Anaerobic Blood Storage Container

Abstract

To provide an improved anaerobic blood preservation bag that provides a blood collection kit with a long storage life.SOLUTION: Provided is a blood preservation container for anaerobic blood preservation including enhanced seal method and material for storage of preserved blood.SELECTED DRAWING: Figure 1A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is related to U.S. Provisional Patent Application No. 62 / 151,957, filed April 23, 2015, and U.S. Provisional Patent Application No. 62 / 151,839, filed April 23, 2015, each of which is incorporated herein in its entirety.

[0002] The present disclosure relates to improved anaerobic storage bags (ASBs) and methods for improved storage of whole blood and blood components. More specifically, the present disclosure relates to improved devices and methods for oxygen-depleted and oxygen- and carbon dioxide-depleted anaerobic storage of blood and blood components that provide extended shelf life before use, improved usability at collection centers, and reduced oxygen transfer. The disclosed methods, devices, and kits provide improved blood and blood component quality for transfusion, and improved patient safety and outcomes. [Background technology]

[0003] Currently, the supply of liquid blood and blood components is limited by the storage systems used in conventional blood storage practices. Using current systems, stored blood, as a concentrated blood cell 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 stored worldwide (15.6 million in the United States). During refrigerated storage, RBCs are progressively damaged by complex biological changes collectively referred to as "storage damage." If transfused within the current six-week timeframe, stored RBCs have lower quality and potential toxicity, which can manifest as side effects of transfusion therapy. Among the observed storage damages are alterations in biochemical and physical parameters associated with stored RBCs. Examples of these alterations include in vitro measured parameters such as decreased 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 may be harmful to the ultimate recipient. These and other reasons limit the amount of readily available, high-quality blood needed for transfusion.

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

[0005] Many approaches have been developed with the aim of minimizing storage damage and improving transfusion outcomes. One approach has been the development of additive solutions that are included during storage. Examples of this approach include U.S. Pat. No. 4,769,318 to Hamasaki et al. and U.S. Pat. No. 4,880,786 to Sasakawa et al., which are directed to additive solutions for blood storage and activation. For example, Rejuvesol (available from Citra Lab LLC, Braintree, MA) is added to blood after refrigerated storage (i.e., at 4°C) immediately prior to transfusion or before freezing for long-term storage (i.e., at -80°C with glycerol). U.S. Pat. No. 6,447,987 to Hess et al. is directed to an additive solution for refrigerated storage of human red blood cells. An alternative approach is to freeze the blood to prevent the development of storage damage. While frozen blood storage is known in the art, such frozen blood has limitations. U.S. Patent No. 6,413,713 to Serebrennikov is directed to a method for storing 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 approach relates to a container for blood storage, provided by U.S. Patent No. 4,837,047 to Sato et al.

[0006] One approach that has proven successful in improving blood quality and prolonging its usefulness is by depriving blood of oxygen and storing it under anaerobic conditions. U.S. Patent No. 5,624,794 to Bitensky et al., U.S. Patent No. 6,162,396 to Bitensky et al., and U.S. Patent No. 5,476,764 to Bitensky are directed to the storage of red blood cells under oxygen-deprived conditions. U.S. Patent No. 5,789,151 to Bitensky et al. is directed to a blood storage additive solution. Benefits of storing blood under oxygen-deprived conditions include improved ATP and 2,3-DPG levels and reduced hemolysis. Storage of blood under oxygen-deprived conditions may also result in reduced particulate levels, reduced loss of deformability, reduced lipid and protein oxidation, and higher post-transfusion survival rates compared to blood stored under conventional conditions.

[0007] U.S. Patent No. 6,162,396 to Bitensky et al. (the '396 patent) discloses an anaerobic storage bag for blood storage, comprising an oxygen-impermeable outer layer and an oxygen-permeable red blood cell (RBC)-compatible inner layer, with an oxygen scrubber disposed between the inner and outer layers. The blood storage device further comprises at least two ports for conventional sterile connection for introducing whole blood or RBCs into the device. The '396 patent generally discloses an oxygen-impermeable outer layer, but does not provide guidance regarding specific types of materials or suitable methods of construction. Similarly, the '396 patent generally discloses an inner hemocompatible layer, but does not provide guidance regarding appropriate materials and methods of construction. Similarly, the '396 patent does not provide guidance regarding tubing materials and methods for gaining access to the interior blood bag and contents while maintaining a low-oxygen environment.

[0008] During the course of research into developing an ASB for use in blood collection and depositing operations, it was observed that additional considerations were necessary. First, it was observed that not all of the materials identified in the '396 patent as suitable for preparing the oxygen-impermeable outer layer could be used in a viable device. Specifically, it was observed that certain aluminum foil laminate membranes were impaired when pleated, wrinkled, or folded over. More problematically, upon introduction of blood into such bags, the increase in volume directly led to the formation of pleats that impaired their integrity. To avoid this problem, a suitable material with sufficient flexibility was required. Alternatively, an ASB with suitable expansion features that provided for the containment of blood was required.

[0009] During development, it was also observed that the integrity of the bag needed to be maintained at various ports to prevent oxygen ingress before use and during storage. Another source of oxygen ingress was observed at seams and joints where wider seals were provided to reduce oxygen leakage and prevent external and internal bag rupture. It was further observed that standard PVC tubing used in blood deposit operations had significant oxygen permeability when passed through an external oxygen-impermeable barrier and was incompatible with methods for creating oxygen-impermeable seals. Still further, conventional blood collection kits require transfer tubing extending in lengths of approximately 200 mm or more, as well as collection tubing having lengths of 800 mm or more, which are also potential sources of oxygen introgression. See ISO 3826-1:2013. Therefore, blood collection kits for anaerobic storage of blood must account for this source of oxygen, which can diminish the capacity of the oxygen adsorbent contained within the ASB and significantly reduce the shelf life of the resulting bag.

[0010] Therefore, there is a need for improved anaerobic blood storage bags that provide a long shelf life for blood collection kits containing such bags. There is also a need for improved anaerobic storage bags that can provide for oxygen ingress through the tubing associated with the blood collection kit. Finally, there is a need to identify suitable materials that can accommodate routine handling of blood storage bags without compromising the integrity of the oxygen barrier.

[0011] Finally, the integration of an oxygen indicator into improved anaerobic blood storage bags provides an additional level of quality control to help inform users of the possibility of oxygen ingression large enough to impair the storage bag's ability to maintain depleted blood under oxygen-deficient conditions. Summary of the Invention

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

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

[0015] The present disclosure provides and includes a blood storage device for storing oxygen-depleted blood, comprising a substantially oxygen-impermeable blood-compatible external receptacle, a collapsible blood container, and at least one inlet / outlet that passes through the external receptacle and is in fluid communication with the collapsible container and is substantially oxygen-impermeable, wherein 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, comprising placing the deoxygenated blood in a blood storage device described herein.

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

[0018] Several aspects of the present disclosure are described herein, by way of example only, with reference to the accompanying drawings. Referring now specifically to the drawings, it is emphasized that the items shown are examples and are intended for illustrative discussion of aspects of the present disclosure. In this regard, the description, taken in conjunction with the drawings, will make apparent to those skilled in the art how aspects of the present disclosure may be practiced. [Brief explanation of the drawings]

[0019] [Figure 1A] FIG. 1A illustrates an exemplary embodiment of an improved anaerobic blood storage bag according to the present disclosure. [Figure 1B] FIG. 1B illustrates an exemplary embodiment of an improved anaerobic blood storage bag according to the present disclosure. [Figure 1C] FIG. 1C illustrates an exemplary embodiment of an improved anaerobic blood storage bag according to the present disclosure. [Figure 2A]FIG. 2A shows an exemplary embodiment of an oxygen-reducing disposable storage system having a blood depletion device with two or three compartments, respectively, and an anaerobic storage bag according to the present disclosure. [Figure 2B] FIG. 2B illustrates an exemplary embodiment of an oxygen-reducing disposable storage system having a blood depletion device with two or three compartments, respectively, and an anaerobic storage bag according to the present disclosure. [Figure 3A] FIG. 3A shows an exemplary embodiment of an inlet / outlet barrier crossing pipe 305 . [Figure 3B] FIG. 3B shows an exemplary embodiment of an inlet / outlet barrier crossing pipe 305 . [Figure 3C] FIG. 3C shows an exemplary embodiment of an inlet / outlet barrier crossing pipe 305 . [Figure 3D] FIG. 3D shows an exemplary embodiment of a manifold 301 with three inlet / outlet ports for holding barrier crossing tubes 305 . [Figure 4A] FIG. 4A is a diagram of adhesive layers bonding a barrier crossing tube 305 onto a membrane 208, creating an adhesive joint 302 with a gap 209. [Figure 4B] FIG. 4B is a diagram of the adhesive layer joining the multi-layer barrier crossing tube 305 with the membrane 208. [Figure 5A] FIG. 5A is a diagram of a blood storage device having a barrier crossing tube 305 bonded to create a bond 302, according to an embodiment of the present disclosure. [Figure 5B] FIG. 5B is a diagram of a blood storage device having an adhesive layer 302 joining the manifold 301 with the membrane 208. [Figure 6A] FIG. 6A illustrates a piping management feature according to an embodiment of the present disclosure. [Figure 6B] FIG. 6B illustrates a piping management feature according to an embodiment of the present disclosure. [Figure 6C] FIG. 6C illustrates a piping management feature according to an embodiment of the present disclosure. [Figure 6D] FIG. 6D illustrates a piping management feature according to an embodiment of the present disclosure. [Figure 6E] FIG. 6E illustrates a piping management feature according to an embodiment of the present disclosure. [Figure 6F] FIG. 6F illustrates a piping management feature according to an embodiment of the present disclosure. [Figure 7] FIG. 7 shows an integrated handle 214 according to an embodiment of the present disclosure. [Figure 8] FIG. 8 illustrates an external receptacle 201 incorporating an extension feature 217 according to an embodiment of the present disclosure. [Figure 9] FIG. 9 shows an aluminum die 70 according to an embodiment of the present disclosure. [Figure 10] FIG. 10 shows a graph of oxygen adsorption that occurs within a conventional storage bag. [Figure 11] FIG. 11 depicts a graphical representation of the adsorbent test data according to Example 9. [Figure 12] FIG. 12 shows a graphical representation of hand warmer test data according to Example 10. [Figure 13] FIG. 13 shows a graphical representation of the oxygen absorption that occurs in non-depleted blood during storage in a conventional storage bag without an external receptacle 201. [Figure 14] FIG. 14 shows a graphical representation of oxygen absorption occurring in anaerobic storage vessels with or without sorbent (filled symbols). [Figure 15] FIG. 15 depicts a graphical representation of the partial pressure of oxygen within a prior art three inlet / outlet anaerobic storage vessel that is not substantially oxygen impermeable. [Figure 16] FIG. 16 shows a graphical representation of the partial pressure of oxygen in an anaerobic storage vessel having three inlets / outlets 30 with barrier crossing tubes 305 .

[0020] Corresponding reference characters indicate corresponding parts throughout the several views. The examples described herein illustrate some embodiments of the present invention, but should not be construed as limiting the scope of the invention in any way. DETAILED DESCRIPTION OF THE INVENTION

[0021] Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. Those skilled in the art will recognize that many methods can be used in the implementation of the present disclosure. Indeed, the present disclosure is in no way limited to the methods and materials described. Any references cited herein are incorporated by reference in their entirety. For the purposes of this disclosure, the following terms are defined below.

[0022] As used herein, the term "bag" refers to a collapsible container made from a flexible material, including pouches, tubes, and gusseted bags. As used herein and within this disclosure, the term includes fold-over bags, which have one, two, three, or more folds that are sealed or glued on one, two, three, or more sides. Bags may be prepared using various techniques known in the art, including bonding one or more sheets of material together. Methods of bonding materials to form bags are known in the art. Also included and provided in this disclosure 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 reduced in size for efficient packaging and shipping, yet expandable to accommodate blood or blood components for oxygen reduction. They may also be designed to conform to the volume of blood until fully expanded. As used throughout this disclosure, a bag is a form of collapsible container, and the two terms are used interchangeably throughout this disclosure.

[0023] As used herein, the term "collapsible container" includes bags, containers, enclosures, envelopes, pouches, pockets, receptacles, and other devices capable of containing and holding liquids or fluids. In certain embodiments, the collapsible container can be manufactured by conventional means such as injection molding or insert molding. In other embodiments, the collapsible container can be prepared from sheets of polymeric material that are bonded together using methods known in the art to prepare a container capable of holding a quantity. Such collapsible containers are well known in the art. See, for example, U.S. Pat. No. 3,942,529 issued to Waage, U.S. Pat. No. 4,131,200 issued to Rinfret, and U.S. Pat. No. 5,382,526 issued to Gajewski et al. Suitable methods for bonding polymeric materials to prepare collapsible containers according to the present disclosure include heat welding, ultrasonic welding, radio frequency (RF) welding, and solvent welding. In certain embodiments, a multi-bonding method may be used to prepare a collapsible container according to the present disclosure. Collapsible containers according to the present disclosure include enclosed containers having one or more pleats, flaps, septa, bubbles, and gussets. Methods for preparing collapsible 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 present disclosure also includes and provides containers having a combination of flexible and non-flexible portions. In these, the flexible portions allow for volume expansion, for example, through pleats, flaps, gussets, and other similar geometric features of the package shape, while the non-flexible portions can provide rigidity and geometric definition to the container. Methods and designs for preparing collapsible containers having both flexible and non-flexible portions are known in the art and are described, for example, by Randall in U.S. Pat. No. 6,164,821 and by LaFleur in U.S. Pat. No. 5,328,268.Others are described by Yeager in U.S. Pat. No. 6,076,664 and by David in U.S. Patent Application Publication No. 2014 / 0248005A1, and are also known in the art as "stand-up pouches."

[0024] As used herein, the term "incoming oxygen" refers to oxygen that enters a blood storage device during storage of oxygen-depleted blood. Incoming oxygen further includes oxygen that enters a blood storage device during shelf storage. If not minimized, or preferably eliminated, such incoming oxygen can render the blood storage device inoperable during shelf storage. In certain embodiments, incoming oxygen can result in consumption of the gas-binding capacity of the solvent (either oxygen or carbon dioxide), causing the device to fail, making it impossible to maintain the blood storage device in an anaerobic state and further impossible to maintain oxygen-depleted stored blood. Incoming oxygen includes oxygen that enters the device through a substantially impermeable barrier of the device, where absolute integrity within a typical device is either not possible or cost-prohibitive. More generally, incoming oxygen can enter the device through seals or welds in the external receptacle 201, the inlet / outlet 30, the tubing 304, and the tubing 205. More specifically, it was discovered that the standard tubing (e.g., collection and transfer tubing) used in blood collection systems was a significant source of transmigrated oxygen, rendering anaerobic blood storage systems previously known in the art unsuitable. As shown in the examples below, the tubing was the primary source of transmigrated oxygen. Furthermore, while the present design eliminates a significant portion of the transmigrated oxygen observed in previous anaerobic storage bags, it will be understood that complete elimination of transmigrated oxygen may not be possible. The problem of transmigrated oxygen manifests itself in significantly reduced storage life as well as the inability to maintain blood in a suitable oxygen-depleted state. Furthermore, even incorporating elements of the blood storage system 20 of the present disclosure, it is preferable to include an oxygen sorbent 207 capable of absorbing not only any residual oxygen present in oxygen-depleted blood, but also the amount of undesirable transmigrated oxygen that still enters the system.

[0025] As used herein, the term "blood" refers to whole blood, leukocyte-depleted RBCs, platelet-depleted RBCs, and leukocyte- and platelet-depleted RBCs. The term blood further includes packed red blood cells, platelet-depleted packed red blood cells, leukocyte-depleted packed red blood cells (LRpRBCs), and leukocyte- and platelet-depleted packed red blood cells. The temperature of blood can vary depending on the stage of the collection process, starting at a normothermic temperature of 37°C at the time of collection, but rapidly decreasing to approximately 30°C as soon as the blood leaves the patient's body, then decreasing to room temperature over approximately 6 hours if unprocessed, and finally refrigerated at approximately 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), and platelets suspended in plasma, and containing electrolytes, hormones, vitamins, antibodies, etc. In whole blood, white blood cells typically range from 4.5 to 11.0 x 10 9 cells / L, and the normal RBC range at sea level is 4.6–6.2 × 10 12 / L, and 4.2–5.4 × 10 for women. 12 / L. Normal hematocrit or hematocrit is approximately 40-54% for men and 38-47% for women. Platelet counts are usually between 150 and 450 x 10 for both men and women. 9 / L. Whole blood is collected from a blood donor and typically combined with an anticoagulant. When collected, whole blood is initially at about 37°C, rapidly cooled to about 30°C during and immediately after collection, and then gradually cooled to ambient temperature over about 6 hours. Whole blood may be processed by the disclosed methods starting at 30-37°C upon collection, or at room temperature (typically about 25°C). As used herein, a "unit" of blood is about 450-500 mL, including anticoagulant.

[0027] As used herein, "red blood cells" (RBCs) include RBCs present in whole blood, leukocyte-reduced RBCs, thrombocytopenic RBCs, and leukocyte- and thrombocytopenic RBCs. Human red blood cells are dynamic 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 the corpuscular volume that is composed of red blood cells is called the hematocrit. As used herein, unless otherwise specified, RBCs also include packed red blood cells (pRBCs). Packed red blood cells are prepared from whole blood using centrifugation 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 "about" refers to ±10%.

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

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

[0031] The term "consisting essentially of" means that a composition, method, or structure may include additional ingredients, steps, and / or moieties, but only if those additional ingredients, steps, and / or moieties 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 referents unless the context clearly dictates otherwise. For example, the terms "a compound" or "at least one compound" may include and include mixtures of a plurality of compounds.

[0033] Throughout this application, various aspects of the present disclosure may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the present disclosure. Thus, the description of a range should be considered to have specifically disclosed all possible subranges, as well as individual numerical values ​​within that range. For example, the description of a range such as "1 to 6" should be considered to have specifically disclosed subranges such as "1 to 3," "1 to 4," "1 to 5," "2 to 4," "2 to 6," "3 to 6," etc., as well as individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0034] Whenever a range of values ​​is given herein, it is meant to include any and all numbers (fractional or integer) recited within the range given. The phrases "ranging from / ranging from a first designated number to a second designated number" and "ranging from" a first designated number to a second designated number are used interchangeably herein and are meant to include the first and second designated numbers, and all fractional and integer numbers therebetween.

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

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

[0037] As used herein, the external receptacle 201 is prepared from a membrane material 208 that is substantially impermeable to oxygen and, optionally, carbon dioxide. In certain embodiments, the external receptacle 201 is prepared from a flexible membrane material 208. As illustrated in a non-limiting embodiment of the present disclosure in FIG. 1C , the external receptacle 201 may be prepared from one or more sheets of membrane material 208. In other embodiments, as described below, the external receptacle 201 can be prepared as a tube and sealed at the ends to create the external receptacle. Also provided by the present disclosure is an external receptacle 201 that includes a single sheet of membrane material 208 that is folded and sealed to create the external receptacle 201. In further embodiments, the external receptacle 201 may include two sheets of membrane material 208 joined together. In yet other embodiments, 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 expansion feature 217 to accommodate the increased volume of the collapsible blood container 202 that occurs when oxygen-depleted blood is transferred to the blood storage device 20. The present disclosure provides a blood storage device 20 having a drooping feature 203. The present disclosure also provides and includes a blow-molded external receptacle 201 comprising a suitable membrane material 208 that is substantially impermeable to oxygen and optionally impermeable to carbon dioxide.

[0038] The present 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 no more than 10 cc of oxygen within the receptacle over a three-month period, and more preferably no more than 5 cc of oxygen over a six-month period. As used herein, the term "substantially oxygen-impermeable" (SIO) refers to materials and compositions that provide a barrier sufficient to prevent significant increases in oxygen partial pressure from passing from one side of the barrier to the other. In certain embodiments, a substantially oxygen-impermeable membrane suitable for use in preparing the external receptacle 201 is characterized by a Barrer value of less than 1.0 Barrer. In other embodiments, a substantially oxygen-impermeable membrane suitable for use in preparing the external receptacle 201 is characterized by a Barrer value of 0.001 to 0.2 Barrer. In certain embodiments, membranes suitable for use in preparing the external receptacles and other elements of the present disclosure are materials characterized by a Barrer value of less than 0.02 Barrer. In certain embodiments, membranes suitable for use in preparing the external receptacles and other elements of the present disclosure are materials characterized by a Barrer value of less than 0.002 Barrer.

[0039] The present disclosure also provides oxygen at approximately 0.5 cc / m 2

[0023] The present disclosure provides and includes a substantially oxygen-impermeable external receptacle 101 having an oxygen permeability of less than 1.0 barrers / day. In certain embodiments, membranes suitable for use in preparing the external receptacles and other elements of the present disclosure are materials characterized by a barrer value of less than 1.0 barrers. In certain embodiments, membranes suitable for use in preparing the external receptacles and other elements of the present disclosure are materials characterized by a barrer value of less than 0.2 barrers.

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

[0041] In one embodiment of the present disclosure, the manifold is a seal adapter 301. In other embodiments, the inlet / outlet 30 may be configured with multiple inlets / outlets. In some embodiments, the inlet / outlet 30 incorporates two barrier crossing tubes 305 and a manifold 301. In some embodiments, the inlet / outlet 30 incorporates three barrier crossing tubes 305 and a manifold 301. An example of a manifold seal adapter 301 having three inlets / outlets 30 and three barrier crossing tubes 305 is provided in FIG. 3D. The present disclosure further provides and includes barrier crossing tubes 305 having different diameters and functions. In one embodiment of the present disclosure, the barrier crossing tube 305 is a double-layer tube, for example, as shown in FIG. 3C. In another embodiment, the barrier crossing tube(s) 305 is a triple-layer tube, for example, as shown in FIGS. 3A and 3B. In some embodiments, the inlet / outlet port 30 allows for transfusion (e.g., an outlet for flowing blood from the internal collapsible blood container 202) and has tubing (e.g., a spike port) for adding nutrients to the internal collapsible blood container 202 of the blood storage device 20. Also provided is and includes the use of such spike ports to direct oxygen into the internal collapsible blood container 202 to reoxygenate the blood prior to transfusion.

[0042] The present disclosure also provides a method for reducing oxygen levels by approximately 0.5 cc oxygen / m 2

[0023] The present disclosure provides and includes a substantially oxygen-impermeable external receptacle 201 having an oxygen permeability of less than 1.0 barrer / day. In certain embodiments, membranes suitable for use in preparing external receptacles and other elements of the present disclosure are materials characterized by a barrer value of less than 1.0 barrer. In certain embodiments, membranes suitable for use in preparing external receptacles and other elements of the present disclosure are materials characterized by a barrer value of less than 0.2 barrer. In certain embodiments, membranes suitable for use in preparing external receptacles and other elements of the present disclosure are materials characterized by a barrer value of less than 0.02 barrer. In certain embodiments, membranes suitable for use in preparing external receptacles and other elements of the present disclosure are materials characterized by a barrer value of less than 0.002 barrer.

[0043] Materials and methods for preparing the outer 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 to McDorman, each of which is incorporated herein by reference in its entirety. 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 constructed of layers of ethylene-vinyl alcohol copolymer and modified ethylene-vinyl acetate copolymer that are impermeable to carbon and carbon dioxide ingress. In another embodiment, the external receptacle 201 is impermeable to oxygen and carbon dioxide.

[0044] In certain embodiments, the substantially oxygen-impermeable membrane may be a laminated membrane. In some embodiments, the substantially oxygen-impermeable laminated membrane is a laminated foil membrane. The membrane material may be a multilayer construction of a polymer, a foil material, or a combination of foil and polymer. In some embodiments, the laminated membrane may be an aluminum-laminated polyester membrane. Examples of suitable substantially oxygen-impermeable aluminum-laminated membranes, also known as laminated foils, are known in the art. For example, U.S. Patent No. 4,798,728 to Sugisawa discloses aluminum-laminated foils of nylon, polyethylene, polyester, polypropylene, and vinylidene chloride. Other laminated films are known in the art. For example, U.S. Patent No. 7,713,614 to Chow et al. discloses a multilayer container comprising a substantially oxygen-impermeable ethylene-vinyl alcohol copolymer (EVOH) resin. Additional materials suitable for the outer 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 heat sealing. The bag is constructed of a multi-layer construction including materials that enhance O2 and CO2 barrier properties. The bag is constructed of a multi-layer construction including materials that enhance O2 and CO2 barrier properties.

[0045] Table 1 below shows the oxygen transfer rates (Barrers) of various bulk polymeric materials tested at 23° C. and 0% RH using 25.4 μm (1 mil) thick samples. Table 1: Oxygen Transfer Rates (OTR) of various bulk polymer materials (Barrer) TIFF0007784467000001.tif78156

[0046] EVOH has excellent barrier properties as a neat film, but rapidly loses these properties upon exposure to water vapor, especially at RH above 70%. Similarly, nylon-6 has good barrier properties that are susceptible to degradation under high moisture conditions. It is well known in the art to create multilayer laminate and / or coated structures to enhance barrier properties over the bulk materials listed above. Such techniques and compositions include using layers of EVOH disposed 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 are commercially available, for example, from Kurary Company of America (Pasadena, TX), in the EVAL™ series of EVOH films.

[0047] Another method known in the art for producing reinforced multilayer structures is by coating or metallizing a polymer substrate. Examples of such reinforced barrier films are shown in Table 2 below, and because they are composite structures, the OTR is not dependent on the properties or thickness of the bulk film. An example of a suitable aluminum laminate film, also known as a foil laminate, that is substantially oxygen impermeable is available from Protective Packaging Corp. (Carrollton, TX). Table 2: Reinforced barrier films TIFF0007784467000002.tif61160

[0048] Another method known in the art for producing reinforced multilayer structures is by coating a polymer substrate with a silicon or alumina barrier coating followed by an additional coating or polymer laminate to protect the silicon or alumina coating. In some embodiments, the silica can be silicon oxide (SiOx). Examples of such reinforced barrier films are shown in Table 3 below. Table 3: RollPrint® ClearFoil® Enhanced Barrier Film TIFF0007784467000003.tif78156

[0049] A preferred construction includes a PET-based polymer outer layer that has good inherent oxygen barrier properties as a bulk material and is coated with an intermediate layer of alumina to provide enhanced oxygen barrier properties over PET and good optical clarity over a silica intermediate layer, followed by a polyethylene inner layer for heat sealability when fabricating the outer receptacle 201. The relative thicknesses of the alumina or silica layers determine the oxygen barrier properties of the final structure of the film used to fabricate the outer receptacle 201.

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

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

[0052] Another approach 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), incorporated herein by reference in its entirety. Nanoparticles for enhancing oxygen barrier properties are also known in the art, such as the multilayer barrier laminate film 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.

[0053] In embodiments according to the present disclosure, external receptacle 201 can be prepared from a gas-impermeable plastic. In some embodiments, the gas-impermeable plastic can be a laminate. In certain embodiments, the laminate can be a transparent barrier film, such as a nylon polymer or ethylene vinyl acetate (EVA). In some embodiments, the laminate can be a polyester film. In some embodiments, the laminate can be Mylar®. In certain embodiments, the laminate can be a metallized film. In some embodiments, the metallized film can be coated with aluminum. In another embodiment, the coating can be aluminum oxide. In another embodiment, the coating can be silicone oxide. In another embodiment, the coating can be ethylene vinyl alcohol copolymer (EVOH) laminated between layers of low-density polyethylene (LDPE).

[0054] The external receptacle 201 of the present disclosure may be formed of one or more sections made from a gas-impermeable material, including plastic or other durable, lightweight material. In some embodiments, the enclosure may be made from more than one material. In some embodiments, the external receptacle 201 may be made from a material and coated with a gas-impermeable material to make a gas-impermeable enclosure. In some embodiments, the rigid or flexible external receptacle 201 may be made from a plastic that can be injection molded or blow molded. In embodiments according to the present disclosure, the plastic may be selected from polystyrene, polyvinyl chloride, or nylon. In one embodiment, the external 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 external receptacle 201 may be selected from the group consisting of polyaniline (PAN), polycarbonate (PC), polycarbonate / acrylonitrile butadiene styrene (PC / ABS), polyurethane (PU), melamine formaldehyde (MF), plasticized starch materials, phenolics (PF), polyetheretherketone (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 part of a multi-layer laminate. In certain embodiments, the external receptacle 201 comprises polyethylene terephthalate (PET). In certain embodiments, the external receptacle 201 comprises nylon-6. In certain embodiments, the external receptacle 201 may be polyethylene.In some embodiments, the polyethylene outer receptacle 201 may include one or more polyethylene components that are welded together.

[0055] The present disclosure provides for and includes preparing the external receptacle 201 and the 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 the passage of one or more substances from one side of the sheet to the other side of the sheet. As used herein, membranes may be prepared as tubes suitable for connecting together components of a blood storage device 20, blood collection kits, or elements of a blood collection device, additive solution bags, leukocyte reduction filters, and depletion devices, including the depletion devices provided in U.S. Provisional Application No. 62 / 131,130, filed March 15, 2015. As used throughout, the membranes of the present disclosure may be formed as sheets or tubes depending on the application. Also, as previously provided, the membrane for preparing the outer receptacle 201 is substantially impermeable to oxygen, while the inner collapsible blood container 202 is permeable to oxygen.

[0056] The present disclosure provides and includes the preparation of the outer receptacle 201 using heat sealing, blow molding, and injection molding techniques. Suitable materials for preparing the outer receptacle 201 using heat 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 outer receptacles 201, such as the multilayer structure composed of a barrier layer of ethyl vinyl alcohol (EVOH or EVA) positioned between two layers of polypropylene (PP) and provided by Kortec (Kortec, Inc., Rowley, MA) and described in U.S. Pat. No. 5,906,285 issued to Slat, are known in the art. Additives that enhance the oxygen and CO2 barrier properties of polymers before molding, or during their formation or setting, are known in the art. One example is multilayer polymer co-injection, resulting in multilayer PET. Such barrier resins are typically incorporated at the pre-forming stage as an inner layer flanked by PET, making PET the liquid contact layer as well as the outer layer. As provided below, suitable blow-molded or injection-molded outer receptacle 201 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 and includes two types of materials for preparing either permeable or substantially impermeable membranes. In certain embodiments, permeable membranes according to the present disclosure provide for the passage of substances, specifically, but not exclusively, oxygen, through the material. In certain embodiments, the membrane is selected to allow 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 a material depends on one or more properties, including particle size, the material's phase (liquid vs. gas), hydrophilicity, hydrophobicity, or solubility. The rate of passage or flux through a material also depends on the presence or absence of a driving force, such as a pressure (or partial pressure) difference, a temperature difference, or a concentration difference between one side and the other side of the membrane. The flux through a membrane is known as the transmembrane flux. The transmembrane flux of a substance through a membrane is inversely proportional to the membrane thickness.

[0058] The membrane flux of a gas is defined as the flow rate through the membrane per unit area per unit time. The SI units used are m 3 / m 2 s. For gases and vapors, the quantity depends strongly on pressure and temperature. Therefore, gas permeation flux is often given in terms of standard temperature and pressure (STP), defined as 0°C and 1 atmosphere (1.0013 bar) (e.g., 273°K and 760 Torr). As mentioned 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 permeate flux per unit of driving force per unit of membrane thickness. The SI units of the permeability coefficient P are provided in Table 4. The common unit for gas separation, as in this disclosure, is the Barrer, which is also presented in Table 4. "cm 3 Gas (STP) / cm 2 The term "s" refers to the volumetric transmembrane flux of a diffusing species relative to standard conditions of 0 °C and 1 atmosphere of pressure, and the term "cm" refers to the transmembrane partial pressure driving force for this diffusing species. Permeabilities must be determined experimentally. Table 4: Permeability units TIFF0007784467000004.tif42156

[0060] Membranes suitable for the methods and devices of the present 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. Dense membranes are membranes prepared from solid materials without pores or voids. Materials penetrate the dense membrane by dissolution and diffusion processes. 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), urethane, and silicone membranes (polydimethylsiloxane, or PDMS). Also included and provided in the present disclosure are porous membranes with specific size ranges that separate based on size exclusion. Examples of porous membranes suitable for use in the present disclosure include PVDF and polysulfone membranes. An example of a composite membrane suitable for use in accordance with the present disclosure is EMD Millipore's GVHP Hydrophobic PVDF with a pore size of 1.0 μm or 0.22 μm.

[0061] Composite membranes made of more than one material, often as a laminate, are included and provided by the present disclosure, where a dense material is applied to a porous support layer. An example of a composite membrane suitable for use with the present disclosure is EMD Millipore's GVSP superhydrophobic PVDF, with pore sizes of 1.0 μm or 0.22 μm. Table 5: Permeability of fluoropolymers (200 μm thick, 23 °C): TIFF0007784467000005.tif76160

[0062] The present disclosure provides and includes an internally collapsible blood container 202 prepared from a membrane 206 characterized primarily by its oxygen permeability. Unless otherwise indicated, a "substantially impermeable membrane" refers to a membrane that is substantially impermeable to oxygen. However, in certain devices and methods, the membrane may be further characterized by carbon dioxide permeability or impermeability. For certain applications, the membrane material is substantially oxygen impermeable to provide a barrier to the introduction of oxygen into blood, blood components, or blood collection kits comprised of multiple components. Such substantially impermeable membranes are generally used to prepare the external receptacles of the present disclosure. Suitable substantially impermeable membranes may also be used to prepare tubing for connecting components of devices and kits. The substantially impermeable membrane may comprise a single layer or may be a laminated sheet or tube having two or more layers.

[0063] The present disclosure provides and includes an internal collapsible blood container 202 having a permeability of at least 3 Barrers. In certain embodiments, the collapsible blood container 202 is substantially oxygen permeable and has a permeability of 3 to 350 Barrers. In certain embodiments, the internal collapsible blood container 202 is substantially oxygen permeable and has a permeability of 3 to 11 Barrers. In certain embodiments, the internal collapsible blood container 202 is substantially oxygen permeable and has a permeability of 11 to 350 Barrers. In certain embodiments, the internal collapsible blood container 202 is substantially oxygen permeable and has a permeability of 11 to 99 Barrers. In certain embodiments, the internal collapsible blood container 202 is substantially oxygen permeable and has a permeability of 99 to 250 Barrers.

[0064] Applications for using an internal collapsible blood container 202 having a permeability of 3 to 350 Barrers include those where blood transferred to and contained within the internal collapsible blood container has a suitably reduced oxygen content and is desired to be protected from oxygen ingress during storage. In certain embodiments, the internal collapsible blood container 202 has a permeability of 3 to 11 Barrers. In certain embodiments, the internal collapsible blood container 202 has a permeability of 11 to 350 Barrers. In certain embodiments, the internal collapsible blood container 202 is substantially oxygen permeable and has a permeability of 11 to 99 Barrers. In certain embodiments, the internal collapsible blood container 202 has a permeability of 99 to 250 Barrers. In certain embodiments, the internal collapsible blood container 202 does not have a permeability greater than 350 Barrers. In other embodiments, the internal collapsible blood container 202 does not have a permeability of 350 to 500 Barrers.

[0065] The present disclosure provides and includes an internal collapsible blood container 202 having a membrane 206 with an oxygen permeability of 3 to 11 Barrers. In certain embodiments, the internal collapsible blood container is oxygen permeable and has a permeability of 3 to 11 Barrers, as exemplified by an internal collapsible blood container made from PVC-DEHP, PVC-citrate, or PVC-DINCH. In certain embodiments, the internal collapsible blood container is oxygen permeable and has a permeability of 4.3 Barrers, as exemplified by an internal collapsible blood container made from PVC-DEHP.

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

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

[0068] In one embodiment, an oxygen-permeable membrane 206 having an oxygen permeability greater than 11 Barrers is used in the preparation of the collapsible blood container 202. In another embodiment, an oxygen-permeable membrane 206 having an oxygen permeability greater than 99 Barrers is used in the preparation of the collapsible blood container 202. In yet another embodiment, the oxygen-permeable membrane 206 has an oxygen permeability greater than 200 Barrers. In certain embodiments, an oxygen-permeable membrane 206 suitable for use in the preparation of the collapsible blood container 202 is characterized by a Barrer value greater than 3. In other embodiments, an oxygen-permeable membrane 206 suitable for use in the preparation of the collapsible blood container 202 is characterized by a Barrer value greater than 11. In certain other embodiments, an oxygen-permeable membrane 206 suitable for use in the preparation of the collapsible blood container 202 is characterized by a Barrer value greater than 99.Examples of oxygen-permeable membranes 206 suitable for use in preparing the collapsible blood container 202 include Membrana Accurel® PP flat sheet membrane (Membrana division of Celgard, LLC, Charlotte, NC), PP flat sheet membrane from Sterlitech (Kent, WA), Metricel® PP hydrophobic filter membrane (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), Millipore (EMD These include PVDF microporous membranes such as the GVHP and GVSP series from Millipore (Bedford, MA), and polysulfone microporous membranes such as from Pacific Membranes (Pacific Membranes, Inc., San Diego, CA), or MicroPES® membranes from Membrana.

[0069] In one embodiment, the substantially oxygen-permeable membrane 206 can be a dense membrane prepared from a non-porous material. Examples of suitable materials that allow for high oxygen transmission rates include silicone, polyolefin, epoxy, and polyester. In another embodiment, the substantially oxygen-permeable membrane can 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 hydrophobized PVDF, polytetrafluoroethylene (PTFE), polyamide (nylon), cellulose ester, polysulfone, polyethersulfone, hydrophobized polypropylene, and polyacrylonitrile.

[0070] The present disclosure provides for and includes preparing a membrane 206 that is substantially oxygen permeable not only by selecting a material, but also by selecting and controlling a thickness. As noted above, permeability is proportional to the thickness of the membrane. Thus, improved permeability may be achieved by reducing the thickness of the membrane. In certain embodiments, the minimum thickness is determined by its strength and resistance to puncture and tearing.

[0071] The present disclosure also provides and includes a substantially oxygen-permeable membrane 206 prepared using blow molding and injection molding techniques. Suitable materials for preparing the internal collapsible blood container 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 selected for well-controlled wall pressure, followed by 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, U.S. Pat. No. 4,398,642 issued to Okudaira et al., U.S. Pat. No. 7,666,486 issued to Sato et al., U.S. Pat. No. 8,864,735 issued to Sano et al., and U.S. Patent Application Publication No. 2012 / 0146266 by Oda et al. In certain embodiments, the blow-molded collapsible blood container 202 can be prepared using LDPE, which is used in the manufacture of collapsible water containers. As described below, suitable blow-molded or injection-molded collapsible blood containers 202 have an oxygen permeability of at least 3 barrers.

[0072] Applications for using the oxygen permeable internal collapsible blood container 202 having a permeability of 3 to 350 barrers include when the blood transferred to and contained within the internal collapsible blood container has a reduced oxygen content and further oxygen reduction is desired during storage.

[0073] The present 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 is often, but not always, accompanied by water vapor permeability, as well as other gases. Furthermore, those skilled in the art will recognize that as oxygen permeability increases, water vapor permeability may necessarily increase as well. According to the present disclosure, the membrane 206 may be selected based on its selective permeability to oxygen or oxygen and carbon dioxide while minimizing water permeability. The membrane 206 for use in the collapsible blood container 202 is selected to minimize water vapor permeability and prevent water escape from the plasma or additive solution during storage. To properly preserve blood in a storage container for extended periods of up to 64 days, the blood should not be allowed to lose significant amounts of water from its contained plasma. Therefore, the collapsible blood container 202 is prepared from a membrane 206 selected with consideration for the material's moisture vapor transfer rate (MVTR). In embodiments according to the present disclosure, the substantially oxygen permeable membrane 206 has a moisture vapor transfer rate (MVTR) of 30 g / m when tested at 23° C. and 100% RH. 2 / 24 hours or less. MVTR above 30 necessarily means 30 g / m 2 / Above 24 hours is inappropriate.

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

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

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

[0077] The outer receptacle 201 provides additional moisture barrier protection in addition to the oxygen barrier protection of the inner collapsible blood container 202. Due to the added protection of the outer receptacle 201, materials with a higher MVTR relative to the exemplary Renolit ES-3000 PVC-DEHP material are suitable for use in manufacturing the inner collapsible blood container 202, while providing a higher OTR for deoxygenation of stored blood.

[0078] In an embodiment according to the present disclosure, the collapsible blood container 202 has a density of 30 to 0.001 g / m 2 For certain embodiments, the MVTR is between 0.1 and 10 g / m 2 In yet another embodiment, the MVTR is 1 to 8 g / m 2 / day.

[0079] In embodiments according to the present disclosure, the MVTR is expressed in g / m at 23° C. and 100% RH. 2 / day, and the collapsible blood container 202 has a capacity of approximately 3 g / m 2 In another embodiment, the PVC contains DEHP and is prepared from a membrane material 206 that is PVC with an MVTR of about 8 g / m 2 In other embodiments, the PVC contains DINCH and has an MVTR of about 5 g / m 2 In other embodiments, the PVC contains citrate and has an MVTR of about 10 g / m 2 The membrane material 206 may also have an MVTR of 0.001 g / m² / day. 2 The film may be prepared from a foil film, such as an aluminum foil film, which may provide a low MVTR / 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 / m 2 / day MVTR but 2500cc / m 2 / day, while nylon is reported to have an OTR of 260 g / m 2 / day MVTR and 95cc / m 2 It has been reported that polyethylene has an OTR of 6 g / m² / day. The barrier performance of polyethylene is proportional to the polymer density, so low density PE materials have lower barrier performance characteristics than high density PE materials. 2A film such as 76 μm thick polyethylene that provides an MVTR of 52 or 97 g / m² can provide oxygen breathability without compromising moisture content. 2 MVTR films can provide a good moisture barrier to blood products. Polyethylene and other polyolefin materials with good moisture barrier properties are suitable for use as the permeable membrane 206 in preparing the internally collapsible blood container 202. Table 6: Water vapor permeability and water vapor / N selectivity of various polymers at 30 °C estimated for a water vapor activity of 0 TIFF0007784467000006.tif186156

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

[0082] The permeability of the inner collapsible blood container 202 need only be sufficient to allow for the transfer of oxygen out of the stored blood, which may leak into the stored blood, for example, from the tube 205. In other embodiments, the permeability of the inner collapsible blood container 202 may be sufficient to provide additional deoxygenation of the stored blood when combined with a sufficient amount of the adsorbent 207. In certain embodiments, the outer receptacle 201 and the collapsible blood container 202 may be a single, integrated device 20 comprising a multi-layer membrane having a substantially impermeable layer and an innermost blood-compatible layer. The single, integrated device 20 may further include the adsorbent 207, included as a layer between the substantially impermeable layer and the innermost blood-compatible layer.

[0083] During the development of the blood storage device 20 of the present disclosure, it was observed that the need for efficient and continuous removal of trans-oxygen can be significantly reduced through the appropriate selection and design of the inlet / outlet 30, tubing 304, tubing 205, and combinations thereof. The selection of an internal collapsible blood container 202 with a permeability of 3 to 11 Barrers provides a device in which trans-oxygen is essentially reduced or eliminated. Without being limited by theory, it is believed that trans-oxygen enters the system primarily through the tubing 205 or its adhesive 302, which may form gaps 209 and is transported to the collapsible blood container 202. To maintain the blood's oxygen-depleted state, oxygen must be removed by diffusing out of the oxygen-permeable collapsible blood container 202, through the headspace, and by binding to the oxygen adsorbent 207. Therefore, materials used to prepare the collapsible blood container 202 should be selected to be as permeable as possible. In contrast, where oxygen transfer can be largely excluded, suitable material choices for the collapsible blood container 202 can include low permeability materials as provided herein.

[0084] As used herein, an internal collapsible blood container with significantly low oxygen permeability is a collapsible blood container 202 that has a permeability of 3 to 11 Barrers.

[0085] The present disclosure provides and includes a collapsible blood container 202 having a membrane 206 that is relatively oxygen permeable and prepared from polyvinyl chloride (PVC). In embodiments according to the present disclosure, the collapsible blood container 202 can 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 collapsible blood container 202 can be prepared from a PVC membrane 206 having a thickness of 25 μm to 250 μm. In other embodiments, the collapsible blood container 202 can be prepared from a PVC membrane 206 having a thickness of 350 μm to 450 μm. In some embodiments, the collapsible 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 long-term storage of red blood cells. In addition to increasing the flexibility of PVC, DEHP also increases the oxygen permeability of PVC. Therefore, the present disclosure provides and includes a collapsible blood container 202 comprising PVC to which DEHP has been added to enhance permeability. Typical fabrication of collapsible blood containers from PVC-DEHP advantageously uses radio frequency (RF) welding of a pair of films to produce a pouch structure, with each individual film having 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 and the need for higher oxygen permeability for platelet storage, other plasticizers for PVC have found utility in the manufacture of collapsible blood containers, including the use of citrate, among others (see, e.g., "The Role of Poly(Vinyl Chloride) in Healthcare" by Colin R. Blass, copyright 2001 Rapra Technology, Ltd., ISBN: 1-85957-258-8). A suitable example of a PVC-citrate film is Renolit ES-4000 film (American Renolit Corp., City of Commerce, CA). The plasticity and permeability of PVC may also be enhanced by the inclusion of DINCH, bis(7-methyloctyl)cyclohexane-1,2-dicarboxylate (also identifiable as EC No. 431-890-2 and available from BASF as Hexamoll® DINCH). The collapsible blood container 202 of the present disclosure may be constructed of PVC with added DINCH to enhance oxygen permeability. Among the benefits of using citrate or DINCH in the collapsible blood container 202, some concerns have been raised regarding the safety of DEHP, even though DEHP improves the preservation of red blood cells. Without being limited by theory, it is believed 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] The present disclosure provides suitable PVC materials for use in collapsible blood containers 202 that are oxygen-permeable. The use of PVC-citrate membranes such as Renolit ES-4000, having a thickness of 25 μm to 450 μm, preferably 50 μm to 400 μm, and more preferably 150 μm to 400 μm, is suitable for providing collapsible blood containers with the desirable characteristics of relatively high oxygen permeability for PVC membranes, oxygen permeability of at least 3 barrers, good RF welding and bonding characteristics, and high tensile strength. In certain embodiments, the present disclosure provides collapsible blood containers 202 prepared from relatively oxygen-permeable PVC membranes 206 having a thickness of 25 μm to 450 μm, suitable for continued deoxygenation of blood contained therein over a storage period of up to 42 days, or 64 days. In certain embodiments, the present disclosure provides a collapsible blood container 202 prepared from a relatively oxygen-permeable PVC membrane 206 having a thickness of 350 μm to 400 μm suitable for maintaining reduced oxygen levels in the blood contained therein over a storage period of up to 42 days, or 64 days.

[0089] The present disclosure provides and includes a collapsible blood container 202 having a substantially oxygen-permeable membrane 206 prepared from silicone. In embodiments according to the present disclosure, the collapsible blood container 202 can be prepared from a silicone membrane 206 having a thickness of 20 μm to 500 μm. In other embodiments, the collapsible blood container 202 can have a thickness of 30 μm to 400 μm. In other embodiments, the collapsible blood container 202 can have a thickness of 30 μm to 200 μm. In another embodiment, the collapsible blood container 202 is 50 μm to 150 μm thick. In certain embodiments, the present disclosure provides a collapsible blood container 202 prepared from a substantially oxygen-permeable silicone membrane 206 having a thickness of 50 μm to 150 μm, suitable for continued deoxygenation of blood contained therein over a storage period of up to 42 days, or 64 days.

[0090] In an embodiment according to the present disclosure, the collapsible blood container 202 can be prepared from a silicone membrane 206 having a thickness of 20 μm to 400 μm. In another embodiment, the collapsible blood container 202 can have a thickness of 20 μm to 200 μm. In another embodiment, the collapsible blood container 202 can have a thickness of 40 μm to 300 μm. In another embodiment, the collapsible blood container 202 is 40 μm to 400 μm thick. In yet another embodiment, the collapsible blood container 202 is 300 μm to 450 μm thick. In a further embodiment, the thickness of the collapsible blood container 202 can be 350 μm to 450 μm. The present disclosure provides and includes a collapsible blood container 202 that is 450 μm thick. In another embodiment, the collapsible blood container 202 is 425 μm thick. In yet another embodiment, the collapsible blood container 202 is 400 μm thick. In an additional embodiment, the collapsible blood container 202 is 350 μm thick. In certain embodiments, the present disclosure provides a collapsible blood container 202 prepared from a substantially oxygen-permeable silicone membrane 206 having a thickness of 350 μm to 500 μm suitable for maintaining reduced oxygen levels of blood contained therein over a storage period of up to 42 days, 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 Silpuran® brand medical-grade silicone sheet membranes (Wacker Silicones, Adrian, MI), and Polymer Sciences PS-1033 and PS-1044 P-Derm® silicone elastomer membranes (Polymer Sciences, Inc., Monticello, IN). In some embodiments, the silicone membrane may be Polymer Sciences PS-1033 or Silpuran® 6000 silicone. Silicone membranes may be prepared from various liquid silicone rubber (LSR) materials, 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), to name a few.

[0092] In certain embodiments according to the present disclosure, the collapsible blood container 202 can be manufactured from silicone by various molding methods, such as compression molding, injection molding, and insert molding, as well as adhesive bonding of silicone sheets using silicone adhesive. In one embodiment according to the present disclosure, a pair of silicone sheets are bonded together along the periphery with a portion of the silicone inlet tubing in place at the seam using silicone adhesive. In another embodiment according to the present disclosure, silicone liquid rubber is injection molded into a form to create a three-sided shape, which is then further bonded using silicone adhesive to close along the silicone inlet tubing on the remaining fourth side. In another embodiment according to the present disclosure, silicone liquid rubber is injection molded into a form to create a three-sided shape, which is then insert molded onto the closed shape on the remaining fourth side, which incorporates the inlet tubing into the closed shape. In another embodiment according to the present disclosure, silicone liquid rubber is diluted in a suitable solvent, such as xylene, hexane, or tetrahydrofuran, dip coated onto a form to create a three-sided shape, and then insert molded onto the closed shape on the remaining fourth side, which incorporates the inlet tubing into the closed shape. mixed membrane inner bag

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

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

[0095] In embodiments according to the present disclosure, the microporous PVDF membrane 206 includes pores having a diameter ranging from 0.01 μm to 2.0 μm. In other embodiments, the microporous PVDF membrane 206 includes pores having a diameter ranging from 0.01 μm to 1.0 μm. In some embodiments, the microporous PVDF membrane 206 has pores having a diameter ranging from 0.03 μm to 1.0 μm. In other embodiments, the microporous PVDF membrane 206 has pores having a diameter ranging from 0.03 μm to 0.45 μm.

[0096] In an embodiment according to the present disclosure, the porosity of the PVDF membrane 206 used to prepare the collapsible blood container 202 is 20-80%. In another embodiment, the porosity of the PVDF membrane 206 used to prepare the collapsible blood container 202 is 35-50%.

[0097] In certain embodiments, the permeability of a PVDF membrane 206 with pores larger than about 1.0 μm can allow fluids to pass through the membrane, impairing both fluid confinement and oxygen and carbon dioxide permeability. To overcome this permeability with large pore sizes, so-called "superhydrophobic" membranes can be used, with contact angles greater than 150°. As used herein and known in the art, contact angle quantifies the wettability of a solid surface and is theoretically described by Young's equation. In certain embodiments according to the present disclosure, the use of non-hydrophobic PVDF materials is not recommended because the material's low surface tension allows fluids to seep through the pores, even in the above range.

[0098] In certain embodiments according to the present disclosure, the collapsible 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 pores of the porous PVDF membrane may be 0.22 to 0.8 μm in diameter. In some embodiments, the pores of the porous PVDF membrane are 0.2 to 1.0 μm in diameter. In other embodiments, the pores of the porous PVDF membrane may be greater than 0.1 μm and less than 1.0 μm in diameter. In further embodiments, the pores of the porous PVDF membrane are in the range of 0.05 to 1.0 μm. In some embodiments, the pores of the porous PVDF membrane may be greater than 0.3 or 0.4 μm. In other embodiments, the pores of the porous PVDF membrane may be greater than 0.5 or 0.6 μm.

[0099] In an embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having pores less than 1.0 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size less than 0.8 μm. In one particular embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size less than 0.65 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size less than 0.45 μm.

[0100] In an embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size of 0.1 μm. In another embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size of 0.22 μm. In another embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size of 0.20 μm. In a further embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size of 0.45 μm. In yet a further embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a PVDF membrane 206 having a pore size of 0.65 μm. In another embodiment according to the present disclosure, a blood storage device 20 includes an inner collapsible blood container 202 including a PVDF membrane 206 having a pore size of 0.8 μm.

[0101] In embodiments according to the present disclosure, the PVDF membrane can be less than 250 μm thick. In certain embodiments, the membrane is greater than 10 μm thick. In some embodiments, the PVDF membrane can be 10-250 μm thick. In other embodiments, the PVDF membrane can be 10-125 μm thick, or 25-150 μm thick. In certain embodiments, the PVDF membrane can be 50-125 μm thick, 75-125 μm thick, 50-150 μm thick, 75-150 μm thick, 100-125 μm thick, 150-250 μm thick, or 25-150 μm thick. In certain embodiments, the membrane 206 of the internal collapsible blood container 202 is 20 μm thick. In another embodiment, the membrane 206 of the internal collapsible blood container 202 is 30 μm thick. In yet another embodiment, the membrane 206 of the internal collapsible blood container 202 is 50 μm thick. In a further embodiment, the membrane 206 of the internal collapsible blood container 202 is 76 μm thick. In one embodiment, the membrane 206 of the internal collapsible blood container 202 is 120 μm thick.

[0102] In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a PVDF permeable membrane 206 that is 100 to 125 μm thick. In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a PVDF permeable membrane 206 that has a pore size of 0.1 μm to 0.8 μm in diameter and is 100 to 125 μm thick. In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a PVDF permeable membrane 206 that has a pore size of 0.1 μm to 0.8 μm in diameter and is 50 to 150 μm thick.

[0103] Examples of suitable PVDF membranes for preparing oxygen permeable internal collapsible blood containers according to the present 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 certain embodiments, the PVDF membrane 206 may be obtained from Millipore Corporation (Bedford, MA). Examples of such PVDF membranes 206 are VVSP, GVSP, HVSP, DVSP, BVSP, VVHP, GVHP, HVHP, or DVHP.

[0105] The present disclosure provides and includes a collapsible blood container 202 that is substantially oxygen permeable and is a microporous membrane 206 prepared from polysulfone. In certain embodiments, the polysulfone membrane 206 is a hydrophobic microporous membrane 206 that is substantially oxygen permeable.

[0106] In embodiments according to the present disclosure, the microporous polysulfone membrane 206 includes pores having a diameter ranging from 0.01 μm to 2.0 μm. In other embodiments, the microporous polysulfone membrane 206 includes pores having a diameter ranging from 0.01 μm to 1.0 μm. In some embodiments, the microporous polysulfone membrane 206 has pores having a diameter ranging from 0.03 μm to 1.0 μm. In other embodiments, the microporous polysulfone membrane 206 has pores having a diameter ranging from 0.03 μm to 0.45 μm.

[0107] In an embodiment according to the present disclosure, the porosity of the polysulfone membrane 206 used to prepare the collapsible blood container 202 is between 20 and 80%. In another embodiment, the porosity of the polysulfone membrane 206 used to prepare the collapsible blood container 202 is between 35 and 50%.

[0108] In certain embodiments, the permeability of polysulfone membranes with pores larger than about 0.2 μm can allow fluids to pass through the membrane, impairing both fluid confinement and oxygen and carbon dioxide permeability. To overcome this permeability problem with large pore sizes, so-called "superhydrophobic" membranes can be used, with contact angles greater than 150°. As used herein and known in the art, contact angles quantify the wettability of a solid surface and are theoretically described by Young's equation. In certain embodiments according to the present disclosure, the use of non-hydrophobic polysulfone materials is not recommended because the material's low surface tension allows fluids to seep through the pores, even in the above range.

[0109] In certain embodiments according to the present disclosure, the collapsible 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 pores of the porous polysulfone membrane can be 0.22 μm to 0.8 μm in diameter. In certain embodiments, the pores of the porous polysulfone membrane can be 0.2 μm to 1.0 μm in diameter. In other embodiments, the pores of the porous polysulfone membrane can be greater than 0.1 μm to less than 1.0 μm in diameter. In further embodiments, the pores of the porous polysulfone membrane range from 0.05 μm to 1.0 μm in diameter. In some embodiments, the pores of the porous polysulfone membrane can be greater than 0.3 μm or 0.4 μm in diameter. In other embodiments, the pores of the porous polysulfone membrane can be greater than 0.5 μm or 0.6 μm in diameter.

[0110] In an embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having pores less than 1.0 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having pores less than 0.8 μm. In one particular embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having pores less than 0.65 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having pores less than 0.45 μm.

[0111] In an embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.1 μm. In another embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.22 μm. In another embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.20 μm. In a further embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.45 μm. In yet a further embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.65 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.8 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.03 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 0.05 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 comprising a polysulfone membrane 206 having a pore size of 1.2 μm.

[0112] In embodiments according to the present disclosure, the polysulfone membrane can be less than 250 μm thick. In certain embodiments, the membrane is greater than 10 μm thick. In some embodiments, the polysulfone membrane can be 10-250 μm thick. In other embodiments, the polysulfone membrane can be 10-125 μm thick, or 25-150 μm thick. In certain embodiments, the polysulfone membrane can be 50-125 μm thick, 75-125 μm thick, 50-150 μm thick, 75-150 μm thick, 100-125 μm thick, 150-250 μm thick, or 25-150 μm thick. In certain embodiments, the membrane 206 of the internal collapsible blood container 202 is 20 μm thick. In another embodiment, the membrane 206 of the internal collapsible blood container 202 is 30 μm thick. In yet another embodiment, the membrane 206 of the internal collapsible blood container 202 is 50 μm thick. In a further embodiment, the membrane 206 of the internal collapsible blood container 202 is 76 μm thick. In one embodiment, the membrane 206 of the internal collapsible blood container 202 is 120 μm thick.

[0113] In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a polysulfone permeable membrane 206 that is 100 to 125 μm thick. In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a polysulfone permeable membrane 206 that is 100 to 125 μm thick and has a pore size of 0.1 μm to 0.8 μm in diameter. In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a polysulfone permeable membrane 206 that is 50 to 150 μm thick and has a pore size of 0.1 μm to 0.8 μm in diameter.

[0114] Examples of suitable polysulfone membranes 206 for preparing oxygen permeable internal collapsible blood containers according to the present 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 certain embodiments, the polysulfone membrane can be SS120AH, SS080AH, SS065AH, SS045AH, SS020AH, SS010AH, SS005AH, or SS003AH.

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

[0117] In embodiments according to the present disclosure, the microporous polyolefin membrane 206 comprises pores having a diameter ranging from 0.01 μm to 2.0 μm. In other embodiments, the microporous polyolefin membrane 206 comprises pores having a diameter ranging from 0.01 μm to 1.0 μm. In some embodiments, the microporous polyolefin membrane 206 has pores having a diameter ranging from 0.03 μm to 1.0 μm. In other embodiments, the microporous polyolefin membrane 206 has pores having a diameter ranging from 0.1 μm to 0.45 μm.

[0118] In certain aspects according to the present disclosure, the use of non-hydrophobic polyolefin materials is not recommended because the surface tension of the materials is low, allowing fluid to seep through the pores even in the above ranges.

[0119] In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a polyolefin permeable membrane 206 having pores with a diameter of 0.1 μm to 0.45 μm. In other embodiments, the pores in the porous polyolefin membrane can be 0.1 μm to 0.2 μm in diameter.

[0120] In an embodiment according to the present disclosure, the blood storage device 20 comprises an internal collapsible blood container 202 comprising a polyolefin membrane 206 having pores less than 1.0 μm. In another embodiment according to the present disclosure, the blood storage device 20 comprises an internal collapsible blood container 202 comprising a polyolefin membrane 206 having pores less than 0.5 μm. In one particular embodiment according to the present disclosure, the blood storage device 20 comprises an internal collapsible blood container 202 comprising a polyolefin membrane 206 having pores less than 0.2 μm.

[0121] In an embodiment according to the present disclosure, the blood storage device 20 comprises an internal collapsible blood container 202 comprising a polyolefin membrane 206 having a pore size of 0.1 μm. In another embodiment, the blood storage device 20 comprises an internal collapsible blood container 202 comprising a polyolefin membrane 206 having a pore size of 0.2 μm. In a further embodiment according to the present disclosure, the blood storage device 20 comprises an internal collapsible blood container 202 comprising a polyolefin membrane 206 having a pore size of 0.45 μm.

[0122] In embodiments according to the present disclosure, the polyolefin membrane can be less than 250 μm thick. In certain embodiments, the membrane is greater than 50 μm thick. In some embodiments, the polyolefin membrane can be 50 to 250 μm thick. In other embodiments, the polyolefin membrane can be 75 to 110 μm thick, or 140 to 180 μm thick.

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

[0124] Examples of polyolefin membranes suitable for preparing oxygen-permeable, internally collapsible blood containers according to the present disclosure include those described in U.S. Pat. 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 Propafilm™ RGP, RF, and RGN series biaxially oriented polypropylene (BOPP) films from Innovia (Innovia Films, Inc., Atlanta, GA).

[0125] In certain embodiments, a suitable substantially oxygen permeable membrane 206 can be a multilayer membrane. In certain embodiments, the multilayer membrane is a substantially oxygen permeable hydrophobic microporous membrane. Suitable multilayer membranes 206 include multilayer membranes having two or more materials selected from the group consisting of hydrophobized PVDF, PTFE, nylon, cellulose esters, polysulfone, polyethersulfone, hydrophobized polypropylene, and polyacrylonitrile.

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

[0127] In embodiments according to the present disclosure, the microporous multilayer membrane includes pores having a diameter ranging from 0.01 μm to 2.0 μm. In other embodiments, the microporous multilayer membrane 206 includes pores having a diameter ranging from 0.01 μm to 1.0 μm. In some embodiments, the microporous multilayer membrane 206 has pores having a diameter ranging from 0.03 μm to 1.0 μm. In other embodiments, the microporous multilayer membrane 206 has pores having a diameter ranging from 0.03 μm to 0.45 μm.

[0128] In an embodiment according to the present disclosure, the porosity of the multilayer membrane 206 used to prepare the collapsible blood container 202 is 20-80%. In another embodiment, the porosity of the multilayer membrane 206 used to prepare the collapsible blood container 202 is 35-50%.

[0129] In certain embodiments, the permeability of polysulfone membranes with pores larger than about 1.0 μm can allow fluids to pass through the membrane, hindering both fluid confinement and oxygen and carbon dioxide permeability. To overcome this permeability problem with large pore sizes, so-called "superhydrophobic" membranes can be used, with contact angles greater than 150°. As used herein and known in the art, contact angles quantify the wettability of a solid surface and are theoretically described by Young's equation. In certain embodiments according to the present disclosure, the use of non-hydrophobic multilayer materials is not recommended because the surface tension of the material is low, allowing fluids to seep through the pores even in the above range.

[0130] In certain embodiments according to the present disclosure, the collapsible 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 pores of the porous multilayer membrane can be 0.22 μm to 0.8 μm in diameter. In some embodiments, the pores of the porous multilayer membrane can be 0.2 μm to 1.0 μm in diameter. In other embodiments, the pores of the porous multilayer membrane can be greater than 0.1 μm to less than 1.0 μm. In further embodiments, the pores of the porous multilayer membrane range from 0.05 μm to 1.0 μm. In some embodiments, the pores of the porous multilayer membrane can be greater than 0.3 or 0.4 μm. In other embodiments, the pores of the porous multilayer membrane can be greater than 0.5 or 0.6 μm.

[0131] In an embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having pores less than 1.0 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having pores less than 0.8 μm. In one particular embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having pores less than 0.65 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having pores less than 0.45 μm.

[0132] In an embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having a pore size of 0.1 μm. In another embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 including a polysulfone membrane 206 having a pore size of 0.22 μm. In another embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having a pore size of 0.20 μm. In a further embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having a pore size of 0.45 μm. In yet a further embodiment, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having a pore size of 0.65 μm. In another embodiment according to the present disclosure, a blood storage device 20 comprises an internal collapsible blood container 202 including a multi-layer membrane 206 having a pore size of 0.8 μm.

[0133] In embodiments according to the present disclosure, the multilayer membrane 206 can be less than 250 μm thick. In certain embodiments, the membrane is greater than 10 μm thick. In some embodiments, the multilayer membrane 206 can be 10-250 μm thick. In other embodiments, the multilayer membrane can be 10-125 μm thick, or 25-150 μm thick. In certain embodiments, the multilayer membrane 206 can be 50-125 μm thick, 75-125 μm thick, 50-150 μm thick, 75-150 μm thick, 100-125 μm thick, 150-250 μm thick, or 25-150 μm thick, 100-125 μm thick, 150-250 μm thick, or 25-150 μm thick. In another embodiment, the membrane 206 of the internal collapsible blood container 202 is 30 μm thick. In yet another embodiment, the membrane 206 of the internal collapsible blood container 202 is 50 μm. In a further embodiment, the membrane 206 of the internal collapsible blood container 202 is 76 μm. In one embodiment, the membrane 206 of the internal collapsible blood container 202 is 120 μm thick.

[0134] In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a multi-layer permeable membrane 206 having a thickness of 100 to 125 μm. In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a multi-layer permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 100 μm to 125 μm. In certain embodiments according to the present disclosure, the collapsible blood container 202 is prepared from a multi-layer permeable membrane 206 having a pore size of 0.1 μm to 0.8 μm in diameter and a thickness of 50 μm to 150 μm.

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

[0136] In certain embodiments according to the present disclosure, the collapsible blood container 202 should be prepared from an oxygen-permeable material having a tear strength of at least 10 N / mm per test method ASTM D-1004. In certain embodiments, the tear strength is at least 25 N / mm. In some embodiments, the tear strength is at least 50 N / mm. In some embodiments, the tear strength is at least 100 N / mm. The blood storage device 20 further provides and includes a collapsible blood container 202 prepared from a material having a tear strength of 10-100 N / mm. In embodiments of the present disclosure, a reduced tear strength is provided in the collapsible blood container 202, with the external receptacle 201 having a tear strength of at least 50 N / mm. Generally, the tear strength of the collapsible blood container 202 decreases as 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 should the device 20 be roughly handled (e.g., dropped or broken) during processing, given the potentially biohazardous blood materials contained therein.

[0137] The present disclosure includes and provides a blood storage device 20 having an internal collapsible blood container 202 and further including one or more spacers 213 that ensure separation between the external receptacle 201 and the internal collapsible blood container 202. The spacers 213 provide for the maintenance of a headspace in the blood storage device 20 to ensure efficient diffusion of oxygen to the adsorbent 207. The spacers 213 may be prepared from one or more materials selected from the group consisting of mesh, molded mat, woven mat, nonwoven mat, strand veil, and strand mat. In certain embodiments, the spacers 213 may be incorporated directly into the collapsible blood container 202 as ridges, depressions, or other raised features that maintain separation between the external receptacle 201 and the internal collapsible blood container 202. The present specification also includes and provides spacers 213 incorporated directly into the external receptacle 201 as ridges, depressions, or other suitable raised features that can maintain separation between the external receptacle 201 and the internal collapsible blood container 102. In certain embodiments, the presence of the spacers 213 provides consistency to the assembly in terms of manufacturing techniques and layering of the internal and external films, allowing for repeatable oxygen level maintenance. In other embodiments, the presence of the spacers 213 promotes further oxygen reduction during storage. Providing the spacers 213 can prevent the internal membrane 206 from laminating or "sticking" to the membrane or material of the external receptacle 201 through mechanical or physical means. Without being limited by theory, if adhesion or lamination occurs, oxygen preservation or further oxygen reduction of the assembly may be impaired because oxygen encounters an additional barrier and diffuses.

[0138] In certain embodiments, the spacer 213 also provides a protective, surrounding layer around the periphery of the collapsible blood container 202, increasing the collapsible blood container's resistance to burst failure, for example, if accidentally dropped or subjected to other traumatic forces during handling. In certain embodiments, the spacer 213 providing the protective layer comprises an open-cell reticulated polyurethane foam as the spacer 213 material. Such spacer 213 material may have about 10 pores per inch (ppi) to about 100 ppi. In certain embodiments, the spacer 213 has a pore density of 45 ppi and is 3.2 mm (0.125 in) tall.

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

[0140] The present disclosure provides and includes a blood storage device 20 for storing oxygen-depleted 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 certain embodiments, the oxygen adsorbent 207 is located between the external receptacle 201 and the collapsible blood container 202. In other embodiments, the oxygen adsorbent is located within the collapsible blood container 202 and is contained in a second blood-compatible container. In still other embodiments, the oxygen adsorbent 207 is positioned as a layer of a multi-layer film, with the external layer being the external receptacle 201 and the innermost layer being the collapsible blood container 202.

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

[0142] As used herein, standard temperature and pressure (e.g., 0°C (273.15 Kelvin) and 1.01 x 10 5 An amount of adsorbent having a certain oxygen-binding capacity, measured by volume (e.g., cubic centimeters (cc) or milliliters (mL)) at a pressure of 100 kPa (1 bar, 0.986 atm, 760 mmHg), is provided. In other embodiments, the oxygen adsorbents and scavengers are also capable of binding and removing carbon dioxide from the environment. In certain embodiments, the adsorbent 103 can be a mixture of non-toxic inorganic and / or organic salts and divalent iron ions or other materials highly reactive to oxygen, carbon dioxide, or oxygen and carbon dioxide. In certain embodiments, the oxygen adsorbent or scavenger is combined with a carbon dioxide adsorbent. In other embodiments, the presence or absence of carbon dioxide binding capacity of the oxygen adsorbent is not required.

[0143] Suitable oxygen adsorbents or scavengers are known in the art. A suitable oxygen adsorbent according to the present disclosure has a minimum oxygen adsorption rate of 0.8 mL / min. Adsorbents with a suitable adsorption profile will bind at least 45 mL of O2 within 60 minutes, 70 mL of O2 within 120 minutes, and 80 mL of O2 within 180 minutes. Suitable adsorbents may have both higher 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 chelators. 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 can be formed into or incorporated into fibers, microfibers, microspheres, particulates, 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 the present disclosure. Suitable oxygen adsorbents include the MGC Ageless® SS-200 oxygen absorber.

[0146] In embodiments according to the present disclosure, the adsorbent can be an oxidizable organic polymer having a polymer backbone and multiple pendant groups. Examples of adsorbents with a polymer backbone include saturated hydrocarbons (less than 0.01% carbon-carbon double bonds). In some embodiments, the backbone can contain ethylene or styrene monomers. In certain embodiments, the polymer backbone can be ethylenically based. In another embodiment, the oxidizable organic compound can be ethylene / vinylcyclohexane copolymer (EVCH). Additional examples of substitution moieties and catalysts are provided in U.S. Patent Publication No. 2003 / 0183801 by Yang et al., which is incorporated herein by reference in its entirety. In additional embodiments, the oxidizable organic polymer can also contain substituted hydrocarbon moieties. Examples of oxygen-scavenging polymers include those described by International Patent Publication No. WO 99 / 48963 by Ching et al., which is incorporated herein by reference in its entirety. Oxygen scavenging materials may include those provided in U.S. Pat. No. 7,754,798 issued to Ebner et al., U.S. Pat. No. 7,452,601 issued to Ebner et al., or U.S. Pat. No. 6,387,461 issued to Ebner et al., each of which is incorporated herein by reference in its entirety.

[0147] As used herein, the adsorbents of the present disclosure can be either free or contained in a permeable enclosure, container, envelope, etc. In certain embodiments, the adsorbents are provided in one or more pouches formed of a material that is highly porous and essentially non-resistant to gas transfer. Examples of such materials include stretched polyester film, perforated metal foil, stretched polyethylene film (Tyvek®), perforated foil, polymers, paper, and combinations thereof.

[0148] The present disclosure further includes and provides for sorbents 207 incorporated as one or more laminate layers of the substantially oxygen-impermeable outer receptacle 201. Polymeric sorbents such as those described above may be laminated to the sheets used to prepare the outer receptacle using methods known in the art, including soft contact lamination, heat lamination, or solvent lamination.

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

[0150] The present disclosure provides and includes an adequate amount of sorbent 207 sufficient to absorb and retain residual oxygen present after manufacture, ingress oxygen during storage and prior to use of device 20, oxygen introduced during filling of device 20, residual oxygen contained in oxygen-depleted blood, and oxygen ingress during blood storage. Previous anaerobic blood storage devices, such as those described by Bitensky, do not recognize or address the problem of oxygen ingress, particularly through transfer and collection tubing. Traditional inlets and outlets do not provide an adequate oxygen barrier. Furthermore, while the present disclosure provides certain elements that minimize or even significantly eliminate oxygen ingress, absolute impermeability is not feasible. Thus, the blood storage device 20 of the present disclosure incorporates a sorbent 207 that has both sufficient capacity and suitable binding kinetics to ensure an anaerobic environment is maintained. Furthermore, in certain embodiments, sorbent 207 may be provided to further reduce oxygen levels in oxygen-depleted blood. Finally, the amount of adsorbent 207 must also provide a reliable and reproducible shelf life for the blood storage device 20 .

[0151] In embodiments according to the present disclosure, blood storage device 20 has a quantity of oxygen sorbent 207 having an oxygen-binding capacity of at least 20 cc of oxygen. In some embodiments, the oxygen-binding capacity of sorbent 207 of blood storage device 20 is at least 30 cc of oxygen. In some embodiments, the oxygen-binding capacity of sorbent 207 of blood storage device 20 is at least 50 cc of oxygen. In some embodiments, the oxygen-binding capacity of sorbent 207 of blood storage device 20 is at least 100 cc of oxygen. In some embodiments, the oxygen-binding capacity of sorbent 207 is at least 25 or 30 cc of oxygen. In still further embodiments, the oxygen-binding capacity of sorbent 207 is at least 30 or 45 cc of oxygen.

[0152] In embodiments according to the present disclosure, the oxygen capacity of the sorbent 207 is at least 20 cc. In certain embodiments, the oxygen capacity of the sorbent 207 is at least 20 cc but less than 100 cc. In certain embodiments, the oxygen capacity of the sorbent 207 is at least 20 cc but less than 75 cc. In certain embodiments, the oxygen capacity of the sorbent 207 is at least 30 cc but less than 50 cc. In certain embodiments, the oxygen capacity of the sorbent 207 is at least 20 cc but less than 250 cc. In certain embodiments, the oxygen capacity of the sorbent 207 is between 50 and 200 cc. In other embodiments, the oxygen capacity of the sorbent 207 is between 100 and 200 cc. In other embodiments, the oxygen capacity of the sorbent 207 is between 20 and 50 cc.

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

[0154] As used herein, a "carbon dioxide sequestering agent" is a material that binds or combines with carbon dioxide under conditions of use. The term "carbon dioxide sorbent" may be used interchangeably with "carbon dioxide sequestering agent" herein. In certain embodiments, the carbon dioxide sorbent may be non-reactive or minimally reactive with oxygen. In other embodiments, the oxygen sorbent may exhibit a secondary functionality of carbon dioxide capture. Carbon dioxide sequestering agents 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 according to the present disclosure, the material may irreversibly bind or combine with CO2. In embodiments according to the present disclosure, the material may bind CO2 with a higher affinity than hemoglobin. In other embodiments, the sorbent material may bind CO2 with a high affinity such that carbonic acid present in the blood or RBC cytoplasm is released and absorbed by the sorbent. In other embodiments, CO2 binds to the sorbent material and exhibits a very slow release rate (k オフ In some embodiments, the carbon dioxide can chemically react with some components of the material and be converted into another compound.

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

[0156] Non-limiting examples of CO2 scavengers include oxygen and carbon dioxide scavengers from Multisorb Technologies (Buffalo, NY) and Sodasorb® from Grace. Oxygen scavengers may exhibit a secondary functionality of carbon dioxide scavenging.

[0157] In embodiments according to the present disclosure, O2-depleted media and CO2-depleted media can be blended in desired ratios to achieve the desired results. In another embodiment, the sorbent chemistry can have an affinity for both O2 and CO2.

[0158] The present disclosure further includes and provides an adsorbent contained in a pouch. As used herein, a "pouch" is any enclosure that encloses and contains an oxygen adsorbent, a carbon dioxide adsorbent, or a combination of an oxygen adsorbent and a carbon dioxide adsorbent(s). A pouch according to the present disclosure is contained within an overwrap material that is permeable to both oxygen and carbon dioxide. In certain embodiments, the overwrap material may be a combination of two or more materials, at least one of which is permeable to oxygen and carbon dioxide. Suitable overwrap materials have a known biocompatibility profile or comply with ISO 10993.

[0159] The pouches are sealed so that the absorbent contents are entirely contained within the overwrap material and do not allow the absorbent to leak, seep, migrate, or otherwise exit the overwrap package. The pouches may be any shape, but are typically rectangular or square. In some embodiments, the pouches are approximately 50 x 60 mm. In some embodiments, the oxygen adsorbent 207 binds 20 cc of oxygen per pouch at STP. In some embodiments, the oxygen adsorbent 207 binds 10 cc of oxygen per pouch at STP. In some embodiments, the oxygen adsorbent 207 binds 25 cc of oxygen per pouch at STP. In some embodiments, the oxygen adsorbent 207 binds 10-50 cc of oxygen per pouch at STP. In some embodiments, the oxygen adsorbent 207 binds 10-75 cc of oxygen per pouch at STP. In some embodiments, the oxygen adsorbent 207 binds 10-20 cc of oxygen per pouch at STP. In certain embodiments according to the present disclosure, the pouch has a total oxygen adsorption capacity of 50 cc O2 at STP. In certain embodiments of the present disclosure, the pouch has a total oxygen adsorption capacity of at least 100 cc O2 at STP.

[0160] In embodiments according to the present disclosure, oxygen sorbent 207 may be provided in one or more pouches. In another embodiment, oxygen sorbent 207 is provided in a single larger pouch. In another embodiment, oxygen sorbent 207 is provided in two pouches dispensed within the headspace between collapsible container 202 and external receptacle 201. In yet another embodiment, oxygen sorbent 207 is provided in four pouches dispensed within the headspace between collapsible container 202 and external receptacle 201. In embodiments according to the present disclosure, blood storage device 20 may include between 2 and 20 sorbent packages.

[0161] In embodiments according to the present disclosure, the blood storage device 20 includes 0.5 to 150 grams of adsorbent 207 contained in one or more pouches. Suitable adsorbents are provided above in

[0161] through

[0164] . In some embodiments, the blood storage device 20 includes 0.5 to 5 grams of adsorbent 207 contained in one or more pouches. In other embodiments, the blood storage device 20 includes 8 to 24 grams of adsorbent 207 contained in one or more pouches. In other embodiments, the blood storage device 20 includes 8, 16, or 24 grams of adsorbent 207. In some embodiments, the blood storage device 20 includes 8 grams of SS-200 adsorbent 207, or its equivalent, contained in one pouch. In other embodiments, the blood storage device 20 includes 16 grams of SS-200 adsorbent 207, or its equivalent, contained in two pouches. In another embodiment, blood storage device 20 contains 24 grams of SS-200 sorbent 207, or its equivalent, contained in three pouches. In a further embodiment, blood storage device 20 contains 14 grams of sorbent 207, or its equivalent, contained in one Dessicare pack. In some embodiments, blood storage device 20 contains approximately 1 gram of sorbent 207. In yet another embodiment, blood storage device 20 contains approximately 2 grams of sorbent 103. In some embodiments, blood storage device 20 contains approximately 3 or 4 grams of sorbent 207 contained in one or more pouches. In some embodiments, blood storage device 20 contains approximately 0.75 or 1.0 gram of sorbent 207 contained in one or more pouches. The pouches may be square, rectangular, circular, or oval.

[0162] In embodiments according to the present disclosure, the blood storage device 20 includes an oxygen indicator 215 that can serve as an early warning to the user that the storage device has been compromised. In embodiments according to the present disclosure, compromise of the outer barrier bag 102 or the inlet / outlet port 30 results in oxygen in the outer bag headspace. Such unwanted oxygen ingress can occur before use (e.g., during shelf storage) or after the device 20 is filled with oxygen-deficient blood. The oxygen indicator 215 according to the present disclosure includes a device constructed of a chemical reaction, typically in paper or tablet form, enclosed in an oxygen-permeable film pack. As used herein, the oxygen indicator 215 is sensitive enough to detect oxygen levels above 1 Torr of partial oxygen pressure. In the presence of oxygen, the indicator changes color (e.g., from pink to purple). This alerts the user of the device 20 that the oxygen-impermeable protection may be compromised and to take additional action if necessary. In some embodiments, the blood in a compromised device 20 can 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 manufacture. In certain embodiments, the oxygen indicator 215 is laminated to 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] The present disclosure provides and includes tubing 205 for connecting the blood storage device 10 and other components of the blood collection kit together. Tubing 205 serves many functions for the blood collection kit, including, but not limited to, preventing contamination of the blood collection kit and providing sterile transfer and docking when connection to external sterile tubing is required. During the development of the anaerobic storage bag, it became apparent that the primary source of oxygen transfer before and during use of the blood storage device was tubing 205, as illustrated below in Example 8. Thus, the devices and methods of the present disclosure overcome limitations of the prior art and minimize oxygen impact in the storage environment.

[0164] In embodiments according to the present disclosure, the tubing 205 is prepared from a material that is substantially oxygen-impermeable and optionally carbon dioxide-permeable. In many embodiments, the tubing 205 is prepared from a dense material without pores or voids. In other embodiments, the tubing 205 is prepared as a barrier crossing tube 305, as illustrated in FIG. 3, having at least one oxygen barrier layer 307 and at least one hemocompatible layer 306. In certain embodiments, the oxygen barrier layer 307 and the hemocompatible layer 306 are the same layer. The present disclosure also provides and includes a barrier crossing tube 305 having an inner hemocompatible layer 306, a middle oxygen barrier layer 307, and an outer layer 308. In certain embodiments, the outer layer 308 provides protection for the oxygen barrier layer 307 and prevents the formation of holes, cracks, or other breaches in the oxygen barrier. In certain embodiments, the outer layer 308 also provides for the formation of the adhesive joint 302. The present disclosure provides a barrier crossing tube 305 having two layers: a hemocompatible layer 306 and an outer layer 308. In certain embodiments, oxygen barrier layer 307 and outer layer 308 are the same layer. In certain embodiments, outer layer 308 is suitable to act as seal adapter 301. In addition to permeability, tubing 205 should be suitable for sterile welding, which provides for the joining of two opposing ends of tubing while maintaining a sterile fluid pathway. In some embodiments, tubing 205 is comprised of barrier crossing tubing 305 that is suitable for sterile welding. In further embodiments, tubing 205 should be resistant to kinks, twists, and folds. As noted above, it will be understood by those skilled in the art that the thickness of the tubing wall is proportional to the permeability of the tubing. Thus, while many materials may be suitable if provided with sufficient thickness, such materials may not be suitable because they lack flexibility or are simply too large or cumbersome for use in a blood collection set or for docking with other tubing.

[0165] As used herein, substantially oxygen-impermeable piping 205 is a material characterized by a Barrer value of less than 1 Barrer, preferably less than 0.2 Barrer. In other embodiments, substantially oxygen-impermeable piping 205 is a material characterized by a Barrer value of less than 0.01 Barrer. In other embodiments, substantially oxygen-impermeable piping 205 is a material characterized by a Barrer value of less than 0.002 Barrer. In other embodiments, substantially oxygen-impermeable piping 205 is a material characterized by a Barrer value of less than 100 cc / mil·100 in 2 In another embodiment, the substantially oxygen impermeable tubing 205 has an oxygen transmission rate of 80 cc / mil 100 in 2 In other embodiments, the substantially oxygen impermeable tubing 205 has an oxygen transmission rate of 35 cc / mil 100 in 2 205 has an oxygen transmission rate of 0.002-1 barrer. In some embodiments, piping 205 has an oxygen permeability of 0.002-0.20 barrer. In some embodiments, piping 205 has an oxygen permeability of 0.01-0.10 barrer.

[0166] In embodiments according to the present disclosure, the tubing 205 may be 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 styrene (ACSB), or the like. The tubing 205 may be prepared from a material selected from the group consisting of polyethylene (ABS), polycarbonate (PC), polycarbonate / acrylonitrile butadiene styrene (PC / ABS), polyurethane (PU), melamine formaldehyde (MF), plasticized starch materials, phenolics (PF), polyetheretherketone (PEEK), polyetherimide (PEI) (Ultem), polylactic acid (PLA), polymethyl methacrylate (PMMA), polytetrafluoroethylene (PTFE), urea-formaldehyde, ethylene vinyl alcohol copolymer (EVOH), and polyamide. In some embodiments, the tubing 205 is prepared from polyethylene. In some embodiments, the tubing 205 is prepared from polyvinyl chloride.

[0167] The present disclosure also provides and includes a blood storage device 20 having tubing 205 that is a barrier traversing 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 some embodiments, the barrier traversing tube 305 used in tubing 205 includes an oxygen barrier layer 307 comprising PET. In some embodiments, the barrier traversing tube 305 used in tubing 205 includes an oxygen barrier layer 307 comprising EVA. In other embodiments, the barrier traversing tube 305 used in tubing 205 includes an oxygen barrier layer 307 comprising EVOH. In certain embodiments, the tubing 205 includes a hemocompatible inner layer 306 comprising PVC. In certain embodiments, the barrier crossing tube 305 used in the tubing 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 crossing tube 305 used in the tubing 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), where the PE outer layer 308 has a thickness of 150 μm, the EVA oxygen barrier layer 307 has a thickness of 10 μm, and the PVC inner layer 306 has a thickness of 350 μm, thereby providing a multi-layer tubing that is easily used with current sterile tubing connection equipment. 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 tubing equivalent to tubing 205 of the present disclosure. Such PVC tubing is not suitable for use in some embodiments of the blood storage device of the present disclosure and, when used as tubing 205, is a significant source of oxygen ingress.Such PVC tubing typically allows for approximately 1 cc of oxygen ingress per day over a 1-meter length of tubing at ambient conditions; therefore, the blood collection systems and kits of the present invention require an oxygen barrier overpack with an oxygen adsorbent to protect and maintain the interior space and volume of the blood collection kit from unwanted oxygen ingress. Because most of the PVC tubing in the blood collection kit is discarded after collection and processing, the anaerobic storage apparatus 20 is left with only the 150 mm length of exposed inlet tubing before storage, and the oxygen ingress rate through that remaining 150 mm length of exposed PVC tubing is limited to approximately 0.16 cc / day at ambient conditions, or approximately 7 cc oxygen at ambient conditions over 42 days, and approximately 10 cc after 64 days. The actual oxygen ingress rate is much lower at the 4°C refrigerated storage temperature used for long-term blood storage than the amount of oxygen ingress measured at ambient conditions.

[0168] The present disclosure includes and provides a blood storage device 10 having a substantially oxygen-impermeable, one-piece tubing design that combines tubing 205, adhesive 302, and tubing 304 into a single structure. Benefits of this design include reducing the number of individual components and eliminating potential sources of oxygen ingress. Furthermore, the incorporation of a one-piece tubing design including multilayered, oxygen-impermeable tubing provides for the preparation of a simplified blood storage device 20 with a hemocompatible external receptacle 201 capable of storing oxygen-depleted blood directly attached to one or more inlets or outlets with impermeable tubing. By essentially eliminating a potential source of oxygen, suitable oxygen-depleted blood can be stored directly in the hemocompatible external receptacle 201, while eliminating the need for a collapsible blood container 202 and oxygen absorber 207. The present disclosure also provides for the preparation of a blood storage device comprising a multi-layer container that combines an external receptacle 201, an oxygen adsorbent 207, and a collapsible blood container 202 as a single multi-layer device adhered to one or more tubing 205 via an oxygen-impermeable adhesive.

[0169] In embodiments according to the present disclosure, the external receptacle 201 includes one or more inlets / outlets 30. In certain embodiments, the 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 in fluid communication with the collapsible blood container 202. In yet other embodiments, the external receptacle 201 includes a third inlet / outlet 30 in fluid communication with the collapsible blood container 202. Each inlet / outlet 30 may further include a spike port 303.

[0170] It is worth noting that few materials offer complete impermeability, and even highly permeable materials may be compromised when joining, welding, folding, and otherwise assembling the outer receptacle 201. As described below, the blood storage device 20 can further incorporate optional spike ports 303 and inlets / outlets 30 and must be designed to accommodate changes in the volume of the inner collapsible blood container 202. Therefore, special attention is paid to incorporating certain design elements and manufacturing methods to ensure the integrity of the impermeable barrier and maximize the integrity of material performance.

[0171] Spike ports 303 for use in blood collection kits and systems are generally 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 prior to use and also provides some degree of oxygen impermeability to the contents. In some embodiments, the spike port 303 is covered by a sealed, frangible portion of an outer receptacle film, thereby providing a sterile barrier and an additional degree of oxygen impermeability. Improved oxygen impermeability is desirable because it increases the shelf life of kits and systems containing the blood storage device 20.

[0172] Of course, conventional ports, inlets, and outlets are potential sources of unwanted oxygen ingress, depending on both the choice of material and the method used to bond the port, inlet, or outlet to the external receptacle 201. Methods of bonding materials to prepare the bond 302 are well known in the art. As provided herein, the inlet / outlet 30 comprises a seal adapter 301 joined to the external receptacle 201 using the bond 302, which creates an oxygen-impermeable seal to the external receptacle 201. In one embodiment of the present disclosure, the manifold is the seal adapter 301. As used herein, a substantially oxygen-impermeable bond 302 has a Barrer value of less than 1 Barrer, preferably less than 0.10 Barrer, and more preferably less than 0.01 Barrer.

[0173] As provided herein, the substantially oxygen-impermeable bond 302 can be solvent sealed, heat sealed, adhesively bonded, ultrasonically welded, or radio frequency welded. In certain embodiments, the bond 302 is achieved by using a constant heat sealing die heated and maintained at approximately 260°F. In certain embodiments, the film is placed between the heated dies and clamped together for approximately 3-7 seconds to achieve a heat-welded seam. In certain embodiments, the heat seal is created in approximately 5 seconds. In certain embodiments, the sealing dies have grooves machined into them to accommodate the intermediate component. In some embodiments, the seal adapter 301 comprises an intermediate component, which may be a length of barrier crossing tubing, as described below, or a small block of machined, extruded, molded, or laminated polymer wedge. In embodiments according to the present disclosure, the grooves are approximately 5% smaller than the component features, thereby providing compression and material flow during sealing.

[0174] In some embodiments, the oxygen-impermeable adhesive is comprised of a portion of the barrier crossing tubing (e.g., seal adapter 301) that is heat sealed to the seam of the external receptacle 201. In certain embodiments, the barrier crossing tubing is comprised 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 crossing tubing is comprised 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 section of PVC tubing is solvent bonded to the multilayer tubing using, for example, cyclohexanone.

[0175] In some embodiments, the inlet / outlet 30 is comprised of a seal adapter 301, a small device that is a machined, extruded, molded, or laminated polymer wedge or block. The molded device can 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 device can be ethylene-vinyl acetate (e.g., EVA). In certain embodiments, the machined, extruded, molded, or laminated polymer device can be a small diamond, oval, or other suitable shaped polymer block with a hole in the center, whereby the shaped device can be heat sealed to the seam of the external receptacle, providing an oxygen-impermeable bond 302 while the central through-hole provides fluid connectivity to the contents. In certain embodiments, a section of PVC tubing is glued into the central bore of diamond-shaped seal adapter 301 using an oxygen-impermeable adhesive capable of bonding to polyethylene, such as Loctite 4310, Masterbond X17, or 3M Scotchweld 4693, thereby providing fluid connectivity to the contents therein through an oxygen-impermeable external receptacle. In other embodiments, barrier-crossing tubing can be glued into the central bore of diamond-shaped seal adapter 301 using methods known in the art. In other embodiments, barrier-crossing tubing can be insert molded into diamond-shaped seal adapter 301 using methods known in the art. In other embodiments, barrier-crossing tubing can be used in place of standard PVC intravenous tubing to provide enhanced oxygen barrier properties.

[0176] The present disclosure provides and includes positioning features that align the external receptacle 201, the collapsible blood container 202, and the inlet / outlet 30 and ensure the integrity of the oxygen-impermeable barrier. Misalignment can result in breaches in the barrier and ingress of oxygen during storage and prior to use. In accordance with the present disclosure, the positioning features can be selected from the group consisting of geometric cutouts, tactile surface markings, die-cut fiducials, spacers, interlocking cutouts, plumbing fittings, and printed markings.

[0177] The present disclosure provides and includes an expansion feature 217 to accommodate the blood solution and avoid 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 breaches of the impermeable barrier. Such folds and folds result in unacceptable levels of oxygen ingress, leading to an unacceptable increase in oxygen saturation of the stored blood during storage. The expansion feature also provides unlimited filling of the storage device 20, the outer enclosure 201, and the collapsible blood container 202.

[0178] In embodiments according to the present disclosure, the expansion feature 217 is selected from the group consisting of a pleat, a septum, a bubble, one or more flaps, a fold-over pouch, and a geometric expansion of the package shape. In some embodiments, the expansion feature 217 is comprised of a gusseted flap along one or more edges of the external receptacle 201. In certain embodiments, a flap of approximately 1 / 8 to 1 / 4 inch is adequate to provide an expansion of the internal container 202, and the flaps are seam-sealed at the edges. In some embodiments, as illustrated in FIG. 8, the expansion feature 217 is comprised of a third panel or tri-fold of barrier film sealed along the bottom of the external receptacle 201 to provide a three-dimensional bag.

[0179] In certain embodiments, the collapsible blood container 202 may also include expansion features to facilitate filling of the container, although the oxygen impermeable integrity of the container 202 is obviously not a concern.

[0180] The present 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 include a tubing management component 40. The tubing management component 40 may be selected from the group consisting of a separate clip or strap as illustrated in FIGS. 6A and 6B, a strap attached to the external surface of the external receptacle, such as those illustrated in FIGS. 6C and 6D, and a hook-and-loop fastener (VELCRO®). In certain embodiments, for example, as illustrated in FIGS. 6E and 6F, the tubing management component 40 is a cutout feature in 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] The present disclosure provides and includes an integral handle 214 within the external receptacle 201, for example as illustrated in FIG.

[0182] The present disclosure provides and includes one or more transparent or translucent windows 212 to provide for visual inspection of the blood. Such windows allow for inspection of the blood's color and also allow visualization of undesirable characteristics of contaminants, such as blood clots or bacterial colonies, if present in the blood.

[0183] Among other factors, the shelf 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, can degrade when exposed to high temperatures. Such a degraded device is unsuitable for blood storage and can lead to undesirable patient outcomes. As known to those skilled in the art, the amount of time the device is exposed to undesirable temperatures is equally important. Accordingly, the present disclosure provides a device that further includes a temperature-time monitor. Such monitors are known in the art, for example, as provided in U.S. Patent Nos. 7,517,146, 6,042,264, and 5,709,472. In certain embodiments, a BT-10 time strip from Genesis (Genesis BPS, Ramsey, NJ) can be incorporated into the collapsible blood container to monitor the duration of any temperature incursion above 10°C.

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

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

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

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

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

[0189] The present 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 storage 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 one embodiment, the storage period is 28 days and the initial SO2 level is 20% or less. In a further embodiment, the storage period is 42 days and the initial SO2 level is 20% or less. In a further embodiment, the storage period is 56 days and the initial SO2 level is 20% or less. In 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 a further 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 some embodiments, 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 a further embodiment, the storage period is 42 days and the initial SO2 level is 10% or less. In a further 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 some embodiments, the storage period is 21 days and the initial SO2 level is about 5%. In some embodiments, the storage period is 28 days and the initial SO2 level is about 5% or the storage period is 42 days. In a further embodiment, the storage period is 56 days and the initial SO2 level is about 5%, or the storage period is 64 days. In yet another embodiment, the storage period is 21 days and the initial SO2 level is about 3%. In another embodiment, the storage period is 28 days and the initial SO2 level is about 3%, or the storage period is 42 days and the initial SO2 level is about 3%.In a further embodiment, the storage period is 56 days and the initial SO2 level is about 3%. In yet another embodiment, the storage period is 64 days and the initial SO2 level is about 3%.

[0190] The present 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 sorbent 207, which provides an oxygen saturation level (SO2) during a storage period that is lower than the oxygen saturation level at the beginning of storage, the storage period being at least one week. In an embodiment according to the present disclosure, the oxygen saturation level after one week of storage is 2% lower than the oxygen saturation level at the beginning of storage. In other embodiments, the present disclosure provides a decrease in oxygen saturation level at a rate of at least 0.00010% SO2 / min. In certain embodiments, the oxygen saturation level decreases at a rate of at least 0.00020% SO2 / min. In other specific embodiments, the oxygen saturation level decreases at a rate of at least 0.0003% and 0.0001% SO2 / min. In other embodiments, the storage period is 21 or 28 days. In still other embodiments, the storage period is 42 or 56 days. In other embodiments, the blood storage device 20 provides reduced oxygen saturation levels after 64 days.

[0191] The present disclosure provides and includes a blood storage device 20 comprising an external receptacle 201, a collapsible blood container 202, and at least one inlet / outlet 30, wherein blood stored within the collapsible blood container 202 and the blood provides an oxygen saturation level (SO2) during storage that increases by less than 5% over the oxygen saturation level at the beginning of storage, the storage period being 64 days. In other embodiments, the oxygen saturation level (SO2) during storage increases by less than 3% over the oxygen saturation level at the beginning of storage, the storage period being 64 days.

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

[0193] In some embodiments according to the present disclosure, the collapsible blood container 202 is prepared by heat sealing one or more membranes 206. In another embodiment, the collapsible blood container 202 is prepared by adhesively bonding one or more membranes 206. In other embodiments, the collapsible blood container 202 is prepared by ultrasonically welding one or more membranes 206. In other embodiments, the collapsible blood container 202 is prepared by radio frequency welding one or more membranes 206. In still other embodiments, the collapsible blood container 202 is prepared by one or more methods selected from heat sealing, adhesive bonding, ultrasonic welding, or radio frequency welding.

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

[0195] In certain embodiments according to the present disclosure, the collapsible blood container 202 can be fabricated from the porous membrane 206 by various sealing methods, such as heat sealing, thermal staking, and adhesive bonding. In one embodiment according to the present disclosure, a pair of PVDF porous membranes are bonded together along the periphery with a section of PVC inlet tubing in place within the seams using an adhesive such as Locite 4011 in conjunction with an adhesive primer such as Locite 770. In another embodiment according to the present disclosure, the collapsible blood container can be fabricated from a pair of porous membranes by heat sealing three or four seams of the pair of membranes with a section of multilayer tubing sealed to the seams to provide fluid connectivity.

[0196] The present disclosure provides and includes a method for storing deoxygenated blood for up to 64 weeks using a blood storage device 20, resulting in reduced storage damage to blood stored in the presence of oxygen. According to the disclosed method, a blood storage device 20, as described above, is used for blood storage. In some embodiments, the blood comprises packed red blood cells. In other embodiments, the blood comprises whole blood. In yet other embodiments, the stored blood comprises oxygen-depleted packed red blood cells further comprising an additive solution.

[0197] In certain embodiments, deoxygenated blood having an oxygen saturation of less than 20% is placed and stored in blood storage device 20 according to the methods of the present disclosure. In certain embodiments, the storage period is between 1 day and 64 days. In other embodiments, the storage period is 1 week. In other embodiments, the storage period is 2 weeks. In other embodiments, the storage period is 3 weeks or 4 weeks. In other embodiments, the storage period is 8 weeks. In yet other embodiments, the storage period is 9 weeks. According to the methods of the present disclosure, blood storage device 20 maintains the oxygen-depleted state of the oxygen-depleted blood at or below the initial saturation level SO2.

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

[0199] Example 1: Internally collapsible blood container comprising PVC Collapsible blood containers 202 (blood bags) with two inlet / outlets 30 configured as spike ports and one inlet / outlet 30 configured as an IV inlet tube are fabricated from a pair of PVC sheets (Renolit Solmed ES-3000, Renolit America) by welding the seams together with radio frequency (RF) welding. The blood bags are leak-tested by blowing them with compressed air up to 3 psig, submerging them in water, and observing them for air bubbles before use. Alternatively, the blood bags are leak-tested by blowing them in, and the negative pressure change is monitored using a pressure decay tester (Sprint MT, Zaxis). The leak-tested blood bags are then placed into an outer receptacle 201 fabricated from RollPrint Clearfoil® Z Film #37-1275 (RollPrint Packaging Products, Inc., Addison, IL), which has a heat-sealable PE inner layer, an aluminum barrier middle layer, and a PET outer layer, as described in Example 2.

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

[0201] To prepare the outer receptacle 201, an approximately 11 x 12 inch sheet of barrier film is folded in half along the 12-inch dimension, with the polyethylene layer inside, and an approximately 1 / 4 inch gusset flap is incorporated into the folded edge. The gusset flap is held in place with small grippers at each end, and the film is then placed into a custom heat sealer to align with one of the short edges of the sealing die. A small piece of oxygen-impermeable multi-layer tubing (seal adapter 301) having a 0.156 inch inner diameter x 0.218 inch outer diameter x approximately 1 / 2 inch long polyethylene outer layer 308, a PVC inner layer 306, and an EVA intermediate adhesive layer 307 (Extrusion Alternatives, Inc., Portsmouth, NH) is placed onto a solid aluminum mandrel approximately 0.156 inch in diameter x approximately 1 inch long, then placed between the films and positioned within the transverse grooves 703 or 704 of the sealing die 70. The press is activated and set at 80 pounds per 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 multi-layer tubing (seal adapter 301) together with the adhesive section 302. The combination of the seal adapter 301 and the short multi-layer tubing of the adhesive section 302 provides an oxygen-impermeable seal along the outer diameter of the tubing while providing fluid connectivity through the seal. The folded edges provide for expansion of the barrier bag when the collapsible blood container 202 is filled with fluid.

[0202] Approximately 12 inches of standard IV tubing (0.118 inch ID x 0.161 inch OD PVC tubing (Pexco, Inc., Athol, MA) (tubing 205) is solvent bonded to the multi-layer tubing from the outside of the bag using cyclohexanone and heat sealed approximately ½ inch from the end. The inner blood bag inlet tubing (tubing 304) is cut to a length of approximately 2 inches, and the inner blood bag is placed inside the barrier bag. Inlet tubing 304 is solvent bonded to the multi-layer tubing, thereby providing fluid connectivity for the inner blood bag inlet tubing through the oxygen-impermeable seal of the barrier bag for up to 12 inches of the length of tubing 205 outside the barrier bag.

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

[0204] Example 3: Conventional storage bags allow for reoxygenation of blood The extent and rate of reoxygenation during storage in conventional PVC blood storage bags is determined by transferring 150 mL of packed red blood cells (pRBCs) with approximately 60% initial SO2 into a conventional PVC blood transfer bag. The pRBC-containing bag is placed under ambient atmospheric conditions at 4°C and left unmixed. Samples are removed and the mean SO2 is determined at days 0, 7, 14, 21, 28, 52, and 56. Six independent samples are taken per time point. The results are presented in Table 7 and graphically displayed in Figure 10. Table 7: Reoxygenation of blood during storage in conventional PVC bags TIFF0007784467000007.tif51155

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

[0206] Example 4: Oxygen transfer occurs primarily through collection and transfer tubing Based on calculations and comparison with bags made from RollPrint 37-1275, the 8.53 mL oxygen infusion over 42 days would come mostly through the 6 inch length of inlet tubing. Therefore, based on 8.53 mL infusion + 10 mL in blood, a minimum sorbent capacity of 20 cc is indicated.

[0207] Example 5: Continuous oxygen depletion during storage at 4°C Oxygen depletion is significantly affected by temperature. To evaluate the ability to continuously deplete oxygen from stored blood, conventional blood storage bags were prepared and filled with blood having different initial oxygen saturation levels. Packed red blood cells were prepared in PAGGSM or SAGM additive solution and stored anaerobically in plastic canisters pressurized with 100% nitrogen gas at approximately 5 mmHg. Additionally, each canister contained a 2ZB adsorbent pouch to help maintain negligible oxygen levels. As shown in Table 8, at higher oxygen saturation levels, the reaction rate was approximately twice that at lower saturation levels. Table 8: First-order rate constants for oxygen depletion during refrigerated storage TIFF0007784467000008.tif50155

[0208] A determination constant (R 2), there also appears to be a logarithmic relationship between the initial SO2 set point and the total amount of O2 removed during storage. Deriving a line of best fit from this data allows for an estimation of the O2 fluctuations expected to inform a given initial SO2 set point (Equation 1). TIFF0007784467000009.tif26147

[0209] Additionally, the time-dependent loss of SO2 can be predicted by plotting the slope of the linear regression and deriving a line of best fit. There appears to be a logarithmic relationship between the initial SO2 value at the beginning of storage and the linear rate at which SO2 is lost during anaerobic storage (Equation 2). TIFF0007784467000010.tif26146

[0210] Example 6: Preparation of the external receptacle Pairs of oxygen barrier films are heat sealed together on all four sides to produce pouches with internal dimensions of approximately 160 x 240 mm. These pouches are sealed using an impact heat sealer with an approximately 3 mm (1 / 8 inch) wide seal (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). Samples of RollPrint Clearfoil® Z film are also prepared using an impulse heat sealer with an approximately 9.5 mm (3 / 8 inch) wide seal (Accu-Seal model 530, Accu-Seal, Inc., San Marcos, Calif.).

[0211] Several samples of each configuration are prepared and tested for oxygen permeability using an Oxtran 2 / 61 oxygen permeability instrument (Mocon, Inc., Minneapolis, MN). For each configuration, two samples are selected for testing using a test gas containing 100% oxygen at 50% relative humidity (RH) and 760 mmHg pressure. The carrier gas is 98% nitrogen / 2% hydrogen at 100% RH, run at 23°C. The results are shown in Table 9 below. Table 9: Permeability of external receptacles 201 prepared from different materials TIFF0007784467000011.tif55155

[0212] All samples showed a low oxygen ingress rate of 0.1 cc / package*day, but Clearfoil® Z film was clearly superior to the other materials by an order of magnitude in lower oxygen ingress rates. The two different seal widths of RollPrint Clearfoil® Z do not reveal any significant differences under the test conditions.

[0213] Example 7: Blood container with anaerobic tubing fittings A collapsible inner blood bag (Model KS-500, KS Mfg., Avon, MA) was used for the test, using 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 accept standard IV inlet tubing with an outer diameter of approximately 4 mm (0.161 inches); the blood bag is supplied without any inlet tubing glued to the inlet port 30. The blood bag is placed within an outer barrier bag fabricated from RollPrint Clearfoil® Z Film #37-1275 (RollPrint Packaging Products, Inc., Addison, IL) as follows:

[0214] For one group of samples, an oxygen impermeable mounting adapter (reference NHS #A097-000-"PE Wedge") is machined from solid polyethylene with a flat tapered sealing surface to mate with the barrier film and a through hole to pass through the center of the inlet tubing 30. For the other group of samples, an oxygen impermeable mounting adapter (reference NHS #A121-000-"Multilayer Tubing") is formed from three-layer tubing with a barrier film to adhere the inlet tubing, a thin EVA intermediate adhesive layer 307, and a polyethylene outer layer 308 to mate with the inner PVC layer 306.

[0215] Barrier bags, approximately 150 x 270 mm, are produced from pairs of sheets of RollPrint Clearfoil® Z film by first heat sealing an oxygen-impermeable mounting adapter (either the PE Wedge version or the multi-layer tubing version) to a seam made in one of the short seams of the film pair using a custom heat sealer with a cutout area to accept the particular style of mounting adapter. The other short edge and one long edge of the barrier bags are then sealed using conventional heat sealing methods and equipment, leaving one long edge of each bag open.

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

[0217] The inner blood bag was then placed inside the barrier bag, and a short section of PVC inlet tubing (tubing 304) was solvent bonded to the PVC inlet port (inlet / outlet 30) of the inner blood bag using cyclohexanone. For the PE wedge specimens, the inlet tubing (tubing 304) was fixedly 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 of the multilayer barrier crossing tubing specimens was performed aside from solvent bonding.

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

[0219] Several such sample blood storage containers are sent to Mocon, Inc. for oxygen permeability testing using an Oxtran 2 / 21 oxygen permeability instrument (Mocon, Inc., Minneapolis, MN). To understand the origin of oxygen ingress, some samples are tested as prepared, some with the inlet tubing cut off near the mounting surface and the inner diameter of the inlet tubing blocked with metallized epoxy, and some with the inlet tubing (tubing 304) cut off and the mounting surface / barrier bag seam area masked with metallized epoxy. Pairs of each configuration are selected for testing. The test gas is 100% oxygen at 50% RH and 760 mmHg pressure, the carrier gas is 98% nitrogen / 2% hydrogen at 100% RH, and the test is conducted at 23°C. Test results for oxygen ingress (cc / package*day) for 100% O2 are presented in Table 10. Table 10: Oxygen ingress test for seal adapters TIFF0007784467000012.tif51162 *The results for Sample #1 using the polyethylene mounting adapter indicate a possible blockage in the tubing near the mounting point, as well as a leak in the oxygen barrier pouch itself caused by the copper tubing used to introduce gas during testing. 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 ingress coming from the PVC tubing. At the refrigerated temperature of 4°C used for blood storage, these ingress rates are significantly reduced. For anaerobic sealing packages with the inlet tubing plugged near the seal, oxygen ingress of only approximately 0.15–0.24 cc over the 42-day period and approximately 0.23–0.36 cc over the 64-day period is expected.

[0221] Example 8: Oxygen transfer in piping Several samples of PVC inlet piping (Qosina #T4306, Qosina Corp., Edgewood, NY) were cut to either approximately 150 mm (6 inches) in length or approximately 200 mm (8 inches) in length and sealed at one end. Additionally, a longer 200 mm sample was sealed approximately 50 mm (2 inches) from the sealed end to mimic a pilot sample section. Several such samples were sent to Mocon, Inc. for oxygen permeability testing using an Oxtran 2 / 21 oxygen permeability instrument (Mocon, Inc., Minneapolis, MN). Pairs of each configuration were 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, with testing conducted at 23°C. Test results for oxygen ingress (cc / day) of 100% O2 are presented in Table 11. Table 11: Oxygen ingress testing of PVC inlet piping TIFF0007784467000013.tif39156

[0222] These results are consistent with previous blood container studies, 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 at ambient conditions (21% O, 23°C). No substantial differences were observed between the shorter samples without a pilot segment and the longer samples with a pilot segment under the conditions tested.

[0223] Example 9: Dynamic Oxygen Absorption of Commercial Adsorbents Three exemplary adsorbents are tested for their ability to absorb oxygen in dynamic tests. The test chamber consists of a 4-inch diameter x 4-inch long 304 stainless steel quick flange fitting (McMaster Carr #4322K35) with end caps, one end cap modified for connection of a sensor, nitrogen purge, and oxygen test gas inlet. A cylindrical polyethylene insert is 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) is used for the tests.

[0224] The system is purged with a 1% oxygen / balance nitrogen gas mixture, followed by 100% nitrogen gas for a two-point calibration before use. A small pouch of the sorbent 207 under test is placed into the system under a nitrogen atmosphere glove box, the system is sealed (holding the cover in place), and then purged with nitrogen before removal from the glove box. A syringe pump with a Hamilton-tight syringe is filled with 5 cc of 100% oxygen, and the syringe line to the test chamber is purged by starting the syringe pump, leaving 5 cc of oxygen in the syringe. The syringe line valve is closed and connected to the system. The dynamic test is initiated by starting the syringe pump to inject 5 cc of oxygen over a 60-minute period. After 60 minutes, the syringe pump line valve is closed, allowing the sorbent to continue absorbing the residual oxygen in the static test.

[0225] The test is conducted at 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 (200 cc capacity, designed to operate in cold environments), O-Buster® (300 cc capacity, standard grade) (Hsiao Sung Non-Oxygen Chemical Co., Ltd., Taiwan), and Sorbent Systems LTECC1K500CS (1000 cc capacity, "fast acting" - designed to operate in cold environments) (Impak Corp., Los Angeles, CA).

[0226] Figure 11 shows that for various adsorbents, oxygen introduction increases to about 0.7-0.8% oxygen within about 10 minutes. In about 10-15 minutes, both the O-Buster® and Sorbent Systems adsorbents are able to reduce the oxygen level in the system to about 0.75% to about 0.3-0.5% oxygen. The SS-200 adsorbent was unable to reduce the oxygen level, which continued to increase to about 1% oxygen at 60 minutes.

[0227] After 60 minutes, the dynamic oxygen introduction was terminated, and all adsorbents showed a continued reduction in oxygen levels when the system was under static testing. While the SS-200 showed a dramatic increase in oxygen reduction rate under static conditions, the Sorbent Systems adsorbent showed a slight increase in oxygen reduction rate under static conditions, and the O-Buster® adsorbent showed no difference in oxygen reduction rate under static conditions. This indicates that adsorbent capacity does not appear to have a direct effect on the rate of oxygen absorption, as evidenced by the relative performance of the 300cc O-Buster® adsorbent compared to the 1000cc capacity Sorbent adsorbent, as claimed by the manufacturer. Two adsorbents (MGC SS-200 and Sorbent Systems LTECC1K500CS) formulated to perform well at cold conditions appeared to perform worse than the standard O-Buster® adsorbent, as claimed by the manufacturer. Test data was not conducted or collected at temperatures other than 23°C.

[0228] Example 10: Dynamic oxygen absorption of commercially available portable hand warmers Several commercially available hand warmers are 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 chemistry is the same commercially available sorbent used in food preservation as that tested in Example 9, although the formulation may vary slightly to modify the kinetics of the reaction.

[0229] Figure 12 shows data for several commercially available hand warmers tested as described above. The data, shown in the table below, indicate that the introduction of oxygen increases oxygen levels from about 0.25% to about 0.75% within about 10 minutes, depending on the type of hand warmer. At about 10-15 minutes, the data show that all of the hand warmers are able to quickly reduce oxygen levels from peak values, with significant variation between formulations. The majority of formulations appear to approach a steady state during dynamic testing, with the exception of the Hot Hands and Heat Works versions, which continue to reduce oxygen levels to near zero under dynamic test conditions.

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

[0231] Example 11: Preparation of anaerobic storage bags Several anaerobic storage bags were fabricated as described in Examples 1 and 2 above and completed by incorporating a pouch of SS-200 sorbent (Mitsubishi Gas Chemical America, New York, NY), a plastic spacer, and an oxygen sensor tab (Mocon, Inc., Minneapolis, MN) before heat sealing the final edges in a nitrogen atmosphere glove box. Additionally, several anaerobic storage bags were fabricated using Renolit ES-4000 PVC-citrate, and silicone sheeting (McMaster Carr #87315K61, McMaster Carr, Robbinsville, NJ) was used to fabricate the inner collapsible blood container 202. Headspace oxygen levels were measured through the outer receptacle film (Rollprint Clearfoil® Z) over several days after fabrication to verify the robustness of the seal. Results are shown in Tables 12-14 below. Table 12: ASB (Headspace Oxygen (Torr)) Produced with Renolit ES-3000 Inner Blood Bag TIFF0007784467000014.tif78164 Table 13: ASB (Headspace Oxygen (Torr)) Produced with Renolit ES-4000 Inner Blood Bag TIFF0007784467000015.tif67155 Table 14. ASB manufactured with silicone inner blood bags (headspace oxygen (Torr)) TIFF0007784467000016.tif67155

[0232] The mean oxygen levels on day 0 were significantly higher for both the silicone-inside blood bag group versus the PVC blood bag group, averaging 6.33 Torr versus 4.58 Torr (ES-3000) and 4.69 Torr (ES-4000), p<0.05. These results also indicate that the adsorbent can effectively reduce headspace oxygen levels to less than 1 Torr of oxygen, except for sample #10 in the ES-3000 group and sample #7 in the ES-4000 group. Upon closer examination of the seals on these samples, small creases or wrinkles are observed at the final seal seam.

[0233] Example 12: Mid-seal adapter 301 with multi-layer barrier cross-tube for solvent bonding of piping An anaerobic storage vessel with substantially impermeable joints for fluid connectivity is fabricated by first insert molding three pieces of multi-layer barrier crossing piping 305 into a rod-shaped piece of polyethylene (Dowlex™ 2517) approximately 5 mm wide by 57 mm long with tapered ends ("diamond wedge", seal adapter 301) (Sonicron Corp., Westfield, MA). The multi-layer barrier crossing pipe 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 multilayer barrier crossing tube 305 has an inner diameter suitable for accommodating standard PVC blood line transfer tubing, approximately 3.0 mm by approximately 4.1 mm per ISO 3826-1:2013, or solvent bonding of a blood transfer device such as a PVC spike port, e.g., either Vitalmed #20391 (Vitalmed, Inc., Lakeville, MA) or Qosina #65842 (Qosina Corp., Edgewood, NY). The barrier crossing tube 305 extends approximately 25 mm beyond the width of the diamond wedge on either side to facilitate these connections.

[0234] The diamond wedge with the insert-molded multilayer tube is placed between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL) on a custom-fabricated heat-sealing die with grooves sized and shaped to accept the diamond wedge shape and provide slight compression during heat sealing. This 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 actuated with the film and diamond wedge of the die to compress and heat the assembly for approximately 3-4 seconds to produce a fully sealed seam including one half of the outer receptacle 201 .

[0235] One end of each multi-layer tube is then solvent bonded to a transition PVC tube to connect the flexible collapsible blood container 202 to the external receptacle 201, and the other end of each multi-layer tube is then solvent bonded to either a spike port or a section of standard blood line transfer tubing. A sorbent pouch is then placed on a spacer sheet, which is then placed between the collapsible container and one of the external receptacle films, after which 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: Intermediate block insert molded with double-layered pipe for RF welding of piping Similar to Example 12 above, an anaerobic storage vessel with a substantially impermeable inlet / outlet 30 with fluid connectivity is fabricated by first insert molding three small pieces of barrier crossing piping 305 into a rod-shaped ("diamond wedge") polyethylene (Dowlex™ 2517) (Sonicron Corp., Westfield, MA) approximately 5 mm wide by approximately 57 mm long with tapered ends as shown in FIG. 3D.

[0237] However, in this example, the barrier crossing tube of Example 12 is replaced with a two-layer barrier crossing tube constructed of a polyvinyl chloride (PVC) inner layer 306 and outer EVA layers 307, 308 (Extrusion Alternatives, Inc., Portsmouth, NH). Because EVA is known to have both good RF (frequency) and heat weldability and good adhesion to PVC and PE, the need for any fiber connection tube to the collapsible blood container is eliminated in this configuration. The thickness of the EVA outer layer can be varied as needed; it only needs to meet a minimum thickness to ensure adhesion of the PVC during insert molding to the PE, which is approximately 0.05-0.10 mm. The two-layer tube also has the same inner diameter dimensions as Example 12, extending approximately 25 mm beyond the width of the diamond wedge on each side to facilitate connection, but the outer diameter of the two-layer tube is suitable for fitting into an RF welding die for use in manufacturing the collapsible blood container.

[0238] In the first assembly step, the tubes on one end of the insert-molded diamond wedge are RF-welded to the PVC film to form the collapsible blood container as follows: the three tubes of the diamond wedge are placed on brass mandrels to support each of them, and then placed between a pair of collapsible 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 with three grooves of suitable size and shape to receive the three tubes. The RF sealing die also seals the PVC collapsible blood container film between the tubes, sealing the periphery with the contoured shape of the collapsible blood container 202. The press is activated with the film and tubing in the die and the assembly is compressed with RF energy (Solidyne RF Welder, S / N 3657) for approximately 4-5 seconds to produce a fully sealed seam forming the collapsible blood container 202, which also has a substantially impermeable joint (diamond wedge) positioned around the fluidly connected inlet tubing ready for sealing to the barrier film of the external receptacle 201 in the next step.

[0239] Similar to Example 12, the RF-welded collapsible blood container to the diamond-wedge tubing is now placed between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL). The assembly is placed over a custom-fabricated heat sealing die and sealed on a Franklin press to produce a fully sealed seam containing the fluidly connected collapsible blood container along with one of the external receptacles 201. In the remaining steps, the spike port and PVC blood inlet tubing (inlet / outlet 30) are solvent bonded to the exposed remaining portion of the diamond-wedge double-wall tubing, similar to Example 12, and the sorbent pouch and spacer are also similarly prepared before sealing the remaining three seams of the external receptacle 201 to produce the completed anaerobic blood storage container.

[0240] Example 14: "Three at a Time" Heat Sealed Barrier Crossing Pipe to Solvent Bond Piping An anaerobic storage vessel with substantially impermeable joints with fluid connectivity is fabricated by simultaneously heat sealing three individual pieces of barrier crossover piping between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL) as shown in Figure 4A. The crossover 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 crossing tube is of an inner diameter size suitable to accommodate standard PVC blood line transfer tubing, approximately 3.0 mm by approximately 4.1 mm per ISO 3826-1:2013, or solvent bonding of a blood transfer device such as a PVC spike port, e.g., either Vitalmed #20391 (Vitalmed, Inc., Lakeville, MA) or Qosina #65842 (Qosina Corp., Edgewood, NY).

[0241] The barrier crossing tube is solvent-bonded to a short section of PVC tubing using cyclohexanone to connect the tubing to its respective port on the collapsible blood container. A mandrel is inserted into the barrier crossing tube, and a sorbent pouch (Mitsubishi SS-200, Mitsubishi Gas Chemical America, Inc., NY, NY) is placed on a spacer sheet, and the assembly is held between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL) on a custom-fabricated heat sealing die. The sealing die (aluminum die 70) is suitably sized by reducing its diameter by approximately 0.25 mm and shaped by providing corners with diameters of 0.5–0.8 mm to receive the tubing and has three grooves that provide slight pressure during heat sealing. The sealing process is performed on a modified Franklin Model 2400 hot stamping press (Franklin Mfg. Corp., Norwood, MA) at 80-85 psig. The upper die 701 is fabricated from a solid block of aluminum machined to a complementary shape slightly larger than the outer periphery of the collapsible blood container. The center region of the upper die 705 is loosened to receive and nest the collapsible blood container 202, and the die has grooves as described above for sealing the barrier crossing 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 is comprised of a metal insert surrounded by thermally insulating Garolite® G-10 material. This lower die is similarly shaped to the upper die, providing a nest for the collapsible blood container 202 and a flat mating surface 705 against which the upper die presses. However, the metal insert provides the necessary groove for sealing the barrier crossing tube to the surrounding film, ensuring a substantially impermeable seal. The lower die is constantly heated to 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 periphery is heated from both the upper die and the lower die insert 706.

[0243] The press is started with the film, adsorbent and spacer sheets, and tubing in place in the die as described, and held for a dwell time of approximately 2 seconds to produce a fully sealed seam on the outer receptacle 201, with three barrier crossing tubes with substantially impermeable seals fluidly connected to the inner collapsible blood container 202. The remaining end of each barrier crossing tube is then solvent bonded to either a spike port or a section of standard blood line PVC tubing (inlet / outlet 30) to produce an anaerobic blood storage container.

[0244] Example 15: Extruded Barrier Crossover Pipe "Three at a Time" Heat Sealed to Solvent Bond Piping Similar to Example 14 above, an anaerobic storage vessel with substantially impermeable joints with fluid connectivity is fabricated by simultaneously heat sealing three individual pieces of barrier crossing tubing between a pair of barrier films (RollPrint ClearFoil® Z, RollPrint Packaging Products Inc., Addison, IL). In this example, the barrier crossing tubing has an outer layer of PE extruded into a diamond wedge shape, as shown in FIG. 4B, rather than a circular shape to facilitate edge sealing to the barrier film, and the inner PVC layer retains a circular inner diameter suitable for solvent bonding with other PVC tubing and fittings, such as spike ports.

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

[0246] Example 17: Internal PVC storage bag allows for reoxygenation of blood Several internal PVC storage bags containing a single classical inlet are prepared 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 pRBCs with an initial SO2 of 35-70% into the bag. The PVC bags containing pRBCs are placed at 4°C under ambient atmospheric conditions. Samples are removed from each bag at 1 and 6 weeks, and the SO2 is determined.

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

[0248] Example 18: Reoxygenation in the absence of 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 pRBCs with an initial SO2 of approximately 5% to the anaerobic storage bags 20. Samples are removed from each bag at 1 and 6 weeks, and SO2 is determined. As presented in Figure 14, the anaerobic storage bags 20 containing adsorbent result in reduced SO2 compared to the anaerobic storage bags 20 without adsorbent, resulting in reoxygenation of approximately 15% by week 6.

[0249] Example 19: Blood storage bag with three inlets / outlets (two spike ports and one blood line) lacking an oxygen impermeable adhesive 302 according to the present disclosure Five anaerobic storage bags 20 are fabricated by first RF welding two sheets of Renolit ES-3000 having a thickness of approximately 0.017 inches and three pieces of PVC tubing together without an impermeable adhesive 302 to form an inner collapsible bag 202.

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

[0251] Headspace oxygen levels are measured through the external receptacle 201 film (RollPrint ClearFoil® Z). As shown in Figure 15, all anaerobic storage bags 20 lacking the three oxygen-impermeable adhesives 302 provided by the present disclosure exhibited highly fluctuating oxygen levels over the measurement period (84 days) and are not suitable for anaerobic storage of blood.

[0252] Example 20: ASB with three inlets / outlets 30 (two spike ports and one blood line) Three anaerobic storage bags 20 are fabricated by first RF welding two sheets of Renolit ES-3000 approximately 0.017 inches thick to three lengths of PVC tubing approximately 0.75 inches long to form the inner collapsible bag 202. Multi-layer barrier cross-tubing (inner PVC layer 306, middle EVA layer 307, and outer PE layer 308) is solvent bonded to the outer diameter of each of the three PVC tubing of the inner bag to provide a means for heat sealing the inner (PVC) bag to the outer (PE) barrier bag. The multi-layer tubing is solvent bonded directly to the inner bag PVC tubing.

[0253] The inner collapsible bag with three multi-layer barrier cross tubes 305 is heat sealed to an outer barrier bag made from RollPrint ClearFoil® Z film #37-1275 (RollPrint Packaging Products Inc., Addison, IL) using an aluminum die 70 (shown in FIG. 9) mounted 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 inner 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 top aluminum section and one on the bottom G-10 block. The top aluminum block is heated by a Franklin press, and the bottom block is heated by a heating rod (1 / 4 inch diameter) connected to a temperature controller. The tool has alignment pins in the top half and matte bushings in the bottom half to align the two halves.

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

[0256] While the invention has been described with reference to preferred embodiments, it will be apparent to those skilled in the art that various modifications may be made and equivalents may be substituted for elements thereof to adapt to a particular situation without departing from the scope of the invention. Therefore, it is not intended that the invention be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments coming within the scope and spirit of the appended claims.

Claims

1. A method of manufacturing a barrier bag enclosing an internally collapsible blood bag, comprising the steps of: providing a sheet of barrier film having four edges and a polyethylene layer on one side; folding the sheet of barrier film in half in a gusset fold with the polyethylene layer positioned on the inside of the fold; placing an oxygen-impermeable multi-layer tubing 301 inside the gusset turn-up, the oxygen-impermeable multi-layer tubing comprising a polyethylene outer layer 308, a polyvinyl chloride (PVC) inner layer 306, and an intermediate adhesive layer 307 comprising ethyl vinyl acetate (EVA); heat-pressing the oxygen-impermeable multi-layer tubing 301 into the gusset fold to form a joint 302 that is a continuous oxygen-impermeable seal along the length of the gusset fold; extending piping 205 through oxygen-impermeable multi-layer piping 301; solvent bonding and heat sealing the tubing 205 to the oxygen impermeable multi-layer tubing 301; placing an internal collapsible blood bag 202 with inlet tubing 304 inside the folded sheet of barrier film; solvent bonding the inlet tubing 304 of the internal collapsible blood bag 202 to the inner end of the tubing 205 to provide a fluid connection between the internal collapsible blood bag 202 and the tubing 205; heat sealing together three of the four edges of the folded sheet of barrier film to form a partially sealed barrier bag having an unsealed edge; Mounting an oxygen sensor 215 inside the partially sealed barrier bag; placing the oxygen adsorbent 207 and two mesh spacers 213 within the partially sealed barrier bag such that the oxygen adsorbent 207 and two mesh spacers 213 are positioned between the inner collapsible blood bag 202 and the inside of the partially sealed barrier bag; heat sealing the unsealed edges of the partially sealed barrier bag to form a barrier bag 201 enclosing an inner collapsible blood bag 202; The method of manufacturing, wherein the barrier bag 201 is substantially impermeable to oxygen.

2. The method described in claim 1, wherein two mesh spacers 213 maintain a headspace defined by the barrier bag 201 and the inner collapsible blood bag 202, ensuring that oxygen diffuses efficiently to the oxygen adsorbent 207.

3. 10. The method of claim 1, wherein the heat sealing of the unsealed edges is performed under a nitrogen atmosphere in a glove box.

4. The method described in claim 1, wherein the oxygen-impermeable multilayer piping 301 is a seal adapter 301.

5. The method of claim 4, wherein the seal adapter 301 is a machined, extruded, molded, or laminated polymer wedge or block.

6. The method of claim 1, wherein the inner collapsible blood bag has an oxygen permeability of 3 to 350 barrers.

7. The internal collapsible blood bag 202 has a strength of 10 g / m when tested at 23±2°C. 2 10. The method of claim 1, wherein the composition has a moisture vapor transmission rate (MVTR) of 24 hours or less.

8. The method described in claim 1, wherein the oxygen adsorbent 207 is an oxygen and carbon dioxide adsorbent 207.

9. The method of claim 1, wherein the sheet of barrier film has dimensions of 11 inches by 12 inches and is folded in half along the 12-inch dimension.

10. The method of claim 1, wherein the gusset fold provides expansion of the barrier bag 201 when the internal collapsible blood bag 202 is filled with blood.

11. The method of claim 1, further comprising the step of clamping both ends of the gusset fold before forming the joint 302.

12. The method of claim 1, wherein the heat pressing is performed at a pressure of 80 psig (pounds per square inch gauge) for 5 seconds.

13. The method of claim 1, wherein the solvent bonding is performed using a cyclohexanone solvent.

14. The method of claim 1, wherein heat sealing of three of the four edges of the folded sheet of barrier film is performed by impact heat sealing.

15. The method of claim 1, wherein each of the two mesh spacers 213 has dimensions of 5 inches by 7 inches.

16. The method of claim 1, wherein the oxygen adsorbent 207 is enclosed in a pouch.

17. The method described in claim 1, wherein the step of placing the oxygen adsorbent 207 and two mesh spacers 213 within the partially sealed barrier bag further includes placing the oxygen adsorbent 207 between the two mesh spacers 213.

18. The method of claim 1, wherein the heat sealing of the unsealed edges of the partially sealed barrier bag is accomplished by impact heat sealing.

19. The method of claim 1, wherein the internal collapsible blood bag 202 further comprises two spike ports 303.

20. The method of claim 1, further comprising manufacturing the internal collapsible blood bag 202 from a pair of polyvinyl chloride (PVC) sheets by radio frequency (RF) welding the edges of the pair of PVC sheets together.

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