JP2004500158A - Storage package - Google Patents

Abstract

A storage container package 10 is disclosed. The storage package has an outer container 22, a second outer container completely surrounding the outer container, an access opening traversing the outer container 22, a cell storage chamber 807, and a stabilization chamber 809, The stabilization layer chamber is connected to the cell storage chamber through a semi-permeable barrier, and the semi-permeable barrier can pass molecular species but cannot pass biological cells, and And at least part of the barrier between the cell storage chamber and the cell container, and the outer container completely surrounds the cell storage chamber and the stabilization chamber. The storage container package further includes means for removing the second outer container 801 and means for removing the outer container.

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to the field of housing and using therapeutic biological materials. In particular, the present invention relates to a sterile package of biological material with improved containment characteristics.
[0002]
[Prior art]
In surgical procedures, sterile surgical instruments need to be provided. Devices and methods for aseptically introducing non-biological materials are known in the art, such as disclosed in US Pat. No. 4,065,816 to Sawyer et al. Sawyer discloses a method of packaging a prosthetic device for surgical use. The prosthetic device is packaged, sterilized in a package, and transported to a sterile environment where the package opens.
[0003]
While these conventional devices and methods have been successful with non-biological materials, they have not been successful in moving biological materials from remote locations to sterile locations. After being placed in the container, the non-biological material can be sterilized, but the biological material is adversely affected by the sterilization process, making the process difficult.
[0004]
Biomaterials can be introduced into a sterile environment, but it is difficult. One example of a sterile surgical use of biological material is a blood transfusion bag. Devices and methods for using a blood transfusion bag device aseptically, such as disclosed in U.S. Patent No. 3,942,529 to Waage, are known. Waage shows a package and method for containing blood. Blood transfusion bags are sterile before they are filled, but after they are filled, they are no longer sterile and very strict antibacterial measures must be taken when brought into a sterile environment.
[0005]
Aseptic transport is another method for introducing biological material into a sterile working room. In this method, biological material is aseptically packed into glass bottles. Generally, the outside of the glass bottle is clean but not sterilized. Therefore, in order to use the biological material in a glass bottle in a work room, a non-sterile worker must open the glass bottle and a sterile worker must hold it. The aseptic worker pulls the cell through a straw or other tube into a sterile syringe. In this way, the biological material can be used in a sterile environment.
[0006]
Current methods of transporting biological materials to a sterile workroom are cumbersome and the use of biological materials in a sterile manner consumes more time and labor. Accordingly, a need has arisen for new methods and apparatus for aseptically packaging and delivering biological materials that overcome the shortcomings and inefficiencies of the prior art.
[0007]
[Means for Solving the Problems]
According to a principal aspect of the present invention, a sterile package of biological material with improved storage characteristics is disclosed. It is an object of the present invention to be able to aseptically introduce biological material into a sterile area.
[0008]
An object of the present invention is to provide an apparatus capable of storing and supplying a biological material aseptically.
These and other objects are consistent with one or more of the following embodiments. In one embodiment, the invention provides an outer container, an access opening traversing the outer container, a cell storage chamber, and a stabilization chamber, wherein the cell container is connected to the cell storage chamber through a semi-permeable barrier. The semi-permeable barrier is capable of passing molecular species but is not capable of passing biological cells, and the semi-permeable barrier is at least one of the barriers between the stabilization chamber and the cell storage chamber. Forming a part, wherein the outer container includes a stabilization tank surrounding the cell storage chamber and the stabilization tank chamber, means for removing the outer container, and means for removing the outer container. I do.
[0009]
In another embodiment, the invention provides an inner container and an outer container that completely surrounds the inner container. The access opening traverses the outer container and is operative to introduce an unstable liquid or solid from outside the outer container into the inner container without destroying the integrity of the outer container. The access opening allows an unstable liquid or solid to enter the inner container without opening the outer container. The inner container is preferably detachably connected to the access opening. Further, the outer container is removable.
[0010]
In another embodiment, the present invention provides a method for supplying a liquid to a sterile area. The method includes sterilizing the storage package, the storage package having an outer container completely surrounding the inner container, and a liquid introduction conduit traversing the outer container, the outer container being removable. Further, the method includes inserting the liquid from outside the outer container into the sterilized inner container through a liquid introduction conduit such that the liquid does not interfere with the sterility of the outer container. Generally, the liquid will have a germicidally unstable substance, such as the desired biological cells suspended therein, and the liquid will be free of contaminating cells other than the desired biological cells. In this method, the outer container is opened near the sterile area, and liquid is supplied from the inner container. According to this method, when the liquid is inserted into the storage package, the package is not further completely sterilized.
[0011]
In another embodiment, the present invention discloses a method for containing an unstable liquid or solid. The method includes sterilizing a storage package having an outer container with a sealable access opening completely surrounding the inner container across the outer container. The outer container removably seals around the inner container. The method includes inserting the unstable liquid or solid into the inner container through the access opening from outside the outer container such that the unstable liquid or solid does not interfere with the sterility of the outer container. The package and unstable liquid or solid do not undergo terminal sterilization after insertion of the unstable liquid or solid.
[0012]
According to another embodiment, the present invention discloses a method for aseptically supplying an unstable liquid or solid. The method provides a storage package, the package having an outer container completely surrounding an inner container having an unstable liquid or solid, the inner container removably attached to an access opening across the outer container. Connected. This outer container is removable. The method also includes opening the outer container in the vicinity of a sterile environment and providing an unstable liquid or solid from the inner container.
[0013]
In another embodiment, the present invention provides a storage package having an outer container, an unstable material storage chamber, and a stabilization chamber. The stabilizer chamber surrounds at least a portion of the unstable substance storage chamber through the semi-permeable barrier. The semi-permeable barrier forms at least a part of the barrier between the stabilizing chamber and the unstable substance storage chamber. The outer container completely surrounds the stabilization chamber. The storage device has means for removing unstable substances from the storage device. Further, the storage package has means for discharging the stabilization tank from the storage device.
[0014]
In another embodiment of the present invention, a storage device having an outer container, a stabilizing tank for storing a stable substance and an unstable substance, and a storage apparatus having an unstable substance is disclosed. At least a part of the stabilization tank and the unstable substance chamber is surrounded by the outer container. Means are provided for separating at least a portion of the stable material from the unstable material. The storage device has a stabilizing bath not surrounded by the outer container and a semi-permeable barrier surrounding at least a portion of the unstable material. Means for separating at least a portion of the stable material from the unstable material are connected to the semi-permeable barrier and, when pressed, reduce the predetermined volume of the stabilizer and the unstable material chamber. Thus, the stabilization bath is pushed and filtered through a semi-permeable barrier to separate from unstable materials. As another example, the means for draining the stable material is a stabilizing vessel not surrounded by the outer container and a syringe barrel surrounding the remainder of the unstable material chamber. The syringe barrel has a first end and a second end, the first end being connected to the stabilizing chamber and the unstable material chamber such that the barrel can communicate with the stabilizing chamber and the unstable material chamber. The connected open end is the second end is a movable plunger. The syringe barrel is connected to a semi-permeable barrier, both of which are slidably engaged with the inside of the outer container to reduce the volume of the stabilization bath and the unstable material chamber when the syringe barrel is pushed. I have. Thus, the stabilization bath is pushed and filtered through a semi-permeable barrier and separated from unstable materials.
[0015]
The use of the storage package of the present invention allows a sterile worker to easily handle and use biological materials in a sterile environment while eliminating the risk of soiling the material, the sterile environment or the sterile worker. In particular, the storage package of the present invention is suitable for housing components including cells and implants used in tissue engineering.
[0016]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, an embodiment of the present invention will be described in detail with reference to the drawings.
Generally, sterility is assured for materials that enter a sterile environment, such as a work room, by exposing the biological material to harsh conditions that kill incidental microorganisms. Such conditions include sterilization heating, ion radiation, toxic gases, and the like. When the desired material contains living cells or easily denaturing proteins, nucleic acids, or other organic molecules, other procedures for handling these unstable substances are required.
[0017]
The present invention includes a method and apparatus for providing biological material to a sterile environment in a quick, easy, and improved manner. The apparatus includes a sterile inner container surrounded by an outer container, which can be handled by a non-sterile operator or assistant, ensuring the sterility of the inner container. To use this device, the inner container is filled with biological material under aseptic conditions. The device is transported to a non-sterile environment and can be handled by non-sterile assistants. Non-sterile assistants can place the device near the sterile area, remove the outer container, and aseptic workers can use sterile materials without the risk of compromising the stability of the materials, workers, area or inner container. Can handle the inner container.
[0018]
The present invention is advantageous for handling unstable liquids or solids, ie, materials that are subject to harmful chemical, physical, or biological changes or destruction under sterile conditions. The unstable liquids or solids of the various embodiments shown herein have many types. For example, it is an aqueous suspension containing heat denaturable materials, such as cells, components containing cells, blood, lymph or aqueous protein therapeutic proteins. Also, unstable materials are solids, semi-solids, liquids, sheets (thin or thick), blocks, other three-dimensional structures, gels or hydrogels such as alginic acid, especially or fully cured. Preferably, the labile material has cells supplied to the surface and / or supplied through all or part of the material. The unstable liquid or solid is its own cells, such as a block or sheet of living tissue.
[0019]
Generally, an unstable liquid or solid is a component that contains cells. In a preferred embodiment, the storage package of the present invention is for implantation or tissue engineering as set forth in European Patent Publication Nos. 0299010 and 0469070, International Patent Application Publication No. WO 94/25080, or US Pat. Used to contain components, including cells. Further, particularly in the embodiment shown in FIG. 26, substances that can be used are the components shown in US Pat. No. 5,567,612. As another example, the inner container contains a fluid composed of a living or non-living material. Such materials are subject to change for the sterilization method used to sterilize the storage package. Further, the storage package shown in this embodiment can be used whether sterilized or not.
[0020]
To facilitate a more complete understanding of embodiments of the present invention and its advantages, embodiments will be described in more detail with reference to FIGS. 1 through 26 of the drawings, wherein like numerals are used to refer to the various figures. Used for similar and corresponding parts.
[0021]
With particular reference to FIG. 1A, a storage package according to a first embodiment of the present invention is shown. The storage package, indicated by reference numeral 10, has an inner container 20 completely surrounded by an outer container 22. Outer container 22 has an end that includes peelable member 32. The other three sides of the outer container are sealed with sealed edges 31. The liquid introduction conduit 24 passes through the outer container 22. By passing through the outer container 22, the liquid introduction conduit 24 can enter from the outside of the outer container 22 to the inside of the outer container 22 without opening the outer container 22. The liquid introduction conduit 24 has an end 30 which is closed by a removable closure. For example, the closure at end 30 can have a luer connector, opening, cap, or septum.
[0022]
The liquid introduction conduit 24 is detachably connected to the inner container 20 at a connection point 26. Since the inner container 20 is detachably connected, the inner container 20 can be easily removed from the liquid introduction conduit 24. For example, the detachable connection is a friction fit or a luer connector. The labile liquid or cell-containing component is connected to the liquid inlet conduit at the end 30 of the liquid inlet conduit 24 so that the labile liquid or cell-containing component does not compromise the outer container 22 which compromises sterility. The components containing unstable liquids or cells inserted into the outer container 24 and starting from the outside of the outer container terminate inside the inner container 20, and the liquid components containing cells between the inner container 20 and the inside of the outer container 22 Little or no. Thus, the introduction of components containing unstable liquids or cells does not violate the sterility inside the outer container 22. In addition, components containing unstable liquids or cells are introduced into the inner container without opening the outer container 22.
[0023]
Referring to FIG. 1B, a side view of the storage package is shown. The outer container 22 is formed from a lower layer 34 and an upper layer 36, wherein the lower layer 34 and the upper layer 36 are sealed with three sealed edges and a peelable member 32. Peelable member 32 can be removed to expose inner container 20. The peelable member 32 is formed from a material that can be easily removed. For example, the peelable member 32 can be made from Tyvek (100% high density polyethylene sheet formed from flash spun filaments), paper, nylon, or foil. The peelable member 32 is a breathable or non-breathable material. Non-breathable materials can be made of plastic. The non-breathable member is two layers coated with an adhesive suitable for separating the two layers of peelable member to facilitate removal. The breathable and peelable member is a coated or uncoated material. Uncoated peelable materials produce a strong seal but are difficult to open. As another example, peelable member 32 may be one or more such that opening peelable member 32 separates upper layer 34 and lower layer 36 at peelable sealed edge 31 as shown in FIG. 1A. A plurality of upper layers 34 and lower layers 36 are integrally connected. Further, the peelable member 32 is a ruptured strip as described in U.S. Pat. No. 4,367,816 to Wilk. Further, the peelable member 32 is a sealing rim that can be easily torn or cut.
[0024]
Referring to FIG. 1B, the liquid introduction conduit 24 can access the inner container at reference numeral 38 without violating the seal of the outer container. Preferably, a seal at reference numeral 38 except for the liquid introduction conduit 24 is strong around the liquid introduction conduit 24 so as to prevent leakage so that access to the inner container 20 is prevented from outside the outer container 22. Form a seal.
[0025]
The liquid introduction conduit 24 is, for example, a partition port or a tube. In a typical embodiment, liquid inlet conduit 24 is made of polyethylene. However, the liquid introduction conduit 24 is formed of a material that can be sealed to the outer container 22. For example, such materials include, but are not limited to, polyethylene, terephthalate, polyester (such as Mylar), Sclar (linear low density polyethylene), Tyvec, paper, nylon or foil. In another embodiment, the liquid introduction conduit 24 is replaced by an access opening to facilitate the introduction of an unstable liquid or solid having large particles into the inner container 20.
[0026]
1C, an end view of the storage package 10 is shown. Lower layer 34 and upper layer 36 are shown connected by sealing member 32. The end 30 of the liquid introduction conduit is shown, where components containing unstable liquids or cells are introduced. A luer fitting fitted to the end 30 fits over the end 30 so that it can be easily connected to a syringe or other device to introduce labile liquids or components containing cells. Are combined. As another example, end 30 is a septum that inserts a needle into liquid introduction conduit 24 or an access conduit into which components containing unstable liquids or cells can be introduced.
[0027]
The end of the liquid inlet conduit 24 is generally sealed to prevent leakage of the inner container and maintain sterility. The means for sealing the end 30 of the liquid introduction conduit 24 comprises a method for sealing the end 30 such that a barrier exists between the liquid introduction conduit 24 and the environment outside the outer container 22. For example, the sealing means may include a heated seal at the end to completely seal the end 30, a clasp to clamp the closed end 30, a cap at the end 30, and a liquid seal to seal the end 30. , Housing and valve to seal end 30.
[0028]
In the embodiment shown in FIGS. 1A to 1C, the inner container 20 is a syringe, but the inner container 20 may be another storage container. Inner container 20 is made of a suitable rigid material such as metal, glass, polypropylene, polycarbonate or polyethylene. Preferably, the inner container 20 is configured to facilitate supplying unstable liquids or components including cells on demand. For example, the inner container 20 is a bag made of a flexible material, and the contents are supplied by squeezing the bag. The components of the storage package 10 can be replaced with similar components described with respect to the other components enclosed therein.
[0029]
As shown in FIG. 2, a plurality of inner container storage and storage packages 110 are shown. Also, the second inner container 140 is completely surrounded by the outer container 122. Inner container 120 has an end 142 and inner container 140 has an end 144. Ends 142 and 144 are separately connected to end 126 of liquid inlet conduit 122. Further, additional components such as needles, cannulas, supply valves, bottles, stopcocks, and additional components such as connectors, delivery catheters and mechanisms are also enclosed within outer container 122. In addition, other components that assist in the supply of labile liquids or components, including cells, or that are easily assembled or fitted within outer container 122, are enclosed within outer container 122. In particular, members that can be used in a sterile area in connection with the administration of unstable liquids or components containing cells are enclosed in an outer container, which is maintained in a sterile condition and the unstable liquid or It is readily available to supply components, including cells.
[0030]
Tray 146 can be used as a frame inside outer container 122 to hold inner containers 120 and 140. Tray 146 is shaped into inner containers 120 and 140 to hold inner containers 120 and 140. The use of the tray 146 not only prevents the inner containers 120 and 140 from squeezing during transportation, but also provides a way to easily remove the inner containers 120 and 140. For example, tray 146 can be controlled to extrude inner containers 120 and 140 continuously or simultaneously without directly contacting inner containers 120 and 140 when removing outer container 122. As shown, the tray 146 can hold one or two inner containers, and the structure of the tray 146 can be modified to hold multiple inner containers. Tray 146 is made of a rigid material, for example, polyethylene terephthalate glycol, polyvinyl chloride, polystyrene, polyethylene terephthalate or polyethylene, and tray 146 is preferably capable of flexing elastically. Further, the entire components of the storage package 110 can be replaced with the same components described with respect to other embodiments.
[0031]
In FIG. 3, a storage package 210 is shown, which is an outer container storage having a thermoforming tray 252 and a peelable member 232. The peelable member 232 can be easily removed to expose the inner container 220. It is only necessary to hold the thermoformed tray 252 and pull the peelable member 232 outward to remove the peelable member 232. This separates the peelable member 232 from the thermoforming tray 252, exposing the inner container 220. Further, thermoformed tray 252 can be shaped to hold inner container 220 by a tray similar to tray 146. Thermoformed tray 252 can be made of a strong material such as, but not limited to, polyethylene terephthalate glycol, polyvinyl chloride, polystyrene, polyethylene terephthalate, or polyethylene. The peelable member 232 can be formed of a material that can be easily peeled off. For example, the peelable member 232 can be made of Tyvec (trade name), paper, nylon, or foil. As another example, thermoformed tray 252 replaces a sheet of flexible material that is sealed to peelable member 232 to form outer container 250. Variations on these structures using a combination of flexible and rigid materials will be readily apparent to those skilled in the art, but are within the scope of the present invention (see FIG. 4).
[0032]
Hermetic seal 238 forms a strong seal around liquid introduction conduit 224. The end 230 allows material to enter the interior of the inner container 220 from outside the outer container 222 via the liquid introduction conduit 224. For example, end 230 is a check valve or stopcock. Further, each of the components of the storage package 210 can be replaced with similar components described with respect to other embodiments.
[0033]
As shown in FIG. 4, the storage package 310 has an optional flexible package 362 surrounding the inner container 364. Inner container 364 is similar to outer container 22, 122, and 222 of FIGS. 1-3 and surrounds inner container 320. Inner container 364 has a built-in rigid member 366 that points to liquid inlet conduit 324. The flexible package 362 provides a flexible container that protects the inner container 364 and the inner container 320, and maintains the inner container 364 and the inner container 320 aseptic. Generally, the storage package 310 is sterilized. Next, in a sterile environment, the flexible package 362 is removed and the inner container 320 is filled with an unstable liquid or cell-containing component. This leaves a sterile inner container 320 filled with an unstable liquid or cell containing component surrounded by an inner container 364.
[0034]
Inner container 364 covers inner container 320 and holds rigid member 366. The flexible package 362 and the inner container 364 are made of a flexible material, for example, polyethylene, polyester such as Mylar, Sclar, Tyvec, paper, nylon or foil. Inner container 364 and flexible package 362 can house peelable member 232 to facilitate opening. The rigid member 366 contains the rigid material described in this specification. Rigid member 366 assists in forming a strong seal around liquid introduction conduit 324. The end 330 allows material to enter from outside the inner container 364 via the liquid inlet conduit 324. The end 330 can be covered with an end cap 390 or other capping or sealing mechanism.
[0035]
As shown, inner container 320 has an additional connector 396 that connects septum 392 to inner container 320. The user can operate the inner container 320 with the septum 392 from the outside to the end of the inner container 364 such that the needle fits into the needle housing 398 and the needle 394 passes through the septum 392. After removing the flexible package 362, the components containing unstable cells are inserted into the inner container 320 through the liquid introduction conduit 324. After filling the inner container, the septum 392 can be removed from the needle 394, separating the inner container 320 from the liquid introduction conduit 324. Also, the inner container 320 can be entirely separated from the connector so that a user can assemble the connector with the inner container 320 as needed. Further, a plurality of connectors and securing members, preferably having a female / male luer connector, can be used to facilitate the connection between the inner container 320 and the liquid introduction conduit 324. Further, each of the components of the storage package 310 can be replaced with similar components described with respect to other embodiments.
[0036]
In addition, the storage package 310 is surrounded by a rigid outer tray, such as the tray 146 shown in FIG. 2, and after removing the flexible package, filling the inner container 320, and forming an inner port 364 surrounding the inner container. It can be held in place by a rigid tray. As another example, storage package 310 can be inserted into a rigid outer tray before flexible package 362 is removed. The use of a rigid outer tray can aid in the transport, mechanical handling, and protection of inner container 364 and inner container 320.
[0037]
In FIG. 5, a storage package 410 having a double outer container is shown. First outer container 470 is similar to outer container 250. The first outer container 470 houses a thermoforming tray 472 and a peelable member 474 similar to the thermoforming tray 252 and the peelable member 232. Second outer container 480 completely surrounds first outer container 470. The second outer container 480 houses a thermoforming tray 482 and a peelable member 484 similar to the thermoforming tray 252 and the peelable member 232. However, the liquid introduction conduit 424 extends through the multiple outer containers to the outside of the second outer container 480 and flows unstable liquids or components including cells from the outside of the second outer container 480 to the inner container 420. be able to. The provision of multiple outer containers improves protection and sterility. The storage package 410 can have multiple outer containers as long as the liquid introduction conduit 424 extends through the outermost container. In fact, the components of the storage package 410 can be replaced with similar components described with respect to other embodiments.
[0038]
FIG. 6 shows a storage package 510 according to another embodiment of the present invention. Outer container 522 completely surrounds inner container 520, and tray 546 surrounds inner container 520 in place. The storage package 510 is similar to the storage package 10, but the major difference between the two embodiments is that the outer container 522 has a controlled access opening 556 inside the outer container 522. Generally, opening 556 is sealed before and after inner container 520 is filled with an unstable liquid or cell-containing component. The end 542 of the inner container 520 can be aligned with the opening in the filling operation. The end 542 accommodates an opening, bulkhead, luer connector or stopper. For example, end 542 can be made from cork, rubber, or plastic. As shown, the liquid introduction conduit 524 is a hollow needle connected to a syringe 590, which is part of the filling device. The liquid introduction conduit 524 is detachably connected to the inner container 520 during the filling operation. Needle 524 is threaded through end 542 of inner container 520 and can be removed after inner container 520 is filled. Further, the components of the storage package 510 can be replaced with similar parts described with respect to other embodiments.
[0039]
The needle 524 can be removed after inserting the unstable liquid or cell containing component into the inner container 520. To seal the outer container 522, the opening 556 is sealed with a sealing device 558 as shown in FIG. For example, the sealing device 558 may be a cap, a luer connector, a valve, a liquid valve, a clamp that closes the opening 556, or a heat seal such that the opening 556 is closed with heat.
[0040]
To maintain the sterility of the storage package 510 after sterilization and before filling the inner container 520, an outer sterile barrier 564 can be wrapped around the outer container 522 entirely, as shown in FIG. Outer sterile barrier 564 is made, for example, of a material that can maintain the sterility of outer container 522 and inner container 520. For example, polyethylene, low density polyethylene, polyesters such as Mylar, Sclar, Tyvec, paper, nylon, foil can be used. Further, the outer sterile barrier 564 can be rigid or flexible, for example, using polyethylene terephthalate glycol, polyvinyl chloride, polystyrene, or polyethylene terephthalate glycol, polyvinyl chloride, polystryrene, or polyethylene terephthalate. be able to. Generally, the package 510 has a barrier 564 in place and is sterilized. Barrier 564 is removed shortly before filling inner container 520 with a material that is unstable to sterilization.
[0041]
In operation, the storage packages of all embodiments operate similarly. The storage package is sterilized by known sterilization means. Generally, the storage package is filled aseptically, preferably using a biosafety cabinet-containing sterile filling device. Unstable liquids or solids are inserted into the inner container from outside the outer container through the access opening to fill the inner container, which may be a liquid inlet conduit. The access opening allows an unstable liquid or solid to be introduced into the inner container without opening the outer container. In addition, unstable liquids or solids do not violate the sterility inside the outer container. Thus, unstable liquids or solids do not enter the area between the outside of the inner container and the inside of the outer container. Unstable liquids or solids may or may not be sterilized. If the labile solid or liquid contains the desired number of live cell reservoirs without contaminating cells other than live cells, only the non-sterile material in the sterile storage package is the desired live cell . However, if the unstable solid or liquid does not contain living cells and is a non-living material, the entire storage package is sterile.
[0042]
After inserting the desired liquid or solid into the inner container, any excess labile liquid left in the access opening or liquid introduction conduit may require some means to remove the excess labile liquid or solid. Can be pushed into the inner container. Other means can also be used to clean up excess unstable liquid or solid access openings or liquid introduction conduits. For example, excess material can be pushed using a rod by forcing air into the access opening or liquid introduction conduit, or by hitting the access opening or liquid introduction conduit. Thereafter, the access opening or the end of the liquid introduction conduit is closed. Sealing means can be used as long as the sealing means creates a good seal that sterilizes the inner container. The storage package is located in a sterile area such as an operation room.
[0043]
If the storage package is filled with an unstable liquid or solid, no final sterilization will take place. Final sterilization will kill all biological material in the storage package. Preferably, the final sterilization adversely affects the unstable liquid or solid, since the unstable liquid or solid contains aseptically unstable unstable biological or other substances. Thus, the entire sterilization of the package takes place only before insertion of the unstable liquid or solid.
[0044]
A non-sterile worker or assistant removes the storage package and brings it to the work room or a location adjacent to the sterile area. A non-sterile assistant can remove the outer container of the storage package. A non-sterile worker simply removes the peelable member of the outer container, tears or tears the outer container, or breaks the outer container to remove the outer package. Once the outer container is opened, the aseptic operator grasps the inner container (one of them, if there are more than one) and, if attached, from the access opening or liquid introduction conduit. To separate. As another example, if the inner container is contained by a tray, a non-sterile assistant can bend the tray so that the inner container pops out into a sterile area or the hands of a sterile worker. As another example, the sterile assistant releases the inner container from the outer container when the outer container is opened. If the inner container is a pouch, the aseptic worker can grab the pouch. As another example, if a biological material such as a skin sample is used, the non-sterile assistant opens the inner container and causes the sterile assistant to grab the sample. As another example, if a sample is to be cured into the desired shape in the inner container, the sterile assistant can open the inner container and remove the sample. Generally, a cured sample is a cell-containing component or substance, such as a preform implant, which is unstable to sterile conditions, such as therapeutic proteins but not cells. Material containment is within the scope of the present invention. The outer container according to the invention can be removed or opened such that the inner container is not soiled and the inner container is not exposed to a non-sterile surface.
[0045]
When the aseptic operator holds the inner container, the aseptic operator supplies an unstable liquid or solid. If the inner container is a syringe, the plunger of the syringe can be pushed to supply the contents. If the inner container is a container, the inner container can be squeezed to release the desired unstable liquid or solid.
[0046]
In order to more fully describe the method of the present invention, the method will be further described with respect to the specific embodiment shown in FIGS. 1A-1C. However, the method as described below can be easily operated by the storage package of any of the embodiments described below. The end 30 of the liquid introduction conduit 24 is sealed. The means for sealing the end 30 may include heat sealing the end, cap, liquid valve, value, or clamping the closed end 30. The storage package 10 with the sealed end 30 is sterilized to kill anything that contaminates the tissue within the storage package 10. Preferably, the residual contaminants are below levels that can be approved under good manufacturing standards for medical devices. The storage package 10 can be sterilized in any suitable manner, for example, by steam, ethylene oxide, gamma radiation, electron beam radiation, or ultraviolet radiation.
[0047]
After sterilization by a suitable method, the inner container is filled aseptically. In one example, the storage package 10 has a removable seal removed at the end 30 of the liquid introduction conduit 24 inside a cabinet safe for biological research, such as a Class 100 sterile food product. An unstable liquid or a component containing cells is inserted into the inner container 20 of the storage package 10. Unstable liquids or components containing cells are inserted using any one of a number of methods. In one embodiment, a sterile fill syringe with a luer lock is connected to the end 30 of the liquid introduction conduit 24. The fill syringe is connected by hand or mechanically so that the sterility inside the secure cabinet is not violated in biological studies. The fill syringe is emptied into the liquid introduction conduit 24 and opened to the unstable liquid or cell containing component, and the unstable liquid or cell containing component is extruded into the inner container 20. After filling the inner container 20, the filling syringe is removed. Optimally, any excess labile liquid or cell-containing components remaining in the liquid introduction conduit 24 can be removed by using a means to purge excess liquid in the liquid introduction conduit 24, for example, by removing excess liquid from the inner container 20. Can be pushed into the inner container 20 by using a rod to push in, or by forcing air into the liquid introduction conduit 24 or by hitting the liquid introduction conduit 24. After the unstable liquid or cell-containing component has been inserted into the inner container 20, the end 30 of the liquid introduction conduit 24 is resealed in the manner described above. The end 30 can be permanently sealed by heating. The containment package 10 does not undergo terminal sterilization at this point that affects labile liquids or components containing cells.
[0048]
Final disinfection is a final disinfection that kills the entire biological material before transporting the sterile product. Therefore, the final sterilization will adversely affect the unstable liquid or cell-containing components after the inner container 20 of the storage package 10 has been filled. However, unstable liquids or components containing cells are sterilized before inserting the unstable liquids or components containing cells unless the contaminants other than the desired cells are present. When an unstable fluid or component containing cells is aseptically inserted, the inner container 20 is free of live cells except for the desired cells that are completely surrounded by the inner container 20. Of course, if the liquid contains only non-biological material, the storage package 10 will contain the non-biological material after it is inserted into the inner container 20 unless the non-biological material is unstable under the conditions of final sterilization. , Final sterilization is performed.
[0049]
The storage package 10 is transported to a use place which is a working room in a sterile environment. At this location, the inside of the outer container 22 and the outside of the container 20 are sterile (ie, free of contaminants). Furthermore, the interior of the inner container 20 is sterile except for the desired unstable liquid or components containing cells. A non-sterile assistant in the working room tears open the outer container and exposes the inner container without soiling it. The aseptic operator grasps the inner container 20 and twists the inner container 20 to disconnect it from the luer connector. As another example, if a tray 46 is used, the non-sterile assistant may remove the inner container 20 from the tray from which the outer container 22 is removed by indirectly applying pressure without soiling the outside of the inner container 20. The inner container 20 can be placed either in a sterile environment or in the hands of a sterile worker. As another example, if the inner container 20 is disconnected from the liquid guide conduit 24, the outer container 22 can be removed by a non-sterile assistant without directly touching the inner container 20, and the aseptic worker can The container can be gripped or the inner container can be removed from the outer container and placed in a sterile area.
[0050]
After removing the inner container 20, the aseptic operator can use the inner container to supply unstable liquids or components including cells. For example, if the inner container 20 is a syringe, labile liquids or components containing cells can be delivered through the syringe. As another example, if the inner container is a flexible bag, the inner container 20 can squeeze or squirt components containing unstable liquids or cells.
[0051]
It should be noted that everything contained within the outer container 22 and transferred to the sterile environment is generally sterile and clean until grasped by a sterile operator. Further, if the inner container 20 is a syringe or bag, only the outside of the inner container is touched by a sterile operator. Needles, components or liquids containing cells are generally not touched entirely by the operator. Thus, components containing unstable liquids or cells are aseptically introduced into a sterile area or patient.
[0052]
The method of using another embodiment of the invention to manipulate unstable liquids or solids in a sterile environment is similar to the method described in detail using the embodiment of FIG. 1 with components comprising cells. ing.
[0053]
As shown in FIG. 9, a storage package 610 according to another embodiment of the present invention is shown. Outer container 622 completely surrounds inner container 620, and tray 646 holds inner container 620 in place. The storage package 610 is similar to the storage package 510, but the major difference between the two embodiments is that they have a flap 664. Flap 664 has an access opening 624. Access opening 624 is aligned with the end of inner container 620. Access opening 624 allows unstable liquids or solids to enter inner container 620 from outside outer container 622. Further, all or any of the components of the storage package 610 can be replaced with components similar to those of the other embodiments.
[0054]
In operation, the storage package 610 operates as follows. The end 642 of the inner container 620 is not initially connected to the access opening 624, but the inner container 620 is free floating within the outer container 622. The storage package 610 is sterilized and transported to a filling station, for example, a cabinet safe for biological research. The end 642 can be connected to the access opening 624 while in a biological research safe cabinet. The ends 624 can be connected using known connection means. Preferably, outer container 622 is a flexible material and is manipulated to align access opening 624 with end 642. After sterilizing the storage package 610 and the connection end 642 to access the opening 624, an unstable liquid or solid inside the inner container 620 is inserted from outside the outer container. After the unstable liquid or solid has been inserted, end 642 is disengaged from access opening 624 and access opening 624 is closed. The access region 624 can be sealed and the access opening 624 fused together by heating the outer container at the region indicated by reference numeral 668. As another example, a method of providing a barrier to sterile soil inside the outer container 622 by clamping, for example, by melting the end of the access opening 624 with other means, caps, valves, liquid valves or stoppers. Can be sealed. Thus, the inner container 620 is free floating within the outer container 622 that is completely sealed. As another example, the tip of end 642 may be fused with access opening 624 and heat closed. In this case, the inner container 620 is connected to a completely sealed outer container 622. Regardless, the access opening 624 has been removed and is no longer part of the storage package 610.
[0055]
The storage package 610 is moved to a sterile environment or location adjacent to the area. When at or near the sterile environment or area, the non-sterile assistant can remove the outer container 622. One such method is to cut, tear, tear, and remove the flap portion 668 along the dotted line 676. However, it can be removed in a conventional manner as long as the non-sterile assistant does not touch the inner container 620. After removing outer container 622, a sterile operator can grasp inner container 620. If the inner container 620 has a portion that can be easily gripped, the inner container can be removed from the outer container 622. If the inner container 620 is connected to the outer container 622, the inner container 620 can be aseptically removed by any suitable means. Unstable liquids or solids can be supplied aseptically.
[0056]
As shown in FIG. 10, a storage package 710 according to another embodiment of the present invention is shown. The storage package 710 is a sample of living skin, but works better with component storage materials that include other unstable liquids or cells, such as, for example, thin or thick sheets, blocks, or other three-dimensional structures. Suitable for handling sample-bearing solid materials. Generally, the solid material is a cell-containing material, such as a preform tissue graft, but it is also within the scope of the present invention that the solid material be a matrix material that is unstable to non-cellular sterilization conditions, such as proteins used for treatment. It is. Inner container 720 is a container for storing and dispensing the skin dressing container shown in U.S. Pat. No. 5,040,677 to Tubo et al. Except that access opening 724 extends into inner container 720. It's similar to. In a typical example, inner container 720 has thermoformed tray 772 and peelable member 774. Outer container 722 completely surrounds the inner container, and access opening 724 passes through outer container 722. As another example, access opening 724 is the junction of inner container 720 and outer container 722 as shown in FIG. Outer container 722 can also be made from a flexible material as described above. Further, all or any of the components of the storage package 710 can be replaced with the same components described with respect to other embodiments.
[0057]
After the storage package 710 has been sterilized, it can be aseptically inserted into the inner container 720 through an access opening 724 in a sterile stylus or other environment suitable for sterile filing. After inserting the sample 790, it is sealed by the means capable of containing and sealing as described above. After sealing, the storage package 710 is transferred to a sterile area. When the package 710 is near the sterile area, the outer container 722 can be removed by the means described above that separates and detaches the peelable member 784. The aseptic operator can remove the sterile peelable member 774 and remove the sample 790.
[0058]
As another example, inner container 720 is a molded shape. Once inside, the cell-containing component or other unstable liquid can be inserted into the inner container such that the cell-containing component or other unstable liquid hardens into the shape of the molded inner container 720. . Outer container 722 and inner container 720 can be removed for use, exposing the molded sample for handling by a sterile operator.
[0059]
As another example, a peelable member can be placed in the inner container 720 before or after the storage package 710 is sterilized. If the substrate is placed in the inner container 720 before the storage package 710 is sterilized, the storage package 710 must be sterilized before introducing living biological material into the inner container 720. As mentioned above, in order to implant cells or cell-containing components on a substrate, the cells or cell-containing components must be aseptically introduced into the inner container. When removing components, including cells implanted on the substrate, they must be removed as described above.
[0060]
FIG. 11 is one embodiment of a storage package according to the present invention. As shown in FIG. 11, the cell storage chamber 807 is surrounded by the stabilization chamber 809. The stabilization chamber 809 is surrounded by an outer sterile container 804. Outer sterile container 804 is selectively surrounded by a second outer container 801. The cell storage chamber 807 and the stabilization chamber 809 have a releasable chamber 832. In a preferred embodiment, the releasable container 832 is freely removable from the storage package when the outer sterile container 804 is released. Molded conduit 803 is integrated into outer sterile container 804. Passage 812 passes through forming conduit 803. Preferably, the passage 812 integrally includes the liquid transport unit 805. The liquid transfer section 805 can be inserted into the cell storage chamber 807 through the access opening 810 of the stabilization chamber 809. By moving the forming conduit 803 and the access opening 810, the liquid carrier 805 can approach the inside of the cell chamber 807 from outside the outer sterile container 804 without releasing the outer sterile container 804. Generally, the storage package is processed to make it sterile, and a liquid component including living cells is introduced into the cell storage chamber 807 through the liquid transport unit 805. As shown in FIG. 11, the cell storage chamber 807 holds an unstable substance like the cell storage chamber. The cell storage chamber 807 prevents the liquid containing the cell-stabilizing substance 808 and the cell-containing component 811 from coming into contact with the liquid while preventing the cell-containing component 811 from being released to the cell-stabilizing substance 808. Generally, the cell containing wall 807 is configured to facilitate the exchange of certain components between the cell stabilizing material 808 and the cell-containing component 811. The size of the hole in the wall of the cell storage chamber 807 allows the desired components to move, but not the cells. The size of the hole in the wall of the cell compartment 807 is preferably between 0.1 and 0.4 microns. The walls of the cell compartment can be made of a suitable microporous material. Further, the walls of the cell compartment may be made of Gortex, PTPE, polycarbonate, polyacrylonitrile, porous polyethylene, PDMS, PET, nylon, a copolymer of polyacrylonitrile and vinyl chloride, or a suitable porous silicon-based material. able to make. The walls of the cell compartment are flexible or rigid. A suitable matrix that surrounds the labile material, particularly the cells, and allows the movement of the desired components, but not the cells, can be used in place of the cell compartment.
[0061]
The shape of the cell storage chamber 807 is configured to maximize exchange of desired components between the cell stabilizing material 808 and the cell-containing component 811. By maximizing the surface area to volume ratio of the cell receiving chamber 807, for example by using a flat shaped cell receiving chamber 807, the exchange of desired components is maximized. Cell storage chamber 807 is attached to access opening 810 by a suitable attachment mechanism such as an adhesive. The cell storage chamber 807 is surrounded by a stabilization chamber 809. Preferably, the surface area of the walls of the cell receiving chamber 807 is maximized and is proportional to the desired ratio between the cell stabilizer 8 and the cell-containing component 811.
[0062]
The cell stabilizing material 808 supports a component 811 including cells contained inside the cell storage chamber 807, and contains a soluble component for stabilization. Cell stabilizing material 808 is contained within a stabilizing chamber 809, which includes an access opening 810 and is bounded by a cell containing chamber. Preferably, the cell stabilizing material 808 surrounds the cell compartment 807 to maximize solute transport. The cell stabilizer 808 includes a solution for maintaining the component 811 containing cells and a solution for stabilizing the component. For example, the maintenance solution is a nutrient storage medium for cells in the cell-containing component 811 such as a culture nutrient medium, M199, RPM1, or DMEM, or a physiological solution such as saline. Cell stabilizer 808 contains serum or no serum. It may or may not contain a buffer. The most common substance that can be used as the cell stabilizing substance 808 is a cell culture medium, but those skilled in the art can recognize that the medium described below is a solute-containing solution that can stabilize the cells to be stored. Would. The cell stabilizing medium 808 is of a sufficient amount such that the cell-containing component 811 does not undergo significant changes in the environment over time, for example, due to changes in the cell-containing component caused by cell metabolism. In general, properly maintaining the environment of a cell requires a greater amount of the cell stabilizing medium 808 than the volume of the component 811 containing the cell. The volume ratio of cell stabilizing medium 808 to cell-containing component 811 ranges from 5: 1 to 200: 1. If a longer storage time is required, a larger ratio can be used.
[0063]
Cell stabilizing medium 808 can be introduced into cell receiving chamber 809 in various ways. For example, if the cell stabilizing medium 808 is stable to a sterilization procedure (eg, heat sterilization in saline or gamma radiation to the cell culture medium), the cell stabilizing medium 808 will cause the package to be sterilized. Before being sealed in the stabilization chamber. This procedure eliminates the need for a separate port for the introduction of the cell stabilizing medium. As another example, as shown in FIG. 12, the cell stabilizing medium 908 is inserted into the stabilizing chamber 909 after sterilizing the package through the access opening 920 of the stabilizing chamber 909. The cell stabilizing medium 908 passes the cell stabilizing medium 908 through a 0.2 micron filter before introducing it into the stabilizing chamber 909.
[0064]
Referring again to FIG. 11, after filling the cell storage chamber 807 with the cells 811, the cells 811 in contact with the cell stabilizing medium 808 are stored in a suitable storage state. Generally, cells are housed at a temperature between 1 ° C and 40 ° C. The gaseous atmosphere surrounding the containment device contains 5% CO2 depending on whether the walls of the containment device are gas permeable and whether the CO2 atmosphere is advantageous for certain cell types. Cell containment times are considered over hours to days to weeks. In a preferred embodiment, the cells are housed for 14 days, but a formal USP bactericidal test involving a 14 day culture period has been performed to confirm the sterility of the package.
[0065]
The volume and type of cell stabilizing medium 808 will vary depending on the desired shelf life of the cells. Changes in storage temperature, cell density, and cell type affect the shelf life of stored cells. One skilled in the art will optimize all of these parameters to optimize the package for the desired shelf life. For example, increasing the ratio of media to cells increases the weight of the package and degrades its handling characteristics, but prolongs shelf life. As another example, in one embodiment of the storage device of the present invention, old media can be withdrawn and new media replaced periodically to increase the shelf life of cells without increasing the weight of the package. . Similarly, the shelf life of most cells is prolonged by lowering the storage temperature, making it possible to reduce the medium to cell ratio and reduce the package weight at similar storage times.
[0066]
Stabilization chamber 809 holds cell stabilizing medium 808 in a compact and operable form. The stabilization chamber 809 holds the cell stabilizing medium 808 inside its wall and allows for the exchange of desired components between the cell stabilizing medium 808 and the cell-containing component 811. The stabilizing chamber 809 including the access opening 810 is heat-sealed and connected to the access opening 810. Stabilizer chamber 809 is made of a suitable material to hold cell stabilizing medium 808 and to connect to access opening 810. Stabilizer chamber 809 is preferably made of polyethylene if access opening 810 is made of polyethylene to facilitate heat sealing of these two parts. The stabilization chamber 809 is made of a flexible material such as E. coli. I. Made from polyester, SCLAIR, TYVEK, paper, or foil, such as MYLAR from duPont de Nemours and Company. Access opening 810 is made of a material suitable for being connected to the stabilizing chamber, such as polyethylene, if stabilizing chamber 809 is made of polyethylene. The material capable of contacting cells, including the cell containment solution 811 or cell stabilizing medium 808, stabilization chamber 809, access opening 810, cell chamber 807, injection site, liquid transporter, is made from a biocompatible material .
[0067]
The access opening 810 allows the liquid carrier 805 to insert a component 811 containing cells into the cell receiving chamber 807 from outside the outer sterile container 804. The access opening 810 is connected to the cell storage chamber 807 and the stabilization chamber 809. Access opening 810 is preferably connected to injection site 806. The injection site 806 maintains the sterility of the cell-containing component 811 by penetrating materials other than the material that can penetrate the injection site 806, such as the liquid carrier 805 and its contents. The injection site 806 is made of a material that is opened after removing the penetrator. For example, the injection site 806 is made from rubber and polycarbonate. The injection site 806 can be made of a biocompatible material suitable for being connected to the stabilizer chamber 809, such as polyethylene if the stabilizer chamber 809 is made of polyethylene.
[0068]
Passage 812 traverses forming conduit 803. The passage 812 is capped by, for example, a dead-end plug. Passage 812 includes liquid transporter 805. The liquid carrier 805 can introduce the component 811 containing cells from the outside of the outer container 804 to the inside of the cell storage chamber 807 without opening the outer sterile container 804. Liquid transporter 805 can traverse forming conduit 803, access opening 810 and injection location 806. The liquid carrier 805 allows liquid inserted at one end of the liquid carrier 805 to exit from the opposite side of the liquid carrier. In one embodiment, the liquid transporter 805 is a KLEEN-NEEDLE as shown in US Pat. No. 5,088,984 to Field et al. And US Pat. No. 5,098,395 to Field et al. (Tri-State Hospital Supply Corporation) or KLEEN-NEEDLE configured by selectively omitting one or more structural parts. The dead-end plug 802 is attached to the liquid carrier 805 as a cap. As another example, the liquid carrier 5 is completely removable and the dead-end plug 802 is capped on the molding conduit 3.
[0069]
The outer sterile container 804 prevents components 811 including cells from being contaminated. The outer sterile container 804 surrounds the cell storage chamber 807 and the stabilization chamber 809. The outer sterile container 804 is surrounded and connected by a molded conduit 803 to prevent the transfer of unwanted material from outside the outer sterile container 804 to the inside of the outer sterile container 804. Outer sterile container 804 and molded conduit 803 are made of a material suitable for connecting to each other, such as polyethylene. Non-limiting examples of suitable fixation processes are made from heat-sealed and suitable materials, for example, polyesters such as MYLAR, SCLAIR, TYVEK, paper or foil.
[0070]
The outer sterile container 804 can be handled by non-sterile workers or assistants without the sterility of the stabilization chamber 809. The outer sterile container 804 is made from paper or foil, such as polyester or TYVEK. Outer sterile container 804 has an end that includes peelable member 825. The stabilizing chamber 809 can be removed to expose it. The peelable member 825 can be formed of a material that can be easily removed. For example, the peelable member 825 can be made from TYVEX, paper, nylon, or foil. Peelable member 825 is a breathable or non-breathable material. Generally, the non-breathable, peelable material is made from plastic. Non-breathable, peelable members are two layers coated with an adhesive that can separate the two layers of the peelable member to facilitate removal. The breathable and peelable material may be coated or uncoated. An uncoated peelable material creates a stronger seal, but is hard to open. As another example, the peelable member 825 is constantly connected to one or more upper and lower layers such that opening the peelable member 825 removes the upper and lower layers. Further, the peelable member 825 is a ruptured strip as disclosed in US Pat. No. 4,367,816 to Wilke. Further, the peelable member 825 is a sealing edge that can be easily torn or cut. When opening the sterile container 804 with the peelable member 825, the releasable container can be easily removed from the storage package.
[0071]
The aseptic container 804 is handled by a sterile operator and the releasable container 832 is opened such that the releasable container 832 is provided to the aseptic operator or the releasable container 832 without sacrificing the sterility of the releasable container. Is done. Further, the second outer container 801 completely surrounds the outer sterile container 804 during sterilization of the storage package and includes a peelable member or a tear strip as described above. Facilitating opening of the second outer container 801 to fill the cell receiving chamber 807.
[0072]
When using a cell storage device that includes an integral media reservoir to stabilize stored cells, the procedure for supplying cells is similar to the method used for other cell storage and transport procedures of the present invention. is there. The following description of the method of providing a releasable container using FIG. 11 as an example applies to all drawings. In general, both cell storage chamber 807 and stabilization chamber 809, along with releasable container 832, are released from the package to a sterile area. If the cell storage chamber 807 is the barrel of a syringe, the cells may be supplied manually by pressing the plunger or a suitable cannula may be attached to the syringe. If the cell storage chamber 807 is a flexible tube, the contents are pushed out by hand by squeezing the tube. The component 811 containing cells contained inside the cell receiving chamber 807 can be transferred to another component, for example, a syringe. Cells from the cell receiving tube are pushed into the barrel of the syringe and injected at the desired location.
[0073]
As shown in FIG. 12, an access opening 920 containing and storing package 909 connected to the stabilizing chamber 909 but not connected to the cell containing chamber 907 is shown. The access opening 920 may be used to initially and optionally periodically cycle cells to periodically insert a cell stabilizing medium 908, for example, to increase storage time or promote new cell growth of the cell-containing component 911. Allows introduction of a stabilizing medium 908.
[0074]
As shown in FIG. 12, in one embodiment of a storage package having one or more access openings, the access openings 920 allow the liquid transporter 905 to provide cell stabilization from outside the liquid transport outer sterile container 904 to the stabilization chamber 909. The medium 908 can be inserted. Liquid transporter 905 traversing passage 912 is a preferred method of introducing cell stabilizing medium 908 inside stabilization chamber 909. Access opening 920 is connected to stabilization chamber 909. Stabilizer chamber 909, if made from polyethylene, is made of a biocompatible material to connect to stabilizer chamber 909, such as polyethylene. Preferably, access opening 920 includes an injection location 916. The injection site 916 is fixed to the access opening 920 and the stabilization chamber 909. The injection site 906 maintains the sterility of the cell stabilizing medium 908 by preventing anything other than material that can penetrate the injection site 916, such as the liquid transporter 905, from penetrating the injection site 916. Injection site 916 is made from a material as described above. The cell storage chamber 907 and the stabilization chamber 909 have a releasable container 932. The outer sterile container 904 completely surrounds the stabilizing chamber 909 and includes a peelable member or rupture strip as described above. Optionally, the second outer container 901 completely encloses the outer sterile chamber 904 or includes a peelable member or a rupturable strip as described above.
[0075]
In another embodiment of a storage package having a plurality of access openings as shown in FIG. 12, additional passages in addition to passages 912 traverse shaped conduit 903. The added passage is capped, for example, by a dead-end plug. Preferably, the additional passage includes an additional liquid carrier. The added liquid carrier 915 introduces the cell stabilizer 908 from inside the outer sterile container to the inside of the stabilization chamber 909 without opening the outer sterile container 904. Also, additional liquid carriers traverse the forming conduit 903, the outer sterile container 904, and the access opening 920. If the injection site 916 is connected to the access opening 920, the additional liquid carrier will traverse the injection site 916. The added liquid carrier is one in which the inserted liquid at one end can exit from the other end. In one embodiment, the additional liquid carrier is KLEEN-NEEDLE as described above.
[0076]
As shown in FIG. 13, a storage package 1010 according to another embodiment of the present invention is shown. The storage package 1010 handles a solid tissue sample or a solid material such as a polymer matrix suitable for forming or expanding cells containing a polymer matrix or an effective amount of discrete human cells and breast tissue. It is particularly suitable, but works well with other cell-containing materials or liquids. Solids comprising cells generally within this embodiment of the invention are described in US Pat. No. 5,716,404 to Vacanti et al., Entitled "Methods for Augmenting or Regenerating Breast Tissue." I have. In a typical example, a stabilizing chamber 1039 surrounds a cell-containing solid 1037 and a cell stabilizing medium 1039. Accordingly, the stabilization chamber 1039 corresponds to the releasable container of FIGS. The cell-containing solid 1037 allows the liquid to contact the cell stabilizing medium 1038 and allows the components of the medium to diffuse into the cells 1041. Further, the cell-containing solid 1037 is surrounded by a semi-permeable membrane similar to the cell-containing wall of FIGS. Stabilizer chamber 1039 is made of the materials described for similar components in other embodiments. The cell-containing solid 1037 can be surrounded by a porous wall as described above. The cell stabilizing medium 1038 is bounded by a stabilizing chamber 1039. Preferably, the cell stabilizing material 1038 surrounds the cell-containing solid 1037 so that the desired components can be maximally exchanged between the cell stabilizing material 1038 and the cells 1041. Cell stabilizer 1038 has a stabilizing medium as described above. The volume ratio of the cell stabilizing material 1038 to the cell-containing solid 1037 is as if connected for other embodiments. The outer sterile container 1034 completely surrounds the stabilization chamber 1039. An outer sterile container 1034 completely surrounds the stabilization chamber 1039. The second outer container 1031 includes the peelable member 1032 as described above. Access opening 1040 intersects the second outer container. As another example, access opening 1040 is a junction between outer sterile container 1034 and second outer container 1031 as shown in FIG. The second outer container 1031 and the outer sterile container 1034 are made of the flexible material described above. Further, any or all of the components of the storage package 1010 can be replaced with the same components as described for other embodiments.
[0077]
After sterilizing the storage package 1010, the cell-containing solid 1037 can be aseptically inserted into the access opening 1040 through a sterile hood or other environment suitable for aseptically filling. After inserting the cell-containing solid 1037, the access opening 1040 may be sealed by sealing means, including those described above. Generally, the cell-containing solid 1037 is placed in the stabilizing chamber 1039 when or before it is placed in the inner sterile chamber 1034.
[0078]
Optionally, the liquid transporter has traversed the access opening 1040 through the stabilization chamber 1039 for media exchange during storage. As another example, the liquid carrier has traversed the second outer container 1031 and the outer sterile container 1034 by a port other than the access opening 1040 for media exchange during storage.
[0079]
One embodiment of the releasable container of FIGS. 11 and 12 is shown in FIG.
The coated syringe device 1100 is enclosed inside the outer sterile container of the storage device as shown in the embodiment in FIGS. Referring again to FIG. 14, the coated injection device 1100 is positioned inside the outer sterile container of FIGS. 11 and 12 and the outer sterile container is released to allow for the storage of the component 1111 including cells. When released, it is released so that a sterile worker can inject the component 1111 containing cells into a desired location. The coated injection device 1110 has a syringe 1120 surrounded by a jacket 1130. The surface area of the syringe 1120 in contact with the cell stabilizer 1108 is less than or equal to a maximum. The wall of the syringe 1120 is made of a porous material as described above to allow for the exchange of desired components between the cell-containing components 1111 and the cell stabilizer 1108.
[0080]
In the embodiment of the releasable container shown in FIG. 15, the plunger storage device 1200 is enclosed inside the outer sterile container of the storage device as shown in the embodiment of FIGS. 10, 11, 12 and 13. I have. Referring again to FIG. 15, the plunger storage device 1200 allows for the storage of the component 1211 containing cells and allows a sterile operator to inject the component 1211 containing cells into a desired location. The plunger storage device 1200 has a barrel 1201 and a plunger shaft 1202. Plunger shaft 1202 is removable from barrel 1201. The barrel 1201 can hold a component 1211 including cells. Plunger shaft 1202 can hold cell stabilizing medium 1208. Plunger shaft 1202 has a porous wall 1204, which is connected to the end of plunger shaft 1204 opposite plunger handle 1206. The porous wall 1204 is made from a porous material as described above to allow for the exchange of desired components between the cell-containing component 1211 and the cell stabilizing medium 1208. Plunger barrel 1201, plunger handle 1206, and plunger shaft 1202, except for the porous wall, are made of a suitable impermeable rigid material.
[0081]
If the plunger shaft 1202 is manufactured to include the porous wall 1204 and the cell stabilizing medium 1208 in place, the plunger storage device 1200 may be placed in a storage package according to an embodiment of the present invention and sterilized. Is done. After sterilization, the cell-containing component 1211 is introduced as described herein. As another example, the injection barrel 1201 and the plunger shaft 1202 are separately sterilized, and the cell-containing component 1211 is placed in the barrel 1201, then the porous wall 1024, the cell stabilizer 1208 and the plunger shaft 1202 are placed in the syringe barrel 1201. . Thus, the assembled plunger storage device 1200 is placed in the storage package of the present invention, for example, by insertion through the port 724 of FIG. 10 and the access opening 1040 of FIG.
[0082]
In the embodiment shown in FIG. 16, a media packet device 1300 having a syringe 1300 is enclosed inside an outer sterile container of a storage device as shown in FIGS. Referring again to FIG. 16, a media packet device having a syringe 1300 enables storage of the cell-containing component 1311 and allows a sterile worker to inject the cell-containing component 1311 into a desired location. A media packet device having a syringe 1300 has a syringe barrel 1301 that can hold a component 1311 including cells and can hold a media packet 1308. Media packet 1303 can hold cell stabilizer 1308. The wall of the media packet 1303 can hold the cell-containing component 1311 and the cell stabilizer 1308. The cross-sectional area of each media packet 1303 at any angle is preferably greater than the cross-sectional area of the syringe orifice 1307 so that when the syringe plunger 1309 is depressed, components 1311 containing cells can exit the syringe orifice 1307. However, the media packet 1303 cannot exit the syringe orifice 1307. The media packet 1303 is placed in the syringe barrel 1301 in front of the syringe plunger 1309, which is then inserted into the syringe barrel 1301 over a limited distance. Syringe barrel 1301 and syringe plunger are made from a rigid, impermeable solid formed into the desired shape.
[0083]
If the cell stabilizing medium is stable for sterilization, the assembled media packet device syringe 1300 can be placed in place inside the outer sterile container introduced after sterilization as described for the other embodiments. Sterilized in. As another receptacle, the pre-sterilized syringe barrel 1301 is filled with a mixture of the cell-containing component 1311 and the media packet 1303 before the pre-sterilized syringe plunger 1309 is inserted and the assembled media packet device syringe 1300 is inserted through access opening 724 or access opening 1040 of FIG. 10 for storage.
[0084]
In the embodiment shown in FIG. 17A, a storage packaging device 1405 having a syringe 1405 is enclosed in a sterile container 1430. The syringe 1405 has a plunger 1409, a porous sleeve 1418, and a container 1412. The sterile container 1430 has an outwardly extending conduit 1424, an end 1425 connected to the conduit 1424, and an inwardly extending housing 1470. Housing 1470 has needle 1420. Syringe 1405 is in communication with end 1425 of sterile container 1430 via needle 1420.
[0085]
Syringe 1405 can be used to contain labile substances, such as components containing cells, in the following method of sterilization. An outer syringe 1460 holding a component 1410 containing cells is connected and used to inject the component 1410 into the end 1425. During injection, components including cells move through conduit 1424 and needle 1420 to porous sleeve 1418 of syringe 1405. Cell stabilizing medium 1440 is located in syringe 1405 between container 1412 and porous sleeve 1418 prior to injection of the labile material. A porous sleeve 1418 made from the porous material described in the previous embodiment allows the cell stabilizing medium 1440 to contact the component 1410 containing cells. However, as shown in FIG. 17B, when the plunger 1409 is activated, the cell-containing component 1410 is expelled through the tip of the syringe 1405. This is because cell stabilizing medium 1440, but not cells, passes through porous sleeve 1418.
[0086]
The embodiments described above are applicable to solid products as well as components including cells, which are products of the liquid type. As another example, the cell-containing gel component can be introduced into porous sleeve 1418 in liquid form and become a gel itself. For components that include cells having a solid form, a sealable phase tube can be used to insert the solid into the porous sleeve.
[0087]
In the embodiment shown in FIG. 18, porous sleeve 1418 and plunger 1409 are removed from syringe 1405. The drawing on the left shows the syringe 1405 after removal from the sterile container 1430 as in the embodiment of FIG. The container 1412 and the cell stabilizing material 1440 are removed from the syringe 1405, thereby leaving a porous sleeve 1418 having a cell-containing component 1450, as shown in the central drawing of FIG. The porous sleeve 1418, plunger 1409, and cell-containing component 1450 can be placed in an empty syringe 1405 as shown in the drawing to the right.
[0088]
As shown in another embodiment shown in FIG. 19, the syringe 1600 has a plunger 1610 and a valve 1630. Syringe 1600 can hold a component 1620 including cells in the form of a gel rod and a cell stabilizer 1640. Valve 1630 is provided for discharging cell stabilizing material 1640. Valve 1630 is provided with a porous filter so that only cell stable material exits valve 1630 and no unstable material exits.
[0089]
In another embodiment, shown in FIG. 20, the cell-containing component 1720 is drawn from a first container 1760 to a second container 1750. As shown in the drawing on the left, containers 1760 and 1750 are connected along an axis. The container 1760 has a porous sleeve 1770 that separates the cell-containing component 1720 from the cell stabilizing material 1740, but allows for liquid-to-liquid contact between the two. The plunger 1710 of the container 1750 is pulled upward, and the component 1720, including cells, is drawn into the second container 1750. As the porous sleeve 1770 allows the cell stabilizing material 1740 to pass through the porous sleeve 1770 instead of the cell-containing component 1720, only the cell-containing component 1720 flows into the second container 1750 as shown in the drawing on the right. .
[0090]
As shown in FIG. 21, a method and apparatus according to the present invention for transferring a cell storage chamber 1860 and a cell stabilizing material 1870 to a container 1820 having a sterile container 1830 is shown. The upper drawing of FIG. 21 shows a connector 1840 connecting product container 1820 to syringe 1830 within sterile container 1830. Syringe 1825 is connected to syringe 1815 through connector 1850. Plunger 1810 extends through container 1820 and sterile container 1830. Plunger 1810 extends through container 1820 and sterile container 1830. Cell containing material 1860 of syringe 1815 is drawn into container 1820 by pulling plunger 1810 away from syringe 1825. After the material containing the cells has been drawn into the container, the cell stabilizing material 1870 can be replaced with a syringe to inject into the container 1820. When container 1820 receives cell stabilizing material 1870 and cellular material 1860, syringes 1815 and 1825 are separated from sterile container 1830, and sterile container 1830 is cut and sealed.
[0091]
In another embodiment shown in FIG. 22, the shape of the unstable gel 1920 is such that when the syringe 1900 is inverted, the gel does not block the opening of the syringe so that the cell stabilizing medium does not flow. I have.
[0092]
In another embodiment of FIG. 23, the plunger 2040 has a filter at the tip so that the cell stabilizing material can pass through the chamber 2030 and be stored when the plunger is activated.
[0093]
As shown in another embodiment of FIG. 24, an unstable gel rod 2120 is formed at the end of a plunger 2130 and is located inside a container 2100 holding a cell stabilizer 2110. Unstable gel rod 2120 can be removed from container 2100 by lifting plunger 2130 and placing it in empty container 2140 as shown from left to right in the figure.
[0094]
FIG. 25 shows a storage device according to another embodiment of the present invention. The storage device 2200 has a syringe barrel 2208, a porous sleeve 2220, and plungers 2230 and 2240. The porous sleeve 2220 is surrounded by a container 2205. The porous sleeve 2220 allows the unstable gel rod 2250 inside the container to come into contact with the cell stabilizer 2210 as shown in Step 1. Plunger 2230 has a predetermined length that pushes the unstable gel rod against syringe barrel 2208 when fully pushed as shown. Plunger 2240 has a length that pushes the unstable gel rod out of syringe barrel 2208 when fully pushed and away from storage device 2200 as shown in FIG.
[0095]
Another embodiment of the present invention is shown in FIG. The storage device 2300 has a syringe 2305 with plungers 2310 and 2320. The plunger 2310 has a filter tip 2340 such that when activated, the cell stabilizing material 2325 is filtered out of the syringe and the unstable gel 2315 flows into the plunger 2310 chamber. Plunger 2320 is actuated to release the unstable gel from the syringe.
[0096]
Although the aseptic storage package of the present invention has been described in terms of a working room including a sterile area where the package is opened and used by aseptic assistants and aseptic workers, those skilled in the art may include aseptic manufacturing facilities or aseptic areas of outpatients. It easily applies to other environments with similar requirements. A non-sterile assistant can replace the mechanical means released by the second outer container, or one hand of a sterile worker, while preventing the other hands remaining in the sterile area from becoming dirty.
[0097]
The storage effect of cell manufacturing capacity was tested on a recent device using chondrocytes that diffuse into the alginate hydrogel. Chondrocytes are obtained by cartilage biopsy taken from normal human volunteers. Chondrocytes are described in Atala et al. Urol 152: 641 and Klagsbrunn (1979) "A large-scale preparation of chondrocytes", isolated from biopsies using collagen digestion as described in Meth Enzymol 58: 560. Inflated in isolated T-flasks and roller bottle cultured for 4-8 weeks.
[0098]
Test samples suspend cells from M199 expanded chondrocytes and combine them with 2.2% Pronova UPMVP sodium alginate. A hydrogel aliquot is formed by combining 0.25 mL of M199 with 2.75 mL of a cell alginate suspension containing 6.0 mg of solid calcium sulfate. The final cell concentration of the hydrogel was 30 × 10 6 cells / ml.
[0099]
The cell viability of aliquots of these hydrogels under low cell density conditions (ie, 3.8 × 10 ⁴ (Cells / ml) compared to regular cell storage. Aliquots of hydrogel were stored aseptically with or without an enclosure of room temperature or 4 ° C. cell culture medium M199 (30 mL of media for each 3 mL of hydrogel containing cells). The gaseous atmosphere for a room temperature storage room containing a sample with a surrounding bath of M199 is 5% CO2. ₂ Contains.
[0100]
The viability of cells housed under various conditions determines the viability of the cells in solution by removing a portion of the hydrogel, lysing it using a chelating reagent, and exclusion of trypan blue. The results are shown in Table 1. As shown, a hydrogel housed at room temperature with a bath of culture medium surrounding the hydrogel retains cell viability as well as normal cell storage conditions (ie, low cell density or high medium to cell ratio). . Cell viability decreases rapidly under all other conditions. This is an important aspect where cell density (ie, cell-to-medium ratio) affects cell viability upon storage, but cells surround a hydrogel that effectively reduces cell-to-medium without actual dilution. Providing a reservoir of media is stable to accommodate the cell density in a hydrogel containing cells without diluting.
[0101]
Although the present invention has been described in various different embodiments, it has been specialized to guide the structure or design or operation of other embodiments, particularly the structure of materials and dimensions. Accordingly, the particular description of one embodiment does not limit the scope of the invention, but is limited only by the claims.
[Brief description of the drawings]
FIG.
FIG. 1A is a plan view of a storage package according to one embodiment of the present invention.
FIG. 1B is a side view of a storage package according to one embodiment of the present invention.
FIG. 1C is an end view of a storage package according to one embodiment of the present invention.
FIG. 2
FIG. 11 is a view illustrating a storage package including a plurality of inner containers according to another embodiment of the present invention.
FIG. 3
FIG. 7 illustrates a storage package with a thermoformed rigid tray according to another embodiment of the present invention.
FIG. 4
FIG. 11 is a view illustrating a storage package having a flexible bag outside an inner container according to another embodiment of the present invention.
FIG. 5
FIG. 11 is a view illustrating a storage package including a plurality of outer packages according to another embodiment of the present invention;
FIG. 6
FIG. 9 is a view illustrating a storage package including a plurality of packages according to another embodiment of the present invention.
FIG. 7
7 is an example of the storage package of FIG. 6 in use.
FIG. 8
FIG. 7 is a diagram illustrating another example of the storage package of FIG. 6 in use.
FIG. 9
9 is a view of a storage package according to another embodiment of the present invention.
FIG. 10
FIG. 9 is a side view of a storage package according to another embodiment of the present invention.
FIG. 11
FIG. 9 is a plan view of a storage package according to another embodiment of the present invention.
FIG.
FIG. 9 is a perspective view of a storage package according to another embodiment of the present invention.
FIG. 13
FIG. 9 is a view of a storage package according to another embodiment of the present invention.
FIG. 14
FIG. 9 is a perspective view of a storage package according to another embodiment of the present invention.
FIG.
FIG. 9 is a perspective view of a storage package according to another embodiment of the present invention.
FIG.
FIG. 9 is a side view of a storage package according to another embodiment of the present invention.
FIG.
17A and 17B are views of a storage package according to another embodiment of the present invention.
FIG.
FIG. 9 is a perspective view of a storage package according to another embodiment of the present invention.
FIG.
FIG. 9 is a view of a storage package according to another embodiment of the present invention.
FIG.
FIG. 9 is a view of a storage package according to another embodiment of the present invention.
FIG. 21
FIG. 9 is a view of a storage package according to another embodiment of the present invention.
FIG.
FIG. 9 is a perspective view of a storage package according to another embodiment of the present invention.
FIG. 23
FIG. 9 is a perspective view of a storage package according to another embodiment of the present invention.
FIG. 24
FIG. 9 is a view of a storage package according to another embodiment of the present invention.
FIG. 25
FIG. 9 is a view of a storage package according to another embodiment of the present invention.
FIG. 26
FIG. 9 is a view of a storage package according to another embodiment of the present invention.

Claims (22)

An outer container,
An access opening traversing the outer container;
A cell storage chamber,
A stabilization chamber, connected to the cell storage chamber through a semi-permeable barrier, wherein the semi-permeable barrier is capable of passing molecular species, but not allowing the passage of living cells, A stabilization chamber that forms at least a portion of the barrier between the chamber and the cell storage chamber, wherein the outer container completely surrounds the cell storage chamber and the stabilization chamber;
Means for removing the outer container. The storage package according to claim 1, wherein an unstable liquid or solid is in the cell storage chamber. The storage package according to claim 1, further comprising a second outer container completely surrounding the outer container, and means for removing the second outer container. An outer container,
An unstable substance storage chamber;
A stabilizing chamber, wherein the stabilizing chamber surrounds at least a portion of the unstable material through a semi-permeable barrier, wherein the semi-permeable barrier is capable of passing molecular species. A storage device that cannot allow unstable substances to pass therethrough and forms at least a part of the barrier between the stable tank chamber and the unstable substance storage chamber. The storage device according to claim 4, further comprising means for discharging the unstable substance from the storage device. The storage device according to claim 5, wherein the unstable substance storage chamber is a syringe having a plunger, and the means for discharging the unstable substance is the plunger. The unstable substance storage chamber is a syringe having first and second plungers,
The means for discharging the unstable material is the first and second plungers, wherein the first plunger is surrounded by the stable material chamber when the first plunger is fully pressed. Having a predetermined length that is transported from a portion of the unstable substance storage chamber to another part of the unstable substance storage chamber that is not surrounded by the stable substance chamber;
The second plunger is configured such that when fully pressed, the unstable substance is discharged from the other portion of the unstable substance storage chamber not surrounded by the stable substance chamber to the outside of the storage device. The storage device according to claim 5 having a length of: The storage device according to claim 5, wherein the unstable substance is discharged from the storage device without discharging the stable substance. The storage device according to claim 5, wherein the unstable substance storage chamber is detachable from the storage device. The storage device according to claim 4, further comprising means for discharging the stabilization tank from the storage device. The storage device according to claim 10, wherein the stable material is discharged from the storage device without discharging the unstable material. The storage device according to claim 4, wherein the unstable substance is a component containing cells. An outer container,
A stabilizing chamber and an unstable substance chamber containing a stable substance and an unstable substance, at least a part of which is surrounded by the outer container;
Means for separating at least a portion of the stable material from the unstable material. A semipermeable barrier that surrounds a portion of the stabilizer chamber and the unstable material chamber that is not surrounded by the outer container, wherein the semipermeable barrier allows the passage of molecular species but is unstable. 14. The storage device according to claim 13, wherein the substance cannot pass through. The means for separating at least a portion of the stable material from the unstable material is a plunger connected to the semi-permeable barrier, wherein the plunger, when depressed, includes the stabilizing chamber and the unstable material chamber. 15. The storage device according to claim 14, wherein the volume of the liquid is reduced and the stabilizer chamber is pushed to filter through the semi-permeable barrier to separate from the unstable material. The means for discharging the stable substance comprises a syringe barrel surrounding the rest of the stabilizer and the unstable substance chamber not surrounded by the outer container, wherein the syringe barrel comprises first and second syringe barrels. An end, wherein the first end is an open end connected to the stabilizing vessel and the unstable material chamber so that the barrel can communicate with the stable layer and the unstable material chamber; The second end has a movable plunger, the syringe barrel is connected to the semi-permeable barrier, and the syringe barrel connected to the semi-permeable barrier is pressed against the syringe barrel. When engaged with the inside of the outer container, reducing the predetermined volume of the stabilization tank and the unstable substance chamber, pushing the stabilization tank, filtering through the semi-permeable barrier, and separating from the unstable substance The storage device according to claim 14. 17. The plunger of claim 16, wherein the plunger has a predetermined length such that at least a portion of the unstable material is ejected from the storage device when the plunger is fully pushed and the syringe barrel is fully pushed. Storage device. The storage device according to claim 17, wherein the unstable substance is a component containing cells. Sterilizing a storage package having a second outer container completely surrounding the outer container and a liquid transport conduit traversing the outer container, wherein the outer container and the second outer container are removable; Sterilizing the storage package, wherein the outer container completely surrounds the cell storage container;
Wherein said liquid introduction conduit inserts liquid into said cell storage container through said liquid introduction conduit from outside said second outer container so as not to prevent sterility inside said outer container, The liquid contains the desired living cells suspended therein, the liquid has no contaminating cells other than the desired living cells, the liquid is in contact with a cell stabilizing medium, and the cell stabilizing medium is In an unstable chamber separated from the liquid by a semi-permeable barrier, wherein the semi-permeable barrier allows the passage of molecular species between the liquid and the cell stabilizing medium; The container completely surrounds the stabilization chamber, inserting a liquid into the cell storage container,
Removing the second outer container;
Opening the outer container in the vicinity of the sterile area,
Supplying the liquid from the cell storage container to the sterile area, and, after the step of inserting the liquid into the cell storage container, the storage package is not finally sterilized. A method of supplying to a sterile area. Sterilizing a storage package having a removable outer container and an access opening traversing the outer container;
Inserting the unstable liquid or solid into the outer container through the access opening from outside the outer container so that the unstable liquid or solid does not contaminate the sterility of the outer container. Inserting the unstable liquid or solid into the outer container, wherein the unstable liquid or solid is not sterilized following the step of inserting the liquid or solid;
Storing the storage package such that the unstable liquid or solid is supplied with the cell stabilizing medium through the semi-permeable barrier, wherein the semi-permeable barrier contacts the stabilization chamber. Wherein the stabilizing chamber contains the cell stabilizing medium, and the outer container contains an unstable liquid or solid that completely surrounds the stabilizing chamber. 21. The method of claim 20, wherein the unstable liquid or solid is inserted into a cell receiving chamber. Providing a storage package having an outer container, wherein the outer container surrounds a stabilizing chamber and a cell receiving chamber, wherein an unstable liquid or solid is in the cell receiving chamber and has access to the outer container. An opening, wherein the outer container aseptically supplies an unstable liquid or solid that is removable.