阅读说明：本技术 包括多孔管的细胞包封装置 (Cell encapsulation device comprising a porous tube ) 是由 艾登·弗拉纳根 马修·麦克瓦迪 马丁·L·福德里 于 2019-08-21 设计创作，主要内容包括：用于移植于身体中的细胞包封装置,包括一个或多个细胞包封层,该一个或多个细胞包封层的每个细胞包封层包括至少一个膜和导向管。该至少一个膜是半渗透的。该至少一个膜形成用于将细胞包封的室及经过该至少一个膜的至少一个进入端口。导向管从至少一个进入端口延伸进入所述室中。导向管包括沿至少一部分其长度的多孔壁。导向管能够引导导管在所述室内部的移动。(A cell encapsulation device for transplantation into a body, comprising one or more cell encapsulation layers, each cell encapsulation layer of the one or more cell encapsulation layers comprising at least one membrane and a guide tube. The at least one membrane is semi-permeable. The at least one membrane forms a chamber for enclosing cells and at least one access port through the at least one membrane. A guide tube extends from the at least one inlet port into the chamber. The guide tube includes a porous wall along at least a portion of its length. The guide tube is capable of guiding movement of the catheter inside the chamber.)

1. A cell encapsulation device for transplantation in a body, the cell encapsulation device comprising:

one or more cell encapsulation layers, each cell encapsulation layer of the one or more cell encapsulation layers comprising:

at least one membrane that is semi-permeable, the at least one membrane forming a chamber for encapsulating cells and at least one access port through the at least one membrane; and

a guide tube extending from the at least one entry port into the chamber, the guide tube comprising a porous wall along at least a portion of its length, the guide tube being capable of guiding movement of a catheter inside the chamber.

2. The cell encapsulation device of claim 1, wherein the at least one membrane comprises a first membrane and a second membrane, each layer of the one or more cell encapsulation layers further comprising a first plurality of weld lines, the second membrane attached to the first membrane via the first plurality of weld lines, the first membrane, the second membrane, and the first plurality of weld lines defining the chamber.

3. The cell encapsulation device of claim 1 or 2, wherein the guide tube is at least partially comprised of a metal mesh.

4. The cell encapsulation device of any one of claims 1 to 3, wherein each layer of the cell encapsulation layers further comprises:

a second plurality of weld lines defining at least two cell channels inside the chamber; and

a third plurality of weld wires defining a guide tube channel in fluid communication with the at least two cell channels, the guide tube being received within an interior of the guide tube channel.

5. The cell encapsulation device of any one of claims 1 to 4, further comprising at least one entry conduit extending from the at least one entry port in a direction away from the chamber, the at least one entry conduit being fluidly connected to the guide tube.

6. The cell encapsulation device of claim 5, wherein the at least one access port comprises a first access port and a second access port; and the at least one entry conduit comprises a first entry conduit fluidly connected to the first entry port, and a second entry conduit fluidly connected to the second entry port, wherein the guide tube extends from the first entry port, through the chamber, to the second entry port.

7. The cell encapsulation device of claim 6, wherein the one or more cell encapsulation layers comprise a first cell encapsulation layer and a second cell encapsulation layer, the second entry conduit of the first cell encapsulation layer being fluidly connected to the first entry conduit of the second cell encapsulation layer to fluidly connect the first cell encapsulation layer to the second cell encapsulation layer.

8. The cell encapsulation device of any one of claims 5 to 7, wherein the cell encapsulation device further comprises an injection port connected to an end of the access conduit opposite the chamber, the injection port comprising:

a port housing defining a port lumen extending therethrough, an end of the port housing proximate the entry conduit being in fluid communication with the entry conduit;

an outer septum extending across and sealing the port lumen; and

an inner septum extending across and sealing the port lumen, the inner septum being spaced from the outer septum to form a space inside the port lumen between the inner septum and the outer septum, the inner septum being disposed between the outer septum and the access conduit, the outer septum and the inner septum being comprised of an elastomeric polymer.

9. A system for in vivo cell transplantation, the system comprising:

the cell encapsulation device according to any one of claims 5 to 8; and

a first outer conduit capable of passing through the at least one entry conduit into the guide tube to guide movement of the first outer conduit inside the chamber.

10. The system of claim 9, wherein the first outer conduit is capable of distributing cells into the chamber through the porous wall of the guide tube as the first outer conduit moves through the guide tube.

11. The system of claim 9, wherein the first external conduit comprises a first lumen having a first lumen opening and a second lumen having a second lumen opening, the first lumen opening and the second lumen opening being spaced apart from one another along the guide tube, the first lumen opening being capable of distributing fluid into the chamber through the porous wall of the guide tube, and the second lumen opening being capable of extracting the liquid from the chamber through the porous wall of the guide tube.

12. The system of claim 11, wherein the second lumen is disposed coaxially with the first lumen, the first outer catheter further comprising a flange disposed between the first lumen opening and the second lumen opening, the flange projecting outwardly toward the guide tube for deflecting fluid dispensed from the first lumen toward the porous wall of the guide tube.

13. The system of claim 9, wherein the first outer catheter comprises a first lumen, the first outer catheter is capable of passing through the first entry catheter into the guide tube, the system further comprises a second outer catheter having a second lumen, the second outer catheter is capable of passing through the second entry catheter into the guide tube opposite the first outer catheter, the first outer catheter and the second outer catheter are spaced apart from each other inside the chamber, the first outer catheter is capable of dispensing fluid through the porous wall of the guide tube into the chamber, and the second outer catheter is capable of extracting the liquid from the chamber through the porous wall of the guide tube.

14. The system of claim 9, wherein the at least one access port comprises a first access port and a second access port; and the at least one entry conduit comprises a first entry conduit fluidly connected to the first entry port, and a second entry conduit fluidly connected to the second entry port, the guide tube extending from the first entry port through the chamber to the second entry port, the first outer conduit being capable of entering the chamber through the first entry conduit, passing through the guide tube, and exiting the chamber through the second entry conduit.

15. A method of making a cell encapsulation device for transplantation in a body, the method comprising:

placing the first semi-permeable membrane directly on the second semi-permeable membrane;

attaching the first semi-permeable membrane to the second semi-permeable membrane with a first plurality of weld lines defining a chamber for encapsulating cells, a second plurality of weld lines defining at least two cell channels inside the chamber, and a third plurality of weld lines defining a guide tube channel in fluid communication with the at least two cell channels;

inserting a guide tube into the guide tube passage through the access port and into the chamber, the guide tube comprising a porous wall along at least a portion of its length; and

attaching one end of the guide tube to at least one of the first and second semi-permeable membranes surrounding the access port.

Technical Field

The present disclosure relates to implantable medical devices and methods for cell encapsulation. More particularly, the present disclosure relates to implantable devices and methods for achieving encapsulation of insulin secreting cells.

Background

Implantable medical devices that utilize encapsulation of insulin-secreting cells to treat diabetes can present several problems. One problem is the lack of robustness of these devices due to the inability to provide sufficient cell maintenance substances (such as oxygen and nutrients) to keep not only insulin secreting cells viable but also healthy enough to secrete insulin. Other problems include difficulties, trauma and inherent risks that may be associated with the surgery required to implant the encapsulated device.

There is a need for improvements in implantable devices for encapsulating cells that reduce the risks that may be associated with the procedures required to implant an encapsulated device and that improve the robustness of such devices.

Disclosure of Invention

Example 1 is a cell encapsulation device for transplantation in the body. The cell encapsulation device comprises one or more cell encapsulation layers, each layer of the one or more cell encapsulation layers comprising at least one membrane and a guide tube. The at least one membrane is semi-permeable. The at least one membrane forms a chamber for enclosing cells and at least one access port through the at least one membrane. A guide tube extends from the at least one inlet port into the chamber. The guide tube includes a porous wall along at least a portion of its length. The guide tube is capable of guiding movement of the catheter inside the chamber.

Embodiment 2 is the cell encapsulation device of embodiment 1, wherein the at least one membrane comprises a first membrane and a second membrane. Each of the one or more cell encapsulation layers further comprises a first plurality of weld lines. The second film is attached to the first film via a first plurality of weld lines. The first film, the second film, and the first plurality of weld lines define the chamber.

Embodiment 3 is the cell encapsulation device of any one of embodiments 1 or 2, wherein the guide tube is at least partially comprised of a metal mesh.

Embodiment 4 is the cell encapsulation device of any of embodiments 1 to 3, wherein each layer of the cell encapsulation layer further comprises a second plurality of weld lines defining at least two cell channels located inside the chamber, and a third plurality of weld lines defining a guide tube channel in fluid communication with the at least two cell channels. The guide tube is received within the guide tube channel.

Embodiment 5 is the cell encapsulation device of any of embodiments 1 to 4, further comprising at least one entry conduit extending from the at least one entry port in a direction away from the chamber. The at least one inlet conduit is fluidly connected to the guide tube.

Embodiment 6 is the cell encapsulation device of embodiment 5, wherein the at least one access port comprises a first access port and a second access port. The at least one entry conduit includes a first entry conduit fluidly connected to the first entry port, and a second entry conduit fluidly connected to the second entry port. A guide tube extends from the first inlet port through the chamber to the second inlet port.

Embodiment 7 is the cell encapsulation device of embodiment 6, wherein the one or more cell encapsulation layers includes a first cell encapsulation layer and a second cell encapsulation layer. The second inlet conduit of the first cell encapsulation layer is fluidly connected to the first inlet conduit of the second cell encapsulation layer for fluidly connecting the first cell encapsulation layer to the second cell encapsulation layer.

Embodiment 8 is the cell encapsulation device of any of embodiments 5 to 7, wherein the cell encapsulation device further comprises an injection port connected to an end of the access conduit opposite the chamber, the injection port comprising a port housing, an outer membrane, and an inner membrane. The port housing forms a port lumen extending through the port housing. The end of the port housing closest to the inlet conduit is in fluid communication with the inlet conduit. An outer septum extends across and seals the port lumen. An inner septum extends across and seals the port lumen. The inner septum is spaced from the outer septum to form a space inside the port lumen and between the inner septum and the outer septum. The inner septum is disposed between the outer septum and the access conduit. The outer and inner membranes are constructed of an elastomeric polymer.

Example 9 is a system for cell transplantation in a body. The system includes a cell encapsulation device according to any of embodiments 5 to 8 and a first outer catheter that is capable of passing through the at least one entry catheter into the guide tube to guide movement of the first outer catheter inside the chamber.

Embodiment 10 is the system of embodiment 9, wherein the first external conduit is capable of distributing cells into the chamber through the porous wall of the guide tube as the first external conduit moves through the guide tube.

Embodiment 11 is the system of embodiment 9, wherein the first outer catheter comprises a first lumen having a first lumen opening and a second lumen having a second lumen opening. The first lumen opening and the second lumen opening are spaced apart from one another along the guide tube. The first lumen opening is capable of distributing fluid through the porous wall of the guide tube into the chamber. The second lumen opening is capable of drawing fluid from the chamber through the porous wall of the guide tube.

Embodiment 12 is the system of embodiment 11, wherein the second lumen is coaxially disposed with the first lumen. The first outer catheter further includes a flange disposed between the first lumen opening and the second lumen opening. The flange projects outwardly toward the guide tube for deflecting liquid dispensed from the first lumen toward the porous wall of the guide tube.

Embodiment 13 is the system of embodiment 9, wherein the first outer catheter comprises a first lumen and the first outer catheter is capable of passing through the first access catheter into the guide tube. The system further includes a second outer catheter having a second lumen. The second outer conduit is capable of entering the guide tube through the second entry conduit opposite the first outer conduit. The first and second outer conduits are spaced apart from one another inside the chamber. The first external conduit is capable of distributing fluid through the porous wall of the guide tube into the chamber. The second external conduit is capable of withdrawing fluid from the chamber through the porous wall of the guide tube.

Embodiment 14 is the system of embodiment 9, wherein the at least one access port comprises a first access port and a second access port. The at least one entry conduit includes a first entry conduit fluidly connected to the first entry port, and a second entry conduit fluidly connected to the second entry port. A guide tube extends from the first inlet port through the chamber to the second inlet port. A first external conduit can enter the chamber through the first entry conduit, pass through the guide tube, and exit the chamber through the second entry conduit.

Example 15 is a method of making a cell encapsulation device for transplantation in a body. The method comprises the following steps: placing the first semi-permeable membrane directly on the second semi-permeable membrane; attaching the first semi-permeable membrane to the second semi-permeable membrane with a first plurality of weld lines defining a chamber for encapsulating cells, a second plurality of weld lines defining at least two cell channels inside the chamber, and a third plurality of weld lines defining a guide tube channel in fluid communication with the at least two cell channels; inserting a guide tube into the guide tube passage and through the inlet port and into the chamber, the guide tube comprising a porous wall along at least a portion of its length; and attaching an end of the guide tube to at least one of the first and second semi-permeable membranes surrounding the access port.

Example 16 is a cell encapsulation device for transplantation in the body. The cell encapsulation device includes one or more cell encapsulation layers, each of the cell encapsulation layers including a first membrane that is semi-permeable, a second membrane that is semi-permeable, a first plurality of weld lines, and a guide tube. The second film is attached to the first film via a first plurality of weld lines. The first membrane, the second membrane, and the first plurality of weld lines define a chamber for encapsulating cells. The chamber includes at least one inlet port. A guide tube extends from the at least one inlet port into the chamber. The guide tube includes a porous wall along at least a portion of its length. The guide tube is capable of guiding movement of the catheter inside the chamber.

Embodiment 17 is the cell encapsulation device of embodiment 16, wherein the guide tube comprises a metal mesh.

Embodiment 18 is the cell encapsulation device of embodiment 17, wherein the metal mesh comprises a metal selected from the group consisting of stainless steel, titanium, platinum, an alloy of chromium and cobalt, an alloy of nickel and titanium, and an alloy of cobalt, chromium, nickel, and molybdenum.

Embodiment 19 is the cell encapsulation of embodiment 16, wherein each layer of the cell encapsulation layer further comprises a second plurality of weld lines defining at least two cell channels located inside the chamber, and a third plurality of weld lines defining a guide tube channel in fluid communication with the at least two cell channels. The guide tube is received within the guide tube channel.

Embodiment 20 is the cell encapsulation device of embodiment 16, further comprising at least one entry conduit extending from the at least one entry port in a direction away from the chamber, the at least one entry conduit fluidly connected to the guide tube.

Embodiment 21 is the cell encapsulation device of embodiment 20, wherein the at least one access port comprises a first access port and a second access port. The at least one entry conduit includes a first entry conduit fluidly connected to the first entry port, and a second entry conduit fluidly connected to the second entry port. A guide tube extends through the chamber from the first inlet port to the second inlet port.

Embodiment 22 is the cell encapsulation device of embodiment 21, wherein the one or more cell encapsulation layers includes a first cell encapsulation layer and a second cell encapsulation layer. The second inlet conduit of the first cell encapsulation layer is fluidly connected to the first inlet conduit of the second cell encapsulation layer for fluidly connecting the first cell encapsulation layer to the second cell encapsulation layer.

Embodiment 23 is the cell encapsulation device of embodiment 20, wherein the cell encapsulation device further comprises an injection port fluidly connected to an end of the at least one access conduit opposite the chamber. The injection port includes a port housing, an outer septum, and an inner septum. The port housing forms a port lumen extending through the port housing. The end of the port housing closest to the inlet conduit is in fluid communication with the inlet conduit. An outer septum extends through and seals the port lumen. An inner septum extends through and seals the port lumen. The inner septum is spaced from the outer septum to form a space inside the port lumen and between the inner septum and the outer septum. The inner septum is disposed between the outer septum and the access conduit. The outer and inner membranes are constructed of an elastomeric polymer.

Example 24 is a system for cell transplantation in a body. The system includes a cell encapsulation device and at least one access catheter. The cell encapsulation device includes one or more cell encapsulation layers, each of the cell encapsulation layers including a first membrane that is semi-permeable, a second membrane that is semi-permeable, a first plurality of weld lines, and a guide tube. The second film is attached to the first film via a first plurality of weld lines. The first membrane, the second membrane, and the first plurality of weld lines define a chamber for encapsulating cells. The chamber includes at least one inlet port. A guide tube extends from the at least one inlet port into the chamber. The guide tube includes a porous wall along at least a portion of its length. At least one entry conduit extends from the at least one entry port in a direction away from the chamber. At least one inlet conduit is fluidly connected to the guide tube. The first outer catheter is capable of passing through the at least one entry catheter into the guide tube. The guide tube is capable of guiding movement of the first outer conduit inside the chamber.

Embodiment 25 is the system of embodiment 24, wherein the first external conduit is capable of distributing cells into the chamber through the porous wall of the guide tube as the first external conduit moves through the guide tube.

Embodiment 26 is the system of embodiment 24, wherein the first outer catheter comprises a first lumen having a first lumen opening and a second lumen having a second lumen opening. The first lumen opening and the second lumen opening are spaced apart from one another along the guide tube. The first lumen opening is capable of distributing fluid through the porous wall of the guide tube into the chamber. The second lumen opening is capable of withdrawing fluid from the chamber through the porous wall of the guide tube.

Embodiment 27 is the system of embodiment 26, wherein the second lumen is coaxially disposed with the first lumen. The first outer catheter further includes a flange disposed between the first lumen opening and the second lumen opening. The flange projects outwardly toward the guide tube to deflect liquid dispensed from the first lumen toward the porous wall of the guide tube.

Embodiment 28 is the system of embodiment 24, further comprising a second outer catheter having a second lumen. The first outer catheter includes a first lumen. The at least one access port includes a first access port and a second access port. A guide tube extends through the chamber from the first inlet port to the second inlet port. The at least one entry conduit includes a first entry conduit fluidly connected to the first entry port, and a second entry conduit fluidly connected to the second entry port. A first outer catheter can be passed through the first access catheter into the guide tube. The second outer conduit is capable of passing through the second entry conduit into the guide tube opposite the first outer conduit. The first and second outer conduits are spaced apart from one another inside the chamber. The first external conduit is capable of distributing liquid through the porous wall of the guide tube into the chamber. The second external conduit is capable of withdrawing fluid from the chamber through the porous wall of the guide tube.

Embodiment 29 is the system of embodiment 28, further comprising a guidewire extending through the first lumen and the second lumen. The guidewire includes a flange that projects toward the guide tube between the first and second outer catheters to deflect liquid dispensed from the first outer catheter toward the porous wall of the guide tube.

Embodiment 30 is the system of embodiment 24, wherein the at least one access port comprises a first access port and a second access port. The at least one entry conduit includes a first entry conduit fluidly connected to the first entry port, and a second entry conduit fluidly connected to the second entry port. The guide tube extends from the first inlet port through the chamber to the second inlet port. A first external conduit can enter the chamber, pass through the first entry conduit, pass through the guide tube, and exit the chamber through the second entry conduit.

Embodiment 31 includes the system of embodiment 24, wherein the cell encapsulation device further comprises an injection port fluidly connected to an end of the at least one access conduit opposite the chamber. The injection port includes a port housing, an outer septum, and an inner septum. The port housing forms a port lumen extending through the port housing. The end of the port housing closest to the inlet conduit is in fluid communication with the inlet conduit. An outer septum extends through and seals the port lumen. An inner septum extends through and seals the port lumen. The inner septum is spaced from the outer septum to form a space inside the port lumen and between the inner septum and the outer septum. The inner septum is disposed between the outer septum and the access conduit. The outer and inner membranes are constructed of an elastomeric polymer.

Embodiment 32 is the system of embodiment 31, further comprising an outer tubular needle and an inner tubular needle. The outer tubular needle is capable of penetrating the outer septum. The outer septum is capable of sealing adjacent the outer tubular needle. The inner tubular needle is capable of passing through the outer tubular needle and penetrating the inner septum. The inner septum is capable of sealing adjacent to the inner tubular needle. A first outer catheter can be passed through the inner tubular needle, the at least one access catheter, and into the guide tube.

Example 33 is a method of making a cell encapsulation device for transplantation in a body. The method comprises the following steps: the first semi-permeable membrane is placed directly on the second semi-permeable membrane; attaching the first semi-permeable membrane to the second semi-permeable membrane with a first plurality of weld lines defining a chamber for encapsulating the cells; inserting a guide tube into the chamber through the first access port and into the chamber, the guide tube comprising a porous wall along at least a portion of its length; and attaching an end of the guide tube to at least one of the first and second semi-permeable membranes surrounding the first access port.

Embodiment 34 is the method of embodiment 33, wherein the first semi-permeable membrane is attached to the second semi-permeable membrane with a second plurality of weld lines defining at least two cell channels inside the chamber, and with a third plurality of weld lines defining a guide tube channel in fluid communication with the at least two cell channels; and further comprising inserting a guide tube into the chamber comprises inserting a guide tube into a guide tube passageway and into the chamber through the first inlet port.

Embodiment 35 is the method of embodiment 33, further comprising attaching an end of the guide tube opposite an end of the guide tube attached to at least one of the first and second semi-permeable membranes surrounding the first access port to at least one of the first and second semi-permeable membranes surrounding the second access port into the chamber.

While multiple embodiments are disclosed, other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description, which discloses and describes illustrative embodiments of the invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not as restrictive.

Drawings

Fig. 1 is a schematic top view of a cell encapsulation device according to some embodiments of the present disclosure.

Fig. 2 is a schematic cross-sectional top view of a cell encapsulation layer of the cell encapsulation device of fig. 1, according to some embodiments of the present disclosure.

Fig. 3 is a schematic cross-sectional view of a cell encapsulation layer of the cell encapsulation device of fig. 1, according to some embodiments of the present disclosure.

Fig. 4A and 4B are schematic cross-sectional top views of systems for cell transplantation, according to some embodiments of the present disclosure.

Fig. 5 is a schematic side view of a portion of the system of fig. 4A and 4B, according to some embodiments of the present disclosure.

Fig. 6 is a schematic side view of a portion of the system of fig. 4A and 4B, according to yet another embodiment of the present disclosure.

Fig. 7 is a schematic cross-sectional top view of another system for cell transplantation according to some embodiments of the present disclosure.

Fig. 8 is a schematic side view of a portion of yet another system for cell transplantation according to some embodiments of the present disclosure.

Fig. 9 is a side view of another cell encapsulation device according to some embodiments of the present disclosure.

Fig. 10 is a side view of yet another cell encapsulation device according to some embodiments of the present disclosure.

Fig. 11 is a schematic longitudinal cross-sectional view of a portion of a cell encapsulation device including a subcutaneous injection port, according to an embodiment of the present disclosure.

Fig. 12A-12D are schematic longitudinal cross-sectional views of a portion of another system for cell encapsulation according to some embodiments of the present disclosure.

While the disclosed subject matter is susceptible to various modifications and alternative forms, specific embodiments have been disclosed by way of example in the drawings and are described in detail below. However, it is not intended that the disclosure be limited to the specific embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the scope of the disclosed subject matter as defined by the appended claims.

Detailed Description

An apparatus according to the present disclosure includes an implantable device for encapsulating cells. These cell encapsulation devices can facilitate the flow of oxygen and nutrients to the encapsulated cells while isolating the cells from the patient's immune system. Once implanted, the cell encapsulation device can be filled with insulin secreting cells. Timely, if replenishment of insulin secreting cells is required, these cell encapsulation devices can be cleaned and refilled in a minimally invasive manner to reduce the trauma experienced by the patient.

Fig. 1 is a schematic top view of a cell encapsulation device 10 according to some embodiments of the present disclosure. As shown in fig. 1, the cell encapsulation device 10 includes at least one cell encapsulation layer 12. The cell encapsulation layer 12 includes a first membrane 14, a second membrane 16 (shown in fig. 2), a first plurality of weld lines 18, and a first access port 20. A first plurality of weld lines 18 attaches the first membrane 14 to the second membrane 16. The first film 14, the second film 16, and the first plurality of weld lines 18 define at least one chamber 22.

As shown in fig. 1, the cell encapsulation device 10 may further include a second plurality of weld lines 24, a third plurality of weld lines 26, and a first access conduit 28. A second plurality of weld lines 24 attaches first membrane 14 to second membrane 16 to define at least two cell channels 30 of chamber 22. A third plurality of weld lines 26 attaches the first film 14 to the second film 16 to define a guide tube channel 32 inside the chamber 22.

The first inlet conduit 28 is fluidly connected to the guide tube 34 and extends from the first inlet port 20 in a direction away from the chamber 22. The first access catheter 28 may be made of a biocompatible polymer (e.g., high density polyethylene, polyethylene terephthalate, or polytetrafluoroethylene) or a biocompatible metal (e.g., 316VLM stainless steel, nickel titanium alloy, or Elgiloy non-magnetic alloy (Elgiloy)) The tubular structure is formed. The first access conduit 28 may be attached to the first membrane 14 and/or the second membrane 16 by, for example, bonding to the first membrane 14 and/or the second membrane 16, or with a biocompatible adhesive.

First membrane 14 and second membrane 16 are semi-permeable membranes having pores extending through the membranes. The first membrane 14 and the second membrane 16 are semi-permeable in that the pores are sized to allow the passage of oxygen, nutrients and waste but prevent the passage of encapsulated cells or cells of the patient's immune system.

The first membrane 14 and the second membrane 16 may have an average pore size as small as 2 nanometers (nm), 5nm, 10nm, or 20nm, or 50nm, or as large as 200nm, 500nm, 1,000nm, 2,000nm, or 5,000nm, or within any range defined by any two of the preceding values. The average pore size can be in a range of 2nm to 5,000nm, 5nm to 2,000nm, 10nm to 1,000nm, 20nm to 500nm, or 50nm to 200 nm. The pore size of 2nm is sufficient to allow the passage of insulin and glucose through the first membrane 14 and the second membrane 16. Pore sizes of less than 5,000nm are sufficient to prevent vascularisation and immune reactions within the cellular channel 30.

The first membrane 14 and the second membrane 16 may be textile membranes such as those available from Sefar corporation of Hinterbissussaustrale No. 12 of Hoodian 9410, Switzerland. Additionally or alternatively, the first and second films 14, 16 may be nonwoven films made by electrospinning.

Fig. 2 is a schematic cross-sectional top view of the cell encapsulation layer 12 of fig. 1 with the first membrane 14 removed to reveal the second membrane 16. As shown in FIG. 2, cell encapsulation layer 12 further includes a guide tube 34 extending from first entry port 20 into chamber 22. The guide tube 34 includes a porous wall 36 along at least a portion of its length. In the embodiment shown in fig. 2, the porous wall 36 of the guide tube 34 extends the full length of the guide tube 34. Alternatively, the porous wall 36 extends only along one or more portions of the guide tube 34. The porous wall 36 allows liquids, gels, and encapsulated liquids to flow easily between the guide tube 34 and the cell channel 30. The guide tube 34 may be received inside the guide tube channel 32, thereby maintaining the guide tube 34 in a position where it may be fluidly connected to the cell channel 30.

The guide tube 34 may include a mesh pattern, such as a woven mesh, or a slotted mesh pattern as used for implantable stents to form the porous wall 36. The guide tube 34 may comprise a metal mesh. The metal mesh may include a metal selected from the group consisting of stainless steel, titanium, platinum, an alloy of chromium and cobalt, an alloy of nickel and titanium, and an alloy of cobalt, chromium, nickel, and molybdenum. The guide tube 34 may comprise a polymer mesh. The polymer network may comprise a polymer selected from the group consisting of polytetrafluoroethylene, polyether block amide, nylon, polyester, polysiloxane, and polycarbonate urethane.

The pores or openings of the mesh may provide pores through the porous wall 36. The pores in the porous walls 36 may have an average pore size, for example, as small as 0.1 millimeter (mm), 0.2mm, 0.3mm, 0.4mm, 0.6m, 0.8mm, or 1.0mm, or as large as 1.2mm, 1.5mm, 2mm, 2.5mm, 3mm, 4mm, or 5mm, or within any range defined by any two of the foregoing values, such as 0.1mm to 5mm, 0.2mm to 4mm, 0.3mm to 3mm, 0.4mm to 2.5mm, 0.6mm to 2mm, 0.8mm to 1.5mm, 0.6 to 1.0, or 0.8mm to 1.2 mm.

Fig. 3 is a schematic cross-sectional view of the cell encapsulation layer 12 of fig. 1, according to some embodiments of the present disclosure. As shown in fig. 3, the guide tube 34 may have an internal diameter P as small as, for example, 0.5mm, 0.6mm, 0.8mm, 1.0mm, 1.2mm, 1.4mm, or 1.6mm, or as large as 1.8mm, 2.0mm, 2.2mm, 2.4mm, 2.6mm, 2.8mm, or 3.0mm, or within any range defined by any two of the foregoing values, such as 0.5mm to 3.0mm, 0.6mm to 2.8mm, 0.8mm to 2.6mm, 1.0mm to 2.4mm, 1.2mm to 2.2mm, 1.4mm to 2.0mm, 1.6mm to 1.8mm, or 0.8mm to 1.2 mm.

The cell channels 30 can each have an average inner diameter D, for example, as small as 0.01 millimeters (mm), 0.02mm, 0.04mm, 0.06mm, 0.08mm, 0.10mm, 0.12mm, 0.16mm, 0.2mm, 0.4mm, 0.6mm, 0.8mm, 1.0mm, 1.2mm, 1.6mm, 2.0mm, 2.4mm, 2.8mm, 3.2mm, or 3.6mm, or within any range defined by any two of the foregoing values, such as 0.01mm to 3.6mm, 0.1mm to 2.0mm, or 0.01mm to 1.2 mm.

When implanted, the cell channels 30 of the cell encapsulation device 10 may be uninflated, i.e., they may not be filled with liquid or insulin secreting cells prior to implantation to enable implantation in a minimally invasive manner, as described in U.S. patent application No. 15/922,251 entitled "cell encapsulation device" filed 3/15 of 2018, the entire contents of which are incorporated herein by reference. The cell containment device 10 may be implanted in the lower abdomen of a patient, for example, between the transverse fascia and the parietal peritoneum. Alternatively, the cell encapsulation device 10 may be implanted between the internal oblique muscle and the transverse abdominal muscle.

Referring collectively to fig. 1-3, for example, a method of making a cell encapsulation device (e.g., cell encapsulation device 10) according to some embodiments may comprise: the first membrane 14 is placed directly on the second membrane 16, and then the first membrane 14 is attached to the second membrane 16 with a first plurality of weld lines 18 (to define a chamber 22) and with a second plurality of weld lines 24 (to define at least two cell channels 30 inside the chamber 22). A guide tube 34 may be inserted into the chamber 22 through the first access port 20, and one end of the guide tube 34 may be attached to the first membrane 14 and/or the second membrane 16 surrounding the first access port 20. The second plurality of bond wires 24 may be omitted.

Attaching the first membrane 14 to the second membrane 16 may further include a third plurality of weld lines 26 defining a guide tube channel 32 in fluid communication with the cell channel 30. The method may further include inserting a guide tube 34 into the guide tube channel 32 through the first access port 20. The third plurality of weld lines 26 may be omitted.

Fig. 4A and 4B are schematic cross-sectional top views of a system 38 for cell transplantation including a cell encapsulation device 10 and a first external conduit 40. For clarity, the first membrane 14 is shown removed in fig. 4A and 4B to reveal the second membrane 16. Fig. 4A and 4B illustrate a method of filling the cell encapsulation layer 12 of the cell encapsulation device 10 with a first external conduit 40 to inflate the cell channels 30 after implantation according to some embodiments.

Fig. 4A and 4B show the cell encapsulation layer 12 with the first external conduit 40 passing through the first inlet conduit 28, the first inlet port 20 and into the guide tube 34. The first external conduit 40 may be a simple conduit having an opening at its distal end and connected to a source of fluid or insulin secreting cells (not shown), for example, external to the patient. As shown in fig. 4A, the first external conduit 40 is proximal to and inserted into one end of the guide tube 34, away from the first access port 20, and then a flow F of fluid and/or insulin secreting cells can be injected into the chamber 22 and flow through the porous wall 36 of the guide tube 34 into the adjacent cell channels 30, filling the adjacent cell channels 30.

When the cell channel 30 furthest from the first access port 20 is filled, the first external conduit 40 can be retracted towards the first access port 20 and continue to fill more of the cell channel 30 closer to the first access port 20, as shown in fig. 4B. The first external conduit 40 may be withdrawn into the first access port 20 to fill the remaining cell channels 30 and complete the filling of the cell encapsulation layer 12 with fluid and/or insulin secreting cells.

Guide tube 34 may guide first outer conduit 40 through chamber 22 to help position first outer conduit 40 in a controlled manner at a desired location for filling chamber 22, as described above. The guide tube 34 may prevent the first outer catheter 40 from moving inside the chamber 22 in an uncontrolled manner, which may result in under-filling or over-filling of a portion of the cell channel 30. In addition, the guide tube 34 may also prevent the first external conduit 40 from deflecting into the cell channel 30 and possibly damaging or puncturing the first membrane 14 or the second membrane 16.

The cell encapsulation device 10 can be implanted and then immediately filled with insulin secreting cells, as described above. Alternatively, the cell encapsulation device 10 may be implanted and immediately filled with a liquid to inflate the cell channels 30. The cell containment device 10 may then be left implanted in the inflated configuration, allowing a vessel (not shown) from the patient to grow around the cell containment device 10. The inflation fluid may be replaced with insulin secreting cells once the vessel has grown sufficiently to provide oxygen and nutrients to the cell encapsulation device 10. The fluid used to inflate the cell channels 30 may comprise saline. The fluid used to inflate the cell channels 30 may comprise a more viscous fluid, such as native hyaluronic acid. The fluid may reside in the cell channel 30 to maintain the cell encapsulation device 10 in the inflated configuration. The more viscous fluid (e.g., native hyaluronic acid) may reside in the cell channel 30 for a longer period of time than, for example, saline. This may provide additional time for vascular growth prior to injection of insulin secreting cells.

Insulin secreting cells can be injected in a gel matrix. The gel matrix may constrain the movement of the insulin secreting cells so that they will not aggregate together. This aggregation together can reduce the number of insulin secreting cells available to receive cell maintenance substances and secrete insulin. The gel matrix may comprise cross-linked hyaluronic acid and/or alginate gels. The gel matrix may further comprise an emulsion comprising an oxygen-containing fluid. The high oxygen solubility of the oxygen-containing fluid may allow the distance D of the cell channels 30 (fig. 3) to be greater than the distance D where the gel matrix does not include an emulsion comprising the oxygen-containing fluid. The oxygen-containing fluid may be, for example, a perfluorocarbon liquid of the type known in the art. Examples of such perfluorocarbon liquids may include: perfluorodihexyl ether, perfluorodibutylsulfur tetrafluoride, perfluorotriisobutylamine, perfluoro- (N-ethylmorpholine), perfluoro-N, N-dipropylmethylamine, perfluorotriethylamine, perfluoro-N-methylpiperidine, perfluoro-N-methylmorpholine, perfluoro-N, N-dimethyl-N-hexylamine, perfluoro-N-butylmorpholine, perfluoro-4- (N, N-dimethyl-2-aminoethyl) morpholine, and F-tert-butylperfluorocyclohexane, or a combination thereof.

Periodically, insulin-secreting cells may need to be replenished. Fig. 5 is a schematic side view of a portion of a system 38 for cell transplantation according to another embodiment. In the embodiment shown in fig. 5, the first external conduit 40 of fig. 4A and 4B is replaced with a first external conduit 42, which first external conduit 42 may be used to supplement insulin secreting cells while the cell encapsulation device 10 is still implanted inside the patient. The first outer catheter 42 can include a first lumen 44 having a first lumen opening 46, and a second lumen 48 having a second lumen opening 50. The first lumen opening 46 and the second lumen opening 50 are spaced along the guide tube 34. The first lumen 44 may be connected to a source of fluid and/or insulin secreting cells. The second lumen 48 may be connected to a vacuum source.

In use, the first outer catheter 42 can be inserted into the guide tube 34 at the first access port 20 (fig. 4A and 4B) and then moved through the guide tube 34 along the path through each of the cell channels 30. At each cell channel 30 along the path, the contents of the cell channel 30 are removed by the draw stream E through the porous wall 36 of the guide tube 34 and into the second lumen opening 50 to a vacuum source connected to the second lumen 48. Once the cell contents have been removed, a flow F of fluid and/or new insulin secreting cells may be provided from the first lumen opening 46, through the porous wall 36 of the guide tube 34, and into the cell channel 30 (fig. 4A and 4B).

Once the contents of the cell channel 30 have been removed, the cell channel 30 may be filled with fluid to wash the interior of the cell channel 30, and the wash fluid then withdrawn. This removal/filling process can be repeated as necessary to clean the cell channels 30 prior to filling with insulin secreting cells.

In the embodiment shown in fig. 5, the second lumen 48 is disposed coaxially with the first lumen 44, and the first outer catheter 42 further includes a flange 52 disposed between the first lumen opening 46 and the second lumen opening 50. The flange 52 projects outwardly toward the guide tube 34 to deflect the flow F from the first lumen 44 toward the distribution of the porous wall 36 of the guide tube 34 to enhance the flow F through the guide tube 34 into the cell channel 30.

Fig. 6 is a schematic side view of a portion of a system 38 for cell transplantation according to yet another embodiment. In the embodiment shown in fig. 6, the first external conduit 40 of fig. 4A and 4B is replaced with a first external conduit 54, which first external conduit 54 may be used to replenish the insulin secreting cells while the cell encapsulation device 10 is still implanted inside the patient. The first outer catheter 54 may include a first lumen 56 having a first lumen opening 58, and a second lumen 60 having a second lumen opening 62. The first lumen opening 58 is spaced from the second lumen opening 62 along the guide tube 34. The first lumen 56 may be connected to a source of fluid and/or insulin secreting cells. The second lumen 60 may be connected to a vacuum source. The first and second lumen openings 58, 62 may be angled toward the guide tube 34 (as shown in fig. 6) to enhance the extraction flow E and flow F of fluid through the porous wall 36 of the guide tube 34. The first outer conduit 54 may be used as described above for the first outer conduit 42 with respect to fig. 5.

Fig. 7 is a schematic cross-sectional top view of a system 64 for cell transplantation including a cell encapsulation device 66 and a first outer conduit 68. The cell encapsulation device 66 may be similar to the cell encapsulation device 10 described above, except that the cell encapsulation device 66 may include a second inlet port 70 and a second inlet conduit 72. For clarity, fig. 7 shows the first membrane 14 removed to reveal the second membrane 16. As shown in fig. 7, a second inlet conduit 72 is fluidly connected to the second inlet port 70 and extends from the second inlet port 70 in a direction away from the chamber 22. The guide tube 34 extends from the first inlet port 20 through the chamber 22 to the second inlet port 70. The second entry conduit 72 may be a tubular structure, as described above with respect to the first entry conduit 28. The first outer conduit 68 is capable of entering the chamber 22 through the first entry conduit 28, passing through the guide tube 34, and exiting the chamber 22 through the second entry conduit 72.

If the cell containment device 66 is not sufficiently vascular to support the insulin-containing cells therein, the first external conduit 68 may be a thin-walled silicone tube through which gases (such as oxygen and carbon dioxide) may pass. In use, an oxygenated fluid (such as any of the perfluorocarbon liquids disclosed above) may flow through the first external conduit 68 to provide an oxygenation circuit for the insulin secreting cells within the cell channel 30. Oxygen from the oxygen-containing fluid may diffuse out of the first outer conduit 68, through the porous wall 36 of the guide tube 34, and into the cell channels 30 where it may be absorbed by the insulin secreting cells at the cell channels 30. Waste from the insulin secreting cells can flow in the opposite direction and be removed as the oxygenated fluid flows out of the chamber 22 through the first external conduit 68. Alternatively, the oxygenated fluid may be a bodily fluid that may be collected in the peritoneum and then pumped through the first external conduit 68 to provide oxygen and collect waste products from the insulin secreting cells.

Additionally or alternatively, the first outer conduit 68 may be very flexible, and the flow of the oxygenated fluid through the first outer conduit 68 may be accomplished using peristaltic motion, thereby providing a pressure pulse that propagates into and through the cell channel 30. The pressure pulse may provide convective flow in the cell channel 30 to enhance the flow of oxygen and waste products to and from the insulin secreting cells. Once the vascularization of the cell containment device 66 is sufficient to support the insulin-containing cells therein, the first outer catheter 68 can be removed from the cell containment device 66.

Fig. 8 is a schematic side view of a portion of a system 74 for cell transplantation according to another embodiment. The system 74 is similar to the system 64 described above with respect to fig. 7, except that the first outer catheter 68 is replaced with the first outer catheter 40 as described above with respect to fig. 4A and 4B, which further includes a guidewire 78 and optionally a second outer catheter 80. As shown in fig. 8, the first outer catheter 40 includes a first lumen 82, the first lumen 82 being fluidly connected to a source of fluid or insulin secreting cells, e.g., external to the patient, as described above with respect to fig. 4A and 4B. The second outer conduit 80 may include a second lumen 84 connected to a vacuum source. Guidewire 78 may be a guidewire as known in the art.

In use, the guidewire 78 may be inserted into the first access catheter 28, through the guide catheter 34, and out through the second access catheter 72. The first outer catheter 40 can be threaded onto one end of the guidewire 78 and inserted into the first access catheter 28 and then into the guide tube 34 at the first access port 20 of the cell encapsulation device 66 (fig. 7). A second external catheter 80 can be threaded onto the opposite end of the guidewire 78 and inserted into the second access catheter 72 and then into the guide tube 34 at the second access port 70 opposite the first external catheter 40 (fig. 7). The first outer catheter 40 and the second outer catheter 80 are spaced from one another but are collectively movable through the guide tube 34 along the path to pass through each of the cell channels 30. At each of the cell channels 30 along this path, the contents of the cell channel 30 are removed by the draw stream E through the porous wall 36 of the guide tube 34 and into the second lumen 84. Once the cell contents have been withdrawn, a flow F of fluid and/or fresh insulin secreting cells may be provided from the first lumen 82, through the porous wall 36 of the guide tube 34 and into the cell channel 30 (fig. 4A and 4B).

The guidewire 78 may include a flange 86 disposed between the first outer catheter 40 and the second outer catheter 80. The flange 86 projects outwardly toward the guide tube 34 to deflect the flow F dispensed from the first lumen 82 toward the porous wall 36 of the guide tube 34 to enhance the flow F through the guide tube 34 and into the cell channel 30.

For example, the second external conduit 80 may be omitted when the draw stream E is not necessary, such as when the cell encapsulation device 66 is first filled to inflate the cell channel 30.

In the cell encapsulation devices 10 and 66 described above, only a single guide tube 34 is shown inside each cell encapsulation layer 12. However, it is understood that embodiments include cell encapsulation devices 10 and 66 having at least one cell encapsulation layer 12, the cell encapsulation layer 12 including at least two guide tubes 34 extending into the cell encapsulation chamber 22, at least two first access ports 20, at least two second access ports 70, or any combination thereof. For example, including a plurality of guide tubes 34 in the single cell encapsulation layer 12 may increase the speed and efficiency of filling or replenishing the cell encapsulation layer 12 with insulin secreting cells.

In the cell encapsulation devices 10 and 66 described above, the guide tube 34 is illustrated in a generally flat configuration inside the cell encapsulation layer 12. However, it is understood that embodiments include cell encapsulation devices 10 and 66 in which guide tube 34 is bent within the cell encapsulation layer to accommodate different shapes of chamber 22 (e.g., U-shaped chamber 22).

Fig. 9 is a side view of another cell encapsulation device 88 according to some embodiments of the present disclosure. The cell encapsulation device 88 includes two cell encapsulation layers: a first cell encapsulation layer 90 and a second cell encapsulation layer 92. First cell encapsulation layer 90 and second cell encapsulation layer 92 may each be similar to cell encapsulation device 66 described above with respect to fig. 7, except that second inlet conduit 72 of first cell encapsulation layer 90 and first inlet conduit 28 of second cell encapsulation layer 92 may be fluidly connected to form intermediate layer conduit 94 fluidly connecting first cell encapsulation layer 90 to second cell encapsulation layer 92. The first entry conduit 28 of the first cell encapsulation layer 90 and the second entry conduit 72 of the second cell encapsulation layer 92 may each extend outside the patient, or may be connected to a subcutaneous injection port 100 (fig. 11, below) beneath the patient's skin.

Fig. 10 is a side view of another cell encapsulation device 96 according to some embodiments of the present disclosure. The cell encapsulation device 96 is similar to the cell encapsulation device 88 described above and further includes a multi-guide access catheter 98. The multi-guide tube entry conduit 98 may be a single conduit that branches off to fluidly connect to the guide tubes 34 in the first and second cell encapsulation layers 90, 92. In use, the first external conduit 40 (or any other of the first or second external conduits described above) may be inserted into the multi-guide tube entry conduit 98 and then directed to the guide tube 34 in the first cell encapsulation layer 90 or the second cell encapsulation layer 92 as desired. The multi-guide tube access catheter 98 may extend outside the patient or may be connected to a subcutaneous injection port 100 (fig. 11, below) beneath the patient's skin. In this way, the number of external or subcutaneous injection ports for the cell encapsulation device may be reduced. Limiting the number of external or subcutaneous injection ports reduces the chance of interaction between the insulin secreting cells in the cell encapsulation device 88 and the patient's immune system.

Although only two cell encapsulation layers 90 and 92 are shown in fig. 9 and 10, it is understood that the disclosed structure can be extended to include embodiments having as many cell encapsulation devices as needed to provide the desired amount of insulin secreting cells to the patient.

Fig. 11 is a schematic longitudinal cross-sectional view of a portion of any of the devices of cell encapsulation devices 10, 66, 88, or 96 described above, illustrating a hypodermic port 100 (see, e.g., fig. 1) connected to an end of the first access conduit 28 opposite the chamber 22. Hypodermic port 100 may include a port housing 102, and outer and inner septums 104, 106. The port housing 102 may include a port lumen 108. The port lumen 108 may extend through the port housing 102, and an end of the port lumen 108 proximate the first entry conduit 28 is in fluid communication with the first entry conduit 28. The outer septum 104 extends across and seals the port lumen 108. The inner membrane 106 also extends across and seals the port lumen 108. The inner septum 106 is spaced from the outer septum 104 to form a space 110 between the inner septum 106 and the outer septum 104 inside the port lumen 108. An inner diaphragm 106 is disposed between the outer diaphragm 104 and the first inlet conduit 28. The outer membrane 104 and the inner membrane 106 may be constructed of an elastic polymer that can be penetrated by and then sealed around a cannulated needle. The port housing 102, outer membrane 104, and inner membrane 106 may be constructed of, for example, a polymer such as silicone or polycarbonate urethane.

Although a hypodermic port 100 is shown in fig. 11 connected to the first access catheter 28, it will be appreciated that some embodiments of the cell encapsulation device have a hypodermic port similar to hypodermic port 100 connected to other access catheters (such as the second access catheter 72 or the multi-guide access catheter 98 described above).

Fig. 12A-12D are schematic longitudinal cross-sectional views of a portion of another system 112 for cell encapsulation according to some embodiments of the present disclosure. System 112 may be similar to any of the systems described herein except that any of the cell encapsulation devices 10, 66, 88, or 96 described above further includes a subcutaneous injection port 100 as described above with respect to fig. 11, and system 112 may further include an outer tubular needle 114 as shown in fig. 12A-12D and an inner tubular needle 116 as shown in fig. 12C and 12D. The outer tubular needle 114 is capable of penetrating the outer septum 104 and the outer septum 104 seals around the outer tubular needle 114. The inner cannulated needle 116 can pass through the outer cannulated needle 114 and penetrate the inner septum 106 and the inner septum 106 seals around the inner cannulated needle 116.

As shown in fig. 12A and 12B, in use, the outer tubular needle 114 can penetrate the skin of a patient (not shown) to the subcutaneous injection port 100 and then penetrate the outer septum 104 such that one end of the outer tubular needle 114 is in fluid contact with the space 110 inside the port lumen 108 between the outer septum 104 and the inner septum 106. Upon penetrating outer septum 104, some bodily fluids may be transferred into space 110 along with outer tubular needle 114. The body fluid may contain somatic cells that must remain isolated from the insulin-secreting cells inside chamber 2 (fig. 1). To maintain this isolation, the other end (not shown) of outer tubular needle 114 may be fluidly connected to a source (not shown) of antiseptic solution S. For example, the disinfecting liquid S may be glutaraldehyde or ethanol. As shown in fig. 12B, a sterilizing fluid S may be injected into the space 110 through the outer tubular needle 114 to sterilize the walls of the space 110 and the exposed surfaces of the outer tubular needle 114, thereby destroying any somatic cells inside the space 110.

Once the space 110 is sterilized, the inner tubular needle 116 may be passed through the outer tubular needle 114, through the sterilized space 110, and then through the inner membrane 106 such that one end of the inner membrane 106 is in fluid contact with the first access conduit 28, as shown in fig. 12C. The first outer catheter 40 may then be inserted into the other end (not shown) of the inner tubular needle 116 and through the inner tubular needle 116, into the first access catheter 28 (as shown in fig. 12D), and into the guide catheter 34, as described above with respect to fig. 4A. In this way, insulin secreting cells can be injected into the cell encapsulation device while maintaining isolation from the somatic cells.

A stop edge (not shown) may be added to the proximal ends of outer tubular needle 114 and inner tubular needle 116 to prevent outer tubular needle 114 from penetrating inner septum 106 and to prevent the risk of inner tubular needle 116 penetrating too far into first access conduit 28 and piercing first access conduit 28, guide tube 34, first membrane 14 or second membrane 16.

The withdrawal of the first outer conduit 40 while maintaining isolation may be accomplished using a reverse approach. The first outer catheter 40 may be withdrawn through the inner cannulated needle 116 and then the inner cannulated needle 116 may be withdrawn from the first access catheter 28 through the inner septum 106. The inner membrane 106 may be constructed of a polymer that seals the aperture formed by the inner tubular needle 116 when penetrating the inner membrane 106. Additionally or alternatively, the hole may be sealed with alginate gel, silicone polymer, or another biocompatible adhesive added through the inner cannulated needle 116 as the inner cannulated needle 116 is withdrawn through the inner septum 106. When the inner tubular needle 116 is withdrawn through the inner septum 106, insulin secreting cells may be delivered into the space 110 along with the inner tubular needle 116. To maintain isolation between the insulin secreting cells and the body, a sterilizing fluid S may again be injected into the space 110 through the outer tubular needle 114 to sterilize the walls of the space 110 and the exposed surfaces of the outer tubular needle 114, thereby destroying any insulin secreting cells inside the space 110 (fig. 12B).

Once the space 110 is sterilized, the outer tubular needle 114 may be withdrawn from the space 110 through the outer septum 104. The outer septum 104 may be constructed of a polymer that seals the hole formed by the outer tubular needle 114 upon penetration of the outer septum 104. Additionally or alternatively, when the outer tubular needle 114 is withdrawn through the outer septum 104, the hole may be sealed with alginate gel, silicone polymer, or another biocompatible adhesive added through the outer tubular needle 114.

The phrase "in any range defined between any two of the preceding values," as used herein, literally means any range that can be selected from any two values listed before the phrase, whether or not those values are in the lower portion of the list or in the upper portion of the list. For example, a pair of values may be selected from two lower values, two higher values, or one lower value and one higher value.

Various modifications and additions may be made to the exemplary embodiments discussed without departing from the scope of the present invention. For example, while the embodiments described above refer to particular features, the scope of the present invention also includes embodiments having different combinations of features and embodiments that do not include all of the described features. Accordingly, the scope of the present invention is intended to embrace all such alternatives, modifications and variances which fall within the scope of the appended claims, along with all equivalents thereof.