Means and methods for transplanting cells secreting therapeutic compounds - Patents.com

Abstract

The present invention relates to a device for implantation into a mammalian host, comprising: a) a dialysis tubing having a lumen and a dialysis membrane surrounding the lumen, i) the dialysis tubing having an outer diameter of 20 μm to 600 μm, ii) the dialysis membrane having a molecular weight cut-off of 25 kDa to 150 kDa and comprising at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride and polypropylene, and b) a therapeutic composition disposed within the lumen of the dialysis tubing, the therapeutic composition comprising a plurality of cells secreting a therapeutic compound and a matrix material in which the cells secreting the therapeutic compound are embedded, the matrix material being selected from alginate, collagen, fibrin, an extracellular matrix material, a synthetic hydrogel, and an acrylate, in an embodiment the matrix material is alginate. The present invention further relates to the implantation device, the port system, and a method for producing cells secreting a therapeutic compound for use in treating disease by transplanting the cells in the implantation device of the present invention.

Description

[Technical field]

[0001] The present invention relates to a device for implantation into a mammalian host, comprising: a) a dialysis tubing having a lumen and a dialysis membrane surrounding the lumen, i) the dialysis tubing having an outer diameter of 20 μm to 600 μm, ii) the dialysis membrane having a molecular weight cut-off of 25 kDa to 150 kDa and comprising at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride and polypropylene, and b) a therapeutic composition disposed within the lumen of the dialysis tubing, the therapeutic composition comprising a plurality of cells secreting a therapeutic compound and a matrix material in which the cells secreting the therapeutic compound are embedded, the matrix material being selected from alginate, collagen, fibrin, an extracellular matrix material, a synthetic hydrogel, and an acrylate, in an embodiment the matrix material is alginate. The present invention further relates to the implantation device, the port system, and a method for producing cells secreting a therapeutic compound for use in treating disease by transplanting the cells in the implantation device of the present invention. [Background technology]

[0002] Therapeutic proteins are used at an increasing rate for the treatment of chronic diseases, such as neurodegenerative diseases, hemophilia, cancer, anemia, diabetes, autoimmune diseases, etc. Typically, therapeutic polypeptides are administered by repeated injections or infusions, causing variations in the bioavailability of the compound, and the need for repeated administration can cause poor compliance. Therefore, devices have been devised that allow the production of therapeutic polypeptides in the patient's body. Key requirements for such devices are patient safety, production of therapeutic polypeptides over an extended period of time, and the ability to replace if production of therapeutic compounds falls below a desired level. In addition, it would be desirable to be able to remove cells that produce therapeutic polypeptides from the patient's body, for example in the event of an allergic reaction to these cells.

[0003] The basic requirements for transplanting cells into patients are described, for example, in Fotino et al. (2015), Pharmacol Res, 98, 76-85. Also, various devices have been proposed by several companies, such as ViaCyte, Semma Therapeutics, Beat O2 Technologies, and Defymed®.

[0004] Australian Patent Publication No. 2020 210244 and Canadian Patent Publication No. 2190628 teach implantation devices for insulin-producing cells with large pores with diameters in the range of 0.4 μm and internal diameters of more than 1.5 mm. International Publication No. WO 1997 / 013474 discloses a flat plate device for implantation into a mammalian host in which insulin-producing cells are embedded in alginate and the mixture is further covered by another layer of alginate. International Publication No. WO 2014 / 202199 also teaches implantation devices comprising dialysis tubing with pores in the range of 40 to 290 μm.

[0005] Nevertheless, the solutions provided by the prior art were not optimal under at least one of the aforementioned desirable aspects, in particular the productivity over the long term was not optimal, with the option of replacing the cells when the production of the therapeutic compound decreased below a desirable level. Therefore, there is a need for improved means and methods for transplanting cells producing a therapeutic compound into a mammalian host, at least partially avoiding the drawbacks of the prior art. This problem is solved by the means and methods of the present invention using the features of the independent claims. Preferred embodiments, which may be realized in a single manner or in any arbitrary combination, are described in the dependent claims. Summary of the Invention

[0006] Accordingly, the present invention provides a device for implantation into a mammalian host, comprising: a) a dialysis tube having a lumen and a dialysis membrane surrounding the lumen, (i) the dialysis tubing has an outer diameter of 20 μm to 600 μm; (ii) a dialysis tube, the dialysis membrane having a molecular weight cutoff of 25 kDa to 150 kDa and comprising at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride, and polypropylene; b) a therapeutic composition disposed within the lumen of a dialysis tubing, the therapeutic composition comprising a plurality of cells secreting a therapeutic compound and a matrix material embedding said cells secreting a therapeutic compound, the matrix material being selected from alginate, collagen, fibrin, an extracellular matrix material, a synthetic hydrogel, and an acrylate, and in an embodiment, the matrix material is alginate.

[0007] Generally, the terms used herein should be given their ordinary and customary meanings to those skilled in the art, and should not be limited to special or customized meanings unless otherwise indicated. When used below, the terms "have", "comprise", or "include", or any grammatical variations thereof, are used inclusively. Thus, these terms may refer to both the situation where no further features are present in the entity described in this context in addition to the features introduced by these terms, and the situation where one or more additional features are present. As an example, the expressions "A has B", "A comprises B" and "A includes B" may both refer to the situation where, apart from B, no other elements are present in A (i.e., A consists solely and exclusively of B), and the situation where, apart from B, one or more further elements are present in entity A, such as element C, elements C and D, and even further elements. Also, as will be appreciated by those skilled in the art, the expressions "comprising a" and "comprising an" preferably refer to "comprising one or more...", i.e., are equivalent to "comprising at least one...".

[0008] Furthermore, when used hereinafter, the terms "preferably," "more preferably," "most preferably," "particularly," "more particularly," "specifically," "more specifically," or similar terms are used in combination with any feature without restricting further possibilities. Thus, features introduced by these terms are optional features and are not intended to constrain the scope of the claims in any manner. The invention may be implemented by using alternative features, as recognized by those skilled in the art. Similarly, features introduced by "in an embodiment" or similar expressions are intended to be optional features, without any limitations on further embodiments of the invention, without any limitations on the scope of the invention, and without any limitations on the possibility of combining the features so introduced with other optional or non-optional features.

[0009] As used herein, the term "standard conditions" refers to IUPAC standard ambient temperature and pressure (SATP) conditions, unless otherwise specified, i.e., preferably, a temperature of 25°C and an absolute pressure of 100 kPa, and preferably, the standard conditions include a pH of 7. Furthermore, unless otherwise indicated, the term "about" refers to the indicated value with a technical precision generally accepted in the relevant field, preferably, ±20%, more preferably, ±10%, and most preferably, ±5% of the indicated value. Furthermore, the term "essentially" indicates that there is no deviation that affects the results and use shown. That is, the results shown due to potential deviations do not deviate by more than ±20%, more preferably, ±10%, and most preferably, ±5%. Thus, "consisting essentially of" means including the specified components, but excluding other components, except for materials present as impurities, unavoidable materials present as a result of the process used to provide the components, and components added for purposes other than achieving the technical effect of the present invention. For example, a composition defined using the phrase "consisting essentially of" includes any known acceptable additives, excipients, diluents, carriers, etc. Preferably, a composition consisting essentially of a set of components will contain less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1% by weight, and most preferably less than 0.1% by weight of unspecified components.

[0010] The term "implantation device" as used herein relates to any and all devices having the characteristics specified herein and adapted for implantation into a mammalian host. Adaptation for implantation includes that the implantation device has an overall size and structure that allows for implantation into the body of a mammalian host. As the skilled artisan will appreciate, the specific size and structure requirements of the implantation device may vary and may depend, among other factors, on the nature of the mammalian host, such as its species, size and / or age, and the intended location of implantation. In embodiments, the implantation device is implanted into a body cavity of the mammalian host, in embodiments a natural or artificially created body cavity, in further embodiments a natural body cavity. Natural body cavities are, inter alia, the abdomen, peritoneum, circulatory system, oropharyngeal cavity, digestive tract, lung, uterus and vagina. Artificial body cavities may be created, for example, in the subcutaneous tissue, adipose tissue, muscle, skull, pleura, or breast of the mammalian host.

[0011] In an embodiment, suitability for implantation further includes not being harmful to the mammalian host, particularly when the implantation device is maintained in the implanted state for an extended period of time, for example at least one week, in an embodiment at least two weeks, in a further embodiment at least one month, in a further embodiment at least six months, in a further embodiment at least one year. Thus, in an embodiment, the implantation device comprises a biocompatible material, in a further embodiment consists of a biocompatible surface material, in a further embodiment consists of a biocompatible material. Biocompatibility can be achieved in principle by adhesion of cells to extracellular substances, such as matrix substances (fouling), followed by encapsulation. Alternatively, biocompatibility can be achieved by prevention of adhesion of cells and extracellular substances. As will be understood from the explanations elsewhere herein, the dialysis tube of the implantation device can be particularly biocompatible by non-adhesion of biomolecules in order to maintain optimal diffusion over the dialysis membrane. Suitable materials for the dialysis tube are specified herein below.

[0012] In an embodiment, the device further comprises a port, as specified herein below, providing access to the dialysis tubing from the body surface of the mammalian host and / or from the subcutaneous access element. Thus, in an embodiment, the device is adapted for in situ replacement of the dialysis tubing. In a further embodiment, the device further comprises a port, as specified herein below, providing conduction from the lumen of the dialysis tubing to the body surface of the mammalian host and / or from the subcutaneous access element. Thus, in an embodiment, the device is adapted for in situ replacement of the contents of the dialysis tubing. In a further embodiment, the device is adapted for in situ replacement of the dialysis tubing. In an embodiment, the device further comprises at least one sensor element, as specified herein below, accessible via the port and extending at least partially into the lumen of the dialysis tubing.

[0013] In embodiments, the device further comprises an implantable first guide system that guides the dialysis tubing at least partially in a pre-specified direction, e.g., through tissue, as specified herein below. In embodiments, the first guide system, optionally in conjunction with a port, guides the dialysis tubing through all layers of tissue and into the body cavity.

[0014] In particular, when a significant volume of lumen and / or length of dialysis tube is desired, it may be envisaged that the device comprises a specified number of dialysis tubes and / or a number of first guide systems, for example 2, 5, 10, 25, or even 50 dialysis tubes and / or first guide systems. Thus, in an embodiment, the implantation device comprises 2 to 50, in a further embodiment 3 to 25, and in a further embodiment 5 to 15 dialysis tubes and / or first guide systems. In such a case, the dialysis tubes and / or first guide systems may be spatially oriented in any order deemed appropriate by the skilled artisan for the intended use. For example, the dialysis tubes and / or first guide systems may be oriented essentially in the same direction, for example in parallel, or may be arranged in a radial order, which may be three-dimensional radial or two-dimensional radial. In an embodiment, each first guide system guides up to 5, in an embodiment up to 4, in a further embodiment up to 3, in a further embodiment up to 2, and in a further embodiment one dialysis tube. In another embodiment, the device may comprise one dialysis tube spatially oriented to make at least one fold at the port of the device, thus inducing a folded structure. Alternatively, the first guide system may implement a spiral or serpentine arrangement. In an embodiment, the dialysis tube and / or the first guide system are arranged, in an embodiment fixed, in an arrangement that ensures that the dialysis tube contacts the body fluid in the body cavity over at least 50%, in an embodiment at least 75%, in a further embodiment at least 85%, in a further embodiment at least 90% of their surface. Thus, in an embodiment, at least the dialysis tube of the device is at least partially implanted intraperitoneally, subcutaneously, intraarterially, or intravenously, in an embodiment intraperitoneally, in a further embodiment intraperitoneally.

[0015] In embodiments, the implantation device is a percutaneously implantable device, i.e., at least a portion of the structure of the device extends through the skin of the mammalian host, hi embodiments, the portion of the structure that extends through the skin is a percutaneous port, as specified herein below.

[0016] In an embodiment, the implantation device is implanted as a complete device, i.e., including all the specified features and elements. In a further embodiment, the port of the device, including at least a part of the first guide system, is implanted first, and the dialysis tubing is introduced at a later time, for example, after healing. However, it is also envisioned that the port is implanted first, and the first guide system, optionally including the dialysis tubing, is attached later, for example, after healing, and said procedure may be particularly useful, for example, when radial positioning of the first guide system and / or the dialysis tubing is desired.

[0017] The term "mammalian host" as used herein relates to mammals, in embodiments farm animals such as cows, pigs, horses, sheep or goats, pets such as rabbits, guinea pigs, hares, companion animals such as cats or dogs, laboratory animals such as mice or rats, in further embodiments the mammalian host is a human.

[0018] The term "dialysis tube" is known to those skilled in the art as relating in principle to a device that includes a dialysis membrane surrounding a lumen. As referred to herein, the dialysis tube has an outer diameter of 20 μm to 600 μm. In an embodiment, the dialysis tube has an outer diameter of 100 μm to 550 μm, in an embodiment, 200 μm to 500 μm, in a further embodiment, 300 μm to 500 μm, in a further embodiment, 400 μm to 500 μm. In an embodiment, the dialysis tube has an outer diameter of 500 μm ± 10%. As will be understood by those skilled in the art, the length of the dialysis tube depends on the application envisaged, in particular the number of cells that may be desired for the application, the cell density in the dialysis tube, and the diameter of the dialysis tube. Typically, the dialysis tube may have a length of 10 cm to 2000 cm, in an embodiment, 20 cm to 1000 cm, in a further embodiment, 50 cm to 800 cm, especially when the dialysis tube has an outer diameter of about 500 μm. As will be appreciated by those skilled in the art, the dialysis membrane of the dialysis tubing is closed around the dialysis tubing and in embodiments is continuous, and in embodiments the dialysis tubing has openings only at the ends, one of which may be sealed before filling and the other of which may be sealed after filling.

[0019] As detailed elsewhere herein, it may be envisaged to provide multiple dialysis tubes and / or specific spatial arrangements of dialysis tubes to reduce the overall size of the device. Thus, the implantable device may include multiple dialysis tubes. In such cases, the dialysis tubes may be spatially oriented in any order deemed appropriate by the skilled artisan for the intended use, for example, the dialysis tubes may be oriented in essentially the same direction, e.g., parallel directions, or may be arranged in radial orders that may be three-dimensionally radial or two-dimensionally radial. In further embodiments, the dialysis tubes may be spatially oriented to fold back at least once on the port of the device, and thus may have a folded structure. It may also be envisaged that the dialysis tubes have a helical or serpentine orientation. However, the dialysis tubes may also assume a random spatial arrangement, for example, when there is only partial or no guidance by the first guidance system, or when the first guidance system and / or the port is absent. In an embodiment, the dialysis tube is at least partially covered by a biocompatible outer layer, in an embodiment by a hydrogel. Biocompatible layers such as hydrogels are known in the art. As will be appreciated by those skilled in the art, biocompatible layers that prevent the deposition of biological materials are specifically contemplated.

[0020] The term "lumen" of a dialysis tube is understood by those skilled in the art to refer to the volume of the dialysis tube that is essentially enclosed by the dialysis membrane. In embodiments, other structural elements may contribute to defining the lumen, such as fastening and / or sealing elements, e.g., sealing one or both ends of the dialysis tube. In embodiments, the lumen of the dialysis tube is at least 1 mm 3 , in an embodiment at least 10 mm 3 , and in a further embodiment at least 100 mm 3 and in a further embodiment at least 1 cm 3 and in a further embodiment at least 2.5 cm 3 and in a further embodiment at least 5 cm 3In a further embodiment, the lumen of the dialysis tubing has a volume of 1 mm 3 From 5cm 3 , in the embodiment, 10 mm 3 From 2.5cm 3 , in a further embodiment 100 mm 3 From 1.5cm 3 In embodiments, the lumen of the dialysis tubing is accessible from a body surface of the mammalian host via a port.

[0021] The term "dialysis membrane" as used herein refers to a semipermeable membrane having a molecular weight cutoff of 25 kDa to 150 kDa, comprising at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride and polypropylene. As used herein, the term "molecular weight cutoff" refers to the minimum molecular weight of a solute that is retained by the dialysis membrane at least 90%. That is, solutes having at least the molecular weight of the cutoff value are retained by the dialysis membrane at 90% or more, and solutes having a molecular weight lower than the cutoff value are retained less than 90%. Those skilled in the art recognize that not all molecules of a given molecular weight have the same morphology, size, and diffusion properties, and thus the molecular weight cutoff value is an average value. Thus, there is only a rough correlation between the molecular weight cutoff of a dialysis membrane and the diameter of its pores. For example, for a molecular weight cutoff of 100 kDa, the pore size in the embodiment ranges from 9 to 10 nm. Methods for determining the molecular weight cutoff of a dialysis membrane are known in the art. Typically, the value of the molecular weight cutoff of the dialysis membrane is the value provided by the manufacturer. In an embodiment, the molecular weight cutoff of the dialysis membrane is adjusted by the skilled person according to the therapeutic compound produced in the dialysis tube. In one aspect, it can be envisaged to select the molecular weight cutoff of the dialysis membrane to allow the diffusion of nutrients and peptidic growth factors and therapeutic compounds onto the dialysis membrane, but in an embodiment, it has been found that it may be desirable to exclude components of the immune system, particularly immunoglobulins, from the lumen of the dialysis tube. Thus, the dialysis membrane in an embodiment has a molecular weight cutoff of at least 25 kDa, in a further embodiment at least 50 kDa, in a further embodiment at least 80 kDa. And / or the dialysis membrane in an embodiment has a molecular weight cutoff of up to 125 kDa, in a further embodiment at most 110 kDa. Thus, in an embodiment, the dialysis membrane has a molecular weight cut-off of 25 kDa to 125 kDa, in an embodiment 40 kDa to 110 kDa, in a further embodiment 50 kDa to 100 kDa, in a further embodiment 80 kDa to 100 kDa, in a further embodiment 100 kDa ± 10%, and in a further embodiment 100 kDa.

[0022] The dialysis membrane comprises at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride and polypropylene. The polyarylethersulfone is, in embodiments, polyethersulfone, polyphenylenesulfone (PPSU), or polysulfone (PSU). Thus, the dialysis membrane may comprise one or more of the aforementioned materials, or a mixture thereof. In embodiments, the dialysis membrane is made of at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride and polypropylene, or a mixture thereof. In further embodiments, the dialysis membrane is made of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride or polypropylene. Polyethersulfone (Poly(oxy-1,4-phenylenesulfonyl-1,4-phenylene)), CAS number 25667-42-9; Polyphenylenesulfone ((1,1'-biphenyl)-4,4'-diol, polymer with 1,1'-sulfonylbis(4-chlorobenzene)), CAS number 25608-64-4; Polysulfone (Poly(oxy-1,4-phenylenesulfonyl-1,4-phenyleneoxy-1,4-phenylene(1-methylethylidene)-1,4-phenylene), CAS number 25135-51-7; Polyethylene (Polyethylene, CAS number 9002-88-4), Polytetrafluoroethylene (Poly Polyvinylidene fluoride (poly(1,1,2,2-tetrafluoroethylene), CAS No. 9002-84-0), polyvinylidene fluoride (poly(1,1-difluoroethylene), CAS No. 24937-79-9) and polypropylene (poly(1-methylethylene), CAS No. 9003-07-0) are known in the art, as are methods of producing dialysis membranes from these materials. In embodiments, the material of the dialysis membrane is selected to be biocompatible and compatible with the therapeutic compound, i.e., in embodiments, does not cause denaturation and / or aggregation of the therapeutic compound. The aforementioned properties may be tested, for example, as shown in Example 2 herein.

[0023] The term "therapeutic composition" as used herein relates to any and all compositions comprising (i) a plurality of cells secreting a therapeutic compound and (ii) a matrix material, both as specified herein below. In embodiments, the therapeutic composition is liquid upon filling of the dialysis tubing and / or is solid or semi-solid, e.g. a gel, upon implantation or at the latest on day 1 after implantation. The therapeutic composition may comprise further compounds and ingredients in addition to those specified above. Exemplary compounds optionally further present may be salts, e.g. salts that aid in gelling of the matrix material, buffering agents, antibiotics, anti-inflammatory agents, water, organic solvents, etc., which in embodiments are selected so as not to affect the biological activity of the cells secreting the therapeutic compound, in particular the secretion of the therapeutic compound, and / or cell viability. In embodiments, the therapeutic composition comprises at least one further cell type, in embodiments feeder cells and / or modulator cells, e.g. cells that activate the secretion of the therapeutic compound. In embodiments, the therapeutic composition comprises at least insulin-secreting cells, and in further embodiments insulin-secreting cells and glucagon-secreting cells.

[0024] In embodiments, the therapeutic composition comprises at least 10 cells secreting a therapeutic compound. 3 10, in embodiments at least 10 5 and in further embodiments at least 10 6 and in further embodiments at least 10 7 and in further embodiments at least 10 8 and in further embodiments at least 10 9 As referred to herein, the indicated number of cells in the therapeutic composition, as well as the volume of the lumen of the dialysis tubing, refer to the total volume of the therapeutic composition and / or lumen available per device. That is, if the implantation device contains more than one dialysis tube, the number of cells in the therapeutic composition is the number of cells in all the dialysis tubes combined. In embodiments, the density of cells secreting the therapeutic compound in the therapeutic composition is greater than 104 / ml to 10 9 / ml, in embodiments 10 5 / ml to 10 8 / ml. In embodiments, at least 50% of the cells secreting the therapeutic compound remain viable in the therapeutic composition in the implantation device for implantation for at least one week, in embodiments at least one month, in further embodiments at least three months, in further embodiments at least six months, and in further embodiments at least one year. As one skilled in the art will appreciate, the composition of the therapeutic composition may change over time after implantation, for example, nutrients and growth factors may diffuse into the therapeutic composition and / or the therapeutic compound may diffuse out of the therapeutic composition. Thus, in case of doubt, the composition of the therapeutic composition specified is the composition before or at the time of implantation.

[0025] The term "plurality" as used herein relates to a number greater than one, i.e., at least 2, in embodiments at least 3, in further embodiments at least 5, and in further embodiments at least 10. In particular in the context of a plurality of cells, the term plurality in embodiments refers to a number greater than one, i.e., at least 10. 3 10, in embodiments at least 10 5 and in a further embodiment at least 10 6 and in a further embodiment at least 10 7 and in a further embodiment at least 10 8 Regarding the number of cells.

[0026] The term "therapeutic compound" as used herein includes any and all compounds produced and secreted by cells secreting therapeutic compounds as specified herein below. In embodiments, the therapeutic composition is a compound having a molecular weight of less than 150 kDa, in embodiments less than 150 kDa, and in further embodiments less than 100 kDa. As used herein, the term "molecular weight" of a therapeutic compound relates to the molecular weight of the compound secreted by cells secreting the therapeutic compound. Thus, the molecular weight is, for example, the molecular weight of the tetrameric compound if the therapeutic compound is secreted as a tetramer. In embodiments, the therapeutic compound is a compound that needs to be produced at a basal level in a mammalian host. In embodiments, the therapeutic compound is a biological macromolecule such as a polypeptide, polynucleotide, polysaccharide, and in embodiments, a polypeptide. In embodiments, the therapeutic compound is selected from the group consisting of insulin, glucagon, factor IX, human growth hormone (huGH), calcitonin, glucagon-like peptides (GLP-1) and agonists, amylin, levodopa, somatostatin, alpha 1-antitrypsin (AAT), interleukins, and interferons. In further embodiments, the therapeutic compound is insulin or an insulin analog, in embodiments human insulin or an analog of human insulin or a human or humanized insulin analog, in further embodiments human insulin.

[0027] The term "cells secreting a therapeutic compound" includes any eukaryotic cell secreting a therapeutic compound as specified herein above. In an embodiment, said cells are mammalian cells, in a further embodiment, human cells. In an embodiment, the cells are derived from the same species as the mammalian host. The cells can be, but need not be, autologous cells. In an embodiment, the cells secreting a therapeutic compound are pancreatic beta cells differentiated, in an embodiment, from a stem cell line, in a further embodiment, from a pluripotent stem cell line. Preferably, said stem cells were not generated by destruction of an embryo, in particular a human embryo. In an embodiment, the cells secreting a therapeutic compound are comprised in a pancreatic islet or islet-like cluster. In an embodiment, the cells secreting a therapeutic compound are comprised in a therapeutic composition as aggregates comprising at least 10, in an embodiment at least 100, in a further embodiment at least 1000 cells. In a further embodiment, the cells secreting a therapeutic compound are comprised in a therapeutic composition as aggregates having an average diameter of 100 μm to 400 μm, in an embodiment, from 200 μm to 300 μm.

[0028] The term "matrix material" includes any material deemed suitable by the skilled artisan to embed and maintain the viability of cells secreting a therapeutic compound. Thus, the matrix material is, in embodiments, adapted to allow diffusion of nutrients, including oxygen and growth factors, to said cells, and diffusion of the therapeutic compound from the cells. Thus, a matrix material that forms a semi-solid matrix, e.g., a gel, may be used. Also, the matrix material is selected so as not to be harmful to the cells secreting the therapeutic compound and / or the mammalian host. Suitable matrix materials are known in the art. In embodiments, the matrix material is selected from alginate, collagen, fibrin, extracellular matrix materials, synthetic hydrogels and acrylates, and in embodiments, the matrix material is alginate. Extracellular matrix materials are known in the art. For example, an extracellular matrix material secreted by Engelbreth-Holm-Swarm (EHS) mouse sarcoma cells is commercially available under the trade name Matrigel®.

[0029] The term "port" as used herein relates to any device that can be placed at least partially under the skin of a mammalian host and provides access to the dialysis tubing of a device for implantation. Thus, the port comprises a first connection element that connects the dialysis tubing to a fixation element of the port, said fixation element fixes the port in or under the skin of the mammalian host. The first connection element may provide fluid access to the lumen of the dialysis tubing and / or may hold the dialysis tubing in place after implantation. As will be understood from the above description herein, the first connection element may provide a releasable fastening engagement between the dialysis tubing and the fixation element of the port. Thus, the port may be a subcutaneous port that provides a fluid connection to the lumen of the dialysis tubing. In a further embodiment, the port is a percutaneous port, i.e., a percutaneously implantable port. In such a case, the port may further comprise a second connection element that connects the fixation element of the port to an extracorporeal connection head. Said extracorporeal connection head may be a sealing element and / or may comprise one or more connectors that connect any sensor extending into the lumen of the dialysis tubing to the signal converter unit. In an embodiment, the port is a port a as described in EP 1 420 836, which is incorporated herein by reference, and the catheter is adapted to function as a first guidance system as specified herein, optionally having additional elements adapted to perform the functions specified herein.

[0030] The term "first guide system" as used herein relates to a rigid or semi-rigid element of the port that extends at least partially through the tissue of the mammalian host after implantation. In an embodiment, the first guide system has a U-shaped profile or is tubular. Thus, in an embodiment, the first guide system at least partially covers the dialysis tube, and in an embodiment, the first guide system comprises a number of holes that may have any shape deemed appropriate by the skilled artisan, for example, circular, elliptical, slot-shaped, or irregular. In an embodiment, said holes have an equivalent diameter of at least 0.05 μm, in an embodiment at least 0.5 μm, in a further embodiment at least 5 μm, in a further embodiment at least 50 μm, and in a further embodiment at least 150 μm. In an embodiment, the first guide system comprises a material as described herein above for the dialysis membrane, in a further embodiment, polytetrafluoroethylene (PTFE), and in a further embodiment, made of polytetrafluoroethylene. However, it is also envisaged that the first guide system comprises, in an embodiment, polyurethane (PUR).

[0031] The term "sensor element" as used herein includes any and all sensing elements deemed appropriate by a person skilled in the art to provide information regarding the status of cells secreting therapeutic compounds contained in the lumen of the dialysis tubing. Thus, in an embodiment, the sensor element comprises at least one of an oxygen sensor, a glucose sensor, a pH sensor, a lactate sensor, an insulin sensor, a C-peptide sensor, an inflammatory biomarker sensor, and / or a sensor for a marker of cell viability. Suitable sensors are known in the art. In an embodiment, the sensor element is a microsensor, and in a further embodiment, an enzyme microsensor.

[0032] Advantageously, in the research underlying the present invention, the dialysis membrane material, molecular weight cutoff and outer diameter of the dialysis tubing specified after step b) have been found to be, alone or in combination, particularly useful for the maintenance of cells secreting therapeutic compounds as an implant.

[0033] The above definitions apply mutatis mutandis below. The following further additional definitions and explanations also apply mutatis mutandis to all embodiments described herein.

[0034] The present invention further provides a method of manufacturing an implantable device according to the present invention, comprising the steps of: a) filling a dialysis tube with cells secreting a therapeutic compound and a matrix material; b) at least temporarily sealing at least one end of the dialysis tubing; and c) thereby producing an implantable device.

[0035] The method of the present invention is preferably an in vitro method. Moreover, it may include steps in addition to those explicitly mentioned above. Moreover, one or more of said steps may be assisted or performed by automated equipment. Exemplary additional steps may relate to, for example, providing cells secreting therapeutic compounds for step a), sealing the second end of the dialysis tube in step b), and / or attaching the dialysis tube to a port as specified herein above after step b). According to the above, the method may further include mixing feeder cells and / or modulator cells or other compounds with cells secreting therapeutic compounds before filling the dialysis tube.

[0036] The term "loading" is understood by those skilled in the art. In embodiments, the dialysis tube is completely loaded with the therapeutic compound and cells secreting the matrix material or its precursors, i.e., the therapeutic composition as specified herein above. Thus, in embodiments, there is no trapped void volume or gas within the dialysis tube. Loading may also include a step of polymerizing the matrix material. Thus, the therapeutic composition may be loaded into the dialysis tube as a liquid, i.e., as a suspension of cells in the matrix material or its precursors, and the matrix material or its precursors may be induced or left to polymerize within the dialysis tube. In the context of loading the dialysis tube as specified herein, the term "polymerization" should be understood in a broad sense relating to any chemical or physical process that causes at least partial solidification of the matrix material. Thus, polymerization may include the formation of covalent bonds, ionic bonds, and / or van der Waals interactions between molecules of the matrix material or its precursors. For example, if the matrix material is alginate, polymerization may be induced by contacting the loaded dialysis tube with a solution containing divalent cations, in embodiments alkaline earth metal cations, in particular calcium and / or barium ions, that diffuse into the matrix material and cause gelation or solidification. Thus, in embodiments, the dialysis tubing may be washed for an extended period of time, such as 15 minutes, 30 minutes, or 1 hour, to remove polymerization reagents and / or unpolymerized precursors of the matrix material.

[0037] The present invention also provides a port system, comprising: I) an implantable device having a port according to the present invention and / or an implantable device having a port obtained or obtainable according to the method for producing an implantable device; II) an external connection head.

[0038] The port system comprises the specified components, which are described herein in the context of the implantation device. However, the port system may comprise further optional components, such as a signal converter unit as specified herein below, or additional components, such as an additional component that allows access to the dialysis tubing and / or its lumen, such as a membrane, a removable additional fixation element, etc. In an embodiment, the port is a percutaneously implantable port, and comprises a second connection element that connects the port unit to the extracorporeal connection head. In a further embodiment, the extracorporeal connection head may be fastened to the implantation device by a releasable fastening engagement. However, the port may be a subcutaneous port, and the extracorporeal connection head may be fixed to the port by indirect means, such as magnetic forces. In an embodiment, the extracorporeal connection head at one end is adapted to be placed on the skin of a mammalian host.

[0039] The term "signal converter unit" is understood by those skilled in the art to relate to providing a means for converting the signal of the sensor element to a suitable evaluation device, e.g. a measuring, monitoring and / or display device. In an embodiment, the signal converter unit is adapted to output at least one signal obtained by the sensor element. Suitable signal converter units are known to those skilled in the art and include simple output units such as a connector cable or a connector plug. However, the signal converter unit may also be an interface to the evaluation device, said interface being any kind of means for transferring data, including for example a cable connection like USB, a wireless connection like WLAN, Bluetooth etc. or an indirect connection such as data transfer by instant messaging, e.g. email etc.

[0040] In an embodiment, the port system of the present invention is part of a monitoring system comprising the port system and the evaluation device described herein above. As will be understood by those skilled in the art, the evaluation device may be included in the same housing as the port system, e.g. as an evaluation unit included in the extracorporeal connection head, or may be a separate device, e.g. a handheld device. In an embodiment, the evaluation device comprises a microprocessor programmed to receive signals, e.g. output data, from the signal converter unit and perform logic operations to provide an evaluation of said output data. The evaluation of the output data may include, e.g., correcting data of values ​​measured at one or more control sensors, statistical calculations, e.g. calculating a measure of two or more parallel detection reactions, correcting data measurement errors, comparing the output data with reference values, compiling data in a list, etc. In an embodiment, the evaluation device further comprises a data storage unit. In a further embodiment, said data storage unit comprises reference values, e.g. in a reference value database. Furthermore, in an embodiment, the data storage unit is adapted to store the output data received from the sensor element of the present invention, as described above.

[0041] The present invention also relates to cells secreting therapeutic compounds for use in treating a disease by transplanting said cells in a transplantable device according to the present invention and / or in a device obtained or obtainable according to the method for producing a transplantable device according to the present invention.

[0042] The present invention also relates to cells secreting therapeutic compounds for use in treating diabetes, hemophilia B, huGH deficiency, osteoporosis, Parkinson's disease, acromegaly, endocrine tumors, alpha 1-antitrypsin deficiency, infectious diseases, autoimmune diseases, cancer, or chronic viral infections by transplanting the cells in an implantable device of the present invention and / or a device obtained or obtainable according to the method for producing an implantable device of the present invention.

[0043] The present invention also relates to a method for treating and / or preventing a disease comprising implanting an implantable device of the present invention and / or a device obtained or obtainable according to the method for producing an implantable device of the present invention.

[0044] The diseases and disorders referred to herein are well known in the art.As understood by those skilled in the art, the root cause of the disease in the embodiment is the lack or absence of compounds, particularly polypeptides, from the body of the diseased mammalian host.For example, in hemophilia, one or more clotting factors may be produced in insufficient amounts by the mammalian host.In diabetes, the amount of insulin may be insufficient, and so on.In the embodiment, diabetes is type I diabetes.

[0045] The terms "treat" and "treatment" refer to the improvement of the disease or disorder referred to herein or symptoms associated therewith to a significant degree. Said treatment as used herein also includes the complete restoration of health with respect to the disease or disorder referred to herein. As used herein, it should be understood that treating is not necessarily effective in all subjects treated. However, this term should preferably require that a statistically significant portion of subjects suffering from the disease or disorder referred to herein can be successfully treated. Whether the portion is statistically significant can be determined by those skilled in the art without further ado using various well-known statistical evaluation tools, such as determining confidence intervals, determining p-values, Student's t-test, Mann-Whitney test, etc. The preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99%. The p-value is preferably 0.1, 0.05, 0.01, 0.005, or 0.0001. Preferably, a treatment should be effective in at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the subjects in a given cohort or population.

[0046] The term "prevent" refers to maintaining health in a subject with respect to the disease or disorder referred to herein for a certain period of time. It will be understood that said period of time may depend on the amount of drug compound administered and the individual factors of the subject discussed elsewhere herein. It should be understood that prevention is not effective for all subjects treated with the compound according to the present invention. However, the term preferably requires that a statistically significant portion of the subjects of a cohort or population is effectively prevented from suffering from the disease or disorder referred to herein or its associated symptoms. Preferably, in this context, a cohort or population of subjects who would normally, i.e., without the preventive measures according to the present invention, develop the disease or disorder referred to herein is envisaged. Whether the portion is statistically significant can be determined without further difficulty by those skilled in the art using various well-known statistical evaluation tools discussed elsewhere herein.

[0047] In view of the above, the following embodiments are specifically contemplated:

[0048] Embodiment 1: A device for implantation into a mammalian host, comprising: a) a dialysis tube having a lumen and a dialysis membrane surrounding the lumen, i) the dialysis tubing has an outer diameter of 20 μm to 600 μm; ii) a dialysis tube, the dialysis membrane having a molecular weight cutoff of 25 kDa to 150 kDa and comprising at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride, and polypropylene; b) an implantable device comprising: a therapeutic composition disposed within the lumen of the dialysis tubing, the therapeutic composition comprising a plurality of cells secreting a therapeutic compound; and a matrix material embedding the cells secreting the therapeutic compound, the matrix material being selected from alginate, collagen, fibrin, an extracellular matrix material, a synthetic hydrogel, and an acrylate, and in an embodiment, the matrix material is alginate.

[0049] Embodiment 2: The device of claim 1, wherein the dialysis tubing has an outer diameter of 100 μm to 500 μm, in an embodiment 200 μm to 550 μm, in a further embodiment 300 μm to 500 μm, and in a further embodiment 400 μm to 500 μm.

[0050] Embodiment 3: An apparatus according to claim 1 or 2, wherein the dialysis tubing has a length of from 10 cm to 2000 cm, in an embodiment from 20 cm to 1000 cm, in a further embodiment from 50 cm to 800 cm.

[0051] Embodiment 4: The device of any one of claims 1 to 3, wherein the dialysis tubing assumes a serpentine, helical, or radial configuration within the mammalian host.

[0052] Embodiment 5: A device according to any one of claims 1 to 4, wherein the dialysis tubing is at least partially covered by a biocompatible outer layer, in embodiments by a hydrogel.

[0053] Embodiment 6: The lumen of the dialysis tubing is at least 1 mm 3 , in an embodiment at least 10 mm 3 , in another embodiment at least 100 mm 3 and in another embodiment at least 1 cm 3 and in another embodiment at least 2.5 cm 3 and in another embodiment at least 5 cm 3 6. The device according to claim 1 , having a volume of

[0054] Embodiment 7: The lumen of the dialysis tube is 1 mm 3 From 5cm 3 , in the embodiment, 10 mm 3 From 2.5cm 3 , in a further embodiment 100 mm 3 From 1.5cm 3 7. The device according to claim 1, having a volume of

[0055] Embodiment 8: The therapeutic composition comprises at least 10 cells secreting a therapeutic compound. 3 10, in embodiments at least 10 5 and in further embodiments at least 10 6 and in further embodiments at least 10 7 and in further embodiments at least 10 8 and in further embodiments at least 10 9 8. The apparatus of claim 1 , comprising:

[0056] Embodiment 9: The device of any one of claims 1 to 8, wherein the cells secreting a therapeutic compound are included in the therapeutic composition as aggregates comprising at least 10, in an embodiment at least 100, and in a further embodiment at least 1000 cells.

[0057] Embodiment 10: A device according to any one of claims 1 to 9, wherein the cells secreting a therapeutic compound are contained in the therapeutic composition as aggregates having an average diameter of between 100 μm and 400 μm, in embodiments between 200 μm and 300 μm.

[0058] Embodiment 11: A device according to any one of claims 1 to 10, wherein the therapeutic composition, in embodiments, comprises at least one further cell type, feeder cells and / or modulator cells.

[0059] Embodiment 12: A device according to any one of claims 1 to 11, wherein the dialysis membrane has a molecular weight cut-off of 25 kDa to 125 kDa, in embodiments of 40 kDa to 110 kDa.

[0060] Embodiment 13: A device according to any one of claims 1 to 12, wherein the dialysis membrane has a molecular weight cut-off of 50 kDa to 100 kDa.

[0061] Embodiment 14: A device according to any one of claims 1 to 13, wherein the dialysis membrane has a molecular weight cut-off of 80 kDa to 100 kDa.

[0062] Embodiment 15: A device according to any one of claims 1 to 14, wherein the dialysis membrane has a molecular weight cut-off of 100 kDa.

[0063] Embodiment 16: The device of any one of claims 1 to 16, wherein the dialysis membrane is made of a material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride, and polypropylene.

[0064] Embodiment 17: The device according to any one of claims 1 to 16, wherein the device further comprises an implantable first guide system that at least partially guides the dialysis tubing through the subcutaneous tissue.

[0065] Embodiment 18: The device of claim 17, wherein the first guide system at least partially covers the dialysis tube, and in an embodiment, the first guide system comprises a number of pores having an equivalent diameter of at least 0.05 μm, in an embodiment at least 0.5 μm, in a further embodiment at least 5 μm, in a further embodiment at least 50 μm, and in a further embodiment at least 150 μm.

[0066] Embodiment 19: The device of any one of claims 1 to 18, wherein the device further comprises a port providing access to the dialysis tubing from a body surface of the mammalian host and / or from a subcutaneous access element.

[0067] Embodiment 20: The device of claim 19, wherein the port is a percutaneously implantable port.

[0068] Embodiment 21: The device of claim 19 or 20, wherein the port provides conduction from the lumen of the dialysis tubing to a body surface of the mammalian host.

[0069] Embodiment 22: The device of any one of claims 19 to 21, wherein the port comprises a fixation element for fixing the port within or under the skin of the mammalian host.

[0070] Embodiment 23: A device according to any one of claims 19 to 22, wherein the port comprises a first connection element for connecting a dialysis tubing to the port.

[0071] Embodiment 24: A device according to any one of claims 19 to 23, wherein the port comprises a second connection element connecting the fixation element of the port to the extracorporeal connection head.

[0072] Embodiment 25: A device according to any one of claims 19 to 24, wherein the lumen is accessible from a body surface of the mammalian host via a port as defined herein.

[0073] Embodiment 26: A device according to any one of claims 1 to 25, wherein at least the dialysis tubing of the device is at least partially implanted intraperitoneally, subcutaneously, intraarterially or intravenously, in embodiments intraperitoneally.

[0074] Embodiment 27: A device according to any one of claims 1 to 26, further comprising at least one sensor element accessible via a port and extending at least partially within the lumen of the dialysis tubing.

[0075] Embodiment 28: The device of any one of claims 1 to 27, wherein the sensor element comprises at least one of an oxygen sensor, a glucose sensor, a pH sensor, a lactate sensor, an insulin sensor, a C-peptide sensor, an inflammatory biomarker sensor, and / or a sensor for a marker of cell viability.

[0076] Embodiment 29: A device according to any one of claims 1 to 28, wherein the device is adapted for in situ replacement of the dialysis tubing.

[0077] Embodiment 30: A device according to any one of claims 1 to 29, wherein the device is adapted for in situ replacement of the contents of a dialysis tubing.

[0078] Embodiment 31: A device according to any one of claims 1 to 31, wherein the mammalian host is a human, a laboratory animal, a livestock animal, a pet, or a companion animal, in an embodiment a human.

[0079] Embodiment 32: The device of any one of claims 1 to 32, wherein the therapeutic compound is selected from the group consisting of insulin, glucagon, factor IX, human growth hormone (huGH), calcitonin, glucagon-like peptide (GLP-1) and agonists, amylin, levodopa, somatostatin, alpha 1-antitrypsin (AAT), interleukins, and interferons.

[0080] Embodiment 33: A device according to any one of claims 1 to 33, wherein the therapeutic compound is insulin or an insulin analogue, in embodiments human insulin.

[0081] Embodiment 34: A device according to any one of claims 1 to 34, wherein the cells secreting the therapeutic compound are mammalian cells, in embodiments human cells.

[0082] Embodiment 35: A device according to any one of claims 1 to 34, wherein the cells secreting the therapeutic compound are pancreatic beta cells differentiated, in embodiments from stem cells, in embodiments from a stem cell line, in further embodiments from a pluripotent stem cell line.

[0083] Embodiment 36: A device according to any one of claims 1 to 35, wherein the cells secreting the therapeutic compound are contained in pancreatic islets or islet-like clusters.

[0084] Embodiment 37: A method for producing an implantable device according to any one of claims 1 to 36, comprising the steps of: a) filling a dialysis tube with cells secreting a therapeutic compound and a matrix material; b) at least temporarily sealing at least one end of the dialysis tubing; and c) thereby producing an implantable device.

[0085] Embodiment 38: The method of claim 37, wherein the method further comprises polymerizing the matrix material and / or at least one precursor of the matrix material in the dialysis tubing.

[0086] Embodiment 39: The method of claim 37 or 38, wherein the method further comprises washing the dialysis tubing.

[0087] Embodiment 40: In an embodiment as described in any one of claims 20 to 26, the implantable device further comprises a port, and the method further comprises fixing a dialysis tube to the port.

[0088] Embodiment 41: The method of any one of claims 37 to 40, further comprising mixing feeder cells and / or modulator cells with the cells secreting the therapeutic compound prior to filling the dialysis tubing.

[0089] Embodiment 42: A port system, comprising: I) an implantable device comprising a port according to any one of claims 20 to 26 and / or obtained or obtainable according to claim 40, II) A port system comprising an extracorporeal connection head.

[0090] Embodiment 43: The port system of claim 42, wherein the port is a percutaneously implantable port and comprises a second connection element that connects the port unit to an extracorporeal connection head.

[0091] Embodiment 44: The port system of claim 43, wherein the extracorporeal connection head can be fastened to the implantable device by a releasable fastening engagement.

[0092] Embodiment 45: A port system described in any one of claims 42 to 44, wherein the extracorporeal connection head at one end is adapted to be placed on the skin.

[0093] Embodiment 46: Cells secreting a therapeutic compound for use in treating a disease by transplanting said cells in a transplantation device according to any one of claims 1 to 36 and / or obtained or obtainable according to the method according to any one of claims 37 to 41.

[0094] Embodiment 47: Cells secreting a therapeutic compound for use in treating diabetes, hemophilia B, huGH deficiency, osteoporosis, Parkinson's disease, acromegaly, endocrine tumors, alpha 1-antitrypsin deficiency, infectious diseases, autoimmune diseases, cancer, or chronic viral infections by transplanting the cells in a transplantation device according to any one of claims 1 to 36 and / or a transplantation device obtained or obtainable according to the method according to any one of claims 37 to 41.

[0095] Embodiment 48: A method for treating and / or preventing a disease, comprising treating the disease by implanting an implantable device according to any one of claims 1 to 36 and / or a device obtained or obtainable by a method according to any one of claims 37 to 41 into a mammalian subject in need thereof.

[0096] Embodiment 49: The method of treating and / or preventing a disease according to claim 48, wherein the disease is diabetes, hemophilia B, huGH deficiency, osteoporosis, Parkinson's disease, acromegaly, endocrine tumors, alpha 1-antitrypsin deficiency, an infectious disease, an autoimmune disease, cancer, or a chronic viral infection.

[0097] All references cited herein are hereby incorporated by reference with respect to their entire disclosure content and the disclosure content specifically mentioned herein. [Brief description of the drawings]

[0098] [Figure 1] FIG. 1 is a schematic partial view of an implantable device 10 including a dialysis tube 20 and a sealing means 45. [Diagram 2] FIG. 1 is a schematic in situ view of a percutaneous embodiment of an implantable device 10. [Diagram 3] A port system 200 having a first guidance system 140. [Figure 4] 1 is a schematic diagram of a port system 200 including a first guide system 140 having an opening 170. FIG. [Diagram 5] 1 is a schematic diagram of a port system 200 having a sensor element 180. FIG. [Figure 6] FIG. 1 is a schematic in situ view of a percutaneous embodiment of an implantable device 10 including multiple dialysis tubes 20. [Figure 7A] Insulin aggregation, measured as mean fluorescence intensity (MFI) in the thioflavin T assay, induced by membranes made from the following different compounds: A) polyvinylidene fluoride (PVDF), polyethersulfone (PES), polyarylethersulfone (PAES); B) polytetrafluoroethylene (PTFE); C) polypropylene (PP) and nylon 6,6; D) polyamide (PA), polyethylene (PE), polyurethane (PU), polypropylene (PP). [Figure 7B] Insulin aggregation, measured as mean fluorescence intensity (MFI) in the thioflavin T assay, induced by membranes made from the following different compounds: A) polyvinylidene fluoride (PVDF), polyethersulfone (PES), polyarylethersulfone (PAES); B) polytetrafluoroethylene (PTFE); C) polypropylene (PP) and nylon 6,6; D) polyamide (PA), polyethylene (PE), polyurethane (PU), polypropylene (PP). [Figure 7C]Insulin aggregation, measured as mean fluorescence intensity (MFI) in the thioflavin T assay, induced by membranes made from the following different compounds: A) polyvinylidene fluoride (PVDF), polyethersulfone (PES), polyarylethersulfone (PAES); B) polytetrafluoroethylene (PTFE); C) polypropylene (PP) and nylon 6,6; D) polyamide (PA), polyethylene (PE), polyurethane (PU), polypropylene (PP). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0099] The following examples are merely illustrative of the present invention and should not be construed as limiting the scope of the present invention in any way.

[0100] Example 1: Implantable device with optional ports 1.1 Implantation device As shown in Figure 1, the implantation device 10 may include a dialysis tube 20 and a sealing means 45. As shown in Figure 1, the implantation device is open at the bottom, for example, immediately prior to loading and / or integration into port 70. The dialysis tube has a dialysis membrane 40 surrounding a lumen 30. Disposed within lumen 30 are cells secreting at least a therapeutic compound 50 and a matrix material 60.

[0101] 1.2 Percutaneous embodiments of the implantable device As shown in FIG. 2, the implantation device 10 may be adapted for percutaneous implantation. Thus, the implantation device 10 may comprise a dialysis tube 20 connected to a port 70 having a first connection element 90 connected to a first fixation element 80, and a percutaneous portion 130. The percutaneous portion 130 spans the skin 100 of the mammalian host. The first fixation element 80, located in the subcutaneous tissue, secures the port 70 to the skin 100 of the mammalian host, and together with the percutaneous portion 130, provides access to the first connection element and the dialysis tube 20 from outside the mammalian host's body. The port may provide fluid access to the lumen 30 of the dialysis tube 20, as shown in FIG. 2. However, it is also envisioned that the dialysis tube 20 is sealed at both ends, and access through the port allows for removal of the dialysis tube 20, and in embodiments, reintroduction of a new dialysis tube 20.

[0102] 1.3 Port system with first guidance system In Fig. 3, a port system 200 is shown, which comprises an implantable device 10 and an extracorporeal connection head 160. The implantable device comprises a dialysis tube 20 and a port 70, which comprises a first fixation element 80, a percutaneous portion 130, a first connection element 90 and a second connection element 150. From the first connection element 90, a first guide system 140 projects, which may guide the dialysis tube through, for example, subcutaneous tissue and / or may determine the spatial arrangement of the dialysis tube 20. As shown in Fig. 3, the first guide system 140 only partially covers the dialysis tube 20 over its longitudinal extension. However, it is also envisaged that the first guide system 140 completely covers the dialysis tube 20.

[0103] 1.4 First Guidance System with Opening As described herein above and as shown in FIG. 4, the first guide system 140 may include an opening 170, e.g., a hole, which may be introduced, for example, by laser ablation. The opening 170 of the first guide system 140 provides free diffusion access to the dialysis tube 20. As shown in FIG. 4, the diameter of the first guide system 140 may be substantially larger than the diameter of the dialysis tube 20. Thus, the first guide system 140 may also accommodate multiple dialysis tubes 20 and / or loops of dialysis tubes 20. However, the diameter of the first guide system 140 may be selected such that only one dialysis tube 20 can be accommodated within said first guide system 140.

[0104] 1.5 Sensor-equipped port system 5, the port system 200 may include one or more sensors 180 extending into the dialysis tubing 20 and allowing the recording of information regarding the state of cells secreting therapeutic compounds contained therein. The sensors 180 or their connectors may extend through the port 70, optionally through the extracorporeal connection head 160, and may be adapted for connection to a signal converter unit 190.

[0105] 1.6 In FIG. 6, a percutaneous embodiment of the implantation device 10 including a plurality of dialysis tubes 20 is shown in schematic form. As shown in FIG. 6, the implantation device 10 may be adapted for percutaneous implantation. Thus, the implantation device 10 may include a plurality of dialysis tubes 20 connected to a port 70 having a first connection element 90 connected to a first fixation element 80 and a percutaneous portion 130. The dialysis tubes 20 may be oriented in a radial order and may be supported by one or more spreader elements 210, which may be configured to hold the dialysis tubes 20 in a desired orientation, for example by comprising a spring element. The percutaneous portion 130 spans the skin 100 of the mammalian host. The first fixation element 80, located in the subcutaneous tissue, fixes the port 70 to the skin 100 of the mammalian host and, together with the percutaneous portion 130, provides access to the first connection element and the dialysis tube 20 from outside the mammalian host's body. The port may provide fluid access to the lumen 30 of the dialysis tube 20, as shown in FIG. 7. However, it is also envisioned that the dialysis tubing 20 is sealed at both ends, with access via ports allowing for removal of the dialysis tubing 20, and in embodiments, reintroduction of a new dialysis tubing 20.

[0106] Example 2: Insulin compatibility of different membrane materials 2.1 PVDF, PES and PAES Sixteen PES (polyethersulfone) or PAES (polyarylethersulfone) membrane pieces (hollow fiber, CMA 65) were transferred to an Eppendorf tube. Each piece was 3.0 cm long and 0.5 mm in diameter (total surface area approximately 15 cm). 2 The polyvinylidene fluoride (PVDF) membrane strips were placed in Eppendorf tubes (15 cm 2 Each material was incubated with 1.5 ml of insulin solution (1 mg / ml human insulin in phosphate buffered saline, PBS) for 24 h at 37° C. under rotary agitation at 300 rpm. As a positive control, insulin aggregation was induced in one sample by incubation at 70° C. for 2 h.

[0107] Thioflavin T (ThT) staining was performed to assess insulin aggregation / fibrillogenesis. 50 μl of each sample was incubated with 150 μl of PBS and 10 μl of ThT solution (450 μm) for 1 h in the dark. The mean fluorescence intensity (MFI) of the samples was analyzed using a Synergy4 plate reader (BioTek Instruments) at an excitation of λ=450 nm and an emission of λ=482 nm. The results are shown in Figure 7A). A more than two-fold increase in MFI compared to the non-aggregated insulin control (4°C) indicates undesired associated aggregation. PVDF, PES and PAES did not induce insulin aggregation and were identified as insulin-compatible materials.

[0108] 2.2 PTFE A 25 cm long polytetrafluoroethylene (PTFE) tube (diameter: 0.4 mm) was connected to an Accu-Check Spirit Combo insulin pump. The pump reservoir was filled with human insulin solution (3 mg / ml, Insuman Infusat, Sanofi). The pump, connected tubing and Eppendorf tubes for sample collection were placed in a 37°C incubator. The pump basal rate was set to 0.8 U / h (= 8 μl / h). In addition, 3 boli of 7 U (= 70 μl) were delivered within 24 hours. A total sample volume of approximately 400 μl was collected in the Eppendorf tubes over 24 hours.

[0109] Samples collected after 24 and 72 hours were analyzed for insulin aggregation using ThT staining. 50 μl of each sample was incubated with 150 μl of PBS and 10 μl of ThT solution (450 μm) in the dark for 1 hour. The mean fluorescence intensity (MFI) of the samples was analyzed using a Synergy4 plate reader (BioTek Instruments) at an excitation of λ=450 nm and an emission of λ=482 nm. The results are shown in FIG. 7B). A more than two-fold increase in MFI compared to the non-aggregated insulin control (4° C.) indicates undesired associated aggregation. PTFE did not induce insulin aggregation and was identified as an insulin-compatible material.

[0110] 2.3 PA, PE, PU, ​​and PP Polyamide (PA, approx. 30 cm 2 ), polyethylene (PE, approx. 15 cm 2 ), polyurethane (PU, approx. 30 cm 2 ) or polypropylene (PP, approx. 30 cm 2 ) were connected to an Accu-Check Spirit Combo insulin pump. All tubing diameters were 0.4 to 0.6 mm. The pump reservoirs were filled with human insulin solution (3 mg / ml, Humalog, Eli Lilly). The pump, connected tubing and sample collection Eppendorf tubes were placed in a 37°C incubator. The pump basal rate was set at 0.5 U / h (=5 μl / h). A total sample volume of approximately 120 μl was collected in each Eppendorf tube over 24 h. The insulin remaining in the insulin-compatible pump reservoirs at the end of the experiment served as a control.

[0111] Samples collected after 24 hours were analyzed for insulin aggregation using ThT staining. 50 μl of each sample was incubated with 150 μl of PBS and 10 μl of ThT solution (450 μm) for 1 hour in the dark. The mean fluorescence intensity (MFI) of the samples was analyzed using a Synergy4 plate reader (BioTek Instruments) at an excitation of λ = 450 nm and an emission of λ = 482 nm. The results are shown in Figure 7C). A more than two-fold increase in MFI compared to the non-aggregated insulin control (pump reservoir) indicates unwanted associated aggregation. PP and PE did not induce insulin aggregation and were identified as insulin-compatible materials. PA and PU showed high MFI values ​​indicating the formation of insulin aggregates. PA and PU were identified as non-compatible materials.

[0112] References: Australian Patent Application Publication No. 2020 210244 Canadian Patent No. 2190628 European Patent No. 1 420 836 Fotino et al. (2015), Pharmacol Res, 98, 76-85; International Publication No. 2014 / 202199 International Publication No. 1997 / 013474 [Explanation of symbols]

[0113] 10 Implantation devices 20 Dialysis tubing 30 Lumen of dialysis tube 40 Dialysis Membrane 45 Sealing means 50 Cells that secrete therapeutic compounds 60 Matrix Materials 70 Port 80 Fixed elements 90 First connecting element 100 Mammalian host skin 110 Subcutaneous tissue 120 Body cavities, e.g. abdomen 130 Transdermal part 140 First Guidance System 150 Second connecting element 160 External connection head 170 First Guidance System Opening 180 Sensor element 190 Signal converter unit 200 Port System 210 Spreader Element

Claims

1. A device (10) for implantation into a mammalian host, comprising: a) a dialysis tubing (20) having a lumen (30) and a dialysis membrane (40) surrounding said lumen (30), i) the dialysis tube (20) has an outer diameter of 20 μm to 600 μm; ii) a dialysis tube, the dialysis membrane (40) having a molecular weight cut-off of 25 kDa to 150 kDa and comprising at least one material selected from the group consisting of polyethersulfone, polyarylethersulfone, polyethylene, polytetrafluoroethylene, polyvinylidene fluoride, and polypropylene; b) a therapeutic composition disposed within the lumen (30) of the dialysis tubing (20), the therapeutic composition comprising a plurality of cells secreting a therapeutic compound (50) and a matrix material (60) embedding the cells secreting the therapeutic compound (50), the matrix material (60) being selected from alginate, collagen, fibrin, extracellular matrix materials, synthetic hydrogels, and acrylates; An implantable device (10) comprising:

2. The apparatus (10) of claim 1, wherein the dialysis tubing (20) has an outer diameter of 400 μm to 500 μm.

3. The device (10) of claim 1, wherein the dialysis membrane (40) has a molecular weight cut-off of 80 kDa to 100 kDa.

4. 10. The apparatus (10) of claim 1, further comprising an implantable first guide system (140) for at least partially guiding the dialysis tubing (20) through subcutaneous tissue.

5. 10. The device (10) of claim 1, further comprising a port (70) providing access to the dialysis tubing (20) from a body surface of the mammalian host and / or from a subcutaneous access element.

6. The device (10) of claim 5, wherein the port (70) is a percutaneously implantable port.

7. 6. The device (10) of claim 5, wherein the port (70) comprises an anchoring element (80) for anchoring the port (70) within or beneath the skin of the mammalian host.

8. 10. The device (10) of claim 1, wherein at least the dialysis tubing (20) of the device (10) is at least partially implanted intraperitoneally, subcutaneously, intraarterially, or intravenously.

9. 2. The apparatus (10) of claim 1, wherein the apparatus (10) is adapted for in situ replacement of the dialysis tube (20) and / or for in situ replacement of the contents of the dialysis tube (20).

10. 2. The device (10) of claim 1, wherein the therapeutic compound is selected from the group consisting of insulin, glucagon, factor IX, human growth hormone (huGH), calcitonin, glucagon-like peptide (GLP-1) and agonists, amylin, levodopa, somatostatin, alpha 1-antitrypsin (AAT), interleukins and interferons.

11. 2. The device (10) of claim 1, wherein the therapeutic compound is insulin or an insulin analogue, and the plurality of cells secreting the therapeutic compound (50) are adapted to secrete a constant amount of insulin, the amount of insulin secreted being related to the concentration of glucose present in the matrix material.

12. A method of manufacturing an implantable device (10) according to claim 1, comprising the steps of: a) filling said dialysis tubing (20) with a plurality of cells secreting a therapeutic compound (50) and a matrix material (60); b) at least temporarily sealing at least one end of said dialysis tubing (20); c) thereby producing an implantable device (10); A method comprising:

13. A port system (200), I) an implantable device (10) comprising a port (70) according to claim 5; II) an external connection head (160); A port system comprising:

14. 2. Cells secreting a therapeutic compound (50) for use in treating a disease by implanting the cells in an implantable device (10) according to claim 1.

15. 13. Cells secreting a therapeutic compound (50) for use in treating diabetes, hemophilia B, huGH deficiency, osteoporosis, Parkinson's disease, acromegaly, endocrine tumors, alpha 1-antitrypsin deficiency, infectious diseases, autoimmune diseases, cancer, or chronic viral infections by transplanting the cells in the implantable device (10) of claim 1.

Images