Patent Application
20140158604
This invention relates to an improved RBC, leukocyte, or platelet storage method and composition. More particularly, this invention aims to minimize pathogen contamination of the stored platelet concentrates and of packed platelets suitable for transfusion. This invention also presents a new approach that neutralizes the effect of the citric anticoagulant in the re-infused blood products.
Platelets are small cellular (2 μm to 4 μm) megakaryocytes components of the blood that provide primary hemostasis function that leads to the stop of bleeding. Platelets transfusion is an established medical therapy used to help patient's recovery post major surgeries or post chemotherapy treatments. Platelets are either derived from collected units of human whole blood using special hematology techniques or are directly collected from a healthy human donor using special apheresis systems.
In routine blood banking practice, human platelet concentrates (PC) are prepared by drawing a unit of blood (about 450 ml) into a plastic bag containing an anticoagulant and then centrifuging the blood into three fractions: red cells, plasma, and platelets. The separated platelet fraction is then suspended in approximately 50 ml of plasma. This platelet-containing product is then stored until needed for transfusion into a patient.
After platelets collection they are stored for up to 5 days to be infused in patients. Platelets are stored in bags made of plastic film material with high O2 and CO2 permeability to control platelet metabolism and pH level. In order for the platelets to maintain their function for reinfusion, they are stored under constant agitation at 22° C. This storage temperature provides the environment for any viruses or bacteria that are introduced to the blood during the collection process to proliferate and subsequently may cause sepsis complications to the recipient.
Bacterial contamination of platelets represents the most frequent transfusion-associated infectious risk. All blood components are susceptible to bacterial contamination. Unlike the plasma and the red blood cells (RBC) that are stored at low temperature, the platelets are stored at room temperature to preserve its function. By storing platelets at temperature ranging between 20° C. and 24° C., bacteria proliferation becomes a realistic complication. Skin flora is the most common source of bacterial contamination during blood collection. The estimated bacterial load at collection is less than 0.1 CFU/ml. These small bacterial inoculums can proliferate within a short time period to serious and substantial levels in platelet concentrate that are stored at room temperature. Bacterial contamination of platelets can be found in about 1 in 1,000 to 1 in 3,000 units.
In addition to storage time, other storage conditions have been shown to affect platelet metabolism and function. Initial pH, storage temperature, total platelet count, plasma volume, agitation during storage, and hydrogen ion accumulation are some of the factors known to influence the storage of platelets.
A number of other interrelated variables can also affect platelet viability and function during storage, namely, the anticoagulant used for blood collection, the method used to prepare platelet concentrates and the composition, surface area, and thickness of the walls of the storage container.
One of the major problems in PC storage is regulation of pH. Virtually all units of PC show a decrease in pH from their initial value of approximately 7.0. This decrease is primarily due to the production of lactic acid by platelet glycolysis and to a lesser extent to accumulation of CO2 from oxidative phosphorylation.
As pH level in the stored platelets bag falls from 6.8 to 6.0, the platelets progressively change shape from discs to spheres. In this pH range, the change of shape is reversible if the platelets are resuspended in plasma with physiologic pH. However, if the pH falls below 6.0, a further irreversible change occurs which renders the platelets nonviable after infusion in vivo. Oxygen supply to the platelets within the plastic bag is also intimately related to pH maintenance. If the supply is sufficient, glucose will be metabolized oxidatively resulting in CO2 production, which diffuses out of the plastic walls of the PC container. If the supply of oxygen is insufficient, glucose will be metabolized anaerobically, resulting in the production of lactic acid, which must remain within the container and thus lowers the pH. The oxygen tension within the container is governed by several factors: the concentration of platelets which consume oxygen, the permeability of the plastic wall of the PC, the surface area of the container available for gas exchange, and the type of agitation utilized.
The present goal of platelet preservation is to prevent this change in pH and to minimize the pathogens growth in the storage media. There are many attempts in the prior arts to prevent the change in the pH and to eradicate all pathogens. All these methods were founded on chemical and/or radiation treatments of the blood products. Chemicals that proved to be effective in eradicating bacteria and viruses could pose serious side effects on blood cells such as red blood cells (RBC) and platelets.
The object of the current invention is to provide a passive method to prevent unwanted changes in pH and to minimize the bacteria and viruses growth in the blood product storage environment. Whereas the passive method in this invention is not dependent on mixing chemicals with blood products nor utilizes any type of radiation to treat blood products.
The current invention aims to minimize bacterial contamination of the stored platelets. More specifically to minimize bacterial contamination inside the platelet bag during storage. Therefore, diminishing the risk of septicemia acquired in the course of platelets transfusion. In this invention, the platelet bag is designed to incorporate a sachet that contains adsorbent media. The adsorbent media has inherent tendency to capture bacteria and viruses from solutions. These captured bacteria and viruses are prevented from being mixed with the environment that contains plasma and platelets. The media that is contained inside the sachet is safe when it comes in contact with plasma but in some cases it might cause platelet adhesion or red blood cell Hemolysis when it comes in contact with blood cells. Therefore, it is important to keep the blood cells from contacting the adsorbent media.
For convenience all bacteria, micro-organisms, viruses, cytokines, endotoxins, and toxin will be referred to in this study as pathogens.
The sachet that contains the media is made of biocompatible membrane with porosity that prevents any blood cell from passing through while bacteria and viruses suspended in the plasma can pass freely through the membrane. Typically bacteria are 1 μm (micron) or less in size. Viruses are less than 1 μm in size. Platelets are (2 μm to 4 μm) in size and red blood cells (RBC) are 7 μm in size. Platelets usually have a disc shape that could transform to a spherical shape at cold temperatures. RBCs have a disc shape with 7 μm in diameter and 2 μm thick. White blood cells have a spherical shape with 10 μm in diameter.
Platelets with bacteria and viruses are suspended in the plasma inside the platelet bag. The sachet containing adsorbent media is located inside the platelet bag. Platelets cannot penetrate the sachet membrane and they cannot come in contact with the adsorbent media inside the sachet. Platelets are confined in the space inside the platelet bag but outside the sachet. Bacteria and viruses are floating in the plasma can easily penetrate the sachet membrane. Therefore, the bacteria, viruses, and plasma are located inside the whole space defined by the platelet bag including the sachet. As bacteria and viruses cross through the sachet membrane and come in contact with the adsorbent media inside, they stick to the media surface and become trapped. The majority of the bacteria and the viruses that flow inside the sachet adhere to the adsorbent surface and are prevented from becoming loose. Therefore, they are entrapped inside the sachet and do not intermix with the platelets that float in the plasma outside the sachet. In addition, cytokines, endotoxins, and other micro-organisms and toxins that are suspended in the plasma; are also trapped by the activated carbon inside the sachet. U.S. Pat. No. 6,852,224 by Jagtoyen et al. discloses a filter comprised of activated carbon fibers, wherein said filter has a Virus Removal Index (VRI) of at least about 99%, as measured in accordance with the test method described in the specification. U.S. Pat. No. 4,898,676 by Horowitz discloses a method of using grafted activated carbon to remove bacteria from contaminated water. U.S. Pat. No. 6,989,101 by Cumberland et al. discloses activated carbon media filter for the removal of micro-organism from a medium. There are many research papers and published literature and books supporting the concept of pathogen adsorption by activated carbon and by porous polymeric resins of Styrenic matrix.
When platelets are needed for re-infusion, they are pumped out of the bag with the plasma by gravity or by a pump such as peristaltic pump. The bacteria and viruses that crossed the sachet membrane and were absorbed by the media inside remain in the bag. Therefore, a lesser number of bacteria and viruses are mixed with the platelets when exiting the bag for re-infused. It is obvious that the more bacteria and viruses are absorbed by the media, the smaller their number is with the infused platelet product.
In most blood centers the bag containing the platelets is laid down on a shaker that is continuously agitated at a rate of 70 to 80 cycles per minute. The oscillation movement of the shaker flushes the plasma back and forth inside the bag. This flushing movement generates plasma current that flows in and out the sachet through the porous membrane. Bacteria, micro-organisms, viruses, cytokines, endotoxins, lipids, proteins, and other electrolytes flow through the porous membrane with the plasma, while the platelets and other cells are kept out of the sachet.
In a preferred embodiment the media contained in the sachet is made of activated carbon cloth having large surface area (700-2000 m2/g) being predominately microporous, that are commercially available. Bundles of very fine activated carbon fibers are used to weave or knit carbon cloth. The cloth can also be impregnated with chemical treatments to make more sensitive to adsorption of particular molecules. Electrostatic forces could be developed within the cloth to enhance its adsorbing efficiency. The cloth can be woven or knitted with different weights and thickness using fibers, nano-fibers, or nano tubes carbon. The cloth can be made out of felt with different weights and thickness. The media could also be made of particulate (beads, graduals) activated carbons sold by Calgon Carbon Corp. or Norit Americas Inc. (Marshall, Tex., USA). The media could also be made of activated carbon fibers and microfibers sold by Kureha (Tokyo, Japan), nano-fibers, or nano-tubes.
Activated carbon (AC) is adsorbent that is manufactured from a carbon based material. Some of the common carbonaceous substances used as raw materials to make activated carbon are coal lignite, sub-bituminous, and bituminous, coconut shell, petroleum cock, and petroleum pitch. Activated carbon is widely used for water purification applications. Different micro-organism, organic compounds, viruses, bacteria, cysts, volatile organic chemicals are treated by activated carbon. There are many literatures describing the effective use of activated carbon in contamination treatments.
Activated carbons (AC) remove bacteria from the aqueous medium through attractive Van der Waals forces. The AC can also be electrostatic positively or negatively charged to attract ionically charged endotoxins, cytokins, or bacteria membrane.
The sachet in the preferred embodiment is made of expanded polytetrafluoroethylene (ePTFE) membrane that is sold by (W. L. Gore & Associates, Inc. Newark, Del., USA) with such a porosity that allows plasma, bacteria, viruses, and prion to pass through. Types of bacteria include but not restricted to Streptococcus pneumonia, Streptococcus, Staphylococcus, Staphylococcus aureus, Escherichia coli, Bacillus, Klebsiella, Serratia, Corynebacteria diphtheria, Mycobacterium tuberculosis, and Chiamydia Pneumonia. Types of viruses include but not restricted to Poxvirus-Variola, Parainfluenza, Respiratory Syncytial, Varicellazoster, HIV, HCV, SARS, Adenovirus, CMV, Togavirus, Echovirus, Rhinovirus, and Parovirus.
In another embodiment, the adsorbent media is made of porous polystyrene resin commercially known as Purolite (Bala Cynwyd, Pa., USA) Large family of polystyrene resins with high BET surface area and high porosity. Some of these resins that are used for this application are PAD550, PAD600, and PAD900. Another family of Purolite resins commercially known as Macronet with resins MN200 and MN400. Another family of porous polystyrene resins is Amberlite XAD16, XAD4, XAD1180, XAD1600, XAD16HP (Rohm and Haas Company, Philadelphia, Pa., USA). Another polymeric adsorbent media that could be used in this embodiment is Dowex optipore L493 supplied by Dow Chemical Company. This porous media has a BET surface area of 400 m2/g to 1300 m2/g is capable to adsorb bacteria and viruses in a fluid environment.
In addition to their porosity and large (BET) surface area characteristics, these resins could also have ion exchange characteristics. Ion exchange resins are classified as cation exchangers, that have positively charged mobile ions available for exchange, and anion exchangers, whose exchangeable ions are negatively charged. Both anion and cation resins are produced from the same basic organic polymers. Resins can be broadly classified as strong or weak acid cation exchangers or strong or weak base anion exchangers.
All these polymeric particulate resins come in spherical shape of different diameter ranging between (0.2 mm to 2 mm) which are too large to penetrate through the sachet membrane. Therefore these resin beads are captured inside the sachet and can not intermix with the platelets outside the sachet.
In other embodiment the sachet walls are coated with hydrogel layer that improves the hemocompatibility of the sachet surface. The hydrogels have thrombo-compatibility characteristics that prevent platelets adhesion to the sachet surface. The hydrogel could be made of material such as Poly (Hydroxyethyl Methacrylate), 2-Hydroxyethyl Methacrylate, or Poly-HEMA also known by CAS Number 25249-16-5. Different classifications of hydrogel based on ionic charges such as anionic, cationic, ampholytic, and neutral hydrogel can be used. Different classifications of hydrogel based on structure such as amorphous, semi-crystalline, and hydrogen-bonded hydrogel can be used. The hydrogel also can be made of Poly (Vinyl alcohol), Poly (N-vinyl 2-pyrrolidone), and Poly (ethylene glycol).
Hydrogel coating of the sachet walls allows for the use of a membrane with porosities that are greater than the size of the platelets.
The sachet Microporous membrane material could be any of the following material but not restricted to Polyethersulfone (PES), Polyester, Polysulfone, Polyvinylidene flouride (PVDF), Nylon, Polytetraflourethylene (PTFE), Cellulose acetate, and Polypropylene.
It should be known that this invention is not restricted to platelet storage bag. It also can be used for concentrated red blood cell (concentrated RBC) storage bag, white blood cell (Leukocytes) storage bag, plasma storage bag, whole blood storage bag, or any combination of RBC, platelets, leukocyets, and plasma.
The porosity of the sachet membrane is selected in accordance with the cell size that is prevented from crossing through the membrane. For example leukocytes are spherical with diameter size (10 μm to 12 μm), RBC size is (7 μm Diameter and 2 μm thick), and Platelets are disc shape with (2 μm to 4 μm) in size. The sachet membrane porosity used in the leukocyte storage bag is larger than the membrane porosity used for the RBC storage bag. The sachet membrane porosity used for the RBC storage bag is larger than the membrane porosity used for the platelets storage bag. The porosity of the sachet membrane used for the whole blood should prevent all cells from passing through, therefore the porosity size should selected to prevent the smallest cell which is the platelet from passing through.
The adsorbent media inside the sachet can be selected from the family of porous polymer resins, activated carbon particulates, or activated carbon cloth. The adsorbent media could be any combination of these activated carbon and porous polymer resins.
In some cases the adsorbent media biocompatibility characteristics can be enhanced by coating the surface. One of the coating techniques known in the industry is hydrogel. One of very well known hydrogel is Poly-HEMA, PHEMA, or Poly (2-hydroxyethyl methacrylate). Other kinds of hydrogel such as Polyvinyl Alcohol (PVA), Polyethylene Glycol (PEG), Polyvinyl pyrrolidone, and Ethylene glycol dimethacrylate (EGDMA) can be used. Other coating techniques that could be used to enhance the biocompatibility characteristics of the adsorbent carbon or resins are Cellulose, Silicone, and Poly-Methyl Methacrylate (PMMA).
Based on the foregoing, an object of the present invention is to provide an improved passive storage system for blood products and more particularly for platelet concentrate for removing contaminants and pathogens from the transfused platelets. A specific object includes providing passive storage system comprising activated carbon fibers which removes a broad spectrum of contaminants, including very small microorganisms such as bacteriophage to much larger pathogens such as E. coli bacteria. Furthermore the storage system comprising polymeric porous resins and ion exchange resins for the removal of pathogens from the transfused platelets.
Activated carbon and porous polymeric resins having a tendency to adsorb bacteria from solutions can be employed, thereby minimizing the risk of septicemia acquired in the course of a transfusion.
The removal of such pathogens from platelets concentrate using the present passive storage without any chemical additive is at a level not previously demonstrated by the prior art. Another object of the present invention is to provide a method of removing pathogens from blood products, particularly concentrated platelet, using the storage container of the present invention.
Another object of the invention is to provide an article of manufacture comprising the storage container of the present invention.
Another object of the present invention is that the in vivo shelf life of blood platelets can be extended beyond those currently attainable in the prior art by providing adsorbing activated carbon capable of supporting platelet metabolism.
Another object of the present invention is that the in vivo shelf life of blood platelets can be extended beyond those currently attainable in the prior art by providing adsorbing and ionic charged resin capable of supporting platelet metabolism.
Another object of the present invention is to provide a platelet storage system which promotes the preservation of the platelet morphology.
Another object of the present invention is to provide a platelet storage system which buffers the pH of stored platelets.
Another object of the present invention is to provide a platelet storage system which extends the functional life of platelets.
In a different embodiment of the invention, the blood or the blood components are not confined inside a container but rather they are flowing through a system of connecting tubes and containers. For example in apheresis system blood flows from a donor in a closed extracorporeal circuit to be processed by the system and then the blood or certain components of the blood return back to the donor. In this embodiment the blood flows through a mass of activated carbon or porous resin with or without ion exchange characteristics. As it is explained above in this study, the activated carbon and the porous resin capture bacteria, cytokines, endotoxins, and other micro-organisms and toxins that are suspended in the blood. When blood passes through a mass of ionic exchange resin, different types of ions suspended in the blood are captured by the resin.
More specifically, when blood is drawn from an apheresis donor it is mixed with anticoagulant in order to avoid clotting. Depending on the type of the anticoagulant there is a defined ratio for mixing the anticoagulant with blood. The mixture of blood and anticoagulant is called anticoagulated blood. After processing of the anticoagulated blood by the apheresis system, some blood components (Plasma, RBC, or Platelets) are stored in containers for future reinfusion. The rest of the blood components are returned to the donor. It is typical in apheresis procedure to process large amount of donor's blood (in the range of 5 to 6 liters) that flows continuously or in batches (depending on the Apheresis system) from the donor to the system and back again to the donor. The blood flows at a rate that is comfortable to the donor (in a range of 50 to 150 ml/minute) without violating the limit of the allowed extracorporeal volume of the blood. As the blood exits the vein of the donor it is immediately mixed with anticoagulant at a constant ratio. For example for apheresis the ratio is (1:16). As the blood is being processed, it is constantly mixed with anticoagulant. When the blood is returned back to the donor, a large amount of anticoagulant is infused into the donor. For an apheresis procedure that processes 5 liters of blood, more than 300 ml of anticoagulant with citrate content of (0.3 to 0.4 g/100 ml) is infused into the donor. In most cases this amount of citrated anticoagulant causes discomfort to the donor, especially after long apheresis procedures. Approved anticoagulant-preservatives include acid-citrate-dextrose solution (ACD), citrate-phosphate-dextrose solution (CPD), citrate-phosphate-dextrose-dextrose solution (CP2D), and citrate-phosphate-dextrose-adenine solution (CPDA-1). Removing the anticoagulant from the blood that is returned to the donors would increase their level of comfort. Directing the returned blood to pass through a chamber containing ionic exchange resins would help in removing citrate from the blood before it is infused into the donor. More specifically a chamber containing anion exchange resin can remove citrate from the blood. Anion exchange resins, i.e., those possessing functional groups which can undergo reactions with anions in a surrounding solution, particularly weakly basic anion exchange resins, are preferred. Such resins are formed of Styrenic or Acrylic porous matrix with high mechanical stability. Such resins used in the present invention with apheresis systems have the additional properties of adsorbing acids from organic reaction mixtures, exchanging anions in a slightly acidic media, a high exchange capacity, low swelling properties and a tendency to adsorb bacteria from the surrounding solution are particularly advantageous. The anion exchange resin may be used alone or in combination with other anion and/or cation exchange resins suitable for the intended purpose. Weak Base Anion Exchanger resins are commercially available under the trade name of Amberlite IRA92 or IRA96 from Rohm & Haas Company, Macroporous Polystyrenic Purolite A100 and A835 from Purolite, and Dowex MWA-1 or Dowex M43 from Dow Chemical.
In another embodiment of the present invention a strong base anion exchanger resins such as Purolite A500 and A510 from Purolite are used to extract acidic solution such as citrate from the returned blood.
In another embodiment of the present invention activated carbon is used to extract acidic solution such as citrate from the returned blood.
In another embodiment of the present invention different combinations of activated carbon, weak base anion resin, and strong base anion resin are used to extract acidic solution such as citrate from the returned blood.
In another embodiment adsorbent porous resins with high BET surface area and high porosity such as PAD400 and PAD600 from Purolite, Amberlite XAD4 and XAD16 from Rohm and Haas, and Dowex L493 from Dow Chemical are used in the housing that is positioned on the blood return line. As the blood components are re-infused back into the donor, they are directed to pass through the housing containing the adsorbent porous resins. In most apheresis systems, as the blood is drawn from the donor, processed and returned back to the donor; few red blood cells (RBC) are hemolized (damaged) due to different stresses during the processing steps.
Hemolized RBC release hemoglobin to the plasma medium. The free hemoglobin could negatively affect the donor and especially damaging to the kidneys as it is re-infused back with the returned blood components. The adsorbent porous resins have the capacity to adsorb the free hemoglobin from the returned blood components flow. Therefore preventing the free hemoglobin from being re-infused back into the donor.
In another embodiment activated carbon cloth or activated carbon particulates are used in the housing that is positioned on the return line to adsorb the free hemoglobin from the returned blood products before they are re-infused back into the donor. The activated carbon can be used in this housing with or without the adsorbent porous resins.
Citrate is used as anticoagulation in apheresis or dialysis applications. When blood is drawn from a subject and mixed with anticoagulant to be cycled in an extracorporeal circuit repeatedly, the anticoagulant concentration increases in the body of the subject. In platelet pheresis the mean plasma citrate concentration in the donor progressively increase during the apheresis application and reach up to a median of 1.6×10−3 Mole (1.6 mM). This leads to a decrease in ionized calcium. The ionized calcium level drop from the base line can reach 33% on average. This can lead to symptoms of citrate toxicity such as paresthesias (predominantly perioral and acral), light-headedness, tremor and shivering. Hypocalcaemia may cause vascular smooth muscle relaxation, depressed myocardial function, arrhythmia and chronic metabolic (late) effects of citrate (e.g. bone demineralization). Prophylactic oral calcium was associated with only modest improvements in these citrate-induced symptoms.
Citrate also binds magnesium. Citrate administration during dialysis or apheresis applications decrease ionized magnesium by about 30%. This can cause symptoms such as muscle weakness, muscle spasms and impaired myocardial contractility. Steady-state plasma ionized calcium levels inversely correlate with the QT interval. In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. Prolongation of the QTc interval during plateletpheresis is a general finding. It can be considered as a sensitive marker of citrate toxicity at the myocardial tissue level. Citrate infusion has been associated with drop in blood pressure, decreased cardiac output and cardiac arrest.
Patients subjected to hemodialysis and hemofiltartion processes where their blood is circulated in an extracorporeal circuit are induced with citrate that is used to anticoagulate the blood during dialysis operation. Platelets donors and two red blood cell units (2 RBC units) donors are induced with citrate that is used to anticoagulate the blood during apheresis application. Dialysis patients and repeated apheresis donors are exposed to citrate that discomfort them and expose them to long term cardiology problems. Having a device and a method to extract the citrate from the anticoagulated blood just before it is reinfused into the patient's or the donor's body. The citrate filter (anticoagulant filter) is positioned downstream of the extracorporeal circuit (EC) and very close to the reinfusion site. This is done to ensure that the blood is perfectly anticoagulated while it circulates in the EC. The citrate is extracted by the anticoagulant filter (citrate filter) at the vicinity of the reinfusion site to minimize the path of the anticoagulant free blood flow. A filter screen can be added between the anticoagulant filter and the reinfusion site for safety purposes to prevent any inadvertent clot or any loose filtration (ion exchange resin) particulates from being re-infused.
It should be noted that the extracorporeal circuit for the dialysis system or for any apheresis system (2 RBC units or Platelets) can be modified to have a bypass channel to direct the blood flow around the anticoagulant filter. This is important especially for the dialysis or the apheresis systems that utilize the batch (non-continuous) processing, and also for the systems that utilize the same venipuncture site for blood draw and reinfusion. In this case the majority of the blood (or blood products) returning to the human subject is directed through the anticoagulant filter (citrate filter) to extract the citrate, the last chunk (small volume) of the blood is directed to bypass the filter. This is done in order to keep the section of the extracorporeal circuit between the anticoagulant filter and the venipuncture site; filled with coagulated blood toward the end of the batching procedure to prevent any clotting in case the blood (or blood products) flow is stopped. In other cases, the section of the extracorporeal circuit between the anticoagulant filter and the venipuncture site; is flushed with saline (or other therapeutic solution). This is done toward the end of the batching procedure to prevent any clotting in case the blood (or blood products) flow is stopped. In this case, the circuit section post anticoagulant filter is filled with saline when the batch procedure is stopped. Therefore, no clotting can occur in the post anticoagulant filter section.
Further aspects, features and advantages of the present invention will become more fully apparent from the following description of specific embodiments, the attached drawings and the appended claims; to those skilled in the art to which this invention pertains.
The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention.
FIG. 1A—A schematic top view of the storage container demonstrating the activated carbon cloth enveloped inside a porous sachet.
FIG. 1B—A schematic top view of the storage container demonstrating the activated carbon cloth enveloped inside a porous sachet having structural beams.
FIG. 2A—A schematic side view of the storage container demonstrating the activated carbon cloth enveloped inside a porous sachet.
FIG. 2B—A schematic side view of the storage container demonstrating the activated carbon cloth enveloped inside a porous sachet having structural beams.
FIG. 3—A schematic side view of the storage container demonstrating the activated media particulates inside meshed pockets that are attached to the activated carbon cloth with the whole assembly enveloped inside a porous sachet.
FIG. 4—A schematic side view of the storage container demonstrating the activated media particulates stored inside an activated carbon cloth packet that is enveloped inside a porous sachet.
FIG. 5—A schematic side view of the storage container demonstrating the activated media particulates inside a meshed packet that lies besides an activated carbon cloth with the whole assembly is covered by a porous sachet.
FIG. 6—A schematic side view of the storage container demonstrating activated media particulates inside a meshed packet that is covered by a porous sachet.
FIG. 7—A schematic view of the blood circuit between a donor and apheresis system (two needles access) demonstrating the resin chamber on the blood return line.
FIG. 8—A schematic view of the blood circuit between a donor and apheresis system (one needle access) demonstrating the resin chamber on the blood return line.
FIG. 9—A schematic view of the resin chamber with a pouch containing adsorbent resin.
FIG. 10—A schematic view of the resin chamber with screens.
FIG. 11—Schematic view of extracorporeal circuit with free hemoglobin filter.
FIG. 12—Free hemoglobin/Prion filter with a pouch containing adsorbent resin.
FIG. 13—Free hemoglobin/Prion filter with screens.
FIG. 14—Free hemoglobin/Prion filter with structured adsorbent media.
FIG. 15—Blood Reservoir with adsorbent capacity.
FIG. 16—Platelet storage container having loose or pouched adsorbent media.
FIG. 17—Platelet storage container built with compartments encapsulating adsorbent media or activated carbon.
FIG. 18—Platelet storage container having at least one zone containing adsorbent media separated by porous membrane from a zone that contain platelets.
FIG. 20—Schematic view of extracorporeal circuit with anticoagulant filter bypass.
FIGS. 21A & 21B—Platelet storage container with integrated tubing set.
It should be apparent to those skilled in the art to which the present invention pertains that a number of techniques can be employed to provide means that improves platelet concentrate storage conditions by maintaining the level of the pH in the solution, and reducing the pathogen count in the transfused product. These improving means can also apply to other blood products.
Referring to
In blood banks, platelet rich plasma or concentrated platelet solution are introduced in the storage container that is placed on a shaking platform at 22° C. The storage container 30 in the current invention receives the concentrated platelet solution in a normal way and the container is placed on a shaker with a constant horizontal agitation at approximately 70 to 80 cycles per minute and at 22° C. The concentrated platelet solution that is mainly a mixture of platelets and plasma move inside the container due to the platform movement. This movement generates plasma flow between the two zones in and out of the sachet through the porous membrane 42. Plasma can flow through the porous membrane. Bacteria, viruses, cytokines, toxins, endotoxins, and other micro-organisms that are suspended in the plasma, flow through the membrane as well. The porosity size of the membrane allow for these pathogens to pass through and enter in to the sachet. The Platelets have a larger size of the membrane pores therefore; they cannot enter inside the sachet. The pathogens that enter the sachet come in contact with the adsorbent media which is made of activated carbon cloth. The adsorbent media is made of activated carbon fibers that have very large surface area. The pathogens stick to the surface of the adsorbent media and become captured inside the sachet. Platelets and other blood cells inside the storage container, remain in the area outside the sachet. As the pathogens enter the sachet and become trapped inside, they are readily separated from the platelet concentrate. Therefore the number of the pathogens in the platelet concentrate drop. When the concentrated platelets solution is used for transfusion, it has a lower population of pathogens. In another embodiment of the invention, other adsorptive particulates are added to the activated carbon cloth to increase the adsorption capacity of the media inside the sachet. Referring to
For use in the platelet storage system of the present invention, anion exchange resins, and more particularly weakly basic anion exchange resins, are preferred. These weakly basic resin exhibit minimum exchange capacity above a pH of 7.0 and are good to experience reactions with anions where they only adsorb acids from the surrounding medium. Such resins which have the additional properties of adsorbing acids from organic reaction mixtures, exchanging anions in a slightly acidic media, a high exchange capacity, low swelling properties and a tendency to adsorb bacteria from the surrounding solution are particularly advantageous. Glucose in the platelet concentrate solution starts to metabolize. In case of insufficient oxygen supply to the storage bag, glucose is metabolized anaerobically resulting in the production of lactic acid. The excess generation of this lactic acid causes a drop in the stored solution pH. If the pH level drops from 6.8 to 6.0, the platelets progressively change shape from discs to spheres. If the pH falls below 6.0, then platelets become nonviable after infusion in vivo. The presence of the anionic exchange resin in the storage bag and its capability in adsorbing the lactic acid from the medium, it neutralizes the pH in the solution and establishes a favorable environment for the platelets. Therefore the platelets remain viable and effective for post storage in vivo infusion. Such resins are commercially available under the trade name of Amberlite from Rohm & Haas Company, weakly basic, polystyrene-polyamine type anion exchange resin having a styrene-divinylbenzene matrix. Other commercially available ion exchange resins are Purosorb and Macronet from Purolite and Dowex from Dow Chemical.
In another embodiment of the invention, adsorbent particulates are amassed in a pouch made of the activated carbon cloth that is inserted in a sachet inside the storage container. Referring to
In another embodiment demonstrated in
In a new embodiment of the platelet storage container 30 is depicted in
The micro-porous membrane 42 material could be any of the following material but not restricted to Polyethersulfone (PES), Polyester, Polysulfone, Polyvinylidene flouride (PVDF), Nylon, Polytetraflourethylene (PTFE), Cellulose acetate, and Polypropylene. It is preferred to have the membrane 42 made of material that is biocompatible to prevent thrombosis and greatly minimizes platelet activation and platelet adhesion to its surface. In some cases the micro-porous membrane 42 can be made of the same material of the outer wall 32. This membrane could have large number of small pores of size (1 μm or 2 μm) that are drilled through the membrane. Some pore holes could be drilled by laser beams. The micro-porous membrane 42 could be coated with hydrogel layer that improves the hemocompatibility of the surface. The hydrogels have thrombo-compatibility characteristics that prevent platelets activation and platelets adhesion to the sachet surface. The membrane 42 can be coated with silicone or cellulose to improve the biocompatibility characteristics of its surface. It is recommended to maintain the surface area of the membrane 42 to the minimum possible area to reduce the effect of thrombosis, platelets activation, and platelets adhesion.
The porosities of membrane 42 are selected to prevent platelets from passing through and entering inside the pouch or the zone where the adsorbent media is located. Similarly, the small pores of membrane 42 prevent any particulates of the adsorbent media that have the size equal to or larger than the platelets from mixing with the stored platelet solution. Adsorbent media particulate that is capable to pass through the porous membrane to mix with the platelet solution must be much smaller than the platelets. In case that the membrane porosity was selected to be (1 μm) then the size of the adsorbent particulate that passes through the membrane must be less than (1 μm). In general the size of the adsorbent particulates that pass through the membrane porosities must be smaller than the platelets. When these adsorbent particulates are floating in the platelet solution inside the storage container, they could come in contact with larger size platelets. Adsorbent media such as activated carbon or porous resin has light density generally about (0.55 g/ml+/−0.15 g/ml). In case of activated carbon the density can be as low as 0.15 g/ml. The platelets have the density about (1 g/ml). The adsorbent particulate that passes through the membrane would have a size smaller than the platelets and a density about half of the density of the platelets. These adsorbent particulate could not provide a large enough surface for the platelets to adhere to. Also, the mass of each of these particulates is less than the mass of a single platelet cell. The low density adsorbent particulates float on the surface of the fluid inside that container while the platelets are suspended in the fluid. This phenomenon contributes in avoiding contacts between adsorbent particulates and platelets, therefore minimizing platelets activation. It is recommended to wash the adsorbent media thoroughly before it is assembled in platelet storage container. Ultrasonic cleaning can be used to eliminate all small particles and dust residue generated from the adsorbent media. Cleaning can take place for the adsorbent media by itself first, and then another cleaning step can take place after the media is sealed inside the sachet. In this last step the whole sachet with the media inside it are cleaned by ultrasonic cleaner.
The adsorbent media and particularly the activated carbon media is thoroughly cleaned before it is built in the storage container. These media are cleaned in order to eliminate any dust or particulates that could break free and slip through the porous membrane 42 to come in contact with the platelets or other blood cells. The adsorbent media and the activated carbon media are ultrasonically cleaned in de-ionized solution, Ethanol, or Alcohol solutions. The edge of the activated carbon cloth 35 are sealed by Hydrogel, Silicone, PMMA, or Paraffin wax in order to prevent any dust generation or breaking away of any particulate from the edge where the cloth is cut. The edge sealing concept is used to protect the carbon matrix structure.
The pouch 40 containing the adsorbent media can be welded to the container wall 32. A weld 55 is used to fixate the pouch 40 inside the container 30 in order to prevent it from moving loosely while the container is agitated or placed on a moving platform, as shown in
The platelet container of the current invention was tested for bacterial contamination with respect to standard platelet bags used in the industry; at Bioscience Research Associates, Inc (BSR), 767C Concord Avenue, Cambridge, Mass. 02138, USA. The testing design included two containers of the current invention, one standard platelet bag for positive control, and one standard platelet bag for negative control. All containers were filled by 80 ml of human platelet concentrate. Two platelet containers of the current invention with a standard platelet bag used as a positive control were induced by 120 CFU/ml of Staphylococcus Aureus bacteria (CFU: Colony-Forming Unit). All bags and containers were placed on shakers (60 to 80 cycles per minute) at room temperature (22° C.). Bacteria culture test were conducted on samples taken from these bags and containers after 5 days and 7 days of storage. (See Table 1)
These results indicate that the current invention container can completely eliminate Staphylococcus Aureus bacteria from platelet concentrate after 5 days storage. The Staphylococcus Aureus bacteria are the most common bacteria that are found in blood products. These bacteria are originated from the skin surface of the donor and are transmitted to the blood bag by the needle venipuncture. Bacteria count on day 7 for the current invention platelet container is very minimal. One container has zero (0) bacteria and the second container has less than 3,000 CFU/ml. The threshold detection limit for the Verax Biomedical Inc. (Worcester, Mass., USA) testing kit for the Staphylococcus Aureus bacteria is (8.3×103 CFU/ml) after 5 days storage. The Verax PGD testing kit was approved by the FDA for testing for bacteria presence in platelet concentrate product stored for up to 5 days at 22° C. The bacteria counts in platelet concentrate stored for seven days in the current invention containers are well below the threshold limit for Verax system that was approved by the FDA after 5 days storage
In another embodiment of the current invention of the storage container is that adsorbent matrix 88 is placed inside the container 32 without having a membrane 40 to prevent the blood cells from contacting the adsorbent media as shown in
In another embodiment of the current invention of the storage container is that adsorbent media 75 are placed loosely inside the container 32 without having a membrane 40 to prevent the blood cells from contacting the adsorbent media as shown in
In another embodiment of the current invention of the storage container is that adsorbent media 75 are packed inside a pouch made of membrane 85 with porosity large enough to allow all blood cells to pass through but preventing any media particulate from exiting the pouch as shown in
In another embodiment of the current invention of the storage container is that the adsorbent carbon cloths 35 are placed loosely inside the container 32 without having a membrane 40 to prevent the blood cells from contacting the adsorbent media as shown in
The pouch can also be made of multi-layered membrane of different materials with different porosities. Each layer of the pouch can be made of sections of different membrane with different porosities. Some sections of the pouch could be made of biocompatibility materials with no porosity.
Referring to
Referring to
Another embodiment of the current invention of the blood products storage container is illustrated in
Another embodiment of the current invention of the blood products storage container is illustrated in
The storage container 30 can be integrated with any apheresis plastic disposable extracorporeal circuit. The container 30 can be also integrated with any dialysis plastic disposable extracorporeal circuit. Referring to
Referring to AABB (American Association of Blood Banks) Technical Manual 17th edition, the approved types of anticoagulants, their ratio to collected blood, and composition are listed in Table 2.
Referring to
Whole blood or concentrated red blood cell (RBC) are stored at (4° C.) for up to 42 days. Some of the red blood cells are hemolized or destroyed during storage causing the release of the intracellular hemoglobin to be mixed with the medium solution that is mostly plasma and some additive solution (glucose). When the blood is transfused to the patient, the free hemoglobin that was mixed with the plasma is infused into the patient body causing kidney toxicity. This problem is intensified with massive transfusion of many blood units or transfusion of aged blood. Therefore the removal of the free hemoglobin from the transfused blood to the patient would prevent serious complications that include multi-organ dysfunction, respiratory and renal insufficiency, and death.
It should be noted that filter 200 can also be used to extract prion from blood or blood product flow. Filter 200 also defined as “Prion Filter” removes Prion from blood. A prion is an infectious agent that is composed primarily of protein. Usually found in a mis-folded protein state. Prion has been implicated in a number of diseases in a variety of mammals. Human Prion Diseases are Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia, and Kuru. Animal Prion Diseases are Bovine Spongiform Encephalopathy (BSE), Chronic Wasting Disease (CWD), Scrapie, Transmissible mink encephalopathy, Feline spongiform encephalopathy, Ungulate spongiform encephalopathy. All known prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and are always fatal.
In another embodiment, porous resin particulates 120 can be used instead of the AC media inside the filter 200 to extract the free hemoglobin from the infused blood.
In another embodiment, porous resin particulates 120 can be used instead of the AC media inside the filter 200 to extract the free hemoglobin from the infused blood.
The adsorbent media (AC 140 or resin 120) could be coated with biocompatible layer such as hydrogel (pHEMA, PEG, or PVP), cellulose, silicone, or PMMA. The activated carbon 140 could be particulates, powder, pellets, spheres, rods, tubes, channels, chips, or cloth; coated or uncoated. The activated carbon could be impregnated with Silver, Zinc, or other materials to enhance its bactericide characteristics. The activated carbon could be coated with commonly used Silver Nitrate as antibacterial coating agent. The resin 120 could be styrene resin, Acrylic resins, ion exchange resins, or other porous resin.
When stored blood units are added to the reservoir, the adsorbent media inside the reservoir extract the free hemoglobin from the blood. It is very common to have free hemoglobin mixed with the plasma of the stored red blood cell (RBC) concentrate units or whole blood units. As the whole blood or RBC concentrate unit is stored on shelves inside refrigerators at about 4° C., few red blood cells start to hemolize (damage to the cell membrane). The longer the blood is stored the more the possibility for the RBC to be hemolized. A 42 days aged blood unit could have considerable free hemoglobin (hemolysis) in it. Blood is salvaged by suction means during surgery (intra-operative) or by wound drainage means during recovery (post operative). The salvage blood is collected in reservoir to be re-infused back into the autologous patient. In some cases, salvaged blood is washed prior infusion to get rid of clots, lipid, and debris. Blood washing also helps in getting rid of the free hemoglobin. In other cases, salvaged blood is not washed. It is only filtered prior infusion by a screen mesh membrane to get rid of clots, lipid, and debris. When blood is salvaged by suction, the negative pressure gradient causes the blood cell to be hemolized. The suction pressure destroys the RBC and hence it generates high free hemoglobin levels. The same can be said about wound drainage where RBC cells have to flow in narrow perforated paths causing the cells to be destroyed.
The free hemoglobin filter of the current invention aims to reduce the risks associated with the transfusion of aged blood units. The hemoglobin adsorbent chamber of the current invention aims to reduce the risks associated with salvaged blood transfusion. The salvaged blood is the autologous blood that is collected from the bleeding patients during surgery (intra-operative) or during the recovery of surgery (post-operative). The blood is salvaged by wound suction or drainage and storing the blood in a temporary reservoir to be washed by special systems (such as Haemonetics, Braintree, Mass., USA; Cell Saver System) or to be filtered (not washed) before returning the blood to the patient. “Sangvia system” for intra-operative collection and reinfusion of autologous whole blood without washing is marketed by Wellspect HealthCare Company (P.O. Box 14, SE-431 21 Mölndal, Sweden). Another example of autologous blood salvage system that does not have the capability to wash the free hemoglobin from the salvaged blood is the “CBCII Blood Conservation System—ConstaVac” from Stryker (400 East Milham Avenue, Kalamazoo, Mich. 49001, USA).
The hemoglobin adsorbent chamber of the current invention aims to reduce the risks associated with massive blood transfusion of about 10 units or more of concentrated red blood cell units in 24 hours period. Massive blood transfusion is defined as the replacement of 50% of patient's blood volume in 12 to 24 hours. With the transfusion of such a large volume of blood in a short time leads to the infusion of a large volume of free hemoglobin that intoxicates the kidneys that causes death to the patient.
Having now described a few embodiments of the invention, it should be apparent to those skilled in the art that the foregoing is merely illustrative and not limiting, having been presented by way of example only. Numerous modifications and other embodiments are within the scope of ordinary skill in the art and are contemplated as falling within the scope of the invention as defined by the appended claims and equivalents thereto. The contents of all references, issued patents, and published patent applications cited throughout this application are hereby incorporated by reference. The appropriate components, processes, and methods of those patents, applications and other documents may be selected for the present invention and embodiments thereof.
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13711613 | Dec 2012 | US |
| Child | 14105045 | US |
