal of O2 from RBCs before storage and maintaining anaerobic conditions throughout the storage period. Two forms of anaerobic storage have been evaluated to maintain the quality of blood cells during storage. In one approach, oxygen is reduced before the start of storage (e.g., depletion and storage).Yoshida et al. “Extended storage of red blood cells under anaerobic conditions.” Vox Sang.92:22-31(2007) of red cells,”Transfusion.48(10):2096-2105(2008), Dumont et al.,“Anaerobic storage of red blood cells in a novel additive solution improves in vivo recovery,”Transfusion.49(3):458-464(2009), D'Alessandro et al.,“Hypoxic storage of red blood cells improves metabolism and post-transfusion recovery,”Transfusion.[published online ahead of See print (Feb. 2020), international publication No. 2016 / 172645 by Yoshida, T. et al., and WO2016 / 145210 by Wolf, M. et al. Storing blood under oxygen-depleted conditions increases ATP and 2,3-DPG levels compared to blood stored conventionally for the same amount of time, maintaining a hemolysis level below 0.8% after 42 days. Alternative approaches involving the storage of red blood cells packaged under anaerobic conditions without pre-storage deoxygenation have been studied (e.g., storage and depletion). See Hogman et al., “Effects of oxygen on red cells during liquid storage at +4 degrees C,” Vox Sang. 51(1):27-34 (1986).While preservation and depletion methods are more convenient, it has not been possible to match the quality of depletion and preservation approaches to this specification.

[0009] Further research demonstrates that carbon dioxide levels, when combined with deoxygenation in depletion and storage methods, directly contribute to the enhancement of 2,3-diphosphoglycerate (DPG) levels in red blood cells (RBCs). See International Publication 2012 / 027582 ("Publication 582"). Publication 582 further shows that 2,3-DPG enhancement is independent of pH, i.e., the state previously thought to be controlled. See Dumont et al., "CO2 dependent metabolic modulation in red blood cells stored under anaerobic condition," Transfusion 56(2):392-403 (2016).

[0010] Various preservation solutions have been developed to reduce the adverse effects of preserved lesions and improve RBC quality and clinical outcomes. Modifications in preservation solutions are known to increase ATP and 2,3-DPG production and reduce hemolysis. Efforts to reduce oxidative damage to RBCs include incorporating antioxidants into preservation formulations. Hogman et al., “Storage of red blood cells with improved maintenance of 2,3-bisphosphoglycerate,” Transfusion.46(9):1543-52 (2006), Radwanski et al., “Red cell storage in E-Sol 5 and Adsol additive solutions: paired comparison using mixed and non-mixed study designs,” Vox Sang 106(4):322-329(2014), Cancelas et al.,“Additive solution-7 reduces the red blood cell cold storage lesion,”Transfusion 55(3):491-498(2015), Lagerberg et al.,“Prevention of red cell storage lesion:a comparison of five different additive solutions,”Blood Transfus.15(5):456-462(2017), and Pallotta et al., “Storing red blood cells with vitamin C and N-acetylcysteine ​​prevents oxidative stress-related lesions:a See "Metabolomics Overview," Blood Transfus. 12(3):376-387 (2014).

[0011] An unexpected benefit of the development of plastic storage containers, particularly PVC, is the protective effect of the plasticizer DEHP used in most PVC blood storage bags. See U.S. Patent No. 4,386,069 issued to Estep. However, recently, due to concerns that DEHP may function as an endocrine disruptor, authorities are considering removing DEHP from blood bags. However, the removal of DEHP has proven problematic because its presence can mask or reduce lesions. See D'Alessandro, A., et al. “Rapid detection of DEHP in packed red blood cells stored under European and US standard conditions.” Blood Transfus. 14(2):140-144 (2016). Removing plasticizers from storage systems results in significant changes in the quality of red blood cells, as follows: 1) Increased erythrocyte hemolysis, 2) Reduced shelf life of erythrocytes in additive solution to less than 42 days, 3) Reduced in vivo recovery within erythrocytes, 4) Increased erythrocyte osmotic embrittlement, 5) Increased microvesicle formation, 6) Reduced erythrocyte deformability, and 7) Reduced erythrocyte morphology score. Therefore, since each of these advantages of DEHP is necessary to maintain the stability and quality of erythrocytes during long-term storage at refrigerated temperatures, replacing DEHP in blood storage bags presents significant technical challenges. This disclosure overcomes all of these technical challenges and produces erythrocytes of superior quality and erythrocyte hemolysis that meets regulatory requirements of less than 0.8% at the end of storage.

[0012] Preventing and reducing preservation-related lesions remains a challenge. The growing interest in removing DEHP from supplies necessitates the development of new storage containers and methods that replace the benefits previously provided by DEHP. Furthermore, there is a need to develop additive solutions that function well and safely when DEHP is removed and are suitable for storage conditions.

[0013] In light of current technology, to help minimize transfusion-related morbidity, it is necessary to improve the quality of blood and blood components, such as stored red blood cells, before transfusion, and to extend the shelf life of such blood and blood components. To comply with regulatory requirements and ensure reliability, the preparation and processing of red blood cells must be completed within a limited timeframe. Furthermore, the process for preparing reduced-carbon dioxide blood and blood components must not introduce lesions, including hemolysis of the blood, although this is not limited to these processes. Finally, methods and devices compatible with existing anticoagulant and additive solutions are needed to obtain improved-quality blood and blood components.

[0014] To address such and other needs, the Disclosure includes and provides devices, compositions, and methodologies for the preservation of blood and blood components in which the preparation of carbon dioxide, or carbon dioxide and oxygen-reduced blood and blood components, is initiated at the donor collection stage.

[0015] This specification describes the construction and use of blood storage bags containing a DEHP-free, gas-permeable, biocompatible polymer in a method for storing blood products having reduced levels of CO2 and O2 compared to conventionally stored cells. The method and container described herein improve upon anaerobic storage approaches with initial oxygen depletion of less than 20% before storage. This specification is the first to demonstrate that reducing CO2 levels and preventing oxygenation during storage maintains better hygiene of RBCs than both conventional storage and depletion / anaerobic storage methods. [Overview of the project]

[0016] This disclosure relates to a method for preserving blood products, comprising: obtaining a blood product having more than 30% SO2%; adding an additive solution to the blood product to prepare a storable blood product; and preserving the storable blood product at 25°C and about 1 atm, at least 0.62 cubic centimeters per square centimeter (cm²). 3 / cm 2Storing it in a di-2-ethylhexyl phthalate-free (DEHP-free) blood-compatible (BC) carbon dioxide-permeable bag having gas permeability with respect to carbon dioxide, and the method includes and comprises.

[0017] The present disclosure provides and includes a container for storing blood containing a DEHP-free carbon dioxide-permeable and oxygen-impermeable material, the material having a gas permeability with respect to oxygen of less than 0.05 cm 3 / cm 2 at 25 °C and 1 atm, and a gas permeability with respect to carbon dioxide of at least 0.62 cubic centimeters (cm 3 / cm 2 ) per square centimeter at 25 °C and 1 atm.

[0018] The present disclosure also provides and includes a method for handling a blood product, comprising adding an additive solution to the blood product and storing the blood product in a DEHP-free blood-compatible (BC) carbon dioxide-permeable bag having a gas permeability with respect to carbon dioxide of at least 0.62 cm 3 / cm 2 at 25 °C and about 1 atm for at least 7 days, the storage being at least 7 days, the blood product including an oxygen level during the 7-day storage, which is decreased or approximately the same as the oxygen level in the blood product on the first day of storage.

[0019] Furthermore, the present disclosure provides and includes a method for storing storable blood, comprising placing a blood product in a storage container containing a DEHP-free blood-compatible (BC) material having a permeability with respect to carbon dioxide of at least 0.62 cm 3 / cm 2 at 25 °C and about 1 atm and a permeability with respect to oxygen of less than 0.3 cm 3 / cm 2 at about 1 atm, and a carbon dioxide adsorbent, and storing a container containing storable blood for a period of time to prepare the stored blood.

[0020] Furthermore, this disclosure relates to a method for preserving red blood cells, wherein the cells are stored at a temperature of 25°C and approximately 1 atm for at least 0.62 cm³. 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 The present invention provides and includes a method for preparing a stored blood product by placing red blood cells in a storage container that has an outer oxygen and carbon dioxide impermeable container, which contains a permeable, inwardly collapsible container made of the following oxygen-permeable material, and an outer oxygen and carbon dioxide impermeable container in which a carbon dioxide adsorbent, an oxygen adsorbent, or an oxygen and carbon dioxide adsorbent is sealed between the inner bag and the outer bag, and storing the container containing the red blood cells for at least 7 days.

[0021] This disclosure relates to a method for maintaining the level of 2,3-DPG in a blood product, wherein the level is at least 0.62 cm at 25°C and about 1 atm. 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 The present invention further provides and includes a method comprising: placing a blood product containing at least 10% oxygen saturation in a storage container comprising an outer oxygen and carbon dioxide impermeable container, which contains a blood-compatible (BC) material having the following oxygen permeability, and a carbon dioxide adsorbent sealed between the inner bag and the outer bag; and storing the container containing the blood product, wherein the level of 2,3-DPG increases during storage for up to 14 days compared to the level of 2,3-DPG in blood products stored by conventional methods.

[0022] This disclosure relates to a method for maintaining the level of ATP in a blood product, wherein the ATP level is at least 0.62 cm³ at 25°C and about 1 atm. 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2The present invention provides and includes a method comprising: placing a blood product containing at least 10% oxygen saturation in a storage container equipped with an outer oxygen and carbon dioxide impermeable container, which contains a blood-compatible (BC) material having the following oxygen permeability, and a carbon dioxide adsorbent sealed between the inner bag and the outer bag; and storing the container containing the blood product, wherein the ATP level increases after 42 days of storage compared to the ATP level of a blood product stored in a conventional method.

[0023] The present disclosure further provides and includes a composition comprising a blood product selected from the group consisting of whole blood, platelets, and leukocytes, and an additive solution comprising sodium bicarbonate (NaHCO3), sodium phosphate dibasate (Na2HPO4), adenine, guanosine, glucose, mannitol, N-acetyl-cysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid (vitamin C).

[0024] This disclosure further provides and includes an additive composition comprising N-acetyl-cysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid at certain concentrations, wherein the additive composition comprises a pH of 8 to 9.

[0025] The present disclosure further provides and includes a composition comprising a blood product selected from the group consisting of whole blood, platelets, and leukocytes, and an additive solution comprising certain concentrations of disodium phosphate (Na2HPO4), sodium citrate, adenine, guanosine, glucose, and mannitol.

[0026] Some aspects of the present disclosure are described herein by reference to the accompanying drawings, merely as examples. It is emphasized hereby that, with particular reference to the drawings, the details shown are illustrative and for the purpose of illustrative consideration of embodiments of the present disclosure. In this regard, the description as interpreted together with the drawings will make it clear to those skilled in the art how embodiments of the present disclosure may be carried out. [Brief explanation of the drawing]

[0027] [Figure 1] This is a schematic diagram of an experimental setup according to the aspects of this disclosure. [Figure 2A] This graph shows the ATP levels after 21 days of storage in a DEHP-free carbon dioxide permeable bag, with or without a gas-impermeable barrier bag. [Figure 2B] This graph shows the oxygen saturation percentage (SO2%), carbon dioxide partial pressure (pCO2), hemolysis, and ATP levels of red blood cell hemoglobin in an alkaline additive solution (AS7G-NAC) after 42 days of storage in a DEHP-free carbon dioxide permeable bag, with or without a gas-impermeable barrier bag, according to aspects of this disclosure. The data are mean ± SD of 10 independent studies (N=10). [Figure 3A-3B] In aspects of this disclosure, graphs show the effect of blood preservation in DEHP-free carbon dioxide-permeable bags, with or without gas-impermeable barrier bags, on the level of 2,3-DPG in red blood cells in an alkaline additive solution (AS7G-NAC) after 21 days of storage (Figure 3A) or 42 days of storage (Figure 3B). The data are mean ± SD of 10 independent studies (N=10). [Figure 4A-4B] This graph shows the effect of blood preservation in a DEHP-free carbon dioxide permeable bag, with or without a gas-impermeable barrier bag, on the levels of SO2%, pCO2, hemolysis, and ATP in an AS3 additive solution according to the embodiments of this disclosure. Figure 4A shows the ATP level after 21 days, and Figure 4B shows the ATP level after 42 days. The data are mean ± SD from five independent studies (N=5). [Figure 5A-5B]This graph shows the effect of preserving blood in a DEHP-free carbon dioxide-permeable bag, with or without a gas-impermeable barrier bag, in terms of SO2%, pCO2, hemolysis, and 2,3-DPG levels in the AS3 additive solution according to aspects of this disclosure. Figure 5A shows the 2,3-DPG level on day 21, and Figure 5B shows the 2,3-DPG level on day 42. The data are mean ± SD from five independent studies (N=5). [Figure 6A-6B] This graph shows the effect of preserving blood in a DEHP-free carbon dioxide permeable bag, with or without a gas-impermeable barrier bag, in terms of SO2%, pCO2, hemolysis, and 2,3-DPG levels in an AS7G-NAC (SOLX-NAC) additive solution according to the embodiments of this disclosure. Figure 6A shows the 2,3-DPG level on day 21, and Figure 6B shows the 2,3-DPG level on day 42. The data are mean ± SD from three independent studies (N=3). [Figures 7A-7B] This graph shows the effect of storing blood in a DEHP-free carbon dioxide-permeable bag, with or without a gas-impermeable barrier bag, on the level of ATP in red blood cells in AS7G-NAC additive solution after 21 days or 42 days of storage, according to aspects of this disclosure. Figure 7A shows the ATP level on day 21, and Figure 7B shows the ATP level on day 42. The data are mean ± SD from three independent studies (N=3).

[0028] Corresponding reference numerals indicate corresponding parts across several figures. The embodiments described herein illustrate some embodiments of the invention, but should not be construed as limiting the scope of the invention in any way. [Modes for carrying out the invention]

[0029] definition Unless otherwise defined, technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art. Those skilled in the art will recognize many methods that can be used in implementing this disclosure. Indeed, this disclosure is by no means limited to the methods and materials described. Any references cited herein are incorporated in their entirety by reference. For the purposes of this disclosure, the following terms are defined below:

[0030] As used herein, the term “approximately” refers to ±10%.

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

[0032] The term "consisting of" means "including and limiting to."

[0033] The phrase "consisting essentially of" means that a composition, method, or structure may include additional components, processes, and / or parts only if the additional components, processes, and / or parts do not substantially alter the basic and novel features of the claimed composition, method, or structure.

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

[0035] Through this application, various embodiments of the disclosure may be presented in range format. Therefore, a range description should be considered to specifically disclose all possible subranges and the individual values ​​within those ranges. For example, a range description such as “1 to 6” should be considered to specifically disclose subranges such as “1 to 3,” “1 to 4,” “1 to 5,” “2 to 4,” “2 to 6,” “3 to 6,” and the individual numbers within those ranges, e.g., 1, 2, 3, 4, 5, and 6. Furthermore, “1 to 3” includes both 1 and 3. This applies regardless of the width of the range. As used herein, “between” means that the range includes all possible subranges and the individual numerical values ​​within those ranges, but does not include external values. For example, “1 to 7” does not include the value 1 or 7, and “0 to 7” does not include the value 0 or 7.

[0036] As used herein, the term “method” means any method for accomplishing a given task, including, but not limited to, methods, means, techniques, and procedures known from, or readily developed from, known to practitioners of the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0037] As used herein, the term “bag” refers to a foldable container prepared from a flexible material, including pouches, tubes, and gusseted bags. In certain embodiments, a bag refers to a non-foldable container. As used herein and included in this disclosure, the term bag includes a foldable bag having one, two, three, or more folds and being sealed or joined on one, two, three, or more sides. Bags may be prepared using various techniques known in the art, including joining sheets of one or more materials. Methods for joining materials to form a bag are known in the art. See International Publication No. 2016 / 145210. This disclosure also includes and provides containers prepared by injection and blow molding. Methods for preparing blow-molded and injection-molded containers are known in the art. See U.S. Patents No. 4,280,859 and No. 9,096,010. A preferred type of blow-molded or injection-molded container is a flexible container that can be expanded to accommodate blood or blood components with respect to oxygen reduction, while also being able to reduce its size for efficient packaging and shipping. They can also be designed to conform to the volume of blood until fully expanded. As used throughout this disclosure, bag is a form of collapsible container, and the two terms are used interchangeably throughout this disclosure.

[0038] As used herein, the terms “blood” and “blood products” refer to whole blood, leukocyte-reduced RBCs, thrombocytopenic RBCs, leukocytes and thrombocytopenic RBCs, platelets, and leukocytes. The term “blood” further includes packed red blood cells, thrombocytopenic packed red blood cells, leukocyte-reduced packed red blood cells (LRpRBCs), and leukocytes and thrombocytopenic packed red blood cells. The temperature of blood changes with each stage of the collection process, starting at normal body temperature of 37°C at collection and the collection site, but rapidly decreasing to about 30°C once removed from the patient’s body. If unprocessed, collected blood will cool to room temperature in about 6 hours. In practice, blood is processed within 24 hours and refrigerated at about 2°C to 6°C, usually 4°C.

[0039] As used herein, the term “whole blood” refers to a suspension of blood cells containing red blood cells (RBCs), white blood cells (WBCs), platelets suspended in plasma, and also containing electrolytes, hormones, vitamins, antibodies, etc. In certain embodiments, whole blood is leukocyte-treated whole blood. In some embodiments, whole blood is whole blood from which pathogens have been reduced or inactivated. In other embodiments, whole blood is irradiated whole blood. In whole blood, the number of white blood cells is typically 4.5 to 11.0 × 10⁴ 9 They are present in the range of cells / L, and the normal RBC range at sea level is 4.6–6.2 × 10 in males. 12 / L, for women: 4.2~5.4×10 12 The value is / L. Normal hematocrit, or filling cell volume percentage, is approximately 40-54% in men and approximately 38-47% in women. Platelet count is typically 150-450 x 10¹⁶ in both men and women. 9 The volume is / L. Whole blood is collected from a blood donor and is usually combined with an anticoagulant. When collected, whole blood is initially at about 37°C and is rapidly cooled to about 30°C during and immediately after collection, but is slowly cooled to ambient temperature over about 6 hours. Whole blood may be processed at room temperature (typically about 25°C) starting at 30–37°C at collection, or at room temperature according to the methods of this disclosure. As used herein, a “unit” of blood is about 450–500 ml including an anticoagulant.

[0040] As used herein, “blood donor” typically refers to a healthy individual from whom whole blood is collected by venotomy or venipuncture, the donated blood is processed and held in a blood bank for later use, and ultimately used by a recipient other than the donor. Blood donors may be selected based on biomarkers presented in the donor’s blood. Blood donors may be subjects scheduled for surgery or other treatment and may donate blood for themselves in a process known as autologous blood donation. Alternatively, most commonly, blood is donated for use by another person in a process known as xenotransfusion. In the case of collecting whole blood samples drawn from a donor, or autologous blood transfusion from a patient, this can be achieved by techniques known in the art, such as blood donation or apheresis. Fresh whole blood obtained from a donor using venipuncture has an oxygen saturation in the range of about 30% to about 88% saturated oxygen (SO2) after the addition of an anticoagulant.

[0041] As used herein, “red blood cells” (RBCs) include RBCs present in whole blood, leukopenic RBCs, thrombocytopenic RBCs, and leukocytes and thrombocytopenic RBCs. In vivo human red blood cells are in a dynamic state. Red blood cells contain hemoglobin, an iron-containing protein that carries oxygen throughout the body and gives red blood cells their color. The percentage of blood volume composed of red blood cells is called hematocrit. As used herein, unless otherwise limited, RBCs also include packed red blood cells (pRBCs). Packed red blood cells are prepared from whole blood using techniques generally known in the art.

[0042] Platelets are small cell components of blood that promote the clotting process by adhering to the inner lining of blood vessels and, when activated, promote healing by releasing growth factors. Like red blood cells, platelets are produced in the bone marrow and remain in the circulatory system for 9-10 days until they are removed by the spleen. Platelets are often prepared using a centrifuge to separate them from the pia mater, which is sandwiched between the plasma layer and the red blood cell pellet.

[0043] Platelet preservation has been extensively studied to identify the most favorable conditions, including temperature, pH, and O2 and CO2 concentrations. The results of this research concluded that, for platelets to persist in recipients after transfusion, they need access to oxygen and be stored at room temperature. Murphy and Gardner noted in 1975 that undesirable morphological changes were associated with reduced oxygen consumption. See Murphy et al., “Platelet storage at 22 degrees C: role of gas transport across plastic containers in maintenance of viability,” Blood 46(2):209-218(1975). The authors observed that increased oxygen access enabled aerobic metabolism (oxidative phosphorylation) and reduced the rate of lactate production. At low PO2 levels, lactate production increased, consistent with the Pasteur effect. Moroff et al. noted that continuous oxygen consumption is necessary to maintain the pH of preserved platelets at pH 7. See Moroff et al., “Factors Influencing Changes in pH during Storage of Platelet Concentrates at 20-24℃,” Vox Sanguinis 42(1):33-45 (1982). Specially designed container systems allow permeability to carbon dioxide and oxygen to prevent lethal pH drops. As shown by Kakaiya et al., “Platelet preservation in large containers,” Vox Sanguinis 46(2):111-118 (1984), maintaining platelet quality was a result of improved gas exchange conditions, achieved by increasing the surface area available for gas exchange. The importance of maintaining oxygen levels during platelet preservation led to the development of gas-permeable containers and the preservation of platelets in an oxygen-concentrated atmosphere. See U.S. Patent No. 4,455,299, issued to Grode on June 19, 1984.The importance of oxygen for the viability of stored platelets was reinforced by the observation that lactate levels increase 5 to 8 times under poor oxygen conditions. See Kilkson et al., “Platelet metabolism during storage of platelet concentrates at 22 degrees C.”, Blood 64(2):406-14 (1984). Wallvik et al., “Platelet Concentrates Stored at 22℃ Need Oxygen The Significance of Plastics in Platelet Preservation.” Vox Sanguinis 45(4):303-311 (1983) reported that maintaining oxygen for the first 5 days of storage is important for platelet preservation. Wallvik and colleagues also showed that the maximum number of platelets that can be stored for 5 days can be predicted based on the determination of the oxygen diffusion capacity of the storage bag. See Wallvik et al, “The platelet storage capability of different plastic containers,” Vox Sanguinis 58(1):40-4 (1990). By providing a blood bag with appropriate gas exchange properties, pH was maintained and ATP loss and release of alpha-granular platelet factor 4 (PF4) were prevented. Each of the aforementioned references, in whole, is incorporated herein by reference.

[0044] These findings have led to the practice of standardizing the oxygenation of platelets during room temperature storage, particularly to maximize post-transfusion survival rates. However, more recent studies have shown the effects of oxygen depletion on whole blood. For example, Yoshida et al. found that low-temperature storage enables anaerobic storage of platelets, providing the known advantages of anaerobic storage RBCs observed in packed red blood cells in whole blood. See International Publication No. 2016 / 187353 in paragraph

[0009] . "More specifically, deoxygenated whole blood provides improved 2,3-DPG levels while unexpectedly maintaining coagulation without adverse effects." See id.

[0045] Plasma is a protein salt solution, the liquid portion of blood in which red blood cells, white blood cells, and platelets are suspended. Plasma is 90% water and makes up about 55 percent of blood volume. One function of plasma is to aid in blood clotting and immunity. Plasma is obtained by separating the liquid portion of blood from the cells. Often, plasma is collected from cells by centrifugation.

[0046] Reactive oxygen species (ROS) are produced by living organisms as a result of normal cellular metabolism. At high concentrations and without a proper oxidant / antioxidant balance, ROS can cause harmful displacements in cellular components. While not limited to theory, naturally occurring antioxidants in RBCs combined with antioxidants in the storage solution are considered sufficient to reduce the effects of oxidative damage to, for example, RBC membranes, as long as the accumulation of additional oxygen is prevented. Given the initial antioxidant capacity, much of the observed oxidative damage is thought to be the result of accumulation and continuous exposure rather than the result of initial levels of O2. The results presented herein demonstrate that the benefits of oxygen reduction can be achieved by preventing oxygen intrusion into cells during storage. This results in maintaining oxygen levels far below the amount required for saturation by naturally occurring antioxidants. Furthermore, under high carbon dioxide permeability conditions with alkaline additive solutions, high levels of 2,3-DPG can be maintained even at high oxygen saturation levels. In contrast, oxygen and carbon dioxide levels during storage under conventional methods increase throughout the storage period, and a decrease in ATP and 2,3-DPG levels is observed. By preventing oxygen intrusion, or by preventing oxygen intrusion and maintaining initial low levels of oxygen in the blood during processing requirements, the oxygen present during storage can be reduced so as not to overwhelm the cellular antioxidant capacity. The results presented below demonstrate that reducing CO2 levels during storage, when combined with external barriers and adsorbents to manage oxygen during the storage period, leads to an increase in 2,3-DPG concentration, as well as an increase in the levels of 2,3-DPG and ATP.

[0047] To achieve this result, the present disclosure relates to a method for preserving blood products, comprising obtaining an oxygenated blood product having more than 30% SO2%, adding an additive solution to the blood product, and storing the blood product at 25°C and about 1 atm, at least 0.62 cubic centimeters per square centimeter (cm²). 3 / cm 2The present invention provides and includes a method comprising storing in a di-2-ethylhexylphthalate-free (DEHP-free) blood-compatible (BC) carbon dioxide permeable bag having gas permeability to carbon dioxide. In one embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag further comprises butyryltrihexylcitrate (BTHC). In another embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag further comprises 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH).

[0048] method Storage in a CO2 permeable bag without oxygen control In one aspect of this disclosure, the method provides a blood product stored for at least 7 days in a (DEHP-free) blood-compatible (BC) carbon dioxide-permeable bag. In this aspect, the 2,3-DPG level increases above the level in conventionally stored blood. In another aspect, the method provides a blood product stored for at least 14 days. In yet another aspect, the method provides a blood product stored for at least 21 days. In yet another aspect, the method provides a blood product stored for at least 28 days. In yet another aspect, the method provides a blood product stored for at least 35 days. In yet another aspect, the blood product is stored for at least 40 days. The method further provides a blood product stored for 56 days. Notably, this is the first reported storage condition that provides transfusion-ready blood on day 56. In another aspect, the blood product is stored for a maximum of 7, 14, 21, 35, 42, or 56 days. In yet another embodiment, the blood product is stored for 1 to 7 days, 1 to 14 days, 1 to 21 days, 1 to 35 days, 1 to 42 days, 1 to 56 days, 7 to 14 days, 7 to 21 days, 7 to 35 days, 7 to 42 days, 7 to 56 days, 14 to 21 days, 14 to 28 days, 14 to 35 days, 14 to 42 days, 14 to 56 days, 21 to 35 days, 21 to 42 days, 35 to 42 days, or 35 to 56 days.

[0049] The method of this disclosure provides storage of venously collected blood products having an initial SO2% in the range of 30–100% before being stored in a DEHP-free blood-compatible (BC) carbon dioxide-permeable bag without being treated to reduce oxygen. In one aspect of this disclosure, the method provides storage of venously collected blood products having an SO2% greater than 40% at the start of the storage period (e.g., day zero). In another aspect, the method provides storage of oxygenated blood products having an SO2% greater than 50%. In another aspect, the method provides storage of oxygenated blood products having an SO2% greater than 60%. In another aspect, the oxygenated blood product has an SO2% greater than 70%. In another aspect, the oxygenated blood product has an SO2% greater than 80%. In another aspect, the oxygenated blood product has an SO2% greater than 90%. In another aspect, the oxygenated blood product has an SO2% between 30–80%. In another aspect, the oxygenated blood product has an SO2% between 50–90%. In another embodiment, the oxygenated blood product has an SO2 of 40-100%. In another embodiment, the oxygenated blood product has an SO2 of at least 30%. In another embodiment, the oxygenated blood product has an SO2 of at least 50%.

[0050] This disclosure relates to a method for preserving blood products, comprising: obtaining a venously collected blood product having more than 30% SO2%; adding an additive solution to the blood product; and preserving the blood product at 25°C and about 1 atm, at least 0.62 cubic centimeters per square centimeter (cm²). 3 / cm 2 The present invention provides and includes a method comprising storing in a DEHP-free blood-compatible (BC) carbon dioxide permeable bag having gas permeability to carbon dioxide. In one embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag is a PVC bag further comprising BTHC. In another embodiment, the DEHP-free BC carbon dioxide permeable bag is a PVC bag further comprising DINCH. In yet another embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag further comprises EXP500.

[0051] In one aspect of this disclosure, the stored blood product has a pCO2 of less than 125 mmHg at the time of initial blood collection. In another aspect, the blood product has a pCO2 of less than 100 mmHg. In another aspect, the blood product has a pCO2 of less than 75 mmHg. In another aspect, the blood product has a pCO2 of less than 50 mmHg. In another aspect, the blood product has a pCO2 of less than 25 mmHg. In another aspect, the blood product has a pCO2 of 125 to 100 mmHg. In another aspect, the blood product has a pCO2 of 100 to 75 mmHg. In another aspect, the blood product has a pCO2 of 75 to 25 mmHg. In an aspect of the method, the 2,3-DPG level in the stored blood product is increased by at least 10% compared to the 2,3-DPG level of a blood product stored by a conventional method. In another embodiment, the ATP level in the stored blood product increases by at least 10% during storage compared to the ATP level of a blood product stored by a conventional method. In yet another embodiment, the 2,3-DPG level in the stored blood product increases by at least 10% and the ATP level increases by at least 10% compared to the 2,3-DPG and ATP levels of a blood product stored by a conventional method. In an embodiment of the method, the 2,3-DPG level in the stored blood product increases by at least 15% compared to the 2,3-DPG level of a blood product stored by a conventional method. In yet another embodiment, the 2,3-DPG level increases by at least 10% and the ATP level increases by at least 15% compared to the 2,3-DPG and ATP levels of a blood product stored by a conventional method.

[0052] In aspects of the present disclosure, the method further includes producing a CO2-reduced stored blood product by depleting the CO2 during the storage period to a level of 125 mmHg to 25 mmHg after a maximum storage period of 56 days. In one aspect, the stored blood product has a pCO2 of less than 125 mmHg and an SO2% of more than 20% after storage for at least 7 days. In another aspect, the blood product has a pCO2 of less than 100 mmHg and an SO2% of more than 20%. In another aspect, the blood product has a pCO2 of less than 75 mmHg and an SO2% of more than 20%. In another aspect, the blood product has a pCO2 of less than 50 mmHg and an SO2% of more than 20%. In another aspect, on day 56 of storage, the blood product has a pCO2 of less than 25 mmHg and an SO2% of more than 20%. In another aspect, on day 56 of storage, the blood product has a pCO2 of 125 mmHg to 25 mmHg and an SO2% of more than 20%. In another embodiment, on day 56 of storage, the blood product has a pCO2 of 125 mmHg to 25 mmHg and an SO2% of 5%. In yet another embodiment, on day 56 of storage, the blood product has a pCO2 of 125 mmHg to 25 mmHg and an SO2% of 3% to 20%. In yet another embodiment, the blood product has a pCO2 of less than 125 mmHg and an SO2% of 15%. In yet another embodiment, the blood product has a pCO2 of less than 100 mmHg and an SO2% of 15%. In yet another embodiment, the blood product has a pCO2 of less than 75 mmHg and an SO2% of 15%. In yet another embodiment, the blood product has a pCO2 of less than 50 mmHg and an SO2% of 15%. In yet another embodiment, the blood product has a pCO2 of less than 25 mmHg and an SO2% of 15%. In yet another embodiment, the blood product has a pCO2 of less than 125 mmHg and an SO2% of 10%. In another embodiment, the blood product has a pCO2 of less than 100 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of less than 75 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of less than 50 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of more than 25 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of less than 125 mmHg and an SO2% of 5-30%.In another embodiment, the blood product has a pCO2 of less than 100 mmHg and an SO2% of 5-30%. In another embodiment, the blood product has a pCO2 of less than 75 mmHg and an SO2% of 5-30%. In another embodiment, the blood product has a pCO2 of less than 50 mmHg and an SO2% of 5-30%. In another embodiment, the blood product has a pCO2 of less than 25 mmHg and an SO2% of 5-30%.

[0053] In another embodiment, the method provides for producing a CO2-reduced stored blood product having more than 20% SO2% and increased 2,3-DPG levels compared to blood products stored by conventional methods, after a 21-day storage period during which CO2 is depleted to levels of 125 mmHg to 25 mmHg. In one embodiment, the method provides for producing a CO2-reduced stored blood product having more than 20% SO2% and increased 2,3-DPG and ATP levels compared to blood products stored by conventional methods, after a 21-day storage period during which CO2 is depleted to levels of 125 mmHg to 25 mmHg. In another embodiment, the blood product has a pCO2 of less than 125 mmHg and more than 20% SO2%. In another embodiment, the blood product has a pCO2 of less than 100 mmHg and more than 20% SO2%. In yet another embodiment, on day 21 of storage, the blood product has a pCO2 of less than 75 mmHg and more than 20% SO2%. In another embodiment, the blood product has a pCO2 of less than 50 mmHg and an SO2% of more than 20%. In yet another embodiment, the blood product has a pCO2 of less than 25 mmHg and an SO2% of more than 20%. In yet another embodiment, the blood product has a pCO2 of less than 125 mmHg and an SO2% of more than 15%. In yet another embodiment, the blood product has a pCO2 of less than 100 mmHg and an SO2% of more than 15%. In yet another embodiment, the blood product has a pCO2 of less than 75 mmHg and an SO2% of more than 15%. In yet another embodiment, the blood product has a pCO2 of less than 50 mmHg and an SO2% of more than 15%. In yet another embodiment, the blood product has a pCO2 of less than 25 mmHg and an SO2% of more than 15%. In yet another embodiment, the blood product has a pCO2 of less than 125 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of less than 100 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of less than 75 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of less than 50 mmHg and an SO2% of more than 10%. In another embodiment, the blood product has a pCO2 of less than 25 mmHg and an SO2% of more than 10%.In one embodiment of the method, the 2,3-DPG level increases by at least 10% compared to the 2,3-DPG level of a blood product stored by a conventional method. In another embodiment, the ATP level increases by at least 10% in the storable blood product during storage compared to the ATP level of a blood product stored by a conventional method. In yet another embodiment, the 2,3-DPG level increases by at least 10% and the ATP level increases by at least 10% compared to the 2,3-DPG and ATP levels of a blood product stored by a conventional method. In one embodiment of the method, the 2,3-DPG level increases by at least 15% compared to the 2,3-DPG level of a blood product stored by a conventional method. In yet another embodiment, the 2,3-DPG level increases by at least 10% and the ATP level increases by at least 15% compared to the 2,3-DPG and ATP levels of a blood product stored by a conventional method.

[0054] Storage in an oxygen-controlled CO2-permeable bag This disclosure relates to a method for preserving blood products, comprising: obtaining an oxygenated blood product having more than 30% SO2%; adding an additive solution to the blood product; and preserving the blood product at 25°C and about 1 atm, with a volume of at least 0.62 cubic centimeters per square centimeter (cm²). 3 / cm 2 The present invention provides and includes storing in a di-2-ethylhexylphthalate-free (DEHP-free) blood-compatible (BC) carbon dioxide permeable bag, which further comprises an oxygen-impermeable barrier bag and an adsorbent for preventing oxygen gene transfer and blood saturation, and which has gas permeability to carbon dioxide. In one embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag further comprises BTHC. In another embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag further comprises DINCH.

[0055] In one embodiment, the method further comprises an oxygen-impermeable barrier bag for preventing oxygen gene transfer and blood saturation. In another embodiment, the DEHP-free blood-compatible (BC) carbon dioxide-permeable bag further comprises BTHC. In yet another embodiment, the DEHP-free blood-compatible (BC) carbon dioxide-permeable bag further comprises DINCH. In yet another embodiment, the method of the present disclosure comprises adding an additive solution to a blood product and at 25°C and about 1 atm, at least 0.62 cm 3 / cm 2 The present invention provides a method for handling blood products, including storing blood products in a blood-compatible (BC) carbon dioxide permeable bag having gas permeability to carbon dioxide, wherein the storage bag further comprises an outer bag impermeable to oxygen and carbon dioxide, and the outer bag contains a carbon dioxide and oxygen adsorbent placed between the BC carbon dioxide permeable bag and the outer bag. In one embodiment of the method, the storage is for at least 7 days, and the blood product contains an oxygen level of 5-30% after 7 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of 5-30% after 14 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In yet another embodiment, the blood product contains an oxygen level of 5-30% after 21 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of 5-30% on day 28 of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of 5-30% on day 32 of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of 5-30% on day 38 of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of 5-30% on day 42 of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage.

[0056] In yet another embodiment, the method of the present disclosure involves adding an additive solution to a blood product and at 25°C and about 1 atm, at least 0.62 cm 3 / cm 2The present invention provides a method for handling blood products, comprising storing the blood product in a blood-compatible (BC) carbon dioxide permeable bag having gas permeability to carbon dioxide, wherein the storage bag further comprises an outer bag impermeable to oxygen and carbon dioxide, the outer bag containing a carbon dioxide and oxygen adsorbent placed between the BC carbon dioxide permeable bag and the outer bag. In one embodiment of the method, the storage is for at least 7 days, and the blood product contains an oxygen level of more than 30% after 7 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of more than 30% after 14 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In yet another embodiment, the blood product contains an oxygen level of more than 30% after 21 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of over 30% after 28 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of over 30% after 32 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of over 30% after 38 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In another embodiment, the blood product contains an oxygen level of over 30% after 42 days of storage, which is lower than or approximately the same as the oxygen level in the blood product on day 1 of storage. In an embodiment of the method, the 2,3-DPG level increases by at least 10% compared to the 2,3-DPG level of a blood product stored by a conventional method. In another embodiment, the ATP level increases by at least 10% in the storable blood product during storage compared to the ATP level of a blood product stored by a conventional method. In yet another embodiment, the 2,3-DPG level is increased by at least 10% and the ATP level is increased by at least 10% compared to the 2,3-DPG and ATP levels of blood products stored by conventional methods.In one embodiment of the method, the 2,3-DPG level is increased by at least 15% compared to the 2,3-DPG level of blood products stored by conventional methods. In yet another embodiment, the 2,3-DPG level is increased by at least 10% and the ATP level is increased by at least 15% compared to the 2,3-DPG and ATP levels of blood products stored by conventional methods.

[0057] This disclosure relates to a method for maintaining the level of 2,3-DPG in a blood product, wherein the level is at least 0.62 cm at 25°C and about 1 atm. 3 / cm 2 It has permeability to carbon dioxide and a tolerance of 0.3 cm at approximately 1 atm. 3 / cm 2A method is provided, comprising: placing a non-deoxygenated blood product in a storage container containing a blood-compatible (BC) material having the following oxygen permeability, wherein the storage bag is enclosed within an oxygen and carbon dioxide-impermeable outer bag further containing a carbon dioxide adsorbent, and the blood product has an initial oxygen saturation of at least 10%; and storing the container containing the blood product, wherein the level of 2,3-DPG increases after 14 days of storage compared to the level of 2,3-DPG in a blood product stored in a conventional manner. In another embodiment, the level of 2,3-DPG increases after 21 days of storage compared to the level of 2,3-DPG in a blood product stored in a conventional manner. In another embodiment, the level of 2,3-DPG increases after 28 days of storage compared to the level of 2,3-DPG in a blood product stored in a conventional manner. In another embodiment, the level of 2,3-DPG increases after 35 days of storage compared to the level of 2,3-DPG in a blood product stored in a conventional manner. In another embodiment, the 2,3-DPG level increases after 42 days of storage compared to the 2,3-DPG level of blood products stored in a conventional manner. In one embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag is a PVC bag further containing BTHC. In another embodiment, the DEHP-free BC carbon dioxide permeable bag is a PVC bag further containing DINCH. In yet another embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag further contains EXP500.

[0058] In another embodiment, a method for maintaining the level of 2,3-DPG in a blood product provides an increase of 10% to 70% in the 2,3-DPG level compared to blood stored in a conventional manner. In one embodiment, the method provides a 2,3-DPG level that is increased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or more compared to the level of 2,3-DPG in a blood product stored in a conventional manner. In a particular embodiment, the 2,3-DPG level increases by at least 10% after 7 days of storage compared to the level of 2,3-DPG in a blood product stored in a conventional manner. In another embodiment, the 2,3-DPG level increases by at least 10% after 14 days of storage compared to the level of 2,3-DPG in a blood product stored in a conventional manner. In another embodiment, the 2,3-DPG level increases by at least 10% after 21 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In a particular embodiment, the 2,3-DPG level increases by at least 10% after 28 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 10% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In a particular embodiment, the 2,3-DPG level increases by at least 20% after 7 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 20% after 14 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In another embodiment, the 2,3-DPG level increases by at least 20% after 21 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In a particular embodiment, the 2,3-DPG level increases by at least 20% after 28 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 20% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods.In certain embodiments, the 2,3-DPG level increases by at least 30% after 7 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In other embodiments, the 2,3-DPG level increases by at least 30% after 14 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 30% after 21 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In certain embodiments, the 2,3-DPG level increases by at least 30% after 28 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 30% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In a further embodiment, the 2,3-DPG level increases by at least 40% after 28 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 40% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 50% after 28 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 50% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 60% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In another embodiment, the 2,3-DPG level increases by at least 70% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 80% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods. In yet another embodiment, the 2,3-DPG level increases by at least 90% after 42 days of storage compared to the 2,3-DPG level of blood products stored using conventional methods.In yet another embodiment, 2,3-DPG levels increase by 50-90% after 42 days of storage compared to 2,3-DPG levels in blood products stored using conventional methods.

[0059] This disclosure relates to a method for maintaining the level of ATP in a blood product, wherein the ATP level is at least 0.62 cm³ at 25°C and about 1 atm. 3 / cm 2 It has permeability to carbon dioxide and a tolerance of 0.3 cm at approximately 1 atm. 3 / cm 2The present invention provides and includes a method for placing an oxygenated blood product in a storage container comprising a blood-compatible (BC) material having the following oxygen permeability, wherein the storage bag is enclosed within an outer bag impermeable to oxygen and carbon dioxide, which further contains carbon dioxide and an oxygen adsorbent, and the blood product has an initial oxygen saturation of at least 10%; and storing the container containing the blood product, wherein the ATP level increases after 7 days of storage compared to the ATP level of a blood product stored in a conventional manner. In another embodiment, the ATP level increases after 14 days of storage compared to the ATP level of a blood product stored in a conventional manner. In another embodiment, the ATP level increases after 21 days of storage compared to the ATP level of a blood product stored in a conventional manner. In another embodiment, the ATP level increases after up to 28 days of storage compared to the ATP level of a blood product stored in a conventional manner. In another embodiment, the ATP level increases after up to 35 days of storage compared to the ATP level of a blood product stored in a conventional manner. In another embodiment, the ATP level increases after up to 42 days of storage compared to the ATP level of conventionally stored blood products. In another embodiment, the ATP level increases by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, or more compared to the ATP level of conventionally stored blood products. In a particular embodiment, the ATP level increases by at least 10% after 7 days of storage compared to the ATP level of conventionally stored blood products. In another embodiment, the ATP level increases by at least 10% after 14 days of storage compared to the ATP level of conventionally stored blood products. In another embodiment, the ATP level increases by at least 10% after 21 days of storage compared to the ATP level of conventionally stored blood products. In a particular embodiment, the ATP level increases by at least 10% after 28 days of storage compared to the ATP level of conventionally stored blood products. In yet another embodiment, the ATP level increases by at least 10% after 42 days of storage compared to the ATP level of blood products stored using conventional methods.In certain embodiments, the ATP level increases by at least 20% after 7 days of storage compared to the ATP level of blood products stored using conventional methods. In other embodiments, the ATP level increases by at least 20% after 14 days of storage compared to the ATP level of blood products stored using conventional methods. In other embodiments, the ATP level increases by at least 20% after 21 days of storage compared to the ATP level of blood products stored using conventional methods. In certain embodiments, the ATP level increases by at least 20% after 28 days of storage compared to the ATP level of blood products stored using conventional methods. In yet another embodiment, the ATP level increases by at least 20% after 42 days of storage compared to the ATP level of blood products stored using conventional methods. In certain embodiments, the ATP level increases by at least 30% after 7 days of storage compared to the ATP level of blood products stored using conventional methods. In other embodiments, the ATP level increases by at least 30% after 14 days of storage compared to the ATP level of blood products stored using conventional methods. In another embodiment, the ATP level increases by at least 30% after 21 days of storage compared to the ATP level of blood products stored in a conventional manner. In a particular embodiment, the ATP level increases by at least 30% after 28 days of storage compared to the ATP level of blood products stored in a conventional manner. In yet another embodiment, the ATP level increases by at least 30% after 42 days of storage compared to the ATP level of blood products stored in a conventional manner. In yet another embodiment, the ATP level increases by at least 40% after 28 days of storage compared to the ATP level of blood products stored in a conventional manner. In yet another embodiment, the ATP level increases by at least 40% after 42 days of storage compared to the ATP level of blood products stored in a conventional manner. In another embodiment, the ATP level increases by at least 50% after 28 days of storage compared to the ATP level of blood products stored in a conventional manner. In yet another embodiment, the ATP level increases by at least 50% after 42 days of storage compared to the ATP level of blood products stored in a conventional manner. In one embodiment, the DEHP-free blood-compatible (BC) carbon dioxide-permeable bag is a PVC bag further containing BTHC.In one embodiment, the DEHP-free BC carbon dioxide permeable bag is a PVC bag further comprising DINCH. In yet another embodiment, the DEHP-free blood-compatible (BC) carbon dioxide permeable bag further comprises EXP500.

[0060] This disclosure provides and includes a method for maintaining the level of hemolysis in a blood product below 0.8% after 7 days of storage in the absence of DEHP. In another embodiment, the level of hemolysis in the blood product is maintained below 0.8% after 14 days of storage. In another embodiment, the level of hemolysis in the blood product is maintained below 0.8% after 21 days of storage. In another embodiment, the level of hemolysis in the blood product is maintained below 0.8% after 28 days of storage. In another embodiment, the level of hemolysis in the blood product is maintained below 0.8% after 35 days of storage. In another embodiment, the level of hemolysis in the blood product is maintained below 0.8% after 42 days of storage.

[0061] DEHP and other plasticizers 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, and specifically, diethylhexyl phthalate (DEHP) is widely used for the long-term storage of red blood cells. In addition to increasing the flexibility of PVC, DEHP also increases the oxygen permeability of PVC. For these reasons, DEHP is used as a plasticizer for storing red blood cells. An example PVC-DEHP film is Renolit ES-3000 film (American Renolit Corp., City of Commerce, CA).

[0062] DEHP improves the preservation of red blood cells, but recently concerns have been raised about the safety of DEHP. RBC compositions stored in PVC-DEHP bags extract DEHP from the bags. A study showed that by day 28 of storage, RBCs stored in PVC-DEHP contained approximately 80 μg / mL of DEHP. Rock et al., “Distribution of di(2-ethylhexyl) phthalate and products in blood and blood components,” Environ Health Perspect. 65:309-316 (1986). Although still controversial and debated, some reports suggest that DEHP may interfere with normal hormonal function and may interfere with asthma, breast cancer, obesity and type 2 diabetes, brain development problems, attention deficit hyperactivity disorder (ADHD), autism spectrum disorder, and male fertility. Other studies have shown that DEHP induces oral cell formation in red blood cell suspensions and increases phosphatidylserine exposure. See Melzak et al., “The Blood Bag Plasticizer Di-2-Ethylhexylphthalate Causes Red Blood Cells to Form Stomatocytes, Possibly by Inducing Lipid Flip-Flop” Transfus Med Hemother. 45(6):413-422 (2018). For this reason, Europe is considering adopting measures to protect people from DEHP exposure.

[0063] In the course of research investigating DEHP-free materials suitable for blood preservation, the results reveal for the first time the sole role of CO2 depletion in maintaining high levels of major metabolites (e.g., 2,3-DPG and ATP) during preservation. Prior to the results provided below, control of CO2 during preservation was largely limited to preventing changes in pH and reactions with CO2-sensitive reagents. For example, U.S. Patent No. 4,228,032, issued to Talcott on April 4, 1978, taught CO2 absorption during preservation of bicarbonate-containing buffers such as BAGPAM to maintain an alkaline preservation environment. Talcott shows that CO2 absorption during preservation by silicone rubber compounded with Ca(OH)2 maintains an alkaline pH. However, Talcott does not teach or suggest any specific effect of CO2 on blood preservation, nor does it suggest that levels of blood metabolites are affected by CO2 during preservation. Instead, Talcott teaches maintaining an alkaline preservation environment to maintain levels of 2,3-DPG. More recently, the role of carbon dioxide during the storage of oxygen-depleted pRBCs suggested a role for CO2 in 2,3-DPG levels. See International Patent Publication 2012 / 027582 ("582PCT"), published March 1, 2012. '582PCT' demonstrated that removing oxygen depletion to approximately 10 mmHg and carbon dioxide depletion to 5 mmHg before storage can improve 2,3-DPG and ATP levels compared to conventionally stored blood. '582PCT also showed that the impact on 2,3-DPG is largely due to carbon dioxide depletion. This disclosure is the first to demonstrate that CO2 depletion and oxygen level maintenance during storage can maintain 2,3-DPG and ATP levels during storage. Prior to this disclosure, research has demonstrated the importance of pH and oxygen depletion before storage, not the importance of CO2 depletion alone during storage (while maintaining oxygen) for maintaining key metabolites, including 2,3-DPG and ATP. The unexpected finding that gas exchange management during storage can achieve similar results to depletion and storage methods greatly simplifies the preparation of blood for storage and transfusion.Furthermore, these results demonstrate that the CO2 effect can be achieved at CO2 levels more than 10 times higher than those tested in '582PCT'.

[0064] This disclosure provides various materials and plasticizers that can be used as substitutes for DEHP. This disclosure provides preferred materials with increased carbon dioxide permeability.

[0065] This disclosure provides suitable PVC materials for use in foldable blood containers that are substantially permeable to carbon dioxide. The use of PVC-citrate films such as Renolit ES-4000 (American Renolit Corp., City of Commerce, CA) having a thickness of about 5 μm to about 250 μm, and more preferably about 10 μm to about 100 μm, is suitable for providing foldable blood containers having the desired properties of high carbon dioxide permeability, high-frequency (RF) welding and joining, and high tensile strength. RF welding is also known in the art as high-frequency welding or dielectric welding. RF welding is a method of joining thin sheets of material or film together using high-frequency electromagnetic energy to fuse the materials. In aspects of this disclosure, RF welding is used to fuse films together to avoid gas leakage or ingress while forming a foldable blood container.

[0066] In certain embodiments, a carbon dioxide permeable membrane suitable for use in the preparation of foldable blood containers comprises PVC without the plasticizer di-2-ethylhexyl phthalate (DEHP). In other embodiments, a carbon dioxide permeable membrane suitable for use in the preparation of foldable blood containers comprises PVC without di-2-ethylhexyl terephthalate (DEHT). In other embodiments, a carbon dioxide permeable membrane suitable for use in the preparation of foldable blood containers comprises PVC containing 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH). In other embodiments, a carbon dioxide permeable membrane suitable for use in the preparation of foldable blood containers comprises PVC containing butyryl trihexyl citrate (BTHC). In certain embodiments, the concentration of the plasticizer is 20-70% by weight in the PVC. In certain embodiments, the concentration of the plasticizer is 20-40% by weight in the PVC. In certain embodiments, the concentration of the plasticizer is 40-70% by weight in the PVC. In other embodiments, the concentration of the plasticizer exceeds 20% by weight in the PVC. In other embodiments, the concentration of the plasticizer exceeds 30% by weight in the PVC. In other embodiments, the concentration of the plasticizer exceeds 40% by weight in the PVC. In other embodiments, the concentration of the plasticizer exceeds 50% by weight in the PVC. In other embodiments, the concentration of the plasticizer exceeds 60% by weight in the PVC. In certain embodiments, the plasticizer DINCH is more preferably 20-45% by weight in the PVC. In certain embodiments, the plasticizer DINCH exceeds 20% by weight in the PVC. In certain embodiments, the plasticizer DINCH exceeds 30% by weight in the PVC. In certain embodiments, the plasticizer DINCH exceeds 40% by weight in the PVC.

[0067] In another embodiment, a carbon dioxide permeable membrane suitable for use in the preparation of a foldable blood container comprises a polyolefin. In yet another embodiment, a carbon dioxide permeable membrane suitable for use in the preparation of a foldable blood container comprises a silicone. In yet another embodiment, a carbon dioxide permeable membrane suitable for use in the preparation of a foldable blood container comprises polyvinylidene fluoride (PVDF), however these membranes are not strong enough for storage and further increase hemolysis. In yet another embodiment, a carbon dioxide permeable membrane suitable for use in the preparation of a foldable blood container comprises polysulfone (PS), but, similar to PVDF, exhibits increased hemolysis and brittleness. In yet another embodiment, a carbon dioxide permeable membrane suitable for use in the preparation of a foldable blood container comprises polypropylene (PP). In yet another embodiment, a carbon dioxide permeable membrane suitable for use in the preparation of a foldable blood container comprises polyurethane.

[0068] Inner bag material and permeability This disclosure provides and includes a blood storage container for depleting carbon dioxide from blood during storage, comprising a carbon dioxide permeable bag that is permeable to carbon dioxide and impermeable to oxygen. Preferably, the blood storage container is prepared from a DEHP-free carbon dioxide permeable material.

[0069] This disclosure provides and includes DEHP-free carbon dioxide permeable bags prepared from a membrane primarily characterized by its permeability to carbon dioxide.

[0070] This disclosure also provides and includes membranes that are permeable to carbon dioxide. The membranes permeable to carbon dioxide are used in this disclosure for the preparation of carbon dioxide permeable bags, preferably DEHP-free carbon dioxide permeable membranes. In certain embodiments, the membranes permeable to carbon dioxide are also biocompatible membranes and are approved and preferred for long-term contact with blood transfused to patients. Similar to substantially impermeable membranes, substantially permeable membranes may comprise a single layer or a laminated structure having two or more layers.

[0071] In one embodiment, the carbon dioxide permeable membrane is 0.6-2.5 cm 3 / cm 2 It has permeability to carbon dioxide. In one embodiment, the material for constructing a DEHP-free BC carbon dioxide permeable bag has a permeability of about 0.6 cubic centimeters per square centimeter at 25°C and about 1 atm. 3 / cm 2 It has a carbon dioxide permeability exceeding 0.43 cm. 3 / cm 2 This is an improvement over conventional bags made from DEHP-containing PVC, which have carbon dioxide permeability of approximately 0.7 cm. In another embodiment, approximately 0.7 cm 3 / cm 2 DEHP-free BC carbon dioxide permeable material having permeability to carbon dioxide exceeding 0.8 cm is used for the preparation of carbon dioxide permeable bags. In another embodiment, about 0.8 cm 3 / cm 2 A DEHP-free BC carbon dioxide permeable material having permeability to carbon dioxide exceeding 1.5 cm is used for the preparation of carbon dioxide permeable bags. In yet another embodiment, about 1.5 cm 3 / cm 2 A carbon dioxide permeable material having permeability to carbon dioxide exceeding 2 cm is used for the preparation of carbon dioxide permeable bags. In certain embodiments, approximately 2 cm 3 / cm 2 A carbon dioxide permeable material having permeability to carbon dioxide exceeding 2.2 cm is used for the preparation of carbon dioxide permeable bags. In another embodiment, about 2.2 cm 3 / cm 2 DEHP-free BC carbon dioxide permeable material having permeability to carbon dioxide exceeding 0.5 cm is used for the preparation of carbon dioxide permeable bags. In other embodiments, 0.6-0.8, 0.7-0.9, 2-2.5, and 0.6-2.5 cm are used. 3 / cm 2A carbon dioxide permeable material having permeability to carbon dioxide is used for the preparation of a carbon dioxide permeable bag. In yet another embodiment, the carbon dioxide permeable material is selected from the materials provided in Table 1. In a particular embodiment, the carbon dioxide permeable material has permeability of 0.6-0.8, 0.7-0.9, 2-2.5, and 0.6-2.5 cm 3 / cm 2 A PVC membrane having carbon dioxide permeability, used for the preparation of carbon dioxide permeable bags. In another embodiment, the carbon dioxide permeable material is 0.6-0.8, 0.7-0.9, 2-2.5, and 0.6-2.5 cm 3 / cm 2 This is a polyolefin membrane that is permeable to carbon dioxide and is used for the preparation of carbon dioxide permeable bags. Preferably, the carbon dioxide permeable material is a DEHP-free BC carbon dioxide permeable membrane. [Table 1]

[0072] In one embodiment, the carbon dioxide permeable membrane is also permeable to oxygen. However, in a preferred embodiment, the carbon dioxide permeable membrane for use in the preparation of carbon dioxide permeable bags is impermeable to oxygen and is particularly suitable for the preparation of outer barrier-free blood storage containers. In another embodiment, at 25°C and about 1 atm, about 0.6 cm 3 / cm 2 Permeability to carbon dioxide exceeding 0.15 cm, and 0.15 cm 3 / cm 2 A carbon dioxide permeable membrane having oxygen permeability exceeding 0.6 cm² is used for the preparation of blood-compatible (BC) carbon dioxide permeable bags. In another embodiment, at 25°C and approximately 1 atm, approximately 0.6 cm² 3 / cm 2 Permeability to carbon dioxide exceeding 0.2 cm, and 0.2 cm 3 / cm 2 A carbon dioxide permeable membrane having oxygen permeability exceeding 0.6 cm² is used for the preparation of BC carbon dioxide permeable bags. In another embodiment, at 25°C and approximately 1 atm, approximately 0.6 cm²3 / cm 2 Permeability to carbon dioxide exceeding, and permeability to oxygen less than 3.0 cm 3 / cm 2 The carbon dioxide permeable membrane having permeability to carbon dioxide exceeding and permeability to oxygen less than is used for the preparation of BC carbon dioxide permeable bags. In another aspect, at 25 °C and about 1 atm, about 0.6 cm 3 / cm 2 Permeability to carbon dioxide exceeding, and permeability to oxygen less than 2.5 cm 3 / cm 2 The carbon dioxide permeable membrane having permeability to carbon dioxide exceeding and permeability to oxygen less than is used for the preparation of BC carbon dioxide permeable bags. In another aspect, at 25 °C and about 1 atm, about 0.6 cm 3 / cm 2 Permeability to carbon dioxide exceeding, and permeability to oxygen less than 3 cm 3 / cm 2 The carbon dioxide permeable membrane having permeability to carbon dioxide exceeding and permeability to oxygen less than is used for the preparation of BC carbon dioxide permeable bags. In yet another aspect, at 25 °C and about 1 atm, about 0.6 cm 3 / cm 2 Permeability to carbon dioxide exceeding, and permeability to oxygen of 0 to 3 cm 3 / cm 2 The carbon dioxide permeable membrane having permeability to carbon dioxide exceeding and permeability to oxygen of is used for the preparation of BC carbon dioxide permeable bags.

[0073] As used herein, a DEHP-free carbon dioxide permeable bag is permeable to carbon dioxide. In certain aspects, a DEHP-free carbon dioxide permeable bag is permeable to oxygen and carbon dioxide. In other aspects, a DEHP-free carbon dioxide permeable bag is impermeable to oxygen and permeable to carbon dioxide.

[0074] In aspects of this disclosure, other suitable DEHP-free BC carbon dioxide permeable membranes for the methods and devices according to this disclosure include high-density membranes, porous membranes, asymmetric membranes, and composite membranes. In certain embodiments, the suitable membrane may be a multilayer membrane. In other embodiments, the suitable membrane is prepared from an inorganic material. A high-density membrane is a membrane prepared from a solid material that does not have pores or voids. The material penetrates into the high-density membrane by a process of solution and diffusion. An example of a high-density membrane is a silicone membrane (polydimethylsiloxane (PDMS)). Also included and provided in this disclosure are porous membranes having pores of a specific size range that are separated based on size exclusion. Examples of porous membranes suitable for use according to this disclosure include PVDF and polysulfone membranes.

[0075] Outer barrier bag This disclosure also provides and includes a carbon dioxide permeable container for storing blood sealed in a gas-impermeable barrier bag to deplete carbon dioxide from the blood during storage, comprising a gas-impermeable barrier bag that is substantially impermeable to carbon dioxide, a DEHP-free carbon dioxide permeable bag that is permeable to carbon dioxide, and a carbon dioxide adsorbent located within the gas-impermeable barrier bag. In particular, the addition of an outer barrier bag and adsorbent can increase both 2,3-DPG levels and ATP levels, although certain bags with high carbon dioxide permeability can maintain significantly high levels of 2,3-DPG for 42 days of storage. See Figures 3A and 3B. Thus, storage bags prepared from materials with high carbon dioxide permeability and low oxygen permeability can eliminate the need for a barrier. Oxygen permeable bags benefit most from the addition of a combination of an outer barrier bag and adsorbent, but are also expected to benefit from low oxygen permeability membranes, as oxygen is actively removed, leading to enhanced ATP levels. See Figures 2-6.

[0076] This disclosure provides and includes the preparation of gas-impermeable barrier bags from films and DEHP-free carbon dioxide permeable bags from membranes. As used herein, membrane generally refers to the material used to prepare DEHP-free carbon dioxide permeable bags, and film is used to refer to the material used to prepare gas-impermeable barrier bags. It is understood that certain materials may be referred to as “membrane” by the manufacturer, or may be known as “membrane” in general, but for clarity, unless otherwise indicated, films are considered substantially impermeable. A membrane comprises one or more layers of material in the form 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, the outer acceptor is prepared from a material that is substantially impermeable to carbon dioxide and optionally impermeable to oxygen. In certain embodiments, gas-impermeable barrier bags are prepared from flexible film materials. In other embodiments, gas-impermeable barrier bags are prepared from rigid or non-flexible film materials.

[0077] This disclosure provides and includes gas-impermeable barrier bags that are substantially impermeable to carbon dioxide. As used herein, a gas-impermeable barrier bag that is substantially impermeable to carbon dioxide is sufficiently impermeable to carbon dioxide to allow 10 cc or less of carbon dioxide inside the acceptor over a period of 3 months, more preferably 5 cc or less of carbon dioxide over a period of 6 months. As used herein, the term substantially impermeable to carbon dioxide (SICO) refers to materials and compositions that provide a barrier against the passage of carbon dioxide from one side of the barrier to the other, sufficient to prevent a significant increase in the partial pressure of carbon dioxide over a period of 42 days or more.

[0078] Unless otherwise specified, “substantially impermeable membrane” means a membrane that is substantially impermeable to carbon dioxide. As used herein, substantially impermeable to carbon dioxide means permeability to carbon dioxide of less than approximately 1.0 cc per square meter per day. However, in certain devices and methods, membranes may be further characterized by their permeability or impermeability to oxygen. For certain applications, membrane materials are substantially impermeable to carbon dioxide and provide a barrier against the introduction of carbon dioxide into blood, blood components, or blood collection kits consisting of multiple components. Such substantially impermeable membranes are generally used to prepare the outer receptors of this disclosure. Suitable substantially impermeable membranes may also be used to prepare tubing for connecting components of devices and kits. A substantially impermeable membrane may consist of a single layer or a laminated sheet or tube having two or more layers.

[0079] This disclosure also provides and includes gas-impermeable barrier bags that are substantially impermeable to oxygen. As used herein, substantially impermeable to oxygen means permeability to oxygen of less than about 1.0 cc per square meter per day. In certain embodiments, films suitable for use in the preparation of gas-impermeable barrier bags and other elements of this disclosure are materials characterized by a barrel value of less than about 0.140 barrels.

[0080] Materials and methods for preparing gas-impermeable barrier bags are known in the art. See, for example, U.S. Patent No. 7,041,800 issued by Gawryl et al., U.S. Patent No. 6,007,529 issued by Gustafsson et al., and U.S. Patent Application Publication No. 3013 / 0327677 by McDorman. Each of these is incorporated herein by reference in whole. Impermeable materials are used as prescribed in the art, and any suitable material may be used. In the case of molded polymers, additives are added as prescribed to enhance oxygen and carbon dioxide barrier properties. See, for example, U.S. Patent No. 4,837,047 issued by Sato et al. For example, U.S. Patent No. 7,431,995 issued by Smith et al. describes an oxygen and carbon dioxide impermeable acceptor consisting of layers of ethylene vinyl alcohol copolymer and modified ethylene vinyl acetate copolymer that are impermeable to oxygen and carbon dioxide intrusion. In another embodiment, the gas-impermeable barrier bag is impermeable to oxygen and carbon dioxide.

[0081] In certain embodiments, a film that is substantially impermeable to carbon dioxide, oxygen, or both carbon dioxide and oxygen may be a laminated film. In some embodiments, a laminated film that is substantially impermeable to carbon dioxide, oxygen, or both carbon dioxide and oxygen may be a laminated foil film. The film material may be a polymer or a multilayer structure, a combination of foil and polymer. In some embodiments, the laminated film may be a polyester film laminated with aluminum. Examples of suitable aluminum laminated films, also known as laminated foils, that are substantially impermeable to oxygen are known in the art. For example, Sugisawa's U.S. Patent No. 4,798,728 discloses aluminum laminated foils of nylon, polyethylene, polyester, polypropylene, and vinylidene chloride. Other laminated films are known in the art. For example, Chow et al.'s U.S. Patent No. 7,713,614 discloses a multilayer container comprising an ethylene-vinyl alcohol copolymer (EVOH) resin that is substantially impermeable to oxygen. In one embodiment, the gas-impermeable barrier bag may be a barrier bag constructed by sealing three or four sides by heat sealing. The bag is constructed in a multilayer structure containing a material that provides enhanced carbon dioxide and oxygen barrier properties. The bag is composed of a multilayer structure containing a material that provides enhanced carbon dioxide and oxygen barrier properties. Such a material may contain 0.01 cc / 100 in 2 Rollprint Clearfoil® V2 film, with a 24-hour oxygen permeability of 0.004cc / 100in. 2 Rollprint Clearfoil® X film has an oxygen permeability of 0.0008cc / 100in / 24 hours. 2One example is Clearfoil® Z film (Rollprint Packaging Products, Addison, IL) with a 24-hour oxygen permeability. Other manufacturers produce similar products with similar oxygen permeability, such as Renolit Solmed Wrapflex® film (American Renolit Corp., City of Commerce, CA). Examples of suitable aluminum laminated films, also known as laminated foils and substantially impermeable to oxygen, are available from Protective Packaging Corp. (Carrollton, TX).

[0082] Another approach applicable to the preparation of SICO materials is the production of multilayer graphite films by the mild 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 5:4843 (2014), which is incorporated herein by reference in its entirety. Nanoparticles for enhancing oxygen barrier properties are also known in the art, e.g., multilayer barrier laminates provided by Tera-Barrier (Tera-Barrier Films Pte, Ltd, The Aries, Singapore), described by Rick Lingle in Packaging Digest Magazine, August 12, 2014.

[0083] In embodiments of this disclosure, gas-impermeable barrier bags may be prepared from gas-impermeable plastics. 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).

[0084] The gas-impermeable barrier bags of this disclosure may be formed from one or more components prepared from a gas-impermeable material, including plastic or other durable, lightweight materials. In some embodiments, the housing may be formed from two or more materials. In one embodiment, the gas-impermeable barrier bag may be formed from a material for preparing a gas-impermeable housing and may be coated with a gas-impermeable material. In one embodiment, a rigid or flexible gas-impermeable barrier bag may be prepared from an injection-molded plastic. In embodiments of this disclosure, the plastic may be selected from polystyrene, polyvinyl chloride, or nylon. In one embodiment, the gas-impermeable barrier bag material 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), plastic materials, phenolics (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 gas-impermeable barrier bag may be polyethylene. In some embodiments, the polyethylene gas-impermeable barrier bag may contain one or more polyethylene components that are welded together. In certain embodiments, the outer acceptor is a multilayer film having a polyethylene outer layer, a polyester inner layer, and an aluminum oxide barrier layer dispersed between the inner and outer layers, for example, 0.0008 cc / 100 in 2It consists of Clearfoil® Z film (Rollprint Packaging Products, Addison, IL) with a 24-hour oxygen permeability.

[0085] This disclosure provides and includes the preparation of gas-impermeable barrier bags using heat-sealing, blow-molding, and injection-molding techniques. Suitable materials for preparing gas-impermeable barrier bags 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 preparing blow-molded and injection-molded gas-impermeable barrier bags are known in the art, for example, a multilayer structure consisting of a barrier layer of ethyl vinyl alcohol (EVOH) or ethyl vinyl acetate (EVA) located between two layers of polypropylene (PP), provided by Kortec (Kortec, Inc., Rowley, MA) and also described in U.S. Patent No. 5,906,285 issued to Slat. Additives that enhance the oxygen and CO2 barrier properties of polymers before molding, during their formulation, or during setting are known in the art. One example is multilayer polymer co-injection, which results in multilayer PET. Such barrier resins are typically incorporated in the preform stage as an inner layer with PET on both sides, creating the PET as the liquid contact layer and the outer layer. Suitable blow-molded or injection-molded gas-impermeable barrier bags, as provided below, are impermeable to oxygen. In certain embodiments, suitable heat-sealed, blow-molded, or injection-molded gas-impermeable barrier bags are substantially impermeable to both oxygen and carbon dioxide.

[0086] Adsorbent The present disclosure provides and includes an adsorbent that binds to oxygen, carbon dioxide, or both oxygen and carbon dioxide and can remove oxygen, carbon dioxide, or both oxygen and carbon dioxide from the environment. Unless otherwise specified, the term "adsorbent" refers to oxygen, carbon dioxide, or both oxygen and carbon dioxide adsorbents and scavengers. In certain aspects of the present disclosure, the carbon dioxide adsorbent includes calcium oxide. Other suitable carbon dioxide adsorbents include sodium hydroxide nanoparticles, calcium hydroxide and silica mixtures, calcium chloride, potassium hydroxide, perlite, activated carbon, zeolites, activated alumina, silica gel, and solid amines. In another aspect, the carbon dioxide adsorbent further includes an oxygen adsorbent.

[0087] As used herein, an "oxygen scavenger" or "oxygen adsorbent" is a material that irreversibly binds to O2 or combines with O2 under the conditions of use. As used herein, a "carbon dioxide scavenger" or "carbon dioxide adsorbent" is a material that irreversibly binds to CO2 or combines with CO2 under the conditions of use. The terms "oxygen adsorbent" or "carbon dioxide adsorbent" may be used interchangeably herein with "oxygen scavenger" or "carbon dioxide," respectively. In certain embodiments according to the present disclosure, the material can irreversibly bind to or combine with oxygen or carbon dioxide. In other embodiments, oxygen or carbon dioxide binds to the adsorbent material and can have a very slow release rate, k off and can be. In one aspect, oxygen or carbon dioxide can chemically react with some of the components of the material and be converted to another compound. Any material in which the off-rate of the bound oxygen is much less than the residence time of the blood can serve as an oxygen scavenger. Further, any material in which the off-rate of the bound carbon dioxide is much less than the residence time of the blood can serve as a carbon dioxide scavenger.

[0088] As used herein, the amount of adsorbent is at standard temperature and pressure (e.g., 0 °C (273.15 Kelvin) and 1.01×10 5The oxygen adsorbent and scavenger are provided to have a certain oxygen-binding capacity measured by volume (e.g., cubic centimeters (cc) or milliliters (ml)) at a pressure of Pa (100 kPa, 1 bar, 0.986 atm, 760 mmHg). In other embodiments, the oxygen adsorbent and scavenger can further bind to carbon dioxide and remove it from the environment. In certain embodiments, the adsorbent may be a mixture of a non-toxic inorganic and / or organic salt with oxygen, carbon dioxide, or divalent iron or other material highly reactive to oxygen and carbon dioxide. In certain embodiments, the oxygen adsorbent or scavenger is combined with a carbon dioxide adsorbent. In other embodiments, the presence or absence of carbon dioxide-binding capacity of the oxygen adsorbent is not required.

[0089] Suitable oxygen adsorbents or scavengers are known in the art. The suitable oxygen adsorbent according to this disclosure has a minimum oxygen adsorption rate of 0.44 ml / min. Adsorbents having a suitable adsorption profile bind to at least 45 ml of O2 within 60 minutes, 70 ml of O2 within 120 minutes, and 80 ml of O2 within 180 minutes. Suitable adsorbents may have both higher volume and binding rates.

[0090] Non-limiting examples of oxygen scavengers or adsorbents include iron powder and organic compounds. Examples of O2 adsorbents include cobalt, iron, and Schiff base chelates. Additional non-limiting examples of O2 adsorbents 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., each of which is incorporated herein by reference in whole. Oxygen adsorbent materials may be formed into or incorporated into fibers, microfibers, microspheres, fine particles, and foams.

[0091] In certain embodiments, suitable adsorbents include those available from Multisorb Technologies (Buffalo, NY), Sorbent Systems / Impak Corporation (Los Angeles, CA), or Mitsubishi Gas Chemical America (MGC) (New York, NY). Exemplary oxygen adsorbents include Multisorb Technologies StabilOx® packets, Sorbent Systems P / N SF100PK100 100 cc oxygen absorber, and Mitsubishi Gas Chemical America Ageless® SS-200 oxygen absorber. MGC also provides adsorbents suitable for the methods and devices of this disclosure. Such suitable oxygen adsorbents include MGC Ageless® and SS-200 oxygen absorber.

[0092] In aspects of this disclosure, the adsorbent may be an oxidizable organic polymer having a polymer backbone and a plurality of pendant groups. Examples of adsorbents having a polymer backbone include saturated hydrocarbons (<0.01% carbon-carbon double bonds). In some aspects, the backbone may contain ethylene or styrene monomers. In some aspects, the polymer backbone may be ethylene-based. In other aspects, the oxidizable organic compound may be ethylene / vinylcyclohexene copolymer (EVCH). Examples of additional substitution moieties and catalysts are provided in U.S. Patent Publication 2003 / 0183801 by Yang et al., which is incorporated herein by reference in its entirety. In additional aspects, the oxidizable organic polymer may also include a substituted hydrocarbon moiety. Examples of oxygen-scavenging polymers are described in International Patent Publication 99 / 48963 by Ching et al., which is incorporated herein by reference in its entirety. Oxygen-scavenging materials may include those provided 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, by reference, is incorporated herein by reference in whole.

[0093] When used herein, the adsorbents of this disclosure may be free or contained within a permeable enclosure, container, or package. In certain embodiments, the adsorbent is provided in one or more bags made of a material that is highly porous and intrinsically inresistant to gas transport. Examples of such materials include spun polyester film, perforated metal foil, and combinations thereof.

[0094] The disclosure further includes and provides adsorbents incorporated as one or more laminated layers of an outer article substantially impermeable to oxygen. Polymer adsorbents, such as those described above, may be laminated onto a sheet used to prepare an outer acceptor using methods known in the art, including soft contact lamination, thermal lamination, or solvent lamination.

[0095] This disclosure further includes and provides adsorbents formed inside the pores of porous microglass fibers or encapsulated in other inert materials. Encapsulation of transition metal complexes within the pores of porous materials can be achieved by using ship-in-a-bottle synthesis, in which the final molecule is prepared inside the pores by reacting smaller precursors. Examples of such encapsulated adsorbents are known in the art, as described, for example, by 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), and the whole thereof is incorporated herein by reference. In some embodiments, porous glass fibers may be manufactured as provided in U.S. Patent No. 4,748,121 issued to Beaver, the whole thereof is incorporated herein by reference. In other embodiments, adsorbents may be formed as porous sheet products using papermaking / nonwoven wet laying equipment. A sheet having an O2-capturing compound may be as described in U.S. Patent No. 4,769,175 issued to Inoue, which is incorporated herein by reference in whole, and which may be formed and then encapsulated in a silicone film.

[0096] As used herein, “carbon dioxide scavenger” or “carbon dioxide adsorbent” is a material that binds to or combines with carbon dioxide under the conditions of use. The term “carbon dioxide adsorbent” may be used interchangeably with “carbon dioxide scavenger” herein. In certain embodiments, the carbon dioxide adsorbent may be nonreactive or minimally reactive with oxygen. In other embodiments, the oxygen adsorbent may exhibit a secondary function of carbon dioxide scavenging. Examples of carbon dioxide scavengers include metal oxides and metal hydroxides. Metal oxides react with water to produce metal hydroxides. Metal hydroxides react with carbon dioxide to form water and metal carbonates. In certain embodiments of this disclosure, the material may irreversibly bind to or bind to CO2. In embodiments of this disclosure, the material may bind to CO2 with a higher affinity than hemoglobin. In other embodiments, the adsorbent material may bind to CO2 with a high affinity such that carbon dioxide present in the blood or RBC cytoplasm is released and absorbed by the adsorbent. In other embodiments, CO2 binds to the adsorbent material and has a very slow release rate, k off It has the following properties. In one embodiment, carbon dioxide can chemically react with some components of the material and be converted into another compound.

[0097] Carbon dioxide scavengers are known in the art. In certain embodiments of this disclosure, the carbon dioxide scavenger may be calcium oxide. The reaction of calcium oxide with water produces calcium hydroxide, which can react with carbon dioxide to form calcium carbonate and water. In certain embodiments of this disclosure, the water for the production of calcium hydroxide is obtained by diffusion through an oxygen-permeable container inside a blood-derived water vapor. In another embodiment, the water may be provided by the environment through an external receptor that is substantially impermeable to oxygen. In yet another embodiment, the water may be contained in an external receptor of a carbon dioxide-permeable container for storing blood sealed in a gas-impermeable barrier bag.

[0098] Non-limiting examples of CO2 scavengers include oxygen scavengers and carbon dioxide scavengers provided by Multisorb Technologies (Buffalo, NY). Oxygen scavengers may exhibit a secondary function of carbon dioxide scavenging.

[0099] In the embodiments of this disclosure, the O2 depletion medium and the CO2 depletion medium can be blended in a desired ratio to achieve the desired result.

[0100] This disclosure includes and provides a scavenger or adsorbent contained within a bag. As used herein, “bag” is any enclosure that encapsulates and contains an oxygen adsorbent, a carbon dioxide adsorbent, or a combination of oxygen and carbon dioxide adsorbents. The bag according to this disclosure is contained within an overlap material that is permeable to both oxygen and carbon dioxide. In certain embodiments, the overlap material may be a combination of two or more materials, at least one of which is permeable to oxygen and carbon dioxide. Suitable overlap materials have a known biocompatibility profile or meet the requirements of the International Organization for Standardization (ISO) 10993.

[0101] The bag is sealed so that the contents of the adsorbent are completely contained within the overlapping material and the adsorbent does not leak or otherwise escape from the overlapping packaging. The bag can take any shape, but is typically rectangular or square. In one embodiment, the bag is approximately 50 x 60 mm. In one embodiment, the oxygen adsorbent binds to 30 cc of oxygen per bag at standard temperature and pressure (STP). In one embodiment, the oxygen adsorbent binds to 60 cc of oxygen per bag at STP. In one embodiment, the oxygen adsorbent binds to 120 cc of oxygen per bag at STP. In one embodiment, the oxygen adsorbent binds to 30-120 cc of oxygen per bag at STP. In one embodiment, the oxygen adsorbent binds to 30-120 cc of oxygen per bag at STP. In one embodiment, the oxygen adsorbent binds to 50-200 cc of oxygen per bag at STP. In certain embodiments of this disclosure, the bag has a total oxygen adsorption capacity of 100 cc O2 in the STP. In certain other embodiments of this disclosure, the bag has a total oxygen absorption capacity of at least 200 cc O2 in the STP.

[0102] In aspects of this disclosure, the oxygen adsorbent may be provided in one or more bags. In another aspect, the oxygen adsorbent may be provided in a single larger bag. In yet another aspect, the oxygen adsorbent may be provided in two bags dispersed in the headspace between a DEHP-free carbon dioxide permeable bag and a gas-impermeable barrier bag. In yet another aspect, the oxygen adsorbent may be provided in four bags dispersed in the headspace between a DEHP-free carbon dioxide permeable bag and a gas-impermeable barrier bag. In aspects of this disclosure, a carbon dioxide permeable container for storing blood sealed in a gas-impermeable barrier bag may comprise 2 to 20 adsorbent packages.

[0103] In some embodiments of this disclosure, a carbon dioxide permeable container for storing blood is enclosed within a gas-impermeable barrier bag and contains 1 to 50 grams of adsorbent contained in one or more bags. In one embodiment, a carbon dioxide permeable container for storing blood enclosed within a gas-impermeable barrier bag contains 1 to 100 g of adsorbent contained in one or more bags. In another embodiment, a carbon dioxide permeable container for storing blood enclosed within a gas-impermeable barrier bag contains 25 to 75 grams of adsorbent contained in one or more bags. In a further embodiment, a carbon dioxide permeable container for storing blood enclosed within a gas-impermeable barrier bag contains about 25 grams of adsorbent. In yet another embodiment, a carbon dioxide permeable container for storing blood enclosed within a gas-impermeable barrier bag contains about 50 g of adsorbent. In one embodiment, a carbon dioxide permeable container for storing blood enclosed within a gas-impermeable barrier bag contains about 35 or 45 grams of adsorbent contained in one or more bags. In one embodiment, a carbon dioxide-permeable container for storing blood sealed in a gas-impermeable barrier bag comprises about 10 or 15 grams of adsorbent contained in one or more bags. The bags may be square, rectangular, circular, or oval in shape and have an outer circumference of 40 to 150 mm.

[0104] The bags according to this disclosure may further include a carbon dioxide adsorbent. In one embodiment, the oxygen adsorbent also provides carbon dioxide adsorption. In one embodiment, the oxygen adsorbent binds to 30 cc of carbon dioxide in the STP. In another embodiment, the oxygen adsorbent binds to at least 170 cc of oxygen and at least 30 cc of carbon dioxide, and both gases are measured in the STP.

[0105] Additive solution / composition This disclosure provides and includes compositions comprising an additive solution and methods for adding the additive solution to a blood product. In another embodiment, the composition and method include adding the additive solution to red blood cells. In another embodiment, the composition and method include adding the additive solution to platelets. In another embodiment, the composition and method include adding the additive solution to whole blood. In another embodiment, the composition and method include adding the additive solution to a filled RBC to form a suspension.

[0106] In certain embodiments, the additive solution may be selected, either alone or in combination, from the group consisting of additive solutions (AS)-1, AS-3 (Nutricel®), AS-5, AS7 (SOLX), SAGM, PAGG-SM, PAGG-GM, MAP, ESOL, EAS61, OFAS1, and OFAS3. See Table 2. [Table 2-1] [Table 2-2]

[0107] In a further embodiment, the additive solution may have a pH of 5.0 to 7.0. In another embodiment, the additive solution has a pH of 7.0 to 9.0. In yet another embodiment, the additive may contain antioxidants. In some embodiments of this disclosure, the antioxidant may be quercetin, alpha-tocopherol, ascorbic acid, or an enzyme inhibitor for oxidase. In yet another embodiment, the additive solution further comprises quercetin. In yet another embodiment, the additive solution further comprises alpha-tocopherol. In yet another embodiment, the additive solution further comprises ascorbic acid. In yet another embodiment, the additive solution further comprises an enzyme inhibitor for oxidase. In yet another embodiment, the additive solution comprises N-acetylcysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid (vitamin C).

[0108] In aspects of the present disclosure, the additive solution is selected from the group consisting of AS7, AS7G-NAC, or AS7-NAC having a gluconate (AS7GG-NAC), as provided in Table 3. In aspects of the present disclosure, the additive solution comprises sodium bicarbonate (NaHCO3), disodium phosphate (Na2HPO4), adenine, guanosine, glucose, mannitol, N-acetylcysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid (vitamin C). In another embodiment, the additive solution comprises 10-60 mM sodium bicarbonate (NaHCO3), 10-20 mM disodium phosphate (Na2HPO4), 0-5 mM adenine, 0-5 mM guanosine, 50-100 mM glucose, 40-80 mM mannitol, 0-1 mM N-acetylcysteine, 0-1 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, and 0-1 mM l-ascorbic acid. In certain embodiments, the additive solution comprises 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, and 0.25 mM l-ascorbic acid. In certain embodiments, the additive solution comprises 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, 0.25 mM l-ascorbic acid, and 4 mM gluconate. [Table 3]

[0109] In another aspect of the present disclosure, the additive solution is selected from the group consisting of Erythrosol-5, Erythrosol-5G (Erythrosol-5GG) having 5 mM gluconate, or Erythrosol-5G without gluconate, as provided in Table 4. In another aspect, the additive solution further comprises N-acetylcysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid (vitamin C). In another aspect of the present disclosure, the additive solution comprises 10–40 mM Na2HPO4, 10–40 mM sodium citrate, 0.5–3 mM adenine, 30–60 mM glucose, and 80–130 mM mannitol. In another embodiment, the additive solution contains 10-40 mM Na2HPO4, 10-40 mM sodium citrate, 0.5-3 mM adenine, 30-60 mM glucose, 80-130 mM mannitol, and 0.5-3 mM guanosine. In yet another embodiment, the additive solution also contains 2-8 mM gluconate. In yet another embodiment, the additive solution has a pH of 7.5-9. In yet another embodiment, the additive solution has a pH of at least 7.0, 7.2, 7.4, 7.5, 7.6, 7.8, 8.0, 8.2, 8.4, 8.5, 8.6, and 8.8. In yet another embodiment, the additive solution has a pH of 7.0-7.5, 7.5-8, 8-8.2, 8-8.4, 8-8.6, 8-8.8, and 8.4-9.

[0110] In certain embodiments of this disclosure, the additive solution comprises 20 mM Na2HPO4, 25 mM sodium citrate, 1.5 mM adenine, 45.5 mM glucose, 110 mM mannitol, and a pH of 8.8. In another embodiment, the additive solution comprises 20 mM Na2HPO4, 25 mM sodium citrate, 1.5 mM adenine, 45.5 mM glucose, 110 mM mannitol, 5 mM gluconate, and a pH of 8.8. [Table 4]

[0111] This disclosure provides and includes a composition comprising a blood product selected from the group consisting of whole blood, platelets, and leukocytes, and an additive solution comprising sodium bicarbonate (NaHCO3), sodium phosphate dibasate (Na2HPO4), adenine, guanosine, glucose, mannitol, N-acetyl-cysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid (vitamin C).

[0112] The disclosure further provides and includes a composition comprising a blood product selected from the group consisting of whole blood, platelets, and leukocytes having a pCO2 of less than 125 mmHg, and an additive solution comprising a certain concentration of disodium phosphate (Na2HPO4), sodium citrate, adenine, glucose, and mannitol.

[0113] This disclosure provides and includes a preserved blood product comprising a pCO2 of less than 125 mmHg, a SO2% of more than 20%, and an additive solution comprising 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C). In one embodiment, the preserved blood composition further comprises an ATP concentration of at least 4 μmol / g Hb and a CO2 concentration of less than 60 mmHg after 42 days of storage. In another embodiment, the preserved blood composition further comprises a 2,3-DPG concentration of at least 6 μmol / g Hb after 21 days of storage. In one embodiment, the stored blood composition further contains a 2,3-DPG concentration of at least 4 μmol / gHb after storage for 42 days.

[0114] In another embodiment, the blood product has an additive solution comprising pCO2 less than 100 mmHg, SO2% greater than 20%, 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C). In one embodiment, the stored blood composition further contains an ATP concentration of at least 4 μmol / gHb, a pCO2 of less than 50 mmHg, and an SO2% of less than 50% after 42 days of storage, compared to red blood cells stored in a conventional method with a 3 μmol / gHb, 92 mmHg pCO2, and 89% SO2% after 42 days of storage. In another embodiment, the stored blood composition further contains a 2,3-DPG concentration of at least 6 μmol / gHb after 21 days of storage. In yet another embodiment, the stored blood composition further contains a 2,3-DPG concentration of at least 4 μmol / gHb after 42 days of storage, with a pCO2 of less than 50 mmHg, compared to red blood cells stored in a conventional method having a 2,3-DPG concentration of 0.5 μmol / gHb and a pCO2 of 92 mmHg on the 42nd day of storage.

[0115] In another embodiment, the blood product has an additive solution comprising pCO2 less than 75 mmHg, SO2% greater than 20%, 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C).

[0116] In another embodiment, the blood product has a pCO2 of less than 25 mmHg, SO2% greater than 20%, and an additive solution comprising 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C).

[0117] In another embodiment, the blood product has an additive solution comprising pCO2 less than 125 mmHg, 5-30% SO2%, 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C).

[0118] In another embodiment, the blood product has a pCO2 of less than 100 mmHg, 5-30% SO2%, and an additive solution comprising 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C).

[0119] In another embodiment, the blood product has an additive solution comprising pCO2 less than 75 mmHg, 5-30% SO2%, 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C).

[0120] In another embodiment, the blood product has an additive solution comprising pCO2 less than 50 mmHg, 5-30% SO2%, 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C).

[0121] In another embodiment, the blood product has a pCO2 of less than 25 mmHg, 5-30% SO2%, and an additive solution comprising 40 mM sodium bicarbonate (NaHCO3), 12 mM disodium phosphate (Na2HPO4), 2 mM adenine, 1.4 mM guanosine, 80 mM glucose, 55 mM mannitol, 0.5 mM N-acetylcysteine, 0.5 mM 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and 0.25 mM l-ascorbic acid (vitamin C).

[0122] In yet another embodiment, the blood product has a pCO2 of less than 50 mmHg, 5-30% SO2%, and an additive solution provided in Table 3 or Table 4.

[0123] This disclosure provides and includes the following embodiments:

[0124] Embodiment 1. A method for preserving blood products, comprising: obtaining a blood product having more than 30% SO2%; preparing a storable blood product by adding an additive solution to the blood product; and preserving the storable blood product at 25°C and about 1 atm, with at least 0.62 cubic centimeters (cm²) per square centimeter. 3 / cm 2 A method comprising storing the blood in a di-2-ethylhexyl phthalate-free (DEHP-free) blood-compatible (BC) carbon dioxide-permeable bag having gas permeability to carbon dioxide.

[0125] Embodiment 2. The method according to Embodiment 1, wherein the storable blood product is not deoxygenated before storage.

[0126] Embodiment 3. The method according to any one of Embodiments 1 or 2, wherein the storable blood product is not deoxygenated during storage.

[0127] Embodiment 4. The method according to Embodiment 2, comprising depleting the oxygen from the storable blood product during storage.

[0128] Embodiment 5. The BC carbon dioxide permeable bag is 0.3 cm cm 3 / cm 2 The method according to any one of Embodiments 1 to 4, having an oxygen permeability of less than 1.

[0129] Embodiment 6. The method according to any one of Embodiments 1 to 5, wherein the BC carbon dioxide permeable bag does not contain di(2-ethylhexyl) terephthalate (DEHT).

[0130] Embodiment 7. The method according to any one of Embodiments 1 to 6, wherein the BC carbon dioxide permeable bag comprises 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or butyryl trihexyl citrate (BTHC) as a plasticizer.

[0131] Embodiment 8. The method according to any one of Embodiments 1 to 7, wherein the BC carbon dioxide permeable bag is enclosed in an outer bag that is impermeable to oxygen and carbon dioxide.

[0132] Embodiment 9. The method according to any one of Embodiments 1 to 8, wherein the outer bag further encloses a carbon dioxide adsorbent placed between the BC carbon dioxide permeable bag and the outer bag.

[0133] Embodiment 10. The method according to any one of Embodiments 1 to 9, wherein the 2,3-DPG level increases by at least 10% in the storable blood product during storage compared to the 2,3-DPG level of the blood product stored by a conventional method.

[0134] Embodiment 11. The method according to any one of Embodiments 1 to 10, wherein the 2,3-DPG level increases by at least 15% in the storable blood product during storage compared to the 2,3-DPG level of a blood product stored in a conventional manner.

[0135] Embodiment 12. The method according to any one of Embodiments 1 to 11, wherein the ATP level increases in the storable blood product during storage compared to the ATP level of a blood product stored in a conventional manner.

[0136] Embodiment 13. The method according to Embodiment 12, wherein the ATP level in the storable blood product increases by at least 10% during storage compared to the ATP level of a blood product stored in a conventional manner.

[0137] Embodiment 14. The method according to any one of Embodiments 1 to 13, wherein the additive solution has a pH of 7.0 to 8.5.

[0138] Embodiment 15. The method according to any one of Embodiments 1 to 14, wherein the additive solution has a pH of at least 8.5.

[0139] Embodiment 16. The method according to Embodiment 9, wherein the carbon dioxide adsorbent further comprises an oxygen adsorbent.

[0140] Embodiment 17. The BC carbon dioxide permeable bag is heated at 25°C for 24 hours (hrs.) to at least 0.05 centimeters. 3 (cm 3 ) / cm 2 The method according to any one of Embodiments 1 to 16, having gas permeability for oxygen at / atm over 24 hours (hrs.).

[0141] Embodiment 18. The BC carbon dioxide permeable bag is subjected to a filtration of at least 0.15 cm at 25°C for 24 hours. 3 / cm 2 The method according to Embodiment 17, which has gas permeability for oxygen at / atm.

[0142] Embodiment 19. The BC carbon dioxide permeable bag was subjected to approximately 0.22 cm of permeability at 25°C for 24 hours. 3 / cm 2 The method according to Embodiment 18, which has gas permeability with respect to oxygen at atmospheric pressure.

[0143] Embodiment 20. The method according to any one of Embodiments 1 to 19, wherein the blood product contains more than 15% saturated oxygen (SO2) during storage for up to 42 days.

[0144] Embodiment 21. The method according to Embodiment 20, wherein the blood product contains more than 20% SO2 during storage for up to 42 days.

[0145] Embodiment 22. The method according to any one of Embodiments 1 to 21, wherein the blood product contains less than 125 mmHg of pCO2 during storage for up to 42 days.

[0146] Embodiment 23. The method according to Embodiment 22, wherein the blood product contains less than 100 mmHg of pCO2 during the storage period of up to 42 days.

[0147] Embodiment 24. The method according to Embodiment 23, wherein the blood product contains less than 75 mmHg of pCO2 during the storage period of up to 42 days.

[0148] Embodiment 25. The method according to Embodiment 24, wherein the blood product contains less than 50 mmHg of pCO2 during the storage period of up to 42 days.

[0149] Embodiment 26. The method according to any one of Embodiments 1 to 25, wherein the storage period is less than 42 days.

[0150] Embodiment 27. The method according to any one of Embodiments 10, 11, 12, or 13, wherein the storage period is less than 28 days.

[0151] Embodiment 28. The method according to any one of Embodiments 10, 11, 12, or 13, wherein the storage period is less than 21 days.

[0152] Embodiment 29. The method according to any one of Embodiments 10, 11, 12, or 13, wherein the storage period is less than 14 days.

[0153] Embodiment 30. The method according to any one of Embodiments 10, 11, 12, or 13, wherein the storage period is less than 7 days.

[0154] Embodiment 31. The method according to any one of Embodiments 1 to 30, wherein the additive solution is selected from the group consisting of AS7, AS7G-NAC, AS7G-NAC (AS7GG-NAC) having 4 mM gluconate, AS3 having gluconate, erythrosol-5, erythrosol-5G, and erythrosol-5G (erythrosol-5GG) having 5 mM gluconate.

[0155] Embodiment 32. The method according to any one of Embodiments 1 to 31, wherein the blood product contains 0.8% or less hemolysis after 42 days of storage.

[0156] Embodiment 33. The method according to any one of Embodiments 1 to 32, wherein the blood product comprises whole blood, platelets, white blood cells, or red blood cells.

[0157] Embodiment 34. The method according to any one of Embodiments 1 to 33, wherein the BC carbon dioxide permeable bag comprises polyvinyl chloride (PVC) or polyolefin, silicone, polyvinylidene fluoride (PVDF), polysulfone (PS), polypropylene (PP), or polyurethane (PU).

[0158] Embodiment 35. A container for storing blood comprising a DEHP-free carbon dioxide permeable and oxygen-impermeable material, wherein the material has a capacity of 0.05 cm at 1 atm at 25°C. 3 / cm 2 Gas permeability of less than less oxygen, and at least 0.62 cubic centimeters per square centimeter at 1 atm at 25°C (cm³). 3 / cm 2 A container that has gas permeability to carbon dioxide.

[0159] Embodiment 36. The container according to Embodiment 35, wherein the material is selected from the group consisting of polyvinyl chloride (PVC), polyolefin, silicone, polyvinylidene fluoride (PVDF), polysulfone (PS), polypropylene (PP), or polyurethane.

[0160] Embodiment 37. The method according to any one of Embodiments 35 to 36, wherein the material comprises 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or butyryl trihexyl citrate (BTHC) as a plasticizer.

[0161] Embodiment 38. A method for handling blood products, The blood product is to be given an additive solution, and the blood product is to be heated at 25°C and approximately 1 atm for at least 0.62 cm 3 / cm 2 A method comprising storing a blood product in a DEHP-free blood-compatible (BC) carbon dioxide-permeable bag having gas permeability to carbon dioxide, wherein the storage is for at least 7 days, and the oxygen level of the blood product during the 7-day storage is such that it is lower than or approximately the same as the oxygen level of the blood product on day 1 of storage.

[0162] Embodiment 39. The method according to Embodiment 38, wherein the blood product comprises whole blood, platelets, white blood cells, or red blood cells.

[0163] Embodiment 40. The method according to any one of Embodiments 38 to 39, wherein the BC carbon dioxide permeable bag comprises PVC or polyolefin.

[0164] Embodiment 41. The method according to Embodiment 40, wherein the BC carbon dioxide permeable bag contains 20-70% by weight / weight of 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or butyryl trihexyl citrate (BTHC) in the PVC as a plasticizer.

[0165] Embodiment 42. The method according to Embodiment 41, wherein the plasticizer is 20-45% by weight of BTHC in PVC.

[0166] Embodiment 43. The BC carbon dioxide permeable bag is at least 2.0 cm at 25°C and about 1 atm. 3 / cm 2 The method according to any one of embodiments 38 to 42, having gas permeability for carbon dioxide.

[0167] Embodiment 44. The method according to any one of embodiments 38 to 43, wherein the BC carbon dioxide permeable bag further comprises an outer bag that is impermeable to oxygen and carbon dioxide.

[0168] Embodiment 45. The method according to any one of Embodiments 38 to 44, further comprising a carbon dioxide adsorbent between the BC carbon dioxide permeable bag and the outer bag.

[0169] Embodiment 46. The method according to Embodiment 45, wherein the carbon dioxide adsorbent further comprises an oxygen adsorbent.

[0170] Embodiment 47. The BC carbon dioxide permeable bag is subjected to a filtration of at least 0.05 cm at 25°C for 24 hours. 3 / cm2 The method according to any one of embodiments 38 to 46, having gas permeability for oxygen at / atm4.

[0171] Embodiment 48. The BC carbon dioxide permeable bag is subjected to a filtration of at least 0.15 cm at 25°C for 24 hours. 3 / cm 2 The method according to Embodiment 47, which has gas permeability for oxygen at / atm4.

[0172] Embodiment 49. The BC carbon dioxide permeable bag is subjected to approximately 0.2 cm of vaporization at 25°C for 24 hours. 3 / cm 2 The method according to Embodiment 48, having gas permeability for oxygen at atmospheric pressure 4.

[0173] Embodiment 50. The method according to any one of Embodiments 38 to 49, wherein the blood product contains more than 15% SO2 after storage for at least 7 days.

[0174] Embodiment 51. The method according to Embodiment 50, wherein the blood product contains more than 20% SO2 after storage for at least 7 days.

[0175] Embodiment 52. The method according to any one of Embodiments 38 to 51, wherein the blood product contains a pCO2 of less than 125 mmHg.

[0176] Embodiment 53. The method according to Embodiment 52, wherein the blood product contains a pCO2 of less than 100 mmHg.

[0177] Embodiment 54. The method according to Embodiment 53, wherein the blood product contains a pCO2 of less than 75 mmHg.

[0178] Embodiment 55. The method according to Embodiment 54, wherein the blood product contains a pCO2 of less than 50 mmHg.

[0179] Embodiment 56. The method according to any one of Embodiments 38 to 55, wherein the storage is for at least 14 days.

[0180] Embodiment 57. The method according to Embodiment 56, wherein the storage is for at least 21 days.

[0181] Embodiment 58. The method according to Embodiment 57, wherein the storage is for at least 28 days.

[0182] Embodiment 59. The method according to Embodiment 58, wherein the storage is for at least 42 days.

[0183] Embodiment 60. The method according to Embodiment 59, wherein the storage is for at least 56 days.

[0184] Embodiment 61. The method according to any one of Embodiments 38 to 60, wherein the additive solution is selected from the group consisting of additive solution 7 (AS7), AS7G-NAC, AS7G-NAC (AS7GG-NAC) having 4 mM gluconate, Erythrosol-5, Erythrosol-5G, and Erythrosol-5G having 5 mM gluconate.

[0185] Embodiment 62. The method according to any one of Embodiments 38 to 61, wherein the blood product contains 0.8% or less hemolysis.

[0186] Embodiment 63. The method according to any one of Embodiments 38 to 62, wherein the blood product comprises whole blood, platelets, white blood cells, or red blood cells.

[0187] Embodiment 64. A method for preserving storable blood, At 25℃ and approximately 1 atm, at least 0.62 cm 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 A method comprising: placing a blood product in a storage container comprising a DEHP-free blood-compatible (BC) material having the following oxygen permeability and a carbon dioxide adsorbent; and storing the container containing the storable blood for a period of time to prepare the stored blood.

[0188] Embodiment 65. The method according to Embodiment 64, wherein the storable blood comprises whole blood, platelets, white blood cells, or red blood cells.

[0189] Embodiment 66. The method according to any one of Embodiments 64 to 65, wherein the storable blood contains 0.8% or less hemolysis after 42 days of storage.

[0190] Embodiment 67. The method according to any one of Embodiments 64 to 66, wherein the blood contains 0.5% or less hemolysis after storage for 42 days.

[0191] Embodiment 68. The method according to Embodiment 66, wherein the blood contains 0.5% or less hemolysis after storage for 56 days.

[0192] Embodiment 69. The method according to Embodiment 66, wherein the blood contains 0.4% or less hemolysis after storage for 56 days.

[0193] Embodiment 70. The method according to any one of Embodiments 64 to 69, wherein the 2,3-DPG level increases in the blood product on the 7th, 21st, 28th, 35th, 42nd, or 56th day of storage, compared to the 2,3-DPG level of the blood product stored in a conventional method.

[0194] Embodiment 71. The method according to Embodiment 70, wherein the 2,3-DPG level is increased by 10, 20, 30, 40, 50, 60, 70, or 80%.

[0195] Embodiment 72. The method according to any one of Embodiments 64 to 71, wherein the 2,3-DPG level increases in the blood product over a maximum of 21 days of storage compared to the 2,3-DPG level of the blood product stored in a conventional method.

[0196] Embodiment 73. The method according to any one of Embodiments 64 to 72, wherein the 2,3-DPG level increases in the blood product over a maximum of 28 days of storage compared to the 2,3-DPG level of the blood product stored in a conventional method.

[0197] Embodiment 74. The method according to any one of Embodiments 64 to 73, wherein the 2,3-DPG level increases in the blood product over a maximum of 35 days of storage compared to the 2,3-DPG level of the blood product stored in a conventional method.

[0198] Embodiment 75. The method according to any one of Embodiments 64 to 74, wherein the 2,3-DPG level increases in the blood product for up to 42 days of storage compared to the 2,3-DPG level of the blood product stored in a conventional method.

[0199] Embodiment 76. The method according to any one of Embodiments 64 to 75, wherein the 2,3-DPG level increases in the blood product over a maximum of 56 days of storage compared to the 2,3-DPG level of the blood product stored in a conventional method.

[0200] Embodiment 77. The method according to any one of Embodiments 64 to 76, wherein the ATP level is increased compared to the ATP level of a blood product stored in a conventional manner.

[0201] Embodiment 78. The method according to any one of Embodiments 64 to 77, wherein the ATP level increases after 21 days of storage compared to the ATP level of a blood product stored in a conventional manner.

[0202] Embodiment 79. The method according to any one of Embodiments 64 to 78, wherein the ATP level increases after 28 days of storage compared to the ATP level of a blood product stored in a conventional manner.

[0203] Embodiment 80. The method according to any one of Embodiments 64 to 79, wherein the ATP level increases after 35 days of storage compared to the ATP level of a blood product stored in a conventional manner.

[0204] Embodiment 81. The method according to any one of Embodiments 64 to 80, wherein the ATP level increases after 42 days of storage compared to the ATP level of a blood product stored in a conventional manner.

[0205] Embodiment 82. The method according to any one of Embodiments 64 to 81, wherein the ATP level increases after 56 days of storage compared to the ATP level of a blood product stored in a conventional manner.

[0206] Embodiment 83. The method according to any one of Embodiments 64 to 82, wherein the BC material comprises 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or butyryl trihexyl citrate BTHC as a plasticizer.

[0207] Embodiment 84. The method according to Embodiment 83, wherein the plasticizer is 20-40%, 25-45%, 20-70%, and 40-70% by weight in the PVC.

[0208] Embodiment 85. The method according to any one of Embodiments 64 to 84, wherein the storage container further comprises an oxygen adsorbent between the BC material and the outer bag.

[0209] Embodiment 86. The method according to any one of Embodiments 64 to 85, further comprising adding an additive solution to the blood product, wherein the method is selected from the group consisting of AS7, AS7G-NAC, AS7G-NAC (AS7GG-NAC) having 4 mM gluconate, Erythrosol-5, Erythrosol-5G, and Erythrosol-5G containing 5 mM gluconate.

[0210] Embodiment 87. The method according to any one of Embodiments 64 to 86, wherein the BC material comprises polyvinyl chloride (PVC) or polyolefin.

[0211] Embodiment 88. The method according to any one of Embodiments 64 to 87, wherein the blood product contains more than 10% SO2 on the 1st, 7th, 14th, 21st, 42nd, or 56th day of storage.

[0212] Embodiment 89. The method according to Embodiment 61, wherein the blood product contains more than 20% SO2.

[0213] Embodiment 90. The BC material is at least 2 cm at 25°C and about 1 atm. 3 / cm 2 The method according to any one of embodiments 64 to 89, having permeability to carbon dioxide.

[0214] Embodiment 91. The method according to any one of Embodiments 64 to 90, wherein the storage container further comprises an oxygen adsorbent between the BC material and the outer bag.

[0215] Embodiment 92. A method for preserving red blood cells, wherein the cells are stored at 25°C and about 1 atm for at least 0.62 cm³. 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 A method comprising: placing red blood cells in a storage container having an outer oxygen and carbon dioxide impermeable container, which contains a permeable, inwardly collapsible container made of the following oxygen-permeable material, and an outer oxygen and carbon dioxide impermeable container, in which a carbon dioxide adsorbent, an oxygen adsorbent, or an oxygen and carbon dioxide adsorbent is sealed between the inner bag and the outer bag; and storing the container containing the red blood cells for at least 7 days to prepare a stored blood product.

[0216] Embodiment 93. The method according to Embodiment 92, wherein the storage temperature is 4°C.

[0217] Embodiment 94. A method for maintaining the level of 2,3-DPG in a blood product, wherein the level is at least 0.62 cm at 25°C and about 1 atm. 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2A method comprising: placing a blood product containing at least 10% oxygen saturation in a storage container comprising an outer oxygen and carbon dioxide impermeable container, which contains a blood-compatible (BC) material having the following oxygen permeability, with a carbon dioxide adsorbent sealed between the inner bag and the outer bag; and storing the container containing the blood product, wherein the level of 2,3-DPG increases over a maximum of 14 days of storage compared to the level of 2,3-DPG in blood products stored in a conventional method.

[0218] Embodiment 95. The method according to Embodiment 94, wherein the 2,3-DPG level increases for up to 21 days of storage compared to the level of 2,3-DPG in blood products stored in a conventional manner.

[0219] Embodiment 96. The method according to Embodiment 94, wherein the BC material comprises PVC or polyolefin.

[0220] Embodiment 97. The method according to Embodiment 94, wherein the BC material comprises a DINCH or BTHC plasticizer.

[0221] Embodiment 98. A method for maintaining the level of ATP in a blood product, wherein at 25°C and about 1 atm, the ATP level is at least 0.62 cm³. 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 A method comprising: placing a blood product containing at least 10% oxygen saturation in a storage container having an outer oxygen and carbon dioxide impermeable container, which contains a blood-compatible (BC) material having the following oxygen permeability, and a carbon dioxide adsorbent sealed between the inner bag and the outer bag; and storing the container containing the blood product, wherein the ATP level increases after 42 days of storage compared to the ATP level of a blood product stored in a conventional method.

[0222] Embodiment 99. The method according to Embodiment 98, wherein the ATP is increased by at least 10% compared to the level of ATP in a blood product stored in a conventional manner.

[0223] Embodiment 100. The method according to Embodiment 98, wherein the ATP is increased by at least 20% compared to the level of ATP in a blood product stored in a conventional manner.

[0224] Embodiment 101. The method according to Embodiment 98, wherein the 2,3-DPG level increases for up to 21 days of storage compared to the level of 2,3-DPG in blood products stored in a conventional manner.

[0225] Embodiment 102. The method according to Embodiment 101, wherein the 2,3-DPG is increased by at least 10% compared to the semantically preserved blood product.

[0226] Embodiment 103. The method according to Embodiment 98, wherein the BC material comprises PVC or polyolefin.

[0227] Embodiment 104. The method according to Embodiment 98, wherein the BC material comprises a DINCH or BTHC plasticizer.

[0228] Embodiment 105. A composition comprising a blood product selected from the group consisting of whole blood, platelets, and leukocytes, and an additive solution containing sodium bicarbonate (NaHCO3), sodium phosphate dibasate (Na2HPO4), adenine, guanosine, glucose, mannitol, N-acetyl-cysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid (vitamin C).

[0229] Embodiment 106. The composition according to Embodiment 105, further comprising a gluconate.

[0230] Embodiment 107. The composition according to Embodiment 105, wherein the concentration of sodium bicarbonate is 10 to 60 millimoles (mM).

[0231] Embodiment 108. The composition according to Embodiment 105, wherein the concentration of disodium phosphate (Na2HPO4) is 10 to 20 mM.

[0232] Embodiment 109. The composition according to Embodiment 105, wherein the concentration of gluconate is 0 to 10 mM.

[0233] Embodiment 110. The composition according to Embodiment 105, wherein the concentration of adenine is 0 to 5 mM.

[0234] Embodiment 111. The composition according to Embodiment 105, wherein the concentration of guanosine is 0 to 5 mM.

[0235] Embodiment 112. The composition according to Embodiment 105, wherein the concentration of glucose is 50 to 100 mM.

[0236] Embodiment 113. The composition according to Embodiment 105, wherein the concentration of mannitol is 40 to 80 mM.

[0237] [[ID=!]] Embodiment 114. The composition according to Embodiment 105, wherein the concentration of N-acetyl-cysteine is 0 to 1 mM.

[0238] Embodiment 115. The composition according to Embodiment 105, wherein the concentration of Trolox is 0 to 1 mM.

[0239] Embodiment 116. The composition according to Embodiment 105, wherein the concentration of vitamin C is 0 to 1 mM.

[0240] Embodiment 117. The composition according to Embodiment 105, wherein the composition has a pH of 6 to 7.

[0241] <000[]926>Embodiment 118. An additive composition comprising a certain concentration of N-acetyl-cysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid, and the additive composition has a pH of 8 to 9. It should be noted that there seems to be an error in the original text where line ID 24 has " " repeated in the translation. Also, line ID 40 in the original has " " which is likely incorrect as it has "[]" in the middle in the provided text. I've translated it as best as possible based on the given content.

[0242] Embodiment 119. The composition according to Embodiment 118, further comprising sodium bicarbonate (NaHCO3), disodium phosphate (Na2HPO4), adenine, guanosine, glucose, and mannitol in a certain concentration.

[0243] Embodiment 120. The composition according to Embodiment 118, further comprising a gluconate.

[0244] Embodiment 121. The composition according to Embodiment 119, wherein the concentration of sodium bicarbonate is 10 to 60 millimoles (mM).

[0245] Embodiment 122. The composition according to Embodiment 121, wherein the concentration of sodium bicarbonate (NaHCO3) is 20 to 50 mM.

[0246] Embodiment 123. The composition according to Embodiment 122, wherein the concentration of sodium bicarbonate (NaHCO3) is 25 to 45 mM.

[0247] Embodiment 124. The composition according to Embodiment 123, wherein the concentration of sodium bicarbonate (NaHCO3) is 26 mM.

[0248] Embodiment 125. The composition according to Embodiment 122, wherein the concentration of sodium bicarbonate (NaHCO3) is 40 mM.

[0249] Embodiment 126. The composition according to Embodiment 106, wherein the concentration of sodium bicarbonate (NaHCO3) is at least 25 mM.

[0250] Embodiment 127. The composition according to Embodiment 119, wherein the concentration of disodium phosphate (Na2HPO4) is 10 to 20 mM.

[0251] Embodiment 128. The composition according to Embodiment 119, wherein the concentration of disodium phosphate (Na2HPO4) is at least 10 mM.

[0252] Embodiment 129. The composition according to Embodiment 119, wherein the concentration of the disodium hydrogen phosphate (Na2HPO4) is 12 mM.

[0253] Embodiment 130. The composition according to Embodiment 120, wherein the concentration of the gluconate is 0 to 10 mM.

[0254] Embodiment 131. The composition according to Embodiment 130, wherein the concentration of the gluconate is about 4 mM.

[0255] Embodiment 132. The composition according to Embodiment 119, wherein the concentration of the adenine is 0 to 5 mM.

[0256] Embodiment 133. The composition according to Embodiment 132, wherein the concentration of the adenine is 2 mM. \

[0257] Embodiment 134. The composition according to Embodiment 119, wherein the concentration of the guanosine is 0 to 5 mM.

[0258] Embodiment 135. The composition according to Embodiment 119, wherein the concentration of the guanosine is 1 to 2 mM.

[0259] Embodiment 136. The composition according to Embodiment 135, wherein the concentration of the guanosine is about 1.4 mM.

[0260] Embodiment 137. The composition according to Embodiment 119, wherein the concentration of the glucose is 50 to 100 mM.

[0261] Embodiment 138. The composition according to Embodiment 137, wherein the concentration of the glucose is about 80 mM.

[0262] Embodiment 139.The composition according to Embodiment 119, wherein the concentration of the mannitol is 40 to 80 mM.

[0263] Embodiment 140. The composition according to Embodiment 139, wherein the concentration of the mannitol is about 55 mM.

[0264] Embodiment 141. The composition according to Embodiment 118, wherein the concentration of N-acetyl-cysteine ​​is 0 to 1 mM.

[0265] Embodiment 142. The composition according to Embodiment 141, wherein the concentration of the N-acetyl-cysteine ​​is about 0.5 mM.

[0266] Embodiment 143. The composition according to Embodiment 118, wherein the concentration of Trolox is 0 to 1 mM.

[0267] Embodiment 144. The composition according to Embodiment 143, wherein the concentration of 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) is about 0.5 mM.

[0268] Embodiment 145. The composition according to Embodiment 118, wherein the concentration of vitamin C is 0 to 1 mM.

[0269] Embodiment 146. The composition according to Embodiment 145, wherein the concentration of vitamin C is about 0.25 mM.

[0270] Embodiment 147. The composition according to Embodiment 118, wherein the composition comprises pH 8.75.

[0271] Embodiment 148. A composition comprising a blood product selected from the group consisting of whole blood, platelets, and leukocytes, and an additive solution containing a certain concentration of disodium phosphate (Na2HPO4), sodium citrate, adenine, guanosine, glucose, and mannitol.

[0272] Embodiment 149. The composition according to Embodiment 148, wherein the guanosine is present at a concentration of 1 to 2 mM.

[0273] Embodiment 150. The composition according to Embodiment 149, wherein the guanosine is 1.5 mM.

[0274] Embodiment 151. The composition according to Embodiment 148, further comprising a gluconate in a concentration of 2 to 8 mM.

[0275] Embodiment 152. The composition according to Embodiment 148, wherein the gluconate is 5 mM.

[0276] Embodiment 153. The composition according to Embodiment 148, wherein the concentration of the disodium phosphate dibasic acid (Na2HPO4) is 10 to 30 mM.

[0277] Embodiment 154. The composition according to Embodiment 148, wherein the concentration of the disodium phosphate dibasic acid (Na2HPO4) is at least 15 mM.

[0278] Embodiment 155. The composition according to Embodiment 148, wherein the concentration of the disodium phosphate dibasic acid (Na2HPO4) is 20 mM.

[0279] Embodiment 156. The composition according to Embodiment 148, wherein the concentration of sodium citrate is 10 to 30 mM.

[0280] Embodiment 157. The composition according to Embodiment 148, wherein the concentration of the sodium citrate is about 25 mM.

[0281] Embodiment 158. The composition according to Embodiment 148, wherein the concentration of adenine is 0 to 5 mM.

[0282] Embodiment 159. The composition according to Embodiment 148, wherein the concentration of adenine is about 1.5 mM.

[0283] Embodiment 160. The composition according to Embodiment 148, wherein the glucose concentration is 30 to 60 mM.

[0284] Embodiment 161. The composition according to Embodiment 160, wherein the concentration of glucose is about 45.5 mM.

[0285] Embodiment 162. The composition according to Embodiment 148, wherein the concentration of mannitol is 80 to 140 mM.

[0286] Embodiment 163. The composition according to Embodiment 162, wherein the concentration of mannitol is about 110 mM.

[0287] Embodiment 164. The composition according to Embodiment 148, wherein the composition comprises a pH of 8.8. [Examples]

[0288] Example 1: Preparation and storage of RBCs for sampling Approximately 450–500 mL of whole blood was collected from a healthy blood donor and placed in a dextrose biphosphate (CP2D) anticoagulant (Haemonetics, Braintree, MA, Catalog number HAE PN 129-92 CP2D / AS3 set). Leukocyte-reduced plastinated regenerative cell block (LR-pRBC) was prepared from whole blood after leukocyte reduction and centrifugation at room temperature, according to the standard protocol at the Rhode Island Blood Center (RIBC). The AS7G-NAC (Examples 1, 3, and 5) or AS3 (Example 4) additive solution was added to the LR-pRBC to prepare the LR-pRBC. See Figure 1. For each test, ABO-matched LR-RBCs (300–350 mL each) in five units of additive solution were pooled together in a 3-liter non-DEHP pooling bag. Equal volumes of aliquots (300 mL each) were transferred to either a blood bag having a single bag, as provided in Table 5, or to a blood bag sealed within a gas-impermeable barrier (e.g., an oxygen and carbon dioxide-impermeable bag or outer packaging) with an oxygen and carbon dioxide adsorbent [Mitsubishi Gas Chemical Company, Tokyo, Japan, Mitsubishi SS-200 catalog number COM-600-0011, Desicare Inc., Mississippi, USA; Catalog number M1200BO3] placed between the inner bag and the outer packaging.

[0289] The blood storage bags are stored in ambient air for up to 56 days at ambient temperature (control, bag A) or 1-4°C (bags B-F). [Table 5]

[0290] Example 2: Preservation of RBCs in an ASB preservation bag with AS3 preservation solution maintains higher levels of major metabolites compared to conventional preservation. In this embodiment, a 300 mL unit of LR-RBC in AS3 is obtained from Rhode Island Blood Center (Rhode Island, US), divided into equal 150 mL aliquots, and then divided into either a single standard PVC DEHP bag A configured for a 150 mL volume, or a similar blood bag B enclosed within a gas-impermeable barrier (e.g., an oxygen and carbon dioxide-impermeable bag or outer packaging) with oxygen and carbon dioxide adsorbents placed between the inner bag and the outer packaging.

[0291] Aliquotes were collected from bags A and B on days 0, 7, 14, 21, 28, 35, and 42. Aliquotes were analyzed for blood gases, p50, pH, lactate, glucose (using an ABL90 gas analyzer equipped with a cooximeter, radiometer, and Denmark), ATP, 2,3-DPG, and hemolysis. Data regarding p50 were calculated from data from the gas analyzer (ABL90 with cooximeter, radiometer) using a linear regression equation from p50 values ​​measured with a Hemox analyzer (TCS Scientific, New Hope, PA, USA) at pH 7.4, pCO2 of 40 mmHg, and a temperature of 37°C, and compared with a calibration curve to convert the p50 data from the ABL90 to the Hemox analyzer values.

[0292] Data obtained from replicated samples are analyzed by analysis of variance (ANOVA) using Neuman-Keuls multiple comparison studies, where probability levels less than 0.05 are considered significant. Results are presented as mean ± standard error of the mean (SEM) or standard deviation (SD).

[0293] The percentage of saturated oxygen (SO2%) increased as a function of storage duration for RBCs stored in conventional bag A (Table 6). In contrast, the level remained constant, with only a slight decrease for RBCs stored in ASB bag B, which has an O2 / CO2 impermeable barrier (Table 7). pCO2 increased for up to 28 days for both RBCs initially stored in storage bags A and B, and then gradually decreased during storage from 28 to 42 days. pCO2 levels in RBCs stored using the conventional method were significantly higher than those in RBCs in ASB storage bags on all measurement days during the storage period (p<0.0001). The results of hemolysis in RBCs in conventional and ASB storage bags are also summarized in Tables 6 and 7. There was no significant difference in hemolysis between conventional and Hemanext storage conditions during the storage period (p>0.05).

[0294] Storage of RBCs in bag B (Table 7) results in significantly higher ATP concentrations on days 28, 35, and 42 of storage compared to conventional storage (p<0.005, Table 6). Storage conditions in ASB bag B result in significantly higher 2,3-DPG concentrations on days 7 and 14 of storage compared to blood stored using the conventional method (p<0.05). 2,3-DPG concentrations rapidly decrease during storage, reaching the detection limit of the assay at 0.25 μmol / gHb by day 21. RBCs stored in bag B also show a significant increase in lactate and p50 levels during storage compared to RBCs stored using the conventional method (lactate p<0.0001 for all data points, p50 p<0.001 at points 7-42). Furthermore, pH levels remain significantly higher in RBCs stored in ASB storage bag (B) compared to RBCs stored using the conventional method in bag A. Importantly, 2,3-DPG levels did not correlate with pH. For example, pH varied from 6.631±0.075 to 6.279±0.052 under conventional storage and from 6.638±0.076 to 6.329±0.054 under Hemanext storage.

[0295] The p50 data is calculated using a linear regression equation based on p50 values ​​measured with a Hemox analyzer (TCS Scientific, New Hope, PA, USA) at pH 7.4, pCO2 at 40 mmHg, and a temperature of 37°C, using data from a gas analyzer (ABL90, Radiometer with cooximeter). [Table 6] [Table 7]

[0296] Example 3: Storing RBCs in a bag with increased CO2 permeability maintains higher levels of major metabolites compared to conventional storage. The roles of DEHP and permeability are tested by comparing the results of bags containing DEHP (Bag A) with those of bags without DEHP (Bags C, D, E, F). See Table 8. [Table 8]

[0297] The SO2% in RBCs increases over 42 days of storage in conventional storage bags A, C, and E. Adding oxygen and carbon dioxide impermeable overlap to bags D and F results in maintaining or decreasing SO2% compared to day 1. Similarly, pCO2 increases on day 42 of storage in conventional bag A compared to day 0 (p<0.05). In contrast to RBCs stored using the conventional method, pCO2 decreases significantly over 42 days when RBCs are stored in high CO2 permeable storage bags, with or without overlap.

[0298] Without being limited by theory, the data show that ATP remains unchanged compared to conventional bags containing DEHP by maintaining a constant or decreasing O2 level while depleting the CO2 level. Adding barrier bags to PVC with BTHC (Bag C) and PVC with DINCH (Bag E) reduces the O2 level to less than 30% and significantly increases the ATP level by 12% and 14%, respectively. For example, ATP concentrations are significantly higher in the DINCH bag (Bag D) and BTHC bag (Bag E) with gas-impermeable barriers compared to any of the control DEHP or BTHC and DINCH bags without barriers. See Figure 2B and Table 9. [Table 9]

[0299] Surprisingly, maintaining O2 levels while depleting CO2 by placing blood in highly CO2-permeable bags (Bags C and D) results in a significant increase in 2,3-DPG levels compared to conventional storage. The concentration of 2,3-DPG in RBCs stored in a DEHP bag (Bag A) rapidly decreases to approximately 79% of the initial level at day 21 of storage (Figure 3). 2,3-DPG levels in both BTHC and DINCH are higher after 21 days than in RBCs stored using conventional methods. 2,3-DPG levels increase by approximately 20% after 21 days in both BTHC and DINCH using a gas-impermeable barrier compared to BTHC and DINCH bags without a barrier. Importantly, the effect of CO2 on 2,3-DPG levels does not appear to be due to pH, but rather closely correlates with CO2 levels. This is surprising, as much of the literature focuses on pH as the causative factor.

[0300] Importantly, hemolysis remained below the maximum safety levels of 1% and 0.8% established by US and European regulatory authorities, respectively, with and without DEHP (Tables 10, 11, and 12).

[0301] In summary, these data demonstrate that preventing CO2 depletion and O2 increase during storage (either through depletion or maintenance) is an improved method for reducing the harmful effects of various storage lesions. Therefore, storage systems incorporating at least two features increase the ability to maintain the quality of RBCs during refrigerated storage. First, storage bags that prevent an increase in O2 levels in RBCs by maintaining or decreasing the initial O2 content during long-term storage at 1–6°C help maintain ATP levels. This maintenance or decrease in O2 levels can be favorably achieved through the selective permeability of the polymer and, optionally, through the selection of a polymer that provides the presence of an outer wrap or polymer that is impermeable to both CO2 and O2 as an O2 / CO2 adsorbent. Second, storage bags also maintain low levels of CO2 during storage, resulting in an increase in 2,3-DPG levels, and surprisingly, maintain 2,3-DPG at or near pre-storage levels. [Table 10] [Table 11] [Table 12]

[0302] Example 4: RBC in AS3 additive solution stored in a bag with increased gas permeability The study in Example 3 is repeated with AS3 to determine whether the improvements in metabolites (e.g., ATP and 2,3-DPG) observed in various non-DEHP bags as provided above remain stable when AS3 is used as an additive solution.

[0303] As seen in AS7G-NAC (Figures 2A, 2B, 3A, and 3B), SO2% levels decrease significantly after 42 days in DINCH and BTHC bags with gas-impermeable barrier bags compared to DEHP, DINCH, and BTHC bags without barrier bags. Unlike oxygen levels, pCO2 levels remain similar across each non-DEHP bag selection (BTHC or DINCH), regardless of the presence or absence of a gas-impermeable outer barrier bag. Both DINCH and BTHC show reduced pCO2 levels compared to DEHP after 21 days of storage (Figures 4 and 5).

[0304] Similar to the results for the AS7G-NAG additive solution, ATP and 2,3-DPG levels were elevated in RBCs stored in DINCH and BTHC inner bags with gas-impermeable barrier bags compared to RBCs stored in conventional DINCH and BTHC bags without an outer bag (Figures 4 and 5). All RBC samples also remained below the required hemolysis cutoff. Importantly, hemolysis remained below the maximum safe levels of 1% and 0.8% established by US and European regulatory authorities, with and without DEHP (Tables 13, 14, and 15). [Table 13] [Table 14] [Table 15]

[0305] Example 5: RBC in AS7G-NAC additive solution stored in a bag with increased gas permeability As provided in Examples 1 and 2, red blood cells are prepared in an AS7G-NAC additive solution. The RBCs are then placed in one of the following bags. A. Conventional PVC with DEHP C.BTHC holds PVC PVC with a BTHC inner bag and a D.CO2 / O2 impermeable outer barrier. F. Polyolefin G. Polyolefin inner bag with CO2 / O2 impermeable outer barrier

[0306] The concentration of 2,3-DPG in RBCs stored in DEHP bags decreases by day 21 of storage compared to the starting level (Figure 6). Levels of 2,3-DPG in both BTHC (bag C) and polyolefin (EXP500, bag F) are higher after 21 days than in RBCs stored using conventional methods. These levels further increase in the BTHC and polyolefin bags when the inner bag is sealed by a gas-impermeable outer barrier bag.

[0307] ATP concentrations were also significantly higher in the BTHC and polyolefin bags with a gas-impermeable barrier compared to either the control DEHP or BTHC and polyolefin bag without a barrier (Figure 7).

[0308] Hemolysis remained below the required cutoff levels of 1% and 0.8% established by US and European regulatory authorities, respectively (Figures 6 and 7). [Table 16] [Table 17] [Table 18]

[0309] While the present invention has been described in relation to specific embodiments, those skilled in the art will understand that various modifications can be made and equivalents can be substituted for their elements without departing from the scope of the invention. In addition, many modifications can be made to adapt the teachings of the invention to specific situations or materials without departing from the scope of the invention.

[0310] Therefore, the present invention is not limited to any particular embodiment disclosed as the best mode intended to carry out the invention, and the present invention is intended to include all embodiments that fall within the scope and spirit of the appended claims.

Claims

1. A method for preserving blood products, Over 30% SO 2 Obtaining a blood product containing a certain percentage, To prepare a storable blood product by adding an additive solution to the aforementioned blood product, The aforementioned storable blood product is stored at 25°C and approximately 1 atm, at least 0.62 cubic centimeters per square centimeter (cm³). 3 / cm 2 The method comprising storing the contents in a di-2-ethylhexyl phthalate-free (DEHP-free) blood-compatible (BC) carbon dioxide-permeable bag having gas permeability to carbon dioxide.

2. The method according to claim 1, wherein the storable blood product has not been deoxygenated before storage.

3. The method according to claim 1, wherein the storable blood product is not deoxygenated during storage.

4. The method according to claim 2, comprising depleting oxygen from the storable blood product during storage.

5. The aforementioned BC carbon dioxide permeable bag is 0.3 cm². 3 / cm 2 The method according to claim 1, having an oxygen permeability of less than 1.

6. The method according to claim 1, wherein the BC carbon dioxide permeable bag does not contain di(2-ethylhexyl) terephthalate (DEHT).

7. The method according to claim 1, wherein the BC carbon dioxide permeable bag contains 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or butyryl trihexyl citrate (BTHC) as a plasticizer.

8. The method according to claim 1, wherein the BC carbon dioxide permeable bag is sealed inside an outer bag that is impermeable to oxygen and carbon dioxide.

9. A blood storage container comprising a DEHP-free carbon dioxide-permeable and oxygen-impermeable material, the material having a gas permeability with respect to oxygen of less than 0.05 cm 3 / cm 2 at 25 °C and 1 atm, and a gas permeability with respect to carbon dioxide of at least 0.62 cubic centimeters (cm 3 / cm 2 ) per square centimeter at 25 °C and 1 atm, said container.

10. The container according to claim 9, wherein the material is selected from the group consisting of polyvinyl chloride (PVC), polyolefin, silicone, polyvinylidene fluoride (PVDF), polysulfone (PS), polypropylene (PP), or polyurethane.

11. The container according to claim 9, wherein the material comprises 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or butyryl trihexyl citrate (BTHC) as a plasticizer.

12. Methods for handling blood products, Adding an additive solution to the blood product, and heating the blood product at 25°C and about 1 atm for at least 0.62 cm 3 / cm 2 The method comprising storing the blood product in a DEHP-free blood-compatible (BC) carbon dioxide-permeable bag having gas permeability to carbon dioxide, wherein the storage is for at least 7 days, and the oxygen level of the blood product during the 7 days of storage is lower than or approximately the same as the oxygen level in the blood product on the first day of storage.

13. The method according to claim 12, wherein the BC carbon dioxide permeable bag comprises PVC or polyolefin.

14. The method according to claim 13, wherein the BC carbon dioxide permeable bag contains 20 to 70% by weight / weight of 1,2-cyclohexanedicarboxylic acid diisononyl ester (DINCH) or butyryl trihexyl citrate (BTHC) in the PVC as a plasticizer.

15. A method for preserving storable blood, Blood products, At 25°C and approximately 1 atm, at least 0.62 cm 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 DEHP-free blood-compatible (BC) materials having the following oxygen permeability, and It should be placed inside a storage container containing a carbon dioxide adsorbent. The method comprising storing the container containing the storable blood for a certain period of time to prepare the stored blood.

16. A method for preserving red blood cells, The aforementioned red blood cells, At 25°C and approximately 1 atm, at least 0.62 cm 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 The storage container comprises an outer oxygen and carbon dioxide impermeable container, which contains a permeable, inwardly foldable container made of a material having the following oxygen permeability: a DEHP-free blood-compatible (BC) container enclosed within the outer bag, and a carbon dioxide adsorbent, an oxygen adsorbent, or an oxygen and carbon dioxide adsorbent sealed between the inner bag and the outer bag. The method comprising storing the container containing the red blood cells for at least seven days to prepare a stored blood product.

17. A method for maintaining the level of 2,3-DPG in a blood product, Blood products containing at least 10% oxygen saturation, At 25°C and approximately 1 atm, at least 0.62 cm 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 The following storage containers are provided, each containing a blood-compatible (BC) material with oxygen permeability, a carbon dioxide adsorbent, and an outer oxygen and carbon dioxide impermeable container, with the material sealed between the inner and outer bags. The method comprising storing the container containing the blood product, wherein the level of 2,3-DPG increases for up to 14 days of storage compared to the level of 2,3-DPG in a blood product stored by a conventional method.

18. A method for maintaining the ATP level of blood products, Blood products containing at least 10% oxygen saturation, At 25°C and approximately 1 atm, at least 0.62 cm 3 / cm 2 The permeability to carbon dioxide, and 0.3 cm at approximately 1 atm. 3 / cm 2 The following storage containers are provided, each containing a blood-compatible (BC) material with oxygen permeability, a carbon dioxide adsorbent, and an outer oxygen and carbon dioxide impermeable container, with the material sealed between the inner and outer bags. The method comprising storing the container containing the blood product such that the ATP level increases after 42 days of storage compared to the ATP level of a blood product stored by a conventional method.

19. Blood products selected from the group consisting of whole blood, platelets, and white blood cells, Sodium bicarbonate (NaHCO) 3 ), disodium phosphate (Na 2 HPO 4 A composition comprising an additive solution containing adenine, guanosine, glucose, mannitol, N-acetyl-cysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and l-ascorbic acid (vitamin C).

20. An additive composition, having a certain concentration, N-acetyl-cysteine, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox), and The additive composition comprises l-ascorbic acid, wherein the additive composition has a pH of 8 to 9.

21. Blood products selected from the group consisting of whole blood, platelets, and white blood cells, A certain concentration of disodium phosphate (Na 2 HPO 4 A composition comprising an additive solution containing sodium citrate, adenine, and guanosine, having concentrations of 1-2 mM glucose and mannitol.

22. A device that is essentially as shown and described.

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