The water activity (aw) of a material is primarily dependent on the characteristic water content of the material in its native state and on the nature and kind of components that comprise the material. The manner in which the components of the hydrated material interact with water is also relevant to water activity. In regard to certain biologically important products, such as blood component products (red blood cells, platelets, plasma, hemoglobin, etc.), the water activity level greatly affects the susceptibility of the material to the growth of bacteria and molds.
It has been found that organisms struggle to grow at water activities less than 0.9. Enzyme activity has also been reported to decrease significantly below a water activity of about 0.9. Therefore, a major goal in preserving cellular and/or potentially perishable materials and an aspect of the present invention is to achieve a reduction of the water activity of the sample to at least about 0.9 or below. In this manner, microbial growth may be reduced and/or inhibited, and enzymatic activity in the material may be reduced.
Maintenance and distribution of adequate perishable supplies of foodstuffs, pharmaceuticals and biological products, such as blood and blood components, have historically constituted a significant problem in societies around the world.
In the case of perishable and necessary biological products, such as blood, a recent study reports that current methods of storing blood products compromises the blood unit in such a way as to increase risk of serious side-effects in coronary patients. In one study (Relationship of Blood Transfusion and Clinical Outcomes in Patients with Acute Coronary Syndromes, Rao et. al., JAMA, 2004, 1555-1562), 24, 112 patients characterized as having acute coronary syndromes, and grouped according to whether they received transfusions of red blood cells during hospitalization, were examined. Of these patients, 2,401 (10.0%) received at least one stored red blood cell unit. This group was reported to have a higher 30-day mortality and a higher occurrence of myocardial infarction than the group that received no transfusion. The reason for this increased mortality and morbidity is unclear, but may at least in part be due to a phenomenon known as “storage lesion” formation. Specifically, the stored red blood cells used in these transfusions may have had altered nitric oxide biology and reduced 2,3, diphosphoglycerate levels, resulting in higher oxygen affinity hemoglobin, as well as an increase in inflammatory mediators.
This study illustrates the profound effect that the phenomena known as “storage lesions” associated with conventional collection and storage has on a large percentage of coronary patients, and the urgent need for improving these techniques.
Using conventional collection techniques, the maximum storage time for red blood cells at 1-6° C. is 42 days. During this relatively short storage time, storage lesions develop that significantly affect the function of RBCs. The RBC changes that occur as a consequence of the formation of storage lesions include decreased 2,3-diphosphoglycerate, decreased ATP, increased potassium, decreased cell viability, and decreased pH. The shelf life of RBCs is determined as a measure of the number of days a collected unit of RBCs can be stored and retain a viability of at least 75% of the number of infused RBCs in circulation in the patient 24 hours after transfusion of the stored unit. Using conventional preparation and storage methods, the shelf life of a unit of whole blood is about 21 days.
The current shelf life of red blood cells, leukoreduced (having a residual leukocyte content less than 5×106) is about 42 days. The shelf life for washed red blood cells and for deglycerolized red blood cells is about 24 hours. The shelf life of fresh frozen plasma is one-year. The shelf life for leukoreduced random donor platelets as well as for leukoreduced single donor platelets (apheresis platelets) is about 5 days. (American Red Cross, Hospital Resource Center, Products, December 2004).
In addition to difficulties associated with the relatively short shelf life of stored blood products, the current requirement that these units be stored under refrigerated conditions still leaves blood supplies subject to potential bacterial contamination. Even an incremental increase in the standard shelf life and/or increase in the range of acceptable storage conditions/temperatures required to maintain viable biological and pharmaceutical products would present a significant advantage in these industries.
Fresh frozen plasma (FFP) is primarily indicated for patients with active or threatened bleeding who need short-term correction of coagulation factor deficiencies. For the average adult, each unit raises clotting factor levels 2-3%. More than two units are usually needed for replacement therapy. FFP alone should not be used for volume replacement. Each unit of FFP contains 200 to 225 ml of plasma derived from a single whole blood unit, and is frozen at −18° C. or colder in order to preserve the labile factors V and VIII at hemostatic levels. FFP also contains a variety of stable proteins involved in the complement and fibrinolytic systems, in the maintenance of oncotic pressure and in the modulation of immunity. Units of FFP are labeled specifically for the ABO blood type of the donor from whom they are prepared. Each unit is also tested for the presence of syphilis, hepatitis B, hepatitis C, HTLV-1, HIV-1 and HIV-2. This testing and labeling protocol is also characteristic of the procedure used for red blood cells and platelets.
Another major indication for FFP is as a replacement therapy for documented single or multiple coagulation factor deficiencies. Documentation may be by direct measurement of clotting factor levels or by prolongation of the prothrombin time (PT) or activated partial thromboplastin time (PIT). Other indications are for thrombotic thrombocytopenic purpura (TTP) and during massive blood transfusion (>1 blood volume within 24 hours). FFP may be used for patients having a coumadin overdose or that suffer from hereditary antithrombin III deficiency or hereditary protein C deficiency. However, prothrombin complex or antithrombin III concentrates may be the therapy of choice depending on availability and the specific clinical situation. The use of FFP for the treatment of selected immunodeficiencies has been replaced by intravenous immunoglobulin preparations.
The dose of FFP for coagulopathies should be determined by the amount required to adequately replace deficient clotting factor levels or to correct the PT and APTT. The average adult will require at least 3-4 units of FFP as replacement therapy. Administering 3-4 units of FFP will usually raise levels of each clotting factor level into the hemostatic range, which is 20-40% of normal depending on the clotting factor or factors involved.
As with any blood product, infusion of FFP requires a standard blood administration set. If the patient's circulatory status permits, FFP may be rapidly infused over 20-30 minutes. Depending on the blood type of the donor, FFP may contain A or B antibodies. Therefore, type specific or type compatible plasma is required. Thawing of FFP requires 30 minutes or more, and the unit must be administered within six hours of thawing.
Problems associated with the use of stored blood products include allergic reactions and viral contamination. For example, allergic reactions occur in about 1% of patients receiving FFP. These allergic reactions usually consist of pruritus or hives, which typically respond to treatment with antihistamines. However, rare fatal anaphylactic reactions have been reported. Most of these reactions are related to a specific donor unit and do not preclude further FFP use. The risks of viral transmission from FFP are similar to those for red cells and platelets. However, there is probably no risk of transmission of CMV or HTLV-1 since these viruses require cellular vectors for transmission. Circulatory overload occurs in many patients receiving large amounts of FFP due to the typically high volume of this product that is administered. This particular disadvantage limits the use of high volume FFP administration for patients with cardiac disease.
A recent development in blood component products has been the commercial introduction of pooled FFP. Up to 2500 units can be collected and processed to constitute a “pool” of plasma. Pooled FFP is plasma that has been treated with a solvent detergent prior to freezing in order to reduce the possibility of viral transmission by eliminating envelope viruses. While the solvent/detergent treatment process inactivates lipid-enveloped viruses, the process does not inactivate non-enveloped viruses. Therefore, medical heath risk from exposure to parvovirus B19, hepatitis A, and yet unidentified pathogens that might contaminate the pool, continue to exist.
Pooled FFP product is sold and used extensively in Europe and other countries outside the United States. A major disadvantage of blood bank or commercial FFP is the need to insure maintenance of the frozen state during storage and shipping. This creates major logistical problems and increases shipping and storage expense to assure that the product remains frozen during distribution and until use.
Stored platelet components also suffer from the effects of storage lesions. Formation of these lesions result in the release of alpha and dense granules, morphological changes to the cytoskeleton, altered surface proteins including receptors related to activation and aggregation, and loss of membrane asymmetry. All of these changes are associated with procoagulant activities of platelets, and represent degradation of the stored platelet's capacity to function normally, as well as exposing the patient to components with potentially adverse, thrombotic side effects. In addition, storage at 20° C. does not prevent growth of pathogenic organisms, thus exposing the patient to potential infectious agents.
Because of the several technical storage, degradation, and physiological phenomenon to which important and perishable products are affected, especially blood products and pharmaceutical agents, a major unmet need continues to exist for a process and/or processing system that would stabilize and extend the shelf life of these commodities. Such a process would preferably reduce the need for blood product to be stored at −18° C. and/or extend the shelf life of these products after thawing/defrosting. Currently, it is necessary to maintain a cold-chain distribution system for blood products that is cost effective and that satisfies logistically time-sensitive distribution criteria.
A societal need continues to exist for a perishable product collection and storage technique that would eliminate and/or reduce the various medical, pharmaceutical, and food preservative associated issues noted herein. The presently disclosed invention addresses these and other significant deficiencies in the art.
USPTO Backgrounds
USPTO Backgrounds