# Patent

## Title
Oxygen depletion devices and methods for removing oxygen from red blood cells

## Abstract

An oxygen depletion device. The device has a cartridge; a plurality of hollow fibers extending within the cartridge from an entrance to an exit thereof; an amount of an oxygen scavenger packed within the cartridge and contiguous to and in between the plurality of hollow fibers. The hollow fibers are adapted to receiving and conveying red blood cells. There is another embodiment of an oxygen depletion device and method for removing oxygen from red blood cells.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation application of U.S. application Ser. No. 13/115,532, filed May 25, 2011, now U.S. Pat. No. 8,569,052, issued Oct. 29, 2013, which claims the benefit under 35 U.S.C. §119(e) to U.S. application Ser. No. 12/903,057, filed on Oct. 12, 2010, which claims priority to U.S. Provisional Application No. 61/250,661, filed Oct. 12, 2009. All of the foregoing applications are hereby incorporated by reference in their entireties.


STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
This invention was made with government support under grants awarded by the National Institutes of Health (NIH) and the National Heart Lung and Blood Institute (NHLBI). The government has certain rights in the invention.


BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to devices for depleting oxygen from red blood cells to enhance storage life. The present invention relates to methods for depleting oxygen from red blood cells.
2. Background of the Art
Adequate blood supply and the storage thereof is a problem facing every major hospital and health organization around the world. Often, the amount of blood supply in storage is considerably smaller than the need therefor. This is especially true during crisis periods such as natural catastrophes, war and the like, when the blood supply is often perilously close to running out. It is at critical times such as these that the cry for more donations of fresh blood is often heard. However, unfortunately, even when there is no crisis period, the blood supply and that kept in storage must be constantly monitored and replenished, because stored blood does not maintain its viability for long.
Stored blood undergoes steady deterioration which is, in part, caused by hemoglobin oxidation and degradation and adenosine triphosphate (ATP) and 2-3,biphosphoglycerate (DPG) depletion. Oxygen causes hemoglobin (Hb) carried by the red blood cells (RBCs) to convert to met-Hb, the breakdown of which produces toxic products such as hemichrome, hemin and free Fe3+. Together with the oxygen, these products catalyze the formation of hydroxyl radicals (OH.cndot.), and both the OH.cndot. and the met-Hb breakdown products damage the red blood cell lipid membrane, the membrane skeleton, and the cell contents. As such, stored blood is considered unusable after 6 weeks, as determined by the relative inability of the red blood cells to survive in the circulation of the transfusion recipient. The depletion of DPG prevents adequate transport of oxygen to tissue thereby lowering the efficacy of transfusion immediately after administration (levels of DPG recover once in recipient after 8-48 hrs). In addition, these deleterious effects also result in reduced overall efficacy and increased side effects of transfusion therapy with stored blood before expiration date, but possibly older than two weeks are used.
There is, therefore, a need to be able to deplete oxygen levels in red blood cells prior to storage on a long-term basis without the stored blood undergoing the harmful effects caused by the oxygen and hemoglobin interaction.
SUMMARY OF THE INVENTION
Accordingly, the present disclosure provides for a disposable device that is able to remove oxygen from red blood cells.
The present disclosure provides for an oxygen depletion device. The device has a cartridge; a plurality of hollow fibers extending within the cartridge from an entrance to an exit thereof; an amount of an oxygen scavenger packed within the cartridge and contiguous to and in between the plurality of hollow fibers. The hollow fibers are adapted to receiving and conveying red blood cells.
The present disclosure provides for an oxygen depletion device. The device has a receptacle of a solid material having an inlet and an outlet adapted to receiving and expelling a flushing gas and a plurality of hollow fibers extending within the receptacle from an entrance to an exit thereof. The hollow fibers are adapted to receiving and conveying red blood cells.
The present disclosure provides for a method for removing oxygen from red blood cells. The method has the step of passing the red blood cells through an oxygen device. The device has a cartridge; a plurality of hollow fibers extending within the cartridge from an entrance to an exit thereof; and an amount of an oxygen scavenger packed within the cartridge and contiguous to and in between the plurality of hollow fibers. The hollow fibers are adapted to receiving and conveying red blood cells.
The present disclosure provides for a method for removing oxygen from red blood cells. The method has the step of passing the red blood cells through an oxygen device. The device has a receptacle of a solid material having an inlet and an outlet adapted to receiving and expelling a flushing gas; and a plurality of hollow fibers films extending within the receptacle from an entrance to an exit thereof. The hollow fibers are adapted to receiving and conveying red blood cells.
The present disclosure and its features and advantages will become more apparent from the following detailed description with reference to the accompanying drawings.



BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 illustrates a pre-storage oxygen depletion device of the present invention.
FIG. 2a illustrates an embodiment of a depletion device that depletes oxygen from red blood cells prior to storage by a flushing inert gas around a hollow fiber inside the assembly.
FIG. 2b illustrates an embodiment of a depletion device that depletes oxygen from red blood cells prior to storage by a flushing inert gas around a hollow fiber inside the assembly.
FIG. 2c illustrates an embodiment of a depletion device that depletes oxygen from red blood cells prior to storage by a flushing inert gas around a hollow fiber inside the assembly.
FIG. 3a illustrates another embodiment of a depletion device that depletes oxygen from red blood cells prior to storage.
FIG. 3b illustrates another embodiment of a depletion device that depletes oxygen from red blood cells prior to storage.
FIG. 3c illustrates another embodiment of a depletion device that depletes oxygen from red blood cells prior to storage.
FIG. 4a illustrates another embodiment of a depletion device that depletes oxygen from red blood cells prior to storage wherein oxygen is scavenged by scavenger materials in the core of the cylinder, surrounded by hollow fibers.
FIG. 4b illustrates another embodiment of a depletion device that depletes oxygen from red blood cells prior to storage wherein oxygen is scavenged by scavenger materials in the core of the cylinder, surrounded by hollow fibers.
FIG. 4c illustrates another embodiment of a depletion device that depletes oxygen from red blood cells prior to storage wherein oxygen is scavenged by scavenger materials in the core of the cylinder, surrounded by hollow fibers.
FIG. 5a illustrates another embodiment of a depletion device that depletes oxygen from red blood cells wherein oxygen is scavenged by scavenger materials surrounding cylinders of hollow fibers.
FIG. 5b illustrates another embodiment of a depletion device that depletes oxygen from red blood cells wherein oxygen is scavenged by scavenger materials surrounding cylinders of hollow fibers.
FIG. 5c illustrates another embodiment of a depletion device that depletes oxygen from red blood cells wherein oxygen is scavenged by scavenger materials surrounding cylinders of hollow fibers.
FIG. 6 illustrates a plot of flow rate of RBC suspension per minute versus oxygen partial pressure for the depletion devices of FIGS. 2a through 2c, FIGS. 3a through 3c, FIGS. 4a through 4c and FIGS. 5a through 5c. 



DETAILED DESCRIPTION OF THE DISCLOSURE
Referring to FIG. 2, an oxygen depletion device (ODD) 101 contains an oxygen sorbent 110. ODD 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 iron or other materials with high reactivity toward oxygen. Oxygen sorbent 110 is made from particles that have significant absorbing capacity for O2 (more than 5 ml O2/g) and can maintain the inside of cartridge 105 to less than 0.01%, which corresponds to PO2 less than 0.08 mmHg. Oxygen sorbent 110 is either free or contained in an oxygen permeable envelope. ODD 101 of the present disclosure can deplete approximately 100 mL of oxygen from a unit of blood.
RBCs pass through hollow porous fibers 115. Porous fibers are capable of high oxygen permeability rates. Suitable materials for porous fibers include polyolefins, TEFLON® (polytetrafluoroethylene), polyesters, polyvinylidene fluoride (PVDF), polysulfone, and other hydrophobic polymers as well as inorganic materials (ceramics). Oxygen depletion takes place as RBCs pass through membrane 115. ODD provides a simple structure having a large surface area to remove oxygen and maintain constant flow of blood therethrough. The oxygen depletion or removal is accomplished by irreversible reaction of ferrous ion in oxygen sorbent 110 with ambient oxygen to form ferric oxide. ODD 101 does not need agitation for oxygen removal and can be manufactured easily to withstand centrifugation as part of a blood collection system as necessary.
Referring to FIGS. 2a through 2c and FIGS. 3a through 3c, examples of flushing depletion devices are disclosed. The depletion devices function to deplete O2 by supplying appropriate composition of flushing gas. Gases appropriate for depletion devices include, for example, Ar, He, CO2, N2.
FIGS. 4a through 4c and 5a through 5c, also disclose scavenging depletion devices. Depletion takes place with the use of scavengers or sorbents and without the use of external gases. In both types of depletion devices however, oxygen depletion is effective to enhance DPG and ATP, respectively, prior to storage in blood storage bags.
Referring to FIGS. 2a through 2c, a depletion device 20 is shown. Depletion device 20 includes a plurality of fibers 25, approximately 5000 in number, through which red blood cells flow. Plurality of fibers 25 are surrounded by a plastic cylinder 30. Plastic cylinder 30 contains a gas inlet 35 and a gas outlet 40 through which a flushing gas or a combination of flushing gases, such as those mentioned above, are supplied to remove oxygen from blood. Specifications for depletion device 20 are shown in Table 1 below.











TABLE 1







Prototype
Eternal Gas
External



Specification
Pathways
Gas Pathways









Prototype Serial
Device 20




#:



Fiber Type:
Celgard
Celgard




200/150-66FPI
200/150-66FPI



Number of Fibers:
5000
5000



Active Length of
13
28



Fibers (cm):



Fiber OD
200
200



(microns):



Fiber ID
150
150



(microns):



Total Length of
15
30



Fibers



Active Fiber
0.4084
0.8796



Surface Area



(m2):










Referring to FIGS. 3a through 3c, a depletion device 45 is shown. Depletion device 45, like device 20 of FIGS. 2a to 2c, includes a plurality of fibers 50, approximately 5000 in number, through which red blood cells flow. Plurality of fibers 50 are surrounded by a plastic cylinder 55. Plastic cylinder 55 contains a gas inlet 60 and a gas outlet 65 through which a gas or a combination of gases, such as those mentioned above are supplied to remove oxygen from blood. Specifications for depletion device 45 are shown in Table 2 below. The active surface area of depletion of device 45 is twice that of device 20 because device 45 is twice as long as device 20.











TABLE 2







Prototype
Eternal
External



Specification
Gas Pathways
Gas Pathways









Prototype Serial

Device 45



#:



Fiber Type:
Celgard
Celgard




200/150-66FPI
200/150-66FPI



Number of
5000
5000



Fibers:



Active Length of
13
28



Fibers (cm):



Fiber OD
200
200



(microns):



Fiber ID
150
150



(microns):



Total Length of
15
30



Fibers



Active Fiber
0.4084
0.8796



Surface Area



(m2):










FIGS. 4a through 4c disclose a depletion device 70 having a core 75 containing scavenging materials for O2. Core 75 is packed by a gas permeable film with very low liquid permeability. Hollow fibers 80 are wound around core 75, and a plastic cylinder 82 contains and envelopes hollow fibers 80. In this particular embodiment, the active surface area for depletion is approximately 0.8796 m2 as shown in Table 3 below.











TABLE 3








Center
10




Core
individual



Prototype
125 grams
Bundles 200 grams



Specification
Sorbent
Sorbent









Prototype
Device 70




Serial #:



Fiber Type:
Celgard
Celgard




200/150-66FPI
200/150-66FPI



Number of
5000
5000



Fibers:



Active Length
13
28



of Fibers (cm):



Fiber OD
200
200



(microns):



Fiber ID
150
150



(microns):



Total Length of
15
30



Fibers



Active Fiber
0.8796
0.8796



Surface Area



(m2):










FIGS. 5a through 5c disclose a depletion device 85 containing fiber bundles 87 enclosed in gas permeable film with very low liquid permeability. Fiber bundles 87 are surrounded by scavenger materials 89 for O2. Fiber bundles 87 and scavenger 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.











TABLE 4








Center
10




Core
individual



Prototype
125 grams
Bundles 200 grams



Specification
Sorbent
Sorbent









Prototype Serial

Device 85



#:



Fiber Type:
Celgard
Celgard




200/150-66FPI
200/150-66FPI



Number of
5000
5000



Fibers:



Active Length
13
28



of Fibers (cm):



Fiber OD
200
200



(microns):



Fiber ID
150
150



(microns):



Total Length of
15
30



Fibers



Active Fiber
0.8796
0.8796



Surface Area



(m2):










FIG. 6 is a plot of the performance of flushing depletion devices 20 and 45 and scavenging depletion devices 70 and 85. The data of FIG. 6 was plotted using the following conditions: Hematocrit, 62% (pooled 3 units of pRBC), and 21° C. at various head heights to produce different flow rates. Oxygen scavenger (Multisorb Technologies, Buffalo, N.Y.) was activated with adding 5% and 12% w/w water vapor for device 79 and device 85, respectively. Data are plotted with flow rate (g RBC suspension per min) vs. pO2 (mmHg).
In the oxygen depletion devices disclosed herein, the hollow fibers may be packed in any suitable configuration within the cartridge, such as linear or longitudinal, spiral, or coil, so long as they can receive and convey red blood cells.
FIG. 6 shows that lowest oxygen saturation is achieved using devices 45 and 85. Device 45 exhibits a larger active surface area exposed to gases along length of fibers 50. Device 85 also has a long surface area of exposure to scavenging materials. Device 85 has bundles 87 surrounded by scavenging materials 89. The space occupied by scavenging materials 89 between bundles 87 promotes dispersion of oxygen from red blood cells contained in fiber bundles 87, thus aiding scavenging of oxygen from red blood cells.
A further use of the depletion devices is to add back oxygen prior to transfusion by flushing with pure oxygen or air. This use is for special cases, such as massive transfusions, where the capacity of the lung to reoxygenate transfused blood is not adequate, or sickle cell anemia.
Similarly, depletion devices can be used to obtain intermediate levels or states of depletion of oxygen depending needs of the patient to obtain optimal levels in the transfused blood depending upon the patients needs.
It is within the scope of the present invention to remove oxygen from the RBCs or to strip oxygen from the blood prior to storage in the storage bags. An oxygen scavenger can be used to remove the oxygen from the RBCs prior to storage in the blood bags. As used herein, “oxygen scavenger” is a material that irreversibly binds to or combines with oxygen under the conditions of use. For example, the oxygen can chemically react with some component of the material and be converted into another compound. Any material where the off-rate of bound oxygen is zero can serve as an oxygen scavenger. Examples of oxygen scavengers include iron powders and organic compounds. The term “oxygen sorbent” may be used interchangeably herein with oxygen scavenger. For example, oxygen scavengers are provided by Multisorb Technologies (Buffalo, N.Y.). Such materials can be blended to a desired ratio to achieve desired results.
It will be appreciated that scavengers can be incorporated into storage receptacles and bags in any known form, such as in sachets, patches, coatings, pockets, and packets.
Although the present invention describes in detail certain embodiments, it is understood that variations and modifications exist known to those skilled in the art that are within the invention. Accordingly, the present invention is intended to encompass all such alternatives, modifications and variations that are within the scope of the invention as set forth in the disclosure.

## Claims

1. A method for adding oxygen to red blood cells comprising: passing red blood cells through an oxygen addition device, wherein said device comprises:
a receptacle of a solid material having an inlet and an outlet receiving and expelling a gas; and
a plurality of hollow fibers extending within said receptacle from an entrance to an exit thereof, wherein said plurality of hollow fibers receive and convey said red blood cells, wherein said red blood cells are passaged within said hollow fibers.

2. The method of claim 1, wherein said red blood cells entering said oxygen addition device are oxygen-depleted red blood cells.

3. The method of claim 1, wherein said gas is pure oxygen.

4. The method of claim 1, wherein said gas is air.

5. The method of claim 1, wherein said plurality of hollow fibers are formed from an oxygen-permeable material selected from the group consisting of polyolefin, polytetrafluoroethylene, polyester, polyvinylidene fluoride (PVDF), and polysulfone.

6. The method of claim 1, wherein said plurality of hollow fibers are formed from a hydrophobic polymer.

7. The method of claim 1, wherein said plurality of hollow fibers are formed from an inorganic ceramic.

8. The method of claim 1, wherein said plurality of hollow fibers are configured as a linear spiral, a longitudinal spiral, or a coil.

9. A method for preparing red blood cells for transfusion into a subject in need thereof, comprising: passing red blood cells through an oxygen addition device and transfusing re-oxygenated red blood cells to said subject, wherein said device comprises:
a receptacle of a solid material having an inlet and an outlet receiving and expelling a gas; and
a plurality of hollow fibers extending within said receptacle from an entrance to an exit thereof, wherein said plurality of hollow fibers receive and convey said red blood cells, wherein said red blood cells are passaged within said hollow fibers.

10. The method of claim 9, wherein said subject is a patient with inadequate lung capacity to re-oxygenate transfused blood.

11. The method of claim 9, wherein said subject is a patient with sickle cell anemia.

12. The method of claim 9, wherein said red blood cells entering said oxygen addition device are oxygen-depleted red blood cells.

13. The method of claim 9, wherein said gas is pure oxygen.

14. The method of claim 9, wherein said gas is air.

15. The method of claim 9, wherein said plurality of hollow fibers are formed from an oxygen-permeable material selected from the group consisting of polyolefin, polytetrafluoroethylene, polyester, polyvinylidene fluoride (PVDF), and polysulfone.

16. The method of claim 9, wherein said plurality of hollow fibers are formed from a hydrophobic polymer.

17. The method of claim 9, wherein said plurality of hollow fibers are formed from an inorganic ceramic.

18. The method of claim 9, wherein said plurality of hollow fibers are configured as a linear spiral, a longitudinal spiral, or a coil.