|Publication number||WO1991000119 A1|
|Publication date||10 Jan 1991|
|Filing date||2 Jul 1990|
|Priority date||30 Jun 1989|
|Publication number||PCT/1990/281, PCT/AU/1990/000281, PCT/AU/1990/00281, PCT/AU/90/000281, PCT/AU/90/00281, PCT/AU1990/000281, PCT/AU1990/00281, PCT/AU1990000281, PCT/AU199000281, PCT/AU90/000281, PCT/AU90/00281, PCT/AU90000281, PCT/AU9000281, WO 1991/000119 A1, WO 1991000119 A1, WO 1991000119A1, WO 9100119 A1, WO 9100119A1, WO-A1-1991000119, WO-A1-9100119, WO1991/000119A1, WO1991000119 A1, WO1991000119A1, WO9100119 A1, WO9100119A1|
|Inventors||Thomas Eli Mandel, Brett Charlton, John Edward Moran, Thomas Loudovaris|
|Applicant||Baxter International Inc., The Walter And Eliza Hall Institute Of Medical Research|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (7), Referenced by (73), Classifications (11), Legal Events (4)|
|External Links: Patentscope, Espacenet|
The present invention relates to an i plantable device for keeping transplanted cells alive in vivo, and to methods of implanting such a device, whereby vascularisation of the exterior of the device is achieved in vivo, before or after instilment of the living cells into the device. The invention also relates to methods of treating animals comprising implantation of the device containing selected cells, or the subsequent instilment of selected cells into the empty device after vascularisation has occurred.
Endocrine deficiency diseases are currently treated with hormone replacement therapy. The therapeutic regimens employed range from multiple daily injections or oral therapy to implants that provide a steady hormone level over months. While this mode of therapy maintains an improved quality of life over the untreated disease state, it is not equivalent to the normal state where an organ maintains relative homeostasis in the individual by supplying a hormone in response to a sensed, variable metabolic need. Current inability to produce artificial infusion devices that can mimic normal endocrine organ function has motivated research efforts to transplant endocrine organs or their essential cellular elements into deficient individuals.
Human organ transplant recipients generally require Hfe-long i munosuppression to prevent Immune rejection of the organ. The undesirable side effects of current immunosuppressive agents are outweighed by the individual's need for major organ transplants, such as heart, lung, Hver or kidney. However, because the morbidity and mortality associated with those side effects may be worse than those which endocrine deficiency patients experience with conventional therapy, alternate means are being sought to prevent immune attack on transplanted endocrine organs.
One such alternative, called im unoisolation, surrounds the transplanted organ, or its essential elements, with a physical barrier that is impermeable to the active molecules and cells of the immune system, but is permeable to nutrients, the hormone(s) secreted by that organ, and the metabolite(s) that trigger the release of the hormone(s). Extant immunoisol tion devices can be divided Into vascular and extravascular types. Vascular devices generally contain endocrine cells in a chamber surrounding artificial blood vessels, wherein the vessel walls serve both as an immune barrier and as an extension of the circulatory system. The advantage of vascular devices 1s the proximity of the endocrine cells to the blood, which permits adequate access to nutrients and oxygen, and shortens the time for the cells to receive a metabolic stimulus and deliver the hormone response into the circulation. Vascular devices have been unsuccessful because blood clotting could not be prevented on the blood contacting surfaces.
Extravascul r devices contain endocrine cells in a chamber bounded by an Immune barrier membrane. The cells depend on molecules diffusing from adjacent blood vessels through tissues, body fluids and the limiting membrane to supply their nutrients and oxygen, and to sense the concentration of the metabolites that trigger their secretory response. In turn the secreted hormone must diffuse back through the limiting membrane, body tissues and then body fluids to reach the circulatory system.
It follows that the proximity of capillary beds to the semipermeable membrane surface of an Implanted hybrid organ becomes a critical factor in two essential processes: a) whether the endocrine cells receive sufficient oxygen and nutrients to live and function normally, and b) whether the time required for a hormone to be delivered into the circulatory system 1n response to a metabolite change 1s short enough to maintain the normal homeostasis. Design of a device that rigorously mimics the anatomy of natural endocrine organs would require that all cells be positioned within about 10 - 20 micrometers from a blood capillary. For example, islets of Langerhans, the active elements of the endocrine pancreas, average about 150 micrometers in diameter and typically contain 3 - 5,000 cells, and are intensely vascularised such that any cell 1s within 2 cell diameters from a capillary. It follows, that an artificial device containing Intact islets, even when the surface of each islet is closely Invested by a capillary network, does not provide as short a diffusion path as the native islet environment.
Current and previous extravascular devices are thought to have failed because they were not designed to maintain their contained cells sufficiently close to a blood supply. Some designs packed endocrine cells Into a semipermeable tube having an Internal diameter of about 1000 micrometers, which typically caused death or malfunction of those cells nearer the center (more distant from the wall). Other designs placed small 150-200 micrometer clumps of cells inside spherical icrocapsules of 500-800 micrometer diameter. Under such conditions the cells would be far from the surface through which nutrients and metabolites must diffuse and the surface itself would be far from capillary beds.
Extravascular devices are also thought to have failed because their surface initiated a foreign body response by the surrounding tissue. Foreign body responses typically establish a thick and dense fibrous capsule, relatively devoid of blood vessels, around the implanted material. This capsule is thought to seriously retard diffusion of essential nutrients, metabolites and hormones between the device and blood vessels, whether by distance effects or by diffusive resistance of the fibrous capsule. The establishment of this fibrous capsule is causally related to recognition of the foreign implant by macrophages. Stimulated macrophages attempt to digest the surface of the implant by releasing enzymes and toxins at Its surface. It 1s believed to be advantageous for endocrine cells within the Implant to avoid the release of such toxic material in their near vicinity, since they may also be damaged by these agents.
Objects of the invention
It is therefore an object of the invention to provide a device capable of maintaining viable transplanted cells in vivo.
It is a further object of the invention to provide methods of implanting such a device in an animal.
Another object of the invention is to provide methods of treating disorders such as endocrine hormone deficiency states in an animal.
Disclosure of the Invention
The present invention derives from the entirely unexpected finding that living cells may be transplanted into the body and maintained in a functionally viable state in an implantable device according to the invention. The empty device is initially implanted in an animal and left to allow vascularisation of the exterior of the device to occur. A substantial number of viable cells can then be instilled into the device in vivo some time after original implantation of the device, without contamination of the instilled cells. Alternatively the device may be pre-filled with selected viable cells prior to implantation. In either case the cells may later be emptied and the device replenished in situ. The size and integrity of the device allows it to be stably located in the body by a surgeon and be maintained as a recoverable entity.
Thus according to a first embodiment of the invention there 1s provided, an implantable device for keeping transplanted cells alive in vivo, in an animal, comprising: at least one thin walled, hollow, cell closeable, semi-permeable tube having: an Internal diameter appropriate to enable cells within the tube to remain functionally viable; and a large pore hydrophobic membrane wall of appropriate thickness, inducing vascularisation on Implanting thereby permitting nutrient and metabolite transfer between body fluids surrounding the tube and the cells, providing an immune barrier between the cells and the body fluids, and enabling the cells within the tube to remain viable.
The length of the tubes will vary according to their other dimensions such as wall thickness and Internal diameter and also according to the cell type and implantation site within the body. Advantageously, tubes of about 30cm in length are employed.
The device may further comprise means to close the tube, which may be 1n the form of a plug, a cap, a clamp or the like.
In accordance with a second embodiment of the invention there is provided an Implantable device for keeping transplanted cells alive in vivo. In an animal, comprising: a plurality of thin walled, hollow, cell closeable, semi-permeable tubes, each tube having a first and a second end and having: an internal diameter appropriate to enable cells within the tube to remain functionally viable; a large pore hydrophobic membrane wall of appropriate thickness, inducing vascularisation on implanting thereby permitting nutrient and metabolite transfer between body fluids surrounding the tube and the cells, providing an immune barrier between the cells and the body fluids, and enabling the cells within the tube to remain viable; a first support operatively associated with the first ends of said tubes having a closeable entrance; a second support operatively associated with the second ends of said tubes having a closeable exit; the closeable entrance and exit permitting filling of the tubes with selected viable cells.
This form of the invention generally includes means to close the entrance and exit which typically are in the form of first and second closure caps for closing the entrance and exit respectively.
The length and number of the tubes will vary according to the volume of cells required, and other factors such as implantation site and access to the systemic circulation. Generally 3 to 12 tubes are present, the length of the tubes varying between about 3 to about 30 cm. Advantageously 4 or 5 tubes of approximately 10cm in length are employed.
The first and second ends of the tubes may be manifolded so as to communicate with the respective exit and entrance of the device. In one form the entrance and exit may communicate with chambers inside the first and second supports respectively which in turn communicate with the first and second ends of the tubes. Alternatively the tubes are drawn together at the first and second ends to fit within the entrance and exit respectively.
According to a third embodiment of the invention there is provided an Implantable device for keeping transplanted cells alive 1n vivo. 1n an animal, comprising: a plurality of thin walled, hollow, cell closeable, semi-permeable tubes, each tube having a first and a second end and having: an internal diameter appropriate to enable cells within the tube to remain functionally viable; a large pore hydrophobic membrane wall of appropriate thickness, inducing vascularisation on implanting thereby permitting nutrient and metabolite transfer between body fluids surrounding the tube and the cells, providing an immune barrier between the cells and the body fluids, and enabling the cells within the tube to remain viable; the first ends of said tubes communicating with a closeable entrance thereby permitting filling and closure of the tubes; and a support operatively associated with the tubes, for holding at least a portion of the tubes in proximal relationship with each other.
Desirably the components of the device are constructed of, or are coated with, bio-compatible materials such as medical implant grade silicone rubber, polyethylene, polypropylene, cuprophane, polyacrylonitrile or teflon to protect against a foreign body response being mounted against the implant. In the practice of the invention small diameter thin walled hollow-tubes are used to provide shorter diffusion paths between the blood vessels outside the wall and all the cells inside the tube.
The hollow tubes are constructed of a large pore hydrophobic semi- permeable material, which is capable of encapsulating the living cells and of inducing vascularisation to occur about the tube on implanting in the body of any animal. Thus allowing transfer of nutrients and desired compounds or elements required to trigger a desired response by cells, into the cells, and secreted products from the implanted cells. Suitable materials therefore are those having a pore-size generally greater than about 150,000 daltons, (i.e. greater than about 0.005μm), such as appropriate grades of polyethylene, polypropylene or polyacrylonitrile. Goretex (Registered Trade Mark) may also be used. Generally the pore size of the material is 1n the range of about 0.005 μm to 1.0 μm, typically from about 0.05 μm to about 0.6 μm with a pore size of 0.5 μm being desirable.
The lower limit of pore size is related to the dimension of wall thickness 1n that the thinner the wall of the tube, the smaller the pore size can be. Thus, pore sizes less than 150,000 daltons should be achievable with tubes having appropriately thin walls. The upper limit of pore dimensions should be less than those which permit transfer of undesirable contaminants from the blood Into the tube. The bięcompatibility of the material from which the tube Is made is also a factor.
The tubes may be coated with biocompatlbllity-enhancing substances such as fibronectln, laminin, or collagen, and/or be coated with a biodegradable gel containing corticosterolds or other drugs that regulate the formation of flbrotlc tissue around the device.
The internal dimensions of a tube should be no greater than those which permit adequate nutrient transfer between blood capillaries surrounding the tube and cells within the tube so that the cells remain viable in vjvp.
Desirably the wall thickness of the tubes 1s less than about lOOμm, typically from about 45 μm to about 95 μm, and their internal diameter 1s generally from about 20 μm to 1 mm, typically from about 200 μm to about 500 μm.
Generally the support(s) will be in the form of a block of silicone rubber or other suitable material into which the tubes are embedded. Alternatively the support may comprise any appropriate means of holding the tubes together such as a band or ligature or a suitable housing.
Typically the tubes on implantation in the body are closed to the entry of external cells at both ends by means of a cap, plug, or filter, or other suitable closure means, which are removable to allow Instilment of cells.
According to a fourth embodiment of the invention there is provided a method of Implanting a device of the first embodiment 1n an animal comprising: implanting the device in the animal under aseptic conditions, with the tube of the device closed to intrusion by external cells; leaving the device in the animal whereby vascularisation occurs about the tube; filling the tube of the Implanted device under aseptic conditions with selected viable cells ; and closing the tube of the implanted device under aseptic conditions.
According to a fifth embodiment of the invention there is provided a method of Implanting a device of the second or third embodiment in an animal comprising:
Implanting the device in the animal under asceptlc conditions with the tubes closed to intrusion by external cells; leaving the device 1n the animal whereby vascularisation occurs about the tubes; filling the tubes of the implanted device under asceptic conditions with selected viable cells; and closing the tubes under asceptlc conditions.
According to a sixth embodiment of this invention there is provided a method of implanting a device of the first embodiment, in an animal comprising: filling the tube of the device with selected viable cells under aseptic conditions; closing the tube under aseptic conditions; implanting the device in an animal under aseptic conditions; and leaving the implanted device in the animal whereby vascularisation occurs about the tube.
According to a seventh embodiment of the invention there is provided a method of implanting a device of the second or third embodiment in an animal comprising: filling the tubes of the device with selected viable cells under asceptic conditions; closing the tubes under asceptic conditions; implanting the device 1n an animal under asceptic conditions; and leaving the Implanted device in the animal whereby vascularisation occurs about the tubes.
Optionally in a further step the implanted device may be emptied and refilled with cells.
The exit of the device may be adapted to attach to a vacuum pump so that on attachment of the device to the pump a vacuum 1s created inside the tube to facilitate filling of the tube with the selected cells. The pressure inside the tube being controlled by means of a valve connected with the pump.
Typically the device is implanted into highly vascularised host tissue e.g., a surgically-formed pouch (fold) in the omentum or into subcutaneous or other adipose tissue. It is anticipated that the device may also be implanted and/or filled percutaneously under radiological control or other means, or that one end of a tube of the device can be left in communication with the external surface of the animal's body and be filled externally without the need for further invasive procedures.
In practice the steps of implantation and Instilment of cells into the device are carried out under as strict aseptic conditions as possible in order to prevent contamination of the Inside of the tube, and cells contained therein.
To enhance the vascularisation process, the exterior of the hollow tubes may be coated with anglogenic factors, or a biodegradable gel containing anglogenic factors, which are capable of enhancing capillary growth proximate to the external surface of the tubes. Suitable anglogenic factors include slow release heparin, platelet derived growth factor, epidermal growth factor, or cis-hydroxyproline.
According to an eighth embodiment of this invention there is provided a method of providing an animal with transplanted viable cells in vivo which secrete a substance required by the animal, which method comprises:
Implanting a device according to the first embodiment into the animal in accordance with the method of the fourth or sixth embodiment; and wherein the tube Is filled with a quantity of selected viable cells which secrete an effective amount of the substance. According to a ninth embodiment of the invention there is provided a method of providing an animal with transplanted viable cells in vivo which secrete a substance required by the animal, which method comprises: implanting a device according to the second or third embodiment into the animal in accordance with the method of the fifth or seventh embodiment; and wherein the tubes are filled with a quantity of cells which secrete an effective amount of the substance.
In particular the invention provides a method of treating an animal with an endocrine hormone deficiency state, wherein the selected cells are capable of producing at least one appropriate endocrine hormone.
In practice the method of treatment 1s particularly important 1n the therapy of pancreatic deficiency states, such as deficiency of the pancreatic hormone Insulin 1n Diabetes Mellitus. However, the treatment of deficiency states due to the absence or failure of other endocrine organs such as the thyroid, adrenals, pituitary, ovaries or testes, 1s also within the scope of the present invention.
Where a deficiency state involves more than one hormone such as in generalised pituitary failure, 1 is possible to Instill more than one cell type producing the appropriate hormone into an Individual tube or alternatively different cell types may be Inserted into different tubes In the same device or Into separate devices, for implantation in the animal.
The effective number of cells of a selected cell type required will obviously vary according to the particular deficiency state and its severity, and according to the age, sex, weight, general condition, etc of the patient and other variables affecting the clinical state such as intercurrent illnesses. In addition the site of implantation in the body will also Influence the number of cells required, due to factors such as distance from target organ and degree of access to the systemic circulation.
According to a tenth embodiment of this Invention there 1s provided a method of providing an animal with transplanted viable cells in vivo which metabolise a substance in the animal, which method comprises: implanting a device according to the first embodiment into the animal in accordance with the method of the fourth or sixth embodiment; and wherein the tube is filled with a quantity of selected viable cells which metabolise an effective amount of the substance.
According to a eleventh embodiment there is provided a method of providing an animal with transplanted viable cells in vivo which metabolise a substance in the animal, which method comprises: implanting a device according to the second or third embodiment Into the animal in accordance with the method of the fifth or seventh embodiment, and wherein the tubes are filled with a quantity of selected viable cells which metabolise an effective amount of the substance.
Substances to be metabolised Include metabolites or waste products produced by the animal, or externally derived toxins, which the animal Is incapable of dealing with effectively itself, and which would be harmful to the animal 1f allowed to accumulate.
The invention also includes within its scope methods of sensing the presence of, or monitoring the concentration of, compounds or elements within the body of an an animal. Such methods may be used in the diagnosis or monitoring of disease or deficiency states.
In this case the selected cells implanted according to the Invention, are capable of responding to or reacting with an appropriate compound, element, or condition and of producing a detectable entity.
The compound or element may be a hormone, an enzyme, an enzyme cofactor, an antigen, an antibody, a metabolite, a toxin, a vitamin, a protein, a trace element, and a gas, for example. The detectable entity may be a metabolic product detectable in the blood or urine, or an alteration 1n celV membrane potential, detected by suitable sensing means. The signal may be quantitatively measured where the compound or element 1s being monitored over a given time period.
The methods of the Invention are applicable to all animals, and are especially useful 1n the treatment of humans and mammals generally.
The cells used 1n the practice of the Invention are typically taken from an animal of the same species as the recipient, or of a different species, or the cells may be obtained from special cell lines or from tissue culture. Alternatively it would be possible to use autologous cells, which have been taken from the recipient animal and stored under appropriate conditions, and/or cultured in v1trot before reimplantatlon according to the invention.
The device according to the invention overcomes many of the enumerated problems of prior art devices. Previous literature on both icrocapsule and hollow fibre systems, seems to point to the use of fibres of inappropriate wall thickness, internal diameter, and pore size. In particular, materials with large pore size were avoided since it was thought prior to the present invention that such materials would allow the entry of antibodies into the interior of the device resulting in destruction of the cells. The inventors have found a number of advantages in using a large pore size membrane, namely: that large pore size membranes are easier to fabricate, they allow easier passage of large molecular weight nutrients (e.g. large fatty adds) from the blood stream to the Implanted cells and also they may be less effected by clogging with protein and other body substances.
Previous hollow fibre devices have used pre-filled single fibres which did not provide a large enough mass of cells to be really effective. Furthermore, in the past, thick walled, large Internal diameter hollow fibres have been used for encapsulation. These have the disadvantage of providing very long nutrient diffusion paths to the implanted cells, particularly cells at the centre of the fibres, which often died or at least were not healthy functioning cells.
Thus the present device is the first device that both contains enough viable cells to be effective and more significantly allows a mechanism for Instilling cells Into the tubes some time after implantation and after vascularised tissue has grown around the tubes.
In addition the shape of the present device allows for firm anchorage both by the surgeon being able to suture the semi-rigid ends to host tissue as well as through the device obtaining firm anchorage through tissue ingrowth around and between the multiple hollow fibres. This has not been achieved with previous devices which have just used isolated hollow fibres. Also, the single Integrated entity structure allows easy location and removal of the device 1f there are problems. This is much harder with single hollow fibres and impossible with implanted islet mlcrocapsule systems.
The device of the invention has the following additional advantages:
1. A tube of the device acts as an immune barrier that allows free passage of essential nutrients, oxygen and the secreted hormones, but is impermeable to active elements of the immune system.
2. The thickness of a tube of the device in effect minimizes the distance between any one cell contained inside the barrier and adjacent blood capillaries outside the barrier.
3. The device is capable of causing blood capillaries to form and remain near the surface of the immune barrier prior to, or after, instilment of cells inside the device. 4. The device avoids establishment of a thick, dense fibrous capsule relatively devoid of blood vessels at the surface of the implant.
Brief description of the drawing
A preferred form of the present invention will now be described by way of example with reference to the accompanying drawings, wherein:
Figure 1 illustrates a schematic top plan view of a device of the invention.
Figure 2 illustrates a schematic top plan view of an alternative device of the invention.
Best mode for carrying out the Invention
The Figures illustrate preferred embodiments of the device according to the invention. Although 6 tubes are shown for the purpose of Illustration the number of tubes can be varied as required as may the length of the tubes.
Device 10 consists of multiple hollow tubes 1 having first ends 2 and second ends 3. First ends 2 of hollow tubes 1 are operatively associated with first support 4. First support 4, has a closeable entrance 5 for filling tubes 1 with cells, Into which first ends 2 of tubes 1 are Inserted. Entrance 5 1s reduced 1n size to fit a standard Record lock syringe. Second ends 3 of tubes 1 are operatively associated with second support 7. Second support 7 has a closeable exit 8, into which second ends 3 of tubes 1 are inserted, permitting the filling of tubes 1 with cells via entrance 5. Hollow tubes 1 are composed of a polyethylene or polypropylene semi-permeable membrane material that elicits minimal foreign body response in the host and resists build-up of flbrotlc tissue on the exterior surface, with a pore size of about 0.5μm, wall thickness of about 90μm and internal diameter about 330μm. First support 4 and second support 7 may be composed of any appropriate potting substance such as epoxy resin, which may then be coated with a more biocompatible substance such as medical implant grade silicone rubber to render it more inert. Entrance 5 and exit 8 at each extremity of device 10 have removable caps 9, caps 9 being constructed of or coated with a biocompatible substance such as silicone rubber. Between first ends 2, and second ends 3, hollow tubes 1 are left free so that vascular and connective tissue can grow around and between them to provide nutrients to, and allow passage of secreted products from, the encapsulated cells. Implantation of device 10 is a two-stage procedure carried out under strict aseptic conditions. The first stage is to implant empty device 10, which may or may not be pretreated, externally and/or internally with biocompatibility-enhanclng factors such as fibronectin, and/or externally with angiogenic factors such as slow release heparin, Into subcutaneous tissue of the recipient. When vascular and connective tissue has grown around device 10, the second stage is performed. This involves carefully removing both of caps 9 from entrance 5 and exit 8, of device 10 and aseptlcally loading hollow tubes 1 of device 10 with selected cells via entrance 5, by means of a standard Record lock syringe. To facilitate filling of hollow tubes 1, exit 8 may be connected to vacuum pump 11 by means of conduit 12. On operation of vacuum pump 11 a vacuum 1s created in hollow tubes 1 prior to loading with selected cells via entrance 5. The pressure 1n hollow tubes 1 is controlled by valve 13 connected to vacuum pump 11. Caps 9 are then reinserted either as a friction fit or with the aid of a sealant or glue.
In preparation for instilment in device 10, the selected cells are Isolated from suitable tissue by enzymatic digestion and purification procedures known In the art, to obtain as pure a cell preparation as possible, free from unwanted cells and other contaminants.
In implantation experiments in mice, the above device has been shown to elicit a minimal fibrotic response and not to discourage the growth of vascular tissue close to the tubes. A tube internal diameter of 330μm and wall thickness of 90μm has proved satisfactory to maintain viability of implanted pancreatic islet cells in mice for up to 60 days. However it is anticipated that a thinner walled hollow tube should be better.
Alternatively, implantation of device 10 is carried out in a single step under strict aseptic conditions. This involves carefully removing both of caps 9 from entrance 5 and exit 8, of device 10 and aseptically loading hollow tubes 1 of device 10 with selected cells via entrance 5, by means of a standard Record lock syringe. In preparation for instilment in device 10, the selected cells are isolated from suitable tissue by enzymatic digestion and purification procedures known 1n the art, to obtain as pure a cell preparation as possible, free from unwanted cells and other contaminants. To facilitate filling of hollow tubes 1, exit 8 may be connected to vacuum pump 11 by means of conduit 12. On operation of vacuum pump 11 a vacuum is created in hollow tubes 1 prior to loading with selected cells via entrance 5. The pressure 1n hollow tubes 1 is controlled by valve 13 connected to vacuum pump 11. Caps 9 are then reinserted either as a friction fit or with the aid of a sealant or glue. The filled device 10, which may or may not be pretreated, externally and/or internally with biocompatibility-enhanclng factors such as fibronectin, and/or externally with angiogenic factors such as slow release heparin, is then aseptlcally implanted into subcutaneous tissue of the recipient. Vascular and connective tissue then grow around device 10, to supply the cells with essential nutrients.
The device of the present Invention will find wide application in the medical and veterinary fields.
Although the foregoing description is oriented towards a biohybrld artificial pancreas containing pancreatic islet cells, it will be obvious that the device and method can be applied to any transplanted cell types which need to be implanted extra-vascularly but in close communication with the circulatory system.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|WO1984001287A1 *||9 Sep 1983||12 Apr 1984||Theodore E Spielberg||Encapsulated genetically programmed living organisms producing therapeutic substances|
|WO1989004655A1 *||16 Nov 1988||1 Jun 1989||Brown University Research Foundation||In vivo delivery of neurotransmitters by implanted, encapsulated cells|
|AU6174986A *||Title not available|
|EP0147939A2 *||14 Nov 1984||10 Jul 1985||JOHNSON & JOHNSON||Implantable module for gylcemia regulation|
|EP0161640A2 *||10 May 1985||21 Nov 1985||Merck & Co., Inc.||Encapsulated mouse cells transformed with avian retrovirus-bovine growth hormone DNA, and a method of administering BGH in vivo|
|GB2185408A *||Title not available|
|US3625198 *||9 May 1969||7 Dec 1971||Charles H Sparks||Die and holder for implanting in a living body to grow tissue grafts|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|WO1992009311A1 *||27 Nov 1991||11 Jun 1992||Bioricerche S.N.C. Di Carla Zedda||Biocompatible synthetic double-wall vascular prosthesis containing hormone-secreting cells|
|WO1993000127A1 *||25 Jun 1992||7 Jan 1993||Brown University Research Foundation||Neural implant system|
|WO1993002635A1 *||9 Jul 1992||18 Feb 1993||Baxter International Inc.||Foramenous implant|
|WO1993021902A1 *||23 Apr 1993||11 Nov 1993||Somatix Therapy Corporation||Biocompatible, therapeutic, implantable device|
|WO1994001166A1 *||12 Jul 1993||20 Jan 1994||Brown University Research Foundation||Implanting devices for release of neuroinhibitory compounds|
|WO1994018906A1 *||18 Feb 1994||1 Sep 1994||New England Deaconess Hospital, Corp.||Implantable artificial organ|
|WO1998051236A1 *||13 May 1998||19 Nov 1998||Cedars-Sinai Medical Center||Artificial gut|
|WO2002056956A1 *||10 Dec 2001||25 Jul 2002||Vladimir Kalina||Apparatus for inducing an immune response in cancer therapy|
|WO2008079997A2 *||20 Dec 2007||3 Jul 2008||Medtronic, Inc.||Implantable device, angiogenesis mechanism and methods|
|WO2008079997A3 *||20 Dec 2007||11 Dec 2008||Micahel Theodore Beck||Implantable device, angiogenesis mechanism and methods|
|WO2009125332A1 *||6 Apr 2009||15 Oct 2009||Peter Bromley||New and safe procedure for immunization against infectious diseases agents|
|WO2012075184A2||30 Nov 2011||7 Jun 2012||Neurotech Usa, Inc.||Cell lines that secrete anti-angiogenic antibody-scaffolds and soluble receptors and uses thereof|
|EP0746343A1 *||11 Oct 1994||11 Dec 1996||The Regents Of The University Of Michigan||METHODS AND COMPOSITIONS OF A BIOARTIFICIAL KIDNEY SUITABLE FOR USE $i(IN VIVO) OR $i(EX VIVO)|
|EP0746343A4 *||11 Oct 1994||3 Dec 1997||Univ Michigan||METHODS AND COMPOSITIONS OF A BIOARTIFICIAL KIDNEY SUITABLE FOR USE -i(IN VIVO) OR -i(EX VIVO)|
|EP0758553A2 *||25 Jun 1992||19 Feb 1997||Brown University Research Foundation||Composition comprising encapsulated cells|
|EP0758553A3 *||25 Jun 1992||23 Apr 1997||Univ Brown Res Found||Composition comprising encapsulated cells|
|EP1639972A1||22 Jul 2002||29 Mar 2006||Anecova SA||Intrauterine device, method of making such a device and method for putting active elements within the uterine cavity|
|EP1781205A2 *||20 Jul 2005||9 May 2007||University of Miami||Hybrid device for cell therapies|
|EP1781205A4 *||20 Jul 2005||30 Mar 2011||Univ Miami||Hybrid device for cell therapies|
|EP1983053A2||20 Jul 1995||22 Oct 2008||Neurotech USA, Inc.||Cell distribution control for cells within bioartifical organs|
|US5314471 *||1 Apr 1992||24 May 1994||Baxter International Inc.||Tissue inplant systems and methods for sustaining viable high cell densities within a host|
|US5344454 *||1 Apr 1992||6 Sep 1994||Baxter International Inc.||Closed porous chambers for implanting tissue in a host|
|US5487739 *||2 Jun 1995||30 Jan 1996||Brown University Research Foundation||Implantable therapy systems and methods|
|US5554148 *||26 May 1995||10 Sep 1996||Brown University Research Foundation||Renewable neural implant device and method|
|US5593440 *||23 May 1994||14 Jan 1997||Baxter International Inc.||Tissue implant systems and methods for sustaining viable high cell densities within a host|
|US5681740 *||5 Jun 1995||28 Oct 1997||Cytotherapeutics, Inc.||Apparatus and method for storage and transporation of bioartificial organs|
|US5713888 *||5 Jun 1995||3 Feb 1998||Baxter International, Inc.||Tissue implant systems|
|US5741330 *||7 Jun 1995||21 Apr 1998||Baxter International, Inc.||Close vascularization implant material|
|US5773286 *||24 May 1995||30 Jun 1998||Cytotherapeutics, Inc.||Inner supported biocompatible cell capsules|
|US5776747 *||23 May 1995||7 Jul 1998||Cytotherapeutics, Inc.||Method for controlling the distribution of cells within a bioartificial organ using polycthylene oxide-poly (dimethylsiloxane) copolymer|
|US5782912 *||17 Mar 1994||21 Jul 1998||Baxter International, Inc.||Close vascularization implant material|
|US5786216 *||10 Nov 1994||28 Jul 1998||Cytotherapeutics, Inc.||Inner-supported, biocompatible cell capsules|
|US5795790 *||23 May 1995||18 Aug 1998||Cytotherapeutics, Inc.||Method for controlling proliferation and differentiation of cells encapsulated within bioartificial organs|
|US5798113 *||24 May 1995||25 Aug 1998||Brown University Research Foundation||Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products|
|US5800529 *||7 Jun 1995||1 Sep 1998||Baxter International, Inc.||Close vascularization implant material|
|US5800828 *||10 Jan 1994||1 Sep 1998||Brown University Research Foundation||Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products|
|US5800829 *||24 May 1995||1 Sep 1998||Brown University Research Foundation||Methods for coextruding immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core|
|US5833979 *||23 May 1995||10 Nov 1998||Cytotherapeutics, Inc.||Methods and compositions of growth control for cells encapsulated within bioartificial organs|
|US5834001 *||24 May 1995||10 Nov 1998||Brown University Research Foundation||Methods for making immunoisolatory implantable vehicles with a biocompatiable jacket and a biocompatible matrix core|
|US5837234 *||7 Jun 1995||17 Nov 1998||Cytotherapeutics, Inc.||Bioartificial organ containing cells encapsulated in a permselective polyether suflfone membrane|
|US5840576 *||23 May 1995||24 Nov 1998||Cytotherapeutics, Inc.||Methods and compositions of growth control for cells encapsulated within bioartificial organs|
|US5843431 *||9 May 1995||1 Dec 1998||Cytotherapeutics, Inc.||Controlling proliferation of cells before and after encapsulation in a bioartificial organ by gene transformation|
|US5853717 *||23 May 1995||29 Dec 1998||Cytotherapeutics, Inc.||Methods and compositions of growth control for cells encapsulated within bioartificial organs|
|US5858747 *||23 May 1995||12 Jan 1999||Cytotherapeutics, Inc.||Control of cell growth in a bioartificial organ with extracellular matrix coated microcarriers|
|US5869077 *||24 May 1995||9 Feb 1999||Brown University Research Foundation||Methods for treating diabetes by delivering insulin from biocompatible cell-containing devices|
|US5871472 *||13 Jul 1992||16 Feb 1999||Brown University Research Foundation||Planting devices for the focal release of neuroinhibitory compounds|
|US5871767 *||24 May 1995||16 Feb 1999||Brown University Research Foundation||Methods for treatment or prevention of neurodegenerative conditions using immunoisolatory implantable vehicles with a biocompatible jacket and a biocompatible matrix core|
|US5874099 *||24 May 1995||23 Feb 1999||Brown University Research Foundation||Methods for making immunoisolatary implantable vehicles with a biocompatible jacket and a biocompatible matrix core|
|US5882354 *||7 Jun 1995||16 Mar 1999||Baxter International Inc.||Close vascularization implant material|
|US5902745 *||21 May 1997||11 May 1999||Gore Hybrid Technologies, Inc.||Cell encapsulation device|
|US5935849 *||20 Jul 1994||10 Aug 1999||Cytotherapeutics, Inc.||Methods and compositions of growth control for cells encapsulated within bioartificial organs|
|US5980889 *||5 Aug 1997||9 Nov 1999||Gore Hybrid Technologies, Inc.||Cell encapsulating device containing a cell displacing core for maintaining cell viability|
|US5993406 *||14 May 1997||30 Nov 1999||Cedars-Sinai Medical Center||Artificial gut|
|US6054142 *||1 Aug 1996||25 Apr 2000||Cyto Therapeutics, Inc.||Biocompatible devices with foam scaffolds|
|US6083523 *||4 Sep 1998||4 Jul 2000||Brown University Research Foundation||Implantable biocompatable immunoisolatory vehicle for delivery of selected therapeutic products|
|US6179826||29 Oct 1996||30 Jan 2001||Brown University Research Foundation||Implantable therapy systems and methods|
|US6231879||31 Jul 1997||15 May 2001||Neurotech S.A.||Biocompatible devices with foam scaffolds|
|US6322804||2 May 2000||27 Nov 2001||Neurotech S.A.||Implantable biocompatible immunoisolatory vehicle for the delivery of selected therapeutic products|
|US6392118||23 May 1995||21 May 2002||Neurotech S.A.||Mx-1 conditionally immortalized cells|
|US6410320||31 Jan 2000||25 Jun 2002||The University Of Michigan||Method and compositions for isolation and growth of kidney tubule stem cells, in vitro kidney tubulogenesis and ex vivo construction of renal tubules|
|US6426214||8 Nov 1999||30 Jul 2002||Gore Enterprise Holdings, Inc.||Cell encapsulating device containing a cell displacing core for maintaining cell viability|
|US6495364 *||7 Mar 2001||17 Dec 2002||Neurotech, S.A.||Mx-1 conditionally immortalized cells|
|US6653131||30 Aug 2001||25 Nov 2003||The Regents Of The University Of Michigan||Method of treating systemic inflammatory response syndrome|
|US6942879||11 Dec 2002||13 Sep 2005||The Regents Of The University Of Michigan||Bioartificial filtration device for filtering blood to mimic kidney function|
|US6960351||21 Jul 2003||1 Nov 2005||Brown University Research Foundation||Implantable biocompatible immunoisolatory vehicle for delivery of selected therapeutic products|
|US7160716||9 May 2003||9 Jan 2007||Vladimir Kalina||Device for inducing an immune response in cancer therapy|
|US7332330||11 Sep 2001||19 Feb 2008||Renamed Biologics, Inc.||Device for maintaining vascularization near an implant|
|US7442546||25 Feb 2003||28 Oct 2008||The Regents Of The University Of Michigan||Method of modulating inflammatory response|
|US7615567||14 Nov 2005||10 Nov 2009||Research Triangle Institute||Compounds and methods for promoting smoking cessation|
|US7820195||18 Dec 2006||26 Oct 2010||Neurotech Usa, Inc.||Micronized device for the delivery of biologically active molecules and methods of use thereof|
|US9149427||30 Nov 2011||6 Oct 2015||Neurotech Usa, Inc.||Cell lines that secrete anti-angiogenic antibody-scaffolds and soluble receptors and uses thereof|
|US9265814||18 Dec 2006||23 Feb 2016||Neurotech Usa, Inc.||Micronized device for the delivery of biologically active molecules and methods of use thereof|
|US20100196439 *||20 Dec 2007||5 Aug 2010||Medtronic, Inc.||Angiogenesis Mechanism and Method, and Implantable Device|
|International Classification||A61M31/00, A61K9/00, A61F2/02|
|Cooperative Classification||A61F2/022, A61K9/0092, A61M31/002, A61K9/0024|
|European Classification||A61K9/00Z4, A61M31/00D, A61F2/02B, A61K9/00M5D|
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