JP6888150B2 - Equipment and methods for loading cells into implantable devices - Google Patents

Description

Statement of Government Support This study was partially made possible by a grant from the California Institute for Regenerative Medicine (Grant DR1-01423). The content of this document is solely the responsibility of the inventor and does not necessarily represent the official view of CIRM or any other agency in California.

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

Cell replacement therapy for some diseases can be treated by transplanting cells, tissues, or organs into a patient with a particular disease. A major obstacle to commercial cell therapy remains a regenerative cell source, and an encapsulation source that allows allogeneic protection against host immunity. Ideally, such implantable devices allow allogeneic protection and minimize or eliminate the long-term use of immunosuppressants by patients.

Applicants have previously described both regenerative cell sources and macroencapsulated drug delivery systems, at least suitable for the purpose of delivering pancreatic progenitor cells to produce insulin in vivo in response to glucose stimulation. .. For example, at least Patent Document 1 entitled "METHODS OF PRODUCING PANCREATIC HORMONES" filed on April 8, 2008, and "ENCAPSULATION OF PANCREATIC LINEAGE CELLS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS" filed on November 13, 2009. Patent Document 2 entitled "IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND IMMATURE BETA CELLS" filed on December 12, 2013, March 7, 2014 Patent Document 4 filed on the same day, and Patent Document 5 named "IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND ENDOCRINE CELLS" filed on March 13, 2014, March 2014. Patent Document 6 named "3-DIMENSIONAL LARGE CAPACITY CELL ENCAPSULATION DEVICE" filed on the 7th, 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 with the name, Patent Document 19 with the name "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014, "TOOLS AND INSTRUMENTS" filed on April 16, 2014 Patent Document 20 entitled "FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" and "CASE FOR AN ENCAPSULATION DEV" filed on April 16, 2014. Patent Document 21 named "ICE", Patent Document 22 named "DEPLOYMENT TOOL FOR AN ENCAPSULATION DEVICE" filed on April 16, 2014, and "SIZING TOOL FOR AN" filed on April 16, 2014. Please refer to Patent Document 23 entitled "ENCAPSULATION DEVICE" and Patent Document 24 entitled "FILL POUCH ASSEMBLY FOR ENCAPSULATION DEVICE" filed on April 16, 2014. All of these applications are incorporated herein by reference in their entirety.

The cell replacement therapies described herein and in the applicant's prior disclosures generally relate to macroencapsulated transplantable cell products (“combination”) for the treatment of diabetes that are not commercially available. There are no semi-automated sterile methods and devices for loading and filling such implantable devices, except for the methods and devices described in detail below.

U.S. Patent Application No. 12 / 099,759 U.S. Patent Application No. 12 / 618,659 US Patent Application No. 14 / 106,330 U.S. Patent Application No. 14/201,630 International Application No. PCT / US2014 / 026529 International Application No. PCT / US2014 / 022109 US Design Application No. 29 / 408,366 US Design Application No. 29 / 408,368 US Design Application No. 29 / 423,365 US Design Application No. 29 / 447,944 US Design Application No. 29 / 484,363 US Design Application No. 29 / 484,359 US Design Application No. 29 / 484,360 US Design Application No. 29 / 484,357 US Design Application No. 29 / 484,356 US Design Application No. 29 / 484,355 US Design Application No. 29 / 484,362 US Design Application No. 29 / 484,35 International Application No. PCT / US2014 / 034425 U.S. Patent Application No. 14 / 254,844 U.S. Patent Application No. 29 / 488,209 US Design Application No. 29 / 488,204 US Design Application No. 29 / 488,191 US 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, devices, and / or devices for aseptically loading and filling a implantable device with cells and sealing the device in at least one other sterile container.

In one embodiment, a sterile system for loading cells into a implantable device is provided. The system was coupled to (i) a cell source and / or a therapeutic agent source and (ii) a pump to obtain the cells and / or the therapeutic agent and dispense the cells and / or the therapeutic agent into a transplantable device. A tube assembly and (iii) at least two components that can be adjusted to at least a first position and a second position, the position of which depends on the function performed. It comprises a plurality of components and elements, (iv) a sealing means for selectively sealing the implantable device inside a sterile container or package.

In one embodiment, there is provided a cell loading system comprising a rotatable platform, wherein the rotating platform further comprises means for acquiring the cells and dispensing the cells into a implantable device. .. In one embodiment, the means for obtaining cells comprises a tube assembly. In one embodiment, the rotatable platform is located 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 operated manually, or can be fully automated or semi-automated. For example, in one embodiment, the cell loading system is semi-automated by detachably connecting the tube assembly to the pump and controlling the pump remotely. In a preferred embodiment, the cell loading system is semi-automated by detachably connecting the tube assembly to the implantable device port and dispensing cells within the tube assembly to the device through the port by controlling the pump remotely. Will be done. In one embodiment, the implantable device comprises pancreatic cells. In a preferred embodiment, the implantable device comprises pancreatic cells and pancreatic progenitor cells.

In one embodiment, a method for loading cells into a implantable device, a step of placing the implantable device having a device port in a compartment, the device port to a tube assembly comprising a cell reservoir. A step in which the device is ligated and detachably attached to the rotatable platform, and a step in which the platform is rotated to a position between about 0 ° and about 180 °, and the cells are separated from the tube assembly into the implantable device. A method is provided that includes a step of loading the cells into the implantable device, and thereby. In one embodiment, the implantable device is located inside a sterile package. In one embodiment, the implantable device and sterile package are placed between 45 ° and 90 °. In one embodiment, the device port on the implantable device is sealed by sterile means, which is a source from which the device port can be sealed 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 a preferred embodiment, the cell is a pancreatic cell or a pancreatic progenitor cell.

In one embodiment, a method for releasing residual air from a bag, eg, a device case storage bag, comprising at least a liquid medium by storing the bag in a first set and a second set of plates. , The first set of plates secures the bag, the second set of plates can open and close the bag, and sealing the second plates together pushes the residual air in the bag out of the bag, which Provides a way for residual air to be expelled from the bag. In one embodiment, the device case storage bag and the first set of plates are aligned to secure the bags onto the plates.

In one embodiment, a method of selectively sealing a radio frequency (RF) energy sensitive material in a sterile state, wherein the RF energy sensitive first material is inside a second material that is not RF energy sensitive. A second material that includes a step of arranging in the first material and a step of applying RF energy to the first material and the second material at the same time, and the first material that is sensitive to RF energy is sealed and is not sensitive to RF energy. Is not sealed, thereby providing a method in which the RF sensitive material is selectively sealed in a sterile condition. 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 a given nylon 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 a polyester film or polychlorotrifluoroethylene (PCTFE) fluoropolymer film made from polyethylene terephthalate (trademark is Mylar) or stretched polyethylene terephthalate (PET), high density polyethylene. (HDPE), polystyrene, polyetheretherketone (PEEK), polypropylene, polytetrafluoroethylene (PTFE / Teflon®), polyethylene, or polymethylmethacrylate, or epoxy, silicone, or parylene.

In one embodiment, a method for aseptically sealing a device having at least one device port, the step of placing the device containing at least one port in a sterile container and the device port in the sterile container. Methods are provided that include a step of selectively sealing, while the sterile container is not sealed. In one embodiment, the step of sealing the device port comprises RF energy. In another embodiment, the step of sealing the device port comprises 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 a transplantable device, wherein at least first a predetermined flushing amount, cell amount, and priming amount are loaded into the tube assembly, and first a predetermined flushing amount, cell amount, And a method comprising dispensing a priming amount from the tube assembly into the implantable device, thereby loading cells into the implantable device, is provided.

Other embodiments of the invention will be described with reference to the list of numbered paragraphs below.
1. 1. A cell loading system comprising a rotatable platform, wherein the rotatable platform further comprises means for acquiring the cells and dispensing the cells into a implantable device.
2. Further equipped with a tube assembly,
The cell loading system according to claim 1, wherein the tube assembly is a cell reservoir containing a predetermined cell dose.
3. 3. The cell loading system of claim 1, wherein the rotatable platform is located between about 0 ° and about 180 °.
4. The cell loading system of claim 1, wherein the rotatable platform is located between about 0 ° and about 90 °.
5. The cell loading system of claim 1, wherein the rotatable platform is located at about 90 °.
6. The cell loading system of claim 1, wherein the rotatable platform is located at about 45 °.
7. The cell loading system of claim 1, which is manual, fully automated, or semi-automated.
8. The cell loading system according to claim 7, wherein the tube assembly is detachably connected to the pump and automated by controlling the pump.
9. The cell loading system of claim 8, wherein the tube assembly is detachably connected to a implantable device port and a pump dispenses cells in the tube assembly into the device through the port.
10. The cell loading system according to claim 1, wherein the cells are pancreatic cells.
11. The cell loading system according to claim 10, wherein the cells are pancreatic progenitor cells.
12. A method of loading cells into a transplantable device,
a. A step of placing a implantable device with a device port in a compartment, in which the device port is connected to a tube assembly with a cell reservoir and the device is detachably coupled to a rotatable platform.
b. With the step of rotating the platform to a position between about 0 ° and about 180 °,
c. A method comprising dispensing cells from a tube assembly into a transplantable device, thereby loading the cells into the transplantable device.
13. 12. The method of claim 12, wherein the device is located inside a sterile package.
14. 13. The method of claim 13, wherein the device and package are located on a rotatable platform and are located between 45 ° and 90 °.
15. 14. The method of claim 14, wherein the device port is sealed by sterile means.
16. 15. The method of claim 15, wherein the aseptic means selectively seals the device port and does not seal the sterile package outside the device.
17. 15. The method of claim 15, wherein the aseptic means is RF sealed.
18. 12. The method of claim 12, wherein the cells are agglomerates of cells in suspension.
19. The method of claim 12, wherein the cell is a pancreatic cell.
20. A method for expelling residual air from a bag containing at least a liquid medium, comprising the step of preparing a first set of plates and a second set of plates, the first set of plates fixing the bag. A method in which a second set of plates can open and close the bag, and when the second plate is sealed, residual air in the bag is pushed out of the bag, thereby discharging residual air from the bag.
21. 20. The method of claim 20, wherein the first set of bags and plates is aligned so that the bags are secured onto the plates.
22. A method for selectively aseptically sealing radio frequency (RF) energy sensitive materials.
a. The step of arranging the first material that is sensitive to RF energy inside the second material that is not sensitive to RF energy, and
b. In the step of simultaneously applying RF energy to the first material and the second material, the RF energy sensitive first material is sealed and the RF energy insensitive second material is not sealed, thereby. A method comprising steps, in which the RF sensitive material is selectively sealed in a sterile condition.
23. RF sensitive materials consist of a group consisting of polycarbonate-urethane, polyvinyl chloride (PVC), urethane, ethylene vinyl acetate (EVA), polyethylene vinyl acetate (PEVA), acrylonitrile butadiene styrene (ABS), or predetermined nylon or polyethylene terephthalate. 22. The method of claim 22, which is composed of a biocompatible polymer of choice.
24. RF insensitive materials are polyethylene terephthalate (trademark is Mylar) or polyester film made from stretched polyethylene terephthalate (PET) or polychlorotrifluoroethylene (PCTFE) fluoropolymer film, high density polyethylene (HDPE), polystyrene, 21. The claim 21 is composed of polyetheretherketone (PEEK), polypropylene, polytetrafluoroethylene (PTFE / Teflon®), polyethylene, or polymethylmethacrylate, or epoxy, silicone, or parylene. Method.
25. A method for aseptically sealing a device having at least one device port.
a. With the step of placing the device with at least one port in a sterile container,
b. A method comprising selectively sealing the device port in the sterilization vessel, while not sealing the sterilization vessel.
26. 25. The method of claim 25, further comprising RF energy for sealing the device port.
27. 25. The method of claim 25, further comprising a sealing ring or band around the device port.
28. 27. The method of claim 27, wherein the sealing ring or band is crimpable.
29. A method of loading cells into a transplantable device,
(A) At least first, a step of loading a tube assembly with a predetermined flushing amount, cell amount, and priming amount.
(B) A method comprising first dispensing a predetermined flushing amount, cell amount, and priming amount from step (a) into a transplantable device, thereby loading the transplantable device with cells.

The above embodiments, features, and advantages of the present invention as well as additional embodiments, features, and advantages are disclosed and will become apparent below, in particular, description of preferred embodiments of the invention, accompanying drawings, and patents. It will be clear from the claims.

In order to better understand the embodiments of the present invention and their advantages, the following description will then be referred to in connection with the accompanying drawings briefly described below.

A priming and cell loading system in which the assembly is a syringe and syringe pump, a dosing tube assembly, a rotatable platform detachably connected to a flexplate mount, and a cell source (vial) and device filling pouch assembly. It consists of a multi-position block capable of accommodating a solid (DFPA), a DFSA nesting block, and a sliding carriage connecting the multi-position block and the DFSA nesting block, and the rotatable platform rotates only between 0 ° and 180 °. It is a perspective view of a priming and cell loading system which can be done. It is a perspective view of the administration tube assembly. FIG. 3 is a perspective view of a priming and cell loading system according to an embodiment of the invention, showing where the DFPA containing the device case and the implantable device is at the time of priming and loading by alternate long and short dash lines. It is a perspective view of the device case which includes a portable device inside by one Embodiment of this invention. FIG. 5 is a perspective side view of a priming and cell loading system in which a rotatable platform is rotated and placed 90 degrees from a base according to an embodiment of the present invention. FIG. 6 is a perspective view of a handheld radio frequency (RF) sealer at a stowed position according to an embodiment of the present invention. FIG. 5 is a perspective view of a handheld radio frequency (RF) sealer at an engaging position that seals a device port according to an embodiment of the present invention. A device case storage bag holder having a pair of first holder plates and a pair of second rocking plates for holding a device case storage bag having an RF reaction portion or a sensitive portion, and a first plate and a second. A device case storage bag sealer consisting of an adjustable opening and closing system for each plate pair of plates, in which the holder moves the holder from the lower loading position of the sealing head assembly to move the device case storage bag. FIG. 3 is a perspective view of a device case storage bag sealer located on a sliding carriage that can be sealed. A larger perspective view of the device case storage bag holder, located on a sliding carriage for the device case storage bag holder and an adjustable opening and closing system, according to one embodiment of the invention, where the device case storage bag is opened and unsealed. Is. FIG. 6 is a larger perspective view of a device case storage bag holder in which the device case storage bag is closed and sealed according to an embodiment of the present invention. It is a side view of the device case storage bag holder below the sealing head assembly according to one embodiment of the present invention. It is a perspective view of the transport bag for accommodating the device case storage bag, and the sealer for sealing the transport bag according to one embodiment of the present invention. FIG. 5 is a flow chart showing a comprehensive step for loading a tube assembly having a predetermined flushing amount, cell amount, and priming amount according to one embodiment of the present invention. FIG. 5 is a flow chart showing a comprehensive step for dispensing a flushing amount, a cell amount, and a priming amount into a tube assembly according to an embodiment of the present invention. It is a flowchart which shows the overall steps for sealing a device, storing and sealing a device case storage bag, and sealing a carrying bag according to one embodiment of the present invention.

Further features and advantages of the present invention, as well as the structure and operation of various embodiments of the present invention, will be described in detail below with reference to FIGS. 1 to 11 attached. The same reference numerals refer to the same elements, and the present invention is not limited to the elements described in the drawings or embodiments.

Embodiments of the invention describe transplantable devices containing pancreatic progenitor cells and / or immature β cells, but to those skilled in the art, the invention is limited to, but not limited to, thyroid cells, parathyroid cells, pancreas. Cells, intestinal cells, thymus cells, hepatocytes, endocrine cells, skin cells, hematopoietic cells, bone marrow stem cells, renal cells, muscle cells, nerve cells, stem cells, embryonic stem cells, lineage-limited cells, primordial cells, precursor cells, gene sets Cell clumping suspensions, therapeutic agents, or mixtures thereof, comprising replacement 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. Cells that produce cell-based products, such as proteins for therapeutic indicators (eg, hormones and / or other proteins that are deficient in human diseases, etc.), antibodies, antibiotics, phosphokines, etc. are also conceivable. Those skilled in the art will also appreciate that this embodiment is applicable to a variety of portable device types, materials, sizes, and / or configurations.

When the terms "device" or "portable device" are used herein, the priming and loading described herein, including, but not limited to, the portable device of the invention, in accordance with embodiments of the invention. Refers to any macroencapsulation device or cell encapsulation device that can be used in. Such macro-encapsulation device or cell-encapsulation device is not limited, but is patent document 6 of the applicant having the name of 3-DIMENSIONAL LARGE CAPACITY CELL ENCAPSULATION DEVICE filed on March 7, 2014. , And the patent document 7 of the applicant filed on December 12, 2011, the patent document 8 of the applicant filed on December 12, 2011, and the patent of the applicant filed on May 31, 2012. Document 9, Patent Document 10 of the applicant filed on March 13, 2013, and Patent Documents 11-18 of the applicant filed on March 7, 2014 are included.

As used herein, the term "case" or "cage" or "device case" or "device cage" 74 refers to any container that can contain the device. The case can be used, for example, in pursuing embodiments of the present invention to prime and load the device and seal the device port to maintain device integrity and sterility, in such cases. Is not limited, but is patent document 19 named "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014, and "FILL POUCH ASSEMBLY FOR" filed on April 16, 2014. Includes Patent Document 24 entitled "ENCAPSULATION DEVICE" and Patent Document 21 entitled "CASE FOR AN ENCAPSULATION DEVICE" filed on April 16, 2014.

As used herein, "filling pouch", "device filling pouch", or "device filling pouch assembly" or "DFPA" 62 refers to any container or pouch that can contain the device and case. DFSA can be used, for example, in pursuing embodiments of the present invention to prime the device, load the device, and seal the device to maintain the integrity and sterility of the case and device. Such DFPA is, but is not limited to, the applicant's patent document 19 and April 16, 2014, which have the name "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014. Includes the applicant's patent document 24, which has the name "FILL POUCH ASSEMBLY FOR ENCAPSULATION DEVICE" filed on the same day.

When the term "device case storage bag" or "storage bag" 124 is used herein, any device case and device can be contained so as to be sealed, according to an embodiment of the present invention. Refers to a bag or pouch or a sterilizable bag or pouch, such a device case storage bag having the name "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014. Includes a storage bag as described in Human Patent Document 19. Generally, the device case storage bag 124 has an RF reaction part.

When the terms "carrying bag," "carrying package," or "carrying pouch" 126 are used herein, according to embodiments of the present invention, device case storage bags, device cases, and devices. Refers to any bag or pouch or sterilable bag or pouch that can contain multiple elements, including a case, so as to be sealed inside, such carrying bags, but not limited to, April 2014. Includes a carrying bag used in the applicant's Patent Document 19, which has the name "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on the 16th.

As used herein, the terms "assembly," "system," "fitting," "device," "component," "platform," and / or "means," 1, 2, 68, 76 are used. When, they have the same meaning and are used without distinction according to the embodiment of the present invention.

When "adjustable," "movable," or "multi-position" 14, 22, 58, 106 are used herein, according to embodiments of the invention, but not limited to, laterally. Components that can move, move vertically, or rotate from 0 degrees to 180 degrees or more in various positions, or have 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 vessel", and / or "alicoat vial" 36 are used herein, cells according to embodiments of the present invention. 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 their context, but various embodiments are limited to such. It is not intended to be done. The priming and loading system embodiments described herein may be utilized not only for agglomeration, but also for different types of cell sources in different forms.

When the terms "pancreatic endoplasmic cells", "PDX1-positive endoplasmic reticulum", "PEC", and "pancreatic progenitor cells" are used herein, they refer to therapeutic cell sources according to embodiments of the present invention. The applicant's Patent Document 1, which has the name "METHODS OF PRODUCING PANCREATIC HORMONES" filed on April 8, 2008, is not limited to such therapeutic cell sources, on November 13, 2009. The applicant's patent document 2, which has the name "ENCAPSULATION OF PANCREATIC LINEAGE CELLS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS", was filed on December 12, 2013, and "IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS TO PANCREATIC Applicant's Patent Document 3 with the name "(PEC) AND IMMATURE BETA CELLS", Patent Document 4 filed on March 7, 2014, and "IN VITRO DIFFERENTIATION OF" filed on March 13, 2014. Includes the applicant's Patent Document 5 having the name "PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND ENDOCRINE CELLS".

As used herein, the terms "cell loading system" or "priming and cell loading system" or "loading system" mean any system for loading a therapeutic agent or cell into a device.

When the term "administration tube platform" or "tube mount" is used herein, it means any platform or mount that constitutes a means for the tube assembly to remain held on the mount. ..

When the terms "device loading port" or "device loading tube" or "device port" or "device tube" are used herein, drug and / or cell priming or drug and / or cell Means any tube for loading into the device and later sealing the device.

When "radio frequency", "electromagnetic energy", or their equivalents are used herein, certain thermoplastic membrane materials are selectively sealed and other thermoplastic membrane materials are not sealed by means. is there.

When the term "cell dose" or "dose" is used herein, it is generally a reference to any number of cells or cell clumps or therapeutic agents. For example, the cell container or vial, 1 to 10 ^6, 10 ^7, but may have a 10 ⁹ or more cells, in these embodiments, any amount of the above in one vial of cells It 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 masses, so system 1 can accommodate varying amounts and thus can accommodate large cell doses. .. In one embodiment, the system 1 is one, two, depending on the number of cell doses required for treatment and / or needing to be filled with a particular size device or devices for each manufacturing run. It can be programmed to store cell doses such as 3, 4, 5, and so on. Determining the amount of cells for one cell dose and the amount of cells for multiple cell doses for this system does not require additional invention and is within the skill of one of ordinary skill in the art.

As used herein, "coupling system", "mounting system", "sealing system", "locking system", "latch system", or their equivalents are hinges, snaps, buttons, strings, hooks, latches, fasteners, etc. Attach, join, and connect one or more components, such as clips, clamps, nuts, bolts, or other types of fasteners used to detachably or permanently connect components or fixtures to each other. And refers to any means for latching.

As used herein, a given component or component is pulled or pushed (eg, pushed down or pulled up), which is not important as to whether the component is closed or opened. Closed or opened by using a latch or cam lever. It is possible for any movement (pulling or pushing) to perform any function (opening or closing) that the opening and closing of the component is independent of whether the latch or cam lever is pulled or pushed. Because.

As used herein, the term "loaded" refers to filling or putting something into something else, such as filling or loading a device, or loading a dosing tube assembly. It is a reference of that.

Portable Devices Although not the purpose of this embodiment, portable devices will be described and illustrated throughout this application. For example, FIG. 2, FIG. 3, FIG. 4, FIG. 5, FIG. 6, and FIG. 8 show a device case 74 in which the portable device 200 is fixed internally. However, the embodiments described herein are not limited to these portable devices, but may be other portable or non-portable 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 embodiment. Applicants are of a variety of planes, including, but not limited to, self-expandable implantable devices, large or macroencapsulated, planar and non-planar implantable devices, or 3D macroencapsulated implantable devices. Transplantable devices that are planar and non-planar (eg, three-dimensional) have been described. For example, the applicant's patent document 6 having the name "3-DIMENSIONAL LARGE CAPACITY CELL ENCAPSULATION DEVICE" filed on March 7, 2014, and the applicant's patent document 7 filed on December 12, 2011. , Patent Documents of Applicants Filed on December 12, 2011 8, Patent Documents of Applicants Filed on May 31, 2013 9, Patent Documents of Applicants Filed on March 13, 2013 10. Other encapsulated implantable devices have been described by the applicant's patent documents 11-18, which have the name "3-DIMENSIONAL LARGE CAPACITY CELL ENCAPSULATION DEVICE" filed on March 7, 2014.

Therapeutic cells and agents In the embodiments herein, priming the therapeutic cells and the therapeutic agent to load the therapeutic cells and the therapeutic agent into a transplantable device. In particular, therapeutic cells and drugs consisting of cell agglomeration suspensions will be described. Applicants are developing cell therapies for diabetes, specifically encapsulated cell therapies for the treatment of diabetes, various endoderm lineage cells or endoderm lineage cells, specifically described herein. The pancreatic lineage cells used with the embodiments have been described in detail. For example, the applicant is at least Patent Document 1 named "METHODS OF PRODUCING PANCREATIC HORMONES" filed on April 8, 2008, and "ENCAPSULATION OF PANCREATIC LINEAGE CELLS DERIVED FROM" filed on November 13, 2009. Patent Document 2 named "HUMAN PLURIPOTENT STEM CELLS" 2, Patent Document 3 named "IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND IMMATURE BETA CELLS" filed on December 12, 2013 In Patent Document 4 filed on March 7, 2014, and Patent Document 5 named "IN VITRO DIFFERENTIATION OF PLURIPOTENT STEM CELLS TO PANCREATIC ENDODERM CELLS (PEC) AND ENDOCRINE CELLS" filed on March 13, 2014. The mesoendoderm cells and the germ layer lineage cells in the embryo are described in detail. In a preferred embodiment, the implantable device is a therapeutic agent, living cell, endoderm lineage cell, endoderm germ layer lineage cell, pancreatic progenitor cell, pluripotent cell (human embryo or fetal, umbilical cord blood stem cell, induced pluripotency). Humans induced by currently known or future discovered methods, including induction using non-destructive stem cells, reprogrammed cells, participatory germ cells, gonad germ cells, and mesenchymal or hematopoietic stem cells. It is composed of pancreatic primordial cells different from germ layer stem cells), PDX-1-positive pancreatic primordial cells, endocrine precursor cells, endocrine cells, immature β cells, immature pancreatic islet cells and the like.

In the present specification, various documents including scientific journal articles, patent documents, and patents are referred to, and the entire disclosure of each of these documents is incorporated by reference. For example, generate a pancreatic primordial cell population and / or an immature β-cell population, sterilize, store, fix, and transfer the device, size and prepare the anatomical site, and apply the combination drug to the transplant site. Devices and methods for delivering and arranging and allowing hormone-secreting cells to function in the body are disclosed in the applicant's patent application above and are incorporated herein by reference in their entirety.

Priming and Loading Systems Figures 1-3 are non-limiting and non-exclusive of System 1 for priming cells (or any fluid suspension containing a therapeutic agent) to load cells into a transplantable device. Embodiment is shown. System 1 at least (i) loads the fluid reservoir 44 and the dosing tube 38 (collectively dosing tube assemblies 44, 38), and (ii) puts the dosing tube assemblies 44, 38 and device 200 inside the DFPA 62, respectively. Capturing the cell vial 36 and the DFPA 62 containing the device case 74 and the device 200 so that it can be loaded into (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 control, aseptically, manually, semi-automatically and / or automatically.

1 to 3 show a syringe 54 and a syringe pump 52, an administration tube platform 10, a fluid reservoir 44 and an administration tube 38, a flex plate mount 16, a rotary handle 50 connected to a rotary bearing 48, and a counterweight 12 The present invention includes a rotatable platform 14 having a first vial position 4 and an adjustable sliding carriage 22 including an adjustable multi-position block 58 having a first vial position 4 and a second DFSA position 6 and a DFSA nesting block 30. A non-limiting and non-exclusive embodiment is shown. All components are connected to a frame 60 mounted on the base 34 (administration tube platform 10, rotatable platform 14, and sliding carriage 22). Specific embodiments will be described in more detail below.

The priming and cell loading system 1 is also referred to as a "cell loader", a "cell loader system", or a "cell filling assembly" or an equivalent thereof. In any embodiment, the priming and cell loading system 1 performs its function in a sterile condition, thereby maintaining the integrity and sterility of the various components of the system and / or the components used with the system. Will 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) in accordance with at least US and European regulatory bodies.

Additional components, such as external sensors such as cell counters, pressure converters, thermal sensors, speed sensors, etc., can be added to the priming and cell loading system 1.

Administration Tube Assembly To ensure sterilization, disposable administration tube assemblies 44, 38 comprising a fluid reservoir 44 and an administration tube 38 are connected to a syringe 54 and further to a syringe pump 52. The dosing tube 38 is sometimes referred to as the loading tube 38. The fluid reservoir 44 holds a liquid medium for priming the device 200 and is used to store the cell agglomerates or liquid medium for flushing the cell clumps to the device 200. In one embodiment, there is also a fitting 42 that separates the fluid reservoir 44 and the dosing tube 38, which is connected to a syringe and these components are sterilized together as one unit. The sterilization unit is then connected to a syringe pump 52. In one embodiment, the dosing tube assemblies 44, 38 are uniform diameter tubes. The diameter of the tube was chosen to facilitate connectivity between the various components of the priming and cell loading system 1, such as the syringe 54, flexplate mount 16, and device port 72. The use of tubes with an overall constant diameter eliminates the transitions and additional fittings or valves that would be required if the tube size (diameter) changes. For example, when the tube diameter changes, fittings or valves are used to accommodate changes in tube size, and this change causes cells, especially suspension agglomerates, to differ from each other in the tube system, in some cases. Clogged in the area or confined in the fitting during transport (eg, cell clumps may settle in small grooves in the fitting and affect the movement of other cell clumps), or especially smaller diameters May be destroyed by shearing when transitioning to a tube. Therefore, maintaining a constant diameter with respect to the tube system is advantageous as it reduces the likelihood that cell clumps will be trapped near or inside the junction or fitting. Tubes with a constant diameter are also fluids that are responsive when using liquid pumping media, including, but not limited to, sterile phosphate buffered saline (“PBS” or “saline”), stem cell medium, and the like. Allows volume transfer. In a fluid reservoir 44 with fewer tubing 42 and / or valves, mechanically sensitive materials, particularly but not limited to animal, human, and / or plant cells, viruses, and protein precipitates in suspension. It allows for more gentle transport of shear-affected biomaterials, including agglomerates of objects, protein crystals, natural proteins, antibodies, liposomes, and cell clumps. Reducing the number of fittings also reduces the potential for contamination, especially when used by humans, and maintains a sterile, sterile environment. In one embodiment, additional fittings in the dosing tube 38 by using a tube with a radius smaller than the device port 72 so that the dosing tube 38 can be inserted directly into the device port 72 when loading cells. In some cases, contamination of the dosing tube 38 and / or the device port 72 and the device 200 within it is prevented.

Various sizes, diameters, lengths, tapers, spheres, balloons, and other features of the fluid reservoir 44 are possible and depend on the material to be aspirated and loaded and / or the device for receiving such material. You may. The tip of the dosing tube 38 is connected to the device port 72 of the implantable device 200 and therefore the dosing tube 38 should have about the same diameter as the device port 72 for exactly the same reasons as described above.

In one embodiment, the physiological saline is used as the pumping fluid in the dosing tube assemblies 44, 38. This is advantageous because the pumping fluid can be given a higher degree of control than pumping air through the tube assembly. In addition, regulatory compliance when using air is more cumbersome and cumbersome than with liquid pumping fluids.

In one embodiment, the length of the tube selected depends in part on the maximum volume of medium and cell clumps when loading the maximum volume device. For example, a tube length of about 20 feet can hold a total tube volume of about 5 mL when loaded with at least EN250 devices (about 250 μL).

In one embodiment, the fluid reservoir 44 can be mounted or held on the dosing tube platform 10 or accommodated by other means known in the art.

Tube Platform The dosing tube platform 10 constitutes a means for maintaining or holding dosing tubes 44, 38, in particular fluid reservoir 44, for example, a longer dosing tube can be wound and held on the gantry 10. The gantry 10 keeps 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 attempts to achieve a more vertical position (rather than horizontal), subsequent media flow heads may submerge below the air bolus and form bubbles. This is prevented by keeping the tube horizontal.

In one embodiment, the dosing tube platform 10 further comprises a cylindrical recess 40 and a rotation retention latch and / or a fixed thumbscrew to secure and / or hold the tube in place. be able to.

Syringes and Syringe Pumps Typical surgical (manual) syringes use pistons and cylinders and are suitable for delivering (dispensing) small amounts of measured fluids used in daily laboratory studies. There is. For example, Applicants explained that a Hamilton syringe is used to measure small amounts of pancreatic progenitor cells and load them into a transplantable device to be transplanted. At least, Patent Document 1 named "METHODS OF PRODUCING PANCREATIC HORMONES" filed on April 8, 2008, and "ENCAPSULATION OF PANCREATIC LINEAGE CELLS DERIVED FROM HUMAN PLURIPOTENT STEM CELLS" filed on November 13, 2009. Please refer to Patent Document 2 entitled. However, in commercial treatments where multiple devices, or larger devices, or 3D devices need to be primed and filled, 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 perform rigorous and accurate priming and loading (dispensing) of large doses while maintaining cell viability (eg, reducing shear stress). Is.

1 and 2 show non-limiting and non-exclusive embodiments of the syringe 54 and the syringe pump 52. Syringe 54 and syringe pump 52 are commercially available from various manufacturers, including, but not limited to, Cavro, Parker, Kloehn, Hamilton, and the like.

The pump can be used with syringes of various sizes for dispensing volumes in the range of 1 microliter to 50 milliliters. Syringe pumps generally consist of a syringe barrel, inlet and outlet valves, a piston, and a motor. In one embodiment, the syringe barrel is inserted directly into the valve and a seal can be used to substantially separate the valve from the syringe. In this example, the syringe area and the amount of syringe fluid dispensed by the linear displacement of the piston are specified. In another embodiment, the syringe pump comprises a piston and a cylinder, in which case the piston can perform valve function. In a preferred embodiment, the syringe barrel is inserted directly into the fitting (rather than the valve) and a seal can be used to substantially separate the fitting from the syringe. In yet another embodiment, a motor (eg, a stepping 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 used to aspirate and dispense the applicant's candidate cell product, a pancreatic progenitor cell agglomerate suspension (or PEC). The pump consists of a stepper motor precision syringe pump powered by a 24V DC power brick and capable of operating at 12000 steps, 24000 steps, or 48000 steps per full stroke. The full stroke of the pump is about 6 cm (60 mm). Syringes of various sizes from 25 μL to 50 mL can be attached to the pump. The suction and dispensing volume is accurately determined by the syringe volume and the number of steps per stroke, the smaller the syringe volume, the higher the accuracy. In one embodiment, a cell loading system EN250 (maximum capacity about 250 μL) device and EN20 (maximum capacity about 20 μL) device can be implemented using a 10 mL syringe capable of about 48,000 steps per full stroke of the pump. The nominal fluid 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 for various suction (tension, negative pressure) commands, pause commands, and dispensing (positive pressure) commands. The Kloehn pump comprises, for example, a multi-functional command set in which various command strings are stored in the controller software application and sent to the pump 52 when requested by the user. The response from 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 input, thus being required by the syringe pump 52 by a simple push-button interface. It is possible to order suction, rest, and dispensing depending on the situation.

In another embodiment, the syringe pump 52 can receive hardware inputs from the integrated assembly machine control system. The use of a computer has been chosen for convenience, but any automated or manual method for aspirating, resting, and dispensing fluids or cells, especially cell suspension aggregates, will be available to those of skill in the art. Is rational.

Rotatable Platform A unique feature of the priming and loading system 1 is the rotatable platform 14 coupled to the sliding carriage 22 (discussed in more detail below), the rotatable platform 14 and the sliding carriage 22 both together. It can rotate from 0 degrees to 180 degrees. The rotatable platform 14 can further consist of a flexplate mount 16 (described in more detail below). A rotary handle 50 that moves around a rotary bearing 48 mounted on the frame 60 and base 34 of the priming and cell loading system 1 is used to rotate the rotatable platform 14 180 ° from vertical downward to vertical upward. be able to. See FIG. 3, which shows a side perspective view of the priming and cell loading system 1. FIG. 3 also shows a rotating platform 14 and a sliding carriage 22 rotated about 90 degrees with respect to the base. When fixing or tightening the rotatable platform 14 in a desired position, the rotary bearing 48 can be fixed by one or more locknuts. In other embodiments, it is also possible, but not limited to, to secure the position of the rotatable platform 14 by an alternative locking or locking mechanism, including, but not limited to, a toggle clamp, friction clutch, ratchet, and the like.

In one embodiment, when removing and installing the vial 36 and / or DFSA62, the rotatable platform 14 is oriented vertically downwards as shown in FIGS. 1 and 2. For smaller devices (eg, devices with a maximum capacitance of 20 μL, such as EN20 devices), wetting or priming may be achieved at various azimuth angles. For larger devices (eg, devices with a maximum capacitance of 250 μL, such as EN250 devices), wetting or priming will be more efficient if the rotatable platform is oriented vertically upwards, as in FIG. It is within the knowledge of those skilled in the art to optimize and change the position of the rotatable platform 14 to load the desired device, for example, some devices load the rotatable platform 14 horizontally. On the other hand, for other devices it is more appropriate to place and load upwards so that the rotatable platform 14 is placed at an angle between, for example, 180 ° and 90 °. Changing the angle of rotation to dispense and load the device also helps to distribute the cells more evenly inside the device chamber and can reduce the number of bubbles or pockets that may form. is there. Bubbles or pockets trapped inside the device can adversely affect the device's ability to accept cell clumps, which can adversely affect the cell distribution within the device, as well as the cells at the site of the bubble. Growth, proliferation, maturation, and development, and cell growth, proliferation, maturation, and development near or near its site may be affected. Therefore, avoiding the formation of bubbles is important for proper (equal) cell distribution, and the rotatable platform 14 can be easily manipulated by small or large movements that affect orientation. This may be facilitated by doing so.

In one embodiment, due to weight components such as the multiposition block 58 and the DFSA nesting block 30, the rotatable platform 14 has a counterweight 12 proximal to the platform 14 for stability. May be good.

Flex plate pedestal The flex plate pedestal 16 works so when presented to center the dosing tube 38 in the vial 36, and when presented to align the dosing tube 38 with the device port 72. Work like. The flex plate may flex slightly and is a sealed connection between the tube 38 and the fitting of the device port 72 when the administration tube 38 and the fitting of the device port 72 are fully engaged inside the DFSA62. Apply a certain amount of force to maintain the part. In one embodiment, the flexplate mount 16 can accommodate fluid reservoir tubes 44 and dosing tubes 38 of various sizes by selecting pipe fittings 42.

In one embodiment, one or more dosing tube assemblies 44, 38, one or more fittings 42, and one or more latches 46 are added to simultaneously load or synchronously load one or more devices. Can handle loading. Therefore, the flexplate mount 16 can be adjusted or optimized to perform several priming and loading functions. Such modifications to the flex plate mount 16 can be accomplished by one of ordinary skill in the art.

In one embodiment, the plurality of dosing tube systems 44, 38 can be used with the plurality of fittings 42, but the same device or different devices can be loaded simultaneously or synchronously.

In one embodiment, when loading cells into the implantable device 200 as further described in FIG. 10, the flexplate mount flexes to maintain a tight connection between the dosing tube and the device port 72 inside the DFSA62. ..

The sliding carriage rotatable platform 14 is detachably coupled to the sliding carriage 22 and moves above the rod 18. The rod 18 can engage and disengage the dosing tube 38 by moving the carriage 22 up or down on the rod 18.

In a preferred embodiment, there are three major activities and amounts, namely priming by priming amount, cells in cell amount, and flushing by flushing amount. The dosing tube assemblies 44, 38 are held in place by the flexplate mount 16 as described above. The flex plate mount 16 is removably connected to the sliding carriage 22, which can be located at three positions with respect to the tip of the administration tube 38. To allow the device 200 to be loaded or filled with cells, first, the administration tube assemblies 44, 38 are loaded or filled with flushing amounts, cell clumping amounts, and priming amounts, as described in more detail below.

(2) Central position: The sliding carriage 22 is placed in the central position, whereby the administration tube 38 is immersed in the vial medium and suspended above the bottom of the vial 36 (just above the precipitated cell clump). Ru. In one embodiment, this central position can be used to aspirate or draw only cell or flushing amounts into the dosing tube assemblies 44, 38 (without aspirating cell clumps). It is desirable to load the cell culture medium without loading the cell clumps into the dosing tube assemblies 44, 38 in order for the cell culture medium to (i) wet (or "prime") the device 200. Because it has at least two functions of being used and (ii) being used to flush (or "chase") cells from dosing tube assemblies 44, 38 into the device.

(1) Full engagement: The sliding carriage 22 is located most proximally and abuts or is in close proximity to the rotatable platform 14 and the flexplate mount 16. When the multiposition block 58 is located at the first vial position 4 (FIG. 2A), the dosing tube 38 is centered above the vial 36 and the tip of the dosing tube 38 is located near the bottom of the vial 36. When the multiposition block 58 is located at the second filling position 6, the tip of the dosing tube 38 is aligned and inserted into the device port 72 in the DFSA 62. In another embodiment, for example, if the dosing tube 38 and the device port 72 have different radii, a fitting can be provided between the device port 72 and the dosing tube 38. In one embodiment, this fully engaged position is used to pull the cell clumps into the dosing tube assembly 44, 38.

(3) Complete withdrawal: The sliding carriage 22 is located at the farthest position (farthest from the flexplate mount 16 and rotatable platform 14) so that the dosing tube 38 is completely detached from the device port 72 and / or the DFSA 62 or vial 36. Be placed. In one embodiment, this detachment position is used to remove or install the DFSA 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 in the vial or the therapeutic agent. It is decided. For example, the present specification describes preferred embodiments that describe loading of dosing tube assemblies 44, 38 and loading of device 200, but with a therapeutic agent in which System 1 may be a more homogeneous mixture. When used, there may not be a separate physical layer. In such embodiments, it may be necessary to use separate vials containing cell culture medium for priming and flushing the therapeutic agent.

One preferred embodiment of loading the dosing tube assemblies 44, 38 and loading the device 200 will be described with reference to FIGS. 9 and 10.

To keep the sliding carriage 22 in that position, magnets can be used to hold or lock the position of the carriage 22 in different moving positions (“stop”). In one embodiment, fine tuning and fine tuning can be addressed by adding a magnetic adjusting screw that can come into contact with the magnet at either end when moved in either direction. This stop prevents further movement of the carriage 22 and misalignment of the dosing tube 38 with respect to either the DFSA 62 or the vial 36. Other stopping methods, including magnets and other mechanical means, can also be used in the adjustable multiposition block 58, which will be described in more detail below.

In one embodiment, the sliding carriage 22 further comprises an adjustable multiposition block 58 and a DFSA nesting block 30, as described in more detail below.

Adjustable Multi-Position Blocks In one embodiment, the sliding carriage 22 further comprises an adjustable multi-position block 58. The adjustable multi-position block 58 is a laterally sliding platform with at least two positions. FIG. 2 shows a first position 4 (“vial position”) where the vial 36 can be inserted into the block 58 and a second position 6 where the DFSA 62 can be partially or completely located within the multi-position block 58. ("Filling position") is shown. Therefore, the multi-position block 58 can be adjusted according to the function. In one embodiment, when loading cells or the desired therapeutic agent into the dosing tube assemblies 44, 38, the first vial position 4 is used and the first vial position 4 houses the cell container or vial 36. Can be done. In another embodiment, when dispensing (or loading) cells from the dosing tube assemblies 44, 38 into the device, a second filling position 6 is used, at the second filling position 6 the port. It can accommodate a DFSA or similar sterile device, including the device 200 with. Each of these embodiments will be described in more detail below with reference to FIGS. 9 and 10.

DFSA Nesting Block In another embodiment, the sliding carriage 22 further comprises a DFSA nesting block 30, held in any device case and device shape, eg, DFSA 62, similar to that described in FIG. 2B. The 74 and the device 200 can be accommodated. Therefore, the DFSA nesting block 30 can have recesses that accommodate the shape and size of the device case and device.

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

Overcenter (“Toggle”) Clamp In one embodiment, the adjustable multiposition block 58 and the DFSA nesting block 30 further provide an overcenter clamp (or toggle clamp) 28 for fixing the vial 36 or DFSA 62 in place. , 32. In one embodiment, the toggle clamps 28, 32 may be in the form of an elongated contact bar that enters a predetermined position during operation to hold the aliquot vial 36 and / or DFSA62. In one embodiment, the clamps (or contact bars in this example) 28, 32 are connected to the clamp levers 24, 26 so that the clamp levers 24, 26 open and release the clamp to hold the vial 36 or DFSA 62. It is operated by. As with other embodiments, the method for fixing or holding the vial 36 or DFSA 62 in place can be implemented in any number of applications in which the clamp-like grip or holder can be opened and closed. Clamps 28, 32 allow the fingers on the clamp to cope with changes in the size of the vial 36 or the thickness of the DFSA 62, thereby using the priming and loading system 1 for a variety of devices for those devices. It can be made with a flexible material that allows for optimization. At least for the adjustable multiposition block 58, any clamp 32 causes the adjustable multiposition block 58 to slide between the two positions of the block 58 with the clamps 28, 32 fully depressed. Should be possible. Other holding mechanisms, including, but not limited to, latches, snaps, locking female and male parts, tabs, etc. are also conceivable.

Therefore, embodiments of the priming and cell loading system 1 have features that include multiple adjustable components to address various functions and applications. The adjustable multiposition block 58 has a flushing amount, a cell amount, and a priming amount, a priming amount, and a priming amount, a cell amount, from a first vial position 4 for aspirating cells into the dosing tube assemblies 38, 44 having the priming amount 4. And slide to the second filling 6 position for dispensing the flushing amount. Further, 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 DFSA 62. This multi-functionality reduces the risk of contamination as the operation is performed in one area. The various system 1 components allow 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 is primed (wetting), the device is loaded with cells, and the cells are flushed from the dosing tube. The device needs to be sealed in order to do so. FIG. 4 shows a non-limiting and non-exclusive embodiment of such a device port sealer 68.

Generally, the device port sealer 68 is a custom of at least four parts: an RF generator, a transmission cable, a sealing wand with an internal matching network, and a sealer electrode 70 whose electrodes are located at the ends of the C-shaped jaw. With a set. This C-shaped configuration allows access to device port 72. In a preferred embodiment, the C-jaw covers the sealed port area of the device case 74 and seals the device port 72 without destroying the DFSA 62. The C-shape also allows the jaw to slide above the DFSA 62 from each side, allowing the electrodes to directly access approximately the center of the DFSA 62, where the device port 72 normally resides. The sealer electrode 70 is cylindrical and fits into the corresponding cylindrical notch in the device case 74. The electrode position can be adjusted within the jaw to allow a constant electrode gap to exist when the sealer wand handle is fully closed. The sealer electrode 70 in the jaw can be quickly replaced if it becomes dirty, damaged or dented due to RF arching. Other electrode shapes and configurations are also feasible.

In one embodiment, radio frequency (RF) power from the handheld device port sealer 68 is used to aseptically seal the device loading port 72 (ie, the device loading port 72 is still in the device case 74 and DFSA 62). Sealed while located inside).

In a preferred embodiment, the device 200 does not necessarily have an adjustable second filling position on the multi-position block 58 as long as it is held in place to prevent accidental leakage or creep of cells from the device 200. Not necessarily at 6, but still sealed while located within the DFSA nesting block 30.

In one embodiment, the device loading port 72 is made of any biocompatible flexible plastic tube that responds specifically or selectively to RF energy and has a rapidly heated and cooled interior. In contrast, other materials in DFSA 62 and device case 74 do not respond similarly to RF energy. For example, by using moderate pressure, the heated device loading port 72 may be compressed to close and additional sealing material (eg, encapsulant or adhesive film) may be introduced, or the device loading port 72 may be used. A permanent seal is formed in the tube without damaging the case, while keeping the case 74 and DFSA 62 unaffected by the RF sealer (not sealed, eg, the DFSA sheets do not melt together). Can be done. In this example, the DFSA material acts as a buffer material. Other cushioning materials will be described below. This ability to permanently seal the device tube in a sterile condition 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 necessary, to address the connection with the dosing tube 38, and the device port is these. It can be sealed in any of the areas, but is usually sealed in the area closest to the body of the device 200 itself.

Therefore, during the priming and loading of the implantable device 200, the device 200 is untouched by human hands, undergoes minimal operation, and all operations are within the sterile environment of DFSA62.

Buffer Material Not Responsive to RF Energy In one embodiment, the buffer material used to make DFSA or other sterile bags and pouches was utilized. The DFSA consists of a thin laminate of polyester (eg, Mylar) and polyethylene, which has a nominal thickness of about 0.0025 inches (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, whereby the electrode does not come into direct contact with the device loading port and can nevertheless seal the device loading port. .. During sealing, the device port 72 generates heat in response to the applied RF energy, while, for example, the buffering material laminate of DFSA62 does not respond to RF energy. Therefore, under moderate clamping pressure, the heated device loading port 72 forms a permanent seal, while at the same time the cooler buffer material laminate also adheres to the heated loading port. Nor. Releasing 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 buffer material is not important, but thinner materials are preferred as they are easier to use and less costly. Alternative materials include polyethylene (eg, Tyvek), polytetrafluoroethylene, polypropylene, polyamide and the like. In the embodiment, a polyester / polyethylene laminate was selected. The reason is that the polyester / polyethylene laminate is available at low cost as a thin and easy-to-use sheet. Further transparent cushioning materials, such as Mylar polyester, allow the operator to quickly visually inspect the resulting seal in a sterile condition without the need to open the DFSA62.

Further, other materials of the buffer material are patent document 19 named "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014, and "TOOLS" filed on April 16, 2014. It is described in Patent Document 20 named "AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" and Patent Document 21 named "CASE FOR AN ENCAPSULATION DEVICES" filed on April 16, 2014.

Radio Frequency (RF) Generator In one embodiment, the RF generator used to seal the device port 72 includes a self-regulating power output that is output until one of the two output conditions is met. (I) Power is supplied until the total energy threshold is achieved, or (ii) power is supplied until a predetermined period (for example, 2 seconds) has elapsed. Due to the design of the RF generator and the fixed matching network in the sealing wand, the actual power output will fluctuate until the seal is complete. The nominal power output is about 25W. Patent Document 25 describes in detail the power generation and supply of RF energy for tube sealing applications.

In one embodiment, a "Haemonetics" (formerly known as "Sebra") model 2600RF generator was used to power the RF and seal the loading port 72 of the implantable device. The generator outputs RF power at the FCC mandated frequency of 40.68 MHz via 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 600 W and can be driven in pulse mode or continuous mode. Alternative RF generators can be used, in which case additional controls may be required to provide adequate power over the specific duration required to properly seal the device loading tube. is there. RF generators with such characteristics are commercially available from other manufacturers, including, but not limited to, Seren IPS, Comdel, Lesker, MKS Instruments, and the like.

RF Cable In one embodiment, an industry standard 50 ohm impedance RG-223 RF cable with double shielding is used to transfer RF energy from the RF generator to the sealing wand. The length of this cable is about 95.8 ", which is specifically tuned to 1/2 wavelength at 40.68 MHz, which maximizes transmission efficiency and RF. Minimize backward reflection 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 the stiffness, shielding (decreased efficiency), or current capacity is not constant. ..

In one embodiment, a "Haemonetics" (formerly known as "Sebra") sealing wand is used to match the RF impedance between the RF source and the load, while the user wraps the sealed jaw around the DFSA62. Allows ergonomic access to place in position. Due to the unique shape and configuration of the jaw of the device loading port sealer 68, the sealer head load impedance differs from the industry standard 50 ohm resistance impedance. To compensate for this difference, an intermediate correction induction / capacitive impedance (matching network) is placed between the RF source and the load. The sealing wand comprises an internal matching network of constant values capacitors and inductors. The sealing wand matching network is manually tuned in the factory to be a lightweight, compact and efficient matching network. Patent Document 26 (whole incorporated by reference) describes in detail a constant value matching network located within the sealing wand.

In another embodiment, a tunable matching network can be used, which requires 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, Manitousys, Materials Science Inc., and others. Using a Haemonetics Model 1105 sealing wand with a fixed matching network provides a lower cost and smaller sealing solution.

Device Case Storage Bag Sealing Station FIGS. 5-7 show a non-limiting and non-exclusive embodiment of the device case storage bag sealing station 2 for sealing or sealing the device case storage bag 124. The device case storage bag 124 further comprises a loaded portable device 200 inside the device case 74.

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

Device Case Storage Bags FIGS. 6A and 6B are non-limiting and non-exclusive implementations of means for storing cell-filled or loaded devices (or cell-encapsulated devices) in storage bag 124. Shows the morphology.

The configuration of the device case storage bag 124 was designed in connection with the sealing station 2. The elements on the sealing station 2 interact directly with, for example, the device case storage bag 124 to (i) protect the device and the therapeutic cells or agents inside the device during transport and carriage, and (ii) final. It was based on at least two basic requirements to allow the seal to be applied in a sterile condition. A detailed description of this storage bag and similar storage bags is provided in Patent Documents 19 and 2014 of the applicant, which has the name "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014. It is described in Patent Document 20 of the applicant having the name "TOOLS AND INSTRUMENTS FOR USE WITH IMPLANTABLE ENCAPSULATION DEVICES" filed on April 16, 2014.

In one embodiment, certain elements, such as holes or notches that align with the corresponding elements or markings (eg, ink markings) on the first holder plate 88, are incorporated into the device case storage bag 124 during design and manufacture. Can be done. This is similar to the male and female parts of latches or fittings. Thus, any ceiling station 2 may incorporate an element of the sealed portion or has a corresponding element at the sealed portion (eg, a device case storage bag 124 and an alignment element on the ceiling station 2). You may.

Device Case Storage Bag Holder In one embodiment, the device case storage bag holder 76 is located on the sliding carriage 106 and comprises a first holder plate 88 and a second swing plate 90. In one embodiment, the two plates that make up the holder plate 88 move or rotate differently, for example, the front plate rotates while the rear plate is stationary. The first holder plate 88 holds the device case storage bag 124 and is further controlled by a cam or lever 112 connected to the bar or plate 110, which is connected to the spring 108 and rotates the bar / plate 110. The lever 112 to be moved can be moved (or rotated). For example, when locking the device case storage bag to the first holder plate 88, the lever 112 is pulled upwards, the first holder plate 88 mechanically translates to the front plate 88, and the device case storage bag holder 124. Is sandwiched between the holders 76 and the device case storage bag 124 is released, the lever 112 is pushed downward.

The device case storage bag holder 76 holds the device case storage bag 124 together with the device case 74 and the device 200 loaded with cells. In one embodiment, prior to sealing the device case storage bag 124, the device 200 loaded with cells inside the device case 74 is removed and transferred from the DFSA 62 to the open and unsealed bag 124. The first holder plate 88 primarily serves to keep the storage bag 124 in place, while the storage bag 124 is filled, i.e., while the device case 74 and device 200 are transferred into the storage bag 124. The device case 74 and device 200 are opened while being filled with a liquid medium for long-term storage, i.e., a storage bag 124 sufficient to soak in a storage buffer or cover with such a liquid medium.

In another embodiment, the second rocking plate 90 serves to close the storage bag 124 of the current device and medium-filled and 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 the cam guide.

In one embodiment, before sealing the device case storage bag 124, it is necessary to remove residual air or excess air in the bag 124 so that the amount of air in the bag 124 after sealing is as small as possible. When removing the residual air in the bag 124, the rotatable cam lever 98 is moved to the closed position along the cam guide, whereby the cam lever 98 is stored in the device case existing between the first holder plates 88. Compress the bag 124. This action pushes the residual air upward from the device case storage bag 124 to remove it so that the storage medium is located near the top of the bag 124 prior to sealing. The sealing of the device case storage bag 124 will be described in more detail below.

Device Case Storage Bag Sliding Carriage The device case storage bag holder 76 can be located on the sliding carriage 106, which slides the holder 76 horizontally (left and right), especially 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 being located or placed on any number of rails or grooves. In another embodiment, the rail has stops 102, 116 at each end to prevent the sliding carriage 106 from further traveling or coming off. For example, in one embodiment, the sliding carriage 106 is located on two rails and the stops 102, 116 are mounted or placed on the base 100, but any number of rails can act. The stops 102, 116 can be placed at any position, whereby the stops 102, 116 prevent further movement of the sliding carriage 106.

The sliding carriage 106 is open (unsealed) so that it can accept the device case 74 and the loaded portable device and be sealed in a storage bag using the sealer 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 comprises a sealing head assembly 78 protected by a shield 80 and attached, horizontally opposed RF electrodes 84, 86. The rear electrode 84 is mounted on the air cylinder 81, and the front electrode 86 is fixed. When sealing the device case storage bag 124, the sliding carriage 106 moves the entire holder 76 below the sealing head assembly 78.

When sealing the storage bag 124, a nominal gap allows the device case storage bag 124 to be inserted between the electrodes 84, 86 (thus separating the two electrodes), extending the air cylinder 81 and extending the air cylinder 81. The rear electrode 84 advances to seal the device case bag 124 between the two electrodes 84 and 86, and by applying RF power, the RF reaction portion of the bag 124 is heated and a seal is formed on the bag 124. (Fig. 6B). When the air cylinder 81 is pulled in, the device case storage bag 124 is released from the electrodes 84 and 86, and the sliding carriage 106 is returned to a position away from below the sealing head assembly 78 (moved to the left as shown). Can be done.

RF Sealer Automation 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 a sealing operation. Both RF generators and matching networks are fully configurable for a variety of user applications, but at least Seren's RF generator and matching network examples require specific action commands from an external controller. (That is, the RF generator and matching network are not made operational by the software programmed to perform the above operations).

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 at the request of the user. Seren matching networks are usually empirically determined for their initial configuration and do not need to issue periodic commands after the internal configuration has been done. In one embodiment, a PC for the control method is used.

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

RF Generator In one embodiment, the Seren Industrial Power Supplies R601 Radio Frequency Generator was used to apply rigorous 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, with 40.68 MHz selected in one embodiment. The model R601 RF generator has a maximum power output of 600 W and can be driven in pulse mode or continuous mode. The RF output of this RF generator is an output via an industry standard N connector and an industry standard 50 ohm impedance transmission cable. RF generators with similar characteristics are commercially available from other manufacturers (eg, Comdel, Lesker, MKS Instruments, etc.). We chose Seren for its rich set of elements 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 was significantly different from the industry standard 50 ohm resistance impedance. To compensate for this difference, an intermediate correction inductive / capacitive impedance is placed between the RF source and the load. The Seren ATS-10M Matching Network realizes this intermediate correction and realizes a simple tuning adjustment by the operator made possible via RS-232 serial communication.

In another embodiment, the matching network can be manually configured, including fixed inductors and capacitors, if desired. With this technique, it takes time to empirically test both inductance and capacitance differences at the same time to match the impedance, resulting in lower final costs but higher labor costs.

Other tunable matching networks are commercially available from certain manufacturers (eg TC Power Conversion, Manitousys, Materials Science Inc., etc.). Seren was selected to ensure vendor compatibility between the RF generator and the matching network.

Crimping Sealer In an alternative embodiment, a crimpable band or ring may be used around the device port 72 to reduce the flexibility property of the device port 72. The crimpable band or ring may be made of metal or metal material or high strength polymer material. In one embodiment, the metal or polymer material is stronger than the material that forms the device port.

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

Conceptually similar to the handheld device described in FIG. 4, in one embodiment the sealing is achieved by a crimping device. Examples of crimping devices are described, but not limited to, in Patent Documents, including Patent Documents 27-29, which are incorporated herein by reference in their entirety. Such crimping instruments are mechanisms for adjusting the crimping position by providing a stop that allows the crimping portion on the device port (eg, the region closest to the device 200) to be positioned in a fixed position. May be configured.

Carrying bag sealer FIG. 8 illustrates a non-limiting and 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 carrying bag 126 containing a device inside. Shown.

In one embodiment, the sealer is a temperature controlled pneumatic impulse heat sealer, generally designed for use in heat sealing pouches or bags. In one embodiment, the heat sealer is an Impulse Sealer (eg, Model 5300-5400 Series) commercially available from Accu-Seal. 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 almost any tabletop or tabletop position. The heat sealer has a heat generating element that can be removably connected below the contactable sea rubber 122. The transport package or bag 126 is to place the bag opening below the heating element or below the contactable sealer pressure bar 122, and then perform sealing parameters (heating temperature, pause, pressure, etc.). Sealed by. In this model, after the sealing parameters have been performed, the seal bar opens and the transport package 126 can be removed.

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

How to Prime, Cell Load, and Seal Devices and Related Storage Bags and Transport Bags FIGS. 9-11 are for priming, cell loading, flushing, and sealing devices and related storage bags and transport bags. Demonstrates non-limiting and non-exclusive methods and means.

In FIG. 9, the cell loading system 1 is used to prepare the tube assembly for loading the flushing amount, cell amount, and priming amount (306), loading the flushing amount (308), and loading the cell amount. (310), embodiments and / or operations for loading the priming amount (312) will be described. In operation 306, the system 1 is first prepared and assembled by loading the dosing tube assemblies 44, 38. The administration tube assemblies 44, 38 are previously connected 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 and negative or positive pressures are applied to draw (or load or aspirate) varying amounts of fluid into the dosing tube assemblies 44, 38, respectively, from the dosing tube assemblies 44, 38. Note (or load). In another operation 310, the fluid volume is loaded into the dosing tube assemblies 44, 38 in the reverse order of dispensing this volume. For example, when loading cells into device 200, the device is first primed or wetted (priming amount), then the cells are loaded (cell volume or cell agglomeration volume), and finally from the dosing tube assemblies 44, 38. Flush or chasing cells (flushing amount or chasing amount). This order is reversed in operations 308, 310, and 312 of FIG. 9 and the same amount is loaded in reverse into the dosing tube assemblies 44, 38. Therefore, the dosing tube assemblies 44, 38 are first loaded with the flushing amount in operation 308, the cell clumping amount in operation 310, and then the priming amount in operation 312.

In another preferred embodiment, the cell vial 36 containing the cell clumps comprises all three amounts, a flushing amount, a cell clumping amount, and a priming amount. The sliding carriage 22 is described above so that the tip of the dosing tube 38 aspirates a particular amount of the above amounts from the aliquot vial or cell vial 36, especially when the multiposition block 58 is in the first vial position 4. Adjust in the vertical direction (y-axis) so as to (center position, engagement position, disengagement position). If all three quantities can be loaded from one vial, the tip can be adjusted to aspirate the flushing amount at the central position and the cell clumping and priming amount at the fully engaged position. However, if three volumes or additional amounts (eg, wash amount, additional priming or wetting amount, additional cells, additional therapeutic agent, etc.) cannot be loaded from a single vial, a specific amount may be added accordingly. Multiple vials containing can be inserted.

In FIG. 10, an embodiment for dispensing the priming amount (316), the cell amount (318), and the flushing amount (320) from the dosing tube assemblies 44, 38 to the device 200 using the cell loading system 1. And / or the operation will be described. In operation 314, the multi-position block 58 is moved to the second filling position 6, the distal portion of the DFSA 62 is inserted into the DFSA nesting block 30, and the proximal portion of the DFSA 62 is slid to be inserted into the second filling position 6. System 1 is prepared by moving the carriage 22 to a completely detached position. The sliding carriage 22 is then moved to the fully engaged position, the dosing tube 38 is connected to the device port, and the rotatable platform is placed between 45 and 90 degrees with respect to the base 34. When loading cells into the device, in movements 316, 318, 320, the pump is turned on and positive pressure is applied to dispense the priming (or wetting) amount (316) to wetting the device 200 and the cells. The agglomerated amount is dispensed (318) and then the flushing amount is dispensed (320) to chasing or flushing the cells (cells remaining in the dosing tube assemblies 44, 38).

These amounts can be repeated if there are multiple devices to be filled, or a smaller or additional amount can be aspirated and dispensed from the dosing tube assembly 44, 38 depending on the function and type of device. It will be apparent to those skilled in the art that each individual amount can be aspirated into the dosing tube assemblies 44, 38 to be supplied by a different vial or cell source, therapeutic agent source, or medium source. .. In one embodiment, actions relating to priming, cell volume, and flushing amounts are performed twice, as needed, by the same vial or fluid reservoir into dosing tube assemblies 44, 38, as long as there is sufficient tube length. It can be repeated 4 times, 5 times, 6 times, 7 times, 8 times, or more. In another embodiment, one, two, three, four, five, six, seven, eight, or more amounts are administered from various vials or fluid reservoirs tube assemblies 44, 38. Can be sucked into.

In FIG. 11, a step and / or operation for sealing the device (322), a step for storing and sealing the device case storage bag (324), a carrying bag, at least the device case storage bag, the device case, and A step (326) for sealing a transport bag containing a device loaded with cells will be described.

In operation 322, cells are prevented from leaking from the device 200 by sealing the device port 72 immediately or promptly after loading the device 200 as described above. With the DFPA still located within the DFPA nesting block 30, place the C-jaw of the handheld RF sealer 68 near the device port 72 area around the DFPA or near the device port sealing area of the device case 74. Deploy. When the sealer handle is closed, sufficient pressure is applied to the electrodes 70 on the device port 72 to generate RF energy, which seals the device port 72. Importantly, the RF electrode does not seal each sheet of DFSA62 together, nor does it seal DFSA62 against device port 72. As mentioned above, there are other materials that selectively react to RF energy, while other materials do not react to RF energy. The advantage of RF energy reactive and non-reactive materials for any bag or container (made of one material) for DFSA62 or device 200 is that the device port 72 (made of a second material) is still It can be aseptically sealed while located within the DFSA62.

After loading the device with cells and sealing the device port 72, the cell-filled or loaded device is ready to be stored and transported to the transplant or surgical site for transplantation. FIG. 10 describes an operation 326 for storing the 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 the device filled with cells, the device case storage bag 124 is placed and aligned between the first holder plates 88 of the device case storage bag holder 76, and the clamp lever 112 is pulled up. close. The device case 74 and the cell-filled device are then carefully removed from the DFSA 62 (eg, removed through a fragile, removable transparent window on the front or one side of the DFSA) and the extra 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. Both the device case 74 and the cell-filled device are immersed in sufficient medium. When removing or discharging residual air from the device case bag 124, the cam lever 98 is used to close the second rocking plate 90. The swing plate 90 and the holder plate 88 can be operated independently of each other or can be coupled to each other. In one embodiment, the first holder plate 88 was also closed by joining the plates 90, 88 and closing the rocking plate 90, applying pressure to the device case storage bag 124 to open all residual air. Extrude to the top of the unsealed bag 124. In another embodiment, the plates 90, 88 are not coupled or independent of each other, and closing one does not close the other.

The device case storage bag holder 76 is located on the sliding carriage 106, which then moves the holder 76 below the sealing head assembly 78 to seal the open, unsealed storage bag 124. .. As the holder 76 moves below the sealing head assembly 78, the opening of the storage bag 124 is located between the two electrodes 84, 86. The air cylinder 81 is extended and the RF electrodes 84, 86 are turned on to seal the device case 74 and the storage bag 124 in which the cell-filled device is immersed in the internal storage medium.

Once the cell-filled device case 74 is safely located within the storage bag 124, the storage bag 124 is ready to be transported to the surgical site or transplant site. In operation 326, the sterile transport bag 126 is placed in the transport bag holder 118 and the sealed device case storage bag 124 is inserted into the sterile transport bag 126. When sealing the transport bag 126, the unsealed or open portion of the bag 126 is placed below the sealing bar 122 and the sealing bar 122 is lowered to self-operate heat generation to seal the transport bag 126.

The terms and expressions used herein are used as descriptive terms and expressions without limitation, and in the use of such terms and expressions, exclude any equivalent or part of the features illustrated and described. Not intended to be done. Further, although some embodiments of the present invention have been described, those skilled in the art will use other embodiments incorporating the concepts disclosed herein without departing from the spirit and scope of the present invention. It will be clear that it is okay. In particular, embodiments of the present invention need not include all of the features described herein, nor do they need to have all of the advantages described herein. Alternatively, embodiments of the invention may have any portion or combination of features and advantages. Therefore, the above embodiments are considered in all respects as exemplary only and not as limiting.

1 Cell loading system 2 Device case storage bag Sealing station 4 1st vial position 6 2nd filling position 10 Administration tube platform 12 Balanced weight 14 Rotatable platform 16 Flex plate mount 18 Rod 22 Sliding carriage 24 Clamp lever 28 Toggle clamp 30 DFPA Nesting Block 34 Base 36 Cell Vial 38 Administration Tube 40 Cylindrical Indentation 42 Tube Joint 44 Administration Tube Assembly 48 Rotating Bearing 50 Rotating Handle 52 Syringe Pump 54 Syringe 58 Adjustable Multiposition Block 60 Frame 62 DFPA
68 Device Port Sealer 70 Sheila 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 Swing 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 Contactable Sheila Pressurized Bar 124 Device Case Storage Bag 126 Carrying Bag 200 Portable Device

Claims (18)

A method of loading cells into a transplantable device,
(A) A step of obtaining a container containing a flushing amount, a cell amount and a priming amount, and
(B) First, the flushing amount, then the cell amount, and then the priming amount are sucked from the container into the administration tube assembly body under a negative pressure generated by a pump. The first end of the dosing tube assembly is detachably coupled to the pump, with the step.
(C) First the priming amount, then the cell amount, then the flushing amount from the dosing tube assembly into the implantable device under negative pressure generated by the pump. Dispensing through the possible device port, during the dispensing operation, the second end of the dosing tube assembly is removable into the device port such that cells are loaded into the implantable device. A method that includes steps and <br /> connected to. The method of claim 1, wherein the first end of the dosing tube assembly is detachably connected to a syringe detachably connected to the pump. The method of claim 1, wherein the dosing tube assembly comprises a fluid reservoir and a dosing tube. The method of claim 3, wherein the first end of the dosing tube assembly comprises the fluid reservoir. The method according to claim 4, wherein the flushing amount, the cell amount, and the priming amount once sucked are contained in the fluid reservoir. The method of claim 3, wherein the second end of the dosing tube assembly comprises the dosing tube. The method of claim 6, wherein during the dispensing operation, the dosing tube is detachably connected to the device port by a fitting. The method of claim 1, wherein the cell is a pancreatic genealogy cell, or the cell is a pancreatic genealogy cell aggregate. The eighth claim, wherein the pancreatic lineage cell or pancreatic lineage cell aggregate is a pancreatic progenitor cell, a PDX-1-positive pancreatic progenitor cell, an endocrine precursor cell, an endocrine cell, an immature β cell, or an immature pancreatic islet cell. Method. The method of claim 1, wherein the method is automated, semi-automated, or manual. The method of claim 1, further comprising a step (d) of sealing the device port after step (c). The implantable device comprises a plurality of device ports, the step (b) comprising aspirating a plurality of sets of flushing amount, cell amount and priming amount from the container into the dosing tube assembly. The method of claim 1, wherein step (c) comprises dispensing each set of priming, cell and flushing amounts into the implantable device via one of the device ports. The implantable device comprises a plurality of implantable devices, the step (b) comprising aspirating a plurality of sets of flushing amount, cell amount and priming amount from the container into the dosing tube assembly. The method of claim 1, wherein step (c) comprises dispensing each set of priming, cell and flushing amounts into one of the implantable devices. A method of loading cells into a transplantable device,
(A) A step of obtaining a container containing a flushing amount, a cell amount and a priming amount, and
(B) A step of first sucking the flushing amount, then the cell amount, and then the priming amount from the container into the administration tube assembly.
(C) First, the priming amount, then the cell amount, and then the flushing amount are transplanted from the administration tube assembly into the transplantable device so that the cells are loaded into the transplantable device. With steps to dispense via possible device ports
How to include. The step (b) is (i) a step of sucking the flushing amount from the container, the flushing amount is a step consisting of a liquid containing no cells, and (ii) the cells are resuspended in the container. For this purpose, a step of applying positive pressure to the container using a pump, and (iii) a step of sucking the cell amount from the container, wherein the cell amount consists of a liquid containing floating cells, (iii). iv) The step of sucking the priming amount from the container, and the priming amount is a step consisting of a liquid containing no cells.
14. The method of claim 14. In step (b), the first end of the dosing tube assembly is fluidly coupled to the pump and the tip of the second end of the dosing tube assembly is inserted into the container. In this state, the step of sucking the flushing amount, then the cell amount, and then the priming amount from the container into the administration tube assembly under negative pressure generated by a pump is performed. In the step (c), the first end of the dosing tube assembly is fluidly coupled to the pump and the tip of the second end of the dosing tube assembly. Is connected to the implantable device port, the pump first generates the priming amount, then the cell amount, and then the flushing amount from the dosing tube assembly into the implantable device. 14. The method of claim 14, comprising the step of dispensing through the implantable device port under exerted negative pressure. A method of loading cells into a transplantable device,
(A) A step of obtaining a first container containing a flushing amount, a second container containing a cell amount, and a third container containing a priming amount.
(B) A step of first loading the administration tube assembly with the flushing amount from the first container, then the cell amount from the second container, and then the priming amount from the third container. ,
(C) A device port for loading the priming amount, then the cell amount, then the flushing amount from the dosing tube assembly into the implantable device and into the implantable device. With the steps to dispense via
How to include. 14. The amount of flushing comprises a liquid substantially free of cells, the amount of cells comprises a liquid containing floating cells, and the amount of priming comprises a liquid substantially free of cells, claim 14 or 17. The method described.

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