DEVICE FOR CELL TRANSPLANTATION

专利摘要:
method and devices for cell transplantation. the present invention relates to devices and methods for transplanting cells into a host body. the cell comprises a porous structure that allows incorporation of vascular and connective tissue, a plug or plug system configured for installation within a porous structure, and a seal configured to enclose a proximal opening in the porous structure. the device may further comprise a cell delivery device for delivering cells within a porous structure. the method for transplanting cells comprises a two-step process. the device is incubated in the host body to form a vascularized collagen matrix around a plug positioned within a porous structure. the plug is then withdrawn from the porous structure, and cells are distributed within the vascularized space created within a porous structure.
公开号:BR112012004385B1
申请号:R112012004385-4
申请日:2010-08-27
公开日:2021-09-14
发明作者:Craig Hasilo；Justin Leushner；Daniel Nicholas Haworth；Simon Shohet；Philip Michael Toleikis；Delfina Maria Mazzuca Siroen
申请人:Sernova Corporation；
IPC主号:

专利说明:

[001] This application claims priority to U.S. provisional application no. 61/238,011, filed August 28, 2009, which is incorporated herein by reference in its entirety.
[002] This description is related to the field of cell therapy and, more specifically, to methods and devices for transplanting cells into a host body.
[003] Recent discoveries in the field of cell therapy present new opportunities for the use of cell transplantation in disease areas with unmet and critical medical needs. Currently, there are no fully effective drug therapies for many congenital and acquired disease conditions, such as diabetes or Parkinson's disease, which are caused by the loss of or damage to cells that produce biomolecules necessary for the control of physiological functions. Cell therapy holds the promise of replacing damaged or lost cells with donor cells or stem cells to improve impaired physiological functions. For example, islet transplantation of Langerhans cells would provide a means of restoring carbohydrate control in patients with insulin-dependent diabetes. Similarly, transplantation of dopaminergic neurons or neural stem cells has emerged as a promising cell-based therapy for Parkinson's disease.
[004] The main limiting factors in the application of cell therapy are the difficulty in transplanting cells into host tissue and ensuring that the transplanted cells continue to function without producing an immune response or causing other harmful side effects in the host. Attempts have been made to deliver therapeutic cells directly into the host body, for example, into the vascular system or by implantation into an organ or tissue. However, with direct cell transplantation, the patient is required to remain on immunosuppressive therapy throughout life and immunosuppressive drugs can cause toxicity to the host and to the implanted cells. Additionally, direct exposure of cells to blood can lead to an immediate blood-mediated inflammatory reaction (IBMIR) that initiates a coagulation cascade and can destroy a significant part of the transplanted cells. Additionally, the cells can become lodged in microvessels and cause blockage and thrombosis of the vessels, which can result in a loss of function of the transplanted cells and damage to local tissue.
[005] Another therapeutic approach is the delivery of cells with the use of devices that provide a biologically suitable environment for cells to reside in the host body. The biggest challenges with this approach are the unsatisfactory incorporation of blood vessels into the device to nourish the cells and maintain an optimal environment within the device for the long-term survival of the cells. In the absence of an immediately vascularized environment, transplanted cells are unable to obtain enough oxygen or easily eliminate waste, and can quickly die or become damaged through the effects of ischemia or hypoxia. Additionally, even in situations where some vessels develop initially, the vessels may not be maintained. Furthermore, the body's natural inflammatory cascade can also result in the death of or damage to cells. Some other difficulties encountered with this approach include excessive scarring and/or isolation of the device, incompatibility of the device material with the biological environment, difficulties in obtaining images of the device and the implant environment, inadequate dimensions of the device that affect the biological function of the cells, inability to load the proper number of cells for prolonged therapeutic effect, and difficulty in removing the device when it needs replacement. Additionally, the configuration of the device may not be receptive to the external contours of the body, which may result in abnormal bulges of the device, making the device unacceptable to the patient from an aesthetic perspective.
[006] Thus, there still remains a need to find an effective technique for successful transplantation of therapeutic cells. The present description provides methods and devices for the delivery and maintenance of cells in vivo for an extended period of time, while alleviating many of the problems associated with existing device-based cell therapy approaches.
[007] In one aspect of the present description, a device for transplanting cells into a host body is provided. The device comprises a porous structure comprising at least one chamber having a proximal end and a distal end, and at least one removable plug configured to be positioned within the at least one chamber. The porous structure comprises a mesh that has pores sized to facilitate the growth of vascular and connective tissue within the at least one chamber. In some embodiments, the porous structure comprises a polypropylene mesh.
[008] Another embodiment of the present description consists of a device for implanting cells in a host body, wherein the device comprises a porous structure comprising one or more chambers having a proximal end and a distal end, and an opening in either or both the proximal and distal ends. The porous structure comprises pores sized to facilitate the growth of vascular and connective tissue within the one or more chambers. The device also comprises one or more dual plug systems comprising an external plug configured to be positioned within the one or more chambers, and an internal plug configured to be positioned within the external plug. Additionally, the device comprises at least one seal configured to enclose the plug system in the chamber and enclose the opening at either or both the proximal and distal ends of the chamber.
[009] In another aspect of the present description, a method of transplanting cells into a host body is provided. The method comprises the steps of implanting a device to hold cells in the host body, wherein the device comprises a porous structure comprising at least one chamber having a proximal end and a distal end. The porous structure comprises a mesh that has pores sized to facilitate the growth of vascular and connective tissue within the at least one chamber. In some embodiments, the porous structure comprises a polypropylene mesh. The device further comprises at least one plug configured to be positioned within the at least one chamber, and the at least one chamber comprises an opening at either or both of the proximal and distal ends. The method comprises the steps of closing the opening at either or both the proximal and distal ends of the chamber after implantation of the device. The method further comprises keeping the device in the host body until the porous structure is infiltrated by vascular and connective tissues, accessing the device through a surgical incision, reopening either or both the proximal and distal ends of the chamber, extracting the plug of the chamber to create a space within the porous structure that is encapsulated in the vascularized collagen matrix, distribute a cell preparation within the vascularized space, and reclose an opening at either or both the proximal and distal ends of the chamber.
[0010] In another alternative embodiment, the method of implanting cells in a host body provides an implantable device to maintain cells in the host body, wherein the implantable device comprises a porous structure that has pores sized to facilitate vascular tissue growth and connective within the porous structure, at least one double plug system configured to be positioned within the porous structure. The porous structure of the implantable device comprises at least one chamber that has an opening at either or both the proximal and distal ends of the chamber. The device comprises a seal for enclosing the opening in either or both of the proximal and distal ends of the at least one chamber. The at least one plug system of the implantable device comprises an external plug configured to be positioned within the at least one chamber and an internal plug configured to be positioned within the external plug. The method further comprises the steps of implanting the device in the host body, maintaining the device in the host body until the device is infiltrated by vascular and connective tissues, and providing a cell delivery device comprising at least one infusion tube of cells loaded with a cell preparation, wherein the cell infusion tube is configured to be positioned within the outer plug of the at least one plug system. Additionally, the method comprises accessing the implanted device through a surgical incision and opening the seal at either or both the proximal and distal ends of the device, removing the internal plug from the plug system, inserting the cell infusion tube into the external plug, withdraw the external plug from at least one chamber and simultaneously infuse the chamber with the cell preparation and reseal the seal. It is to be understood that both the aforementioned general description and the following detailed description are only explanatory and exemplary and are not restrictive of the invention as claimed.
[0011] Another aspect of the description provides a cell transplant device comprising a porous structure that has pores sized to facilitate the growth of vascular and connective tissues within the porous structure comprising at least one chamber and preferably between two to twelve chambers, in which the porous structure is coated with a biodegradable and biocompatible material designed to temporarily fill the pores of the structure. In certain embodiments, the porous structure comprises a polypropylene mesh. Suitable biodegradable and biocompatible materials include, for example, collagen, fibronectin, extracellular matrix proteins and cytoskeletal membrane proteins. The description also provides a method for transplanting cells into a host body which comprises implanting a transplant device comprising a porous structure which has pores sized to facilitate the growth of vascular and connective tissues within the porous structure which comprises at least one chamber and preferably between two to twelve chambers, in which the porous structure is coated with a biodegradable and biocompatible material that temporarily fills the pores of the structure, and in which the at least one chamber is filled with the cells to be transplanted and the chamber is fenced.
[0012] The accompanying drawings, which are incorporated in and constitute a part of this descriptive report, together with the description, illustrate the methods and embodiments of the invention. Brief description of the drawings
[0013] Figures 1A-1E illustrate various embodiments of a single chamber cell transplant device in accordance with the present description;
[0014] Figure 1F illustrates an embodiment of a multi-chambered cell transplant device in accordance with the present description;
[0015] Figures 2A-2D illustrate various mesh configurations that can be used for forming a cell transplant device in accordance with the present description;
[0016] Figure 3A illustrates a cell transplant device according to an embodiment of the present description;
[0017] Figure 3B illustrates the components of the cell transplant device of Figure 1A;
[0018] Figure 4 illustrates a porous structure of a cell transplant device according to an embodiment of the present description;
[0019] Figure 5A illustrates a seal of a cell transplant device according to an embodiment of the present description;
[0020] Figure 5B is a cross-sectional view of the seal shown in Figure 3A;
[0021] Figure 6A illustrates multiple external plugs of a two-part plug system of a cell transplant device according to an embodiment of the present description;
[0022] Figure 6B is a cross-sectional view of an external plug illustrated in Figure 5A;
[0023] Figure 6C is a cross-sectional view of a plug system and a single porous structure assembly prior to implantation into a host body;
[0024] Figure 6D is a cross-sectional view of the assembly illustrated in Figure 4C after incubation in a host body;
[0025] Figure 6E is a cross-sectional view of a porous structure implanted in a host body after removal of the plug system;
[0026] Figure 7 illustrates multiple internal plugs of a two-part plug system of a cell transplant device according to an embodiment of the present description;
[0027] Figure 8 illustrates a seal for enclosing cells within a vascularized chamber of a cell transplant device according to an embodiment of the present description;
[0028] Figure 9A illustrates a device for delivering cells to a cell transplant device, in accordance with an embodiment of the present description;
[0029] Figure 9B shows a cell infusion mechanism of the delivery device illustrated in Figure 8A;
[0030] Figure 9C shows the additional steps of the cell infusion mechanism of the delivery device illustrated in Figures 8A-8B;
[0031] Figure 10 is a flowchart showing the steps of a cell transplantation method in accordance with the present description;
[0032] Figures 11A-11D show a schematic overview of certain steps of a cell infusion procedure in accordance with the present description;
[0033] Figure 12A shows line graphs of blood glucose measurements after intraperitoneal implantation of cell transplant devices as described in example 1;
[0034] Figure 12B shows line graphs of blood glucose measurements after subcutaneous implantation of cell transplant devices as described in example 1;
[0035] Figure 12C shows line graphs of IVGTT responses in Lewis rats transplanted with islet cells at 40 days after transplantation, 80 days after transplantation, and after device removal (at 110 days after transplantation), as shown in Figure 12C. described in example 1;
[0036] Figure 12D shows line graphs of insulin levels in response to glucose challenge in Lewis rats transplanted with islet cells as described in example 1;
[0037] Figure 13A demonstrates histological staining of insulin within the chamber of an implanted device as described in example 2;
[0038] Figure 13B demonstrates the histological staining of vascularization (microvasculature) within the chamber of an implanted device, as described in example 2;
[0039] Figure 14 is a table of mean collagen thickness and total blood vessel/cm2 calculated for four cell transplantation devices, according to the modalities of the present description, as described in example 3;
[0040] Figure 15A demonstrates tissue incorporation into a cell transplant device at 2, 4 and 8 weeks after implantation, as described in example 3;
[0041] Figure 15B shows blood vessel formation at various edges of an implanted device prior to cell transplantation, as described in example 3;
[0042] Figure 16 shows bar graphs of insulin levels produced by mature and immature islets, as described in example 4;
[0043] Figure 17A demonstrates histological staining of insulin and microvasculature within the chamber of an implanted device as described in example 4;
[0044] Figure 17B demonstrates histological staining of microvasculature within the chamber of an implanted device after cell transplantation, as described in example 4;
[0045] Figure 18 shows line graphs of blood glucose levels after islet autograft transplantation as described in example 4;
[0046] Figure 19A shows line graphs of absolute blood glucose levels in response to glucose challenge in Yorkshire-Landrace pigs transplanted with islet cells as described in example 4;
[0047] Figure 19B shows bar graphs of area under the curve (AUC) for blood glucose levels in response to glucose challenge in Yorkshire-Landrace pigs transplanted with islet cells as described in example 4;
Figure 19C shows line graphs of successive changes in C-peptide levels in response to glucose challenge in Yorkshire-Landrace pigs transplanted with islet cells as described in example 4. Description of exemplifying modalities
[0049] Reference will now be made in detail to the modalities of this description, examples of which are illustrated in the attached drawings. Wherever possible, the same reference numerals will be used throughout the drawings to refer to like or like parts. Throughout this description, the terms cell infusion and cell transplantation are used interchangeably.
[0050] A cell transplant device for containing therapeutic cells in vivo is provided. In an exemplary embodiment, the cell transplant device comprises at least one porous structure comprising a chamber therein and having an opening in either or both the proximal and distal ends of the structure, and at least one plug configured to be housed in the chamber. The opening at one or both ends of the chamber is sized to allow insertion and withdrawal of the chamber plug. In one embodiment, the at least one porous structure is tubular in shape and the at least one plug is cylindrical and extends along a lumen of the at least one porous structure. In some embodiments, the porous structure is open only at the proximal end. In such an embodiment, the distal end of the tubular porous structure comprises a surface with a flat or round bottom. In another embodiment, the edges at the distal end of the porous structure are tapered and contact each other to seal the distal end.
[0051] In another exemplary embodiment, the cell transplant device comprises a porous structure comprising one or more chambers having a proximal end and a distal end. The one or more chambers comprise an opening at the proximal end. The device also comprises one or more plug systems which comprise an external plug configured to be positioned within the one or more chambers, and an internal plug configured to be positioned within the external plug. Additionally, the device comprises at least one seal configured to enclose the plug system within the chamber and seal the opening at the proximal end of the chamber.
[0052] The porous structure is formed of a biocompatible material that should only produce a mild inflammatory response in the body. Mild inflammatory components stimulate angiogenesis and promote the incorporation of a vascularized collagen matrix into the device, but do not result in significant inflammation around the device. An example of such a biocompatible material is polypropylene. In exemplary embodiments, the porous structure comprises a woven polypropylene mesh that has sufficient stiffness to facilitate fabrication of the device. Polypropylene mesh is also selected to allow microvessels to enter the device and be maintained as healthy and robust vessels, which is critical for the survival and normal functioning of therapeutic cells infused into the device.
[0053] By inciting the regulated growth of vascularized tissue in the device, the porous structure prevents encapsulation of the device with scar tissue. Tissues that grow internally also stabilize the implant and prevent inadvertent movement of the device in situ. Additionally, in some modalities, the porous structure is coated with biological or non-biological agents to stimulate tissue incorporation and angiogenesis, eg, growth factors. The device can be coated by dipping into a polymer-drug formulation or other known technique for applying the coating to the device. Examples of biological or non-biological agents to stimulate tissue uptake and angiogenesis include, but are not limited to: VEGF (vascular endothelial growth factor), PDGF (blood platelet-derived growth factor), FGF-1 (factor of fibroblast growth), NRP-1 (neuropilin-1), Ang-1, Ang2 (angiopoetin 1,2), TGF-β, endoglin, MCP-1, αvβ3, αvβ5, CD-31, VE-cadherin, ephrin , plasminogen activators, angiogenin, Del-1, aFGF (acidic fibroblast growth factor), vFGF (basic fibroblast growth factor), follistatin, G-CSF (granulocyte colony stimulating factor), HGF (growth factor of hepatocyte), Il-8 (interleukin -8), Leptin, midkine, placental growth factor, PD-ECGF (blood platelet-derived endothelial growth factor), PTN (pleiotrophin), progranulin, proliferin, TGF-α and TNF-α.
[0054] In some embodiments, the outer surface of the porous structure is roughened to encourage tissue ingress. In certain embodiments, the porous structure includes various drug-eluting polymer coatings. In other embodiments, the porous structure can be coated with a biodegradable or non-biodegradable polymer without a drug. The structure can be partially or completely coated with the polymer. Representative polymers that can be used for drug coating and/or elution include, but are not limited to: methacrylate polymers, polyethyleneimine and dextran sulfate, poly(vinylsiloxane)ecopolymer,polyethyleneimine, phosphorylcholine, poly(ethyl methacrylate ), polyurethane, poly(ethylene glycol), poly(lactic-glycolic acid), hydroxyapatite, poly(lactic acid), polyhydroxyvalerte and copolymers, polyhydroxybutyrate and copolymers, polycaprolactone, polydiaxanone, polyanhydrides, polycyanoacrylates, poly(amino acids), poly(orthoesters) ), polyesters, collagen, gelatin, cellulose polymers, chitosans and alginates, or combinations thereof. Additional examples that can be used to coat the structure include, but are not limited to: collagen, fibronectin, extracellular matrix proteins, vinculin, agar and agarose. It should be understood that various blends of the polymers can be used.
[0055] With regard to drug elution, in some illustrative embodiments, the porous structure includes an antibiotic coating to minimize infections. Antibiotics include, but are not limited to: ampicillin, tetracycline, nafcillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, vancomycin, kanamycin, gentamicin, streptomycin, clindamycin, trimethoprim-sulfamethoxazole, linezolide, teicoplanin, eryfloxacillin, ciprocin amoxicillin, sulfonamides, nalidixic acid, norfloxacin, ciprofloxacin, ofloxacin, sparfloxacin, lomefloxacin, fleroxacin, pefloxacin, amifloxacin, 5-fluorouracil, chloramphenicol, polymyxin, mitomycin, chloroquine, novobiocin, nitroimazoline. In another embodiment, the porous structure includes a bactericidal agent. Representative bactericidal agents include, but are not limited to: benzalkonium chloride, chlorhexidine gluconate, sorbic acid and salt thereof, thimerosal, chlorobutanol, phenethyl alcohol, and p-hydroxybenzoate.
[0056] In some other embodiments, parts of the cell transplant device are coated with antifibrotic drugs to inhibit the encapsulation of fibrous tissue. Representative antifibrotic agents include, but are not limited to: paclitaxel, everolimus, tacrolimus, rapamycin, halofuginone hydrobromide, combretastatin and analogues and derivatives thereof (such as, combretastatin A-1, A-2, A-3, A -4, A-5, A-6, B-1, B-2, B-3, B-4, D-1, D-2, and combretastatin A-4 phosphate (Oxygen)), docetaxel, vinblastine , vincristine, vincristine sulfate, vindesine and vinorelbine, camptothecin topotecan, irinotecan, etoposide or teniposide anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A3, and plicamycin, methotrexate, trimethreptreptyrum , tomudex, pteropterin, and derivatives and analogues thereof. In some embodiments, the cell transplant device can also include polymethyl methacrylate or bone cement or other types of cyanoacrylates.
[0057] In some modalities, the porous structure is formed from a material that allows obtaining images of the implanted device with the use, for example, of MRIs, fMRIs, CT scans, X-rays, ultrasound, PET scans, etc. In such an embodiment, the porous structure comprises a polymer mesh (e.g., polypropylene, polytetrafluoroethylene (PTFE), polyurethane, polyesters, and silk meshes, etc.) that is immunologically compatible and allows imaging of the neovascularized tissue. In another embodiment, the porous structure comprises a combination of materials. In such an embodiment, the porous structure comprises interwoven polypropylene and silk filaments.
[0058] The pore size of the framework material is selected to facilitate tissue incorporation and vascularization within the porous framework chamber. In some embodiments, pore sizes can be in a range from about 50 nm to 5 mm. In an exemplary embodiment, the porous structure comprises a woven polypropylene mesh 0.53 mm in pore diameter.
[0059] In some embodiments, pore size is selected to exclude immune cells or immune agents from penetration into the implanted device. In some other embodiments, pore size need not necessarily exclude immune cells or agents from infiltrating the device. This would be the case, for example, when the device is used to transplant a combination of cells, which include immunoprotective cells, (eg Sertoli cells, mensenchymal stem cells, etc.) which can provide immune protection for the cells co-transplanted. This would also be the case, for example, when the device is used to transplant syngeneic cells or cells derived from the patient receiving the transplant.
[0060] The cell transplant device plug or plug system is configured to fit the chamber within the porous structure. The plug or plug system may comprise a non-porous material (eg, polytetrafluoroethylene (PTFE), polypropylene, etc.) that inhibits the ingrowth of biological tissue within the plug or plug system. The plug or plug system can consist of a hollow or solid structure. However, if a hollow plug is used, care could be taken to avoid infiltration of collagen or any other biological material into the lumen of the plug when the device is implanted into host tissue. The plug system is discussed in further detail below.
[0061] In some embodiments, the proximal end of the plug or plug system is connected to a seal. In such an embodiment, the seal is configured to close the proximal opening of the chamber when the plug or plug system is fully inserted into the chamber of the porous structure. The seal is structured to hold the plug or plug system in place within the porous structure. In another embodiment, the seal is separated from the plug or plug system. In yet another modality, the seal is connected to the porous structure. Additionally, in some exemplary embodiments, the proximal end of the chamber is closed using surgical sutures and/or vascular staples without using a separate seal.
[0062] When implanted in a host body, the porous structure of the device encourages the ingrowth of vascular and connective tissue, such that the plug or plug system housed within the structure becomes encapsulated in a matrix of vascularized tissue. When the plug or plug system is removed from the porous structure, a neovascularized chamber is created within the device, which can then be used to maintain a cell preparation in the host body.
[0063] The sizes of the porous structure and the plug or plug system are selected to provide an optimal surface area to volume ratio to maintain the cells in vivo and to ensure the long-term survival of the cells within the neovascularized chamber. Similarly, the number of chambers in the transplant device is determined based on the volume and/or number of cells that are to be transplanted. In some embodiments, the total volume of the cell transplant device is adjusted by increasing or decreasing the number of chambers, while maintaining an optimal surface area to volume ratio of each individual chamber. In other modalities, the length of the chambers is adjusted to change the total volume. Alternatively, in various embodiments, the cell transplant device comprises a fixed number of chambers, but only a selected number of chambers are infused with the cells, depending on the total volume requirement of the device. In other modalities the length of the chambers is adjusted, as well as the number of chambers, to change the total volume required.
[0064] The presented cell transplant device can be implanted subcutaneously or intraperitoneally in a host body, which includes the omentum or other suitable location. Alternatively, the disclosed cell implant device may be implanted partially intraperitoneally into a host body, which includes the omentum or other suitable location and extends into the subcutaneous environment. In one embodiment, cells can be loaded into the portion of the device that extends into the subcutaneous environment, while the rest of the device is in the intraperitoneal environment. In another embodiment, the cell transplant device can be implanted in the brain, spinal cord area or any other organ, as required, to produce a therapeutic effect from the transplanted cells. In most cases, the host consists of a human, but it can consist of another mammalian or non-mammalian animal. The cell transplant procedure is a two-step process comprising a device implant step followed by a cell infusion step (cell transplant). The cell infusion step is implanted after an in vivo incubation period during which the implanted device is infiltrated by a matrix of vascularized collagen. In one modality, the incubation period is approximately thirty days, which allows adequate time for angiogenesis and collagen infiltration of the porous structure. The incubation period can be prolonged or shortened, depending on the degree of neovascularization and tissue formation (collagen with cells) needed or desired. For example, transplant devices can vascularize at different rates depending on the material, dimensions or coatings of the device, such as, for example, antibiotic coatings, growth factors, etc. Transplant devices also vascularize at different rates in different hosts, or when located in different body tissues within the same host. It is within the power of a person skilled in the art to determine the appropriate incubation period. For example, imaging studies can be performed prior to cell distribution to ensure that adequate vascular and/or connective tissue is deposited around and through the walls of the porous structure during the incubation period. For the cell infusion step, the implant site is accessed through a surgical incision, and the plug or plug system is removed from the porous structure to create a pocket lined with collagen and blood vessel within the structure. The cell preparation is then distributed into the vascularized pocket and the porous structure is resealed. In another embodiment, the cell transplant procedure is a one-step process, so that the device is placed and the cells implanted at the same time. In this circumstance, cells can be placed in a matrix so that they do not leak through the pores of the device, or alternatively, the device can be coated with a degradable polymer to prevent cells from leaking from the device during the collagen and angiogenesis.
[0065] In some embodiments, the cells to be transplanted can be combined with a biocompatible viscous solution formulation or biodegradable polymer before being loaded into the chamber of any of the transplant devices described herein. This biodegradable polymer will protect the cells until the device is completely vascularized by the host body. These formulations can be placed in the chambers before or after placement of the device in a host, but before a matrix of collagen and vascular structures has formed in the device. Cells combined with a biocompatible viscous solution formulation or biodegradable polymer will be particularly useful in devices designed to be loaded with cells prior to implantation of the device into the host body. Representative polymers that can be used as a biodegradable formulation, in conjunction with cells, include, but are not limited to: polyethyleneimine and dextran sulfate, poly(vinylsiloxane)ecopolymer and polyethyleneimine, phosphorylcholine, poly(ethylene glycol) ), poly(lactic-glycolic acid), poly(lactic acid), polyhydroxyvalerte and copolymers, polyhydroxybutyrate and copolymers, polydiaxanone, polyanhydrides, poly(amino acids), poly(orthoesters), polyesters, collagen, gelatin, cellulose polymers, chitosans, alginates, fibronectin, extracellular matrix proteins, vinculin, agar, agarose, hyaluronic acid, matrigel and combinations thereof.
[0066] It should be noted that cells can be placed in the device; however, cells can also be encapsulated. The following are by way of example and not by way of limitation. Examples of polymeric cell encapsulation systems include alginate encapsulation, polysaccharide hydrogels, chitosan, calcium or barium alginate, a layered matrix of altinate and polylysine, photopolymerizable poly(ethylene glycol) polymer to encapsulate individual cells or clusters of cells, polyacrylates including hydroxyethyl methacrylate, methyl methacrylate, silicon capsules, silicon nanocapsules, and polymembrane (acrylonitrile-co-vinyl chloride).
[0067] Figures 1A-1E illustrate several exemplary embodiments of a cell transplant device 1. Device 1 comprises a polymer mesh (e.g., a polypropylene mesh, a PTFE mesh, or any other suitable material) that forms a porous chamber 2 to contain cells in a host body. In some embodiments, device 1 may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more porous chambers 2. The availability of multiple chambers allows the use of any number or combination of chambers depending on the volume of cell preparation required, which is within the knowledge of persons skilled in the art to determine.
[0068] As shown in Figure 1A, device 1 comprises a proximal end 3, a distal end 4, and a plug 5 housed in porous chamber 2. In one embodiment, porous chamber 2 is tubular in shape, and plug 5 is cylindrical and extends along a lumen of the porous chamber 2. In another exemplary embodiment, the porous chamber 2 comprises an opening at the proximal end 3. The opening at the proximal end 3 is sized to allow insertion and withdrawal of the plug 5 from of the porous chamber 2. In such a modality, the opening at the proximal end 3 is sealed with the use of surgical sutures and/or vascular staples during the incubation of the device and after the infusion of cells into the device. As would be understood by one of ordinary skill in the art, any other surgical sealing element, e.g. microvascular fasteners, clips, etc., can be used to seal the opening at the proximal end 3. In another embodiment, device 1 comprises a flap non-porous 6 at the proximal end 3 as illustrated in Figure 1B. In such an embodiment, the flap 6 is made of silicone. The flap 6 can be sealed using surgical sutures, staples or any other suitable sealing mechanism during the incubation of the device and after the infusion of cells into the device. In an exemplary embodiment, the distal end 4 of the device 1 comprises a surface with a flat or round bottom. In another embodiment, the device 1 comprises an opening at the distal end 4, which can be sealed using surgical sutures, staples or any other surgical sealing element, during incubation of the device and after cell infusion. In yet another exemplary embodiment, as shown in Figure 1C, the distal end 4 comprises a non-porous portion 7, which prevents tissue ingrowth at the distal end of the device and facilitates retraction of the plug 5 from the device prior to cell infusion.
[0069] In some embodiments, as illustrated in Figure 1D, the proximal end of the plug 5 is connected to a seal 8. In such an embodiment, the seal 8 is configured to close the opening in the proximal end 3 when the plug 5 is inserted into the chamber 5. Seal 8 is structured to hold plug 5 in place within the porous chamber. In another embodiment, plug 5 is longer than porous chamber 2 and acts as a seal at both the proximal end 3 and the distal end 4 of the device, as shown in Figure 1E. The edges of the porous chamber 2 around the plug 5 are sealed using surgical sutures and/or surgical glue. After removal of plug 5 prior to cell infusion, openings at proximal end 3 and distal end 4 can be sealed using surgical sutures, vascular staples, or any other suitable sealing mechanism, as would be understood by an element versed in the technique.
[0070] In some exemplary embodiments, the device 1 comprises multiple porous chambers 2 that are laterally connected to each other. In such an embodiment, the multiple porous chambers 2 are formed, for example, by ultrasonic welding of the bottom and top surfaces of a porous material along a line substantially parallel to a longitudinal geometric axis of the device. Figure 1F illustrates a cell transplant device that has eight porous chambers 2. Each chamber 2 houses a plug 5 during the incubation phase of the device. Plugs 5 are removed from chambers 2 before infusing cells into chambers. In one embodiment, device 1 comprises eight porous chambers and has an overall length of 50 mm and a width of 45 mm. Each porous chamber 2 has an internal diameter no larger than 3.5 mm and houses a plug 5 which has a length of approximately 40 mm and a diameter of 2.5 mm. In such an embodiment, the plug 5 is formed from a non-porous biocompatible material, for example, polytetrafluoroethylene (PTFE).
Exemplary cell transplant device embodiments of the present description are formed from medical grade polypropylene mesh, e.g., knitted polypropylene mesh (PPKM) purchased from SURGICALMESH™, Brookfield, Connecticut, USA. In the illustrative embodiments, the meshes are formed from monofilaments that lie in a diameter range from 0.1 mm to 0.3 mm, and mesh pore sizes that fall in a range from 0.3 mm to 1mm, from 0.4mm to 0.85mm and 0.5mm to 0.6mm. Figures 2A-2D illustrate several exemplary mesh configurations that can be used to form cell transplant devices. Figure 2A illustrates a polypropylene mesh (PPKM601) that has a pore size of 0.5 mm and a monofilament thickness of 0.3 mm; Figure 2B shows a polypropylene mesh (PPKM602) having a pore size of 0.53mm and monofilament thickness of 0.18mm; Figure 2C shows a polypropylene mesh (PPKM404) having a pore size of 0.53mm and monofilament thickness of 0.13mm; and Figure 2D shows a polypropylene mesh (PPKM604) having a pore size of 0.85 mm and monofilament thickness of 0.2 mm.
[0072] Figure 3A illustrates another exemplary embodiment of a cell transplant device 10. Figure 3B illustrates the components of the cell transplant device 10. The device 10 comprises a porous structure 12, a primary seal 14, at least one plug system comprising an outer plug 16 and an inner plug 18, and a secondary seal 20.
[0073] As illustrated in Figure 4, the porous structure 12 of the cell transplant device 10 may comprise a polymer mesh (e.g., a polypropylene mesh, a PTFE mesh, or any other suitable material) that forms a or more porous chambers 22 to contain cells in a host body. In some embodiments, porous structure 12 may comprise one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more porous chambers 22. The availability of multiple chambers allows the use of any number or combination of chambers, depending on the volume of cell preparation required, which is within the knowledge and skill of those skilled in the art to determine.
[0074] Porous chambers 22 can be created, for example, by joining the bottom and top surfaces of the porous structure 12 along a line substantially parallel to a longitudinal geometric axis of the device. The multiple porous chambers 22 can have different or equal surface areas and cross-sectional dimensions. In one embodiment, the multiple porous chambers 22 are formed by ultrasonic welding the polymer mesh from a proximal end 24 to a distal end 26 of the frame. The bottom and top surfaces of the porous structure 12 are continuous through one or more porous chambers 22, interrupted only by ultrasound weld lines 28, which extend substantially parallel to a longitudinal geometric axis of the porous structure 12. The surfaces The bottom and top of porous structure 12 can be lightly notched on each weld line, which provides additional surface area for vascularization and provides physical stability for device 10 within a host. In one embodiment, the edges at the distal end 26 are tapered and ultrasonically welded together to seal the distal end 26.
[0075] Referring to Figure 3B, the primary seal 14 is configured to seal to one or more porous chambers 22 during device incubation and after cell infusion. The primary seal 14 comprises an inert, biocompatible polymeric film or any other suitable material. In one embodiment, the primary seal 14 is ultrasonically welded at the side edges to the tapered proximal end 31, as illustrated in Figures 5A and 5B. Distal end 32 of primary seal 14 is secured to proximal end 24 of porous structure 12. In one embodiment, distal end 32 is ultrasonically welded to proximal end 24 of porous structure 12.
[0076] In various embodiments, the primary seal 14 comprises a resealable latch 34, which aids in maintaining the at least one external plug 16 within a porous chamber 22 during the incubation period. Latch 34 also prevents leakage of cell preparation during the cell infusion process. Any suitable resealable latch mechanism can be used as latch 34. In one embodiment, latch 34 comprises interlocking crest and groove features which form a tight seal when pressed together and unlock when the bottom and top surfaces of the seal 14 are pulled apart at the proximal end 31. After the device incubation period, access to the outer plug 16 is achieved by cutting the proximal end 31 of the primary seal 14 and opening the resealable latch 34. After preparation of the cell is distributed in the porous structure 12, the latch 34 is resealed and the proximal end 31 is resealed using, for example, surgical sutures, staples or bioadhesives, or hermetic seals.
[0077] The number of plug systems can correspond to the number of porous chambers 22 in the cell transplant device 10. The outer plug 16 is housed within the porous chamber 22 during the incubation period of the device. In some embodiments, the length of the outer plug 16 is approximately equal to the length of the respective porous chamber 22. As illustrated in Figure 6A, in one embodiment, the multiple outer plugs 16 are connected at a proximal end 40 using a common spine. 42. The common spine 42 may include one or more slots 43 to facilitate removal of the outer plugs 16 from the porous chambers 22. For example, the slots 43 may allow the common spine 42 to be secured using forceps.
[0078] In some embodiments, the outer plug 16 has a hollow core 45 that houses an inner plug 18. As shown in Figure 6B, in one embodiment, the hollow core 45 is constricted with one or more inner protrusions 47 along its length. the inner surface of the plug. Inner protuberances 47 provide an air space between outer plug 16 and inner plug 18 which allows trapped air bubbles to escape during dispensing of the cell preparation, which is described in further detail below. The air space also prevents the formation of a vacuum during the removal of the inner plug 18 and thus maintains the integrity of the newly formed vascularized collagen matrix in and around the porous chamber. Thus, in some aspects, the plug system comprising outer plug 16 and inner plug 18 can facilitate cell delivery to cell transplant device 10 and can also increase the chances of cell survival within a matrix. of intact collagen.
[0079] In some embodiments, the proximal end 40 and distal end 41 of the outer plug 16 comprise sealing mechanisms, for example, inner grooves or tapered surfaces, to ensure an effective seal with the inner plug 18. As shown in Figure 7 , the proximal end 50 and distal end 51 of the inner plug 18 may include complementary sealing mechanisms 53 to prevent infiltration of the collagen matrix into the hollow core 45 during the incubation period. For example, in one embodiment, the sealing mechanism 53 comprises a groove extending around the periphery of the proximal and distal ends of the inner plug 18, and the outer plug 16 comprises a ridge around the periphery of its proximal and distal ends. . In such an embodiment, the crest on the outer plug 16 and the groove on the inner plug 18 interlock when the inner plug 18 is inserted into the hollow core 45 of the outer plug 16 in order to form a complete seal between the inner and outer plugs and prevent permeation of any biological material in the hollow core 45. Additionally, in such embodiments, if the outer plug 16 comprises one or more inner protuberances 47, the height of the ridges at the proximal and distal ends of the outer plug 16 may be greater than the height of the internal lumps 47.
[0080] Figures 6C and 6D illustrate cross-sectional views of the porous chamber 22 and plug assembly 16, 18, according to an embodiment of the present description. Figure 6C is a cross-sectional view of the assembly before deployment into a host body, and Figure 6D illustrates the cross-sectional view of the assembly after incubation into a host body. The inner diameter of the porous chamber 22 and the outer diameter of the outer plug 16 are selected to maintain a space 46 around the periphery of the outer plug 16 for tissue formation. For example, in an illustrative embodiment, the inner diameter of porous chamber 22 is not greater than 4.5 mm and the outer diameter of plug 16 is not greater than 3.5 mm. In another embodiment, the inner diameter of porous chamber 22 is not greater than 3.5 mm and the outer diameter of plug 16 is not greater than 2.5 mm. These modalities provide, for example, approximately 0.5 mm of space around the external plug 16 for the formation of a vascularized collagen matrix. The space around the outer plug 16 also provides sufficient environment for the insertion and withdrawal of the outer plug into and out of the porous chamber.
[0081] When the cell transplant device 10 is implanted in a host body, the vascular and connective tissues penetrate through the porous chamber 22 into space 46 and form a matrix of vascularized tissue 48 around the outer plug 16. The plug 16 prevents penetration of tissue matrix 48 further into the lumen of porous chamber 22. When inner plug 18 and outer plug 16 are collected from porous chamber 22, a pocket 49 is created within porous chamber 22, which can be used to contain cells in the host body. Pouch 49 is enveloped in vascularized tissue matrix 48, as shown in Figure 6E.
[0082] The number of inner plugs 18 can match the number of outer plugs 16. Inner plug 18 is housed within hollow core 45 of outer plug 16 during the device incubation phase. In one embodiment, multiple inner plugs 18 are connected at a proximal end 50 using a common spine 52. In some embodiments, the common spine 52 comprises a clamp feature 54 to aid handling of inner plug 18 during extraction of the external plug 16.
[0083] The secondary seal 20, as illustrated in Figure 8, is used to contain the cell preparation in the porous chambers when the primary seal 14 is re-closed after dispensing a cell preparation into the cell transplant device 10. The secondary seal 20 is positioned at the proximal end 24 of the porous structure 12 after the cell preparation is completely distributed in the porous chamber 22 and the outer plug 16 is withdrawn from the device 10. In some embodiments, the secondary seal 20 comprises grooves 60 to facilitate insertion into device 10 using forceps.
[0084] In another aspect of the present description, a device and method for delivering cells in a cell transplant device is presented and will be explained with reference to the cell transplant device 10. Figure 9A illustrates the various components of a cell delivery device 70. The cell delivery device 70 comprises at least one cell infusion tube 71, connector cap 72 having a clamp feature 73 and a connector spacer 74.
[0085] The cell infusion tube 71 may comprise polymeric tubing (eg, polyethylene tubing) or any other material suitable for distributing the cell preparation in the porous chamber 22 of the device 10 during the cell infusion step. The number of cell infusion tubes in the delivery system can correspond to the number of porous chambers 22.
[0086] The connector spacer 74 is positioned at the distal end of the cell infusion tube 71 and couples or interfaces with the proximal end 40 of the outer plug 16 during the cell dispensing process. The connector spacer 74 includes one or more through holes through which the cell infusion tube 71 is inserted, as shown in Figure 9A. The through holes are configured to provide a lead interference fit with the cell infusion tube 71. The fitting is adapted to hold the cell infusion tube 71 in place during the cell infusion process. Additionally, in certain embodiments, connector spacer 74 comprises passages 76 for expelling air from air spaces in outer plug 16 created by inner bulge 47 during the cell dispensing process, as described further below. In one embodiment, the outer plug 16 comprises a center 78 at the proximal end 40. In such an embodiment, the connector spacer 74 is inserted into the center 78 during the cell infusion process to secure the delivery device 70 to the transplant device. cell 10.
[0087] The proximal end of the cell infusion tube 71 comprises the connector cap 72. As the tube is inserted into the outer plug 16, the connector cap 72 advances distally towards the connector spacer 74. When the tube 71 is fully inserted into outer plug 16, connector cap 72 fits over connector spacer 74 and/or center 78, and clip feature 73 connects with outer plug 16/or center 78 along common spine 42 , as shown in Figure 9C. This enables the connector cap 72, connector spacer 74 and outer plug 16 to be collected as a single unit as the cell preparation is infused into the porous chamber 22.
[0088] In yet another aspect of the present description, a method for cell transplantation is presented and will be explained with reference to cell transplantation device 10 and cell delivery device 70. The cell transplantation method is not limited to the modalities of the device presented herein and can be used with any cell transplantation and cell delivery device.
[0089] Figure 10 is a flowchart illustrating the steps of an exemplary cell transplant procedure. The cell transplant procedure generally consists of a two-step process comprising the device implant step followed by a cell infusion step. Device 10 is implanted in the host body prior to cell delivery to allow adequate time for collagen and blood vessels to infiltrate the porous structure 12. In some embodiments, device 10 is sterilized using ethylene oxide prior to implantation. . Device 10 may be packaged in a self-sealing package or any other sterilizable package along with a sterility indicator strip for an ethylene oxide based sterilization process. In some other embodiments, gamma radiation or dry heat autoclaving is used to sterilize the device prior to implantation. The type of sterilization method used depends on the frame material, as dry heat autoclave is known to deform certain polymeric materials (eg, polypropylene) due to the low heat deflection temperature. Gamma radiation, at a sterilizing dose of 6 M-Rad, can successfully sterilize cell implantation devices; however, gamma radiation can shorten the life of devices made from polypropylene.
Device 10 can be implanted either subcutaneously or intraperitoneally. For example, for subcutaneous implantation of the device in the host body, an incision is made through the dermis and epidermis, followed by careful blind dissection of the connective tissue and adipose tissue, creating a subcutaneous pocket caudal to the incision line (step 810). Once an adequate space is created (approximately the dimensions of the device), device 10 is implanted into the subcutaneous pocket and the incision is sutured (step 820). Alternatively, device 10 can be implanted into the peritoneal cavity through an abdominal incision. The device implant steps (steps 810 and 820) are followed by a device incubation period (step 830), during which a matrix of vascularized collagen is deposited in and around the porous structure 12.
[0091] After the incubation period, device 10 is accessed through a second surgical incision. For example, the proximal end 31 of the primary seal 12 can be cut in situ to open the device 10 (step 840). Inner plug 18 is then extracted from outer plug 16 and discarded (step 850). During the internal plug removal process, air movement is facilitated by internal bulges 47 which prevent the formation of a vacuum within the device which can cause any newly formed blood vessels in and around the device to rupture. . Removal of the inner plug 18 disengages the proximal end 50 and distal end 51 of the inner plug 18 from the proximal end 40 and distal end 41 of the outer plug 16. A cell preparation is then delivered to the device 10 using the device. of cell distribution 70.
[0092] Figures 11A-11D show a schematic overview of certain steps of an exemplary cell infusion procedure and will be explained with reference to the flowchart shown in Figure 10. For the administration of cells in device 10, the infusion tube of cells 71 of delivery device 70 are loaded with cell preparation 79 and tube is inserted into hollow core 45 of outer plug 16 as shown in Figure 11A (step 860). Connector spacer 74 engages with proximal end 41 and/or center 78 of outer plug 16. As tube 71 is advanced into outer plug, air is expelled through inner protuberances 47 of outer plug 16 and passages 76 of the outer plug. connector spacer 74. When tube 71 is advanced all the way into outer plug 16, connector cap 72 interfaces with connector spacer 74. Clamp 73 of connector cap 72 is then connected to center 78 of external plug 16 (step 870). In this case, the outer plug 16, the connector cap 72 and the connector spacer 74 are then slightly retracted from the porous chamber 22 as a single unit to create a space at the distal end of the porous chamber 22 (step 875 ). In some embodiments, outer plug 16 can be slightly retracted from porous chamber 22 before connecting dispensing device 70 with outer plug 16. In other words, step 875 can be performed before step 870. is applied to a syringe connected to the cell infusion tube 71 to deliver the cells into the porous chamber 22 (step 880). Care is taken to ensure that tube 71 remains in porous chamber 22 as pressure is applied to deliver the cell preparation.
[0093] In one embodiment, the outer plug 16 is retracted approximately 5 mm before cell infusion is initiated, as illustrated in Figure 11B. As pressure (P) is applied to the syringe connected to the cell infusion tube 71, the cell preparation 79 infuses into the porous chamber 22. As the cell preparation is dispensed into the porous chamber 22, the outer plug 16 and cell infusion tube 71 are removed from the device as shown in Figures 11C and 11D (step 885). When the device is completely filled with the cell preparation 79, the cell infusion is stopped and the cell infusion tube 71 is completely withdrawn from the device 10 (step 890). Porous chamber 22 is then evaluated for remaining capacity for cell preparation and any remaining cell preparation can be carefully added to the end of the porous chamber. The cell preparation is contained within the porous chamber 22 by placing the secondary seal 20 at the proximal end 40 of the porous chamber 22, followed by closing the resealable latch 34 of the primary seal 12, and securing the proximal end 31 of the primary seal 12 with surgical sutures or staples or other suitable sealing mechanisms (step 895). Finally, the surgical incision is closed using surgical sutures, staples or tissue adhesives, thus completing the cell transplant procedure.
[0094] The devices and methods for cell transplantation presented can be used to transplant any therapeutic cells, or a combination of cells, into a host body, to provide therapeutic biological material to the host for the treatment of a condition of illness. The cells can consist of allogeneic, xenogeneic, or syngeneic donor cells, patient-derived cells, which include stem cells, cord blood cells, and embryonic stem cells. Stem cells can be differentiated into the appropriate therapeutic cells. Cells can be immature, partially or fully differentiated, and mature cells when placed in the device. Cells can also consist of genetically engineered cells or cell lines. In one aspect, an embodiment in accordance with the present disclosure is used for islet of Langerhans cell transplantation to provide a means for the regulation of blood glucose in the host body. In another aspect, one modality of a cell transplant device is used for islet cell co-transplantation from Langerhans and Sertoli, where the Sertoli cells provide immunological protection to the islet cells in the host body. The immune protection provided by Sertoli cells in a host body has previously been disclosed, for example, in U.S. patent no. 5,725,854, which is incorporated herein by reference in its entirety. Consequently, this description also considers methods of treating various diseases by transplanting therapeutic amounts of cells to individuals in need of such treatment, using one modality of a cell transplant device, as presented here.
[0095] The density of transplanted therapeutic cells, or combinations of cells, is determined based on the body weight of the host and the therapeutic effects of the cells. As noted earlier, the dimensions of the cell transplant device and the number of porous chambers to be used (in a multi-chamber device) are determined based on the number of cells required, the extent of vascularization achievable during the incubation period of device and the diffusion characteristics of nutrients and cellular products into and out of the implanted device. Examples
[0096] The following examples are provided to better explain the various modalities and should in no way be interpreted as limiting the scope of this description. The cell transplant devices used in these examples are formed from polypropylene meshes and comprise a single PTFE plug in each porous chamber of the devices. 1. Cell transplantation devices containing islet cells are able to restore normoglycemia in Lewis rats
[0097] Cell transplantation devices were used to implant syngeneic islet cells into Lewis rats to restore normoglycemia. The glucose response of the implanted cells was compared with the glucose response of islet cells administered directly into the portal veins of the rats. Lewis rats were divided into three study groups, with nine rats in each group. In the first and second study groups, the devices were implanted in intraperitoneal and subcutaneous cavities, respectively. In the third group, islet cells were administered directly into the portal veins.
[0098] The implanted devices were incubated in Lewis rats for at least one month to allow vascular ingrowth. Diabetes was then chemically induced in rats by injection of streptozotocin. Rats were considered diabetic if three successive blood glucose readings were at least 18.0 mM. Isolated Lewis rat islet cells (10,000 IEQ/kg weight) were then infused into the implanted devices or directly into the portal veins of diabetic rats. Insulin pellets were removed at 14 days after islet transplantation (denoted by the filled rectangle above the graphs in Figures 11A and 11B). Blood glucose levels in rats were monitored for a period of 100 days. Within 100 days of the transplant, the devices were removed to confirm that the transplanted islands were responsible for reversing diabetes.
[0099] Figures 12A and 12B show glucose normalization results for rats receiving intraperitoneal (omental chamber) and subcutaneous cell transplantation devices, respectively. Successful cell transplantation resulted in normalization of blood glucose levels (glucose reading less than 8.0 mM) as denoted by the solid dashes. Transplants that did not achieve normoglycemia are denoted by dotted dashes. The results indicate that the normal glycemic level was maintained in a statistically significant number of diabetic rats that received the islet cells. After removal of the implanted devices within 100 days of transplantation, rats that previously demonstrated normal blood glucose levels returned to hyperglycemic levels, indicating that the devices contained fully functioning grafts that were responsible for achieving normoglycemia prior to device removal. The rate at which blood glucose concentrations reached non-diabetic levels was statistically different between study groups (p<0.0001, t-test).
[00100] Figure 12C shows IVGTT (intravenous glucose tolerance test) responses in Lewis rats transplanted with islet cells. IVGTTs were performed at 40 days and 80 days after transplantation The glucose response of rats with intraperitoneal and subcutaneous transplants were compared against the glucose response of rats that received the intra-portal islet cells. IVGTTs were performed on three rats in each study category. At 40 days and 80 days after transplantation, blood glucose levels in islet cell transplanted mice dropped below 8.0 mM within 50 minutes of receiving a glucose challenge, as shown in Figure 12C. Cell transplant devices were removed within 100 days. Blood glucose levels did not drop when a glucose bolus was administered within 110 days, indicating that the transplanted islet cells were responsible for the normoglycemia achieved in diabetic rats prior to removal of the implanted devices.
[00101] Figure 12D shows insulin responses in Lewis rats transplanted with islet cells. Insulin levels were tested using enzyme-linked immunosorbent assays (ELISA). The analysis was performed in triplicate. Results indicate a significant difference in blood insulin levels under glucose challenge (p<0.005, t-test). As shown in Figure 12D, insulin levels in rats that received the transplanted devices correlated well with insulin levels in rats that received the intra-portal islet cells. 2. Histological Detection of Insulin and Vascularization Within the Porous Chambers of Cell Transplant Devices
[00102] After removal of the implanted devices within 100 days, insulin was detected in the devices using specific primary antibodies against insulin. Figure 13A shows the result of staining insulin within the porous chamber of a subcutaneously implanted device. Insulin detection within the chamber indicated that the islet cells contained in the devices were viable and functional within 100 days of transplantation.
[00103] Histological evaluation of the implanted devices was also performed to verify the formation of vascular tissue in the collagen matrix deposited in and around the devices. Immunohistochemical staining for fact VIII associated with endothelial cells indicated well-formed vascular structures deeply embedded in connective tissue, as shown in Figure 13B (dark structure indicates endothelium; cell nuclei are indicated by arrows). Histological evaluation also demonstrated the penetration of neovascularized tissue towards the nucleus of cell transplantation devices. 3. Estimation of Angiogenesis and Collagen Deposition in Cell Transplant Devices
[00104] To determine the appropriate length of the implantation phase (time between device implantation and islet engraftment), cell transplantation devices were implanted subcutaneously in eight week old Yorkshire-Landrace pigs for 2, 4 and 8 weeks. After implantation during the respective time period, the devices were explanted and analyzed to determine the level of angiogenesis and collagen deposition. a) Crude estimate of angiogenesis and collagen deposition
[00105] Photographs were taken of both the ventral and dorsal surfaces of the explanted devices for gross analysis of tissue and blood vessel formation. A 1 cm x 1 cm grid was placed over the photographs to quantify microvessel and tissue (celled collagen) formation. Each 1 cm2 box within the grid was scored on vessel formation, allowing a total vessel/cm2 to be calculated for the entire surface of the explanted devices. The mean thickness over the medial and lateral perimeters of the devices was measured to assess the amount of collagen deposition. Figure 14 shows a table of mean collagen thickness and total blood vessel/cm2 calculated for four devices formed using different porous materials (meshes). Sufficient tissue and microvessel formation was observed for all four mesh types within 2 weeks of implantation. The results also indicate that the amount of time required for microvessel formation and collagen deposition may vary depending on the device material (porosity, surface roughness, etc. of the meshes). b) Histological analysis of angiogenesis and collagen deposition
[00106] Angiogenesis was determined by staining endothelial cells with hematoxylin and eosin (H&E) stain (Figure 15A) and von Willebrand factor (Figure 15B). Figure 15A demonstrates tissue incorporation into the devices at 2, 4, and 8 weeks after implantation. Figure 15B shows blood vessel formation at various edges of a device prior to cell transplantation. Estimation of tissue incorporation into the devices showed that the devices incorporate collagen and microvessels at all time points measured before islet transplantation. 4. Estimation of Cell Transplant Devices Receiving Porcine Autograft Islets
[00107] Eight week old Yorkshire-Landrace pigs were implanted with the cell transplant devices for four and eight weeks. To make the animals diabetic, a 90% pancreatectomy was performed followed by an intravenous dose of 150 mg/kg of streptozotocin one day after surgery. Islets were isolated from the pancreas before performing pancreatectomy. Immature islet grafts were transplanted into the animals five days after graft isolation and pancreatectomy to allow sufficient time for recovery and confirmation of diabetes.
[00108] The insulin-producing capabilities of immature islet cells were tested prior to transplantation. As shown in Figure 16, immature islets produced about 10% of the insulin normally expected from adult islets. This fact combined with the low islet transplant number of about 3 to 5K IEQ/Kg (5 to 10% insulin-producing islets commonly used in intraportal transplants) provides rigorous testing of cell transplant devices. Currently in clinical islet transplant therapy, the infusion of an adequate amount of β-cell mass has presented an obstacle to the treatment of insulin-dependent diabetes. Insulin dependence is usually achieved when a sufficient amount of islet cells are delivered, approximately 10,000 IEQ/kg body weight of the recipient. To provide this amount of islet cells, today's islet transplant protocols require more than one donor pancreas per recipient, creating pressure on an already limited donor supply. Therefore, if glycemic control can be achieved using only 5 to 10% of the islets currently used in intra-portal transplants, the number of diabetic patients who could receive islet transplant therapy would significantly increase.
[00109] Histological analyzes of the explanted devices were performed to test the long-term survival and function of transplanted islets. Islet graft function was also monitored using bimonthly intravenous glucose tolerance tests and two-week blood glucose tolerance tests (IVGTTs). a) Histological analysis of islet graft function
[00110] After explantation of the devices within 9 weeks, insulin was detected on the devices using primary insulin-specific antibodies. Figure 17A shows the result of insulin staining within the porous chamber of an explanted device. Insulin detection within the chamber indicated that the islet cells contained in the device were viable and functional within 9 weeks of transplantation. Immunohytochemical staining of explant sections demonstrated well-configured and healthy islets surrounded by robust microvessels (Figure 17B; microvessels indicated by arrows). b) Blood glucose measurements
[00111] Weekly fasting and non-fasting blood glucose levels were measured to monitor islet graft function after transplantation. These measurements helped in determining the overall effectiveness of cell transplantation devices in the long-term control of blood glucose levels. Fasting blood glucose readings provide a controlled measure of graft function. Briefly, a drop (several microliters) of blood is collected from a vein of a recipient animal and the blood glucose level is determined using a Freestyle Lite glucometer or other glucose testing device.
[00112] As shown in Figure 18, the transplanted islets demonstrated long-term glucose control until device explantation within 72 days. Animals in the “glycemic control” group (n=4) were insulin dependent and blood glucose levels were controlled by islets in cell transplant devices alone. Animals in this group showed long-term insulin independence after islet transplantation. Some animals, however, remained hyperglycemic (daily elevated blood glucose levels) after islet transplantation into devices (n=6). This was related to poor metabolic quality of pre-transplant islets and low islet transplant dose (IEQ/Kg). Islet quality before transplantation correlated well with long-term islet function. c) Glucose Tolerance Test
[00113] Glucose tolerance tests are important in estimating islet graft function by comparing pre- and post-transplant IVGTT results. To test the effectiveness of cell transplantation devices, IVGTTs were conducted before pancreatectomy (baseline), at various time points after islet transplantation into devices, and after device explantation. The IVGTT was performed by injecting a dose of dextrose and measuring the time taken for endogenous insulin to bring glucose levels to baseline. In addition to measuring the blood glucose level, blood was sampled at various points in time to measure the level of C-peptide, which is a by-product created when insulin is produced by β cells. The results for an IVGTT were interpreted using absolute values of blood glucose level (Figure 19A), area under curve (AUC) of blood glucose level (Figure 19B) and successive change in C-peptide level (Figure 19C) .
[00114] As shown in Figures 19A and 19B, glucose levels increased significantly (p<0.001, Anova) after the device is explanted, indicating that removal of the device results in the elimination of insulin function similar to a diabetic animal without islets. Although lower glucose levels were detected in animals not undergoing pancreatectomy, islet autograft recipients showed significant reductions in glucose levels after dextrose injection, indicating that immature islets can survive and function after transplantation.
[00115] Serum samples from the IVGTTs were analyzed using the Linco porcine C-peptide radioimmunoassay kit, which uses an antibody made specifically against synthetic porcine C-peptide. Serum samples at 0, 5, 15, 30, 60 and 120 minutes after dextrose injection were analyzed for the presence of porcine C-peptide. The four study groups consisted of untested pancreatectomy pigs (baseline), islet autograft recipients (post islet transplant), autograft recipients who had their devices removed (after device removal ) and diabetic control pigs. When examining the successive changes in C-peptide levels between the different study groups, post-islet transplant recipients and baseline showed very comparable result, although the C-peptide level in post-islet transplant recipients increased by 60 minutes, as opposed to 30 minutes for the baseline group (Figure 19C). Additionally, the successive changes in C-peptide for the group after device removal and the diabetic control group were similar, indicating that the transplanted islets were responsible for the release of C-peptide before device removal.
[00116] Other embodiments of the invention will be apparent to those skilled in the art from consideration of the descriptive report and practice of the invention presented herein. It is intended that the descriptive report and the examples be considered as exemplifying only, with a real scope and spirit of the invention being indicated by the following claims.

权利要求:
Claims (22)
[0001]
1. Device for implanting cells in a host body, characterized in that it comprises: a porous structure comprising at least one chamber having a proximal end and a distal end, the porous structure having pores sized to facilitate vascular tissue growth and connectives within the at least one chamber; and at least one removable plug configured to be positioned within the at least one chamber; wherein the porous structure comprises an immunologically compatible polymer mesh.
[0002]
2. Device according to claim 1, characterized in that the at least one chamber comprises an opening in one or both of the proximal end and the distal end of the chamber, and wherein the device comprises: at least one system of two plugs comprising an outer plug configured to be positioned within the at least one chamber, and an inner plug configured to be positioned within the outer plug; and at least one seal configured to close the opening of one or both the proximal end and the distal end of the chamber.
[0003]
3. Device according to claim 1 or 2, characterized in that it further comprises a non-porous flap connected to the immunologically compatible polymer mesh at an open end of the at least one chamber and/or a seal to close the opening, optionally comprising a surgical staple or surgical sutures.
[0004]
4. Device according to any one of claims 1 to 3, characterized in that at least a part of the porous structure is coated with one or more biodegradable materials that fill pores of the porous structure.
[0005]
5. Device according to claim 4, characterized in that the biodegradable materials comprise at least one of growth factors, an antifibrotic agent, a polymer, and/or substances to stimulate angiogenesis and tissue incorporation within the at least a porous chamber, and/or wherein at least a portion of the porous structure is roughened to encourage tissue incorporation within the at least one porous chamber.
[0006]
6. Device according to any one of claims 1 to 5, characterized in that the porous structure comprises multiple chambers that are connected laterally and optionally comprises a common seal for the multiple chambers or a seal for each chamber.
[0007]
7. Device according to claim 6, characterized in that the at least one seal is a polymer film that is ultrasonically welded to the porous structure.
[0008]
8. Device according to claim 2, characterized in that the external plug and the internal plug comprise complementary sealing mechanisms.
[0009]
9. Device according to claim 8, characterized in that the inner wall of the outer plug comprises at least one protrusion along the length of the outer plug.
[0010]
10. Device according to any one of claims 1 to 9, characterized in that the porous structure allows the growth of vascular and connective tissues within the porous chamber, encapsulating the at least one plug system in a neovascularized collagen matrix and in that removal of the plug system from the chamber creates a space within the chamber that is encapsulated in the neovascularized collagen matrix.
[0011]
11. Device according to any one of claims 1 to 10, characterized in that the at least part of the porous structure is coated with one or more of vascular endothelial growth factor (VEGF), a drug-eluting polymer , collagen, fibronectin, cytoskeletal protein membrane, polyethyleneimine and dextran sulfate, poly(vinylsiloxane)ecopolymerpolyethyleneimine, phosphorylcholine, poly(ethylene glycol), poly(lactic-glycolic acid), poly(lactic acid), polyhydroxyvalerte and copolymers, polyhydroxybutyrate and copolymers, polydiaxanone, polyanhydrides, poly(amino acids), poly(orthoesters), polyesters, collagen, gelatin, cellulose polymers, chitosans, alginates, fibronectin, extracellular matrix proteins, vinculin, agar, agarose , hyaluronic acid, matrigel and combinations thereof.
[0012]
12. Device according to any one of claims 1 to 11, characterized in that it further comprises a cell distribution device comprising at least one cell infusion tube configured to be positioned inside the external plug.
[0013]
13. Device according to claim 12, characterized in that the cell delivery device further comprises a connector configured to connect to the external plug when the at least one cell infusion tube is inserted into the external plug and, optionally, wherein the connector comprises a clamp to attach to the external plug, and optionally, wherein attaching the connector to the external plug allows the connector and external plug to be retracted from the device as a single unit.
[0014]
14. Device according to any one of claims 1 to 13, characterized in that the porous structure comprises a chamber, two chambers, three chambers, four chambers, five chambers, six chambers, seven chambers, eight chambers, nine chambers or ten or more cameras.
[0015]
15. Device according to any one of claims 1 to 14, characterized in that it is for use in a method for transplanting cells into a host body, comprising the steps of: a. providing an implantable device for maintaining cells in the host body, the implantable device comprising: a porous structure comprising at least one chamber having an opening in each or both a proximal end and a distal end of the chamber, the porous structure that it has pores sized to facilitate the growth of vascular and connective tissues within a porous structure; at least one double plug system configured to be positioned within the at least one chamber; and at least one seal configured to enclose the opening at either or both the proximal and distal ends of the porous structure; wherein the at least one double plug system comprises an outer plug configured to be positioned within the at least one chamber, and an inner plug configured to be positioned within the outer plug; B. implant the device into the host body; ç. keep the device in the host body until the device is infiltrated by vascular and connective tissues; d. providing a cell delivery device comprising at least one cell infusion tube loaded with a cell preparation, the cell infusion tube configured to be positioned within the outer plug; and. accessing the implanted device through a surgical incision and opening at least one seal; f. remove the internal plug from the double plug system; g. insert the cell infusion tube into the external plug; H. withdrawing the external plug from the at least one chamber and infusing the chamber with the cell preparation; Hey. reconnect to at least one fence.
[0016]
16. Device according to claim 15, characterized in that it is for use in a method for transplanting cells into a host body, wherein the method further comprises the step of imaging the porous structure before distributing the cells.
[0017]
17. Device according to claim 15 or 16, characterized in that it is for use in a method for transplanting cells into a host body, wherein the cell preparation comprises one or more islets of Langerhans cells, cells Sertoli, mesenchymal stem cells, stem cells, cord blood cells, embryonic stem cells, neural stem cells, genetically engineered cells, encapsulated cells or cell lines, and a combination thereof.
[0018]
18. Device according to any one of claims 15 to 17, characterized in that it is for use in a method for transplanting cells into a host body, wherein the cell preparation comprises allogeneic, xenogenic, syngeneic or donor cells patient-derived.
[0019]
19. Device according to any one of claims 15 to 18, characterized in that it is for use in a method for transplanting cells into a host body, wherein the cell preparation comprises genetically engineered cells or cell lines.
[0020]
20. Device according to any one of claims 15 to 19, characterized in that it is for use in a method for transplanting cells into a host body, wherein the cells comprise islets of Langerhans cells and Sertoli cells.
[0021]
21. Device according to any one of claims 15 to 19, characterized in that it is for use in a method of transplanting cells into a host body, wherein the device comprises stem cells within the chamber, in which the cells stem cells are (i) immature, (ii) partially differentiated, or (iii) fully differentiated.
[0022]
22. Device according to any one of the preceding claims, characterized in that the cells are encapsulated in an encapsulated system comprising alginate, a polysaccharide hydrogel, chitosan, calcium or barium alginate, a layered matrix of altinate and polylysine , photopolymerizable poly(ethylene glycol) polymer, a polyacrylate, hydroxyethyl methacrylate, methyl methacrylate, a silicon shell, a silicon nanocapsule, or a polymembrane (acrylonitrile-co-vinyl chloride).

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WO2021163131A1|2020-02-10|2021-08-19|Youhealth Biotech, Limited|Device, kit, and method for islet transplantation|

法律状态:
2021-02-02| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-05-11| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-08-24| B09W| Correction of the decision to grant [chapter 9.1.4 patent gazette]|Free format text: REFERENTE AO DESPACHO 9.1 NA RPI NO 2627, DE 11/05/2021 |

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2021-09-14| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 27/08/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US23801109P| true| 2009-08-28|2009-08-28|

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US61/238,011|2009-08-28|

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PCT/US2010/047028|WO2011025977A2|2009-08-28|2010-08-27|Methods and devices for cellular transplantation|

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