Abstract:
Metallic containers with high toughness characteristics are utilized to cryopreserve blood products and more particularly neonatal stem and progenitor cells at cryogenic temperatures. Metallic containers with high toughness and strength characteristics are durable at low temperatures and are capable to endure high stresses and impacts at −196° C. These containers are better fit to preserve blood products without compromising their sterility or their medical integrity. Methods for fabricating metallic containers are also disclosed.

Description:
FIELD OF THE INVENTION  
       [0001]     This Invention relates to cryopreservation of blood or blood components at cryogenic temperatures.  
       BACKGROUND OF THE INVENTION  
       [0002]     It has been known in blood bank industry that long-term storage of blood components can be achieved at cryogenic temperature. Plasma can be stored for one year at −18° C. to be thawed and used for therapeutic applications. Concentrated red blood cells (RBC) treated with glycerol can be stored for 10 years at −70° C. to be used again. Recently, a new technique has been established to cryopreserve hematopoietic stem and progenitor cells of neonatal or fetal blood. These cells that have been cryopreserved and thawed can be used for autologous reconstitution. Hematopoietic stem cells treated with cryoprotectant fluids are expected to survive a long-term storage in liquid Nitrogen at −196° C.  
         [0003]     Throughout all these cryogenic preservation applications, plasma, RBC, or progenitor stem cells are stored in plastic bags of different shapes and sizes. The reliability of the plastic bag and its viability to withstand the cryogenic environment is very crucial for the sterility and the integrity of the preserved cells and fluids. It is known that materials become brittle at low temperatures well above that of liquid Nitrogen. Embrittled materials have the tendency to crack or fracture under impact. Thin plastic bags stored at cryogenic temperatures are very vulnerable to fracture and structural rupture. This conundrum is exasperated as the temperature is lowered and the exposure is prolonged.  
         [0004]     Fractured bags render its contents obsolete. This is very costly especially when hematopoietic stem and progenitor cells are involved. These cells are cryopreserved for many years to be used for autologous reconstitution. In most cases these cells are lifesavers when needed. Therefore there is a need for a robust and an absolutely reliable container that can safely preserve cells or fluids without compromising their sterility or integrity.  
       BRIEF DESCRIPTION OF THE INVENTION  
       [0005]     The present invention provides a container, which may be used for collecting and safely storing biological fluids, blood cells, and hematopoietic stem and progenitor cells at temperature ranging from normal body temperature to cryogenic liquid Nitrogen temperature. The container is fabricated of metal that characterized with high strength and high toughness to endure very low cryogenic temperature and to suppress any effect of the embrittlement. The container has the shape of a rectangular parallelepiped with a large flat base and a modest height. All edges are contoured with radius to eliminate high stress concentration spots on the container structure. The significant aspect ratio between the large flat base area and the thin profile of the container enhances the uniformity of phase changing process inside the container. The fine and uniform thickness of the sheet metal coupled with substantial thermal conductivity greatly improves the consistency of the freezing process. The container has sealable ports for channeling blood cells or biological fluids.  
         [0006]     In a preferred embodiment, the container is fabricated of Austenitic stainless steel sheet metal that characterizes with good toughness at cryogenic temperatures such as 304 and 316 type. This steel alloy contains a high concentration of nickel that greatly enhances its ability to withstand very low temperature environments. Titanium can also be used to fabricate the container, but the cost could be higher. Titanium has great characteristics in corrosion resistance. Stainless steel containers are widely used in automotive, household, food and beverages, electronics, and medical industries. For example the housing of a wide range of implantable devices such as Pace Makers or Drug Delivery implants are typically made of stainless steel.  
         [0007]     There are numerous methods of fabricating metallic containers. All these methods are based on processes such as stamping, forming, swaging, drawing, or pressing sheet metals into a specific shapes, then the shapes are joined by crimping, bonding, or welding. For the purpose of this invention, it is preferable to fabricate the metallic container by welding two previously formed half shells. A special tool is used to form the sheet metal in a half shell structure. The half shell having the shape of a shallow rectangle with a base referred to herein forward as planar surface merged by a radius to a surrounding wall referred to herein forward as sidewall. Two symmetrical half shells are matched and welded at the seam to construct a container. Fluid communication ports could be constructed as an integrated portion of the formed half shells. These integrated portions have the shape of half a cylinder sectioned by a plane along its longitudinal axis. When matching half shells are welded, these semicircular cylindrical shells form a tubular port at the edge of the container. Many tubular ports could be added to the container using this method.  
         [0008]     In another embodiment the metallic tubular ports could be welded to any location on the surface of the container after a matching hole is cut on the surface. Plastic tubing could be bonded to the tubular ports for sterile connection of the container to a blood collection bags set. Additionally, needle ports, or spike ports could be added to tubular ports as needed for any aseptic connection to the container.  
         [0009]     In a different embodiment the sidewall that surrounds the planar base on a formed half shell, are extended enough to achieve an overlap between the walls of matching half shells. The two half shells are lap welded and sealed at the overlap between the walls.  
         [0010]     In another preferred embodiment, the sidewall that surrounds the planar base on a formed half shell is terminated with a flat flange of a defined width. The flange circumscribes the wall and is situated in a plane that is parallel to and at a distance from the planar surface. Two symmetrical half shells are matched and welded at the flange forming a sealed container with defined ports. The matching flanges could be laser welded at the seam or heat resistance weld at the mating surfaces. The matching flanges could be brazed or bonded at the mating surfaces.  
         [0011]     In another preferred embodiment, plastic bushings are sealed bonded or heat welded to the metallic tubular ports to facilitate the bonding of plastic tubing, spike ports, or needle ports to the container.  
         [0012]     In another embodiment, the container internal surface is coated by a polymer such as silicone or laminated by a polymeric liner to add another protective layer to the container and to broaden the metal alloy selection.  
         [0013]     It is common in blood bank industry to separate different blood products derived from one collected unit of blood. These products are stored in different containers and each container is labeled per FDA regulations and American Society of Blood Banks (AABB) standards. When blood products derived from one donor, are preserved for long-term storage, it is recommended to use more than one storage chamber. This is done in anticipation that a portion of the product can be used in the future and still keeping another portion in safe storage for potential use. It is also recommended that these stored portions are maintained in physically connected but safely separable containers. This invention provides a way of having metallic containers connected by breakable joints. These connected containers used to store blood products can be safely separated without compromising the sterility of the stored products, by simply breaking the joints in between. The invention also provides a holder that securely clinches on two or more containers to maintain them physically united. These containers can be safely separated by breaking the holder at specified breakable spots without compromising the sterility of the stored products.  
         [0014]     It is preferred in certain applications to have a passageway permitting to channel fluids between the joint containers. These passageways could be made of metal or plastic material, and can be sealed or welded. The containers can be safely separated by first sealing each passageway at two spots and then cut the passageway in between the two sealed spots. The containers are safely separated without compromising the sterility and the medical integrity of the stored product.  
         [0015]     In another embodiment, the container having one enclosure comprising of multiple interconnected compartments. Each compartment having at least one portal for fluid communication and is connected to other compartments by passageways securing fluid communications between the compartments. These passageways can be sealed at two spots by welding means, and then are cut in between the welded spots to sterilely separate the compartments that are connected by the passageway. Each separated compartment can be used by therapeutically processing its content or stored again at the cryogenic environment for future use.  
         [0016]     In another embodiment, the metallic container is fabricated by welding the half shells described above with a flat sheet metal.  
         [0017]     In another embodiment, the metallic container encompasses a cone shaped edge that merges into a tubular port to facilitate the exiting of fluids.  
         [0018]     In another embodiment, the metallic container having at least one face retaining a flexible corrugated geometry. This geometry is flexible enough to adjust the container shape for limited volume expansion caused by frozen fluids inside the container. Typically metallic containers are strong enough and tough enough to withstand any level of stress caused by frozen fluid volume expansion. The flexible geometry feature is used to relief stresses caused by expanding frozen fluid.  
         [0019]     Further aspects of the present invention will be apparent from the following description of specific embodiments, the attached drawings and the appended claims.  
     
    
     BRIEF DESCRIPTION OF DRAWING  
       [0020]     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.  
         [0021]      FIG. 1 —Top View of a Container  
         [0022]      FIG. 2 —Top View of the Internal Section of a Half Shell  
         [0023]      FIG. 3 —Side View of a welded Container with a Cross Section Demonstrating Plastic Bushing  
         [0024]      FIG. 4 —Top View of the Internal Section of a Half Shell with a Flange  
         [0025]      FIG. 5 —Transversal Cross Section View of a Welded Container with a Flange  
         [0026]      FIG. 6 —Top View of Joint Containers with Attaching Strip  
         [0027]      FIG. 7 —Top View of Joint Containers with Fastener and Connected with Tubing  
         [0028]      FIG. 8 —Cross Section View of a Container Fabricated by Welding a Half Shell and a Flat Sheet Metal  
         [0029]      FIG. 9 —Top View of a Container Having a Cone Shaped Side  
         [0030]      FIG. 10 —Top View of a Container Having Two Compartments Joined by a Passageway  
         [0031]      FIG. 11 —Transversal Cross Section View of a welded Container with Tow Compartments Joined by a Passageway  
     
    
     DETAILED DESCRIPTION OF THE INVENTION  
       [0032]     It is the essence of this invention to provide a durable and tough container that can reliably endure long-term storage at very low cryogenic temperature environments. Such containers are essential to preserve valuable and perishable contents such as rare blood or progenitor cells of neonatal. The present invention provides a metallic container characterized with high strength and high toughness to endure very low cryogenic temperature. It is known that cold temperatures embrittle materials causing it to fracture at much lower than normal impacts. By using tough metals that greatly minimize the effect of embrittlement, containers are capable of withstanding stresses or impacts at low temperatures.  
         [0033]     A top view of a metallic container  20  is shown in  FIG. 1 . The container is generally having the shape of a rectangular parallelepiped with a large flat base and a relatively little height. The large flat base and top surfaces are referred to as planar surfaces  24 . The side surface that is substantially perpendicular to and circumscribes the two planar surfaces is referred to as sidewall  25 . The planar surface having rounded corners  26  enabling the sidewall to blend into a matching curvature at each corner. The sidewall also blends with the planar surfaces along the edges forming a merging contour that minimizes any stress concentration in the structure.  FIG. 1  further portrays tubular ports  22  used for fluid channeling are extended from the edge of the container. One portal is connected to a plastic tube  42  that could be integrated with a disposable bags set (not shown) used to collect blood. A second portal is shown having a spike connection port  44 . The third portal is connected to a needle insertion port  46 . Container volume can range from 1 ml to 1000 ml depending on the application. Tubing  42  could also carry at its free end a suitable sterile or aseptic connection device (not shown), to establish communication with a source of material that is to be conveyed into the container  20 . Once the material is transferred into the container, the tubing  42  can be closed by a conventional radio frequency heat seal, which permits tubing  42  beyond the seal to be disconnected from the container  20 .  
         [0034]     In a preferred embodiment, the metallic container is fabricated of Austenitic stainless steel sheet metal alloy. This steel alloy having high concentration of nickel that greatly enhances its ability to withstand very low temperature environments. As alternative material Titanium alloy can also be used to fabricate containers. Although there are many ways of fabricating metallic containers, the most practical fabrication method for this invention is to weld two previously formed half shells. A special tool encompassing the features of the container is used form a half shell  30  shown in  FIG. 2 . A large and flat planar surface  24  is bounded by an undersized sidewall  25 . The sidewall blends with the planar surface in a contoured curvature of a constant radius. A defined number of extensions  32  having the shape of a half cylinder sectioned by a plane passing through its longitudinal axis are originated at the top of the sidewall  25 . Referring to  FIG. 3 , a side view of a welded container is illustrated. Two half shells  30  are matched together and welded at the seam  35 . The two half shells are matched in a way that the free end of the sidewall of each half shell touches the free end of the sidewall of the other half shell. The seam  35  is materialized at the contact line between the two sidewalls. It is preferred to use high precision laser welder technology to join the two half shells. Matching extensions  32  of each half shell form a cylindrical port  22  at the edge of the container. As shown in the cross sectional are in  FIG. 3 , it is preferable in some applications to seal bond plastic bushings  48  to the welded tubular ports  22  to facilitate the bonding of plastic tubing  42 , spike ports  44  or needle ports  46  to the container. The plastic bushings are seal welded or bonded to the metallic tubular ports.  
         [0035]     In an alternative embodiment, the sidewalls  25  on the matching half shells  30  are extended slightly to establish an overlap between the sidewalls used for lap welding.  
         [0036]     A top view of a half shell  40  bounded with a flange is shown in  FIG. 4 . In this configuration, the sidewall  25  that surrounds the planar surface  24  is terminated with a flange  34  that is situated in plane parallel to the planar surface. The flange completely encircles the sidewall and edges all the concaved channels on the extensions  32  along the longitudinal axis. The flange has a constant width and it is oriented away from the planar surface and away from the concaved channels on the extensions.  
         [0037]     Two symmetrical half shells  40  are matched and welded at the flange forming a sealed container with defined ports.  FIG. 5  shows a cross sectional view of a container fabricated by welding two half shells at the flange. The matching flanges  34  could be laser welded at the seam  35 , heat resistance weld, or brazing at the mating flange surfaces  33 . The matching flanges could be brazed or bonded at the mating surfaces.  
         [0038]     In another method, the container  20  is fabricated by welding two half shells  30  or  40  that do not have any extension member  32 . Tubular cylinders  22  are welded afterward to the container surface after a matching hole is cut allowing for the fluid to channel through the tubular port.  
         [0039]     Referring to  FIG. 5 , a plastic laminate  75  covering the inner wall of the enclosure is shown. This laminate is a further step to enhance the biocompatibility characteristics of the container and allows the usage of different metal alloys such as Aluminum to fabricate the container. In other embodiments a biocompatible coating is used to cover the inner surface of the container to protect the contents.  
         [0040]     A top view of rigidly connected containers  20  is shown in  FIG. 6 . These containers are attached by one or more welded metallic strip  36 . These strips having defined cutting lines  56  that can be easily cut by pliers or scissors. Containers are safely separated by cutting the joining metallic strips along the defined cutting lines  56  without compromising the sterility of the content in each container.  
         [0041]     Alternatively, these containers can be fabricated from previously formed half shells that have more than one recessed structure. Such half shells having at least two shallow depressions, each embracing a planar base surrounded by a sidewall, are welded forming two joint containers.  
         [0042]      FIG. 7  depicts an alternative way of joining two or more containers. A holding fastener  38  that securely clinches on two or more containers to maintain them physically in combination. The fastener having defined breakable lines  58  strategically placed between the attached containers. Containers can be easily separated by simply breaking the holding fastener at the breaking line between the containers. The breaking line secures a safe separation of the containers without compromising the sterility of the contents in each container.  FIG. 7  also illustrates a portion of tubing set  50  connected to the joint containers by portals  22 . This tubing set is originally connected to a set of bags and harnesses (not shown in the figure) to collect blood and separate components. Some bags on the set contain cryoprotectant fluids that stabilize the cells or membranes for freezing.  
         [0043]     Referring to  FIG. 8 a  cross section view of a container fabricated by welding a half shell  30  or a flanged half shell  40  to a flat sheet metal  45  is shown.  FIG. 8  also illustrates a flexible corrugated geometry  70 . This geometry is flexible enough to adjust the container shape for limited volume expansion. The flexible geometry feature is used to relief stresses caused by expanding frozen fluid inside the container.  
         [0044]      FIG. 9  demonstrates a top view a container encompassing a coned shape edge  52  that merges into a tubular port  22  to facilitate the exiting of fluids. A little holder  54  attached to the container is used to hold the container to a hook or to an IV pole.  
         [0045]     Referring to  FIG. 10  and  FIG. 11  that demonstrate a container having two compartments  55  connected by a passageway  60 . Each compartment having an identification label  65  secured to its outer surface. The passageway can be seal welded at two spots  62  and then is cut across the line  64  to safely segregate the two compartments. A seal weld  62  assures the integrity of each compartment and secures the sterility of the content.  
         [0046]     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.