METHODS AND DEVICES FOR DELIVERING PANCREATIC ISLET
FUNCTION TO A BODY
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority to U.S. Provisional Application No. 62/582,120 filed November 6, 2017 and U.S. Provisional Application No. 62/620,594 filed January 23, 2018 and U.S. Provisional Application No. 62/632,684 filed February 20, 2018, each of which is incorporated herein by reference in its entirety. This application is also related to US provisional patent application 62/560,559 filed 9/19/2017, US Patent 9,603,558, issued 3/28/2017, and PCT/US2015/065387 filed 11/12/2015, each of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of artificial pancreas and treatments for diabetes.
INCORPORATION BY REFERENCE
[0003] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each such individual publication or patent application were specifically and individually indicated to be so incorporated by reference.
BACKGROUND OF THE INVENTION
[0004] Diabetes is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. Diabetes is the leading cause of blindness in people ages 20 to 70 and is sixth leading cause of death in the United States. Overall, the risk for death among people with diabetes is about 2 times that of people without diabetes. The disease often leads to other complications such as kidney, nerve and heart disease and strokes. It is the leading cause for non-traumatic amputations and kidney failure.
[0005] Diabetes is reaching epidemic proportions in the United States. There are approximately 18.2 million people in the United States, or 6.3% of the population, who have diabetes. While an estimated 13 million have been diagnosed with diabetes, 5.2 million people (or nearly one-third) are unaware that they have the disease. Furthermore, diabetes is one of the most common chronic diseases in children and adolescents; about 151,000 people below the age of 20 years have diabetes.
[0006] Diabetes, and in particular Type 1 diabetes, stems from the pancreas' s failure to produce enough insulin. Efforts have been made to implant pancreatic islet cells from both humans and animals in an attempt to augment the functions of the diabetic' s pancreatic function. There have been several issues with this approach. Human islet cells are not readily available and can trigger immune responses of the host body. Animal islet cells are more available, but also trigger host immune responses.
[0007] It would be valuable to have a system which allows the implantation or exposure to animal islet cells while reducing the host immune responses to the islet cells.
SUMMARY OF THE INVENTION
[0008] Work has been performed on encapsulating animal islet cells within a nanopore membrane. A nanopore membrane has the ability to allow exchange of glucose, insulin, nutrients and small molecules across the membrane, while preventing, or reducing, the ability of larger molecules, such as antibodies and cytokines, to cross the membrane. The small pore size and consistency of the pore size allow for precise control of which molecules can cross the membrane, and which are blocked by the membrane. By encapsulating animal islets in a nanopore membrane, the islet cells can function and react to the presence and concentrations of glucose and insulin in the host body, while preventing or reducing the immune response of the host. For example, see Song, S., Faleo, G., Yeung, R., Kant, R., Posselt, A.M., Desai, T.A., Tang, Q., Roy, S., 2016. Silicon nanopore membrane (SNM) for islet encapsulation and immunoisolation under convective transport. Sci. Rep. 6, srep23679 (2016), and Song, S., Blaha, C, Moses, W., Park, J., Wright, N, Groszek, J., Fissell, W., Vartanian, S., Posselt, A.M., Roy, S., 2017. An intravascular bioartificial pancreas device (iBAP) with silicon nanopore membranes (SNM) for islet encapsulation under convective mass transport. Lab. Chip 17, 1778-1792 (2017) each of which is herein incorporated by reference in its entirety. Islet cells may be used from pigs, cows, primates, mice, or any other suitable animal, including humans.
[0009] Alternatively, artificial islet cells may be used. For example, see Zhaowei Chen, Jinqiang Wang, Wujin Sun, Edikan Archibong, Anna R Kahkoska, Xudong Zhang, Yue Lu, Frances S Ligler, John B Buse, Zhen Gu. Synthetic beta cells for fusion-mediated dynamic insulin secretion. Nature Chemical Biology, 2017; DOI: 10.1038/nchembio.2511 for a description of synthetic beta cells, in the entire contents of which is hereby incorporated by reference.
[0010] The nanopore membrane may be made out of any suitable material known in the art, including the materials disclosed above and in US patent 8,543,184, US patent 7,613,491, and US patent 8,050,731, each of which is hereby incorporated by reference in its entirety. The nanopore membrane may be hydrophilic or hydrophobic. Nanopore materials also include silicon, polysulfone, immunoisolating polysulfone, graphene, box- shaped graphene nanostructure, etc. Pore sizes may be around 5-50 nm, around 5-10 nm, around 7 nm, around 10 nm, around 10-40 nm, etc.
[0011] The intraperitoneal (IP) space has been shown to have more effective, and faster insulin delivery and faster glucose sensing kinetics than the subcutaneous space. In particular, the true pelvis has been shown to have superior dynamics. Some embodiments herein are designed to be located in the IP space, and/or the true pelvis. Alternatively, some embodiments may be implanted subcutaneously, either permanently, or temporarily.
[0012] The artificial pancreas system may include the following components, in addition to other components:
[0013] 1. An encapsulation container for encapsulating islet cells (animal, human, or artificial) at least partially within a nanopore material.
[0014] 2. One or more ports (preferably subcutaneous, but may be other types of ports) for removing islet cells from the encapsulation container, replacing islet cells within the encapsulation container, flushing the encapsulation container, pressurizing the encapsulation container, removing fibrous growth on the encapsulation container or elsewhere in the system etc.
[0015] 3. One or more catheters/tubings/lumens to connect the port(s) to the encapsulation container
[0016] 4. Optionally a controller to control flushing of the system, and/or removal/replacement of the islet cells, and/or pressurizing of lumen(s), or elsewhere, within the system.
[0017] In some embodiments, the encapsulation container is at the distal tip (in the IP space) of the catheter and in fluid communication with the one or more islet lumens of the catheter. Another lumen of the catheter, or another catheter may be used to periodically flush the outside of the encapsulation container to prevent fibrous buildup. Alternatively or additionally, the islet lumen(s) of the catheter may be used to flush, and/or pressurize, the encapsulation container from the inside. Pressure may be used to help with removing fibrous buildup. Pressure may be used to expand the encapsulation container to break up fibrous buildup. Pressure may also be used to aid in transport of molecules across the nanopore membrane. Pressure may be positive or negative and/or may oscillate between positive and negative, and/or pulse positive or negative. Pressurization, flushing, islet removal/replacement, fibrous removal, etc. may be controlled by the controller.
[0018] Implanting the encapsulation container in the IP space may provide faster kinetics, diminished immune response, and more effective function, than implanting the encapsulation container subcutaneously, however, either approach, or other implantation sites, may be used.
[0019] In one embodiment of an apparatus for delivering pancreatic islet function to a body, the apparatus may generally comprise at least one port casing configured to be placed subcutaneously within the body. A catheter may be fluidly coupled to the at least one port casing and an encapsulation container having a nanopore membrane and the catheter may be configured to be placed within a peritoneal cavity of the body. An islet lumen may be defined within or along the catheter and in fluid communication between an islet port and the encapsulation container and a flushing lumen may be defined within or along the catheter and in fluid communication between a flushing port and with an exterior of the encapsulation container.
[0020] In one embodiment of a method for delivering pancreatic islet function to a body, the method may generally comprise receiving a volume of islet cells through an islet lumen defined within or along a catheter and into an encapsulation container, wherein the islet lumen is fluidly coupled to an islet port within at least one port casing placed subcutaneously within the body.
An exchange of an islet cell function between the body and the volume of islet cells within the encapsulation container may occur, wherein the islet cell function is exchanged through a nanopore membrane. Furthermore, an exterior of the encapsulation container may be flushed with a fluid via a flushing lumen defined within or along the catheter and in fluid communication between the exterior and a flushing port.
[0021] Any of the embodiments detailed herein can be used in any potential space, including, but not limited to, the pleural space, the cerebral spinal fluid space, the peritoneal space, the true pelvis, etc.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] Fig. 1 shows an embodiment of the artificial pancreas system after it has been implanted in the body of a subject. [0023] Fig. 2 shows a more detailed close-up of the artificial pancreas system shown in Fig. 1.
[0024] Figs. 3A and 3B show cross sections of the catheter near the distal tip of the flushing lumen.
[0025] Figs. 4 A and 4B show embodiments of the catheter with 2 islet lumens.
[0026] Fig. 5 shows an embodiment of the system which includes a catheter with 2 lumens.
[0027] Figs. 6 A and 6B show embodiments where the syringe functions are performed by a controller.
[0028] Fig. 7 shows encapsulation container 108 with a rounded tip, essentially cylindrical shape.
[0029] Fig. 8 shows an embodiment with a continuously tapering tip to help with fibrous growth flushing.
[0030] Figs. 9A and 9B show an encapsulation container with a wide flat shape.
[0031] Fig 10 shows an embodiment of an encapsulation container with increased surface area.
[0032] Figs. 11A-11D show how the islet lumen may be used to either fully flush, or aid in flushing (with the flushing lumen) of the encapsulation container.
[0033] Fig. 12A shows an embodiment of the catheter with a collapsible encapsulation container.
[0034] Figs. 12B, 12B' and 12B" show cross sectional views of the encapsulation container.
[0035] Figs. 12C and 12C show cross sectional views of the encapsulation container.
[0036] Figs. 12D and 12D' show cross sectional views of the encapsulation container.
[0037] Fig. 12E shows a close-up of the distal end of the catheter shown in Fig. 12A.
[0038] Fig. 13A and 13B show top and side view respectively of an embodiment of a dual port for saline flushes and islet infusion/removal.
[0039] Fig. 14A shows an example of an islet needle.
[0040] Fig. 14B shows an example of a saline flushing needle.
[0041] Fig. 15 shows an embodiment of the catheter with a coiled encapsulation container.
[0042] Fig. 16 shows an embodiment of the catheter with a pigtailed encapsulation container.
[0043] Fig. 17 shows an embodiment of the catheter with a multi-tentacled encapsulation container.
[0044] Figs. 18A and 18B show an embodiment which is implanted subcutaneously. [0045] Figs. 19A-D show embodiments of the artificial pancreas system which include a circulating infusate exchange chamber.
[0046] Fig. 20 is a block diagram of a data processing system.
DETAILED DESCRIPTION OF THE INVENTION
[0047] Fig. 1 shows an embodiment of the artificial pancreas system after it has been implanted in the body of a subject. Artificial pancreas system 102 is shown implanted so that catheter 104, including encapsulation container 108 protrudes into the peritoneal cavity, so that encapsulation container 108 resides at least in part within the IP cavity. Ports 106 are implanted subcutaneously, and are in fluid communication with catheter 104. The encapsulation container is shown here in the deep pelvis. In some embodiments the tip of catheter 104 may be weighted so that the tip, and therefore the encapsulation container, are generally in the peritoneal fluid.
[0048] Fig. 2 shows a more detailed close-up of the artificial pancreas system shown in Fig. 1. In this embodiment, catheter 104 includes islet lumen 202 and flushing lumen 204. Islet lumen 202 is in fluid communication with islet port 206 and flushing lumen 204 is in fluid communication with flushing port 208. The subcutaneous ports may include septums 210 so that a needle, such as the one shown here as part of syringe 212, can access the port through the skin and self-seal after the needle is removed. Anti-adhesion and/or adhesion cuff 216 may also be included. A syringe may be used to flush the catheter tip with fluid (shown here as 214) to help remove fibrous buildup on the encapsulation container. The flushing fluid may be saline, or other fluid. A syringe may be used to remove and/or replace islet cell solution via islet port 206. Islet cells may be first removed using a vacuum exerted by the syringe with its needle in the islet port, the syringe/needle removed, and then islet cells may be replaced by injecting islet cells into the islet port with a different syringe. Alternatively the islet cells may be flushed out of the catheter islet lumen and replaced simultaneously via a catheter with two islet lumens (one for inflow, one for outflow) as disclosed below.
[0049] Figs. 3A and 3B show cross sections of the catheter near the distal tip of the flushing lumen. Fig. 3A shows a single islet lumen, lumen 202 and concentric flushing lumen 204. Fig. 3B shows islet outflow lumen 306 and islet inflow lumen 304 which are divided by divider 302. Islet outflow lumen and islet inflow lumen may alternatively be concentric.
[0050] Fig. 4A shows an embodiment of the catheter with 2 islet lumens, islet outflow lumen 306 and islet inflow lumen 304. Flush lumen 204 is also shown. [0051] Fig. 4B shows an embodiment similar to that shown in Fig. 4A, but with a reduced diameter islet lumen(s). This is to reduce waste of islet cells which are in the catheter, but not in the encapsulation container.
[0052] Fig. 5 shows an embodiment of the system which includes a catheter with 2 islet lumens: islet outflow lumen and islet inflow lumen. Islet outflow port 502 is in fluid communication with the islet outflow lumen of the catheter, while islet inflow port 504 is in fluid communication with the islet inflow lumen of the catheter. Flushing port 208 is also shown. All 3 ports are shown in a single casing in this figure, casing 506. However, each port may be in its own casing or more than one port may be in a single casing, while other port(s) are separate. Flushing syringe 508 is used to flush the catheter tip via the flushing lumen. Islet outflow syringe 510 is used to remove older islets from the system. Islet inflow syringe 512 is used to insert new islet cells into the system, and in particular, into the encapsulation container. The functions of flushing and islet removal and replacement are shown here to be performed manually with independent syringes. However, a syringe may be used that includes more than one function. For example, a specialized syringe which simultaneously removes and replaces islet cells may be used. Or, a specialized syringe which does any one or more of the functions could be used.
[0053] Fig. 6A shows an embodiment where the syringe functions are performed by a controller. The controller here is shown attached to flushing needle 602, islet removal needle 604 and islet replacement needle 606, however, the connection between controller 608 and the needles, or access devices, may be remote, as is shown in Fig. 6B. For example, the controller may be connected by wire or wirelessly to the needle functions. Controller 608 may include various settings, displays, input and output mechanisms etc. The access needles 602, 604, and 606 are in fluid communication with flushing fluid 610, a waste receptacle 612 and an islet cell source 614 respectively. The controller controls the functions of flushing and islet removal and replacement, as well as possibly other functions. For example, as described elsewhere herein, it may be desirable to pressurize the encapsulation container either continuously, to aid in molecule transport across the nanopore membrane of the encapsulation container, or periodically, to help break up fibrous growth on the encapsulation container or catheter. This pressurization (either positive or negative), may be controlled by the controller.
[0054] For example, to periodically flush the fibrous growth from the distal tip of the catheter, the controller may pressurize the islet lumen (via either the islet inflow or outflow lumens), possibly in conjunction with pumping fluid through the flushing lumen. This may help remove any fibrous growth that may have grown into the nanopores of the nanopore membrane. The pressurization of the islet lumen may be pulsed, alternating between positive and negative pressure or at a constant pressure. The flushing lumen fluid flow may likewise be pulsed, alternating or constant. "Pulsed" here may mean pulsed at a relatively high frequency, i.e. once per second or several times per second, or may mean a relatively low frequency, including once per minute, hourly, daily, weekly, etc. The control of the flushing lumen flow and the islet lumen pressure may be coordinated by the controller, for example, the flow of the flushing fluid may be less when the islet lumen is being pressurized, and greater when the islet lumen is not being pressurized, or, the inverse.
[0055] The islet lumen(s) may also be pressurized and sealed to maintain a slight positive pressure to help with both molecule diffusion and also prevent fibrous ingrowth. The pressure differential across the nanopore membrane may be about 1-3 psi, or about 1-5 psi, or about 1 psi, or about 2 psi.
[0056] In some embodiments, the encapsulation container may be implanted subcutaneously, with a catheter connecting the encapsulation container with the IP space. A pump, or other means, may be used to circulate the IP fluid from the IP space to the encapsulation container so that molecular transfer can take place across the nanopore membrane of the encapsulation container. These embodiments may reduce fibrous growth and ease the replacement of the islet cells.
[0057] In some embodiments, a portion of the islet lumen is implanted in proximity to a blood vessel, where the portion of the islet lumen nearest the blood vessel is made from nanopore membrane to allow oxygen transport from the blood vessel to the islet cells.
[0058] In some embodiments a source of oxygen, i.e. a reservoir of oxygen, (possibly replenishable) or an oxygen producing mechanism are incorporated into the system to supply extra oxygen to the islet cells. For example, a slow chemical reaction of one, two or more chemicals within the artificial pancreas system may produce oxygen over time and may not need to be replenished frequently.
[0059] In some embodiments, islet cells are circulated through the system by means of a pump or otherwise to increase diffusion across the membrane surface, and also to use a larger volume of islet cells than can be contained in the encapsulation container itself. The circulation path may include the islet lumen(s). [0060] Figs. 7, 8, 9A, 9B and 10 show some different possible configurations of the encapsulation container. Fig. 7 shows encapsulation container 108 with a rounded tip, essentially cylindrical shape.
[0061] Fig. 8 shows an embodiment with a continuously tapering tip to help with fibrous growth flushing.
[0062] Figs. 9A and 9B show an encapsulation container with a wide flat shape, which may be oval, round, squarish or any other shape. This configuration allows for increased nanopore membrane surface area. The tapered tip may help with dislodging fibrous growth. The flat embodiment may also help dislodge the fibrous growth on the encapsulation container by allowing expansion of the encapsulation container when the islet lumen is pressurized.
[0063] Fig 10 shows an embodiment of an encapsulation container with increased surface area. The encapsulation container may form a loop, or other shape. The shape may be simple or complex.
[0064] Flushing may be performed via the flushing lumen, or alternatively through an islet lumen, or both.
[0065] Figs. 11A-11D show how the islet lumen may be used to either fully flush, or aid in flushing (with the flushing lumen) of the encapsulation container. Fig. 11A shows a close-up of the nanopore membrane of the encapsulation container, where the bottom is inside the encapsulation container (i.e., an islet lumen) and the top is outside the encapsulation container (i.e. the IP cavity or elsewhere in the body). Shown here is nanopore membrane 1102, including pores 1106 and fibrous growth 1104 on the outside of the encapsulation container.
[0066] Fig. 11B shows the direction of force when the islet lumen is pressurized.
[0067] Fig. l lC shows the dislodgement of the fibrous growth as a result of the pressure. Pressurizing the islet lumen may be enough to remove the fibrous growth. However, flushing the encapsulation container via the flushing lumen may also be used (possibly simultaneously) to remove the fibrous material. This additional force is represented by arrow 1108.
[0068] Fig. 1 ID shows an embodiment where the encapsulation container, or portions thereof, respond to positive pressure in the islet lumen by expanding. The expansion of the nanopore membrane breaks the fibrous growth enough to remove it, or for the force from the flush of the flushing lumen to remove it. The expanding pressure may be applied in a pulsatile manner, or may be alternated with negative pressure, or be applied continuously, to help break up the fibrous material. [0069] Fig. 12A shows an embodiment of the catheter with a collapsible encapsulation container. The catheter includes outer layer 1202, which may be made from silicone or other suitable polymer or material, islet lumen (both inflow and outflow in this embodiment) 1204, islet encapsulation container 1206, flush lumen 1208, pores 1210 and cuff 1212, which may be made out of polyester, or any suitable polymer or other material. The figure shows the portion of the catheter which will normally be in the intraperitoneal cavity, and the rectus sheath, during ongoing use.
[0070] In this and possibly other embodiments, encapsulation container 1206 is collapsible. This allows for islet flushing with only one (or fewer or smaller) islet flush lumen. The islet flush lumen may be concentric, as shown in Fig. 12C, or may comprise one or more separate lumens, as shown in Fig. 12C . Figs. 12B, 12B' and 12B" show the collapsible nature of the encapsulation container. Part, or all, of the length of the encapsulation container may be collapsible. Fig. 12B shows the encapsulation container in its collapsed state when a vacuum is pulled on the islet lumen. The encapsulation container may collapse in a preset fashion, such as a star shape as is shown here, pleated in other ways, it may flatten when collapsed, and/or may be made out of a very thin and flexible material which naturally collapses when a vacuum is pulled. The collapsible encapsulation container may be very flexible in the radial direction (either around the entire radius or only part of the radius) and more rigid in the longitudinal direction. The collapsible encapsulation container may alternatively or additionally be fixed at the distal end. This prevents the encapsulation container from trapping islet cells when a vacuum is pulled.
[0071] To replace the islet cells, a vacuum is pulled on the islet lumen to remove the old islet cells. This causes the collapsible encapsulation container to collapse which reduces the volume of the encapsulation container, allowing most of the old islet cells to be removed. Fresh islet cells are then introduced through the islet lumen. These steps may be repeated to increase the portion of fresh islet cells in the islet encapsulation container. One islet lumen is shown here, but two lumens may alternatively be used with a collapsible encapsulation container.
[0072] Fig. 12B' shows a cross section of the collapsible encapsulation container when it is full of fresh islets. In this figure, there still exists a flushing lumen around the encapsulation container so that the catheter may be flushed when the encapsulation container is full. Fig. 12B" shows an embodiment where the walls of the encapsulation container touch the inner wall of the outer layer of the catheter when the encapsulation container is full. In this embodiment, the flushing of the catheter coincides with the flushing of the islet lumen so that the flushing lumen exists as is shown in Fig. 12B.
[0073] Fig. 12D and 12D' show the cross section of the catheter which includes cuff 1212, both with a coaxial flush lumen and separate flush lumens.
[0074] Fig. 12E shows a close-up of the distal end of the catheter shown in Fig. 12A. This figure shows more clearly flow 1214 of the flushing fluid as it flows through the flush lumen and out of the pores. Also shown is the bidirectional flow through islet lumen 1204.
[0075] Although some embodiments may have a collapsible encapsulation container, some embodiments may have an encapsulation container which is similar to those shown in Figs. 12A-E, except that the encapsulation container is rigid, or semi-rigid, and may not be collapsible. For example, a rigid encapsulation container may resemble that shown in Fig. 12B, where it is in a star, or other shape which allows for a high surface area relative to the islet volume, in its full state. This type of encapsulation container may be flushed via two lumens (islet inlet and islet outlet) or may be collapsible or semi-collapsible when a vacuum is pulled, allowing it to be flushed with a single islet lumen.
[0076] Fig. 13A and 13B show top and side view respectively of an embodiment of a dual port for saline flushes and islet infusion/removal. Saline flush port 1302 is in fluid communication with the flushing lumen of the catheter and islet port 1304 is in fluid communication with the islet lumen of the catheter. The ports may include silicone membranes 1306 as well as conductive band 1308 or element 1314 which closes a conductive circuit with a needle used in the port and limits the proper needle to the proper port. The conductivity information may be transmitted to a controller/monitor which may display, or otherwise communicate, that the proper needle is, or is not, in the proper port. Needle openings 1310 and 1314 may be sized to accept the proper needle. Cuff 1312 may also be present.
[0077] For example, conductive ring 1308 may be used on one of the ports, for example the islet port. When a conductive element on the islet needle contacts conductive ring 1308, a signal is sent to the monitor to indicate that the proper needle is in the port and possibly whether or not the needle is in the proper position within the ort. The monitor may prevent injection of islets into, or vacuum of islets out of, the islet port until the monitor senses that the proper needle is in place and in the proper position. An example of an islet needle is shown in Fig. 14A, where islet needle 1402 has a non-coring tip 1404, a conductive element 1406 and a communicating wire or path 1408 from the conductive element back to the monitor (not shown). The non-conducting surfaces or areas or volumes of the needle may be made from, or coated with, non-conducting material, such as polymer. The needle may have more than one conducting element around its radius, and more than one communication wire, to ensure that more than one contact with conductive ring 1310 is made. The distance between the conductive element and the tip of the needle may correspond to the depth of reservoir 1318 to ensure the needle tip is within the reservoir for islet replacement.
[0078] Conductive element 1314 may be used in a similar fashion. Conductive element 1314 may be placed at the bottom of the reservoir as shown in Fig. 13B. Fig. 14B shows an example of a saline flushing needle. Flushing needle 1410 includes a non-coring tip and conductive element 1414 at the tip of the needle, along with communication wire or path 1412. The conductive circuit is closed when the saline flushing needle is introduced into the flushing port and the tip of the needle contacts the conductive element at the bottom of the reservoir. Flushing port opening 1316 may be sized smaller, or differently than the opening of the islet port to prevent the wrong needle from entering the wrong port.
[0079] It is possible to have a conductive element on only one of the ports. For example, the islet port and needle may be larger than the flushing port and needle. This prevents the islet needle from entering the flushing port. To prevent the flushing needle from entering the larger islet port, a conductive element may be used on both the islet port and the islet needle. In this configuration, islets may be introduced or withdrawn only when the islet conductivity circuit is properly closed indicating that the islet needle is in proper position within the islet port.
[0080] These types of port configurations may be used with any number of ports, whether they are in the same casing or in separate casings.
[0081] Fig. 15 shows an embodiment of the catheter with a coiled encapsulation container. In this embodiment, the surface area of the encapsulation container is increased by the coil configuration. This configuration may use two islet lumens, islet inlet lumen 1504 and islet outlet lumen 1502, for replacing islets.
[0082] Fig. 16 shows an embodiment of the catheter with a pigtailed encapsulation container. This embodiment allows for increased surface area of the encapsulation container.
[0083] Fig. 17 shows an embodiment of the catheter with a multi-tentacled encapsulation container.
[0084] Other fibrous growth mechanisms may be used. For example, a separate balloon or pressurized lumen may be used to break up the fibrous material. Other Mechanical mechanisms may also be used. Some of which are disclosed in PCT/US2015/065387 filed 11/12/2015, incorporated herein in its entirety. [0085] Fibrous encapsulation has also been found to be more rapid and more extreme in the upper quadrant of the peritoneal cavity than in the lower quadrants (away from the omentum). Because of this, placing the sensor component in the pelvis (away from the omentum and liver) may be optimal. Alternatively, in the event that a patient has pelvic omentum, a method of catheter placement may be utilized which includes a procedure to tack the omentum up near the liver to keep the omentum away from the pelvic region.
[0086] In some embodiments of the system, the catheter may lie along the wall of a body cavity and not protrude significantly into the IP (or other) space. This may prevent issues with catheter kinking, catheter movement due to peristalsis or direct force from the organs, and catheter obstruction/erosion due to direct organ contact. The catheter portion of the present invention may be placed in the pelvis with a short section of the catheter being tunneled through the rectus sheath or pre-peritoneal space prior to entry into the peritoneal cavity. This allows for the catheter to be angled into the pelvis and away from the omentum to better ensure its continued patency and function.
[0087] Some embodiments include an agitation mechanism which agitates and/or vibrates the encapsulation container to help keep the area clean and free of ingrowth.
[0088] In some embodiments, peritoneal fluid is drawn into the catheter, or circulated through the catheter, via the nanopore membrane or via another port. This fluid may be used to flush the catheter or to aid in removing old islet cells.
[0089] Figs. 18A and 18B show an embodiment of the encapsulation container which is implanted subcutaneously rather than in the IP space. This embodiment may not require the flushing of encapsulation container 1802. In this embodiment, the encapsulation container is implanted subcutaneously and left in place until the islet cells are no longer viable. The device may then be removed or left in place, and another device may be implanted. Several devices may be implanted subcutaneously and left in place, either to biodegrade, or to be removed at a later time.
[0090] Figs. 19A-D show embodiments of the artificial pancreas system which include a circulating infusate exchange chamber, to help nourish and prolong the life of the islet cells. Fig. 19A shows infusate exchange chamber 1904 inside casing 1902. The chamber includes infusate exit port 1906 and infusate entrance port 1908. Infusate pump 1916 may be low energy and/or rechargeable and circulates infusate 1920 through exchange chamber 1904 and through catheter 1922. Distal end of catheter 1922 includes a porous section which allows diffusion of nutrients across back and forth between the infusate and the peritoneal fluid. The pore size of the distal end of the catheter may be larger than the nanopore size of other embodiments disclosed herein. This allows for rapid diffusion of nutrients across the membrane. Nutrients include glucose 1924, insulin 1926 and oxygen 1928. Although the arrows here show the primary direction of nutrient flow because of concentration gradients across the porous membrane, nutrient flow may diffuse in both directions.
[0091] Oxygen will primarily flow from the peritoneal fluid into the infusate to replace oxygen consumed by the islet cells within the exchange chamber. Glucose will primarily flow from the peritoneal fluid into the infusate, and insulin will generally flow from the infusate to the peritoneal fluid because of concentration differences across the catheter membrane.
[0092] Infusate exchange chamber 1904 also includes islet exit port 1910 and islet entrance port 1912, as well as microfibers 1914 which have a large surface area and are made from a nanopore membrane to allow diffusion of small molecules across the membrane. The microfibers containing the islet cells are exposed to the circulating infusate which surrounds the microfibers, similar to a dialysis chamber. Pump 1916 circulates the infusate, drawing the infusate from the catheter, where it has increased its concentration of oxygen and glucose via infusion from the peritoneal fluid, and exposing the islet cells to the infusate. Small molecules, such as insulin, glucose and oxygen, diffuse across the nanopore membrane during this exposure. Because of concentration differentials, oxygen and glucose will primarily flow from the infusate to the islet cells. Insulin will primarily flow from the islet cells to the infusate. Infusate that has been exposed to the islet cells within the exchange chamber is then circulated back to the catheter tip via the pump.
[0093] Catheter flushing lumen 1930, islet lumen(s) 1918 and subcutaneous port 1932 are also shown. Two ports are shown here on the subcutaneous port, but more or fewer may be present.
[0094] This exchange chamber allows oxygen and glucose in the peritoneal cavity to diffuse to the islet cells across a large surface area of nanopore membrane. It also allows insulin to diffuse from the islet cells to the infusate and ultimately to the body via the peritoneal fluid.
[0095] Fig. 19B shows a close-up of infusate exchange chamber 1904. Microfibers 1914 contain islet cells and are separated from circulating infusate 1920 by a nanopore membrane.
[0096] Fig. 19C shows the indicated cross section of the exchange chamber of Fig. 19B/ Shown is the exchange chamber 1904, microfibers 1914 contain islet cells are separated from the circulating infusate 1920 by a nanopore membrane, of which the microfibers are constructed. [0097] Fig. 19D shows an embodiment of the artificial pancreas system with a circulating infusate exchange chamber implanted in the human body. Shown are subcutaneous port 1932, exchange chamber 1904, pump 1916 and catheter 1922.
[0098] Catheter length may be around 300 mm. Alternatively catheter length may be around 250-350mm.
[0099] Example of Data Processing System
[0100] Fig. 20 is a block diagram of a data processing system, which may be used with any embodiment of the invention. For example, the system 2000 may be used as part of the controller. Note that while FIG. 20 illustrates various components of a computer system, it is not intended to represent any particular architecture or manner of interconnecting the components; as such details are not germane to the present invention. It will also be appreciated that network computers, handheld computers, mobile devices, tablets, cell phones and other data processing systems which have fewer components or perhaps more components may also be used with the present invention.
[0101] As shown in FIG. 20, the computer system 2000, which is a form of a data processing system, includes a bus or interconnect 2002 which is coupled to one or more microprocessors 2003 and a ROM 2007, a volatile RAM 2005, and a non- volatile memory 2006. The microprocessor 2003 is coupled to cache memory 2004. The bus 2002 interconnects these various components together and also interconnects these components 2003, 2007, 2005, and 2006 to a display controller and display device 2008, as well as to input/output (I/O) devices 2010, which may be mice, keyboards, modems, network interfaces, printers, and other devices which are well-known in the art.
[0102] Typically, the input/output devices 2010 are coupled to the system through input/output controllers 2009. The volatile RAM 2005 is typically implemented as dynamic RAM (DRAM) which requires power continuously in order to refresh or maintain the data in the memory. The non-volatile memory 2006 is typically a magnetic hard drive, a magnetic optical drive, an optical drive, or a DVD RAM or other type of memory system which maintains data even after power is removed from the system. Typically, the non-volatile memory will also be a random access memory, although this is not required.
[0103] While FIG. 20 shows that the non-volatile memory is a local device coupled directly to the rest of the components in the data processing system, the present invention may utilize a non-volatile memory which is remote from the system; such as, a network storage device which is coupled to the data processing system through a network interface such as a modem or Ethernet interface. The bus 2002 may include one or more buses connected to each other through various bridges, controllers, and/or adapters, as is well-known in the art. In one embodiment, the I/O controller 2009 includes a USB (Universal Serial Bus) adapter for controlling USB peripherals. Alternatively, I/O controller 2009 may include IEEE- 1394 adapter, also known as FireWire adapter, for controlling FireWire devices, SPI (serial peripheral interface), I2C (inter-integrated circuit) or UART (universal asynchronous receiver/transmitter), or any other suitable technology.
[0104] Some portions of the preceding detailed descriptions have been presented in terms of algorithms and symbolic representations of operations on data bits within a computer memory. These algorithmic descriptions and representations are the ways used by those skilled in the data processing arts to most effectively convey the substance of their work to others skilled in the art. An algorithm is here, and generally, conceived to be a self-consistent sequence of operations leading to a desired result. The operations are those requiring physical manipulations of physical quantities.
[0105] It should be borne in mind, however, that all of these and similar terms are to be associated with the appropriate physical quantities and are merely convenient labels applied to these quantities. Unless specifically stated otherwise as apparent from the above discussion, it is appreciated that throughout the description, discussions utilizing terms such as those set forth in the claims below, refer to the action and processes of a computer system, or similar electronic computing device, that manipulates and transforms data represented as physical (electronic) quantities within the computer system's registers and memories into other data similarly represented as physical quantities within the computer system memories or registers or other such information storage, transmission or display devices.
[0106] The techniques shown in the figures can be implemented using code and data stored and executed on one or more electronic devices. Such electronic devices store and communicate (internally and/or with other electronic devices over a network) code and data using computer-readable media, such as non-transitory computer-readable storage media (e.g., magnetic disks; optical disks; random access memory; read only memory; flash memory devices; phase-change memory) and transitory computer-readable transmission media (e.g., electrical, optical, acoustical or other form of propagated signals— such as carrier waves, infrared signals, digital signals).
[0107] The processes or methods depicted in the preceding figures may be performed by processing logic that comprises hardware (e.g. circuitry, dedicated logic, etc.), firmware, software (e.g., embodied on a non-transitory computer readable medium), or a combination of both. Although the processes or methods are described above in terms of some sequential operations, it should be appreciated that some of the operations described may be performed in a different order. Moreover, some operations may be performed in parallel rather than sequentially.
[0108] From the foregoing, it will be appreciated that specific embodiments of the invention have been described herein for purposes of illustration, but that various modifications may be made without deviating from the spirit and scope of the various embodiments of the invention. For example, several embodiments may include various suitable combinations of components, devices and/or systems from any of the embodiments described herein. Further, while various advantages associated with certain embodiments of the invention have been described above in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the invention.