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    • 专利摘要:
    BLOOD STORAGE DEVICE AND SYSTEM, OXYGEN / CARBON DIOXIDE DEPLETION DEVICES, AND OXYGEN AND CARBON DEPLETION DEVICES, AND METHOD FOR REMOVING OXYGEN AND CARBON DIOXIDE FROM HERBAL CELLS. The system has a collection bag for red blood cells; an oxygen / carbon dioxide depletion device; a storage bag for red blood cells; and tubing connecting the collection bag with the depletion device and the depletion device to the storage bag. The depletion device includes a receptacle of solid material having an inlet and an outlet adapted to receive and send a discharge gas; a plurality of hollow fibers or gas-permeable films extending within the receptacle of an inlet to an outlet thereof. Hollow fibers or gas-permeable films are adapted to receive and transport red blood cells.
    公开号:BR112012008683B1
    申请号:R112012008683-9
    申请日:2010-10-08
    公开日:2020-11-24
    发明作者:Tatsuro Yoshida；Paul J. Vernucci
    申请人:New Health Sciences, Inc.；
    IPC主号:
    专利说明:

    [0001] [0001] The present description refers to a blood storage system having an oxygen / carbon dioxide depletion device and a blood storage bag for long-term storage of blood. More particularly, the present description refers to a blood storage system that is capable of removing oxygen and carbon dioxide from red blood cells before storage and during storage, as well as maintaining states subjected to oxygen and / or carbon dioxide depletion. during storage, thereby prolonging storage time and minimizing the deterioration of deoxygenated red blood cells. TECHNICAL FUNDAMENTALS
    [0002] [0002] Adequate blood supply and storage is a problem facing every major hospital and healthcare organization worldwide. Often, the amount of blood supply in storage is considerably less than the need for it. This is especially true during periods of crisis such as natural disasters, war and the like, when the blood supply is often dangerously close to depleting. This is at critical times such as these that the call for more fresh blood donations is often granted. However, unfortunately, even when there is no crisis period, the blood supply and the one kept in storage must be constantly monitored and replenished, because the stored blood does not maintain its viability for a long time.
    [0003] [0003] Stored blood undergoes constant deterioration which is, in part, caused by oxidation and degradation of hemoglobin and depletion of adenosine triphosphate (ATP) and 2-3, bisphosphoglycerate (DPG). Oxygen causes hemoglobin (Hb) carried by erythrocytes (RBCs) to convert to met-Hb, the decomposition of which produces toxic products such as hemichrome, hemine and free Fe3 +. Along with oxygen, these products catalyze the formation of hydroxyl radicals (OH.cndot.), And both OH.cndot. how much the decomposition products of met-Hb damage the lipid membrane of the erythrocyte, the skeleton of the membrane, and the contents of the cell. As such, the stored blood is considered unusable after 6 weeks, as determined by the relative inability of erythrocytes to survive in the transfusion recipient's circulation. DPG depletion prevents adequate oxygen transport to the tissue thereby reducing transfusion efficiency immediately after administration (DPG levels recover once in the recipient after 8 to 48 h). In addition, these deleterious effects also result in reduced overall efficacy and increased side effects of transfusion therapy with blood stored before the expiration date, but possibly more than two weeks old are used. The reduction in the carbon dioxide content in stored blood has the beneficial effect of raising DPG levels in erythrocytes.
    [0004] [0004] There is, therefore, a need to be able to deplete levels of oxygen and carbon dioxide in erythrocytes prior to storage on a long-term basis without the stored blood suffering the harmful effects caused by the interaction of oxygen and hemoglobin. In addition, there is a need to store red blood cells subjected to oxygen and carbon dioxide depletion in bags containing or bag surrounded by a barrier film with oxygen and carbon dioxide depletion materials. In addition, there is a need to optimize levels of ATP and DPG in stored erythrocytes by varying the constituents of depletion or discounting before and / or during storage depending on the needs of the transfused recipient. In addition, blood storage devices and methods must be simple, inexpensive and capable of long-term storage of the blood supply. SUMMARY
    [0005] [0005] A disposable blood storage device that is capable of oxygen depletion and anaerobic storage of erythrocytes for transfusion.
    [0006] [0006] The present description also takes into account a device and method of removing carbon dioxide (CO2) in addition to oxygen (O2) before or at the beginning of anaerobic storage.
    [0007] [0007] The present description also takes into account mixing O2 and CO2 decontaminating materials that are placed in a depletion device to obtain optimal levels of ATP and DPG.
    [0008] [0008] The present description also takes into account a depletion device that has the capacity to decontaminate CO2 before or at the beginning of anaerobic storage.
    [0009] [0009] This description also takes into account the anaerobic storage bag that is capable of storing anaerobically erythrocytes and in one subjected to CO2 depletion.
    [0010] [0010] The present description takes into account the mixture of discounted O2 and CO2 materials to be placed in a sachet or incorporated into the materials of the construction storage bag inside an anaerobic storage bag.
    [0011] [0011] Consequently, the present description takes into account a disposable blood storage device that is capable of depleting oxygen and carbon dioxide as well as anaerobic storage erythrocytes for transfusion.
    [0012] [0012] The present description also takes into account a system of anaerobic storage of RBCs with depletion of oxygen and carbon dioxide in the pre-storage and continuous maintenance of the anaerobic state and subjected to the depression of carbon dioxide during storage.
    [0013] [0013] The present description also takes into account the anaerobic storage of standard storage bags by storing them in a controlled atmosphere container or chamber such as in an inert gas inside a refrigerator.
    [0014] [0014] The present description takes into account a blood collection system that incorporates an oxygen / carbon dioxide depletion device having an oxygen and carbon dioxide sorbent in combination with a filter or membrane to remove oxygen and carbon dioxide of blood during transport to the storage bag.
    [0015] [0015] The present description takes into account a blood collection system that incorporates an oxygen / carbon dioxide depletion device that contains a gas permeable film or membrane that provides sufficient surface area to facilitate the diffusion of oxygen and dioxide carbon from the blood inside the device.
    [0016] [0016] The present description takes into account a blood collection system that incorporates an oxygen / carbon dioxide depletion device having an oxygen and carbon dioxide sorbent embedded in the gas-permeable membrane with a filter or membrane to remove oxygen and carbon dioxide from the blood during transport to the storage bag.
    [0017] [0017] The present description also takes into account a laminated storage bag for storing erythrocytes (RBCs). The storage bag can be a laminated bag having an oxygen and carbon dioxide sorbent or a secondary bag containing an oxygen and carbon dioxide sorbent.
    [0018] [0018] The present description also takes into account a system for subjecting oxygen and carbon dioxide from collected erythrocytes to depletion that includes an additive solution, an oxygen and carbon dioxide depletion device, and a blood storage bag that keeps erythrocytes in one subjected to oxygen and carbon dioxide depletion.
    [0019] [0019] The present description takes into account a system and methodology that allows a reduction in carbon dioxide levels before storage and an increase in DPG levels. By keeping carbon dioxide levels low, and thus high DPG levels, the oxygen affinity for hemoglobin to bind to oxygen is reduced. Having a lower affinity for hemoglobin, greater transmission of oxygen to the tissue is allowed.
    [0020] [0020] The present description takes into account a method of optimizing ATP and DPG in erythrocytes for storage by obtaining an erythrocyte sample from a donor; subjecting oxygen and carbon dioxide levels to the sample to deplete a sample subjected to oxygen and carbon dioxide depletion; store the sample subjected to oxygen and carbon dioxide depletion in a container that maintains the state subjected to oxygen and carbon dioxide depletion of the sample. The depletion range is variable.
    [0021] [0021] The present description also takes into account to optimize the stored blood by treating the individual with stored blood to a depletion device having the appropriate levels of oxygen gas and carbon dioxide passed through it or with the appropriate combination of depletion decontaminants of oxygen and carbon dioxide to obtain a desired level of constituents. Blood is also stored under conditions subjected to oxygen and carbon dioxide depletion. Immediately before transfusion, reoxygenation of stored blood as needed based on the recipient's needs prior to transfusion.
    [0022] [0022] The present description also provides another embodiment of a blood storage device. The device is a sealed receptacle adapted to retain and store erythrocytes. The receptacle has walls formed from a laminate. The laminate has (a) an outer layer of a material substantially impermeable to oxygen and carbon dioxide, (b) an inner layer of a material compatible with erythrocytes, and (c) an interstitial layer between the outer layer and the inner layer. The interstitial layer is of a material having mixed in it an amount of either or both of an oxygen decontaminant and a carbon dioxide decontaminant. Alternatively, the interstitial layer can be removed and the decontaminant (s) mixed (s) in the inner and / or outer layer.
    [0023] [0023] The present description also provides another embodiment of a blood storage system. The system has a collection bag for erythrocytes; a unitary device for depleting oxygen and carbon dioxide and reducing leukocytes and / or red blood cell platelets; a storage bag for erythrocytes; and tubing connecting the collection bag to the unitary device and the unitary device to the storage bag.
    [0024] [0024] The present description and its characteristics and advantages will become more evident from the following detailed description with reference to the attached drawings. BRIEF DESCRIPTION OF THE DRAWINGS
    [0025] [0025] Fig. 1 illustrates the components of a disposable anaerobic blood storage system of the present description.
    [0026] [0026] Fig. 2 illustrates a pre-storage oxygen / carbon dioxide depletion device of the present description.
    [0027] [0027] Fig. 3 illustrates a first embodiment of a blood storage bag having a storage bag with a secondary external oxygen film containing an oxygen sorbent in a bag.
    [0028] [0028] Fig. 4a illustrates a pre-storage oxygen / carbon dioxide depletion pouch having a blood storage pouch with a large sorbent sachet embedded in gas permeable polymers, compatible with erythrocyte in contact with RBCs .
    [0029] [0029] Fig. 4b illustrates a third embodiment of a blood storage bag having a storage bag and a laminated oxygen film barrier with a large sorbent in contact with the RBCs.
    [0030] [0030] Fig. 5a illustrates a fourth embodiment of a blood storage bag having a secondary external barrier bag configured secondary surrounding an internal blood storage bag having an oxygen sorbent.
    [0031] [0031] Fig. 5b illustrates a fifth embodiment of a blood storage bag having a secondary external barrier bag surrounding an internal blood storage bag having a large oxygen sorbent sachet embedded in a gas-permeable polymer. , compatible with erythrocyte in contact with RBCs.
    [0032] [0032] Figs. 6a to 6c illustrate an embodiment of a depletion device that undergoes depletion of oxygen and carbon dioxide from erythrocytes prior to storage by a flow inert gas or mixture of inert gas / C02 of defined composition around a hollow fiber inside the assembly.
    [0033] [0033] Figs. 7a to 7c illustrate another embodiment of a depletion device that undergoes depletion of erythrocyte oxygen and carbon dioxide before storage.
    [0034] [0034] Figs. 8a to 8c illustrate another embodiment of a depletion device that undergoes depletion of oxygen and carbon dioxide from erythrocytes before storage in which oxygen and / or CO2 are decontaminated by decontaminating materials in the cylinder core, surrounded by hollow fibers .
    [0035] [0035] Figs. 9a to 9c illustrate another embodiment of a depletion device that undergoes depletion of oxygen and carbon dioxide from erythrocytes before storage in which oxygen and / or CO2 are decontaminated by decontaminating materials surrounding cylinders of hollow fibers enveloped in material of low water vapor transmission, permeable to gas.
    [0036] [0036] Fig. 10 illustrates a graph of the RBC suspension flow rate per minute versus partial oxygen pressure for the depletion devices of Figs. 6a to 6c, Figs. 7a to 7c, Figs. 8a to 8c and Figs. 9a to 9c.
    [0037] [0037] Figs 11a to 11h illustrate graphs of the effect of oxygen depletion and oxygen and carbon dioxide on the metabolic state of erythrocytes during cold storage.
    [0038] [0038] Fig. 12 illustrates the components of another embodiment of a disposable anaerobic blood storage system of the present description. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
    [0039] [0039] Referring to the drawings and in particular to Fig. 1, a disposable anaerobic blood storage system is shown and referenced using reference numeral 10. The blood storage system includes an oxygen / dioxide depletion device carbon 100 (OCDD 100), an anaerobic blood storage bag 200 and a bag of stored additive solution 300. OCDD 100 removes oxygen and carbon dioxide from erythrocytes by moving through it. The system also contains a leukoreduction filter 400. Components conventionally associated with the blood collection process are a phlebotomy needle 410, a blood collection bag 420 containing an anticoagulant and a bag 430 containing plasma. The tubing can connect the various components of the blood storage system 10 in various configurations (one embodiment shown). Tube 440 connects collection bag 420 with leukoreduction filter 400. Tube 441 connects solution bag 300 with collection bag 420. Tube 442 connects plasma bag 430 with collection bag 420. Tube 443 connects the leukoreduction filter 400 with the OCDD 100. Tube 444 connects the OCDD 100 with the blood storage bag 200. The blood storage system 10 is preferably a single-use, disposable, low-cost system.
    [0040] [0040] The oxygen / carbon dioxide depletion device 100 removes oxygen from RBCs collected before the RBCs are stored in the blood storage bag 200. The oxygen content in RBCs must be subjected to oxyhemoglobin depletion because more than 99% of such oxygen is bound to hemoglobin in venous blood. Preferably, the degree of oxygen saturation should be reduced to less than 4% within 48 hours of blood collection. Depletion of oxygen is preferably carried out at room temperature. The oxygen affinity for hemoglobin is highly temperature dependent, with a p50 of 26 mmHg at 37 ° C dropping to ~ 4 mmHg at 4 ° C. In addition, this increase in O2 affinity (Ka) is mainly due to the reduction in the O2 release rate (k-disassociation), which results in a not nearly low rate of oxygen removal once RBC is cooled to 4 ° Ç. Thus, a concept on oxygen removal is applied such that it may be preferable to perform it before RBCs are cooled to storage temperatures of 1 ° C to 6 ° C.
    [0041] [0041] As an alternative to or in addition to oxygen depletion, carbon dioxide depletion has the beneficial effect of raising DPG levels in erythrocytes. Carbon dioxide exists within RBCs and in plasma in equilibrium with ion "HCO3" (carbonic acid). Carbon dioxide is mainly dissolved in a mixture of RBC / plasma as carbonic acid and the rapid balance between CO2 and carbonic acid is maintained by carbonic anhydrase within carbon dioxide is freely permeable through the RBC membrane, while HCO3- within RBC and plasma is rapidly balanced by anion exchange protein (range 3). When CO2 is removed from the RBC suspension, this results in alkalisation known suspension medium and RBC interior. This results from removing HCO3 "inside and outside RBC; Cytosolic HCO3 "is converted to CO2 by carbonic anhydrase and removed, while plasma HCO3 is removed via anion exchange within RBC. The higher pH within RBC is known to enhance the glucose rate and thereby increase ATP levels and DPG. ATP levels are higher in Ar / CO2 (p <0.0001). DPG was maintained for more than 2 weeks in the argon-purged arm only (p <0.0001). The enhanced glucose rate is also predicted by disinhibition of key glycolytic enzymes through metabolic modulation and isolation of cytosolic free DPG in hemoglobin deoxygenation as a result of the anaerobic condition. DPG was lost at the same rate in both control and Ar / C02 arms (p = 0.6 ) despite complete hemoglobin deoxygenation, while very high levels of ATP were obtained with an OFAS3 additive (Figs. 11a ad).
    [0042] [0042] Referring to the drawings and in particular to Fig. 12, another embodiment of a disposable anaerobic blood storage system is shown and referenced using the reference numeral 500. The blood storage system includes a pouch blood collection device 510, an oxygen depletion / carbon dioxide device 535 (OCDD 535) and an anaerobic blood storage bag 528. OCDD 535 removes oxygen and carbon dioxide from erythrocytes moving through it. The tubing connects the various components of the blood storage system 500. Tube 512 connects collection bag 510 with OCDD 535. Tubes 518 and 520 connect OCDD 535 to the blood storage bag 528. The blood storage system 500 is preferably a single-use, disposable, low-cost system.
    [0043] [0043] Referring to Fig. 2, an oxygen / carbon dioxide depletion device (OCDD) 101 contains an oxygen sorbent 110. OCDD 101 is a disposable cartridge 105 containing oxygen sorbent 110 and a series of hollow fibers 115. Oxygen sorbent 110 is a mixture of non-toxic inorganic and / or organic salts and ferrous oxide or other materials with high reactivity to oxygen. Oxygen sorbent 110 is made of particles that have significant absorbent capacity for O2 (more than 5 ml of 02 / g) and can keep the inside of cartridge 105 less than 0.01% which corresponds to PO2 less than 0.08 mmHg. Oxygen sorbent 110 is free or contained in an oxygen permeable envelope. OCDD 101 of the present description should deplete approximately 100 mL of oxygen from a unit of blood.
    [0044] [0044] After oxygen and carbon dioxide have been removed from RBCs in the OCDD of Fig. 2, RBCs are stored in a 200 blood storage bag. The oxygen content of RBC suspended in additive solution 300 must be reduced equal to or less than 4% SO2 before placing them in cold storage. In addition, RBC subjected to oxygen depletion must be maintained in an anaerobic and low carbon dioxide state for the entire duration of storage.
    [0045] [0045] RBCs pass through an oxygen permeable film or membrane 115. The membranes or films can be constructed in the form of a flat sheet or hollow fiber. Films can be non-porous materials that are capable of high oxygen permeability rates (polyolefins, silicones, epoxies, polyesters etc.) and membranes are hydrophobic porous structures. These can be made of polymers (polyolefins, Teflon, PVDF, polysulfone) or inorganic materials (ceramics). Depletion of oxygen occurs as RBCs pass through the 115 membrane. Hollow fibers can be used as a replacement for oxygen-permeable films or membranes. OCDD provides a simple structure having a large surface area to remove oxygen and maintain a steady flow of blood through it. Depletion or removal of oxygen is carried out by irreversible reaction of ferrous ion in oxygen sorbent 110 with ambient oxygen to form ferric oxide. OCDD 101 does not need agitation to remove oxygen and can be easily manufactured to withstand centrifugation as part of a blood collection system as needed.
    [0046] [0046] Referring to Figs. 6a to 6c and Figs. 7a to 7c, examples of flow depletion devices are described. The depletion devices work to deplete either O2 and CO2, or O2, or CO2 alone, or O2 with specific levels of CO2 by providing the appropriate exhaust gas composition. Gases suitable for depletion devices are, for example, Ar, He, N2, Ar / CO2, or N2 / CO2.
    [0047] [0047] Figs. 8a to 8c and 9a to 9c, also describe decontaminating depletion devices. Depletion occurs with the use of decontaminants or sorbents and without the use of external gases. In both types of depletion devices, however, carbon dioxide depletion in combination with oxygen depletion is effective in enhancing DPG and ATP, respectively, before storage in blood storage bags.
    [0048] [0048] Referring to Figs. 6a to 6c, a depletion device 20 is shown. The depletion device 20 includes a plurality of fibers 25, approximately 5000 in number, through which erythrocytes flow. The plurality of fibers 25 is surrounded by a plastic cylinder 30. The plastic cylinder 30 contains a gas inlet 35 and a gas outlet 40 through which a discharge gas or a combination of exhaust gases, such as those mentioned above, are provided to remove carbon and / or oxygen from the blood. Specifications for depletion device 20 are shown in Table 1 below.
    [0049] [0049] Referring to Figs. 7a to 7c, a depletion device 45 is shown. The depletion device 45, like the device 20 of Figs. 6a to 6c, includes a plurality of fibers 50, approximately 5000 in number, through which erythrocytes flow. The plurality of fibers 50 is surrounded by a plastic cylinder 55. The plastic cylinder 55 contains a gas inlet 60 and a gas outlet 65 through which a gas or combination of gases, such as those mentioned above, are provided to remove dioxide of carbon and / or oxygen from the blood. Specifications for the 45 depletion device are shown in Table 2 below. The active surface area of the depletion of device 45 is twice that of device 20 because device 45 is twice as long as device 20.
    [0050] [0050] Figs. 8a to 8c describe a depletion device 70 having a core 75 containing decontaminating materials for O2, CO2, or both O2 and CO2. Core 75 is packed with a gas-permeable film with very low liquid permeability. Hollow fibers 80 are wound around core 75, and a plastic cylinder 82 contains and wraps hollow fibers 80. In this particular embodiment, the active surface area for depletion is approximately 0.8796 m2 as shown in Table 3 below.
    [0051] [0051] Figs. 9a to 9c describe a depletion device 85 containing bundles of fibers 87 embedded in a gas permeable film with very low liquid permeability. Bundles of fibers 87 are surrounded by decontaminating materials 89 for O2, CO2 or both O2 and CO2. Bundles of fibers 87 and decontaminating materials 89 are contained within a plastic cylinder 90. The active surface area for depletion is approximately 0.8796 m2 as shown in Table 4 below.
    [0052] [0052] Fig. 10 is a graph of the performance of flow depletion devices 20 and 45 and decontaminating depletion devices 70 and 85. The data in Fig. 10 were plotted using the following conditions: Hematocrit, 62% (3 units of pRBC), and 21 ° C at various head heights to produce different flow rates. Oxygen decontaminant / dioxide decontaminant (Multisorb Technologies, Buffalo, NY) was activated with the addition of 5% and 12% w / w water vapor to device 79 and device 85, respectively. Data are plotted with flow rate (g of RBC suspension per min) vs. pO2 (mmHg).
    [0053] [0053] In the oxygen / carbon dioxide depletion devices described here, a plurality of gas-permeable films / membranes can be replaced in place of the plurality of hollow fibers. The films and fibers can be packed in any suitable configuration inside the cartridge, such as linear or longitudinal, spiral, or coil shape, as long as they can receive and transport erythrocytes.
    [0054] [0054] Fig. 10 shows that the lowest oxygen saturation is achieved using devices 45 and 85. Device 45 exhibits a larger active surface area exposed to gases along the length of fibers 50. Device 85 also has a long surface area of exposure to decontaminating materials. Device 85 has bundles 87 surrounded by decontaminating materials 89. The space occupied by decontaminating materials 89 between bundles 87 promotes the dispersion of oxygen and carbon dioxide from erythrocytes contained in bundles of fibers 87, thus helping to decontaminate oxygen and carbon dioxide. erythrocyte carbon.
    [0055] [0055] Another use of depletion devices is to add oxygen and or carbon dioxide back before transfusion by flow with pure oxygen or air. This use is for special cases, such as massive transfusions, where the lung's ability to reoxygenate the transfused blood is not adequate, or sickle cell anemia.
    [0056] [0056] Similarly, depletion devices can be used to achieve intermediate levels or states of oxygen and carbon dioxide depletion depending on the needs of the patient to obtain optimal levels in the transfused blood depending on the needs of the patients.
    [0057] [0057] Referring to Fig. 3, a blood storage bag 200 according to a preferred embodiment of the present description is provided. Blood bag 200 has a compatible internal blood bag 250 (preferably polyvinyl chloride (PVC)), and an outer barrier film bag 255. The material of bag 250 is compatible with RBCs. Arranged between the inner bag 250 and the outer oxygen barrier film bag 255 is a bag that contains an oxygen / carbon dioxide sorbent 110. The barrier film bag 255 is laminated to the entire surface of the inner bag 250. The sorbent 110 is contained in a sachet 260, which is alternately referred to as a bag or pouch. The sorbent 110 is ideally located between the piping 440 leading into and from the bag 200, specifically between the inner bag and the outer oxygen barrier film bag 255. This location will ensure that the oxygen disposed between these two bags will be decontaminated or absorbed. The oxygen sorbent is ideally located in a 260 bag or pouch and not in contact with RBCs. The oxygen sorbent can also be combined with decontaminants or CO2 sorbents, allowing sorbent 110 to subject both oxygen and carbon dioxide to depletion at the same time.
    [0058] [0058] Referring to Figs. 4a and 4b, blood storage bags 201 and 202 are configured to store RBCs for extended periods of time. Internal blood storage bags 205 are preferably made of plasticized PVC with DEHP and are in contact with RBCs. Plasticized PVC with DEHP is approximately 200 times less permeable to oxygen compared to silicone. However, PVC is insufficient as an oxygen barrier to maintain the anaerobic state of RBCs for the duration of storage. Therefore, blood storage bags 201 and 202 are manufactured with external transparent oxygen barrier film 206 (for example nylon polymer) laminated to the internal blood bag with external surface 205. This method, as well as the one shown in Fig. 3 , uses PVC accepted for blood contact surface (providing DEHP for cell stabilization) while preventing oxygen from entering the bag during prolonged storage.
    [0059] [0059] In Fig. 4a, a small sachet 210 containing oxygen sorbent / carbon dioxide 110 wrapped in an oxygen-permeable membrane, compatible with RBC is embedded inside the laminated PVC bag 205 and in contact with RBCs. The small sachet envelope 210 is preferably made of a silicone or siloxane material with high oxygen permeability of biocompatible material. The sachet envelope 210 has a wall thickness of less than 0.13 mm in thickness and ensures that permeability to O2 ceases to become the rate limiting step. The PVC 205 pouch can also contain carbon dioxide decontaminants.
    [0060] [0060] Referring to Fig. 4b, bag 202 has a similar configuration to bag 201 of Fig. 4a. However, pouch 202 has a large sorbent 215 embedded within the PVC pouch 205. Large sorbent 215 preferably has a honeycomb-like configuration to rapidly absorb oxygen during prolonged storage. The benefit of the laminated pouches of Figs. 4a and 4b is that since RBCs are anaerobically stored in bags, no additional special handling is required. Similarly, pouch 202 may contain carbon dioxide decontaminant to provide decontamination of carbon dioxide in addition to oxygen decontamination capacity.
    [0061] [0061] Referring to the embodiments of Figs. 5a and 5b, RBCs are stored in secondary bags 301 and 302, respectively, in order to maintain an anaerobic storage environment for RBC storage. Secondary bags 301 and 302 are transparent oxygen barrier films (for example, nylon polymer) that compensate for the inability of PVC blood bags 305 and 320, respectively, to operate as a sufficient oxygen barrier to keep RBCs in a state anaerobic. Secondary pouches 301 and 302 are manufactured with an oxygen barrier film, preferably a nylon polymer or other transparent, flexible film with low oxygen permeability.
    [0062] [0062] Referring to Fig. 5a, a small oxygen / carbon dioxide sorbent 310 is disposed between a PVC barrier bag 305 and secondary bag 306 to remove slowly diffused oxygen. Fig. 5a is similar to the preferred embodiment of the blood bag of Fig. 3 except that secondary bag 306 is separate from and not attached to bag 305 in this embodiment. The PVC bag 305 including doors are embedded in the secondary barrier bag 305. Oxygen sorbent 310 can optionally contain carbon dioxide decontaminants to provide decontamination capacity for both oxygen and carbon dioxide.
    [0063] [0063] Referring to Fig. 5b, a secondary pouch 302 contains a large sachet 325 inside the PVC pouch 320. Sachet 325 is filled with oxygen sorbent / carbon dioxide 110. Sachet 325 is a molded element with surface texture to increase the surface area. The 325 sachet has a honeycomb-like geometry for rapid oxygen / carbon dioxide depletion. Sachet 325 acts quickly to remove oxygen / carbon dioxide from RBCs before refrigeration and storage of RBCs in place of OCDD in Fig. 2. However, with this configuration, agitation is necessary, therefore sachet 325 must have a surface area large, high oxygen / carbon dioxide permeability and mechanical strength to withstand the centrifugation step during component preparation and prolonged storage. Sachet 325 is preferably manufactured from materials such as 0.15 mm thick silicone membrane with surface texture to increase the surface area. Sachet 325 can be manufactured from materials such as PTFE or other fluoropolymer. The sachet 325 can have a rectangular shape, such as, for example, a 4 ”x 6” rectangle, although other sizes are possible, for anaerobic maintenance. Sachet 325 may contain carbon dioxide decontaminants in addition to oxygen decontaminants to provide oxygen and carbon dioxide decontamination capabilities.
    [0064] [0064] The embodiments of Figs. 5a and 5b are easily made of unmodified components except for the sachet 325 of Fig. 5b. In order to evaluate RBCs for any test, secondary bags 301 and 302 must be opened. Unless the unit is transfused within a short time, RBC must be resealed with fresh sorbent for additional storage. (1 day of exposure to air from a storage bag would not oxygenate blood to an appreciable degree, since plasticized PVC with DEHP has relatively low oxygen permeability).
    [0065] [0065] In Figs. 4a, 4b, 5a and 5b, the PVC bag is preferably formed with the oxygen barrier film, such as a SiO2 layer formed with the sol-gel method. A portion of the sheet material will be sealed in standard heat sealing equipment, such as radio frequency sealers. Material options can be obtained from extruded sheets and each tested for oxygen barrier, lamination integrity, and seal strength / integrity.
    [0066] [0066] For each of the various embodiments treated above, an additive solution from bag 300 is provided before the removal of oxygen and carbon dioxide from the RBCs is used. The additive solution 300 preferably contains the following composition adenine at 2 mmol / L; glucose at 110 mmol / L; 55 mmol / L mannitol; 26 mmol / L NaCI; Na2HPO4 at 12 mmol / L citric acid and a pH of 6.5. Additive solution 300 is preferably an acidic OFAS3 additive solution, although other similar additive solutions can also be used which are shown to enhance storage subjected to oxygen / carbon dioxide depletion. OFAS3 showed enhanced ATP levels and good recovery in vivo as described here. Although OFAS3 is a preferred additive solution, other solutions that offer similar functionality could also be used. Alternatively, additive solutions commonly used in the field, such as AS1, AS3, AS5, SAGM, and MAPS can also be used. Additive solutions help prevent rapid deterioration of RBCs during storage and are typically added before RBCs are made anaerobic.
    [0067] [0067] Additionally, it is envisaged that OCDD and storage bags 100 and 200 can be manufactured independently of other components of the disposable anaerobic blood storage system (ie, each item upstream of and including the leukoreduction filter 400 in the Fig. 1).
    [0068] [0068] It is within the scope of this description to remove oxygen from RBCs or to remove oxygen and carbon dioxide from the blood prior to storage in storage bags. An oxygen decontaminant can be used to remove oxygen from RBCs before storage in blood bags. As used herein, "oxygen decontaminant" is a material that irreversibly binds to or combines with oxygen under conditions of use. For example, oxygen can chemically react with some component of the material and be converted to another compound. Any material where the rate of dissociation of bound oxygen is zero can serve as an oxygen decontaminant. Examples of oxygen decontaminants include iron powders and organic compounds. The term "oxygen sorbent" can be used interchangeably here with oxygen decontaminant. As used herein, “carbon dioxide decontaminant” is a material that irreversibly binds to or combines with carbon dioxide under conditions of use. For example, carbon dioxide can chemically react with some component of the material and be converted to another compound. Any material where the dissociation rate of bound carbon dioxide is zero can serve as a carbon dioxide decontaminant. The term "carbon dioxide sorbent" can be used interchangeably here with carbon dioxide decontaminant. For example, oxygen decontaminants and carbon dioxide decontaminants are provided by Multisorb Technologies (Buffalo, NY). Oxygen decontaminants may exhibit secondary carbon dioxide decontamination functionality. Such materials can be combined with a desired ratio to obtain desired results.
    [0069] [0069] Carbon dioxide decontaminants include metal oxides and metal hydroxides. Metal oxides react with water to produce metal hydroxides. The metal hydroxide reacts with carbon dioxide to form water and a metal carbonate. For example, if calcium oxide is used, calcium oxide will react with water that is added to the sorbent to produce calcium hydroxide. CaO + H2O → Ca (OH) 2
    [0070] [0070] Calcium hydroxide will react with carbon dioxide to form calcium carbonate and water. Ca (OH) 2 + CO2 → CaCO3 + H2O
    [0071] [0071] It will be assessed that decontaminants can be incorporated into receptacles and storage bags in any known form, such as sachets, plasters, coatings, bags, and packaging.
    [0072] [0072] If oxygen removal is completed prior to the introduction of RBCs to the blood storage device, then it can be performed by any method known in the art. For example, a suspension of RBCs can be repeatedly flowed with an inert gas (with or without a defined concentration of carbon dioxide), with or without gentle mixing, until the desired oxygen and / or carbon dioxide content is reached or until that substantially all of the oxygen and carbon dioxide have been removed. The inert gas can be argon, helium, nitrogen, mixtures of these, or any other gas that does not bind to the heme portion of hemoglobin.
    [0073] [0073] The OCDDs and various storage bags of this description can be used in various combinations. For example, OCDD 101 of Fig. 2 can be used with the blood bag of Fig. 3, 201 of Fig. 4a or 301 of Fig. 5a. When oxygen is depleted by the sachet inside the pouch 215 of Fig. 5b, it can be stored as in Fig. 5b or the content subjected to oxygen / carbon dioxide depletion transferred to the final storage bag as in Fig. 3 , Fig. 4a or Fig. 5a for extended storage. Other combinations and configurations are completely within the scope of this description.
    [0074] [0074] The present description also provides another embodiment of a blood storage device. The device is a sealed receptacle adapted to retain and store erythrocytes. The receptacle has walls formed from a laminate. The laminate has (a) an outer layer of a material substantially impermeable to oxygen and carbon dioxide, (b) an inner layer of a material compatible with erythrocytes, and (c) an interstitial layer between the outer layer and the inner layer. The interstitial layer is of a material having mixed in it an amount of either or both of an oxygen decontaminant and a carbon dioxide decontaminant. The layers preferably take the form of polymers. A preferred polymer for the outer layer is nylon. A preferred polymer for the inner layer is PVC. The interstitial layer polymer must provide effective adhesion between the inner and outer layers and provide an effective mixture of oxygen decontaminants and / or carbon dioxide decontaminants therein. Polymers useful for the interstitial layer include, for example, olefin polymers, such as ethylene and propylene homopolymers and copolymers, and acrylic polymers.
    [0075] [0075] The present description also provides another embodiment of a blood storage system. The system has a collection bag for erythrocytes; a unitary device for depleting oxygen and carbon dioxide and reducing leukocytes and / or red blood cell platelets; a storage bag for erythrocytes; and tubing connecting the collection bag to the unitary device and the unitary device to the storage bag. A feature of this embodiment is that the functions of depleting oxygen and carbon dioxide and reducing leukocytes and / or erythrocyte platelets are combined into a single, single device rather than requiring separate devices. For example, the unitary device may take the form of a single cartridge. The leukocyte and / or platelet reduction is typically accomplished by passing the erythrocytes through a mesh. In this embodiment, a mesh can be incorporated into the flow / decontamination oxygen / carbon dioxide depletion device described here. The mesh is preferably located within the device so that leukocyte and / or platelet reduction occurs before the flow or decontamination begins.
    [0076] [0076] The following are examples of the present description and should not be construed as limiting. EXAMPLES
    [0077] [0077] The eight graphs below show the results of a 3-branch study that shows: a control (OFAS3 aerobic with no depletion of O2 or CO2), anaerobic OFAS3 (both O2 and CO2 subjected to depletion with fresh air), and O2 only subjected to depletion with 95% Ar and 5% CO2 (CO2 is not subjected to depletion).
    [0078] [0078] Whole blood was collected in CP2D (Pall), centrifuged 2KxG for 3 minutes, the plasma removed, and an AS-3 additive solution (Nutricel, Pall), or experimental OFAS3 added. The unit was evenly divided into 3 600 mL pouches. 2 bags were exchanged for x7 gas with Ar or Ar / C02, transferred to 150 mL PVC bags and stored at 1 ° C to 6 ° C in anaerobic cylinders with Ar / H2 or Ar / H2ICO2. A control bag was treated in the same way without a gas exchange and stored at 1 ° C to 6 ° C in room air. The bags were tested weekly for up to 9 weeks.
    [0079] [0079] The graphs of Figs. 11a, 11c, 11e and 11g: use the OFAS3 additive solution (200 mL; experimental, proprietary) and the graphs in Figs 11b, 11 d, 11f and 11h use the AS-3 additive solution. Comparing additive solutions, the effects of CO2 depletion on DPG levels were similar. OFAS3 showed higher ATP when oxygen was subjected to depletion (± CO2), and O2 depletion alone showed significant ATP enhancement compared to aerobic control. The AS-3 additive did not exhibit any significant ATP enhancement when O2 alone was subjected to depletion.
    [0080] [0080] Figs. 11a and 11b: DPG levels during storage. DPG levels were maintained for more than 2 weeks, when CO2 was removed in addition to oxygen.
    [0081] [0081] Fig. 11c: ATP levels during storage with OFAS3. Higher ATP levels were obtained with RBC of OFAS3 when O2 was only subjected to depletion. For O2 / CO2 depletion, intermediate levels of ATP were observed compared to the control while very high levels of DPG were achieved during the first 2.5 weeks. Very high levels of ATP may suggest a higher rate of 24-hour post-transfusion recovery. Therefore, the degree of carbon dioxide and oxygen depletion levels can be adjusted to meet the specific needs of the recipient. DPG levels can be kept very high (at the expense of ATP) for the purpose of satisfying the recipient's acute oxygen demand. In contrast, very high levels of ATP may allow a higher 24-hour recovery rate (lower fraction of non-viable RBC in transfusion) thereby reducing the amount of blood needed to be transfused (up to 25% of RBC is non-viable) . Most importantly, this would benefit chronically transfused patients who cannot demand higher oxygen transport efficiency immediately after transfusion (the DPG level recovers in the body after 8 to 48 hours) who suffer from toxic iron overload caused by non-viable RBCs .
    [0082] [0082] Fig. 11 d: ATP levels during storage with AS3. Higher ATP levels were obtained with RBC of AS3 when O2 was only subjected to depletion. No significant difference in ATP levels where observed with O2 control and depletion alone.
    [0083] [0083] Figs. 11e and 11f: RBC cytosol pH (in) and suspension medium (ex). Immediately after the gas exchange (day 0), a significant increase in pH (in and ex) was observed only when CO2 was subjected to depletion together with O2. Rapid rates of pH decline observed with samples subjected to CO2 / O2 depletion were caused by higher rates of lactate production (Figs. 11g and 11h).
    [0084] [0084] Figs. 11 g and 11 h: Glucose and lactate levels normalized (for hemoglobin) during storage with OFAS3 and AS3. Higher rates of glucose depletion and lactate yields correspond to high levels of DPG observed in panels A and B. Legends for symbols / lines are the same for both panels. The OFAS3 additive contains a similar glucose concentration with x2 volume which results in higher normalized glucose levels.
    [0085] [0085] Figs. 11a and 11c taken together, suggest that the degree of increases (compared to control) in ATP and DPG levels can be adjusted by controlling the level of CO2 depletion when O2 is subjected to depletion. Higher glucose utilization and lactate production were observed with enhanced DPG production (Fig. 11g). This can also be effective with the AS3 additive, as a similar trend in the use of glucose and lactate production has been observed (Fig. 11h).
    [0086] [0086] Although the present description describes in detail certain embodiments, it is understood that variations and modifications are known to those skilled in the art that are within the description. Consequently, the present description is intended to cover all such alternatives, modifications and variations that are within the scope of the description as presented in the description.
    权利要求:
    Claims (18)
    [0001]
    Blood storage device to store blood depleted of oxygen and carbon dioxide, characterized by the fact that it comprises: an external receptacle substantially impermeable to oxygen and carbon dioxide; an internal receptacle located within said external receptacle; an amount of a carbon dioxide and oxygen scrubber located within said external receptacle, wherein said blood storage device maintains the blood in a carbon dioxide depleted state.
    [0002]
    Device according to claim 1, characterized by the fact that said carbon dioxide scrubber is located between said external receptacle and said internal receptacle.
    [0003]
    Device according to claim 1, characterized in that the carbon dioxide scrubber is located inside a sachet, plaster, or coating formed of a carbon dioxide permeable material other than said carbon dioxide scrubber.
    [0004]
    Device according to claim 3, characterized in that said material permeable to carbon dioxide is a polymer or combination of polymers.
    [0005]
    Device according to claim 1, characterized by the fact that the carbon dioxide scrubber is selected from the group consisting of metal oxides and metal hydroxides.
    [0006]
    Depletion device for oxygen and carbon dioxide, characterized by the fact that it comprises: a cartridge; one or more gas-permeable films or membranes extending within the cartridge from an inlet to an outlet thereof, wherein said one or more gas-permeable films or membranes are formed of a material that is permeable to both oxygen and oxygen. carbon dioxide and are adapted to receive and transport red blood cells; and an amount of both an oxygen scrubber and a carbon dioxide scrubber packaged within said cartridge and adjacent to and between said one or more gas permeable films or membranes.
    [0007]
    Depletion device for oxygen and carbon dioxide, characterized by the fact that it comprises: a receptacle of solid material having an inlet and an outlet adapted to receive and expel a discharge gas; and one or more gas-permeable films or membranes extending within the receptacle of an inlet to an outlet thereof, wherein said one or more gas-permeable films or membranes are formed of a material permeable to both oxygen and carbon dioxide. carbon and are adapted to receive and transport red blood cells.
    [0008]
    Device according to claim 7, characterized by the fact that it also includes a source of exhaust gas in communication with said inlet of said receptacle.
    [0009]
    Method for removing oxygen and carbon dioxide from red blood cells, characterized by the fact that it comprises: pass red blood cells through an oxygen and carbon dioxide depletion device, in which said device comprises: a cartridge; one or more gas-permeable films or membranes extending within said cartridge from an inlet to an outlet thereof, wherein said one or more gas-permeable films or membranes are formed of a material permeable to both oxygen and dioxide carbon and are adapted to receive and transport red blood cells; and an amount of an oxygen scrubber and a carbon dioxide scrubber packaged within said cartridge and contiguous to and between said one or more gas-permeable films or membranes.
    [0010]
    Method for removing oxygen and carbon dioxide from red blood cells, characterized by the fact that it comprises: pass red blood cells through an oxygen and carbon dioxide depletion device, where the device comprises: a receptacle of solid material having an inlet and an outlet adapted to receive and expel a discharge gas; and one or more gas permeable films or membranes extending within said receptacle from an inlet to an outlet thereof, wherein said one or more gas permeable films or membranes are formed of a material permeable to both oxygen and dioxide carbon and are adapted to receive and transport red blood cells.
    [0011]
    Blood storage system, characterized by the fact that it comprises: a collection bag for red blood cells; an oxygen and carbon dioxide depletion device; a storage bag for red blood cells; and tubing connecting the collection bag to said oxygen and carbon dioxide depletion device and tubing connecting said oxygen and carbon dioxide depletion device to the storage bag, wherein said oxygen and carbon dioxide depletion device comprises: a cartridge; one or more gas-permeable films or membranes extending within said cartridge from an inlet to an outlet thereof, wherein said one or more gas-permeable films or membranes are adapted to receive and transport red blood cells; and an amount of both an oxygen scrubber and a carbon dioxide scrubber packaged within said cartridge and adjacent to and between said one or more gas permeable films or membranes.
    [0012]
    Blood storage system, characterized by the fact that it comprises: a collection bag for red blood cells; an oxygen and carbon dioxide depletion device; a storage bag for red blood cells; and tubing connecting said collection bag to said oxygen and carbon dioxide depletion device and tubing connecting said oxygen and carbon dioxide depletion device to said storage bag, wherein said depletion device comprises: a receptacle of solid material having an inlet and an outlet adapted to receive and expel a discharge gas; and one or more gas permeable films or membranes extending within said receptacle from an inlet to an outlet thereof, wherein said one or more gas permeable films or membranes are formed of a material permeable to both oxygen and dioxide carbon and are adapted to receive and transport red blood cells.
    [0013]
    Blood storage device, characterized by the fact that it comprises: a receptacle adapted to retain and store red blood cells, said receptacle being formed of a laminate, said laminate including (a) an outer layer of a material substantially impermeable to both oxygen and carbon dioxide, (b) an inner layer of a material compatible with erythrocytes, and (c) an interstitial layer between the outer layer and the inner layer, in which the interstitial layer is a material having mixed in it an amount of both an oxygen scrubber and a dioxide scrubber carbon.
    [0014]
    Blood storage system, characterized by the fact that it comprises: a collection bag for red blood cells; a unitary device for depleting oxygen and carbon dioxide and reducing leukocytes and red blood cells; a storage bag for red blood cells; and tubing connecting said collection bag to said unitary device and tubing connecting said unitary device to said storage bag.
    [0015]
    Method for removing oxygen from red blood cells, characterized by the fact that it comprises: passing red blood cells through an oxygen depletion device, in which said device comprises: a) a cartridge; one or more gas-permeable films or membranes extending within said cartridge from an inlet to an outlet thereof, wherein said one or more gas-permeable films or membranes are formed of an oxygen-permeable material and are adapted to receiving and transporting red blood cells; and an amount of an oxygen scrubber contained within said cartridge and contiguous with and between said one or more gas-permeable films or membranes; or b) a solid material receptacle having an inlet and an outlet adapted to receive and expel a discharge gas; and one or more gas-permeable films or membranes extending within said receptacle from an inlet to an outlet thereof, wherein said one or more gas-permeable films or membranes are formed of an oxygen-permeable material and are adapted to receiving and transporting red blood cells.
    [0016]
    Blood storage system, characterized by the fact that it comprises: a collection bag for red blood cells; an oxygen and carbon dioxide depletion device; an anaerobic storage bag for red blood cells; and tubing connecting said collection bag to said oxygen depletion device and tubing connecting said oxygen depletion device to the storage bag, wherein said oxygen and carbon dioxide depletion device comprises: a) a cartridge; one or more gas-permeable films or membranes formed of an oxygen-permeable material and adapted to receive and transport red blood cells, which extend within said cartridge from an inlet to an outlet thereof; and an amount of an oxygen scrubber and a carbon dioxide scrubber packaged within said cartridge and contiguous with and between said one or more gas-permeable films or membranes; or b) a solid material receptacle having an inlet and an outlet adapted to receive and expel a discharge gas; and one or more gas-permeable films or membranes formed from an oxygen-permeable material and adapted to receive and transport red blood cells, which extend within said receptacle from an entrance to an exit from it.
    [0017]
    Blood storage system, characterized by the fact that it comprises: a collection bag for red blood cells; a unitary device for depleting oxygen and reducing red blood cell leukocytes; an anaerobic storage bag for red blood cells; and tubing connecting said collection bag to said unitary device and tubing connecting said unitary device to said storage bag.
    [0018]
    Method for increasing levels of adenosine triphosphate (ATP) in red blood cells, characterized by the fact that it comprises: mixing red blood cells with an acid additive solution and passing said red blood cells through an oxygen depletion device, wherein said oxygen depletion device comprises: a) a cartridge; one or more gas-permeable films or membranes extending within said cartridge from an inlet to an outlet thereof, formed of an oxygen-permeable material and adapted to receive and transport red blood cells; and an amount of an oxygen scrubber contained within said cartridge and contiguous with and between said one or more gas-permeable films or membranes; or b) a solid material receptacle having an inlet and an outlet adapted to receive and expel a discharge gas; and one or more gas-permeable films or membranes formed from an oxygen-permeable material and adapted to receive and transport red blood cells, which extend within said receptacle from an entrance to an exit from it.
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    同族专利:
    公开号 | 公开日
    JP2017018626A|2017-01-26|
    EP2355860A1|2011-08-17|
    NZ599891A|2014-06-27|
    AU2010307084A1|2012-05-31|
    CA2781866C|2019-12-03|
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    WO2011046841A1|2011-04-21|
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    CN102711865B|2015-08-19|
    AU2010307084B2|2015-12-17|
    US20130333561A1|2013-12-19|
    JP6199557B2|2017-09-20|
    BR112012008683B8|2021-06-22|
    US8535421B2|2013-09-17|
    CN102711865A|2012-10-03|
    JP2013507226A|2013-03-04|
    US20120024156A1|2012-02-02|
    BR112012008683A2|2016-04-19|
    US9095662B2|2015-08-04|
    BR112012008683A8|2018-06-26|
    EP2355860A4|2013-06-26|
    CA2781866A1|2011-04-21|
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    法律状态:
    2019-01-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|
    2019-07-30| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|
    2020-05-12| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|
    2020-07-21| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|
    2020-11-24| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 10 (DEZ) ANOS CONTADOS A PARTIR DE 24/11/2020, OBSERVADAS AS CONDICOES LEGAIS. |
    2021-06-22| B16C| Correction of notification of the grant [chapter 16.3 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 08/10/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO |
    优先权:
    申请号 | 申请日 | 专利标题
    US25066109P| true| 2009-10-12|2009-10-12|
    US61/250661|2009-10-12|
    US33169310P| true| 2010-05-05|2010-05-05|
    US61/331693|2010-05-05|
    PCT/US2010/052084|WO2011046841A1|2009-10-12|2010-10-08|Blood storage bag system and depletion devices with oxygen and carbon dioxide depletion capabilities|
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