JP7200293B2 - Apparatus and methods for loading implantable devices with cells - Google Patents

Description

STATEMENT OF GOVERNMENT SUPPORT This work was made possible in part by a grant from the California Institute for Regenerative Medicine (Grant No. DR1-01423). The contents of this document are solely the responsibility of the inventors and do not necessarily represent the official views of CIRM or any other agency of the State of California.

The present invention relates generally to cell therapy and means and methods for loading and filling implantable devices with cells and sealing the cells to the device.

Cell replacement therapy for several diseases can be administered by transplanting cells, tissues, or organs to patients with a particular disease. A major obstacle to commercial cell therapy remains renewable cell sources and encapsulated sources that allow allogeneic protection against host immunity. Ideally, such an implantable device would allow alloprotection and minimize or eliminate the long-term use of immunosuppressants by patients.

Applicants have previously described both a renewable cell source and a macroencapsulated drug delivery system suitable for at least the purpose of delivering pancreatic progenitor cells to produce insulin in vivo in response to glucose stimulation. . For example, at least U.S. Pat. 2013, filed Dec. 12, 2013, entitled "IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND IMMATURE BETA CELLS," Mar. 7, 2014. U.S. Patent Application Publication No. 2004/0020005 filed on March 13, 2014 and entitled “IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND ENDOCRINE CELLS” filed March 13, 2014; Patent Document 6 entitled "3-DIMENSIONAL LARGE CAPACITY CELL ENCAPSULATION DEVICE" filed on December 7, Patent Document 7 filed on December 12, 2011, Patent Document 8 filed on December 12, 2011 , Patent Document 9 filed on May 31, 2012, Patent Document 10 filed on March 13, 2013, and "3-DIMENSIONAL LARGE CAPACITY CELL ENCAPSULATION DEVICE" filed on March 7, 2014 Patent Documents 11-18 entitled "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014; Patent Document 19 entitled "TOOLS AND INSTRUMENTS" filed on April 16, 2014; FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" and "CASE FOR AN ENCAPSULATION DEV U.S. Patent Application No. 2014/0161002 entitled “DEPLOYMENT TOOL FOR AN ENCAPSULATION DEVICE” filed on Apr. 16, 2014 entitled “SIZING TOOL FOR AN See U.S. Patent Application Publication No. 2004/0023005 entitled “ENCAPSULATION DEVICE” and U.S. Patent Application Publication No. 2014/0120028 entitled “FILL POUCH ASSEMBLY FOR ENCAPSULATION DEVICE” filed Apr. 16, 2014. All of these applications are incorporated herein by reference in their entireties.

The cell replacement therapy described herein and in Applicant's prior disclosure above generally relates to non-commercially available macroencapsulated implantable cell products (“combination”) for the treatment of diabetes. Semi-automated aseptic methods and equipment for loading and filling such implantable devices with cells do not exist, except for the methods and equipment described in detail below.

U.S. Patent Application No. 12/099,759 US patent application Ser. No. 12/618,659 US patent application Ser. No. 14/106,330 U.S. Patent Application No. 14/201,630 International Application No. PCT/US2014/026529 International Application No. PCT/US2014/022109 U.S. Design Application No. 29/408,366 U.S. Design Application No. 29/408,368 U.S. Design Application No. 29/423,365 U.S. Design Application No. 29/447,944 U.S. Design Application No. 29/484,363 U.S. Design Application No. 29/484,359 U.S. Design Application No. 29/484,360 U.S. Design Application No. 29/484,357 U.S. Design Application No. 29/484,356 U.S. Design Application No. 29/484,355 U.S. Design Application No. 29/484,362 U.S. Design Application No. 29/484,35 International Application No. PCT/US2014/034425 US patent application Ser. No. 14/254,844 U.S. patent application Ser. No. 29/488,209 U.S. Design Application No. 29/488,204 U.S. Design Application No. 29/488,191 U.S. Design Application No. 29/488,217 U.S. Pat. No. 5,349,166 U.S. Pat. No. 4,013,860 U.S. Pat. No. 7,226,425 U.S. Pat. No. 8,376,741 U.S. Pat. No. 5,267,464

Disclosed herein are instruments, apparatus, and/or instruments for aseptically loading and filling an implantable device with cells and sealing the device within at least one other sterile container.

In one embodiment, a sterile system is provided for loading the implantable device with cells. The system is coupled to (i) a source of cells and/or therapeutic agents and (ii) a pump for acquiring cells and/or therapeutic agents and dispensing the cells and/or therapeutic agents into the implantable device. a tube assembly; and (iii) at least two components that are adjustable to at least a first position and a second position, such positions being dependent on the function to be performed. , (iv) sealing means for selectively sealing the implantable device within a sterile container or package.

In one embodiment there is provided a cell loading system comprising a rotatable platform, the rotatable platform further comprising means for acquiring and dispensing said cells into an implantable device. . In one embodiment, the means for obtaining cells comprises a tube assembly. In one embodiment, the rotatable platform is positioned between about 0° and about 180°, preferably between 0° and about 90°, preferably about 90°, preferably about 45°. In one embodiment, the cell loading system can be manually operated, or can be fully automated or semi-automated. For example, in one embodiment, the cell loading system is semi-automated by removably connecting the tubing assembly to a pump and remotely controlling the pump. In a preferred embodiment, the cell loading system is semi-automated by removably connecting a tube assembly to an implantable device port and remotely controlling a pump to dispense cells within the tube assembly through the port into the device. be done. In one embodiment, the implantable device comprises pancreatic-type cells. In preferred embodiments, the implantable device comprises pancreatic-type cells and pancreatic progenitor cells.

In one embodiment, a method for loading an implantable device with cells comprises placing an implantable device having a device port in a compartment, the device port being in a tubing assembly comprising a cell reservoir. connected and the device is removably coupled to the rotatable platform; rotating the platform to a position between about 0° and about 180°; and separating the cells from the tube assembly into the implantable device. pouring, thereby loading the implantable device with cells. In one embodiment, the implantable device is located inside a sterile package. In one embodiment, the implantable device and sterile package are positioned between 45° and 90°. In one embodiment, the device port on the implantable device is sealed by a sterile means, which is the source that can seal the device port without sealing the sterile package containing the device. In one embodiment, the sterile means is a radio frequency (RF) energy source. In one embodiment, the cells loaded into the implantable device are cell clumps in suspension. In preferred embodiments, the cells are pancreatic-type cells or pancreatic progenitor cells.

In one embodiment, a method for expelling residual air from a bag, e.g., a device case storage bag, containing at least liquid medium by enclosing the bag within a first set and a second set of plates. , a first set of plates secures the bag, a second set of plates can open and close the bag, and sealing the second plates together forces residual air in the bag out of the bag, thereby provides a method by which residual air is released from the bag. In one embodiment, the first set of device case storage bags and plates are aligned to secure the bags onto the plates.

In one embodiment, a method for selectively aseptically sealing a material that is sensitive to radio frequency (RF) energy comprises sealing a first material that is sensitive to RF energy within a second material that is insensitive to RF energy. and simultaneously applying RF energy to a first material and a second material, wherein the first material sensitive to RF energy is sealed and the second material is insensitive to RF energy. is not sealed, thereby selectively sealing the RF sensitive material in an aseptic manner. In one embodiment, the RF sensitive material is polycarbonate-urethane, polyvinyl chloride (PVC), urethane, ethylene vinyl acetate (EVA), polyethylene vinyl acetate (PEVA), acrylonitrile butadiene styrene (ABS), or certain nylons or terephthalic acid It is composed of a biocompatible polymer selected from the group consisting of polyethylene. In another embodiment, the RF insensitive material is polyester film made from polyethylene terephthalate (trademark Mylar) or expanded polyethylene terephthalate (PET) or polychlorotrifluoroethylene (PCTFE) fluoropolymer film, high density polyethylene (HDPE), polystyrene, polyetheretherketone (PEEK), polypropylene, polytetrafluoroethylene (PTFE/Teflon), polyethylene, or polymethyl methacrylate, or epoxy, silicone, or parylene.

In one embodiment, a method for aseptically sealing a device having at least one device port comprises placing the device including the at least one port in a sterile container; selectively sealing while unsealing the sterile container. In one embodiment, sealing the device port includes RF energy. In another embodiment, sealing the device port includes a ring or band around the device port. In another embodiment, the sealing ring or band is crimpable.

In one embodiment, a method of loading cells into an implantable device comprising the steps of: first loading at least a predetermined flushing volume, a cell volume, and a priming volume into a tube assembly; and dispensing the priming volume from the tubing assembly into the implantable device, thereby loading the implantable device with cells.

Other embodiments of the invention are described with reference to the list of numbered paragraphs below.
1. A cell loading system comprising a rotatable platform, the rotatable platform further comprising means for acquiring cells and dispensing said cells into an implantable device.
2. further comprising a tube assembly,
2. The cell loading system of Claim 1, wherein the tube assembly is a cell reservoir containing a predetermined dose of cells.
3. 2. The cell loading system of Claim 1, wherein the rotatable platform is positioned between about 0[deg.] and about 180[deg.].
4. 2. The cell loading system of Claim 1, wherein the rotatable platform is positioned between about 0[deg.] and about 90[deg.].
5. 2. The cell loading system of claim 1, wherein the rotatable platform is arranged at about 90 degrees.
6. 2. The cell loading system of claim 1, wherein the rotatable platform is arranged at about 45[deg.].
7. 2. The cell loading system of claim 1, which is manual, or fully automated or semi-automated.
8. 8. The cell loading system of claim 7, automated by removably connecting the tubing assembly to a pump and controlling the pump.
9. 9. The cell loading system of claim 8, wherein the tubing assembly is removably coupled to the implantable device port and the pump dispenses cells within the tubing assembly through the port into the device.
10. 2. The cell-loading system of claim 1, wherein the cells are pancreatic-type cells.
11. 11. The cell loading system of claim 10, wherein the cells are pancreatic progenitor cells.
12. A method of loading an implantable device with cells, comprising:
a. placing an implantable device having a device port within the compartment, wherein the device port is coupled to a tube assembly with a cell reservoir and the device is removably coupled to a rotatable platform;
b. rotating the platform to a position between about 0° and about 180°;
c. dispensing cells from a tube assembly into an implantable device, thereby loading the implantable device with cells.
13. 13. The method of claim 12, wherein the device is located inside a sterile package.
14. 14. The method of claim 13, wherein the device and package are located on a rotatable platform and positioned between 45[deg.] and 90[deg.].
15. 15. The method of Claim 14, wherein the device port is sealed by aseptic means.
16. 16. The method of claim 15, wherein the aseptic means selectively seals the device port and does not seal the sterile package external to the device.
17. 16. The method of claim 15, wherein the sterile means is an RF seal.
18. 13. The method of claim 12, wherein the cells are cell clumps in suspension.
19. 13. The method of claim 12, wherein the cells are pancreatic-type cells.
20. A method for expelling residual air from a bag containing at least liquid medium, the method comprising providing a first set of plates and a second set of plates, the first set of plates securing the bag. and a method in which a second set of plates can open and close the bag, and sealing the second plate forces the residual air in the bag out of the bag, thereby releasing the residual air out of the bag.
21. 21. The method of claim 20, wherein the first set of bags and plates are aligned to secure the bags on the plates.
22. A method for aseptically selectively sealing a material that is sensitive to radio frequency (RF) energy, comprising:
a. placing a first material that is sensitive to RF energy inside a second material that is insensitive to RF energy;
b. simultaneously applying RF energy to the first material and the second material, wherein the first material that is sensitive to RF energy is sealed and the second material that is not sensitive to RF energy is not sealed, thereby , wherein the RF sensitive material is selectively sealed aseptically.
23. The RF sensitive material is from the group consisting of polycarbonate-urethane, polyvinyl chloride (PVC), urethane, ethylene vinyl acetate (EVA), polyethylene vinyl acetate (PEVA), acrylonitrile butadiene styrene (ABS), or certain nylons or polyethylene terephthalates. 23. The method of claim 22, comprising a selected biocompatible polymer.
24. RF insensitive materials include polyethylene terephthalate (trademark Mylar) or polyester films made from expanded polyethylene terephthalate (PET) or polychlorotrifluoroethylene (PCTFE) fluoropolymer films, high density polyethylene (HDPE), polystyrene, 22. A material according to claim 21, constituted by polyetheretherketone (PEEK), polypropylene, polytetrafluoroethylene (PTFE/Teflon), polyethylene, or polymethyl methacrylate, or epoxy, silicone, or parylene. Method.
25. A method for aseptically sealing a device having at least one device port, comprising:
a. placing a device with at least one port in a sterile container;
b. selectively sealing a device port within a sterile container while not sealing the sterile container.
26. 26. The method of Claim 25, further comprising RF energy to seal the device port.
27. 26. The method of Claim 25, further comprising a sealing ring or band around the device port.
28. 28. The method of claim 27, wherein the sealing ring or band is crimpable.
29. A method of loading an implantable device with cells, comprising:
(a) at least initially loading a tube assembly with a predetermined flush volume, cell volume, and priming volume;
(b) first dispensing the predetermined flushing volume, cell volume, and priming volume from step (a) into the implantable device, thereby loading the implantable device with cells.

The above-described and additional embodiments, features, and advantages of the present invention are disclosed and apparent from the following, particularly the description of preferred embodiments of the invention, the accompanying drawings, and the patent application: It will be clear from the claims.

For a more complete understanding of embodiments of the present invention and its advantages, reference is now made to the following description in connection with the accompanying drawings, which are briefly described below.

A priming and cell loading system, the assembly comprising a syringe and syringe pump, a dosing tube assembly, a rotatable platform removably coupled to a flexplate cradle, and a cell source (vial) and device loading pouch set. A rotatable platform consists of a multi-position block that can accommodate a stereoscopic body (DFPA), a DFPA nesting block, and a sliding carriage connecting the multi-position block and the DFPA nesting block, wherein the rotatable platform rotates between 0° and 180°. 1 is a perspective view of a priming and cell loading system that can be used; FIG. Fig. 3 is a perspective view of a dosing tube assembly; FIG. 1 is a perspective view of a priming and cell loading system, with dash-dot lines showing where a DFPA with a device case and an implantable device inside resides during priming and loading, according to one embodiment of the present invention. 1 is a perspective view of a device case containing an implantable device therein according to one embodiment of the present invention; FIG. FIG. 10 is a perspective side view of the priming and cell loading system with the rotatable platform rotated and positioned 90 degrees from the base, according to one embodiment of the present invention; 1 is a perspective view of a handheld radio frequency (RF) sealer in a retracted position, according to one embodiment of the present invention; FIG. 1 is a perspective view of a handheld radio frequency (RF) sealer in an engaged position sealing a device port according to one embodiment of the present invention; FIG. a device case storage bag holder having a first pair of holder plates and a second pair of rocking plates for holding a device case storage bag having an RF responsive or sensitive portion; and an adjustable opening and closing system for each plate of a pair of plates, wherein the holder moves the holder from a loading position below the sealing head assembly to open the device case storage bag. FIG. 10 is a perspective view of a device case storage bag sealer positioned on a sliding carriage that can be sealed. FIG. 11 is a larger perspective view of a device case storage bag holder with the device case storage bag open and unsealed, located on a sliding carriage and adjustable opening and closing system for the device case storage bag holder, in accordance with one embodiment of the present invention; is. FIG. 4B is a larger perspective view of the device case storage bag holder with the device case storage bag closed and sealed according to one embodiment of the present invention; FIG. 10 is a side view of the device case storage bag holder below the sealing head assembly, according to one embodiment of the present invention; 1 is a perspective view of a carrier bag for containing a device case storage bag and a sealer for sealing the carrier bag, according to one embodiment of the present invention; FIG. FIG. 4 is a flow chart showing the general steps for loading a tube assembly with predetermined flush volume, cell volume, and priming volume, according to one embodiment of the present invention; FIG. FIG. 4 is a flow chart showing the general steps for dispensing a flush volume, a cell volume, and a priming volume into a tube assembly, according to one embodiment of the present invention; FIG. FIG. 2 is a flowchart showing the overall steps for sealing a device, storing and sealing a device case storage bag, and sealing a transport bag, according to one embodiment of the present invention; FIG.

Further features and advantages of the present invention, as well as the structure and operation of various embodiments of the present invention, are described in detail below with reference to accompanying FIGS. Like reference numerals refer to like elements, and the invention is not limited to the elements described in the drawings or embodiments.

Although embodiments of the present invention are described in terms of implantable devices comprising pancreatic progenitor cells and/or immature beta cells, it will be appreciated by those skilled in the art that the present invention may be applied to, but not limited to, thyroid cells, parathyroid cells, pancreatic cells, enterocytes, thymocytes, hepatocytes, endocrine cells, skin cells, hematopoietic cells, bone marrow stem cells, kidney cells, muscle cells, nerve cells, stem cells, embryonic stem cells, lineage-restricted cells, progenitor cells, progenitor cells, gene tissue Cell mass suspensions, therapeutic agents, or mixtures thereof, including recombinant cells, tumor cells, and derivatives and combinations of those cells for the treatment of one or more diseases or disorders, including but not limited to diabetes It will be readily appreciated that it is applicable to macroencapsulation of any type of cell, including Also contemplated are cells that produce cell-based products such as proteins for therapeutic indications (eg, hormones and/or other proteins deficient in human diseases, etc.), antibodies, antibiotics, lymphokines, and the like. Those skilled in the art will also appreciate that the present embodiments are applicable to a variety of implantable device types, materials, sizes, and/or configurations.

When the term "device" or "implantable device" is used herein, according to embodiments of the present invention, including but not limited to the implantable devices of the present invention, the priming and loading described herein. refers to any macroencapsulation device or cell encapsulation device that can be used for Such macroencapsulation devices or cell encapsulation devices include, but are not limited to, applicant's US Pat. , and applicant's U.S. Patent No. 7, filed Dec. 12, 2011; Applicant's Patent Document 10 filed March 13, 2013; Applicant's Patent Document 11-18 filed March 7, 2014;

When the term "case" or "cage" or "device case" or "device cage" 74 is used herein, it refers to any container that can contain a device. The case can be used, for example, in priming and loading a device and sealing the device port to maintain the integrity and sterility of the device, according to embodiments of the present invention, and such a case can include: includes, but is not limited to, US Pat. U.S. Patent Application Publication No. 2004/0210002 entitled “CASE FOR AN ENCAPSULATION DEVICE” filed Apr. 16, 2014.

As used herein, a "filled pouch," "device-filled pouch," or "device-filled pouch assembly" or "DFPA" 62 refers to any container or pouch capable of containing a device and a case. DFPA can be used, for example, in priming the device, loading the device, and sealing the device to maintain the integrity and sterility of the case and device, according to embodiments of the present invention. Such DFPAs include, but are not limited to, Applicant's U.S. Pat. Applicant's U.S. Pat. No. 5,330,500, entitled "FILL POUCH ASSEMBLY FOR ENCAPSULATION DEVICE," filed on Jan.

When the term "device case storage bag" or "storage bag" 124 is used herein, any bag in which the device case and devices can be hermetically accommodated according to embodiments of the present invention. A bag or pouch or a sterilizable bag or pouch, such device case storage bag, having the name "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014. Included are the storage bags described in US Pat. In general, the device case storage bag 124 has an RF active portion.

When the term "transport bag," "transport package," or "transport pouch" 126 is used herein, it refers to, but is not limited to, device case storage bags, device cases, and devices according to embodiments of the present invention. Refers to any bag or pouch or sterilizable bag or pouch that can hermetically contain multiple elements, including a case, within such carrier bags, including but not limited to Included is the carrier bag used in Applicant's US Pat.

The terms "assembly", "system", "fixture", "apparatus", "component", "platform" and/or "means" 1, 2, 68, 76 are used herein. The terms have the same meaning and are used interchangeably according to embodiments of the present invention.

When "adjustable," "movable," or "multi-position" 14, 22, 58, 106 is used herein, it refers to, but is not limited to, lateral movement according to embodiments of the present invention. Components capable of movement, vertical movement, or rotation from 0 degrees to 180 degrees or more in various positions, or having open, semi-open, semi-closed, or closed configurations, and these refers to any means for realizing the configuration of

When the terms "fluid reservoir," "cell reservoir," "cell source," "cell container," and/or "aliquot vial" 36 are used herein, cells according to embodiments of the present invention are Refers to a tube or container that can be stored and held.

When the terms "cell" or "cell clump" are used herein, they may be used interchangeably depending on the context, but various embodiments are limited to such. is not intended to. Embodiments of the priming and loading system described herein may be utilized with various types of cell sources in various forms, not just clumps.

As used herein, the terms “pancreatic endoderm cells,” “PDX1-positive pancreatic endoderm,” “PEC,” and “pancreatic progenitor cells” refer to therapeutic cell sources according to embodiments of the present invention. , such therapeutic cell sources include, but are not limited to, Applicant's US Pat. Applicant's U.S. Pat. (PEC) AND IMMATURE BETA CELLS", filed March 7, 2014, and filed March 13, 2014 entitled "IN VITRO DIFFERENTIATION OF and Applicant's US Pat.

When the term "cell loading system" or "priming and cell loading system" or "loading system" is used herein, it means any system for loading therapeutic agents or cells into the device.

When the term "administration tube platform" or "tube rack" is used herein, it means any platform or rack that constitutes means for keeping the tube assembly held on the rack. .

When the terms "device loading port" or "device loading tube" or "device port" or "device tube" are used herein, agents and/or cells are primed or agents and/or cells are into the device and later to seal the device.

When "radio frequency", "electromagnetic energy", or equivalents thereof are used herein, in a manner that selectively seals certain thermoplastic membrane materials and does not seal other thermoplastic membrane materials. be.

When the term "cell dose" or "dose" is used herein, it generally refers to any number of cells or cell clusters or therapeutic agents. For example, a cell container or vial may have from 1 to 10 ⁶ , 10 ⁷ , 10 ⁹ or more cells, although in these embodiments any of the above amounts in one cell vial is , called the 1-cell dose and does not indicate the number of cells. The priming and cell loading system 1 has successfully tested low and high cell doses, therefore system 1 can accommodate varying volumes and therefore multiple cell doses. . In one embodiment, the system 1 may be one, two, depending on the number of cell doses needed for treatment and/or filling a particular size device or devices per manufacturing run. It can be programmed to store 3, 4, 5, etc. cell doses. Determination of the amount of cells for single cell doses and the amount of cells for multiple cell doses for this system does not require additional invention and is within the purview of those skilled in the art.

As used herein, "coupling system," "mounting system," "sealing system," "locking system," "latch system," or equivalents are defined as hinges, snaps, buttons, strings, hooks, latches, fasteners, Attaching, joining, connecting one or more components such as clips, clamps, nuts, bolts, or other types of fasteners used to removably or permanently connect components or fasteners to each other It refers to any means for holding or latching.

As used herein, a given component or part may be pulled or pushed (e.g., pushed downward or pulled upward) regardless of whether the component is closed or opened. Closed or opened by using a latch or cam lever. The opening and closing of the component is independent of whether the latch or cam lever is pulled or pushed because either movement (pulling or pushing) can perform either function (opening or closing). Because it is.

As used herein, the term "loaded" refers to filling or placing something into something else, e.g., filling or loading a device, or loading an administration tube assembly. This is a reference to

Implantable Devices Although not the purpose of this embodiment, implantable devices are described and illustrated throughout this application. For example, FIGS. 2, 3, 4, 5, 6, and 8 show device case 74 with implantable device 200 secured therein. However, the embodiments described herein are not limited to these implantable devices and are possible with other implantable or non-implantable devices. Those skilled in the art can modify the priming and cell loading system 1 described herein for other devices without departing from the general embodiments. Applicants propose a variety of planar implantable devices including, but not limited to, self-expanding implantable devices, large volume or macroencapsulated implantable devices, planar and non-planar implantable devices, or three-dimensional macroencapsulated implantable devices. Shaped and non-planar (eg, three-dimensional) implantable devices have been described. For example, Applicant's US Pat. , applicant's patent document 8 filed on December 12, 2011, applicant's patent document 9 filed on May 31, 2013, applicant's patent document filed on March 13, 2013 10, another encapsulated implantable device was described by Applicant's US Pat.

Therapeutic Cells and Agents Embodiments herein describe priming of therapeutic cells and agents to load therapeutic cells and agents into an implantable device. In particular, therapeutic cells and agents comprising cell clump suspensions are described. Applicants have developed cell therapies for diabetes, in particular encapsulated cell therapies for treating diabetes, and have used a variety of endoderm or definitive endoderm lineage cells, particularly those described herein. Pancreatic lineage cells for use with embodiments have been described in detail. For example, Applicant has at least US Patent Application Publication No. 2006/0030000 entitled "METHODS OF PRODUCING PANCREATIC HORMONES" filed on April 8, 2008, and "ENCAPSULATION OF PANCREATIC LINEAGE CELLS DERIVED FROM NOVEMBER 13, 2009". U.S. Patent No. 3,2014, entitled “IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND IMMATURE BETA CELLS,” filed Dec. 12, 2013. in U.S. Patent Application Publication No. 2005/0030000 filed Mar. 7, 2014, and U.S. Patent Application Publication No. 2014/0131003 entitled “IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND ENDOCRINE CELLS” filed Mar. 13, 2014. Mesendoderm cells and definitive endoderm lineage-type cells were described in detail. In one preferred embodiment, the implantable device comprises therapeutic agents, biological cells, endoderm lineage cells, definitive endoderm lineage cells, pancreatic progenitor cells, pluripotent cells (human embryos or fetuses, cord blood stem cells, induced pluripotent cells). Humans induced by methods now known or discovered in the future, including induction using non-destructive stem cells, reprogrammed cells, parthenogenetic cells, gonadal germ cells, and mesenchymal or hematopoietic stem cells. It consists of pancreatic progenitor cells different from embryonic stem cells, PDX-1-positive pancreatic progenitor cells, endocrine progenitor cells, endocrine cells, immature β cells, immature pancreatic islet cells, and the like.

Various publications, including scientific journal articles, patents, and patents, are referenced herein, the entire disclosures of each of which being incorporated by reference. For example, generating pancreatic progenitor cell populations and/or immature β-cell populations; sterilizing, storing, fixing, and transferring devices; measuring and preparing anatomic sites; Devices and methods for delivering and placing hormone-secreting cells to function in the body are disclosed in Applicants' above-mentioned patent application, which is incorporated herein by reference in its entirety.

Priming and Loading System FIGS. 1-3 illustrate a non-limiting and non-exclusive system 1 for priming cells (or any fluid suspension containing a therapeutic agent) and loading cells into an implantable device. embodiment. System 1 comprises at least (i) loading fluid reservoir 44 and administration tube 38 (collectively administration tube assemblies 44, 38); (iii) priming, loading, or filling the cells and flushing the cells into the device; It has various elements to perform each function. All functions (functions i, ii and iii) are performed under controlled, sterile conditions, manually, semi-automatically and/or automatically.

1-3 illustrate syringe 54 and syringe pump 52, administration tube platform 10, fluid reservoir 44 and administration tube 38, flexplate cradle 16, rotary handle 50 connected to rotary bearing 48, and counterweight 12. and an adjustable sliding carriage 22 including an adjustable multi-position block 58 having a first vial position 4 and a second DFPA position 6 and a DFPA nesting block 30. Non-limiting, non-exclusive embodiments are shown. All components are connected to a frame 60 (administration tube platform 10, rotatable platform 14, and sliding carriage 22) mounted on base 34. FIG. Specific embodiments are described in more detail below.

The priming and cell loading system 1 is also called "cell loader", "cell loader system", or "cell loading assembly" or equivalents thereof. In any embodiment, the priming and cell loading system 1 performs its functions aseptically, thereby maintaining the integrity and sterility of the various components of the system and/or components used with the system. be done. In one embodiment, all systems, components, means, and methods described herein are performed in a suitable clean room according to Good Manufacturing Practices (GMP) and in compliance with at least US and European regulatory agencies.

Additional components can be added to the priming and cell loading system 1, for example external sensors such as cell counters, pressure transducers, heat sensors, rate sensors.

Administration Tube Assembly A disposable administration tube assembly 44 , 38 comprising a fluid reservoir 44 and an administration tube 38 is connected to the syringe 54 and to the syringe pump 52 to ensure sterility. Administration tube 38 is sometimes referred to as loading tube 38 . Fluid reservoir 44 holds liquid medium for priming device 200 and is used to store cell clumps or liquid medium for flushing cell clumps into device 200 . In one embodiment, there is also a fitting 42 separating the fluid reservoir 44 and the administration tube 38, which is connected to the syringe, and these components are sterilized together as a unit. This sterilization unit is then connected to a syringe pump 52 . In one embodiment, the administration tube assemblies 44, 38 are uniform diameter tubes. The diameter of the tubing was selected to facilitate connections between the various components of the priming and cell loading system 1 (eg, connections with syringe 54, flexplate cradle 16, and device port 72). Utilizing a tube having a generally constant diameter eliminates the need for transitions and additional fittings or valves that would be required if tube size (diameter) changes. For example, when the tube diameter changes, fittings or valves are used to accommodate changes in tube size, which can cause cell, particularly suspension agglomerations, to possibly differ from one another in the tube system. clogged in areas, or trapped in fittings during transport (e.g., cell clumps may settle in small grooves in fittings and affect migration of other cell clumps), or particularly smaller diameters can be destroyed by shear when transitioning to a tube of Therefore, maintaining a constant diameter for the tubing system is advantageous as it reduces the likelihood of cell clumps becoming trapped near or within connections or fittings. Tubing with constant diameter is also fluid responsive when using liquid pumping media including, but not limited to, sterile phosphate buffered saline (“PBS” or “saline”), stem cell media, and the like. Allows volume transfer. For fluid reservoirs 44 with fewer fittings 42 and/or valves, mechanically sensitive materials, particularly but not limited to animal, human, and/or plant cells, viruses, protein precipitates in suspension. It allows for gentler transport of shear-affected biomaterials, including agglomerates, protein crystals, native proteins, antibodies, liposomes, and cell clumps. Reducing the number of fittings also reduces the potential for contamination, especially for human use, and maintains a sterile, aseptic environment. In one embodiment, an additional fitting on the administration tube 38 by using a smaller radius tube than the device port 72 so that the administration tube 38 can be inserted directly into the device port 72 when loading cells. can be avoided, possibly preventing contamination of the administration tube 38 and/or the device port 72 and the device 200 therein.

Various sizes, diameters, lengths, tapers, bulbs, balloons, and other features of fluid reservoir 44 are possible, depending on the material to be aspirated and loaded and/or the device for receiving such material. may The distal end of the administration tube 38 is connected to the device port 72 of the implantable device 200, and therefore the administration tube 38 should have approximately the same diameter as the device port 72 for exactly the same reasons mentioned above.

In one embodiment, saline is used as the pumping fluid in the administration tube assemblies 44,38. This is advantageous as it allows a higher degree of control over the pumping fluid through the tube assembly than the pumping air. Furthermore, regulatory compliance when using air is more cumbersome and onerous than with liquid pumping fluids.

In one embodiment, the tube length selected will depend in part on the maximum volume of medium and cell mass when loading the maximum capacity device. For example, a tube length of about 20 feet can hold a total tube volume of about 5 mL when loading at least an EN250 device (about 250 μL).

In one embodiment, the fluid reservoir 44 may be mounted or retained on the administration tube platform 10 or contained by other means known in the art.

Tubing Platform The administration tube platform 10 constitutes a means for maintaining or retaining the administration tubes 44 , 38 , particularly the fluid reservoir 44 , for example allowing longer administration tubes to be rolled and retained on the cradle 10 . The cradle 10 maintains the fluid reservoir 44 in a horizontal position and prevents air bubbles from forming in the tube as fluid and air pass through the syringe pump 52 . For example, if the fluid reservoir 44 were to achieve a more vertical position (rather than horizontal), subsequent media flow fronts could sink under the air bolus and form air bubbles. Keeping the tube horizontal prevents this.

In one embodiment, the administration tube platform 10 further comprises a cylindrical depression 40 and a pivotal retention latch and/or a locking thumbscrew to secure and/or maintain the tube in place. be able to.

Syringes and Syringe Pumps A typical surgical (manual) syringe uses a piston and cylinder and is suitable for pumping (dispensing) small, measured amounts of fluid used in daily laboratory research. there is For example, Applicants have described using Hamilton syringes to measure and load small amounts of pancreatic progenitor cells into implantable devices to be implanted. At least U.S. Pat. No. 5,300,303 entitled "METHODS OF PRODUCING PANCREATIC HORMONES" filed on Apr. 8, 2008 and "ENCAPSULATION OF PANCREATIC LINEAGE CELLS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS" filed on Nov. 13, 2009. See U.S. Pat. However, in commercial treatments that require priming and filling multiple devices, or larger devices, or three-dimensional devices, manual handheld syringe loading is not effective for this seal. Absent. Therefore, there is a need for an automated or semi-automated system that can precisely and accurately prime and load (dispense) multiple doses while maintaining cell viability (e.g., reducing shear stress). is.

1 and 2 illustrate non-limiting and non-exclusive embodiments of syringe 54 and syringe pump 52. FIG. Syringes 54 and syringe pumps 52 are commercially available from various manufacturers including, but not limited to, Cavro, Parker, Kloehn, and Hamilton.

Pumps are available with various sized syringes for dispensing volumes ranging from 1 microliter to 50 milliliters. A syringe pump generally consists of a syringe barrel, inlet and outlet valves, a piston, and a motor. In one embodiment, the syringe barrel can be plugged directly into the valve and a seal can be used to substantially separate the valve from the syringe. In this example, the amount of syringe fluid dispensed is defined by the syringe area and the linear displacement of the piston. In another embodiment, the syringe pump consists of a piston and a cylinder, in which case the piston can provide the valve function. In a preferred embodiment, the syringe barrel is plugged directly into the fitting (rather than the valve) and a seal can be used to substantially separate the fitting from the syringe. Additionally, in another embodiment, a motor (eg, stepper motor) is used to control (or move) the displacement of the syringe piston.

In a preferred embodiment, a Norgren Kloehn Versa pump ("Kloehn pump") was utilized to aspirate and dispense applicant's candidate cell product, pancreatic progenitor cell clump suspension (or PEC). The pump is powered by a DC 24V power brick and consists of a stepper motor precision syringe pump operable at 12,000, 24,000, or 48,000 steps per full stroke. The full stroke of the pump is approximately 6 cm (60 mm). Various size syringes from 25 μL to 50 mL can be attached to the pump. Aspirate and dispense volumes are accurately determined by syringe volume and steps per stroke, with smaller syringe volumes being more accurate. In one embodiment, a 10 mL syringe capable of about 48,000 steps per full pump stroke can be used to implement the cell loading system EN250 (approximately 250 μL maximum volume) and EN20 (approximately 20 μL maximum volume) devices. The nominal fluid volume resolution achieved by this combination is approximately 0.2 μL/step. For example, a 10 mL syringe by Zinsser North America can be used to load EN250 and EN20 devices.

Syringe Pump Controller A computer can be used to communicate with the syringe pump 52 regarding various aspirate (pull, negative pressure) commands, pause commands, and dispense (positive pressure) commands. The Kloehn pump, for example, has a command set with multiple functions, and various command strings are stored in the controller software application and sent to the pump 52 when requested by the user. A response from the pump 52 is received and displayed in the controller application.

In another embodiment, the pump 52 can store its commands internally (internal non-volatile RAM) and execute them via hardware inputs, thus allowing a simple push-button interface to allow the syringe pump 52 to It can be commanded to aspirate, pause, and dispense accordingly.

In another embodiment, syringe pump 52 may receive hardware input from an integrated assembly machine control system. Although the use of a computer has been chosen for convenience, any automated or manual method for aspirating, pausing, and dispensing fluids or cells, particularly cell suspension clumps, is within the skill of the art. is reasonable.

Rotatable Platform A unique feature of the priming and loading system 1 is a rotatable platform 14 coupled to a sliding carriage 22 (described in more detail below), both of which together are rotatable. It can rotate from 0 to 180 degrees. Rotatable platform 14 may further comprise a flexplate cradle 16 (described in more detail below). The rotatable platform 14 is rotated 180° from vertically downward to vertically upward using a rotating handle 50 that moves around a rotating bearing 48 attached to the frame 60 and base 34 of the priming and cell loading system 1. be able to. See FIG. 3, which shows a side perspective view of the priming and cell loading system 1. FIG. FIG. 3 also shows the rotating platform 14 and sliding carriage 22 rotated approximately 90 degrees relative to the base. Rotation bearings 48 may be secured by one or more locknuts when rotatable platform 14 is fixed or tightened in a desired position. In other embodiments, the position of rotatable platform 14 may be fixed by alternative fixing or locking mechanisms including, but not limited to, toggle clamps, friction clutches, ratchets, and the like.

In one embodiment, when removing and installing vials 36 and/or DFPA 62, rotatable platform 14 is oriented vertically downward, similar to that shown in FIGS. For smaller devices (eg, devices with a maximum volume of 20 μL, such as EN20 devices), wetting or priming may be achieved at various azimuthal angles. For larger devices (eg, devices with a maximum volume of 250 μL such as the EN250 device), wetting or priming is more efficient when the rotatable platform is oriented vertically upwards, similar to FIG. It is within the knowledge of those skilled in the art to optimize and vary the position of the rotatable platform 14 to load a desired device, for example, some devices load with the rotatable platform 14 oriented horizontally. is suitable, while other devices are more suitable for loading in an upward orientation, whereby the rotatable platform 14 is arranged at an angle between, for example, 180° and 90°. Varying the rotation angle to dispense and load the device also helps distribute the cells more evenly within the device chamber, reducing the number of air bubbles or pockets that may form. be. Air bubbles or pockets trapped inside the device can adversely affect the device's ability to accept cell clumps, which can adversely affect cell distribution within the device, and can also affect cell distribution at the site of the bubble. Growth, proliferation, maturation and development of cells at or near the site may be affected. Avoiding bubble formation is therefore important for proper (even) cell distribution, and the rotatable platform 14 can be easily manipulated with small or large movements that affect orientation. You may facilitate this avoidance by making

In one embodiment, due to weight components such as the multi-position block 58 and the DFPA nesting block 30, the rotatable platform 14 has a counterweight 12 on the proximal portion of the platform 14 for stability. good too.

Flexplate Mounting The flexplate mounting 16 acts when presented to center the administration tube 38 in the vial 36 and aligns the administration tube 38 with the device port 72 when presented. work like The flexplate may flex slightly to provide a sealed connection between the tube 38 and the device port 72 fitting when the administration tube 38 and device port 72 fitting are fully engaged within the DFPA 62 . Apply a constant force to maintain the joint. In one embodiment, the flexplate cradle 16 can accommodate various sizes of fluid reservoir tubes 44 and delivery tubes 38 by selecting fittings 42 .

In one embodiment, the simultaneous loading or synchronous Can handle loading. Accordingly, the flexplate cradle 16 can be adjusted or optimized to perform several priming and loading functions. Such modifications to the flexplate cradle 16 can be implemented by those skilled in the art.

In one embodiment, multiple dosing tubing systems 44, 38 can be used with multiple fittings 42, but can be loaded simultaneously or synchronously into the same or different devices.

In one embodiment, when the implantable device 200 is loaded with cells as further described in FIG. 10, the flexplate cradle flexes to maintain a tight connection between the administration tube and the device port 72 inside the DFPA 62. .

Sliding Carriage The rotatable platform 14 is removably coupled to a sliding carriage 22 and travels on pairs of rods 18 . Rod 18 can engage and disengage dosing tube 38 by moving carriage 22 up or down on rod 18 .

In a preferred embodiment, there are three main activities and volumes: priming with a priming volume, cells in a cell volume, and flushing with a flushing volume. The administration tube assemblies 44, 38 are maintained in place by the flexplate cradle 16 as described above. Flexplate cradle 16 is removably coupled to sliding carriage 22 , which can be positioned in three positions relative to the distal end of administration tube 38 . To enable the device 200 to be loaded or filled with cells, the dosing tube assemblies 44, 38 are first loaded or filled with a flush volume, a cell clump volume, and a priming volume as described in greater detail below.

(2) Central position: The sliding carriage 22 is placed in the central position, whereby the dosing tube 38 is immersed in the vial medium and suspended above the bottom of the vial 36 (just above the settled cell mass). be. In one embodiment, this central position can be used to aspirate or draw only a cell volume or flush volume (without aspirating cell clumps) into the dosing tube assembly 44,38. It is desirable to load cell culture medium without loading cell clumps into administration tube assemblies 44 , 38 because the cell culture medium is required to (i) wet (or “prime”) device 200 . and (ii) for flushing (or "chasing") cells from the administration tube assembly 44, 38 into the device.

(1) Full Engagement: Sliding carriage 22 is positioned most proximally, abutting or close to rotatable platform 14 and flexplate cradle 16; When multi-position block 58 is in first vial position 4 (FIG. 2A), administration tube 38 is centered above vial 36 and the tip of administration tube 38 is located near the bottom of vial 36 . When multi-position block 58 is in second filling position 6 , the distal end of administration tube 38 is aligned and inserted into device port 72 within DFPA 62 . In another embodiment, a fitting can be provided between the device port 72 and the administration tube 38, for example where the administration tube 38 and the device port 72 have different radii. In one embodiment, this fully engaged position is used to draw the cell clump into the administration tube assembly 44,38.

(3) Complete Disengagement: Sliding carriage 22 is in the furthest position (farthest from flexplate cradle 16 and rotatable platform 14) such that administration tube 38 is completely disengaged from device port 72 and/or DFPA 62 or vial 36. placed. In one embodiment, this disengaged position is used to remove or install the DFPA 62 or vial 36 .

In one embodiment, which of these three positions (central position, fully engaged position, fully disengaged position) is used and when to use those positions depends on the cells or therapeutic agents in the vial. Determined. For example, although preferred embodiments are described herein describing loading of the administration tube assemblies 44, 38 and loading of the device 200, the system 1 may be used with a therapeutic agent that may be in a more homogeneous mixture. When used, separate physical layers may not be present. In such embodiments, it may be necessary to use separate vials containing cell culture media for priming and flushing of therapeutic agents.

One preferred embodiment for loading the administration tube assemblies 44, 38 and loading the device 200 is described in FIGS.

To maintain the sliding carriage 22 in its position, magnets can be used to hold or lock the position of the carriage 22 in different travel positions ("stop"). In one embodiment, fine tuning and fine tuning can be accommodated by adding a magnetic adjustment screw that can contact the magnet at either end when moved in either direction. This stop prevents further movement of carriage 22 and misalignment of administration tube 38 relative to either DFPA 62 or vial 36 . Other stopping methods, including magnets and other mechanical means, can also be used in adjustable multi-position block 58, which is described in more detail below.

In one embodiment, sliding carriage 22 further consists of adjustable multi-position block 58 and DFPA nesting block 30 as described in more detail below.

Adjustable Multi-Position Block In one embodiment, sliding carriage 22 further comprises an adjustable multi-position block 58 . Adjustable multi-position block 58 is a laterally sliding platform that has at least two positions. FIG. 2 illustrates a first position 4 (“vial position”) where vial 36 can be inserted into block 58 and a second position 6 where DFPA 62 can be partially or completely within multi-position block 58 . ("fill position"). Therefore, the multi-position block 58 can be adjusted according to function. In one embodiment, when loading the administration tube assemblies 44, 38 with cells or desired therapeutic agents, the first vial position 4 is used to house the cell container or vial 36. can be done. In another embodiment, when dispensing cells from the administration tube assembly 44, 38 into the device (or loading the device), the second filling position 6 is used, where the port is opened. A DFPA or similar sterile device, including device 200, can be accommodated. Each of these embodiments is described in more detail below with reference to FIGS. 9 and 10. FIG.

DFPA Nesting Block In another embodiment, the sliding carriage 22 further comprises a DFPA nesting block 30 for any device case and device shape, such as a device case similar to that described in FIG. 2B, held inside the DFPA 62 . 74 and device 200 can be accommodated. Thus, the DFPA nesting block 30 can have recesses to accommodate the shape and size of device cases and devices.

In one embodiment, DFPA nesting block 30 also holds device case 74 and device 200 upright to seal device port 72, as described in more detail below.

Over-Center (“Toggle”) Clamp In one embodiment, the adjustable multi-position block 58 and DFPA nesting block 30 further include an over-center clamp (or toggle clamp) 28 for securing the vial 36 or DFPA 62 in place. , 32. In one embodiment, toggle clamps 28 , 32 may be in the form of elongated contact bars that, in operation, go into place to hold aliquot vials 36 and/or DFPA 62 . In one embodiment, clamps (or contact bars in this example) 28 , 32 are coupled to clamp levers 24 , 26 to open and release the clamps to hold vial 36 or DFPA 62 . to operate. As with other embodiments, the method for securing or holding the vial 36 or DFPA 62 in place can be implemented in any number of applications where clamp-like grips or holders can be opened and closed. Clamps 28, 32 allow fingers on the clamps to accommodate variations in vial 36 size or DFPA 62 thickness, thereby allowing priming and loading system 1 to be used with a variety of devices. It can be made from a flexible material that allows it to be optimized. At least with respect to adjustable multi-position block 58, optional clamp 32 allows adjustable multi-position block 58 to slide between two positions of block 58 with clamps 28, 32 fully depressed. should allow Other retention mechanisms are also contemplated including, but not limited to, latches, snaps, locking female and male portions, tabs, and the like.

Embodiments of the priming and cell loading system 1 thus have features that include multiple adjustable components to accommodate different functions and applications. An adjustable multi-position block 58 controls from a first vial position 4 for aspirating cells into dosing tube assemblies 38, 44 having flushing volume, cell volume, and priming volume 4, priming volume, cell volume, and priming volume. and slide to the second fill 6 position for dispensing the flush volume. Moreover, after loading the device 200 , the device port 72 can be easily sealed while the device 200 is still located inside the device case 74 and inside the DFPA 62 . This multiplexing reduces the risk of contamination because the operations are performed in one area. Various system 1 components allow for user optimization based on the device in use.

Device Port Sealer Prevents leakage of therapeutic cells and/or therapeutic agents loaded into the device after the implantable device has been primed (wet), loaded with cells, and flushed from the administration tube The device must be sealed to do so. FIG. 4 shows a non-limiting, non-exclusive embodiment of such a device port sealer 68. FIG.

In general, the device port sealer 68 consists of at least four parts: an RF generator, a transmission cable, a sealing wand with an internal matching network, and a custom sealer electrode 70 where the electrodes are located at the ends of the C-jaws. A set and a. This C-shaped configuration allows access to device ports 72 . In a preferred embodiment, the C-shaped jaws cover the sealed port area of the device case 74 to seal the device port 72 without breaking the DFPA 62 . This C-shape also allows the jaws to slide over the DFPA 62 from each side, allowing direct electrode access to the general center of the DFPA 62 where the device port 72 normally resides. The sealer electrode 70 is cylindrical and fits into a corresponding cylindrical cutout in the device case 74 . The electrode position is adjustable within the jaws to allow a constant electrode gap to exist when the sealer wand handle is fully closed. The sealer electrode 70 in the jaws can be quickly replaced if it becomes dirty, damaged or dented due to RF arcing. Other electrode shapes and configurations are also possible.

In one embodiment, radio frequency (RF) power from a handheld device port sealer 68 is used to aseptically seal the device loading port 72 (i.e., the device loading port 72 is still attached to the device case 74 and the DFPA 62). sealed while inside).

In a preferred embodiment, device 200 is necessarily placed in a second filling position on adjustable multi-position block 58 as long as device 200 is maintained in place to prevent accidental leakage or creep of cells from device 200. 6, but is sealed while still in the DFPA nesting block 30.

In one embodiment, the device loading port 72 is made of any biocompatible flexible plastic tubing that specifically or selectively responds to RF energy and is rapidly heated and cooled internally. , DFPA 62 and other materials of device case 74 do not respond similarly to RF energy. For example, using moderate pressure, the heated device load port 72 can be squeezed closed to introduce additional sealing material (eg, a sealant or adhesive film), or the device load port 72 can be forming a permanent seal within the tube without damaging the can be done. In this example, the DFPA material acts as a buffer material. Other cushioning materials are described below. This ability to permanently seal the device tube aseptically after the device has been filled is unique to this system.

In one embodiment, the device port 72 extends beyond the device case 74, as shown in FIG. 4, or if desired, to accommodate connection with the administration tube 38, and the device port extends beyond these It can be sealed in any of the areas, but typically it is sealed in the area closest to the body of the device 200 itself.

Thus, during priming and loading of the implantable device 200, the device 200 is not exposed to human hands and is subject to minimal manipulation, all within the sterile environment of the DFPA 62.

Cushioning Materials Insensitive to RF Energy In one embodiment, DFPA or other cushioning material used to make sterilization bags and pouches was utilized. DFPA consists of thin laminates of polyester (eg, Mylar) and polyethylene with a nominal thickness of about 0.0025 inch (or 0.0065 mm, or about 0.01 mm). This material constitutes a protective surface between the device port 72 and the sealer electrode 70 so that the electrodes do not contact the device loading port directly, yet the device loading port can be sealed. . During sealing, device port 72 generates heat in response to applied RF energy, while buffer material laminates, eg, DFPA 62, do not respond to RF energy. Thus, under moderate clamping pressure, the heated device load port 72 forms a permanent seal while the cooler buffer material laminate adheres to the heated load port. Nor. Releasing the pressure after sealing releases the sealed port from the cushioning material laminate.

In another embodiment, any material or laminate of materials that does not respond to RF energy can be used as the buffer material. The actual thickness of the cushioning material is not critical, but thinner materials are preferred due to their ease of use and lower cost. Alternative materials include polyethylene (eg, Tyvek), polytetrafluoroethylene, polypropylene, polyamide, and the like. In embodiments, a polyester/polyethylene laminate was selected. This is because polyester/polyethylene laminates are available at low cost as thin, easy-to-use sheets. Additionally, a transparent cushioning material, such as Mylar polyester, allows the operator to quickly visually inspect the resulting seal under aseptic conditions without having to open the DFPA 62 .

Further, other materials of the cushioning material are described in Patent Document 19 entitled "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014, "TOOLS U.S. Patent Application Publication No. 2004/0020003 entitled “AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES”, and U.S. Patent Application Publication No. 2014/0162021 entitled “CASE FOR AN ENCAPSULATION DEVICE” filed Apr. 16, 2014.

Radio Frequency (RF) Generator In one embodiment, the RF generator utilized to seal device port 72 includes a self-regulating power output that is delivered until one of two output conditions is met. Either (i) power is applied until a total energy threshold is achieved, or (ii) power is applied until a predetermined period of time (eg, 2 seconds) has elapsed. Due to the design of the RF generator and the fixed matching network within the sealing wand, the actual power output will vary until the seal is completed. The nominal power output is about 25W. US Pat. No. 6,200,003 describes in detail the power generation and delivery of RF energy for tube sealing applications.

In one embodiment, a "Haemonetics" (formerly called "Sebra") model 2600 RF generator was used to provide RF power and seal the loading port 72 of the implantable device. The generator outputs RF power at the FCC mandated frequency of 40.68 MHz through an industry standard 50 ohm BNC connector. In another embodiment other frequencies 13.56 MHz, 27.12 MHz and 40.68 MHz may be applied. The model R601 RF generator has a maximum power output of 600W and can be driven in pulsed or continuous mode. Alternative RF generators can be used, but may require additional controls to provide adequate power for the specific duration required to properly seal the device loading tube. be. RF generators with such features are commercially available from other manufacturers including, but not limited to, Seren IPS, Comdel, Lesker, MKS Instruments, and others.

RF Cable In one embodiment, an industry standard 50 ohm impedance RG-223 RF cable with double shielding is used to transmit RF energy from the RF generator to the ceiling wand. The length of this cable is approximately 95.8" and is specifically tuned to be 1/2 wavelength at 40.68 MHz. This length maximizes transmission efficiency and reduces RF Minimize back reflections between the generator and the sealing wand.

In another embodiment, other 50 ohm RF cables can be used (RG-6, RG-58, RG-174, etc.) but not constant in stiffness, shielding (less efficiency), or ampacity .

In one embodiment, a "Haemonetics" (previously called "Sebra") sealing wand is used to match the RF impedance between the RF source and the load, and the user can rotate the sealing jaws around the DFPA 62. Allows ergonomic access to be placed in the position of Due to the unique shape and configuration of the device load port sealer 68 jaws, the sealer head load impedance differs from the industry standard 50 ohm resistive impedance. To compensate for this difference, an intermediate compensating inductive/capacitive impedance (matching network) is placed between the RF source and the load. The sealing wand has an internal matching network of constant value capacitors and inductors. The sealing wand matching network is hand-tuned at the factory resulting in a lightweight, compact and efficient matching network. US Pat. No. 6,200,026 (incorporated by reference in its entirety) describes in detail a constant-value matching network located inside a sealing wand.

In another embodiment, a tunable matching network can be used, but that would require additional cost and space consumption. Other tunable matching networks are commercially available from certain manufacturers including, but not limited to, Seren IPS, TC Power Conversion, Manitoussys, Materials Science Inc., and others. Using a Haemonetics Model 1105 sealing wand with a fixed matching network provides a lower cost, more compact sealing solution.

Device Case Storage Bag Sealing Station FIGS. 5-7 illustrate non-limiting and non-exclusive embodiments of a device case storage bag sealing station 2 for sealing or sealing the device case storage bag 124. FIG. Device case storage bag 124 further consists of a loaded implantable device 200 inside device case 74 .

Generally, the sealing station 2 consists of at least a device case storage bag holder 76 on the base 100 and a sealing head assembly 78 .

Device Case Storage Bag FIGS. 6A and 6B are non-limiting and non-exclusive implementations of means for storing a cell-filled or loaded device (or cell-encapsulated device) within a storage bag 124 . showing morphology.

The configuration of the device case storage bag 124 was designed in relation to the sealing station 2. Elements on the sealing station 2, for example, interact directly with the device case storage bag 124 to (i) protect the device and therapeutic cells or therapeutic agents within the device during transportation and shipping, and (ii) the final It was based on at least two basic requirements to allow the seal to be applied aseptically. A detailed description of this storage bag and similar storage bags can be found in Applicant's US Pat. Applicant's US Pat.

In one embodiment, specific elements such as holes or notches that align with corresponding elements or markings (e.g., ink markings) on the first holder plate 88 are incorporated into the device case storage bag 124 during design and manufacturing. can be done. This is similar to male and female portions of latches or fittings. Thus, any sealing station 2 may incorporate elements of the sealed portion, or have corresponding elements in the sealed portion (e.g., device case storage bag 124 and alignment elements on sealing station 2). may

Device Case Storage Bag Holder In one embodiment, the device case storage bag holder 76 sits on the sliding carriage 106 and consists of a first holder plate 88 and a second swing plate 90 . In one embodiment, the two plates that make up holder plate 88 move or rotate differently, for example, the front plate rotates while the rear plate remains stationary. A first holder plate 88 holds a device case storage bag 124 and is further controlled by a cam or lever 112 connected to a bar or plate 110 , which is connected to a spring 108 to rotate the bar/plate 110 . The moving lever 112 can be moved (or rotated). For example, to lock the device case storage bag to the first holder plate 88 , the lever 112 is pulled upward, mechanically translating the first holder plate 88 to the front plate 88 and locking the device case storage bag holder 124 . is clamped in the holder 76 and the device case storage bag 124 is released, the lever 112 is pushed downward.

Device case storage bag holder 76 holds device case storage bag 124 along with device case 74 and cell-loaded device 200 . In one embodiment, prior to sealing the device case storage bag 124 , the cell-loaded device 200 inside the device case 74 is removed and transferred from the DFPA 62 to an open, unsealed bag 124 . The first holder plate 88 serves primarily to maintain the storage bag 124 in place while the storage bag 124 is being filled, i.e., while the device case 74 and device 200 are being transferred into the storage bag 124 and The device case 74 and device 200 are opened while the storage bag 124 is filled sufficiently to immerse or cover the device case 74 and device 200 with a liquid medium for long-term storage, ie, a storage buffer.

In another embodiment, the second rocking plate 90 serves to close the storage bag 124 of the current device and media filled unsealed device case. The opening and closing of the second swing plate 90 is controlled by a cam 92 and a cam lever 98 that move around cam guides.

In one embodiment, prior to sealing the device case storage bag 124, residual or excess air within the bag 124 should be removed so that the amount of air within the bag 124 after sealing is as small as possible. When removing residual air in the bag 124 , the rotatable cam lever 98 is moved along the cam guide to the closed position, whereby the cam lever 98 moves the device case storage residing between the first holder plates 88 . Compress the bag 124 . This action forces residual air upwardly out of the device case storage bag 124 so that the storage medium is near the top of the bag 124 prior to sealing. The sealing of device case storage bag 124 is described in more detail below.

Device Case Storage Bag Sliding Carriage The device case storage bag holder 76 can be positioned on a sliding carriage 106 which moves the holder 76 horizontally (left and right), particularly below the sealing head 78 of the sealing station 2. can be moved.

In one embodiment, the sliding carriage 106 slides back and forth by resting or resting on any number of rails or grooves. In another embodiment, the rails have stops 102, 116 at each end to prevent the sliding carriage 106 from further travel or disengagement. For example, in one embodiment the sliding carriage 106 rests on two rails and the stops 102, 116 are mounted or located on the base 100, although any number of rails can serve Stops 102 , 116 can be placed at any position such that stops 102 , 116 prevent further movement of sliding carriage 106 .

Sliding carriage 106 is opened (unsealed) so that device case 74 and loaded implantable device can be received and sealed within a storage bag using the sealers described herein. A sterile working environment for capturing the device case storage bag 124 is configured with the device case storage bag holder 76 .

Sealing Head Assembly In one embodiment, the sealing station 2 consists of a sealing head assembly 78 protected by a shield 80 and attached RF electrodes 84, 86 that face each other horizontally. A rear electrode 84 is mounted on the air cylinder 81 and a front electrode 86 is fixed. When sealing the device case storage bag 124 , the sliding carriage 106 moves the entire holder 76 under the sealing head assembly 78 .

When sealing the storage bag 124, the nominal gap allows the device case storage bag 124 to be inserted between the electrodes 84, 86 (thereby separating the two electrodes) and the air cylinder 81 is extended, Rear electrode 84 is advanced to seal device case bag 124 between two electrodes 84 , 86 and RF power is applied to heat the RF-responsive portion of bag 124 and form a seal on bag 124 . (Fig. 6B). Retracting the air cylinder 81 releases the device case storage bag 124 from the electrodes 84, 86 and returns the sliding carriage 106 to a position away from under the sealing head assembly 78 (moved to the left as shown). can be done.

Automating the RF Sealer The operation for sealing the device case storage bag 124 can be fully automated or semi-automated. In one embodiment, a personal computer (PC) is used to communicate with an RF generator (eg, Seren RF Generator) and a matching network (eg, Seren Matching Network) to perform the sealing operation. Both the RF generator and the matching network are fully configurable for a variety of user applications, but at least in the example of Seren's RF generator and matching network, they require specific operating commands from an external controller. (ie, the RF generator and matching network are not enabled by programmed software to perform the operations described above).

In still other embodiments, other control schemes are possible. For example, a programmable logic controller (PLC) can maintain various Seren initialization and RF generation command strings and then send these commands to the Seren RF generator upon user request. A Seren matching network typically has its initial configuration determined empirically and does not need to issue periodic commands after internal configuration has taken place. In one embodiment, a PC for the control scheme is used.

In another embodiment, a simple activation switch 104 can be used to control the sealing station 2 .

RF Generator In one embodiment, a Seren Industrial Power Supplies R601 Radio Frequency Generator was utilized to precisely apply RF power to achieve heating and sealing of the RF responsive EVA layer of the device case storage bag 124 . The FCC mandates frequencies of 13.56 MHz, 27.12 MHz, and 40.68 MHz for these types of applications, and 40.68 MHz was chosen in one embodiment. The model R601 RF generator has a maximum power output of 600W and can be driven in pulsed or continuous mode. The RF output of this RF generator is through an industry standard N connector and an industry standard 50 ohm impedance transmission cable. RF generators with similar features are commercially available from other manufacturers (eg, Comdel, Lesker, MKS Instruments, etc.). We chose Seren because of its rich element set and serial command capabilities.

Due to the unique shape and configuration of the final seal on the matching network device case storage bag 124, the sealer head load impedance differed significantly from the industry standard 50 ohm resistor impedance. To compensate for this difference, an intermediate compensating inductive/capacitive impedance is placed between the RF source and the load. The Seren ATS-10M Matching Network accomplishes this intermediate correction and allows for simple tuning adjustments by the operator enabled via RS-232 serial communication.

In another embodiment, the matching network can be manually configured including fixed inductors and capacitors as needed. This technique has a lower final cost because it is time consuming to empirically test differences in both inductance and capacitance simultaneously to match impedances, but labor costs are high.

Other tunable matching networks are commercially available from certain manufacturers (eg, TC Power Conversion, Manitoussys, Materials Science Inc., etc.). Seren was chosen to ensure vendor compatibility between RF generators and matching networks.

Crimping Sealer In an alternative embodiment, a crimpable band or ring may be used around device port 72 to restrain the flexible nature of device port 72 . The crimpable band or ring may be constructed of metal or metallic materials or high strength polymeric materials. In one embodiment, the metal or polymer material is stronger than the material from which the device port is made.

In another embodiment, the ring or band is configured to snap fit around device port 72 .

Conceptually similar to the handheld instrument described in FIG. 4, in one embodiment, the seal is accomplished by a crimping instrument. Examples of crimping devices are described in the patent documents, including but not limited to US Pat. Such crimping instruments provide a mechanism for adjusting the position of the crimp by providing a stop that allows the crimping portion on the device port (e.g., the area closest to the device 200) to be fixed in a fixed position. may be configured.

Transport Bag Sealer FIG. 8 illustrates a non-limiting, non-exclusive embodiment of a sealing system 120 for sealing or closing, for example, a device case storage bag 124, a device case 74, and a transport bag 126 containing a device therein. show.

In one embodiment, the sealer is a temperature controlled, pneumatic impulse heat sealer designed for use in heat sealing pouches or bags in general. In one embodiment, the heat sealer is an Impulse Sealer commercially available from Accu-Seal (eg, Model 5300-5400 Series). The heat sealer may be controlled by a digital high speed programmable logic controller (PLC) with a compatible screen. Configurable parameters include temperature, seal time (or pause), seal release temperature, and seal pressure. These heat sealers and other heat sealers are portable and can be operated in virtually any tabletop or benchtop position. The heat sealer has a heating element that can be removably coupled below an accessible sealer 122 . The carrier package or bag 126 is placed with the bag opening below the heating element or below the accessible sealer pressure bar 122 and then the sealing parameters (heating temperature, rest, pressure, etc.) are implemented. sealed by In this model, after the sealing parameters have been run, the sealing bar opens and the carrier package 126 can be removed.

FIG. 8 also shows holder 118 for holding or placing carrier bag 126 in preparation for aseptically receiving sealed device case storage bag 124 . Holder 118 can be made of any suitable metal or wire and is mounted on a transportable base. The base can be moved anywhere convenient for the operator and the function to be performed.

Methods for Priming, Cell Loading, and Sealing Devices and Associated Storage and Transport Bags FIGS. Non-limiting and non-exclusive methods and means are presented.

In FIG. 9, the cell loading system 1 is used to prepare the tube assembly for loading 306 a flush volume, a cell volume, a priming volume, load a flush volume 308, and load a cell volume. Embodiments and/or operations for loading 310 and loading 312 a priming volume are described. At operation 306, the system 1 is primed and assembled by first loading the administration tube assemblies 44,38. The administration tube assemblies 44 , 38 are preconnected to the syringe 54 , the two are sterilized together, and then further connected to the syringe pump 52 . In operation 308, pump 52 is turned on to apply negative or positive pressure, respectively, to draw (or load or aspirate) varying amounts of fluid into and out of administration tube assemblies 44,38. Note (or load). In another operation 310, a volume of fluid is loaded into the dosing tube assembly 44, 38 in the reverse order in which the volume was dispensed. For example, when loading cells into the device 200, the device is first primed or wetted (priming volume), then the cells are loaded (cell volume or cell clump volume), and finally from the dosing tube assemblies 44, 38. cells are flushed or chased (flushing volume or chasing volume). This sequence is reversed in operations 308, 310 and 312 of FIG. Thus, the dosing tube assemblies 44 , 38 are first loaded with a flush volume in operation 308 , a cell clump volume in operation 310 , and then a priming volume in operation 312 .

In another preferred embodiment, a cell vial 36 containing cell clumps comprises all three volumes, a flush volume, a cell clump volume and a priming volume. Sliding carriage 22 is positioned as described above so that the tip of dosing tube 38 aspirates a particular one of the above volumes from aliquot or cell vial 36, particularly when multi-position block 58 is in first vial position 4. (center position, engagement position, disengagement position) in the vertical direction (y-axis). If all three volumes can be loaded from one vial, the tip can be adjusted to aspirate the flushing volume in the central position and the cell clump volume and priming volume in the fully engaged position. However, if three volumes or additional volumes (e.g., wash volume, additional priming or wetting volume, additional cells, additional therapeutic agent, etc.) cannot be loaded from a single vial, the specific volume should be adjusted accordingly. Multiple vials containing can be inserted.

In FIG. 10, an embodiment for using the cell loading system 1 to dispense a priming volume (316), a cell volume (318), and a flushing volume (320) from the dosing tube assemblies 44, 38 into the device 200. and/or describe the operation. At operation 314 , the multi-position block 58 is moved to the second filling position 6 and slid to insert the distal portion of the DFPA 62 into the DFPA nesting block 30 and insert the proximal portion of the DFPA 62 into the second filling position 6 . The system 1 is primed by moving the carriage 22 to the fully disengaged position. Sliding carriage 22 is then moved to the fully engaged position, dosing tube 38 is connected to the device port, and rotatable platform is positioned between 45 and 90 degrees relative to base 34 . If the device is to be loaded with cells, in operations 316, 318, 320, the device 200 is wetted by turning on the pump, applying positive pressure, and dispensing (316) a priming (or wetting) volume to wet the device 200 and A clump volume is dispensed (318) and then a flush volume is dispensed (320) to chase or flush cells (those remaining in the dosing tube assemblies 44, 38).

These volumes can be repeated if there are multiple devices to fill, or smaller or additional volumes can be aspirated and dispensed from the dosing tube assemblies 44, 38 depending on device function and type. and that each individual dose can be drawn into the dosing tube assembly 44, 38 to be supplied by a different vial or cell source, therapeutic agent source, or media source. . In one embodiment, the operations for priming volume, cell volume, and flushing volume are performed twice, three times, as needed, by the same vial or fluid reservoir to the administration tube assembly 44, 38 as long as there is sufficient tube length. It can be repeated 4, 5, 6, 7, 8 or more times. In another embodiment, 1, 2, 3, 4, 5, 6, 7, 8, or more doses are delivered from various vials or fluid reservoirs to the administration tube assemblies 44,38. can be aspirated.

In FIG. 11, steps and/or acts for sealing the device (322), steps for storing and sealing the device case storage bag (324), the carrying bag, at least the device case storage bag, the device case, and A step for sealing (326) the carrier bag containing the cell-loaded device is described.

In operation 322, leakage of cells from device 200 is prevented by sealing device port 72 immediately or immediately after loading device 200 as described above. With the DFPA still in the DFPA nesting block 30, place the C-jaw of the handheld RF sealer 68 around the DFPA near the device port 72 area or near the device port sealing area of the device case 74. Deploy. Closing the sealer handle applies a sufficient amount of pressure to the electrode 70 on the device port 72 to generate RF energy and thereby seal the device port 72 . Importantly, the RF electrodes do not seal the sheets of DFPA 62 together or DFPA 62 to device port 72 . As noted above, there are other materials that selectively respond to RF energy, while other materials do not respond to RF energy. An advantage of RF energy responsive and non-reactive materials for DFPA 62 or any bag or container (made of one material) for device 200 is that device port 72 (made of a second material) can still be It can be sealed aseptically while in the DFPA 62 .

After the device is loaded with cells and the device port 72 is sealed, the cell-filled or loaded device is ready to be stored and transported to an implantation or surgical site for implantation. FIG. 10 describes an operation 326 for storing a cell-loaded device in the device case storage bag 124 using the device case storage bag sealing station 2 . When preparing the device case 74 and cell-filled device, place and align the device case storage bag 124 between the first holder plates 88 of the device case storage bag holder 76 and lift the clamp lever 112. close up. The device case 74 and cell-filled device are then carefully removed from the DFPA 62 (eg, via the frangible removable transparent window on the front or one side of the DFPA) and the excess device port 72 removed. The device case 74 and the cell-filled device are then placed in the device case storage bag 124 and the bag is filled with liquid storage medium. Sufficient medium is used to submerge both the device case 74 and the cell-filled device. When removing or venting residual air from device case bag 124 , cam lever 98 is used to close second swing plate 90 . The rocker plate 90 and holder plate 88 can operate independently of each other or can be combined. In one embodiment, by coupling plates 90, 88 and closing rocker plate 90, first holder plate 88 is also closed, applying pressure to device case storage bag 124 to expel any residual air into the open. Push to top of unsealed bag 124 . In another embodiment, plates 90, 88 are not coupled or independent of each other such that closing one does not close the other.

The device case storage bag holder 76 is positioned on the sliding carriage 106 and the sliding carriage 22 then moves the holder 76 under the sealing head assembly 78 to seal the open, unsealed storage bag 124. . When the holder 76 is moved under the sealing head assembly 78, the opening of the storage bag 124 is positioned between the two electrodes 84,86. Air cylinder 81 is extended and RF electrodes 84, 86 are turned on to seal device case 74 and storage bag 124 with the cell-filled device immersed in storage medium inside.

Once the cell-filled device case 74 is safely positioned within the storage bag 124, the storage bag 124 is ready to be transported to the surgical or implantation site. At operation 326 , the sterile carrying bag 126 is placed into the carrying bag holder 118 and the sealed device case storage bag 124 is inserted into the sterile carrying bag 126 . When sealing the carrying bag 126, the unsealed or open part of the bag 126 is placed under the sealing bar 122, and the sealing bar 122 is lowered to self-activate the heat generation to seal the carrying bag 126.

The terms and expressions used herein are used as terms of description and not of limitation, and the use of such terms and expressions excludes any equivalents or portions thereof of the features illustrated and described. not intended to. Moreover, while several embodiments of the present invention have been described, it will be apparent to those skilled in the art that other embodiments incorporating the concepts disclosed herein may be used without departing from the spirit and scope of the invention. It will become clear that you can In particular, embodiments of the invention need not include all of the features described herein, or have all of the advantages described herein. Instead, embodiments of the invention may have any portion or combination of features and advantages. Accordingly, the above-described embodiments are to be considered in all respects only as illustrative and not restrictive.

1 cell loading system 2 device case storage bag sealing station 4 first vial position 6 second filling position 10 dosing tube platform 12 counterweight 14 rotatable platform 16 flexplate mount 18 rod 22 sliding carriage 24 clamping lever 28 toggle clamp 30 DFPA Nesting Block 34 Base 36 Cell Vial 38 Dosing Tube 40 Cylindrical Indentation 42 Fitting 44 Dosing Tube Assembly 48 Rotating Bearing 50 Rotating Handle 52 Syringe Pump 54 Syringe 58 Adjustable Multi-Position Block 60 Frame 62 DFPA
68 device port sealer 70 sealer electrode 72 device port 74 device case 76 device case storage bag holder 78 sealing head assembly 80 shield 81 air cylinder 84 RF electrode 88 first holder plate 90 second rocking plate 92 cam 98 cam lever 100 Base 102 Stop 104 Actuation Switch 106 Sliding Carriage 108 Spring 110 Bar/Plate 112 Clamp Lever 118 Carrying Bag Holder 120 Sealing System 122 Accessible Sealer Pressure Bar 124 Device Case Storage Bag 126 Carrying Bag 200 Implantable Device

Claims (9)

A device case storage bag sealing station comprising:
a) a device case storage bag holder comprising a set of holder plates configured to hold a device case storage bag and a set of rocker plates, the opening and closing of said rocker plates being controlled by a cam; a device case storage bag holder;
b) a ceiling head assembly comprising two opposing radio frequency (RF) electrodes;
c) a device case storage bag sealing station comprising a base; 2. The device case storage bag sealing station of claim 1, wherein a device case storage bag holder is located on a sliding carriage coupled to the base. 3. The device case storage bag sealing station of claim 1 or claim 2, wherein locking and releasing of device case storage bags located between said sets of holder plates is controlled by a lever . 4. The device case storage bag sealing station of any one of claims 1-3, wherein the device case storage bag comprises a device case and a cell-loaded device. 5. The device case storage of claim 4, wherein the cells are pancreatic progenitor cells, PDX-1 positive pancreatic progenitor cells, pancreatic endoderm cells, endocrine progenitor cells, endocrine cells, immature beta cells, or immature pancreatic islet cells. Bag sealing station. 5. The device case storage bag sealing station of claim 4, wherein the cells are pancreatic lineage cells or pancreatic lineage cell clumps. 7. The device case storage bag sealing station of any one of claims 1-6, wherein the cam further comprises a cam lever. 8. The device case storage bag sealing station of any one of claims 1-7, wherein the sealing head assembly further comprises an air cylinder. 9. The device case storage bag sealing station of any one of claims 1-8, wherein the sealing head assembly is coupled to the base.

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