Anaerobic blood storage container

Abstract

To provide an improved anaerobic blood storage bag that offers a longer storage life for blood collection kits. [Solution] A blood storage container for anaerobic storage of blood is provided, having an enhanced sealing method and materials for storing preserved blood.

Description

[Technical Field]

[0001] Cross-reference of related applications This application relates to U.S. Provisional Patent Application No. 62 / 151,957, filed on April 23, 2015, and U.S. Provisional Patent Application No. 62 / 151,839, filed on April 23, 2015, both of which are incorporated herein by reference as a whole.

[0002] This disclosure relates to improved anaerobic storage bags (ASBs) and methods for improved storage of whole blood and blood components. More specifically, this disclosure relates to improved apparatus and methods for anaerobic storage of oxygen-deficient and oxygen and carbon dioxide-deficient blood and blood components, providing longer pre-use storage life, improved utility in collection centers, and reduced oxygen infusion. The methods, apparatus, and kits of this disclosure provide improved quality of transfused blood and blood components, as well as improved patient safety and outcomes. [Background technology]

[0003] Currently, the supply of liquid blood and blood components is limited by the preservation systems used in conventional blood preservation practices. Using current systems, preserved blood, as a concentrated hematopoietic preparation, expires after approximately 42 days of refrigerated storage at temperatures above freezing (i.e., 4°C). For example, in 2007, over 45 million units of red blood cells (RBCs) were collected and preserved worldwide (15.6 million in the United States). During refrigerated storage, RBCs are progressively damaged by complex biological changes collectively referred to as "preservation damage." When transfused within the current 6-week shelf life, preserved RBCs are of lower quality and potentially toxic, which can manifest as side effects of transfusion therapy. Among the observed preservation damages, biochemical and physical parameters associated with preserved red blood cells are altered. Examples of these changes include parameters measured in vitro such as reduced metabolic levels (adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG)), increased cell-free iron levels, hemolysis, increased microparticle levels, reduced surface area, echinocytosis, phosphatidylserine exposure, and reduced deformability. Expired blood cannot be used and must be discarded because it can harm the final recipient. For these and other reasons, the amount of readily available, high-quality blood required for transfusions is limited.

[0004] When stored conventionally, stored blood undergoes steady-state degradation associated with various storage damages, including hemolysis, hemoglobin degradation, and reduced ATP and 2,3-DPG concentrations. When transfused to a patient, the effects of steady-state degradation during storage manifest, for example, as a reduction in 24-hour in vivo recovery. Due to these and other medical sequelae of transfusion of stored blood, various techniques have been developed to minimize the effects of storage on the blood and improve medical outcomes. See, for example, Zimring et al., "Established and theoretical factors to consider in assessing the red cell storage lesion" in Blood, 125:2185-90 (2015).

[0005] Numerous methods have been developed to minimize storage damage and improve transfusion outcomes. One method has been the development of additive solutions that can be included during storage. Examples of this method include U.S. Patent No. 4,769,318 by Hamasaki et al. and U.S. Patent No. 4,880,786 by Sasakawa et al., which concern additive solutions for blood storage and activation. For example, Rejuvesol (available from Citra Lab LLC, Braintree, MA) is added to blood after refrigeration (i.e., 4°C) immediately before transfusion or before freezing for long-term storage (i.e., at -80°C with glycerol). U.S. Patent No. 6,447,987 by Hess et al. concerns additive solutions for the refrigerated storage of human red blood cells. An alternative method is to freeze the blood to prevent the development of storage damage. While the storage of frozen blood is known in the art, such frozen blood has limitations. Serebrennikov's U.S. Patent No. 6,413,713 concerns a method for preserving blood at temperatures below 0°C. See Chaplin et al., "Blood Cells for Transfusion," Blood, 59:1118-20 (1982), and Valeri et al., "The survival, function, and hemolysis of human RBCs stored at 4 degrees C in additive solution (AS-1, AS-3, or AS-5) for 42 days and then biochemically modified, frozen, thawed, washed, and stored at 4 degrees C in sodium chloride and glucose solution for 24 hours," Transfusion, 40:1341-5 (2000). Another method is provided by Sato et al.'s U.S. Patent No. 4,837,047, concerning containers for blood preservation.

[0006] One method that has proven successful in improving blood quality and extending its usefulness is preservation under anaerobic conditions through oxygen deficiency. Bitensky et al.'s U.S. Patent No. 5,624,794, Bitensky et al.'s U.S. Patent No. 6,162,396, and Bitensky's U.S. Patent No. 5,476,764 concern the preservation of red blood cells under oxygen-deficient conditions. Bitensky et al.'s U.S. Patent No. 5,789,151 concerns blood preservation additive solutions. Advantages of preserving blood under oxygen-deficient conditions include improved ATP and 2,3-DPG levels and reduced hemolysis. Furthermore, preserving blood under oxygen-deficient conditions may result in reduced particle levels, reduced loss of deformability, reduced lipid and protein oxidation, and higher post-transfusion survival rates compared to blood preserved under conventional conditions.

[0007] Bitensky et al., U.S. Patent No. 6,162,396 ('396 patent), discloses an anaerobic storage bag for blood storage comprising an oxygen-impermeable outer layer and an oxygen-permeable erythrocyte (RBC)-compatible inner layer, with an oxygen scrubber positioned between the inner and outer layers. The blood storage device further comprises at least two ports for conventional sterile connections for introducing whole blood or RBCs into the device. While the '396 patent generally discloses an oxygen-impermeable outer layer, it does not provide guidance on specific types of materials or preferred construction methods. Similarly, while the '396 patent generally discloses an inner blood-compatible layer, it does not provide guidance on suitable materials and construction methods. Likewise, the '396 patent does not provide guidance on piping materials and methods for obtaining access to the inner blood bag and its contents while maintaining a hypoxic environment.

[0008] In the course of research to develop an ASB for use in blood collection and blood deposit procedures, it was observed that additional considerations were needed. Firstly, when preparing the oxygen-impermeable outer layer, it was observed that not all of the materials identified as suitable in the '396 patent were usable in the operational apparatus. Specifically, certain aluminum foil laminates were observed to be impaired when folds, wrinkles, or folds were made. More problematic was that when introducing blood into such a bag, the increase in volume directly led to the formation of folds that impaired such integrity. To avoid this problem, a suitable material with sufficient flexibility is required. Alternatively, an ASB with a suitable expandable feature that provides blood containment is required.

[0009] Furthermore, during the development process, it was observed that the integrity of the bag needed to be maintained at various ports to prevent oxygen intrusion before use and during storage. Another source of oxygen intrusion was observed at seams and joints where wider seals were provided to reduce oxygen leakage and prevent damage to the external and internal bags. It was further observed that standard PVC piping used in blood collection procedures had significant oxygen permeability and incompatibility with methods for creating oxygen-impermeable seals when passing through the external oxygen-impermeable barrier. Moreover, conventional blood collection kits require transfer piping exceeding approximately 200 mm in length and collection piping exceeding 800 mm in length, which are also potential sources of oxygen introgression. See ISO 3826-1:2013. Therefore, blood collection kits for anaerobic blood storage must explain this source of oxygen, which can reduce the capacity of the oxygen adsorbent placed in the ASB and significantly reduce the resulting bag's shelf life.

[0010] Therefore, there is a need for an improved anaerobic blood storage bag that provides a long storage life for a blood collection kit including such a bag. There is also a need for an improved anaerobic storage bag that can provide for the ingress of oxygen through the tubing associated with the blood collection kit. Finally, there is a need to identify suitable materials that can withstand the everyday handling of the blood storage bag without compromising the integrity of the oxygen barrier.

[0011] Finally, the integration of an oxygen indicator into the improved anaerobic blood storage bag provides an additional level of quality control that helps to notify the user of the possibility of oxygen ingress large enough to impair the ability of the storage bag to maintain stored blood under oxygen-deficient conditions. SUMMARY OF THE INVENTION

[0012] The present disclosure provides and includes a blood storage device for storing oxygen-deficient blood, comprising a substantially oxygen-impermeable outer receptacle, a collapsible blood container, and at least one inlet / outlet that passes through the outer receptacle, is in fluid communication with the collapsible container, and is substantially oxygen-impermeable.

[0013] The present disclosure provides and includes a blood storage device for storing oxygen-deficient blood, comprising a substantially oxygen-impermeable outer receptacle, a collapsible blood container, at least one inlet / outlet that passes through the outer receptacle, is in fluid communication with the collapsible container, and is substantially oxygen-impermeable, and an oxygen adsorbent located within the outer receptacle.

[0014] The present disclosure provides and includes a blood storage device for storing oxygen-deficient blood, comprising a substantially oxygen-impermeable outer receptacle, a collapsible blood container, at least one inlet / outlet that passes through the outer receptacle, is in fluid communication with the collapsible container, and is substantially oxygen-impermeable, and a multilayer film incorporating an oxygen adsorbent located within the multilayer film.

[0015] The present disclosure provides, and includes, a blood storage device for storing oxygen - depleted blood, comprising a substantially oxygen - impermeable blood - compatible outer receptacle, a collapsible blood container, at least one inlet / outlet that passes through the outer receptacle and is in fluid communication with the collapsible container and is substantially oxygen - impermeable. Among them, oxygen - depleted blood having an oxygen saturation level of less than 20% is maintained in an oxygen - depleted state for at least 64 days.

[0016] The present disclosure provides, and includes, a method for storing deoxygenated blood, including placing the deoxygenated blood into a blood storage device as described herein.

[0017] The present disclosure provides, and includes, a method for further reducing the oxygen saturation of blood during storage, including transferring oxygen - depleted blood having an oxygen saturation level of less than 20% for storage into a blood storage device, and storing the oxygen - depleted blood for a period, wherein the period is at least one week.

[0018] Some aspects of the present disclosure are described herein by way of example only, with reference to the accompanying drawings. Here, referring specifically and in detail to the drawings, it is emphasized that the items shown are examples and are for the purpose of illustrative consideration of aspects of the present disclosure. In this regard, this description, together with the drawings, will clarify to those skilled in the art how aspects of the present disclosure can be implemented.

Brief Description of the Drawings

[0019] [Figure 1A] FIG. 1A shows an exemplary embodiment of an improved anaerobic blood storage bag according to the present disclosure. [Figure 1B] FIG. 1B shows an exemplary embodiment of an improved anaerobic blood storage bag according to the present disclosure. [Figure 1C] FIG. 1C shows an exemplary embodiment of an improved anaerobic blood storage bag according to the present disclosure. [Figure 2A]Figure 2A shows exemplary embodiments of oxygen-reducing disposable storage systems having blood-deficient devices, each having two or three compartments, and anaerobic storage bags according to the present disclosure. [Figure 2B] Figure 2B shows exemplary embodiments of oxygen-reducing disposable storage systems having blood-deficient devices having two or three compartments, and anaerobic storage bags according to the present disclosure. [Figure 3A] Figure 3A shows an exemplary embodiment of the inlet / outlet barrier crossing pipe 305. [Figure 3B] Figure 3B shows an exemplary embodiment of the inlet / outlet barrier crossing pipe 305. [Figure 3C] Figure 3C shows an exemplary embodiment of the inlet / outlet barrier crossing pipe 305. [Figure 3D] Figure 3D shows an exemplary embodiment of a manifold 301 having three inlet / outlet ports for holding a barrier cross pipe 305. [Figure 4A] Figure 4A shows an adhesive layer in which a barrier transverse pipe 305 is joined to the membrane 208 to create an adhesive portion 302 having a gap 209. [Figure 4B] Figure 4B shows the adhesive layer that joins the multilayer barrier transverse tube 305 to the film 208. [Figure 5A] Figure 5A is a diagram of a blood storage device having a barrier transverse tube 305 bonded to form an adhesive portion 302, according to an embodiment of the present disclosure. [Figure 5B] Figure 5B shows a blood storage device having an adhesive layer 302 that joins the manifold 301 to the membrane 208. [Figure 6A] Figure 6A shows a piping management feature according to an embodiment of this disclosure. [Figure 6B] Figure 6B shows a piping management feature according to an embodiment of the present disclosure. [Figure 6C] Figure 6C shows a piping management feature according to an embodiment of this disclosure. [Figure 6D] Figure 6D shows a piping management feature according to an embodiment of this disclosure. [Figure 6E] Figure 6E shows a piping management feature according to an embodiment of this disclosure. [Figure 6F] Figure 6F shows a piping management feature according to an embodiment of this disclosure. [Figure 7] Figure 7 shows an integrated handle 214 according to an embodiment of the present disclosure. [Figure 8] Figure 8 shows an external receptacle 201 incorporating the extended feature section 217 according to an aspect of this disclosure. [Figure 9] Figure 9 shows an aluminum die 70 according to an aspect of the present disclosure. [Figure 10] Figure 10 shows a graph of oxygen adsorption occurring inside a conventional storage bag. [Figure 11] Figure 11 shows a graphical representation of the adsorbent test data from Example 9. [Figure 12] Figure 12 shows a graphical representation of the portable hand warmer test data from Example 10. [Figure 13] Figure 13 shows a graphical representation of oxygen absorption occurring in non-deficient blood during storage in a conventional storage bag without the external receptacle 201. [Figure 14] Figure 14 shows a graphical representation of oxygen absorption occurring in anaerobic storage containers, either containing an adsorbent (filled-in symbols) or not containing an adsorbent. [Figure 15] Figure 15 shows a graphic representation of the partial oxygen pressure in an anaerobic storage container with three inlets / outlets, based on prior art that is not substantially oxygen-impermeable. [Figure 16] Figure 16 shows a graphic representation of the partial oxygen pressure in an anaerobic storage container with three inlets / outlets 30 having barrier transverse tubes 305.

[0020] Corresponding reference letters indicate corresponding parts across several figures. The examples described herein illustrate some embodiments of the present invention, but should not be considered to limit the scope of the invention in any way. [Modes for carrying out the invention]

[0021] Unless otherwise defined, the 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 that many methods may be used in the practice of this disclosure. Indeed, this disclosure is by no means limited to the methods and materials described herein. Any references cited herein are incorporated in their entirety by reference. For the purposes of this disclosure, the following terms are defined below:

[0022] As used herein, the term “bag” refers to a collapsible container prepared from a flexible material, including pouches, tubes, and gusset bags. As used herein and included in this disclosure, the term includes fold-over bags having one, two, three, or more folds, which are sealed or bonded on one, two, three, or more sides. Bags may be prepared using a variety of techniques known in the art, including bonding sheets of one or more materials. Methods for bonding materials to form bags are known in the art. Also included in this disclosure and provided are containers prepared by injection molding and blow molding. Methods for preparing blow-molded and injection-molded containers are known in the art. A preferred type of blow-molded or injection-molded container is a flexible container that can be expanded to contain blood or blood components for reduced oxygen, while its size may be reduced for efficient packaging and shipping. They may also be designed to conform to the volume of blood until fully expanded. As used throughout this disclosure, "bag" refers to a collapsible container, and the two terms are used interchangeably throughout this disclosure.

[0023] As used herein, the term “foldable container” includes bags, containers, sealing containers, envelopes, pouches, pockets, receptacles, and other devices capable of containing and holding liquids or fluids. In certain embodiments, foldable containers may be manufactured by conventional means such as injection molding or insert molding. In other embodiments, foldable containers may be prepared from sheets of polymer material that are bonded together using methods known in the art to prepare a container capable of holding a certain amount. Such foldable containers are well known in the art. See, for example, U.S. Patent No. 3,942,529 issued to Waage, U.S. Patent No. 4,131,200 issued to Rinfret, and U.S. Patent No. 5,382,526 issued to Gajewski et al. Preferred methods for bonding polymer materials to prepare foldable containers according to this disclosure include thermal welding, ultrasonic welding, radio frequency (RF) welding, and solvent welding. In certain embodiments, a foldable container according to the Disclosure may be prepared using a multi-bonding method. The foldable containers according to the Disclosure include enclosed containers having one or more folds, folds, diaphragms, bubbles, and gussets. Methods for preparing foldable containers are known in the Art. See, for example, U.S. Patent No. 3,361,041 issued to Grob, U.S. Patent No. 4,731,978 issued to Martensson, U.S. Patent No. 4,998,990 issued to Richter et al., and U.S. Patent No. 4,262,581 issued to Ferrell. The Disclosure also includes and provides containers having a combination of both flexible and non-flexible portions. In these, the flexible portion allows for volume expansion through, for example, folds, folds, or gussets and other similar geometric features of the package shape, while the non-flexible portion can provide rigidity and geometric definition to the container. Methods and designs for preparing foldable containers having both flexible and non-flexible portions are known in the art and are described, for example, by Randall in U.S. Patent No. 6,164,821 and by LaFleur in U.S. Patent No. 5,328,268.Other examples are described by Yeager in U.S. Patent No. 6,076,664 and by David in U.S. Patent Application Publication No. 2014 / 0248005A1, and are also known in the art as “self-standing pouches.”

[0024] As used herein, the term “imported oxygen” refers to oxygen entering a blood storage device during the storage period of oxygen-deficient blood. Imported oxygen further includes oxygen entering the blood storage device during shelf storage. Such imported oxygen, if not minimized or preferably eliminated, may cause the blood storage device to fail to operate during shelf storage. In some embodiments, imported oxygen may result in the consumption of the gas-binding capacity of a solvent (either oxygen or carbon dioxide), causing the device to malfunction, making it impossible to maintain the blood storage device in an anaerobic state, and further making it impossible to maintain oxygen-depleted stored blood. Imported oxygen includes oxygen entering the device through a substantially impermeable barrier of the device, where typical absolute integrity within the device is either impossible or prohibitively expensive. More generally, imported oxygen may enter the device through seals or welds of the external receptacle 201, inlet / outlet 30, piping 304, and piping 205. More specifically, it has been found that standard piping used in blood collection devices (e.g., collection tubes and transfer tubes) is a significant source of incoming oxygen, which rendered previously known anaerobic blood storage devices in the art unsuitable. As shown in the embodiments below, piping was the primary source of incoming oxygen. Furthermore, while this design eliminates most of the incoming oxygen observed in previous anaerobic storage bags, it will be understood that complete elimination of incoming oxygen may not always be possible. The problem of incoming oxygen manifests as a significantly reduced storage life and the inability to maintain blood in a suitable oxygen-deficient state. Moreover, even when incorporating elements of the blood storage device 20 of this disclosure, it is preferable to include an oxygen adsorbent 207 that can absorb not only any residual oxygen present in the oxygen-deficient blood, but also any undesirable amount of incoming oxygen that still enters the system.

[0025] As used herein, the term “blood” refers to whole blood, leukopenic RBCs, thrombocytopenic RBCs, and leukocyte and thrombocytopenic RBCs. The term “blood” further includes concentrated red blood cells, thrombocytopenic concentrated red blood cells, leukopenic concentrated red blood cells (LRpRBCs), and leukocyte and thrombocytopenic concentrated red blood cells. The temperature of the blood may vary depending on the stage of the collection process, starting at normal body temperature of 37°C at the time of collection, but rapidly decreasing to about 30°C as soon as the blood leaves the patient’s body, and then further decreasing to room temperature in about 6 hours if unprocessed, and finally being refrigerated to about 4°C to 6°C.

[0026] 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 whole blood, white blood cells are 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 × 10⁻⁶ for males. 12 / L, for women: 4.2~5.4 x 10 12 The value is / L. Normal hematocrit or blood volume percentage is approximately 40-54% in men and approximately 38-47% in women. Platelet count is usually 150-450 × 10⁶ in both men and women. 9 The volume is / L. Whole blood is collected from a blood donor and is usually compounded with an anticoagulant. When collected, whole blood is initially at about 37°C and cools rapidly to about 30°C during and immediately after collection, but cools gradually to ambient temperature over about 6 hours. Whole blood may be processed by the method of this disclosure starting at 30–37°C at collection, or at room temperature (typically about 25°C). As used herein, a “unit” of blood, including the anticoagulant, is about 450–500 mL.

[0027] As used herein, “red blood cells” (RBCs) include RBCs present in whole blood, leukopenic RBCs, thrombocytopenic RBCs, and leukocytes and thrombocytopenic RBCs. Human red blood cells are in a dynamic state in vivo. 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 cell volume composed of red blood cells is called hematocrit. As used herein, unless otherwise limited, RBCs also include concentrated red blood cells (pRBCs). Concentrated red blood cells are prepared from whole blood using centrifugation techniques commonly known in the art. As used herein, unless otherwise indicated, the hematocrit of pRBCs is approximately 70%.

[0028] As used herein, the term “approximately” refers to ±10%.

[0029] The terms "comprises," "comprising," "includes," "including," and "having," as well as their conjugations, all mean "to include, but not limited to."

[0030] The term "consisting of" means "including and limited to."

[0031] The term “essentially derived from” means that a composition, method, or structure may include additional components, steps, and / or parts, but only if those additional components, steps, and / or parts do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0032] As used herein, the singular forms "a," "an," and "the" include plural corresponding terms unless otherwise specified in the context. For example, the terms "compound" or "at least one compound" may include multiple mixtures, and include those mixtures.

[0033] Throughout this application, various aspects of the disclosure may be presented in scope form. It should be understood that the use of scope form is merely for convenience and conciseness and should not be considered a firm limitation on the scope of the disclosure. Therefore, scope descriptions should be considered to specifically disclose possible sub-scopes and all individual numbers within those scopes. For example, a scope description such as "1 to 6" should be considered to specifically disclose sub-scopes such as "1 to 3," "1 to 4," "1 to 5," "2 to 4," "2 to 6," and "3 to 6," as well as individual numbers within those scopes, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the scope.

[0034] Wherever a numerical range is indicated herein, it means that any number (fraction or integer) listed within that range is included. The expressions "extending / range" from the first indicator to the second indicator, and "extending / range" from the first indicator to the second indicator, are used interchangeably herein and mean that the first and second indicated numbers, as well as all fractions and integers in between, are included.

[0035] As used herein, the term “method” means a set of forms, means, techniques, and procedures for accomplishing a given task, and includes, but is not limited to, forms, means, techniques, and procedures that are known or readily developed from forms, means, techniques, and procedures known by practitioners of the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0036] Referring to Figure 1A, an illustration of an exemplary embodiment of the present disclosure is provided. The blood storage device 20 includes a substantially oxygen-impermeable external receptacle 201, a collapsible blood container 202 passing through the external receptacle 201 and having at least one inlet / outlet 30 comprising a seal adapter 301 and an adhesive portion 302, and an oxygen adsorbent 207 located within the external receptacle 201, wherein the seal adapter 301 and the adhesive portion 302 are substantially oxygen-impermeable, and the inlet / outlet 30 is in fluid communication with the collapsible container 202.

[0037] As used herein, the external receptacle 201 is prepared from a membrane material 208 that is substantially oxygen-impermeable and optionally carbon dioxide-impermeable. In certain embodiments, the external receptacle 201 is prepared from a flexible membrane material 208. As illustrated in a non-limiting aspect of the present disclosure in Figure 1C, the external receptacle 201 may be prepared from one or more membrane materials 208. In other embodiments, as described below, the external receptacle 201 may be prepared as a tube and sealed at the ends to produce the external receptacle. The present disclosure also provides an external receptacle 201 comprising one membrane material 208 that is folded and sealed to prepare the external receptacle 201. In further embodiments, the external receptacle 201 may comprise two membrane materials 208 joined together. In yet another embodiment, the external receptacle 201 may be prepared from two different membrane materials 208, each substantially impermeable to oxygen and optionally impermeable to carbon dioxide. As discussed below, additional sheets of membrane material 208 can be joined together to prepare an external receptacle 201 having an extended feature 217 to accommodate the increase in volume of the collapsible blood container 202 that occurs when oxygen-deficient blood is transferred to the blood storage device 20. The disclosure provides a blood storage device 20 having a drooping feature 203. The disclosure also provides, and includes, a blow-molded external receptacle 201 comprising a preferred membrane material 208 that is substantially impermeable to oxygen and optionally impermeable to carbon dioxide.

[0038] This disclosure provides and includes a substantially oxygen-impermeable external receptacle 201. As used herein, a substantially oxygen-impermeable external receptacle 201 is sufficiently oxygen-impermeable to allow only 10 cc of oxygen in the receptacle over a period of 3 months, more preferably only 5 cc of oxygen over a period of 6 months. As used herein, the term “substantially oxygen-impermeable” (SiO) refers to materials and compositions that provide a barrier sufficient to prevent a significant increase in the partial oxygen pressure in the oxygen passage from one side of the barrier to the other. In certain embodiments, a substantially oxygen-impermeable membrane suitable for use in the preparation of the external receptacle 201 is characterized by a bar value of less than 1.0 bar. In other embodiments, a substantially oxygen-impermeable membrane suitable for use in the preparation of the external receptacle 201 is characterized by a bar value of 0.001 to 0.2 bar. In certain embodiments, a film suitable for use in the preparation of external receptacles and other elements of the present disclosure is a material characterized by a barer value of less than 0.02 barer. In certain embodiments, a film suitable for use in the preparation of external receptacles and other elements of the present disclosure is a material characterized by a barer value of less than 0.002 barer.

[0039] Furthermore, this disclosure states that the oxygen concentration is approximately 0.5 cc / m³. 2 The present disclosure provides and includes a substantially oxygen-impermeable external receptacle 101 having an oxygen permeability of less than 1 / day. In certain embodiments, a membrane suitable for use in the preparation of the external receptacle and other elements of the present disclosure is a material characterized by a Barra value of less than 1.0 Barra. In certain embodiments, a membrane suitable for use in the preparation of the external receptacle and other elements of the present disclosure is a material characterized by a Barra value of less than 0.2 Barra.

[0040] It is worth noting that there are few materials that provide complete impermeability, and even highly permeable materials can be hindered when joining, welding, folding, and otherwise assembling the external receptacle 201. As discussed below, the blood storage device 20 may further incorporate one or more inlets / outlets 30, each comprising a seal adapter 301 and an adhesive section 302, into the external receptacle 201. In other embodiments, the inlet / outlet 30 may comprise a single, substantially oxygen-impermeable, one-piece tube incorporating piping 304, the adhesive section 302, and piping 205. In other embodiments, the one-piece tube is bonded to the external receptacle 201 in place of piping 304 and piping 205. The external receptacle 201 must also be designed to accommodate changes in the volume of the internal collapsible blood container 202. In embodiments of this disclosure, the integrity of the impermeable barrier can be maintained by including the manifold as an inlet / outlet 30 formed in the shape of a seal adapter 301 or a diamond wedge shape as shown in Figure 3C. Therefore, special attention is paid to incorporating specific design elements and manufacturing methods to ensure the integrity of the impermeable barrier.

[0041] In one aspect of this disclosure, the manifold is a seal adapter 301. In another aspect, the inlet / outlet 30 may consist of multiple inlets / outlets. In one aspect, the inlet / outlet 30 incorporates two barrier transverse pipes 305 and a manifold 301. In another aspect, the inlet / outlet 30 incorporates three barrier transverse pipes 305 and a manifold 301. An example of a manifold seal adapter 301 having three inlets / outlets 30 and three barrier transverse pipes 305 is provided in Figure 3D. This disclosure further provides and includes barrier transverse pipes 305 having different diameters and functions. In one aspect of this disclosure, the barrier transverse pipe 305 is, for example, a double-layer pipe as shown in Figure 3C. In another aspect, the barrier transverse pipe(s) 305 is, for example, a triple-layer pipe as shown in Figures 3A and 3B. In one embodiment, the inlet / outlet 30 has a tube (e.g., a spike port) for enabling blood transfusion (e.g., an outlet for letting blood flow from the internal collapsible blood container 202) and for adding nutrients to the internal collapsible blood container 202 of the blood storage device 20. The use of such spike port is also provided and includes for guiding oxygen into the internal collapsible blood container 202 to re-oxygenate the blood before transfusion.

[0042] Furthermore, this disclosure provides approximately 0.5 cc of oxygen / m³. 2 The present disclosure provides and includes a substantially oxygen-impermeable external receptacle 201 having an oxygen permeability of less than 1 / day. In certain embodiments, a membrane suitable for use in the preparation of the external receptacle and other elements of the present disclosure is a material characterized by a Barra value of less than 1.0 Barra. In certain embodiments, a membrane suitable for use in the preparation of the external receptacle and other elements of the present disclosure is a material characterized by a Barra value of less than 0.2 Barra. In certain embodiments, a membrane suitable for use in the preparation of the external receptacle and other elements of the present disclosure is a material characterized by a Barra value of less than 0.02 Barra. In certain embodiments, a membrane suitable for use in the preparation of the external receptacle and other elements of the present disclosure is a material characterized by a Barra value of less than 0.002 Barra.

[0043] Materials and methods for preparing the external receptacle 201 are known in the art. See, for example, U.S. Patent No. 7,041,800 issued to Gawryl et al., U.S. Patent No. 6,007,529 issued to Gustafsson et al., and U.S. Patent Application Publication No. 2013 / 0327677 by McDorman. Each of these is incorporated herein by reference in whole. Impermeable materials are routinely used in the art, and any suitable material may be used. In the case of molded polymers, additives are routinely added to enhance oxygen (and CO2) barrier properties. See, for example, U.S. Patent No. 4,837,047 issued to Sato et al. For example, U.S. Patent No. 7,431,995 issued to Smith et al. describes an oxygen and carbon dioxide impermeable receptacle consisting of layers of ethylene vinyl alcohol copolymer and modified ethylene vinyl acetate copolymer that are impermeable to the transfer of carbon and carbon dioxide. In another embodiment, the external receptacle 201 is impermeable to oxygen and carbon dioxide.

[0044] In certain embodiments, a substantially oxygen-impermeable film may be a laminated film. In certain embodiments, a substantially oxygen-impermeable laminated film is a laminated foil film. The film material may be a polymer, or a foil material, or a multilayer construct of a combination of foil and polymer. In certain embodiments, the laminated film may be a polyester film laminated with aluminum. Examples of suitable aluminum laminates, also known as laminated foils, that are substantially oxygen-impermeable 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 containing a substantially oxygen-impermeable ethylene-vinyl alcohol copolymer (EVOH) resin. Additional suitable materials for the external receptacle 201 include silicone oxide coated polyester, silicone oxide coated polypropylene, and silicone oxide coated nylon films. Suitable silicone oxide coated films include, but are not limited to, CERAMIS® silicone oxide coated films (Celplast Metallized Products Limited, Ontario, Canada). In one embodiment, the external receptacle 201 may be a barrier bag constructed by sealing three or four sides by thermal sealing. This bag is constructed of a multilayer structure containing materials that enhance O2 and CO2 barrier properties.

[0045] Table 1 below shows the oxygen transport rates (barrels) of various bulk polymer materials tested at 23°C and 0% RH using 25.4 μm (1 mil) thick samples. Table 1: Oxygen Transfer Rate (OTR) of various bulk polymer materials JPEG2026053349000002.jpg78156

[0046] EVOH has excellent barrier properties as a neat film, but it rapidly loses these properties upon exposure to water vapor and especially to RH above 70%. Similarly, nylon-6 has good barrier properties but is susceptible to degradation under high moisture conditions. It is well known in the art to create multilayer laminates and / or coated structures to enhance barrier properties compared to the bulk materials described above. Such techniques and compositions use layers of EVOH interposed between layers of other polymers such as PA, PET, PE, PP, or PVC to provide water retention and other desirable properties to the EVOH layer, thereby resulting in excellent barrier properties for the multilayer structure. Such compositions are well known in the art, and for example, the EVAL® series of EVOH films are commercially available from Kurary Company of America (Pasadena, TX).

[0047] Another method for producing reinforced multilayer structures known in the art is by coating or metallizing a polymer substrate. Examples of such reinforced barrier films are shown in Table 2 below, and since they are composite structures, the OTR is independent of the properties or thickness of the bulk film. Examples of suitable aluminum laminates, also known as laminated foils, which are substantially oxygen-impermeable, are available from Protective Packaging Corp. (Carrollton, TX). Table 2: Reinforced barrier film JPEG2026053349000003.jpg61160

[0048] Another method for producing reinforced multilayer structures known in the art involves protecting a silicon or alumina coating by coating a polymer substrate with a silicon or alumina barrier coating, followed by an additional coating or polymer laminate. In some embodiments, silica may be silicon oxide (SiOx). Examples of such reinforced barrier films are shown in Table 3 below. Table 3: RollPrint® ClearFoil® Reinforced Barrier Film JPEG2026053349000004.jpg78156

[0049] A preferred structure includes a PET-based polymer outer layer, which has good inherent oxygen barrier properties as a bulk material and is coated with an alumina intermediate layer to provide enhanced oxygen barrier properties beyond PET and better optical brightness than a silica intermediate layer, followed by a polyethylene inner layer for thermal sealing when processing the outer receptacle 201. The relative thickness of the alumina or silica layer determines the oxygen barrier properties of the final structure of the film used to process the outer receptacle 201.

[0050] In another embodiment, a preferred structure comprises a PET-based polymer outer layer having good inherent oxygen barrier properties as a bulk material, coated with an alumina intermediate layer to provide enhanced oxygen barrier properties beyond PET, and a silica intermediate layer to provide good optical brightness, followed by a PVC inner layer having good blood compatibility for bonding to other PVC components. In some embodiments, the PVC is plasticized with DEHP to provide enhanced blood compatibility when blood is stored in contact with its surface.

[0051] Other manufacturers produce similar products with similar oxygen permeability, such as Renolit Solmed Wrapflex® (American Renolit Corp., City of Commerce, CA) and Celplast Ceramis® films (Celplast Metallized Products, Toronto, Ontario, Canada).

[0052] Another method applicable to the preparation of SiO materials involves multilayer graphite films formed 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, Article number: 4843 (2014) (the entire article is incorporated herein by reference). Multilayer barrier laminates containing nanoparticles for enhancing oxygen barrier properties, such as those provided by Tera-Barrier (Tera-Barrier Films Pte, Ltd, The Aries, Singapore) and described by Rick Lingle in Packaging Digest Magazine on August 12, 2014, are also known in the art.

[0053] In an embodiment of this disclosure, the external receptacle 201 may be prepared from a gas-impermeable plastic. In one embodiment, the gas-impermeable plastic may be a laminate. In a particular embodiment, the laminate may be a transparent barrier film, such as a nylon polymer or ethylene vinyl acetate (EVA). In one 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 an aluminum oxide. In another embodiment, the coating may be a silicone oxide. In another embodiment, the coating may be an ethylene vinyl alcohol copolymer (EVOH) laminated between layers of low-density polyethylene (LDPE).

[0054] The external receptacle 201 of this disclosure may be formed of one or more parts prepared from a gas-impermeable material, including plastic or other resistant lightweight material. In some embodiments, the sealed container may be formed from one or more materials. In some embodiments, the external receptacle 201 may be formed from a certain material and coated with a gas-impermeable material to prepare a gas-impermeable sealed container. In some embodiments, the rigid or flexible external receptacle 201 may be prepared from a plastic that can be injection-molded or blow-molded. In embodiments according to this disclosure, the plastic may be selected from polystyrene, polyvinyl chloride, or nylon. In one embodiment, the outer receptacle 201 material is polyester (PES), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), 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), polyacrylonitrile The material can be selected from the group consisting of (PAN), polycarbonate (PC), polycarbonate / acrylonitrile butadiene styrene (PC / ABS), polyurethane (PU), melamine formaldehyde (MF), plastic starch materials, phenols (PF), polyether ether ketone (PEEK), polyetherimide (PEI) (Ultem), polylactic acid (PLA), polymethyl methacrylate (PMMA), polytetrafluoroethylene (PTFE), and urea-formaldehyde ethyl vinyl acetate (EVA). In some embodiments, ethylene vinyl alcohol copolymer (EVOH) may be used when it is part of a multilayer laminate. In certain embodiments, the outer receptacle 201 comprises polyethylene terephthalate (PET). In certain embodiments, the outer receptacle 201 comprises nylon-6. In certain embodiments, the outer receptacle 201 may be polyethylene.In some embodiments, the polyethylene external receptacle 201 may include one or more polyethylene components that are welded together.

[0055] This disclosure provides, and includes, the preparation of an external receptacle 201 and an internal collapsible blood container 202 from a membrane or film. As used herein, membrane generally refers to the material used to prepare the internal collapsible blood container 202, and film is used to refer to the material used to prepare the external receptacle 201. A membrane comprises one or more layers of material in the form of a sheet that allows or prevents one or more substances from passing from one side of the sheet to the other side. As used herein, a membrane may be prepared as a tube suitable for connecting components of a blood storage device 20, a blood collection kit, or elements of a blood collection device, an additive solution bag, a leukopenic filter, and a depletion device, including a depletion device provided in U.S. Provisional Application No. 62 / 131,130 filed March 15, 2015. When used throughout, the membranes of this disclosure may be formed as sheets or tubes, depending on the application. Furthermore, as previously provided, the membrane for preparing the external receptacle 201 is substantially oxygen-impermeable, while the internal foldable blood container 202 is oxygen-permeable.

[0056] This disclosure provides and includes the preparation of external receptacles 201 using thermal sealing, blow molding, and injection molding techniques. Suitable materials for preparing external receptacles 201 using thermal sealing, blow molding, vacuum forming, and injection molding techniques 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 external receptacles 201, for example, consisting of a barrier layer of ethyl vinyl alcohol (EVOH or EVA) positioned between two layers of polypropylene (PP), as described in U.S. Patent No. 5,906,285, provided by Kortec (Kortec, Inc., Rowley, MA) and issued to Slat, are known in the art. Additives that enhance the oxygen and CO2 barrier properties of polymers before molding, during their formation, or during setting are known in the art. One example is multilayer polymer co-injection resulting in multilayer PET. Such barrier resins are typically incorporated during the pre-forming stage as an inner layer having PET on both sides, with PET serving as the liquid contact layer and outer layer. Suitable blow-molded or injection-molded outer receptacle 201, as provided below, is oxygen impermeable. In certain embodiments, suitable heat-sealed, vacuum-formed, blow-molded, or injection-molded outer receptacle 201 is substantially impermeable to both oxygen and carbon dioxide.

[0057] The present disclosure provides two materials for the preparation of either a permeable membrane or a substantially impermeable membrane and includes the same. In certain embodiments, the permeable membrane according to the present disclosure provides for the passage of substances through the material, not necessarily exclusively, but specifically for the passage of oxygen. In certain particular embodiments, the membrane is selected to permit the passage of oxygen and carbon dioxide while preventing the passage of water, proteins, salts (e.g., plasma components), and blood cells (e.g., red blood cells, white blood cells, and platelets). The rate of passage through the material depends on one or more characteristics including particle size, phase of the material (liquid versus gas), hydrophilicity, hydrophobicity, or solubility. Also, the rate of passage or flux through the material depends on the presence or absence of a driving force such as a difference in pressure (or partial pressure), temperature, or concentration between one side of the membrane and the other side. The flux through the membrane is known as the membrane permeation flux. The membrane permeation flux of a substance through the membrane is inversely proportional to the thickness of the membrane.

[0058] The membrane permeation flux of a gas is defined as the flow rate through the membrane per unit area per unit time. The SI unit used is m 3 / m 2 ·s. For gases and vapors, the quantity depends strongly on pressure and temperature. Thus, the permeation flux of a gas is often given with respect to standard temperature and pressure (STP), defined as 0 °C and 1 atmosphere (1.0013 bar) (e.g., 273 °K and 760 Torr). As noted above, the rate of passage depends on the driving force or difference between the two sides of the membrane, and this dependence is incorporated into the permeability coefficient P, or simply permeability.

[0059] Permeability (P) is defined as the permeation flux per unit of driving force per unit of membrane thickness. The SI unit of the permeability coefficient P is provided in Table 4. The common unit for gas separation is Barrer, as in the present disclosure, which is also presented in Table 4. The term "cm 3 gas (STP) / cm 2 s" refers to the volumetric membrane penetration flux of the diffusing species under standard conditions of 0 °C and 1 atm, and the term cm refers to the membrane penetration partial pressure driving force of this diffusing species. Permeability must be determined experimentally. Table 4: Permeability Units JPEG2026053349000005.jpg42156

[0060] Suitable membranes for the methods and apparatus of this disclosure include dense membranes, porous membranes, asymmetric membranes, and composite membranes. In certain embodiments, suitable membranes may be multilayer membranes. In other embodiments, suitable membranes are prepared from inorganic materials. A dense membrane is a membrane prepared from a solid material that does not have pores or voids. The material penetrates the dense membrane by dissolution and diffusion steps. Examples of dense membranes include standard blood bag materials such as PVC, PVC-DEHP, PVC-citrate, PVC-DINCH, polyolefins (e.g., PE, LDPE, UHMWPE, PP, and OPP), urethanes, and silicone membranes (polydimethylsiloxane, or PDMS). Also included and provided in this disclosure are porous membranes having a specific range of sizes that are separated based on size exclusion. Examples of porous membranes suitable for use in this disclosure include PVDF and polysulfone membranes. Examples of composite films suitable for use according to this disclosure are EMD Millipore GVHP hydrophobic PVDFs having pore sizes of 1.0 μm or 0.22 μm.

[0061] Composite membranes, often manufactured as laminates of one or more materials, are included and provided by this disclosure, with a dense material applied to a porous support layer. An example of a composite membrane suitable for use according to this disclosure is EMD Millipore GVSP superhydrophobic PVDF having a pore size of 1.0 μm or 0.22 μm. Table 5: Permeability of fluoropolymers (200 μm thickness, 23°C): JPEG2026053349000006.jpg76160

[0062] This disclosure provides, and includes, an internally foldable blood container 202 prepared from a membrane 206 primarily characterized by its oxygen permeability. Unless otherwise indicated, “substantially impermeable membrane” means a membrane that is substantially impermeable to oxygen. However, in certain devices and methods, the membrane may further be characterized by carbon dioxide permeability or impermeability. In certain applications, the membrane material is substantially impermeable to oxygen and provides a barrier to the introduction of oxygen into blood, blood components, or a blood collection kit consisting of multiple components. Such substantially impermeable membranes are commonly used to prepare the external receptacles of this disclosure. Also, suitable substantially impermeable membranes may be used to prepare piping for connecting components of devices and kits. A substantially impermeable membrane may consist of a single layer or may be a laminated sheet or tube having two or more layers.

[0063] This disclosure provides and includes an internally foldable blood container 202 having a permeability of at least 3 barers. In a particular embodiment, the foldable blood container 202 is substantially oxygen-permeable and has a permeability of 3 to 350 barers. In a particular embodiment, the internally foldable blood container 202 is substantially oxygen-permeable and has a permeability of 3 to 11 barers. In a particular embodiment, the internally foldable blood container 202 is substantially oxygen-permeable and has a permeability of 11 to 350 barers. In a particular embodiment, the internally foldable blood container 202 is substantially oxygen-permeable and has a permeability of 11 to 99 barers. In a particular embodiment, the internally foldable blood container 202 is substantially oxygen-permeable and has a permeability of 99 to 250 barers.

[0064] Applications for using the internally collapsible blood container 202 having a permeability of 3 to 350 barers include cases where the blood transferred to and contained within the internally collapsible blood container has a suitably reduced oxygen content and protection from oxygen ingress during storage is desired. In certain embodiments, the internally collapsible blood container 202 has a permeability of 3 to 11 barers. In certain embodiments, the internally collapsible blood container 202 has a permeability of 11 to 350 barers. In certain embodiments, the internally collapsible blood container 202 is substantially oxygen-permeable and has a permeability of 11 to 99 barers. In certain embodiments, the internally collapsible blood container 202 has a permeability of 99 to 250 barers. In certain embodiments, the internally collapsible blood container 202 does not have a permeability exceeding 350 barers. In another embodiment, the internally collapsible blood container 202 does not have a permeability of 350 to 500 barers.

[0065] This disclosure provides and includes an internally foldable blood container 202 having a membrane 206 having an oxygen permeability of 3 to 11 bars. In certain embodiments, the internally foldable blood container is oxygen permeable, has an oxygen permeability of 3 to 11 bars, and is exemplified by an internally foldable blood container made from PVC-DEHP, PVC-citrate, or PVC-DINCH. In certain embodiments, the internally foldable blood container is oxygen permeable, has an oxygen permeability of 4.3 bars, and is exemplified by an internally foldable blood container made from PVC-DEHP.

[0066] In certain embodiments, the use of an oxygen-permeable internally foldable blood container 202 having a permeability of 3 to 11 bars includes a case where the transfer of oxygen into the blood through the inlet tube 205 is removed by gas transfer through the internally foldable blood container 202 and can be adsorbed by an oxygen adsorbent 207. In certain embodiments, the use of an oxygen-permeable internally foldable blood container 202 having a permeability of 11 to 99 bars includes a case where the transfer of oxygen into the blood through the inlet tube 205 is removed by gas transfer through the internally foldable blood container 202 and can be adsorbed by an oxygen adsorbent 207.

[0067] Furthermore, the disclosure provides and includes an internally foldable blood container 202 having a substantially oxygen-permeable membrane 206. The substantially oxygen-permeable membrane 206 is generally used in the disclosure for the preparation of the internally foldable blood container 202. The substantially permeable membrane 206 may include a single layer or a laminated structure having two or more layers.

[0068] In one embodiment, an oxygen-permeable membrane 206 having an oxygen permeability greater than 11 bar is used in the preparation of a foldable blood container 202. In another embodiment, an oxygen-permeable membrane 206 having an oxygen permeability greater than 99 bar is used in the preparation of a foldable blood container 202. In yet another embodiment, the oxygen-permeable membrane 206 has an oxygen permeability greater than 200 bar. In one particular embodiment, an oxygen-permeable membrane 206 suitable for use in the preparation of a foldable blood container 202 is characterized by a bar value greater than 3. In another embodiment, an oxygen-permeable membrane 206 suitable for use in the preparation of a foldable blood container 202 is characterized by a bar value greater than 11. In one particular other embodiment, an oxygen-permeable membrane 206 suitable for use in the preparation of a foldable blood container 202 is characterized by a bar value greater than 99.Examples of oxygen-permeable membranes 206 suitable for use in the preparation of foldable blood containers 202 include Membrana Accurel® PP flat sheet membranes (Membrana division of Celgard, LLC, Charlotte, NC), PP flat sheet membranes from Sterlitech (Kent, WA), Metricel® PP hydrophobic filter membranes (Pall Corp., Port Washington, NY), Propafilm® RGP, RF and RGN series biaxially oriented polypropylene (BOPP) films from Innovia (Innovia Films, Inc., Atlanta, GA), P-Derm® PS-1033 and PS-1045 silicone sheets from Polymer Sciences (Polymer Sciences, Inc., Monticello, IN), Silpuran® silicone sheets from Wacker (Wacker Silicones, Inc., Adrian MI), and Millipore (EMD This includes PVDF microporous membranes such as the GVHP and GVSP series from Millipore (Bedford, MA), polysulfone microporous membranes from companies such as Pacific Membranes (Pacific Membranes, Inc., San Diego, CA), or MicroPES® membranes from Membrana.

[0069] In one embodiment, the substantially oxygen-permeable membrane 206 may be a dense membrane prepared from a non-porous material. Examples of suitable materials that enable high oxygen permeability include silicone, polyolefin, epoxy, and polyester. In another embodiment, the substantially oxygen-permeable membrane may be a porous membrane prepared from an organic polymer. The substantially oxygen-permeable membrane 206 may be prepared from a material selected from the group consisting of hydrophobic PVDF, polytetrafluoroethylene (PTFE), polyamide (nylon), cellulose ester, polysulfone, polyethersulfone, hydrophobic polypropylene, and polyacrylonitrile.

[0070] This disclosure provides, and includes, the preparation of a substantially oxygen-permeable membrane 206 by selecting and controlling its thickness as well as the material. As described above, permeability is proportional to the membrane thickness. Therefore, improved permeability may be achieved by reducing the membrane thickness. In certain embodiments, the minimum thickness is determined by its strength and resistance to puncture and tearing.

[0071] Furthermore, this disclosure provides and includes a substantially oxygen-permeable membrane 206 prepared using blow molding and injection molding techniques. Suitable materials for preparing internally foldable blood containers 202 using blow molding and injection molding include silicone materials such as Bluestar 4350, 50 durometer, Silbione grade liquid silicone rubber, and Shin-Etsu KEG-2000-40A / B liquid silicone. The selection of silicone durometer is carefully chosen with respect to well-controlled wall thickness, following foldability and permeability. Thinner materials have higher permeability. Methods for preparing blow-molded and injection-molded collapsible blood containers 202 are known in the art, for example, in U.S. Patent No. 4,398,642 issued by Okudaira et al., U.S. Patent No. 7,666,486 issued by Sato et al., U.S. Patent No. 8,864,735 issued by Sano et al., and U.S. Patent Application Publication No. 2012 / 0146266 by Oda et al. In one embodiment, the blow-molded collapsible blood container 202 may be prepared using LDPE used in the manufacture of collapsible water containers. A suitable blow-molded or injection-molded collapsible blood solution 202 has an oxygen permeability of at least 3 bars, as described below.

[0072] Applications for using the oxygen-permeable internally collapsible blood container 202 having a permeability of 3 to 350 bar include cases where the blood transferred to the internally collapsible blood container and contained therein has a reduced oxygen content and further oxygen reduction during storage is desired.

[0073] This disclosure provides and includes a membrane 206 that is substantially oxygen-permeable and may also be water vapor-permeable. Those skilled in the art will recognize that oxygen permeability, like that of other gases, is often, though not always, accompanied by water vapor permeability. Furthermore, those skilled in the art will recognize that as oxygen permeability increases, water vapor permeability may inevitably increase as well. With this disclosure, the membrane 206 may be selected based on selective permeability of oxygen or oxygen and carbon dioxide while minimizing water permeability. For use in a collapsible blood container 202, the membrane 206 is selected to minimize water vapor permeability and prevent the escape of water from the plasma or additive solution during storage. To properly preserve blood in a storage container for up to 64 days, the blood should not be allowed to lose a substantial amount of water from its contained plasma. Therefore, the collapsible blood container 202 is prepared from a membrane 206 selected considering the water vapor transfer rate (MVTR) of the material. In embodiments according to this disclosure, a substantially oxygen-permeable membrane 206 is 30 g / m² when tested at 23°C and 100% RH. 2 It has a measured MVTR of less than 24 hours. An MVTR above 30 necessarily means 30 g / m². 2 It is inappropriate if it is greater than 24 hours.

[0074] The MVTR of materials used at lower temperatures and conditions than those typically used in standard MVTR tests, such as ASTM F-1249, particularly those used for the refrigerated storage of blood and blood components, will have a much lower actual MVTR than the values ​​reported for standard tests conducted at higher temperatures. The MVTR of most materials is highly dependent on the temperature at which they are used or tested. For example, Propafilm® RHX strong barrier coating film (PVDC coated BOPP, Innovia Films, Inc., Atlanta, GA) has an MVTR of 2.9 g / m² when tested at 38°C and 90% RH. 2 It has a 24-hour MVTR, but when tested at 23°C and 85% RH, it is only 0.3 g / m². 2 It has a 24-hour MVTR.

[0075] The OTR (Oxygen Transmittance) of most materials is independent of RH conditions. For example, Propafilm® RHX strong barrier coating film (PVDC coated BOPP, Innovia Films, Inc., Atlanta, GA) has an OTR of 2.1 bars per ASTM F-1927 when tested at 23°C and 85% RH, or at 25°C and 0% RH.

[0076] Exemplary foldable blood vessel membrane, 8.06 g / m² per ASTM F-1249 under standard test conditions of 23°C and 100% RH. 2 With a reported MVTR of / 24 hours, the moisture loss performance of Renolit ES-3000 (PVC-DEHP) is well known and industry-acceptable for refrigerated storage of blood, resulting in a daily weight loss of less than 2% for plastic blood storage containers as required by ISO 3826-1:2013. Other exemplary membranes used for processing and storing blood and blood components have a moisture loss of 26.4 g / m² at 23°C and 100% RH. 2 Renolit ES-4000 (PVC-citrate) with a reported MVTR of / 24 hours, 5.5 g / m² at 23°C and 100% RH. 2 Renolit 3406 (PVC-DINCH) with a reported standard MVTR of / 24 hours, and 3.5 g / m² at 23°C and 100 RH. 2 Contains Renolit 8300 (polyolefin-elastomer blend) with a reported MVTR of / 24 hours.

[0077] The external receptacle 201 provides additional moisture barrier protection in addition to oxygen barrier protection for the internal foldable blood container 202. Due to the additional protection of the external receptacle 201, materials having a higher MVTR than the exemplary Renolit ES-3000 PVC-DEHP material are suitable for use in manufacturing the foldable internal blood container 202, while also providing a higher OTR against deoxygenation of stored blood.

[0078] In the embodiments of this disclosure, the foldable blood container 202 contains 30 to 0.001 g / m³ of blood. 2 It is prepared from a membrane material 206 having an MVTR of / day. In a particular embodiment, the MVTR is 0.1 to 10 g / m². 2 / day. In another embodiment, MVTR is 1-8 g / m³. 2 / day

[0079] In the embodiments of this disclosure, MVTR is defined as g / m³ at 23°C and 100% RH. 2 Measured per day, the foldable blood container 202 contains approximately 3 g / m³ of blood. 2 It is prepared from membrane material 206, which is PVC having an MVTR of 1 / day. In another embodiment, the PVC contains DEHP, about 8 g / m² 2 It may have an MVTR of / day. In other embodiments, the PVC contains DINCH and is approximately 5 g / m². 2 It may have an MVTR of / day. In other embodiments, the PVC contains citrate and has a concentration of about 10 g / m². 2 It may have an MVTR of / day. In addition, the membrane material 206 allows for very little water loss, 0.001g / m². 2 It may be prepared from a foil film such as an aluminum foil film, which can provide a low MVTR per day.

[0080] Polyethylene films are known to have good moisture barrier properties but relatively poor oxygen barrier properties. For example, LDPE has a density of 17 g / m². 2 It has an MVTR of / day, but 2500cc / m 2 It has been reported to have an OTR of / day, but in comparison, nylon has 260g / m 2 MVTR and 95cc / m / day 2 It has been reported to have an OTR of 6 g / m² / day. The barrier performance of polyethylene is proportional to the polymer density; therefore, low-density PE materials have lower barrier performance characteristics than high-density PE materials. 2A film such as 76 μm thick polyethylene that provides MVTR / day can provide oxygen permeability without impairing water content. Also, 52 or 97 g / m² 2 The MVTR film per day can provide a good moisture barrier to blood products. Polyethylene and other polyolefin materials with good moisture barrier properties are suitable for use as permeable membranes 206 when preparing internally foldable blood containers 202. Table 6: Estimated water vapor permeability and water vapor / N2 selectivity of various polymers at 30°C for a water vapor activity of 0. JPEG2026053349000007.jpg186156

[0081] As used herein, the internally foldable blood container 202 is oxygen-permeable. In certain embodiments, the internally foldable blood container 202 is oxygen and carbon dioxide permeable. In other embodiments, the internally foldable blood container 202 is oxygen-permeable and carbon dioxide-impermeable.

[0082] The permeability of the internal foldable blood container 202 should be sufficient to allow oxygen to move from the stored blood to the outside, for example, through the tube 205 into the stored blood. In other embodiments, the permeability of the internal foldable blood container 202 may be sufficiently permeable to provide additional deoxygenation of the stored blood when combined with a sufficient amount of adsorbent 207. In certain embodiments, the external receptacle 201 and the foldable blood container 202 may be a single integrated device 20 comprising a multilayer membrane having a substantially impermeable layer and an innermost blood-compatible layer. The single integrated device 20 may further include an adsorbent 207 as a layer between the substantially impermeable layer and the innermost blood-compatible layer.

[0083] In the development of the blood storage device 20 of this disclosure, it was observed that the need for efficient and continuous removal of incoming oxygen can be significantly reduced by the appropriate selection and design of the inlet / outlet 30, piping 304, piping 205, and combinations thereof. The selection of an internally foldable blood container 202 with a permeability of 3 to 11 bars is provided in a device in which incoming oxygen is essentially reduced or eliminated. Though not limited to theory, it is thought that incoming oxygen enters the system mainly through the piping 205 or its joints 302, which may form gaps 209 and is carried to the foldable blood container 202. In order to maintain the oxygen-deficient state of the blood, it is necessary to remove the oxygen by letting it out of the oxygen-permeable foldable blood container 202, diffusing it through the headspace, and binding it to the oxygen adsorbent 207. Therefore, the material used to prepare the foldable blood container 202 should be selected to be as permeable as possible. In contrast, if the incoming oxygen can be largely eliminated, suitable material choices for the foldable blood container 202 may include low-permeability materials provided herein.

[0084] As used herein, an internally foldable blood container with significantly low oxygen permeability is a foldable blood container 202 having a permeability of 3 to 11 bars.

[0085] This disclosure provides and includes a foldable blood container 202, which is a relatively oxygen-permeable membrane 206 prepared from polyvinyl chloride (PVC). In embodiments of this disclosure, the foldable blood container 202 may be prepared from a PVC membrane 206 having a thickness of 25 μm to 450 μm, preferably 50 μm to 400 μm, and more preferably 150 μm to 400 μm. In some embodiments, the foldable blood container 202 may be prepared from a PVC membrane 206 having a thickness of 25 μm to 250 μm. In other embodiments, the foldable blood container 202 may be prepared from a PVC membrane 206 having a thickness of 350 μm to 450 μm. In some embodiments, the foldable blood container 202 is prepared from a PVC membrane 206 having a thickness of 381 μm.

[0086] The use of PVC in the manufacture of collapsible blood containers is well known in the art. The use of various plasticizers in various PVC formulations is also well known in the art, including the use of diethylhexyl phthalate (DEHP) for the long-term storage of red blood cells. In addition to increasing the flexibility of PVC, DEHP also increases the oxygen permeability of PVC. Accordingly, this disclosure provides and includes a collapsible blood container 202 comprising PVC to which DEHP has been added to increase permeability. A typical manufacture of a collapsible blood container from PVC-DEHP involves conveniently manufacturing a bag structure using high-frequency (RF) welding of a pair of films, each of which has a thickness of 350 μm to 400 μm. An exemplary PVC-DEHP film is Renolit ES-3000 film (American Renolit Corp., City of Commerce, CA).

[0087] Due to the relatively low oxygen permeability of such films for platelet storage, and the need for higher oxygen permeability, other plasticizers for PVC have been found useful in the manufacture of collapsible blood containers, including the use of citrate (see, for example, "The Role of Poly(Vinyl Chloride) in Healthcare" by Colin R. Blass, copyright 2001 Rapra Technology, Ltd., ISBN: 1-85957-258-8). A preferred example of a PVC-citrate film is Renolit ES-4000 film (American Renolit Corp., City of Commerce, CA). Furthermore, the plasticity and permeability of PVC may be enhanced by the inclusion of DINCH, bis(7-methyloctyl)cyclohexane-1,2-dicarboxylate (also identifiable as EC number 431-890-2, available from BASF as Hexamoll® DINCH). The collapsible blood container 202 of this disclosure may be made of PVC to which DINCH has been added to enhance oxygen permeability. Among the advantages of using citrate or DINCH in the collapsible blood container 202, although DEHP improves the preservation of red blood cells, some concerns have been raised regarding the safety of DEHP. Though not limited to theory, it is thought that deoxygenation of red blood cells allows for the removal of DEHP from the blood storage system, while not impairing the quality and preservation of red blood cells otherwise provided by DEHP.

[0088] This disclosure provides suitable PVC materials for use in an oxygen-permeable foldable blood container 202. The use of PVC-citrates such as Renolit ES-4000 having a thickness of 25 μm to 450 μm, preferably 50 μm to 400 μm, more preferably 150 μm to 400 μm, is suitable for providing a foldable blood container having the desirable characteristic of relatively high oxygen permeability to the PVC membrane, having an oxygen permeability of at least 3 bars, good RF weld and join characteristics, and high tensile strength. In a particular embodiment, this disclosure provides a foldable blood container 202 prepared from a relatively oxygen-permeable PVC membrane 206 having a thickness of 25 μm to 450 μm, suitable for the continuous decrease of oxygen in the blood contained therein over a storage period of 42 days or up to 64 days. In a particular embodiment, the disclosure provides a foldable blood container 202 prepared from a relatively oxygen-permeable PVC membrane 206 having a thickness of 350 μm to 400 μm, which is suitable for maintaining reduced oxygen levels in the blood contained therein over a storage period of up to 42 or 64 days.

[0089] This disclosure provides and includes a foldable blood container 202, which is a substantially oxygen-permeable membrane 206 prepared from silicone. In an embodiment according to this disclosure, the foldable blood container 202 may be prepared from a silicone membrane 206 having a thickness of 20 μm to 500 μm. In another embodiment, the foldable blood container 202 may have a thickness of 30 μm to 400 μm. In another embodiment, the foldable blood container 202 may have a thickness of 30 μm to 200 μm. In yet another embodiment, the foldable blood container 202 has a thickness of 50 μm to 150 μm. In a particular embodiment, this disclosure provides a foldable blood container 202 prepared from a substantially oxygen-permeable silicone membrane 206 having a thickness of 50 μm to 150 μm, which is suitable for the continuous decrease of oxygen in the blood contained therein over a storage period of 42 days or up to 64 days.

[0090] In an embodiment of this disclosure, the foldable blood container 202 may be prepared from a silicone film 206 having a thickness of 20 μm to 400 μm. In another embodiment, the foldable blood container 202 may have a thickness of 20 μm to 200 μm. In another embodiment, the foldable blood container 202 may have a thickness of 40 μm to 300 μm. In yet another embodiment, the foldable blood container 202 is 40 μm to 400 μm thick. In yet another embodiment, the foldable blood container 202 is 300 μm to 450 μm thick. In yet another embodiment, the thickness of the foldable blood container 202 may be 350 μm to 450 μm. This disclosure provides and includes a foldable blood container 202 having a thickness of 450 μm. In another embodiment, the foldable blood container 202 has a thickness of 425 μm. In yet another embodiment, the foldable blood container 202 is 400 μm thick. In an additional embodiment, the foldable blood container 202 is 350 μm thick. In a particular embodiment, the disclosure provides a foldable blood container 202 prepared from a substantially oxygen-permeable silicone membrane 206 having a thickness of 350 μm to 500 μm, which is suitable for maintaining reduced oxygen levels of the blood contained therein over a storage period of up to 42 or 64 days.

[0091] Suitable silicone membranes 206 include commercially available membranes. Non-limiting examples of silicone membranes are available from Wacker Silicones, such as medical-grade silicone sheet membranes under the Silpuran® brand (Wacker Silicones, Adrian, MI), and Polymer Sciences PS-1033 and PS-1044 P-Derm® silicone elastomer membranes (Polymer Sciences, Inc., Monticello, IN). In one embodiment, the silicone membrane may be Polymer Sciences PS-1033 or Silpuran® 6000 silicone. Silicone membranes can be prepared from a variety of liquid silicone rubber (LSR) materials, some examples of which are available from many silicone suppliers, such as Wacker Silicones (Adrian, MI), Shin-Etsu Silicones of America (Akron, OH), NuSil Technology (Carpenteria, CA), and Blue Star Silicones (East Brunswick, NJ).

[0092] In one aspect of the present disclosure, the foldable blood container 202 may be manufactured from silicone by various molding methods such as compression molding, injection molding, and insert molding, as well as by adhesive bonding of silicone sheets using a silicone adhesive. In one aspect of the present disclosure, a pair of silicone sheets are bonded together along the perimeter using a silicone adhesive, having a portion of silicone inlet piping in place at the seam. In another aspect of the present disclosure, a silicone liquid rubber is injection molded into a form to create a three-sided shape, which is then further bonded using a silicone adhesive to close along the silicone inlet tube on the remaining fourth side. In yet another aspect of the present disclosure, a silicone liquid rubber is injection molded into a form to create a three-sided shape, which is then insert molded onto a closing shape on the remaining fourth side, which incorporates the inlet piping into the closing shape. In yet another aspect of the present disclosure, a silicone liquid rubber is diluted in a suitable solvent such as xylene, hexane, or tetrahydrofuran, immersion coated into a form to create a three-sided shape, and then insert molded onto a closing shape on the remaining fourth side, which incorporates the inlet piping into the closing shape. mixed membrane inner bag

[0093] This disclosure provides, and includes, a foldable blood container 202 prepared from one or more types of membranes 206. In one embodiment, the foldable blood container 202 includes a first membrane 206 suitably bonded for preparing the container, and a second different membrane 206. In another embodiment, the foldable blood container 202 includes a membrane 206 combined with a second membrane 206 having permeability less than about 30% of the permeability of the first membrane 206. In one embodiment, the second membrane 206 may comprise a rigid structure bonded to the oxygen-permeable membrane 206. In embodiments according to this disclosure, the second membrane 206 is heat-sealed, laminated, or bonded to the membrane 206.

[0094] This disclosure provides and includes a foldable blood container 202, which is a substantially oxygen-permeable porous membrane 206 prepared from polytetrafluoroethylene, or polyvinylidene fluoride, also known as polyvinylidene difluoride (PVDF). In certain embodiments, the PVDF membrane is a substantially oxygen-permeable hydrophobic porous membrane.

[0095] In some embodiments of this disclosure, the microporous PVDF film 206 contains pores having a diameter in the range of 0.01 μm to 2.0 μm. In other embodiments, the microporous PVDF film 206 contains pores having a diameter in the range of 0.01 μm to 1.0 μm. In some embodiments, the microporous PVDF film 206 has a pore diameter of 0.03 μm to 1.0 μm. In other embodiments, the microporous PVDF film 206 has a pore diameter of 0.03 μm to 0.45 μm.

[0096] In an embodiment of this disclosure, the porosity of the PVDF membrane 206 used in the preparation of the foldable blood container 202 is 20 to 80%. In another embodiment, the porosity of the PVDF membrane 206 used in the preparation of the foldable blood container 202 is 35 to 50%.

[0097] In certain embodiments, the permeability of a PVDF film 206 having micropores larger than approximately 1.0 μm may allow fluids to permeate the film, impairing fluid confinement as well as both oxygen and carbon dioxide permeability. To overcome this permeability at high pore sizes, so-called "superhydrophobic" films can be used, with contact angles greater than 150°. Where used herein and known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of nonhydrophobic PVDF materials is not recommended because the material has low surface tension, allowing fluids to seep out of the pores, even within the above range.

[0098] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a PVDF permeable membrane 206 having a pore size of 0.1 to 0.8 μm in diameter. In other embodiments, the micropores of the porous PVDF membrane may be 0.22 to 0.8 μm in diameter. In some embodiments, the micropores of the porous PVDF membrane are 0.2 to 1.0 μm. In another embodiment, the micropores of the porous PVDF membrane may be greater than 0.1 μm and less than 1.0 μm. In yet another embodiment, the micropores of the porous PVDF membrane are in the range of 0.05 to 1.0 μm. In some embodiments, the micropores of the porous PVDF membrane may be greater than 0.3 or 0.4 μm. In other embodiments, the micropores of the porous PVDF membrane may be greater than 0.5 or 0.6 μm.

[0099] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having micropores of less than 1.0 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having micropores of less than 0.8 μm. In a particular embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having micropores of less than 0.65 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having micropores of less than 0.45 μm.

[0100] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having a micropore size of 0.1 μm. In another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having a micropore size of 0.22 μm. In yet another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having a micropore size of 0.20 μm. In a further embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having a micropore size of 0.45 μm. In yet another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having a micropore size of 0.65 μm. In another embodiment of the present disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a PVDF membrane 206 having a pore size of 0.8 μm.

[0101] In some embodiments of this disclosure, the PVDF membrane may have a thickness of less than 250 μm. In certain embodiments, the membrane is thicker than 10 μm. In some embodiments, the PVDF membrane may have a thickness of 10 to 250 μm. In other embodiments, the PVDF membrane may have a thickness of 10 to 125 μm, or 25 to 150 μm. In some embodiments, the PVDF membrane may have a thickness of 50 to 125 μm, 75 to 125 μm, 50 to 150 μm, 75 to 150 μm, 100 to 125 μm, 150 to 250 μm, or 25 to 150 μm. In some embodiments, the membrane 206 of the internally foldable blood container 202 is 20 μm thick. In other embodiments, the membrane 206 of the internally foldable blood container 202 is 30 μm thick. In yet another embodiment, the membrane 206 of the internally foldable blood container 202 is 50 μm thick. In yet another embodiment, the membrane 206 of the internally foldable blood container 202 is 76 μm thick. In one embodiment, the membrane 206 of the internally foldable blood container 202 is 120 μm thick.

[0102] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a PVDF permeable membrane 206 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a PVDF permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm and a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a PVDF permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm and a thickness of 50 to 150 μm.

[0103] Suitable PVDF membranes for the preparation of oxygen-permeable internally foldable blood vessels according to this disclosure include VVSP 115 μm thick / 0.1 μm pores, GVSP 115 μm thick / 0.22 μm pores, HVSP 115 μm thick / 0.45 μm pores, DVSP 115 μm thick / 0.65 μm pores, BVSP 115 μm thick / 1.0 μm pores, VVHP 107 μm thick / 0.1 μm pores, GVHP 125 μm thick / 0.22 μm pores, HVHP 115 μm thick / 0.45 μm pores, or DVHP 115 μm thick / 0.65 μm pores.

[0104] Suitable PVDF membranes 206 include commercially available membranes. Non-limiting examples of PVDF membranes 206 are available from Millipore Corporation (Bedford, MA). In one embodiment, PVDF membranes 206 may be available from Millipore Corporation (Bedford, MA). Examples of such PVDF membranes 206 are VVSP, GVSP, HVSP, DVSP, BVSP, VVHP, GVHP, HVHP, or DVHP.

[0105] This disclosure provides and includes a foldable blood container 202, which is a substantially oxygen-permeable microporous membrane 206 prepared from polysulfone. In a particular embodiment, the polysulfone membrane 206 is a substantially oxygen-permeable hydrophobic microporous membrane 206.

[0106] In embodiments of this disclosure, the microporous polysulfone film 206 contains pores having a range of 0.01 μm to 2.0 μm. In other embodiments, the microporous polysulfone film 206 contains pores having a range of 0.01 μm to 1.0 μm. In some embodiments, the microporous polysulfone film 206 has a pore diameter of 0.03 μm to 1.0 μm. In other embodiments, the microporous polysulfone film 206 has a pore diameter of 0.03 μm to 0.45 μm.

[0107] In an embodiment of this disclosure, the porosity of the polysulfone membrane 206 used in the preparation of the foldable blood container 202 is 20 to 80%. In another embodiment, the porosity of the polysulfone membrane 206 used in the preparation of the foldable blood container 202 is 35 to 50%.

[0108] In certain embodiments, the permeability of polysulfone films with micropores larger than approximately 0.2 μm may allow fluids to permeate the film, impairing both fluid confinement and oxygen and carbon dioxide permeability. To overcome this permeability at high pore sizes, so-called "superhydrophobic" films can be used, with contact angles greater than 150°. Where used herein and known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of nonhydrophobic polysulfone materials is not recommended because the material has low surface tension, allowing fluids to seep out of the pores, even within the above range.

[0109] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polysulfone permeable membrane 206 having a pore size of 0.03 μm to 0.8 μm in diameter. In other embodiments, the micropores of the porous polysulfone membrane may be 0.22 μm to 0.8 μm in diameter. In some embodiments, the micropores of the porous polysulfone membrane are 0.2 μm to 1.0 μm. In another embodiment, the micropores of the porous polysulfone membrane may be greater than 0.1 μm to less than 1.0 μm. In yet another embodiment, the micropores of the porous polysulfone membrane are in the range of 0.05 μm to 1.0 μm. In some embodiments, the micropores of the porous polysulfone membrane may be greater than 0.3 μm or 0.4 μm. In other embodiments, the micropores of the porous polysulfone membrane may be greater than 0.5 μm or 0.6 μm.

[0110] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having micropores of less than 1.0 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having micropores of less than 0.8 μm. In a particular embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having micropores of less than 0.65 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having micropores of less than 0.45 μm.

[0111] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.1 μm. In another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.22 μm. In yet another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.20 μm. In a further embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.45 μm. In yet another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.65 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.8 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.03 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 0.05 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone membrane 206 having a pore size of 1.2 μm.

[0112] In some embodiments of this disclosure, the polysulfone membrane may have a thickness of less than 250 μm. In certain embodiments, the membrane is thicker than 10 μm. In some embodiments, the polysulfone membrane may have a thickness of 10 to 250 μm. In other embodiments, the polysulfone membrane may have a thickness of 10 to 125 μm, or 25 to 150 μm. In some embodiments, the polysulfone membrane may have a thickness of 50 to 125 μm, 75 to 125 μm, 50 to 150 μm, 75 to 150 μm, 100 to 125 μm, 150 to 250 μm, or 25 to 150 μm. In some embodiments, the membrane 206 of the internally foldable blood container 202 is 20 μm thick. In other embodiments, the membrane 206 of the internally foldable blood container 202 is 30 μm thick. In yet another embodiment, the membrane 206 of the internally foldable blood container 202 is 50 μm thick. In yet another embodiment, the membrane 206 of the internally foldable blood container 202 is 76 μm thick. In one embodiment, the membrane 206 of the internally foldable blood container 202 is 120 μm thick.

[0113] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polysulfone permeable membrane 206 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polysulfone permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm and a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polysulfone permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm and a thickness of 50 to 150 μm.

[0114] Examples of suitable polysulfone membranes 206 for the preparation of oxygen-permeable internally foldable blood vessels according to this disclosure include SS003AH 10-250 μm thick / 0.03 μm pores, SS005AH 10-250 μm thick / 0.05 μm pores, SS010AH 10-250 μm thick / 0.1 μm pores, SS020AH 10-250 μm thick / 0.2 μm pores, SS045AH 10-250 μm thick / 0.45 μm pores, SS065AH 10-250 μm thick / 0.65 μm pores, SS080AH 10-250 μm thick / 0.8 μm pores, or SS120AH 10-250 μm thick / 1.2 μm pores.

[0115] Suitable polysulfone membranes 206 include commercially available membranes. Non-limiting examples of polysulfone membranes 206 are available from Pacific Membranes. In one embodiment, the polysulfone membrane may be SS120AH, SS080AH, SS065AH, SS045AH, SS020AH, SS010AH, SS005AH, or SS003AH.

[0116] This disclosure provides and includes a foldable blood container 202 which is substantially oxygen-permeable and is a microporous membrane 206 prepared from polysulfone. This disclosure also provides and includes a foldable blood container 202 which is oxygen-impermeable and is prepared from a polyolefin film. In certain embodiments, the polyolefin membrane is a substantially oxygen-permeable hydrophobic porous membrane. Examples of oxygen-permeable polyolefin membranes 206 suitable for use in the preparation of foldable blood containers 202 include Membrana Accurel® PP flat sheet membranes (Membrana division of Celgard, LLC, Charlotte, NC), PP flat sheet membranes from Sterlitech (Kent, WA), Metricel® PP hydrophobic filter membranes (Pall Corp., Port Washington, NY), and biaxially oriented polypropylene (BOPP) films of the Propafilm® RGP, RF, and RGN series from Innovia (Innovia Films, Inc., Atlanta, GA). In certain embodiments, the polyolefin film is a substantially oxygen-permeable biaxially oriented polypropylene (BOPP) film. Examples of suitable polyolefin films include biaxially oriented polypropylene (BOPP) co-extruded films from Innovia (Innovia Films, Inc., Atlanta, GA) in the Propafilm® RGP, RF, and RGN series, which have oxygen permeability of 140 to 450 bars.

[0117] In embodiments of this disclosure, the microporous polyolefin film 206 contains pores having a diameter in the range of 0.01 μm to 2.0 μm. In other embodiments, the microporous polyolefin film 206 contains pores having a diameter in the range of 0.01 μm to 1.0 μm. In some embodiments, the microporous polyolefin film 206 has a pore diameter of 0.03 μm to 1.0 μm. In other embodiments, the microporous polyolefin film 206 has a pore diameter of 0.1 μm to 0.45 μm.

[0118] In certain embodiments of this disclosure, the use of non-hydrophobic polyolefin materials is not recommended because the material has low surface tension, which allows fluids to seep out of the pores, even within the limits described above.

[0119] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polyolefin permeable membrane 206 having a pore size of 0.1 μm to 0.45 μm. In other embodiments, the micropores of the porous polyolefin membrane may be 0.1 μm to 0.2 μm in diameter.

[0120] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polyolefin membrane 206 having micropores of less than 1.0 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polyolefin membrane 206 having micropore diameters of less than 0.5 μm. In a particular embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polyolefin membrane 206 having micropore diameters of less than 0.2 μm.

[0121] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polyolefin membrane 206 having a micropore size of 0.1 μm. In another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a polyolefin membrane 206 having a micropore size of 0.2 μm. In a further embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a polyolefin membrane 206 having a micropore size of 0.45 μm.

[0122] In embodiments of this disclosure, the polyolefin film may have a thickness of less than 250 μm. In certain embodiments, the film may have a thickness of more than 50 μm. In some embodiments, the polyolefin film may have a thickness of 50 to 250 μm. In other embodiments, the polyolefin film may have a thickness of 75 to 110 μm, or 140 to 180 μm.

[0123] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polysulfone permeable membrane 206 having a thickness of 50 to 250 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polyolefin permeable membrane 206 having a pore size of 0.1 μm to 0.45 μm and a thickness of 75 μm to 200 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polyolefin permeable membrane 206 having a pore size of 0.1 μm to 0.2 μm and a thickness of 75 μm to 200 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a polyolefin permeable membrane 206 having a pore size of 0.2 μm to 0.45 μm and a thickness of 140 μm to 200 μm.

[0124] Examples of polyolefin membranes suitable for the preparation of oxygen-permeable, internally foldable blood containers as disclosed herein include those described in U.S. Patent No. 4,440,815 issued to Zomorodi et al., Membrana Accurel® PP flat sheet membranes (Membrana division of Celgard, LLC, Charlotte, NC), PP flat sheet membranes from Sterlitech (Kent, WA), Metricel® PP hydrophobic filter membranes (Pall Corp., Port Washington, NY), and biaxially oriented polypropylene (BOPP) films from Innovia (Innovia Films, Inc., Atlanta, GA) in the RGP, RF, and RGN series.

[0125] In certain embodiments, a suitable film 206 that is substantially oxygen-permeable may be a multilayer film. In certain embodiments, the multilayer film is a substantially oxygen-permeable hydrophobic microporous film. Suitable multilayer films 206 include multilayer films having two or more materials selected from the group consisting of hydrophobic PVDF, PTFE, nylon, cellulose ester, polysulfone, polyethersulfone, hydrophobic polypropylene, and polyacrylonitrile.

[0126] This disclosure provides, and includes, a foldable blood container 202, which is a microporous membrane 206 prepared from an extruded, woven, nonwoven single layer, or multilayer film, and is substantially oxygen-permeable. In certain embodiments, the multilayer film is a substantially oxygen-permeable hydrophobic porous membrane.

[0127] In embodiments of this disclosure, the microporous multilayer film includes pores having a diameter in the range of 0.01 μm to 2.0 μm. In other embodiments, the microporous multilayer film 206 includes pores having a diameter in the range of 0.01 μm to 1.0 μm. In some embodiments, the microporous multilayer film 206 has a pore diameter of 0.03 μm to 1.0 μm. In other embodiments, the microporous multilayer film 206 has a pore diameter of 0.03 μm to 0.45 μm.

[0128] In an embodiment of this disclosure, the porosity of the multilayer membrane 206 used in the preparation of the foldable blood container 202 is 20 to 80%. In another embodiment, the porosity of the multilayer membrane 206 used in the preparation of the foldable blood container 202 is 35 to 50%.

[0129] In certain embodiments, the permeability of polysulfone films with micropores larger than approximately 1.0 μm may allow fluids to permeate the film, impairing both fluid confinement and oxygen and carbon dioxide permeability. To overcome this permeability at high pore sizes, so-called "superhydrophobic" films can be used, with contact angles greater than 150°. Where used herein and known in the art, the contact angle quantifies the wettability of a solid surface and is theoretically explained by Young's equation. In certain embodiments of this disclosure, the use of nonhydrophobic multilayer materials is not recommended because the material has low surface tension, allowing fluids to seep out of the pores, even within the above range.

[0130] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a multilayer permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm in diameter. In other embodiments, the micropores of the porous multilayer membrane may be 0.22 μm to 0.8 μm in diameter. In some embodiments, the micropores of the porous multilayer membrane are 0.2 μm to 1.0 μm. In another embodiment, the micropores of the porous multilayer membrane may be greater than 0.1 μm and less than 1.0 μm. In yet another embodiment, the micropores of the porous multilayer membrane are in the range of 0.05 μm to 1.0 μm. In some embodiments, the micropores of the porous multilayer membrane may be greater than 0.3 or 0.4 μm. In other embodiments, the micropores of the porous multilayer membrane may be greater than 0.5 or 0.6 μm.

[0131] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having micropores less than 1.0 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having micropore diameters less than 0.8 μm. In a particular embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having micropore diameters less than 0.65 μm. In another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having micropore diameters less than 0.45 μm.

[0132] In an embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having a micropore size of 0.1 μm. In another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a polysulfone film 206 having a micropore size of 0.22 μm. In yet another embodiment, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having a micropore size of 0.20 μm. In a further embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having a micropore size of 0.45 μm. In yet another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having a micropore size of 0.65 μm. In yet another embodiment of this disclosure, the blood storage device 20 comprises an internally foldable blood container 202 containing a multilayer film 206 having a micropore size of 0.8 μm.

[0133] In embodiments of this disclosure, the multilayer film 206 may have a thickness of less than 250 μm. In certain embodiments, the film is thicker than 10 μm. In some embodiments, the multilayer film 206 may have a thickness of 10 to 250 μm. In other embodiments, the multilayer film may have a thickness of 10 to 125 μm, or 25 to 150 μm. In some embodiments, the multilayer film 206 may have a thickness of 50 to 125 μm, 75 to 125 μm, 50 to 150 μm, 75 to 150 μm, 100 to 125 μm, 150 to 250 μm, or 25 to 150 μm. In another embodiment, the film 206 of the internally foldable blood container 202 is 30 μm thick. In yet another embodiment, the membrane 206 of the internally foldable blood container 202 is 50 μm thick. In yet another embodiment, the membrane 206 of the internally foldable blood container 202 is 76 μm thick. In one embodiment, the membrane 206 of the internally foldable blood container 202 is 120 μm thick.

[0134] In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a multilayer permeable membrane 206 having a thickness of 100 to 125 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a multilayer permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm and a thickness of 100 μm to 125 μm. In certain embodiments of this disclosure, the foldable blood container 202 is prepared from a multilayer permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm and a thickness of 50 μm to 150 μm.

[0135] This disclosure provides and includes a foldable blood container 202 having tear resistance. As used herein, “tear resistance” or “tear strength” is measured in kN / m. In embodiments of this disclosure, the foldable blood container 202 should be prepared from an oxygen-permeable material that is also tear-resistant. Measures of tear resistance, e.g., ASTM D-412, are known in the art and can be used to measure tear strength, modulus, and elongation. In certain embodiments, the foldable blood container 202 should be prepared from an oxygen-permeable material that is resistant to tear formation (e.g., tear initiation). Methods for measuring tear initiation and tear propagation, e.g., ASTM D-624, are known in the art. Other methods include measuring tear strength and elongation at fracture according to DIN 53 504-S1.

[0136] In one aspect of this disclosure, the foldable blood container 202 should be prepared from an oxygen-permeable material having a tear strength of at least 10 N / mm according to the test method ASTM D-1004. In one aspect, the tear strength is at least 25 N / mm. In several aspects, the tear strength is at least 50 N / mm. In several aspects, the tear strength is at least 100 N / mm. The blood storage device 20 further provides and includes a foldable blood container 202 prepared from a material having a tear strength of 10 to 100 N / mm. In an aspect of this disclosure, a reduced tear strength is provided for the foldable blood container 202, and the external receptacle 201 has a tear strength of at least 50 N / mm. Generally, the tear strength of the foldable blood container 202 decreases as the permeability increases. It will be understood by those skilled in the art that the materials are selected to maintain the overall integrity of the blood storage device 20, so that if potentially biohazardous blood material is to be contained, the device 20 will be handled roughly during processing (e.g., dropped or broken).

[0137] This disclosure provides a blood storage device 20 having an internal foldable blood container 202, further comprising one or more spacers 213 to ensure separation between an external receptacle 201 and the internal foldable blood container 202. The spacers 213 provide headspace maintenance in the blood storage device 20 to ensure efficient diffusion of oxygen to an adsorbent 207. The spacers 213 may be prepared from one or more materials selected from the group consisting of mesh, molded mats, woven mats, nonwoven mats, strand bales, and strand mats. In certain embodiments, the spacers 213 may be directly incorporated into the foldable blood container 202 as ridges, depressions, or other raised features that maintain separation between the external receptacle 201 and the internal foldable blood container 202. Furthermore, this specification includes and provides a spacer 213 that is directly incorporated into the external receptacle 201 as a ridge, depression, or other suitable raised feature that can maintain separation between the external receptacle 201 and the internal foldable blood container 102. In certain embodiments, the presence of the spacer 213 provides consistency to the assembly in terms of manufacturing techniques and lamination of the internal and external films, enabling the maintenance of repeatable oxygen levels. In other embodiments, the presence of the spacer 213 facilitates further oxygen loss during storage. By providing the spacer 213, it is possible to prevent the internal membrane 206 from laminating or "adhering" to the membrane or material of the external receptacle 201 via mechanical or physical means. If adhesion or lamination occurs, oxygen preservation or further oxygen loss of the assembly may be hindered as oxygen encounters an additional barrier and diffuses.

[0138] In certain embodiments, the spacer 213 also provides a protective layer surrounding the collapsible blood container 202, increasing its resistance to bursting in the event of accidental dropping or other traumatic forces during handling. In some embodiments, the spacer 213 providing the protective layer comprises an open-cell mesh polyurethane foam as the spacer 213 material. Such spacer 213 material may have approximately 10 pores per inch (ppi) to approximately 100 ppi. In some embodiments, the spacer 213 has 45 ppi and a height of 3.2 mm (0.125 in).

[0139] In addition to the holes, the spacer 213 providing the protective layer has a height of approximately 3.2 mm (0.125 in) to approximately 12.8 mm (0.5 in). In another embodiment, the spacer 213 has a height of approximately 6.4 mm (0.25 in). In another embodiment, the spacer 213 has a height of approximately 1.5 mm (0.064 in) to approximately 12.8 mm (0.50 in). In another embodiment, the spacer 213 has a height of approximately 1.2 mm (0.05 in) to approximately 10 mm (0.4 in). In another embodiment, the spacer 213 has a height of approximately 1.2 mm (0.05 in) to approximately 12.8 mm (0.5 in).

[0140] This disclosure provides and includes a blood storage device 20 for storing oxygen-deficient blood, comprising an external receptacle 201, a collapsible blood container 202, at least one inlet / outlet 30, and an oxygen adsorbent 207 located within the external receptacle 201. In one particular embodiment, the oxygen adsorbent 207 is located between the external receptacle 201 and the collapsible blood container 202. In another embodiment, the oxygen adsorbent is located within the collapsible blood container 202 and contained in a second blood-compatible container. In yet another embodiment, the oxygen adsorbent 207 is positioned as a layer of a multilayer membrane, with the outer layer being the external receptacle 201 and the innermost layer being the collapsible blood container 202.

[0141] This disclosure provides and includes adsorbents 207 that can bind to and remove oxygen from the environment. Unless otherwise provided, the term “adsorbent” refers to oxygen adsorbents and scavengers. As used herein, “oxygen scavenger” or “oxygen adsorbent” is a material that irreversibly binds to or combines with O2 under the conditions of use. The term “oxygen adsorbent” may be used interchangeably with “oxygen scavenger” herein. In certain embodiments of this disclosure, the material may irreversibly bind to or combine with oxygen. In other embodiments, oxygen binds to the adsorbent material and is released at a very slow rate (k オフ ) has. In one embodiment, oxygen can chemically react with some components of the material and be converted into another compound. Any material whose off-rate of bound oxygen is much lower than the residence time of blood can function as an oxygen scavenger.

[0142] When used herein, standard temperature and pressure (e.g., 0°C (273.15 Kelvin) and 1.01 × 10⁻⁶) 5 A quantity of adsorbent having a certain oxygen-binding capacity is provided, 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, oxygen adsorbents and scavengers can further bind to and remove carbon dioxide from the environment. In certain embodiments, the adsorbent 103 may be a mixture of non-toxic inorganic and / or organic salts, as well as divalent iron ions or oxygen, carbon dioxide, or other materials 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 essential.

[0143] Suitable oxygen adsorbents or adsorbents are known in the art. A suitable oxygen adsorbent according to this disclosure has a minimum oxygen adsorption rate of 0.8 mL / min. An adsorbent with a suitable adsorption profile binds 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. A suitable adsorbent may have both higher capacity and binding rate.

[0144] Non-limiting examples of oxygen scavengers or adsorbents include iron powder and organic compounds. Examples of O2 adsorbents include cobalt, iron, and Schiff-based chelating agents. 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., U.S. Patent No. 4,654,053 issued to Sievers et al., and U.S. Patent No. 4,366,179 issued to Nawata et al., each of which is incorporated herein by reference in its entirety. Oxygen adsorbent materials may be formed or incorporated into fibers, microfibers, microspheres, fine particles, and foams.

[0145] In certain embodiments, suitable adsorbents include those available from Multisorb Technologies (Buffalo, NY), Sorbent Systems / Impak Corporation (Los Angeles, CA), Dessicare, Inc. (Reno, NV), or Mitsubishi Gas Chemical America (MGC) (New York, NY). Exemplary oxygen adsorbents include iron-based oxygen scavengers, such as Multisorb Technologies StabilOx® packets, Sorbent Systems P / N SF100PK100 100cc oxygen absorber, and Mitsubishi Gas Chemical America (MGC) Ageless® SS-200 oxygen absorber. MGC also provides adsorbents suitable for the methods and apparatus of this disclosure. Such suitable oxygen adsorbents include MGC Ageless® SS-200 oxygen absorber.

[0146] In embodiments 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 (less than 0.01% carbon-carbon double bonds). In some embodiments, this backbone may contain ethylene or styrene monomers. In some embodiments, the polymer backbone may be ethylene-based. In other embodiments, the oxidizable organic compound may be an ethylene / vinylcyclohexane 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 embodiments, the oxidizable organic polymer may also include a substituted hydrocarbon moiety. Examples of oxygen-scavenging polymers include those described in International Patent Publication WO99 / 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 is incorporated herein by reference in whole.

[0147] When used herein, the adsorbents of this disclosure may be absent or contained in permeable encapsulating containers, vessels, envelopes, etc. In certain embodiments, the adsorbent is provided in one or more pouches formed of a material that is highly porous and essentially impervious to gas transport. Examples of such materials include stretched polyester film, perforated metal foil, stretched polyethylene film (Tyvek®), perforated foil, polymer, paper, and combinations thereof.

[0148] The disclosure further includes and provides adsorbents 207 incorporated as one or more laminated layers of a substantially oxygen-impermeable external receptacle 201. Polymer adsorbents such as those described above may be laminated onto a sheet used to prepare the external receptacle using methods known in the art, including flexible contact lamination, thermal lamination, or solvent lamination.

[0149] This disclosure further includes and provides adsorbents 207 which are formed inside the pores of porous microglass fibers or encapsulated in other inert materials. Encapsulation of transition metal composites within the pores of porous materials may also be achieved by using ship-in-a-bottle rigidity, where the final molecule is prepared inside the pores by reacting smaller precursors. Examples of such encapsulated adsorbents are known in the art, for example, as described in Kuraoka et al., “Ship-in-a-bottle synthesis of a cobalt phthalocyanine / porous glass composite membrane for oxygen separation,” Journal of Membrane Science, 286(1-2):12-14 (2006), which is incorporated herein by reference in its entirety. In some embodiments, porous glass fibers may be manufactured as provided in U.S. Patent No. 4,748,121 issued to Beaver et al., which is incorporated herein by reference in its entirety. In other embodiments, the adsorbent may be formed as a porous sheet product using a papermaking / nonwoven wet apparatus. A sheet having an O2 capture formulation may be as described in U.S. Patent No. 4,769,175 issued to Inoue, which is incorporated herein by reference in whole, and may be encapsulated together with a silicone film after being formed.

[0150] This disclosure provides and includes an adsorbent 207 in an appropriate amount sufficient to absorb and retain residual oxygen present after manufacturing, oxygen introduced during storage of the device 20 and before use, oxygen introduced during filling of the device 20, residual oxygen contained in oxygen-deficient blood, and oxygen introduced during the blood storage period. Previous anaerobic blood storage devices, such as those described by Bitensky, do not recognize or address the problem of oxygen introduction, particularly through the transfer and collection piping. Traditional inlets and outlets do not provide an adequate oxygen barrier. Furthermore, this disclosure provides certain elements that minimize or even significantly eliminate oxygen introduction, but absolute impermeability is not feasible. Therefore, the blood storage device 20 of this disclosure incorporates an adsorbent 207 having both sufficient capacity and appropriate binding kinetics to ensure that an anaerobic environment is maintained. Furthermore, in certain embodiments, the adsorbent 207 may be further provided to further reduce the oxygen level in oxygen-deficient blood. Finally, the amount of adsorbent 207 must also provide a reliable and reproducible storage life for the blood storage device 20.

[0151] In embodiments of this disclosure, the blood storage device 20 has an amount of oxygen adsorbent 207 having an oxygen binding capacity of at least 20 cc of oxygen. In one embodiment, the oxygen binding capacity of the adsorbent 207 of the blood storage device 20 is at least 30 cc of oxygen. In one embodiment, the oxygen binding capacity of the adsorbent 207 of the blood storage device 20 is at least 50 cc of oxygen. In one embodiment, the oxygen binding capacity of the adsorbent 207 of the blood storage device 20 is at least 100 cc of oxygen. In one embodiment, the oxygen binding capacity of the adsorbent 207 is at least 25 or 30 cc of oxygen. In a further embodiment, the oxygen binding capacity of the adsorbent 207 is at least 30 or 45 cc of oxygen.

[0152] In the embodiments of this disclosure, the oxygen capacity of the adsorbent 207 is at least 20 cc. In some embodiments, the oxygen capacity of the adsorbent 207 is at least 20 cc but less than 100 cc. In some embodiments, the oxygen capacity of the adsorbent 207 is at least 20 cc but less than 75 cc. In some embodiments, the oxygen capacity of the adsorbent 207 is at least 30 cc but less than 50 cc. In some embodiments, the oxygen capacity of the adsorbent 207 is at least 20 cc but less than 250 cc. In certain embodiments, the oxygen capacity of the adsorbent 207 is 50 to 200 cc. In other embodiments, the oxygen capacity of the adsorbent 207 is 100 to 200 cc. In other embodiments, the oxygen capacity of the adsorbent 207 is 20 to 50 cc.

[0153] In other embodiments of this disclosure, the oxygen capacity of the adsorbent 207 may be as little as 6 cc. In a particular embodiment, the oxygen capacity of the adsorbent 207 is 6 cc to 20 cc. In another embodiment, the oxygen capacity of the adsorbent 207 is about 6 cc. In one embodiment, the oxygen capacity of the adsorbent 207 is 6 to 10 cc. In yet another embodiment, the oxygen capacity of the adsorbent 207 is 10 cc. This disclosure provides and includes an oxygen adsorbent 207 having a suitable capacity and suitable oxygen binding rate for maintaining oxygen-deficient blood in its deficient state and ensuring a suitable storage life of the blood storage device 20. In an embodiment of this disclosure, the adsorbent 207 has a minimum oxygen absorption rate of at least 11 cc / week / gram. In another embodiment, an adsorbent 207 having an oxygen absorption rate of at least 11 cc / week / gram can bind to at least 22 cc of oxygen within two weeks. In yet another embodiment, an adsorbent 207 having an oxygen absorption rate of at least 11 cc / week / gram can bind to at least 54 cc of oxygen within four weeks. In yet another embodiment, an adsorbent 207 having an oxygen absorption rate of at least 11 cc / week / gram can bind to at least 99 cc of oxygen within 9 weeks.

[0154] As used herein, “carbon dioxide scavenger” 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, carbon dioxide adsorbents may be nonreactive with oxygen or minimally reactive. In other embodiments, oxygen adsorbents may exhibit the secondary functionality of carbon dioxide scavenging. 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, materials may irreversibly bind to or combine with CO2. In embodiments of this disclosure, materials may bind to CO2 with a higher affinity than hemoglobin. In other embodiments, adsorbent materials may bind to CO2 with a high affinity such that carbon dioxide present in blood or RBC cytoplasm is released and absorbed by the adsorbent. In other embodiments, CO2 binds to the adsorbent material and is released at a very slow rate (k オフ ) has. In one embodiment, carbon dioxide can chemically react with some components of the material and be converted into another compound.

[0155] Carbon dioxide scavenging agents are known in the art. In certain embodiments of this disclosure, the carbon dioxide scavenging agent may be calcium oxide. The reaction of calcium oxide with water produces calcium hydroxide, which may react with carbon dioxide to form calcium carbonate and water. In certain embodiments of this disclosure, water for the production of calcium hydroxide is obtained by the diffusion of water vapor from blood through an internal oxygen-permeable container. In another embodiment, water may be provided by the environment through a substantially oxygen-impermeable external receptacle. In yet another embodiment, water may be included together with the external receptacle of the oxygen-deficient device.

[0156] Examples of specific CO2 scavengers include oxygen and carbon dioxide scavengers from Multisorb Technologies (Buffalo, NY), and Sodasorb® from Grace. Oxygen scavengers may exhibit the secondary functionality of carbon dioxide scavenging.

[0157] In embodiments of this disclosure, the desired results can be achieved by blending an O2-deficient medium and a CO2-deficient medium in a desired ratio. In another embodiment, the adsorbent chemical reaction may have affinity for both O2 and CO2.

[0158] This disclosure further includes and provides adsorbents contained in pouches. As used herein, “pouch” is any encapsulation container that encapsulates and contains an oxygen adsorbent, a carbon dioxide adsorbent, or a combination of an oxygen adsorbent and / or carbon dioxide adsorbent. The pouches according to this disclosure are contained within an overlay material that is permeable to both oxygen and carbon dioxide. In certain embodiments, the overlay material may be a combination of two or more materials, at least one of which is permeable to both oxygen and carbon dioxide. Preferred overlay materials have a known biocompatibility profile or conform to ISO 10993.

[0159] The pouch is sealed so that the absorbent material is entirely contained within the outer packaging material and the adsorbent does not leak, seep, migrate, or otherwise escape from the outer packaging. The pouch may take any shape, but is typically rectangular or square. In one embodiment, the pouch is approximately 50 x 60 mm. In one embodiment, the oxygen adsorbent 207 binds to 20 cc of oxygen per pouch in the STP. In one embodiment, the oxygen adsorbent 207 binds to 10 cc of oxygen per pouch in the STP. In one embodiment, the oxygen adsorbent 207 binds to 25 cc of oxygen per pouch in the STP. In one embodiment, the oxygen adsorbent 207 binds to 10-50 cc of oxygen per pouch in the STP. In one embodiment, the oxygen adsorbent 207 binds to 10-75 cc of oxygen per pouch in the STP. In one embodiment, the oxygen adsorbent 207 binds to 10-20 cc of oxygen per pouch in the STP. In certain embodiments of this disclosure, the pouch has a total oxygen adsorption capacity of 50 cc O2 in the STP. In certain embodiments of this disclosure, the pouch has a total oxygen adsorption capacity of at least 100 cc O2 in the STP.

[0160] In an embodiment of this disclosure, the oxygen adsorbent 207 may be provided in one or more pouches. In another embodiment, the oxygen adsorbent 207 may be provided in a single larger pouch. In yet another embodiment, the oxygen adsorbent 207 may be provided in two pouches distributed in the headspace between the collapsible container 202 and the external receptacle 201. In yet another embodiment, the oxygen adsorbent 207 may be provided in four pouches distributed in the headspace between the collapsible container 202 and the external receptacle 201. In an embodiment of this disclosure, the blood storage device 20 may include 2 to 20 adsorbent packages.

[0161] In embodiments of this disclosure, the blood storage device 20 comprises 0.5 to 150 grams of adsorbent 207 contained in one or more pouches. Preferred adsorbents are provided in

[0161] to

[0164] above. In one embodiment, the blood storage device 20 comprises 0.5 to 5 grams of adsorbent 207 contained in one or more pouches. In another embodiment, the blood storage device 20 comprises 8 to 24 grams of adsorbent 207 contained in one or more pouches. In yet another embodiment, the blood storage device 20 comprises 8, 16, or 24 grams of adsorbent 207. In one embodiment, the blood storage device 20 comprises 8 grams of SS-200 adsorbent 207 or an equivalent thereof contained in one pouch. In yet another embodiment, the blood storage device 20 comprises 16 grams of SS-200 adsorbent 207 or an equivalent thereof contained in two pouches. In another embodiment, the blood storage device 20 includes 24 grams of SS-200 adsorbent 207, or an equivalent thereof, contained in three pouches. In yet another embodiment, the blood storage device 20 includes 14 grams of adsorbent 207, or an equivalent thereof, contained in one Dessicare pack. In one embodiment, the blood storage device 20 includes about 1 gram of adsorbent 207. In yet another embodiment, the blood storage device 20 includes about 2 grams of adsorbent 103. In one embodiment, the blood storage device 20 includes about 3 or 4 grams of adsorbent 207, contained in one or more pouches. In one embodiment, the blood storage device 20 includes about 0.75 or 1.0 gram of adsorbent 207, contained in one or more pouches. The pouches may be square, rectangular, circular, or oval in shape.

[0162] In embodiments of this disclosure, the blood storage device 20 includes an oxygen indicator 215 which may function as an early warning to the user that the storage device is malfunctioning. In embodiments of this disclosure, a malfunction of the outer barrier bag 102 or the inlet / outlet 30 brings oxygen into the outer bag headspace. Such unwanted oxygen ingress may occur before use (e.g., during shelf storage) or after the device 20 has been filled with oxygen-deficient blood. The oxygen indicator 215 according to this disclosure includes a device that is typically constructed by a chemical reaction on paper or tablet form and sealed in an oxygen-permeable film pack. When used herein, the oxygen indicator 215 is sensitive enough to detect oxygen levels at a partial oxygen pressure above 1 Torr. In the presence of oxygen, the indicator changes color (e.g., from pink to purple). This warns the user of the device 20 that the oxygen-impermeable protection may be compromised and to take additional action as necessary. In some embodiments, blood in a malfunctioning device 20 may be treated as normal conventional blood during or at the end of storage. As provided herein, the oxygen indicator 215 is typically integrated into the blood storage bag during bag manufacturing. In certain embodiments, the oxygen indicator 215 is laminated onto a transfer tape such as 3M 1524A and dispensed onto the outer bag side facing the inner bag. Exemplary oxygen indicators 215 include, but are not limited to, the Dry Pak Wondersensor (Dry Pak Industries, Inc., Encino, CA).

[0163] This disclosure provides, and includes, a blood storage device 10 and piping 205 for connecting the other components of a blood collection kit together. The piping 205 provides many functions to the blood collection kit, including, but not limited to, preventing contamination of the blood collection kit, and providing sterile transfer and sterile docking when connection to external sterile piping is required. In the process of developing anaerobic storage bags, it became clear that the piping 205 was the main source of oxygen introduced into the blood storage device before and during use, as illustrated below in Example 8. Therefore, the apparatus and method of this disclosure overcome the limitations of the prior art and minimize the impact of oxygen in the storage environment.

[0164] In embodiments of this disclosure, the piping 205 is prepared from a material that is substantially oxygen-impermeable and optionally carbon dioxide-permeable. In many embodiments, the piping 205 is prepared from a dense material that has no pores or voids. In other embodiments, the piping 205 is prepared as a barrier transverse tube 305 illustrated in Figure 3, having at least one oxygen barrier layer 307 and at least one blood compatibility layer 306. In certain embodiments, the oxygen barrier layer 307 and the blood compatibility layer 306 are the same layer. Also provided in this disclosure is a barrier transverse tube 305 having an internal blood compatibility layer 306, an intermediate oxygen barrier layer 307, and an outer layer 308. In certain embodiments, the outer layer 308 provides protection to the oxygen barrier layer 307 and prevents the formation of holes, cracks, or other fissures in the oxygen barrier. In certain embodiments, the outer layer 308 also provides the formation of an adhesive portion 302. This disclosure provides a barrier transverse tube 305 having two layers: a blood compatibility layer 306 and an outer layer 308. In certain embodiments, the oxygen barrier layer 307 and the outer layer 308 are the same layer. In certain embodiments, the outer layer 308 is suitable for acting as a seal adapter 301. In addition to permeability, the piping 205 should be suitable for sterile welding, providing a joint at the two opposing ends of the pipe while maintaining a sterile fluid path. In some embodiments, the piping 205 consists of a barrier transverse pipe 305 suitable for sterile welding. In further embodiments, the piping 205 should be resistant to twisting, torsion, and folding. As stated above, it will be understood by those skilled in the art that the thickness of the pipe wall is proportional to the permeability of the pipe. Thus, many materials may be suitable if provided with sufficient thickness, but such materials may be unsuitable because they lack flexibility or are simply too large or cumbersome to use in a blood collection set or to dock with other piping.

[0165] As used herein, substantially oxygen-impermeable piping 205 is a material characterized by a bar value of less than 1 bar, preferably less than 0.2 bar. In other embodiments, substantially oxygen-impermeable piping 205 is a material characterized by a bar value of less than 0.01 bar. In other embodiments, substantially oxygen-impermeable piping 205 is a material characterized by a bar value of less than 0.002 bar. In other embodiments, substantially oxygen-impermeable piping 205 is 100 cc / mil·100 in 2 It has an oxygen permeability rate of 1 / 20°C at 100 in. In another embodiment, piping 205, which is substantially oxygen-impermeable, has an oxygen permeability rate of 80 cc / mil·100 in. 2 It has an oxygen permeability rate of 1 / 20°C at 100 in. In another embodiment, piping 205, which is substantially oxygen-impermeable, has an oxygen permeability rate of 35 cc / mil·100 in. 2 It has an oxygen permeability rate of 1 / 2000 atm. Examples of suitable piping for use include PVC piping such as Renolit Medituub 3467 (American Renolit Corp., City of Commerce, CA) and Qosina T4306 (Qosia Corp., Edgewood, NY). In some embodiments of this disclosure, piping 205 has an oxygen permeability of 0.002 to 1 bar. In some embodiments of this disclosure, piping 205 has an oxygen permeability of 0.002 to 0.20 bar. In some embodiments of this disclosure, piping 205 has an oxygen permeability of 0.01 to 0.10 bar.

[0166] In embodiments of this disclosure, the piping 205 is made of ethylene-vinyl acetate (EVA), poly(ethylene-vinyl) acetate (PEVA), polypropylene (PP), polyurethane (PU), 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 It can be prepared from materials selected from the group consisting of polyethylene (ABS), polycarbonate (PC), polycarbonate / acrylonitrile butadiene styrene (PC / ABS), polyurethane (PU), melamine formaldehyde (MF), plastic starch materials, phenols (PF), polyether ether ketone (PEEK), polyetherimide (PEI) (Ultem), polylactic acid (PLA), polymethyl methacrylate (PMMA), polytetrafluoroethylene (PTFE), urea-formaldehyde, ethylene vinyl alcohol copolymer (EVOH), and polyamide. In one embodiment, the piping 205 is prepared from polyethylene. In another embodiment, the piping 205 is prepared from polyvinyl chloride.

[0167] Furthermore, this disclosure provides and includes a blood storage device 20 having piping 205 which is a barrier transverse tube 305 having at least one layer selected from the group consisting of ethylene-vinyl acetate (EVA), poly(ethylene-vinyl) acetate (PEVA), polypropylene (PP), biaxially oriented polypropylene (BOPP), biaxially oriented nylon, ethyl vinyl alcohol (EVOH), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), polyurethane (PU), polyethylene (PE), polyvinylidene chloride (PVDC), and polyamide. In one embodiment, the barrier transverse tube 305 used in the piping 205 includes an oxygen barrier layer 307 containing PET. In another embodiment, the barrier transverse tube 305 used in the piping 205 includes an oxygen barrier layer 307 containing EVA. In yet another embodiment, the barrier transverse tube 305 used in the piping 205 includes an oxygen barrier layer 307 containing EVOH. In one particular embodiment, the piping 205 includes a blood-compatible inner layer 306 containing PVC. In certain embodiments, the barrier transverse pipe 305 used in piping 205 is composed of an outer layer 308 of polyethylene (PE), an inner layer 306 of PVC (polyvinyl chloride), and an oxygen barrier layer 307 of EVA (ethyl vinyl acetate) (Pexco, Inc. Athol, MA). In some embodiments, the barrier transverse pipe 305 used in piping 205 is composed of an outer layer 308 of polyethylene (PE), an inner layer 306 of PVC (polyvinyl chloride), and an oxygen barrier layer 307 of EVA (ethyl vinyl acetate), the PE outer layer 308 having a thickness of 150 μm, the EVA oxygen barrier layer 307 having a thickness of 10 μm, and the PVC inner layer 306 having a thickness of 350 μm, thereby providing multilayer piping that can be easily used with current sterile piping connectors. Additives that enhance the oxygen and CO2 barrier properties of polymers before molding, or during their formation or setting are known in the art. Current blood collection kits use PVC for piping corresponding to piping 205 in this disclosure. Such PVC piping is not suitable for use in some embodiments of the blood storage device of this disclosure and, when used as piping 205, becomes a major source of introduced oxygen.Such PVC piping typically allows for approximately 1 cc of oxygen infusion per day over a 1 m length of piping under ambient conditions. Therefore, the blood collection system and kit of the present invention require an oxygen barrier overpack with an oxygen adsorbent to protect and maintain the internal space and volume of the blood collection kit from unwanted oxygen infusion. Since most of the PVC piping in the blood collection kit is discarded after collection and processing, the anaerobic storage device 20 is left with only a 150 mm length of exposed inlet piping before storage. The oxygen infusion rate through this remaining 150 mm length of exposed PVC piping is limited to approximately 0.16 cc / day under ambient conditions, or approximately 7 cc of oxygen over 42 days under ambient conditions, and approximately 10 cc after 64 days. The actual amount of oxygen infusion is much lower at the 4°C refrigerated storage temperature used for long-term blood storage than the amount of oxygen infusion measured under ambient conditions.

[0168] This disclosure includes and provides a blood storage device 10 having a substantially oxygen-impermeable integrated piping design that combines piping 205, adhesive 302, and piping 304 into a single structure. The advantage of this design is that it reduces the number of individual parts and eliminates potential sources of oxygen infiltration. Furthermore, the incorporation of an integrated piping design including multi-layer oxygen-impermeable tubing provides the preparation of a simplified blood storage device 20, which has a blood-compatible external receptacle 201 that can store oxygen-deficient blood directly bonded to one or more inlets or outlets equipped with impermeable piping. By essentially eliminating potential sources of oxygen, suitable oxygen-deficient blood can be stored directly in the blood-compatible external receptacle 201, while eliminating the need for a collapsible blood container 202 and an oxygen adsorbent 207. Furthermore, this disclosure provides the preparation of a blood storage device comprising a multilayer container, which combines an external receptacle 201, an oxygen adsorbent 207, and a foldable blood container 202 as a single multilayer device bonded to one or more pipes 205 via an oxygen-impermeable adhesive.

[0169] In embodiments of this disclosure, the external receptacle 201 includes one or more inlets / outlets 30. In certain embodiments, one or more inlets / outlets 30 further comprise a spike port 303. In some embodiments, the external receptacle 201 includes a second inlet / outlet 30 that is in fluid communication with the collapsible blood container 202. In yet another embodiment, the external receptacle 201 includes a third inlet / outlet 30 that is in fluid communication with the collapsible blood container 202. Each inlet / outlet 30 may further comprise a spike port 303.

[0170] It is worth noting that there are few materials that offer complete impermeability, and even highly permeable materials can be hindered when joining, welding, folding, and otherwise assembling the external receptacle 201. As described below, the blood storage device 20 may further incorporate optional spike ports 303 and inlet / outlet 30, and must also be designed to accommodate changes in the volume of the internal collapsible blood container 202. Therefore, special attention is paid to incorporating specific design elements and manufacturing methods to ensure the maximization of the impermeability barrier integrity and the integrity of the material performance.

[0171] Spike ports 303 for use in blood collection kits and systems are commonly known in the art and include products such as Vitalmed #20391 (Vitalmed, Inc., Lakeville, MA) and Qosina #65842 (Qosina Corp., Edgewood, NY). These ports are typically molded from PVC and have a removable cap that provides a sterile barrier before use and also provides some degree of oxygen impermeability to the contents. In some embodiments, the spike port 303 is covered by a sealed, foldable portion of an external receptacle film, thereby providing a sterile barrier and an additional degree of oxygen impermeability. Improved oxygen impermeability is desirable as it increases the shelf life of kits and systems having a blood storage device 20.

[0172] Naturally, conventional ports, inlets, and outlets are potential sources of undesirable oxygen intrusion and depend on both the choice of material and the method used to bond the port, inlet, or outlet to the external receptacle 201. Methods for bonding materials to prepare the bonded portion 302 are well known in the art. As provided herein, the inlet / outlet 30 comprises a seal adapter 301 bonded to the external receptacle 201 using the bonded portion 302, which creates an oxygen-impermeable seal to the external receptacle 201. In one aspect of this disclosure, the manifold is the seal adapter 301. As used herein, the bonded portion 302, which is substantially oxygen-impermeable, has a bar value of less than 1 bar, preferably less than 0.10 bar, and more preferably less than 0.01 bar.

[0173] As provided in this disclosure, the substantially oxygen-impermeable bonded portion 302 can be solvent-sealed, heat-sealed, adhesive-bonded, ultrasonically welded, or high-frequency welded. In some embodiments, the bonded portion 302 is achieved by using a constant-heat sealing die heated and maintained at about 260°F. In some embodiments, a film is placed between the heating dies and gripped together for about 3–7 seconds to achieve a heat-welded joint. In certain embodiments, the heat seal is produced in about 5 seconds. In certain embodiments, the sealing dies have grooved portions machined from them to accommodate intermediate components. In some embodiments, the seal adapter 301 comprises an intermediate component which may be the length of the barrier transverse piping described later, or a small block of machined, extruded, molded, or laminated polymer wedges. In embodiments according to this disclosure, the groove is about 5% smaller in dimensions than the feature portion of the component, thereby providing compression and material flow during sealing.

[0174] In some embodiments, the oxygen-impermeable bond consists of a portion of the barrier transverse pipe (e.g., seal adapter 301) heat-sealed to the joint of the external receptacle 201. In certain embodiments, the barrier transverse pipe consists of an outer layer of EVA (ethyl vinyl acetate) and an inner layer of PVC (polyvinyl chloride) (Pexco, Inc., Athol, MA). In certain embodiments, the barrier transverse pipe consists of an outer layer of polyethylene, an inner layer of PVC (polyvinyl chloride), and an intermediate layer of EVA (ethyl vinyl acetate) (Extrusion Alternatives, Inc., Portsmouth, NH). In some embodiments, an additional option for PVC piping is solvent-bonded to the multilayer pipe using, for example, cyclohexanone.

[0175] In some embodiments, the inlet / outlet 30 comprises a seal adapter 301, which is a small device that is a machined, extruded, molded, or laminated polymer wedge or block. The molded device may be prepared from a polyolefin such as polyethylene, e.g., Dowlex® 2517 resin. In other embodiments, the machined, extruded, molded, or laminated polymer device may be prepared from a polyether block amide (e.g., PEBAX®). In yet another embodiment, the machined, extruded, molded, or laminated polymer may be ethylene vinyl acetate (e.g., EVA). In certain embodiments, the machined, extruded, molded, or laminated polymer device may be a small diamond, ellipse, or other preferred shape polymer block having a hole in the center, so that the device of that shape is heat-sealed to the seam of the external receptacle, providing an oxygen-impermeable bond 302, while the central through-hole provides fluid connectivity with the contents. In one embodiment, a portion of the PVC piping is bonded to the central hole of the diamond-shaped seal adapter 301 using an oxygen-impermeable adhesive that can bond to polyethylene, such as Loctite 4310, Masterbond X17, or 3M Scotchweld 4693, thereby providing fluid connectivity to its contents through an oxygen-impermeable external receptacle. In another embodiment, the barrier transverse piping can be bonded to the central hole of the diamond-shaped seal adapter 301 using methods known in the art. In yet another embodiment, the barrier transverse piping can be insert-molded into the diamond-shaped seal adapter 301 using methods known in the art. In yet another embodiment, the barrier transverse piping can be used in place of standard PVC intravenous piping to provide enhanced oxygen barrier properties.

[0176] This disclosure provides and includes a positioning feature for aligning the external receptacle 201, the collapsible blood container 202, and the inlet / outlet 30, ensuring the integrity of the oxygen-impermeable barrier. Poor alignment can result in tears for oxygen barrier and transfer during storage and before use. In accordance with this disclosure, the positioning feature may be selected from the group consisting of geometric cutouts, tactile surface markings, die-cut fiducials, spacers, interlocking cutouts, piping fittings, and printed markings.

[0177] This disclosure provides and includes an expanded feature section 217 for containing a blood solution and avoiding wrinkles and folds. During the development of anaerobic storage bags, it was observed that wrinkles and folds that occurred during filling of certain anaerobic storage bags, such as foil-coated bags, resulted in tears in the impermeable barrier. Such folds and wrinkles result in unacceptable levels of oxygen infiltration, leading to an unacceptable increase in the oxygen saturation of the stored blood during storage. The expanded feature section also provides unlimited filling of the storage device 20, the external sealing container 201, and the foldable blood container 202.

[0178] In embodiments of this disclosure, the extended feature 217 is selected from the group consisting of pleats, diaphragms, bubbles, one or more folds, folded pouches, and geometric extensions of the package shape. In some embodiments, the extended feature 217 consists of gusseted folds along one or more edges of the outer receptacle 201. In some embodiments, folds of about 1 / 8 to 1 / 4 inch are suitable for providing an extension of the inner container 202, and the pleats of the folds are sealed at the seams at the ends. In some embodiments, as illustrated in Figure 8, the extended feature 217 consists of a third panel or tri-fold of barrier film sealed along the bottom of the outer receptacle 201, providing a three-dimensional bag.

[0179] In certain embodiments, the collapsible blood container 202 may also include an extended feature to facilitate filling the container, although the oxygen-impermeable integrity of the container 202 is clearly not a concern.

[0180] This disclosure provides and includes methods and systems for managing tubing 205 and other tubing associated with a complete blood collection kit. A blood storage device 20 having an external receptacle 201, a collapsible blood container 202, at least one inlet / outlet 30, and an oxygen adsorbent 207 may further comprise a tubing management component 40. The tubing management component 40 may be selected from the group consisting of separate clips or straps as illustrated in Figures 6A and 6B, straps attached to the external surface of the external receptacle such as those illustrated in Figures 6C and 6D, and hook-and-loop fasteners (VELCRO®). In certain embodiments, for example, as illustrated in Figures 6E and 6F, the tubing management component 40 is a cutout feature on the external surface of the external receptacle. In another embodiment, the tubing management component 40 is a clip attached to the external surface of the external receptacle.

[0181] This disclosure provides, and includes, an integrated handle 214 within an external receptacle 201, as illustrated in Figure 7, for example.

[0182] This disclosure provides, and includes, one or more transparent or translucent windows 212 for providing a visual inspection of blood. Such windows allow for the examination of the color of the blood and allow for the visualization of undesirable features of contaminants, such as thrombi or bacterial colonies, if present in the blood.

[0183] Among other factors, the storage life and stability of the blood storage device 20 can be significantly affected by temperature. Specifically, the blood storage device 20, or one or more of its components, may degrade when exposed to high temperatures. Such a degraded device is unsuitable for blood storage and may lead to undesirable patient outcomes. As is known to those skilled in the art, the amount of time the device is exposed to undesirable temperatures is equally important. Accordingly, this disclosure provides a device further comprising a temperature-time monitor. Such monitors are known in the art, for example, provided in U.S. Patents 7,517,146, 6,042,264, and 5,709,472. In one embodiment, a BT-10 time strip from Genesis (Genesis BPS, Ramsey, NJ) can be incorporated into a foldable blood container to monitor the duration of any temperature intrusion above 10°C.

[0184] This disclosure provides, and includes, a blood storage device 20 for storing oxygen-deficient blood, which provides maintenance of headspace, including the volume between the external receptacle 201 and the collapsible blood container 202, at a low partial oxygen pressure during storage. In some embodiments, the blood storage device can maintain the headspace of the blood storage device 20 without the need to include an adsorbent 207, but such a configuration requires a higher level of oxygen barrier integrity. As provided by this disclosure, the blood storage device 20 maintains the headspace at a partial oxygen pressure of about 1 mmHg or less for a period of 64 days when stored at a temperature of 2 to 6°C. In some embodiments, the blood storage device 20 maintains the headspace at a partial oxygen pressure of about 1 mmHg or less for a period of 64 days when stored at a temperature of 2 to 6°C, without the need to include an adsorbent 207. This disclosure also provides, and includes, a blood storage device that maintains a partial oxygen pressure in the headspace at 1 mmHg or less for at least 6 months prior to use.

[0185] The disclosure further includes a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 that maintains the headspace at a partial oxygen pressure of 1 mmHg or less for a period of at least 21 days. In some embodiments, the blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 is a blood storage device 20 that maintains the headspace at a partial oxygen pressure of 1 mmHg or less for a period of at least 21 days without an adsorbent 207. The disclosure also provides a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30, wherein the headspace is maintained at a partial oxygen pressure of 1 mmHg or less for a period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 1 mmHg or less for a period of at least 28 days without an adsorbent 207. In further embodiments, the headspace is maintained at a partial oxygen pressure of 1 mmHg or less for a storage period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 1 mmHg or less for a period of at least 21 days without an adsorbent 207. In a further embodiment, the headspace is maintained at an oxygen partial pressure of 1 mmHg or less for a period of at least 48 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 1 mmHg or less for a period of at least 48 days without the adsorbent 207. In another embodiment, the headspace is maintained at an oxygen partial pressure of 1 mmHg or less for a period of at least 56 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 1 mmHg or less for a period of at least 56 days without the adsorbent 207. In another embodiment, the headspace is maintained at an oxygen partial pressure of 1 mmHg or less for a storage period of at least 64 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 1 mmHg or less for a storage period of at least 64 days without the adsorbent 207.

[0186] The disclosure further includes a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 that maintains the headspace at a partial oxygen pressure of 3 mmHg or less for a period of at least 21 days. In some embodiments, the blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 is a blood storage device 20 that maintains the headspace at a partial oxygen pressure of 3 mmHg or less for a period of at least 21 days without an adsorbent 207. The disclosure also provides a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30, wherein the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a period of at least 28 days without an adsorbent 207. In further embodiments, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a storage period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a period of at least 21 days without an adsorbent 207. In a further embodiment, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a period of at least 48 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a period of at least 48 days without the adsorbent 207. In another embodiment, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a period of at least 56 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a period of at least 56 days without the adsorbent 207. In another embodiment, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a storage period of at least 64 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 3 mmHg or less for a storage period of at least 64 days without the adsorbent 207.

[0187] The disclosure further includes a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 that maintains the headspace at a partial oxygen pressure of 5 mmHg or less for a period of at least 21 days. In some embodiments, the blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 is a blood storage device 20 that maintains the headspace at a partial oxygen pressure of 5 mmHg or less for a period of at least 21 days without an adsorbent 207. The disclosure also provides a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30, wherein the headspace is maintained at a partial oxygen pressure of 5 mmHg or less for a period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 5 mmHg or less for a period of at least 28 days without an adsorbent 207. In further embodiments, the headspace is maintained at a partial oxygen pressure of 5 mmHg or less for a storage period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 5 mmHg or less for a period of at least 21 days without an adsorbent 207. In a further embodiment, the headspace is maintained at an oxygen partial pressure of 5 mmHg or less for a period of at least 48 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 5 mmHg or less for a period of at least 48 days without the adsorbent 207. In another embodiment, the headspace is maintained at an oxygen partial pressure of 5 mmHg or less for a period of at least 56 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 5 mmHg or less for a period of at least 56 days without the adsorbent 207. In another embodiment, the headspace is maintained at an oxygen partial pressure of 5 mmHg or less for a storage period of at least 64 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 5 mmHg or less for a storage period of at least 64 days without the adsorbent 207.

[0188] The disclosure further includes a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 that maintains the headspace at a partial oxygen pressure of 15 mmHg or less for a period of at least 21 days. In some embodiments, the blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30 is a blood storage device 20 that maintains the headspace at a partial oxygen pressure of 15 mmHg or less for at least 21 days without an adsorbent 207. The disclosure also provides a blood storage device 20 having a substantially oxygen-impermeable inlet / outlet 30, wherein the headspace is maintained at a partial oxygen pressure of 15 mmHg or less for a period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 15 mmHg or less for a period of at least 28 days without an adsorbent 207. In further embodiments, the headspace is maintained at a partial oxygen pressure of 15 mmHg or less for a storage period of at least 28 days. In some embodiments, the headspace is maintained at a partial oxygen pressure of 15 mmHg or less for a period of at least 21 days without an adsorbent 207. In a further embodiment, the headspace is maintained at an oxygen partial pressure of 15 mmHg or less for a period of at least 48 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 15 mmHg or less for a period of at least 48 days without the adsorbent 207. In another embodiment, the headspace is maintained at an oxygen partial pressure of 15 mmHg or less for a period of at least 56 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 15 mmHg or less for a period of at least 56 days without the adsorbent 207. In another embodiment, the headspace is maintained at an oxygen partial pressure of 15 mmHg or less for a storage period of at least 64 days. In some embodiments, the headspace is maintained at an oxygen partial pressure of 15 mmHg or less for a storage period of at least 64 days without the adsorbent 207.

[0189] This disclosure provides a blood storage device 20 comprising an external receptacle 201, a collapsible blood container 202, at least one inlet / outlet 30, and an oxygen adsorbent 207, wherein blood stored in the collapsible blood container 202 maintains an oxygen saturation level (SO2) during the storage period that is approximately equal to the oxygen saturation level at the start of storage. In one embodiment, the storage period is 21 days and the initial SO2 level is 20% or less. In another embodiment, the storage period is 28 days and the initial SO2 level is 20% or less. In yet another embodiment, the storage period is 42 days and the initial SO2 level is 20% or less. In yet another embodiment, the storage period is 56 days and the initial SO2 level is 20% or less. In yet yet another embodiment, the storage period is 64 days and the initial SO2 level is 15% or less. In one embodiment, the storage period is 21 days and the initial SO2 level is 15% or less. In another embodiment, the storage period is 28 days and the initial SO2 level is 15% or less, or the storage period is 42 days and the initial SO2 level is 15% or less. In yet another embodiment, the storage period is 56 days and the initial SO2 level is 15% or less, or the storage period is 64 days and the initial SO2 level is 15% or less. In one embodiment, the storage period is 21 days and the initial SO2 level is 10% or less, or the storage period is 28 days and the initial SO2 level is 10% or less. In yet another embodiment, the storage period is 42 days and the initial SO2 level is 10% or less. In yet another embodiment, the storage period is 56 days and the initial SO2 level is 10% or less, or the storage period is 64 days and the initial SO2 level is 10% or less. In one embodiment, the storage period is 21 days and the initial SO2 level is approximately 5%. In one embodiment, the storage period is 28 days and the initial SO2 level is approximately 5%, or the storage period is 42 days. In a further embodiment, the storage period is 56 days and the initial SO2 level is approximately 5%, or the storage period is 64 days. In yet another embodiment, the storage period is 21 days and the initial SO2 level is approximately 3%. In yet another embodiment, the storage period is 28 days and the initial SO2 level is approximately 3%, or the storage period is 42 days and the initial SO2 level is approximately 3%.In a further embodiment, the storage period is 56 days and the initial SO2 level is approximately 3%. In yet another embodiment, the storage period is 64 days and the initial SO2 level is approximately 3%.

[0190] This disclosure provides, and includes, a blood storage device 20 comprising an external receptacle 201, a collapsible blood container 202, at least one inlet / outlet 30, and an oxygen adsorbent 207, which provides an oxygen saturation level (SO2) during a storage period lower than the oxygen saturation level at the start of storage, for a storage period of at least one week. In an embodiment according to this disclosure, the oxygen saturation level after one week of storage is 2% lower than the oxygen level at the start of storage. In another embodiment, according to this disclosure, the oxygen saturation level decreases at a rate of at least 0.00010%SO2 / min. In a particular embodiment, the oxygen saturation level decreases at a rate of at least 0.00020%SO2 / min. In another particular embodiment, the oxygen saturation level decreases at a rate of at least 0.0003% and 0.0001%SO2 / min. In another embodiment, the storage period is 21 days or 28 days. In yet another embodiment, the storage period is 42 days or 56 days. In another embodiment, the blood storage device 20 provides a reduced oxygen saturation level after 64 days.

[0191] This disclosure provides a blood storage device 20 comprising an external receptacle 201, a collapsible blood container 202, and at least one inlet / outlet 30, wherein the blood stored in the collapsible blood container 202 provides an oxygen saturation level (SO2) during the storage period that is less than 5% higher than the oxygen saturation level at the start of storage, and the storage period is 64 days. In another embodiment, the oxygen saturation level (SO2) during the storage period is less than 3% higher than the oxygen saturation level at the start of storage, and the storage period is 64 days.

[0192] This disclosure provides, and includes, different methods for manufacturing a foldable blood container 202. In one embodiment, the foldable blood container 202 is prepared by blow molding. In another embodiment, the foldable blood container 202 is prepared by compression molding. In a further embodiment, the foldable blood container 202 is prepared by insert molding. Methods of blow molding, compression molding, or insert molding are known in the art, for example, in U.S. Patent Application Publication No. 2004 / 0254560A1, “Rupture resistant blow molded freezer bag for containing blood products,” and in U.S. Patent No. 5,368,808 issued to Koike et al., “Blowbag manufacturing method,” and in U.S. Patent No. 6,878,335, “Blow or vacuum molding thermoplastic resins, then expanding or shaping using compressed air; medical equipment.”

[0193] In some embodiments of this disclosure, the foldable blood container 202 is prepared by heat sealing one or more membranes 206. In another embodiment, the foldable blood container 202 is prepared by adhesive bonding one or more membranes 206. In yet another embodiment, the foldable blood container 202 is prepared by ultrasonic welding one or more membranes 206. In yet another embodiment, the foldable blood container 202 is prepared by high-frequency welding one or more membranes 206. In yet another embodiment, the foldable blood container 202 is prepared by one or more methods selected from heat sealing, adhesive bonding, ultrasonic welding, or high-frequency welding.

[0194] In embodiments of the present disclosure, the collapsible blood container 202 is prepared from one or more membranes 206, each including one or more seals having a width of at least 1 / 8 inch.

[0195] In one embodiment of the present disclosure, a collapsible blood container 202 may be manufactured from a porous membrane 206 by various sealing methods such as thermal sealing, thermal staking, and adhesive bonding. In one embodiment of the present disclosure, a pair of PVDF porous membranes are bonded together along the perimeter, having a portion of PVC inlet piping in a predetermined position within the seam, using an adhesive such as Locite 4011 in conjunction with an adhesive primer such as Locite 770. In another embodiment of the present disclosure, a collapsible blood container may be manufactured from a pair of porous membranes by thermal sealing three or four seams of the pair of membranes with a portion of multilayer piping sealed at the seam to provide fluid connectivity.

[0196] This disclosure provides and includes a method for storing deoxygenated blood for up to 64 weeks using a blood storage device 20, which results in reduced storage damage compared to blood stored in the presence of oxygen. The method of this disclosure uses the blood storage device 20 as described above for blood storage. In one embodiment, the blood comprises concentrated red blood cells. In another embodiment, the blood comprises whole blood. In yet another embodiment, the blood for storage comprises oxygen-depleted concentrated red blood cells further comprising an additive solution.

[0197] In one embodiment, by the method of the present disclosure, deoxygenated blood having an oxygen saturation of less than 20% is placed in and stored in a blood storage device 20. In one particular embodiment, the storage period is 1 to 64 days. In another embodiment, the storage period is 1 week. In yet another embodiment, the storage period is 2 weeks. In yet another embodiment, the storage period is 3 or 4 weeks. In yet another embodiment, the storage period is 8 weeks. In yet another embodiment, the storage period is 9 weeks. By the method of the present disclosure, the blood storage device 20 maintains the oxygen-deficient state of the oxygen-deficient blood at or below the initial saturation level of SO2.

[0198] Furthermore, the Disclosure provides and includes a method of blood preservation comprising placing oxygen-depleted blood in a blood preservation device 20 and preserving the oxygen-depleted blood for a period of 1 to 64 days, wherein the oxygen saturation of the blood is further reduced during the preservation period. In one embodiment, the SO2 of the preserved blood is reduced by at least 3% after one week of preservation. In one embodiment, the initial oxygen saturation of the oxygen-depleted blood is about 20% SO2 and is reduced during preservation. In another embodiment, the initial SO2 is about 15% and is reduced during preservation. In yet another embodiment, the initial SO2 is about 10% and is reduced during preservation. In an embodiment according to the Disclosure, the preserved blood has an oxygen saturation level of less than 20% after one week. In another embodiment, the preserved blood has an oxygen saturation level of less than 10% after two weeks. In yet another embodiment, the preserved blood has an oxygen saturation level of less than 5% after three weeks. [Examples]

[0199] Example 1: Internally foldable blood container containing PVC A collapsible blood container 202 (blood bag) having two inlets / outlets 30 configured as spike ports and one inlet / outlet 30 configured as an IV inlet tube is manufactured from a pair of PVC sheets (Renolit Solmed ES-3000, Renolit America) by welding the seams together using high-frequency welding (RF welding). A leak test is performed by blowing compressed air up to 3 psig into the blood bag, submerging it in water, and observing the bubbles before use. Alternatively, a leak test is performed by blowing air into the blood bag and monitoring the negative pressure change using a pressure decay tester (Sprint MT, Zaxis). The leak-tested blood bag is then placed in an external receptacle 201 manufactured from RollPrint Clearfoil® Z film #37-1275 (RollPrint Packaging Products, Inc., Addison, IL), which has a heat-sealable PE inner layer, an aluminum barrier intermediate layer, and a PET outer layer, as described in Example 2.

[0200] Example 2: External receptacle 201 The substantially oxygen-impermeable external receptacle 201 ("barrier bag") is manufactured by heat-sealing one edge of the oxygen-impermeable portion of the piping using a custom heat sealer, and sealing the other remaining edge using conventional heat-sealing methods and equipment. The custom heat sealer consists of a pair of 12-inch long, 1-square-inch aluminum rods, with a machined 1 / 2-inch wide, 1 / 4-inch high high sealing surface on one side of each rod. Each sealing rod is fitted with a pair of 3 / 8-inch diameter x 5-inch long 200-watt heater cartridges (four in total, McMaster Carr #3618K315, McMaster Carr, Inc., Robbinsville, NJ) and maintained at 260°F by an Athena Controls temperature controller and a K-type thermocouple (McMaster Carr #9251T93, McMaster Carr, Inc., Robbinsville, NJ) inserted into a small hole drilled in one end of one of the aluminum rods. Transverse grooves are machined into each of the two aluminum sealing rods with a 7 / 32-inch ball end mill to a depth of approximately 0.208 inches to provide approximately 0.010 inches of compression when arranging a seal adapter containing a portion of oxygen-impermeable piping within the seal. These rods are bolted facing each other onto a Franklin hot stamping press, so that when the press is operated, pairs of transverse grooves and sealing surfaces align in contact with each other, providing a 1 / 2-inch wide seal along the 12-inch long aluminum sealing rods.

[0201] To prepare the external receptacle 201, a sheet of barrier film approximately 11 × 12 inches is folded in half along the 12-inch dimension with the polyethylene layer facing inward, and a gusset fold of approximately 1 / 4 inch is incorporated into the folded edge. The gusset fold is held in place at each end with small grippers, and the film is then placed in a custom heat sealer and aligned with one of the short edges of the sealing die. A small piece of oxygen-impermeable multilayer piping (seal adapter 301) having a polyethylene outer layer 308 with an inner diameter of 0.156 inches × outer diameter of 0.218 inches × length of approximately 1 / 2 inch, a PVC inner layer 306, and an EVA intermediate adhesive layer 307 (Extrusion Alternatives, Inc., Portsmouth, NH) is placed on a solid aluminum mandrel approximately 0.156 inches in diameter × length of approximately 1 inch, and then positioned between the films and within the transverse groove 703 or 704 of the sealing die 70. The press is activated and set to 80 pounds / square inch gauge (psig) for approximately 5 seconds to create a continuous weld seal along the length of the die, sealing the short piece of multilayer piping (seal adapter 301) together with the adhesive section 302. The combination of the seal adapter 301 and the short multilayer piping of the adhesive section 302 provides an oxygen-impermeable seal along the outer diameter of the piping while providing fluid connectivity through the seal. The folded edge provides expansion of the barrier bag when the collapsible blood container 202 is filled with fluid.

[0202] A standard IV pipe (PVC pipe (Pexco, Inc., Athol, MA)) approximately 12 inches long (0.118 inches inner diameter x 0.161 inches outer diameter) (pipe 205) is solvent-bonded to the multilayer pipe from the outside of the bag using cyclohexanone and heat-sealed to close the end by approximately 1 / 2 inch. The inlet pipe for the internal blood bag (pipe 304) is cut to a length of approximately 2 inches, and the internal blood bag is placed inside the barrier bag. The inlet pipe 304 is solvent-bonded to the multilayer pipe, thereby providing fluid connectivity for the internal blood bag inlet pipe through the oxygen-impermeable seal of the barrier bag up to 12 inches long of pipe 205 on the outside of the barrier bag.

[0203] The remaining short edges of the barrier film are sealed using an impact heat sealer (Accu-Seal Model 530, Accu-Seal, Inc., San Marcos, CA), leaving the last remaining long edge of the barrier bag unsealed, to which the adsorbent 207, a plastic mesh spacer 213 configured as a plastic mesh, and an oxygen sensor 215 are placed. The oxygen sensor 215 (Mocon #050-979, Mocon, Inc., Minneapolis, MN) is fixed to the inside of the barrier bag. Cut a pair of plastic mesh spacers 213 (McMaster Carr #9314T29, NJ McMaster Carr, Inc., Robbinsville, NJ) to approximately 5 x 7 inches, and secure one sachet of oxygen adsorbent 207 (SS-200 type, Mitsubishi Gas Chemical America, New York, NY) near the center of one side of the plastic mesh 213 before placing the plastic mesh spacers 213 between the blood bag 202 and the barrier bag 201. Sealve the final long edge of the barrier bag using impact heat sealer (McMaster Carr #2054T35, McMaster Carr, Inc., Robbinsville, NJ). Take care to minimize assembly time to reduce exposure to ambient oxygen by performing the assembly in a nitrogen-atmosphere glove box.

[0204] Example 3: Conventional storage bags enable blood reoxygenation. The degree and rate of reoxygenation during storage in conventional PVC blood storage bags are determined by transferring 150 mL of concentrated red blood cells (pRBCs) with an initial SO2 of approximately 60% to a conventional PVC blood transfer bag. The pRBC-containing bag is placed at 4°C under ambient conditions and left unmixed. Samples are taken and the mean SO2 is determined on days 0, 7, 14, 21, 28, 52, and 56. Six independent samples are collected at each time point. The results are presented in Table 7 and graphically represented in Figure 10. Table 7: Reoxygenation of blood stored in conventional PVC bags JPEG2026053349000008.jpg51155

[0205] As shown in Table 7 and Figure 10, the blood becomes saturated over a 56-day storage period. SO2 consistently increases over 14–21 days until it reaches approximately 98%, after which there is no significant change in SO2 for the remainder of the storage period (n=6, p<0.001).

[0206] Example 4: Oxygen introduction occurs mainly through collection and transfer piping. Based on calculations and comparisons with bags formed from RollPrint 37-1275, 8.53 mL of oxygen infusion over 42 days mostly enters through a 6-inch inlet pipe. Therefore, based on 8.53 mL infusion + 10 mL in the blood, a minimum adsorbent capacity of 20 cc is shown.

[0207] Example 5: Continuous oxygen deficiency during storage at 4°C Oxygen deficiency is significantly affected by temperature. To evaluate the ability to continuously deprive stored blood of oxygen, conventional blood storage bags were prepared and filled with blood having different initial oxygen saturation levels. Concentrated red blood cells were prepared in PAGGSM or SAGM additive solution and stored anaerobically in plastic canisters pressurized with approximately 5 mmHg and 100% nitrogen gas. Additionally, each canister contained a 2ZB adsorbent sachet to help maintain a very low oxygen level. As shown in Table 8, at higher oxygen saturation levels, the reaction rate was approximately twice as high as at lower saturation levels. Table 8: Primary rate constants of oxygen deficiency during refrigerated storage JPEG2026053349000009.jpg50155

[0208] Decision constant (R) is 0.98 2As shown by ), there appears to be a logarithmic relationship between the initial SO2 setting point and the total amount of O2 removed during storage. Deriving a best-fit line from this data allows for the estimation of the predicted O2 variation to inform a given initial SO2 setting point (Equation 1). JPEG2026053349000010.jpg26147

[0209] Additionally, the time-dependent loss of SO2 can be predicted by plotting the slope of a linear regression and deriving the best-fitting line. There appears to be a logarithmic relationship between the initial SO2 value at the start of conservation and the linear rate at which SO2 is lost during anaerobic conservation (Equation 2). JPEG2026053349000011.jpg26146

[0210] Example 6: Preparation of an external receptacle The pairs of oxygen barrier films are heat-sealed together on all four sides to produce a pouch with internal dimensions of approximately 160 x 240 mm. These pouches are sealed using an impact heat sealer with a seal width of approximately 3 mm (1 / 8 inch) (McMaster Carr #2054T35, McMaster Carr, Inc., Robbinsville, NJ). Samples are prepared from the following barrier films: RollPrint Clearfoil® Z film #37-1275 and Clearfoil® V film #27-1232 (RollPrint Packaging Products, Inc., Addison, IL), and Glenroy ESO 031-002 (Glenroy, Inc., Menomonee Falls, WI). Furthermore, samples of RollPrint Clearfoil® Z film are prepared using an impact heat sealer with a seal approximately 9.5 mm (3 / 8 inch) wide (Accu-Seal model 530, Accu-Seal, Inc., San Marcos, CA).

[0211] Several samples of each configuration were prepared and tested for oxygen permeability using an Oxtran 2 / 61 oxygen permeability apparatus (Mocon, Inc., Minneapolis, MN). For each configuration, two samples were selected to be tested using a test gas containing 100% oxygen at 50% relative humidity (RH) and 760 mmHg pressure. The carrier gas was 98% nitrogen / 2% hydrogen at 100% RH, and the test was conducted at 23°C. The results are shown in Table 9 below. Table 9: Permeability of external receptacle 201 prepared from different materials JPEG2026053349000012.jpg55155

[0212] All samples showed a low oxygen infusion rate of 0.1 cc / package*day, but Clearfoil® Z film was clearly superior to the other materials only in terms of the magnitude of its lower oxygen infusion rate. Two different seal widths of RollPrint Clearfoil® Z did not reveal any significant difference under the test conditions.

[0213] Example 7: Blood container with anaerobic tube attachment A foldable internal blood bag (Model KS-500, KS Mfg., Avon, MA) was used in the test, along with a PVC film (Renolit ES-3000, Renolit America). The KS-500 blood bag has two transfusion spike ports (Vitalmed #20391, Vitalmed. Inc., Lakeville, MA) and one PVC inlet port adapted to receive a standard IV inlet pipe with an outer diameter of approximately 4 mm (0.161 inches), and the blood bag is supplied without any inlet pipe bonded to the inlet port 30. The blood bag is placed inside an outer barrier bag manufactured from RollPrint Clearfoil® Z film #37-1275 (RollPrint Packaging Products, Inc., Addison, IL) as follows:

[0214] For one group of samples, the oxygen-impermeable mounting adapter (reference NHS #A097-000-"PE wedge") is machined from solid polyethylene having a flat, tapered sealing surface for interlocking with a barrier film and a through-hole for passing through the center of the inlet pipe 30. For the other group of samples, the oxygen-impermeable mounting adapter (reference NHS #A121-000-"multilayer pipe") is formed from a three-layer pipe having a barrier film for bonding the inlet pipe, a thin EVA intermediate adhesive layer 307, and a polyethylene outer layer 308 for interlocking with an internal PVC layer 306.

[0215] Barrier bags measuring approximately 150 x 270 mm are manufactured from a pair of sheets of RollPrint Clearfoil® Z film by first heat-sealing an oxygen-impermeable mounting adapter (either the PE Wedge version or the multilayer tube version) to a seam created at one of the short seams of the film pair using a custom heat sealer with a cutout area that accepts a specific type of mounting adapter. The other short edges and one long edge of the barrier bag are then sealed using conventional heat-sealing methods and equipment, leaving one long edge of each bag open.

[0216] For PE wedge samples, an 800mm long PVC inlet pipe (Qosina #T4306, Qosina Corp., Edgewood, NY) is pushed and pulled through the hole in the mounting adapter to expose approximately 25-30mm inside the barrier bag seam. For multilayer barrier transverse tube (tube 305) samples, a PVC inlet pipe (Qosina #T4306, Qosina Corp., Edgewood, NY) approximately 750mm long is solvent-bonded to the exposed end of the multilayer barrier transverse tube 305 on the outside of the barrier bag using cyclohexanone. Another small piece of PVC tube approximately 25-30mm long is solvent-bonded to the end of the multilayer barrier transverse tube 305 on the inside of the barrier bag.

[0217] Next, the internal blood bag is placed inside the barrier bag, and a short portion of the PVC inlet piping (pipe 304) is solvent-bonded to the PVC inlet port (inlet / outlet 30) of the internal blood bag using cyclohexanone. In the case of PE wedge samples, the inlet tube (pipe 304) is fixed and bonded to the mounting adapter (PE Wedge) with Loctite 4310 adhesive (Henkel Corp., Rocky Hill, CT), and cured with UV light using a spot wand (Dymax PC-3 Lightwelder, Dymax Corp., Torrington, CT). No further bonding was performed on the multilayer barrier transverse tube samples apart from the solvent bonding.

[0218] Next, the inlet tubing (tubing 304) on all samples is heat-sealed, closing approximately 150 mm from the mounting adapter and then at 50 mm intervals thereafter, to create 12 dummy pilot sample compartments required for blood sample collection according to ISO 3826-1 using a tube sealer (Genesis SE340, Genesis BPS, Ramsey, NJ). Then, the remaining long edges of the barrier film are sealed using an impact heat sealer after squeezing out as much air as possible from the headspace between the bags (Accu-Seal Model 530, Accu-Seal, Inc., San Marcos, CA).

[0219] Several sample blood storage containers were sent to Mocon, Inc. for oxygen permeability testing using Oxtran 2 / 21 oxygen permeable devices (Mocon, Inc., Minneapolis, MN). To understand the origin of oxygen infiltration, some samples were tested as prepared, some samples had the inlet tube cut near the mounting surface and the inner diameter of the inlet piping sealed with metallized epoxy, and some samples had the inlet piping (piping 304) cut and the seam area of ​​the mounting surface / barrier bag masked with metallized epoxy. A pair of each configuration was selected for testing. The test gas was 100% oxygen at 50% RH and 760 mmHg pressure, and the carrier gas was 98% nitrogen / 2% hydrogen at 100% RH. The tests were performed at 23°C. Test results for oxygen infiltration (cc / package*day) of 100% O2 are presented in Table 10. Table 10: Oxygen injection test of seal adapter JPEG2026053349000013.jpg51162* The results for sample #1 using the polyethylene mounting adapter indicate potential leakage of the oxygen barrier pouch itself due to blockage in the piping near the mounting point, as well as the copper piping used for gas introduction during the test. This leads to inconsistent results.

[0220] These results indicate that, under ambient conditions (21% O2, 23°C), blood containers introduce approximately 7.7–8.6 cc of oxygen over 42 days and 11.8–13.1 cc over 64 days, with the majority of this oxygen import attributable to the PVC piping. At the refrigerated temperature of 4°C used for blood storage, these import rates are significantly reduced. For anaerobic sealed packages with the inlet tube blocked near the seal, only about 0.15–0.24 cc of oxygen is expected over a 42-day period, and about 0.23–0.36 cc over 64 days.

[0221] Example 8: Oxygen transfer into piping Several samples of PVC inlet piping (Qosina #T4306, Qosina Corp., Edgewood, NY) were cut to either approximately 150 mm (6 inches) or 200 mm (8 inches) in length, with one end sealed. Additionally, the longer 200 mm samples were sealed approximately 50 mm (2 inches) from the sealed end to mimic the pilot sample portion. Several such samples were sent to Mocon, Inc. for oxygen permeability testing using an Oxtran 2 / 21 oxygen permeability apparatus (Mocon, Inc., Minneapolis, MN). A pair of each configuration was selected for testing. The test gas was 100% oxygen at 50% RH and 760 mmHg pressure, and the carrier gas was 98% nitrogen / 2% hydrogen at 100% RH. The tests were conducted at 23°C. Test results for oxygen inflow (cc / day) of 100% O2 are presented in Table 11. Table 11: Oxygen injection test of PVC inlet piping JPEG2026053349000014.jpg39156

[0222] These results are consistent with previous blood container tests, showing oxygen transfer through PVC tubing of approximately 8.2–8.5 cc over a 42-day period and 12.6–13.0 cc over a 64-day period under ambient conditions (21% O2, 23°C). No substantial difference was observed between shorter samples without a pilot section and longer samples with a pilot section under the tested conditions.

[0223] Example 9: Dynamic oxygen absorption of commercial adsorbents Three exemplary adsorbents will be tested for their ability to absorb oxygen in a dynamic test. The test chamber will consist of a 4-inch diameter x 4-inch length 304 stainless steel quick flange fitting (McMaster Carr #4322K35) with end caps, one of which will be modified for connection of the sensor, nitrogen purge, and oxygen test gas inlet. A cylindrical polyethylene insert will be formed to reduce the internal chamber volume to a total volume of approximately 50 cc. A PreSens Fibox 3 gas analyzer fitted with a PSt6 oxygen sensor and a PT1000 temperature sensor (PreSens Precision Sensing GmbH, Regensburg, Germany) will be used for the test.

[0224] The system is purged with a 1% oxygen / balanced nitrogen gas mixture, and then purged with 100% nitrogen gas for two-point calibration before use. A sachet of adsorbent 207 under test is placed in the system under a nitrogen-atmosphere glove box, the system is sealed (the cover is held in place), and then purged with nitrogen before being removed from the glove box. A syringe pump with a Hamilton airtight syringe is filled with more than 5cc of 100% oxygen, and the syringe line to the test chamber is purged by starting the syringe pump, leaving 5cc of oxygen in the syringe. The syringe line valve is closed and connected to the system. The dynamic test is started by starting the syringe pump and injecting 5cc of oxygen over a period of 60 minutes. After 60 minutes, the syringe pump line valve is closed, allowing the adsorbent to continue absorbing residual oxygen in the static test.

[0225] This test will be conducted under ambient conditions (23°C) using a single sachet of each of the following commercially available iron-based oxygen scavengers: Mitsubishi Gas Chemical America (MGC) Ageless® SS-200 adsorbent (200cc capacity, designed to operate in cold environments), O-Buster® (300cc capacity, standard grade) (Hsiao Sung Non-Oxygen Chemical Co., Ltd., Taiwan), and Sorbent Systems LTECC1K500CS (1000cc capacity, "fast-acting" - designed to operate in cold environments) (Impak Corp., Los Angeles, CA).

[0226] Figure 11 shows that, with various adsorbents, the oxygen level rises to approximately 0.7-0.8% within about 10 minutes. Between approximately 10-15 minutes, both O-Buster® and Sorbent Systems adsorbents can reduce the oxygen level in the system to approximately 0.75-0.3-0.5%. The SS-200 adsorbent failed to reduce the oxygen level and continued to increase to approximately 1% oxygen after 60 minutes.

[0227] After 60 minutes, with the dynamic oxygen introduction terminated and the system under static testing, all adsorbents showed a continuous reduction in oxygen levels. SS-200 showed a dramatic increase in the rate of oxygen reduction under static conditions, while Sorbent Systems adsorbents showed a slight increase in the rate of oxygen reduction under static conditions, and O-Buster® adsorbents showed no difference in the rate of oxygen reduction under static conditions. The adsorbent capacity does not appear to directly affect the rate of oxygen absorption, as is evident from the relative performance of 300cc O-Buster® adsorbent compared to 1000cc capacity Sorbent adsorbent, as claimed by the manufacturer. Two adsorbents formulated to perform well under cold conditions (MGC SS-200 and Sorbent Systems LTECC1K500CS) appeared to perform worse than the standard O-Buster® adsorbent, as claimed by the manufacturer. Test data were not performed or collected at temperatures other than 23°C.

[0228] Example 10: Dynamic oxygen absorption of a commercially available portable hand warmer Several commercially available portable hand warmers will be tested for their oxygen absorption capacity in a dynamic test using the same system and conditions as described in Example 9 above. The hand warmers are iron-based oxygen scavengers designed to react with ambient oxygen and generate heat. The iron-based chemical reaction is the same as that tested in Example 9, using commercially available adsorbents used for food preservation, although the formulation may differ slightly to modify the reaction dynamics.

[0229] Figure 12 shows data for several commercially available portable hand warmers tested as described above. The data shown in the table below shows that oxygen introduction raises the oxygen level from approximately 0.25% to approximately 0.75% within approximately 10 minutes, depending on the type of hand warmer. Within approximately 10-15 minutes, the data shows that all hand warmers can rapidly reduce the oxygen level from the peak value, with significant variability between formulations. Most formulations appear to approach a stable state during dynamic testing, with the exception of the Hot Hands and Heat Works versions, which continue to reduce the oxygen level to near zero under dynamic testing conditions.

[0230] After 60 minutes, with the dynamic oxygen introduction terminated and the system under static testing, all adsorbents showed a dynamic reduction in oxygen levels to near zero, except for the Hot Hands and Heat Works versions, which were already near zero oxygen. These results indicate that the formulation used in portable hand warmers has a faster oxygen absorption rate than the food-grade oxygen adsorbent shown in Example 9 and can achieve lower oxygen levels over the study period and under the conditions used in this test.

[0231] Example 11: Manufacture of anaerobic storage bags Several anaerobic storage bags were manufactured as described in Examples 1 and 2 above, and completed by incorporating a pouch of SS-200 adsorbent (Mitsubishi Gas Chemical America, New York, NY), a plastic spacer, and an oxygen sensor tab (Mocon, Inc., Minneapolis, MN) before heat sealing the final edge in a nitrogen-atmosphere glove box. Furthermore, several anaerobic storage bags were manufactured using Renolit ES-4000 PVC-citrate, and internally foldable blood containers 202 were manufactured using a silicone sheet (McMaster Carr #87315K61, McMaster Carr, Robbinsville, NJ). After manufacturing, headspace oxygen levels were measured over several days through an external receptacle film (Rollprint Clearfoil® Z) to verify the robustness of the seal. The results are shown in Tables 12-14 below. Table 12: ASB (Headspace Oxygen (Torr)) produced in Renolit ES-3000 internal blood bags JPEG2026053349000015.jpg78164 Table 13: ASB (Headspace Oxygen (Torr)) produced in Renolit ES-4000 internal blood bags JPEG2026053349000016.jpg67155 Table 14 ASB (Headspace Oxygen (Torr)) produced in silicone internal blood bags JPEG2026053349000017.jpg67155

[0232] The mean oxygen levels on day 0 were significantly higher for both the silicone internal blood bag group and the PVC blood bag group, with mean 6.33 Torr versus 4.58 Torr (ES-3000) and 4.69 Torr (ES-4000), respectively, with p<0.05. These results also indicate that the adsorbent can effectively reduce headspace oxygen levels to less than 1 Torr, except for sample #10 in the ES-3000 group and sample #7 in the ES-4000 group. During more detailed testing of the seals on these samples, small folds or wrinkles were observed at the seams of the final seals.

[0233] Example 12: Intermediate seal adapter 301 with multilayer barrier transverse pipe for solvent bonding of piping An anaerobic storage container having a substantially impermeable joint with fluid connectivity is first manufactured by insert molding three small pieces of multilayer barrier transverse piping 305 into a rod-shaped polyethylene (Dowlex® 2517) approximately 5 mm wide and 57 mm long, with tapered ends ("diamond wedge", seal adapter 301) (Sonicron Corp., Westfield, MA). The multilayer barrier transverse piping has a polyvinyl chloride (PVC) inner layer 306 suitable for solvent bonding to PVC piping, a polyethylene (PE) outer layer 308 suitable for thermal bonding to PE and other heat-weldable films, and an intermediate ethyl vinyl acetate (EVA) layer 307 (Extrusion Alternatives, Inc., Portsmouth, NH) suitable for achieving adhesion between the PVC and PE layers. The multilayer barrier transverse tube 305 has an internal diameter size suitable for accommodating standard PVC blood line transfer piping of approximately 3.0 mm × 4.1 mm according to ISO 3826-1:2013, or blood transfer devices such as PVC spike ports, for example, solvent-bonded Vitalmed #20391 (Vitalmed, Inc., Lakeville, MA) or Qosina #65842 (Qosina Corp., Edgewood, NY). The barrier transverse tube 305 extends approximately 25 mm beyond the width of the diamond wedge on both sides to facilitate these connections.

[0234] The diamond wedge, having an insert-molded multilayer tube, is placed between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL) on a custom-made heat-sealing die having grooves of a size and shape that receive the diamond wedge shape and provide slight compression during heat sealing, which is done on a modified Franklin Model 2400 press (Franklin Mfg. Corp., Norwood, MA). The die is heated to a constant temperature of approximately 140°C by a pair of internal cartridge heaters (McMaster Carr #4877K143, McMaster Carr, Inc., Robbinsville, NJ) connected to a process controller (Omega Model CNI-CB120-SB, Omega Engineering, Inc., Stamford, CT). The press is activated with the die film and diamond wedge to compress the assembly for approximately 3-4 seconds, then heated to produce a fully sealed seam including one side of the external receptacle 201.

[0235] Next, one end of each multilayer tube is solvent-bonded to the transition PVC tube to connect the flexible foldable blood container 202 to the external receptacle 201, and then the other end of each multilayer tube is solvent-bonded to either the spike port or the standard blood line transfer piping portion. Then, a sachet of adsorbent is placed on a spacer sheet, and then placed between the foldable container and one of the external receptacle films, and the remaining three seams of the external receptacle 201 are sealed using an impact sealer to produce the completed anaerobic blood storage container.

[0236] Example 13: Insert-molded intermediate block with double-layer pipe for RF welding of piping Similar to Example 12 above, an anaerobic storage container with a substantially impermeable inlet / outlet 30 that is fluid-connected is first manufactured by insert molding three small pieces of barrier transverse piping 305 into a rod shape ("diamond wedge") of polyethylene (Dowlex® 2517) (Sonicron Corp., Westfield, MA) with tapered ends approximately 5 mm wide and 57 mm long, as shown in Figure 3D.

[0237] However, in this embodiment, the barrier transverse tube of Example 12 is replaced with a double-layer barrier transverse tube consisting of a polyvinyl chloride (PVC) inner layer 306 and outer EVA layers 307, 308 (Extrusion Alternatives, Inc., Portsmouth, NH). Since EVA is known to have both good RF (frequency) and heat weldability, as well as good adhesion to PVC and PE, the need for any fiber connecting tubes to the collapsible blood container is eliminated in this configuration. The thickness of the EVA outer layer may vary as needed, and only a minimum thickness is required to ensure adhesion of PVC during insert molding to PE, which is approximately 0.05 to 0.10 mm. The double-layer tube also has the same inner diameter dimensions as in Example 12, extending beyond the width of approximately 25 mm diamond wedges on both sides to facilitate connection, but the outer diameter of the double-layer tube is a suitable dimension for fitting to RF welding dies used when manufacturing the collapsible blood container.

[0238] In the first step of assembly, the tube on one end of the insert-molded diamond wedge is RF-welded to a PVC film to form a foldable blood container as follows: the three tubes of the diamond wedge are placed on a brass mandrel to support each of them, and then positioned between a pair of foldable blood container 202 films (Renolit ES-3000, American Renolit Corp., City of Commerce, CA). The assembly is then placed on a custom RF sealing die 70 having three grooves of suitable dimensions and shape to receive the three tubes. The RF sealing die also seals the PVC foldable blood container film between the tubes and seals the outer circumference with the contour shape of the foldable blood container 202. The press is activated on the die film and tube to compress the assembly with RF energy (Solidyne RF Welder, S / N 3657) for approximately 4-5 seconds to produce a fully sealed seam forming a collapsible blood container 202, which also has a substantially impermeable joint (diamond wedge) positioned around a fluid-connected inlet tube, ready for sealing against the barrier film of the external receptacle 201 in the next step.

[0239] Similar to Example 12, a collapsible blood container RF-welded to a diamond wedge tube is placed here between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL). The assembly is placed on a custom-made heat-sealing die and sealed on a Franklin press to produce a fully sealed seam containing the fluid-connected collapsible blood container, in addition to one of the external receptacles 201. In the remaining steps, the spike port and PVC blood inlet piping (inlet / outlet 30) are solvent-bonded to the remaining exposed portion of the diamond wedge double-layer tube, similar to Example 12, and the adsorbent pouches and spacers are also adjusted similarly before sealing the remaining three seams of the external receptacle 201 to produce a completed anaerobic blood storage container.

[0240] Example 14: Barrier transverse pipe heat-sealed "three at once" for solvent bonding of piping. An anaerobic storage container with a substantially impermeable joint that has fluid connectivity is manufactured by simultaneously heat-sealing three individual segments of a barrier transverse piping between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL), as shown in Figure 4A. The transverse piping has a polyvinyl chloride (PVC) inner layer 306 suitable for solvent bonding to PVC piping, a polyethylene (PE) outer layer 308 suitable for heat bonding to PE and other heat-weldable films, and an intermediate ethyl vinyl acetate (EVA) layer 307 (Extrusion Alternatives, Inc., Portsmouth, NH) suitable for achieving adhesion between the PVC and PE layers. The barrier transverse tube has an inner diameter size suitable for standard PVC blood line transfer tubing of approximately 3.0 mm x 4.1 mm according to ISO 3826-1:2013, or for blood transfer devices such as PVC spike ports, and is compatible with solvent bonding of either Vitalmed #20391 (Vitalmed, Inc., Lakeville, MA) or Qosina #65842 (Qosina Corp., Edgewood, NY).

[0241] The barrier transverse tubes are solvent-bonded to short sections of PVC piping using cyclohexanone, connecting the piping to each port on a collapsible blood container. A mandrel is inserted into the barrier transverse tube, and small bags of adsorbent (Mitsubishi SS-200, Mitsubishi Gas Chemical America, Inc., NY, NY) are placed on a spacer sheet, holding the assembly between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL) on a custom-made heat-sealing die. The sealing die (aluminum die 70) is preferably dimensionally determined by reducing its diameter by approximately 0.25 mm and preferably shaped by providing a diameter of 0.5–0.8 mm at the corners to receive the tube and has three grooves that provide slight pressure during heat sealing. The sealing process is carried out at 80-85 psig on a modified Franklin Model 2400 hot stamping press (Franklin Mfg. Corp., Norwood, MA). The upper die 701 is manufactured from a solid block of aluminum machined to a complementary shape slightly larger than the outer circumference of the collapsible blood vessel. The central region of the upper die 705 is loosened to receive and nest the collapsible blood vessel 202, and the die has grooves as described above for sealing the barrier transverse tube. The upper die is heated to approximately 127°C by direct conduction to the heated upper platen of the Franklin press.

[0242] The lower die 702 consists of a metal insert portion surrounded by a Garolite® G-10 material, which is thermally insulated. This lower die is molded similarly to the upper die and provides nesting to the foldable blood container 202 and the flat mating surface 705 to which the upper die is pressed, but the metal insert portion provides the groove necessary to seal the barrier transverse tube to the surrounding film, ensuring a substantially impermeable seal. The lower die is heated to a constant temperature of approximately 132°C by an internal cartridge heater (McMaster-Carr P / N: 3618K412) connected to a process controller (Omega model CNI-CB120-SB, Omega Engineering, Inc., Stamford, CT). Thus, the entire outer circumference is heated from the upper die and from the insert portion 706 of the lower die.

[0243] The press is activated with a film, an adsorbent and a spacer sheet, as well as a tube positioned in place on the die as described, and a residence time of approximately 2 seconds is maintained to produce a fully sealed seam on the external receptacle 201, having three barrier transverse tubes with a substantially impermeable seal that is fluidly connected to the internal foldable blood container 202. The remaining ends of each barrier transverse tube are then solvent-bonded to either a spike port or a portion of standard blood line PVC piping (inlet / outlet 30) to produce an anaerobic blood storage container.

[0244] Example 15: Extruded barrier transverse pipe heat-sealed "three at once" for solvent bonding of piping. Similar to Example 14 described above, an anaerobic storage container with a substantially impermeable joint that is fluid-connected is manufactured by simultaneously heat-sealing three individual pieces of barrier transverse piping between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL). In this embodiment, the barrier transverse piping has an outer layer of PE extruded into a diamond wedge shape, as shown in Figure 4B, rather than a circular shape to facilitate edge sealing to the barrier film, and the inner PVC layer has a circular inner diameter suitable for solvent bonding with other PVC piping and fittings, such as spike ports.

[0245] Example 16: Individual insert-molded intermediate block Similar to Examples 12 and 14 above, an anaerobic storage container with a substantially impermeable joint having fluid connectivity is manufactured by simultaneously heat-sealing three individual diamond wedges, each having only one barrier transverse tube inserted therein, between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL). In this embodiment, the barrier transverse tube 305 has an inner PVC layer 306, an EVA intermediate layer 307, and an outer PE layer 308 inserted into a PE diamond wedge shape, facilitating edge sealing to the barrier film, and the inner PVC layer maintains a circular inner diameter suitable for solvent bonding with other PVC piping and fittings, such as spike ports. Alternatively, the barrier transverse tube 305 may have an inner PVC layer 306 and an EVA outer layer 308, similar to Example 13 above.

[0246] Example 17: The internal PVC storage bag allows for the reoxygenation of blood. Several internal PVC storage bags containing a single classical inlet are manufactured as described in Example 1. The degree of reoxygenation of blood during storage in the internal PVC storage bags is determined by transferring 330 mL of concentrated pRBC with an initial SO2 of 35 - 70% into the bags. The PVC bags containing pRBC are placed at 4 °C under ambient atmospheric conditions. Samples are taken from each bag at week 1 and week 6, and SO2 is determined.

[0247] The results presented in Figure 13 show that reoxygenation of blood occurs within all internal PVC storage bags.

[0248] Example 18: Reoxygenation without an adsorbent Five anaerobic storage bags 20 are manufactured as described in Examples 1 and 2 above. Two of the five bags are further completed by incorporating a pouch of SS - 200 adsorbent (Mitsubishi Gas Chemical America, New York, NY). The degree of reoxygenation of blood during storage in the anaerobic storage bags is determined by transferring 330 mL of concentrated pRBC with an initial SO2 of approximately 5% into the anaerobic storage bags 20. Samples are taken from each bag at week 1 and week 6, and SO2 is determined. As shown in Figure 14, the anaerobic storage bags 20 containing an adsorbent result in a reduced SO2 compared to the anaerobic storage bags 20 without an adsorbent, resulting in reoxygenation up to approximately 15% by week 6.

[0249] Example 19: A blood storage bag having three inlets / outs (two spike ports and one blood line) lacking an oxygen - impermeable adhesive part 302 according to the present disclosure Five anaerobic storage bags 20 are manufactured by first RF - welding two Renolit ES - 3000 sheets having an approximate thickness of 0.017 inches and three PVC tubes without an impermeable adhesive part 302 to form an internal foldable bag 202.

[0250] An internally foldable bag with three inlet / outlet tubes is heat-sealed onto an outer barrier bag manufactured from RollPrint Clearfoil® Z film #37-1275 (Rollprint Packaging Products Inc., Addison, IL).

[0251] Headspace oxygen levels are measured through an external receptacle 201 film (RollPrint ClearFoil® Z). As shown in Figure 15, all anaerobic storage bags 20 provided in this disclosure that lack the three oxygen-impermeable adhesive sections 302 exhibit highly variable oxygen levels over the measurement period (84 days) and are not suitable for anaerobic storage of blood.

[0252] Example 20: ASB with three inlet / outlet ports 30 (two spike ports and one blood line) Three anaerobic storage bags 20 are manufactured by first RF welding two Renolit ES-3000 sheets, each approximately 0.017 inches thick, to three PVC tubes, each approximately 0.75 inches long, to form an internally foldable bag 202. A multilayer barrier transverse piping (internal PVC layer 306, intermediate EVA layer 307, and external PE layer 308) is solvent-bonded to the outer diameter of each of the three PVC tubes of the internal bag, providing a means for heat-sealing the internal (PVC) bag to the external (PE) barrier bag. The multilayer piping is solvent-bonded directly to the internal bag PVC tubes.

[0253] An internal foldable bag having three multilayer barrier transverse tubes 305 is heat-sealed to an outer barrier bag manufactured from RollPrint ClearFoil® Z film #37-1275 (RollPrint Packaging Products Inc., Addison, IL) using an aluminum die 70 (shown in Figure 9) placed on a Franklin hot stamping press and a bottom G-10 base with an aluminum insert block, sealing around the three ports and sealing the internal PVC bag 202 to the outer barrier bag 201.

[0254] As shown in Figure 9, the aluminum die 70 features two aluminum insert blocks, one mounted on the upper aluminum portion and the other on the bottom G-10 block. The upper aluminum block is heated by a Franklin press, and the bottom block is heated by a heating rod (1 / 4 inch in diameter) connected to a temperature controller. This tool aligns the two halves, with alignment pins on the upper half and a matte bushing on the lower half.

[0255] Headspace oxygen levels were measured through an external receptacle 201 film (RollPrint ClearFoil® Z). As shown in Figure 16, all anaerobic storage bags 20 maintained a headspace below 0.8 mmHg up to day 84.

[0256] Although the present invention has been described with reference to preferred embodiments, it will be understood by those skilled in the art that various modifications may be made, and equivalents may be substituted for its elements to adapt it to specific circumstances without departing from the scope of the invention. Accordingly, the present invention is not limited to the specific embodiments disclosed as the best mode intended for carrying out the invention, but is intended to include all embodiments contained in the appended claims and spirit.

Claims

1. A blood storage device 20 for storing oxygen-deficient blood, A substantially oxygen-impermeable external receptacle 201, Foldable blood container 202, A blood storage device 20 comprising at least one inlet / outlet 30 that passes through the external receptacle 201, is in fluid communication with the foldable container 202, and is substantially oxygen-impermeable.

2. The blood storage device according to claim 1, further comprising an oxygen adsorbent 207 located within the external receptacle 201.

3. The blood storage device according to claim 1, wherein the at least one inlet / outlet 30 comprises a seal adapter 301 and an adhesive portion 302, and the seal adapter 301 and the adhesive portion 302 are substantially oxygen-impermeable.

4. When the aforementioned foldable blood container 202 is tested at a temperature of 23±2℃, it yields 10 g / m². 2 A blood storage device according to claim 1, having a water vapor transmission rate (MVTR) of 24 hours or less.

5. The blood storage device according to claim 3, wherein the seal adapter 301 is connected to the piping 205 and the piping 304.

6. The blood storage device according to claim 1, wherein the at least one inlet / outlet 30 comprises a substantially oxygen-impermeable integrated tube comprising a pipe 304, an adhesive portion 302, and a pipe 205.

7. The blood storage device according to claim 6, wherein the integrated tube is a barrier transverse tube 305 having at least one oxygen barrier layer 307 and at least one blood compatibility layer 306.

8. The blood storage device according to claim 6, wherein the at least one oxygen barrier layer of the barrier transverse tube 305 is selected from the group consisting of ethylene vinyl acetate (EVA), ethyl vinyl alcohol (EVOH), poly(ethylene-vinyl) acetate (PEVA), polypropylene (PP), polyacrylonitrile (PAN), polyvinylidene chloride (PVDC), polyvinylidene fluoride (PVDF), polyurethane (PU), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), and polyamide.

9. The blood storage device according to claim 1, further comprising piping 205.

10. The blood storage device according to claim 9, wherein the piping 205 includes a barrier transverse tube 305 having at least one oxygen barrier layer 307 and at least one blood compatibility layer 306.

11. The blood storage device according to claim 9, wherein the piping 205 contains PVC having a bar value of less than 3 bar.

12. The blood storage device according to claim 10, wherein the oxygen barrier layer 307 is selected from the group consisting of ethylene vinyl acetate (EVA), ethyl vinyl alcohol (EVOH), poly(ethylene-vinyl) acetate (PEVA), polypropylene (PP), polyacrylonitrile (PAN), polyvinylidene chloride (PVDC), polyvinylidene fluoride (PVDF), polyurethane (PU), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), and polyamide.

13. The blood storage device according to claim 1, wherein the external receptacle 201 is substantially oxygen-impermeable, and the foldable blood container 202 further comprises a positioning feature adapted to align the foldable blood container 202 within the shape of the external receptacle 201.

14. The blood storage device according to claim 3, wherein the seal adapter 301 is a substantially oxygen-impermeable barrier transverse pipe, or a machined, extruded, molded, or laminated polyethylene, polyether block amide, or ethylene-vinyl acetate wedge.

15. The blood storage device according to claim 5, wherein the piping 205 and the piping 304 contain polyvinyl chloride (PVC) having a bar value of less than 1 bar.

16. The blood storage device according to claim 5, wherein the piping 304 is a barrier transverse tube having an oxygen barrier layer 307 selected from the group consisting of ethylene vinyl acetate (EVA), ethyl vinyl alcohol (EVOH), poly(ethylene-vinyl) acetate (PEVA), polypropylene (PP), polyacrylonitrile (PAN), polyvinylidene chloride (PVDC), polyvinylidene fluoride (PVDF), polyurethane (PU), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), and polyamide.

17. The blood storage device according to claim 5, wherein the piping 205 is selected from the group consisting of ethylene vinyl acetate (EVA), ethyl vinyl alcohol (EVOH), poly(ethylene-vinyl) acetate (PEVA), polypropylene (PP), polyacrylonitrile (PAN), polyvinylidene chloride (PVDC), polyurethane (PU), polyethylene terephthalate (PET), polyethylene naphthalate (PEN), and polyamide.

18. The blood storage device according to claim 1, further comprising a spacer 213.

19. The blood storage device according to claim 18, wherein the spacer 213 is selected from the group consisting of mesh, molded mat, woven mat, nonwoven mat, open-cell foam, strand bale, and strand mat.

20. The blood storage device according to claim 18, wherein the spacer 213 is integrated with at least one of the internal foldable blood container 202 or the external receptacle 201 as a ridge, recess, or other raised feature that maintains separation between the external receptacle 201 and the internal foldable blood container 202.

21. The external receptacle 201 and the piping 205 are substantially oxygen-impermeable, and the headspace, including the volume between the external receptacle 201 and the collapsible blood container 202, maintains an oxygen partial pressure (PO) of less than 15 mmHg for at least 64 days of storage. 2 The blood storage device according to claim 5, which is maintained by ).

22. The headspace maintains an oxygen partial pressure (PO) of less than 15 mmHg for at least 21 days of storage. 2 The blood preservation device according to claim 21, which is maintained by ).

23. The external receptacle 201, the inlet / outlet 30, and the piping 205 are substantially oxygen-impermeable, and the blood stored in the collapsible blood container 202 maintains an oxygen saturation level (SO2) approximately equal to the oxygen saturation level at the start of storage during the storage period. 2 A blood preservation device according to claim 5, which maintains ).

24. The blood storage device according to claim 21, wherein the storage period is 64 days.

25. The external receptacle 201, the inlet / outlet 30, and the piping 205 are substantially oxygen-impermeable, and the blood stored in the collapsible blood container 202 maintains an oxygen saturation level (SO2) lower than the oxygen saturation level at the start of storage during the storage period. 2 The blood storage device according to claim 5, which provides a blood storage device and wherein the storage period is at least one week.

26. The blood storage device according to claim 25, wherein the oxygen saturation level after one week of storage is 3% lower than the oxygen saturation level at the start of storage.

27. The oxygen saturation level is at least 0.00010% SO 2 The blood storage device according to claim 25, which decreases at a rate of one minute.

28. The external receptacle 201, the inlet / outlet 30, and the piping 205 are substantially oxygen-impermeable, and the blood stored in the collapsible blood container 202 maintains an oxygen saturation level (SO2) that is 5% lower than the oxygen saturation level at the start of storage during the storage period. 2 The blood storage device according to claim 5, which provides a storage period of at least 64 days.

29. The blood storage device according to claim 28, wherein, when the storage period is 64 days, the SO2 content is less than 5%.

30. The blood storage device according to claim 1, wherein the oxygen adsorbent 207 has a capacity of at least 20 cc of oxygen.

31. The blood storage device according to claim 30, wherein the oxygen adsorbent 207 has a volume of approximately 6 cc.

32. The blood storage device according to claim 30, wherein the oxygen adsorbent 207 has a minimum oxygen adsorption rate of 1 cc / week / gram.

33. The blood storage device according to claim 3, wherein the substantially oxygen-impermeable adhesive portion 302 is subjected to solvent sealing, heat sealing, adhesive bonding, ultrasonic welding, or high-frequency welding.

34. The blood storage device according to claim 13, wherein the positioning feature is selected from the group consisting of geometric cutouts, tactile surface markings, die-cut fiducials, spacers, interlocking cutouts, pipe fittings, and printed markings.

35. The blood storage device according to claim 1, wherein the foldable blood container 202 is manufactured by blow molding, compression molding, or insert molding.

36. The blood storage device according to claim 1, wherein the foldable blood container 202 is manufactured by heat sealing, adhesive bonding, ultrasonic welding, or high-frequency welding.

37. The blood storage device according to claim 1, further comprising a second inlet / outlet 30 that is in fluid communication with the foldable blood container 202.

38. The blood storage device according to claim 1, further comprising an integrated handle 214.

39. The blood storage device according to claim 1, wherein the external receptacle 201 comprises an extended feature section 215.

40. The blood storage device according to claim 39, wherein the extended feature section 217 enables unlimited filling of the foldable blood container 202.

41. The blood storage device according to claim 39, wherein the extended feature portion 217 is selected from the group consisting of pleats, diaphragms, bubbles, one or more folds, a folded pouch, a tri-fold, a gusset, and a geometric extension of the package shape.

42. The blood storage device according to claim 1, wherein the foldable blood container 202 has permeability of 3 to 11 bars.

43. The blood storage device according to claim 1, wherein the foldable blood container 202 is highly oxygen permeable with a permeability of 11 to 350 bars.

44. The blood storage device according to claim 1, wherein the foldable blood container 202 has an oxygen permeability of 99 to 350 bars.

45. The blood storage device according to claim 44, wherein the oxygen adsorbent 207 is located on the outside of the foldable blood container 202.

46. The blood storage device according to claim 45, wherein the oxygen adsorbent 207 is provided as one or more small bags.

47. The blood storage device according to claim 45, wherein the adsorbent is provided as an oxygen adsorption film.

48. The blood storage device according to claim 47, wherein the oxygen adsorption film is laminated on the external receptacle 201.

49. The blood storage device according to claim 1, wherein the external receptacle 201, the foldable blood container 202, and the oxygen adsorbent 207 include a multilayer film.

50. The blood storage device according to claim 49, wherein the external receptacle 201 of the multilayer film comprises polyethylene (PE), PET, or EVA.

51. The blood storage device according to claim 49, wherein the foldable blood container 202 of the multilayer film includes one or more layers that are substantially oxygen permeable.

52. The blood storage device according to claim 1, further comprising a tube management component 40.

53. The blood storage device according to claim 52, wherein the tube management component 40 is selected from the group consisting of a strap, hook-and-loop fastener (VELCRO®), tape, and snap attached to the outer surface of the external receptacle.

54. The blood storage device according to claim 52, wherein the tube management component 40 is a cutout feature portion on the outer surface of the external receptacle.

55. The blood storage device according to claim 52, wherein the tube management component 40 is a clip attached to the outer surface of the external receptacle.

56. The blood storage device according to claim 1, wherein the foldable blood container 202 comprises a transparent material selected from the group consisting of polyvinyl chloride (PVC), low-density polyethylene, polypropylene, polyethylene terephthalate (PET), silicone, ethyl vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), and polyurethane.

57. The blood storage device according to claim 1, wherein the foldable blood container 202 comprises opaque or impermeable low-density polyethylene, polypropylene, polysulfone, PVDF, or PET.

58. The blood storage device according to claim 57, wherein the internally foldable blood container 202 further includes a transparent or translucent window 212 on its surface.

59. The blood storage device according to claim 1, wherein the foldable blood container 202 includes a microporous membrane selected from the group consisting of polytetrafluoroethylene, polyvinylidene fluoride, polypropylene, and polysulfone microporous membranes.

60. The blood storage device according to claim 59, wherein the polytetrafluoroethylene, PVDF, polypropylene, or polysulfone (PSU) microporous membrane has pore sizes selected from the group consisting of 0.03 μm, 0.05 μm, 0.1 μm, 0.2 μm, 0.23 μm, 0.45 μm, 0.5 μm, and 1.0 μm.

61. The blood storage device according to claim 60, wherein the polytetrafluoroethylene, PVDF, polypropylene, or polysulfone (PSU) microporous membrane is reinforced by lamination, layering, or adhesion.

62. The blood storage device according to claim 1, further comprising a time-temperature indicator.

63. The blood storage device according to claim 1, wherein the external receptacle 201 includes one or more seals that are substantially oxygen-impermeable and have a width of at least 1 / 16 inch.

64. A blood preservation device for storing oxygen-deficient blood, A blood-compatible external receptacle that is practically oxygen-impermeable, It comprises at least one inlet / outlet 30 that passes through the external receptacle 201, is in fluid communication with the foldable container 202, and is substantially oxygen-impermeable, A blood preservation device that maintains oxygen-deficient blood with an oxygen saturation level of less than 20% in an oxygen-deficient state for at least 21 days.

65. The blood storage device according to claim 64, wherein the substantially oxygen-impermeable blood-compatible external receptacle is selected from the group consisting of polyolefin, polyvinylidene chloride (PVDC), oriented polypropylene (OPP), polyethylene, PET, EVA, and PVC.

66. The blood storage device according to claim 64, wherein the piping is barrier-crossing piping.

67. The blood storage device according to claim 64, further comprising an internal receptacle that is oxygen permeable and contains an oxygen adsorbent 207.

68. The blood storage device according to claim 64, wherein the blood-compatible internal receptacle includes PVC.

69. The blood storage device according to claim 68, wherein the blood-compatible internal receptacle comprises PVC injected with a permeability-enhancing additive selected from the group consisting of DEHP, citrate, and DINCH.

70. A method for storing deoxygenated blood, comprising placing the deoxygenated blood into a blood storage device 20.

71. The method according to claim 70, wherein the deoxygenated blood has an oxygen saturation level of less than 20%.

72. The method according to claim 70, wherein the blood storage device 20 comprises an internally foldable blood container 202 having permeability of 3 to 350 bars.

73. A method for further reducing the oxygen saturation of stored blood, Transferring oxygen-deficient blood for preservation, which has an oxygen saturation level of less than 20%, to the blood preservation device 20, A method comprising storing oxygen-deficient blood for preservation over a period of time, wherein the period is at least one week.

74. The method according to claim 73, wherein the storage is performed at a temperature of approximately 2 to 6°C.

75. The method according to claim 74, wherein the blood has an oxygen saturation level of less than 20% after one week, less than 10% after two weeks, or less than 5% after three weeks.

76. The blood storage device according to claim 1, further comprising an oxygen indicator.

77. The blood storage device according to claim 76, further comprising a temperature and time-sensitive indicator.

78. The blood storage device according to claim 1, wherein the at least one inlet / outlet 30 comprises a manifold.

79. The blood storage device according to claim 78, wherein the manifold includes a pre-molded manifold having integrated piping.

80. The blood storage device according to claim 1, wherein the at least one inlet / outlet 30 passing through the external receptacle 201 is equipped with molded piping.

81. The blood storage device according to claim 80, wherein the molded piping is sealed to the external receptacle 201 to prepare an oxygen-impermeable seal 302.

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