A retrievable intravascular implant and related systems and methods

Abstract

In some embodiments, an implant (e.g., an intravascular implant) is provided. In some embodiments, the implant is a catheter. In some embodiments, the catheter is configured to implantable in and retrievable from a subject. The catheter may be configured to be implanted in the vascular system of the subject. For example, the catheter may be a central venous catheter. In some embodiments, the catheter may contain living cells (e.g., transplanted cells). Such living cells may be encapsulated (e.g., encapsulated in a hydrogel or other polymer matrix). Advantageously, the catheters described herein may facilitate the delivery of and / or enhance the performance of transplanted cells by, for example, allowing for adequate oxygen and nutrient supply to the transplanted cells. In some embodiments, the catheter may be configured to supply a localized, sustained-release therapeutic agent to the vascular system of a subject.

Description

[0001] A RETRIEVABLE INTRAVASCULAR IMPLANT AND RELATED SYSTEMS AND METHODS RELATED APPLICATIONS

[0002] This application claims priority under 35 U.S.C. § 119(c) to U.S. Provisional Patent Application No. 63 / 779,045, filed March 27, 2025, and entitled “A Retrievable Intravascular Implant and Related Systems and Methods,” which is incorporated herein by reference in its entirety for all purposes.

[0003] TECHNICAL FIELD

[0004] The present invention generally relates to retrievable intravascular implants.

[0005] BACKGROUND

[0006] Cell based therapies have emerged as a promising approach for treating various chronic diseases. Such therapies may be particularly effective in treating diseases involving metabolic dysfunction. However, a significant challenge in current cell transplantation is limited oxygen and nutrient supply to transplanted cells. This issue is particularly critical for cells that have high metabolic demands. When these cells do not receive adequate oxygen and nutrients, their functionality is compromised, leading to poor therapeutic outcomes. Common transplantation sites, such as the subcutaneous space, often fail to meet these metabolic needs. Therefore, there is a critical need for a new transplantation platform that can overcome these limitations and create an optimal environment for transplanted cells to maintain their functionality.

[0007] SUMMARY

[0008] The present invention generally relates to retrievable intravascular implants. The subject matter of the present disclosure involves, in some cases, interrelated products, alternative solutions to a particular problem, and / or a plurality of different uses of one or more systems and / or articles.

[0009] In one aspect, implantable and / or retrievable catheters are provided. In some embodiments, the catheter comprises a first lumen, one or more secondary lumens proximate the first lumen, wherein at least a portion of a surface of the implantable catheter is semi-permeable; and wherein the one or more secondary lumens are configured for cell loading in vivo, the catheter having an overall diameter less than or equal to 5 cm.

[0010] In some embodiments, the catheter comprises a first lumen, one or more secondary lumens proximate the first lumen, a plurality of pores associated with at least a portion of a #15083003vlsurface of the implantable catheter, a reservoir associated with the one or more secondary lumens, wherein the one or more secondary lumens are configured for cell loading in vivo, and a refill septum associated with the reservoir, the catheter having an overall diameter less than or equal to 5 cm.

[0011] In another aspect, methods of forming a cell-loaded catheter are provided. In some embodiments, the method comprises providing a multi-lumen tube formed from a polymer, forming a pattern of pores on at least a portion of a surface of the tube, and flowing a fluid comprising living cells into a lumen of the catheter thereby forming the cell-loaded catheter. In some embodiments, the method comprises providing a multi-lumen tube formed from a polymer, wherein at least a portion of the surface of the tube is semi-permeable, and flowing living cells into a lumen of the catheter.

[0012] In some embodiments, methods of treating a subject are provided. In some embodiments, the method comprises implanting a catheter, wherein secondary lumen comprises a plurality of living cell clusters and after a duration of time, removing the catheter and the plurality of living cell clusters.

[0013] In another aspect, systems are provided. In some embodiments, the system comprises a catheter as described herein, wherein a secondary lumen comprises a plurality of living cell clusters and a reinforcement structure configured to support the catheter, thereby enhancing the stiffness of the catheter.

[0014] In yet another aspect, catheter loading systems are provided. In some embodiments, the system comprises a rotation jig, a motor associated with the rotation jig, the system configured to receive a multi-lumen catheter on the rotation jig, and the system configured to load at least a first lumen of the multi-lumen catheter with a plurality of living cells.

[0015] Other advantages and novel features of the present disclosure will become apparent from the following detailed description of various non-limiting embodiments of the disclosure when considered in conjunction with the accompanying figures. In cases where the present specification and a document incorporated by reference include conflicting and / or inconsistent disclosure, the present specification shall control.

[0016] BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale unless otherwise indicated. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not

[0018] #15083003vlevery component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

[0019] FIG. 1A shows a schematic cross-section of a dual-lumen catheter, according to one set of embodiments;

[0020] FIG. IB shows a perspective view of a dual-lumen catheter, according to one set of embodiments;

[0021] FIG. 2A shows a schematic cross-section of a dual-lumen catheter, according to one set of embodiments;

[0022] FIG. 2B shows a perspective view schematic of a dual-lumen catheter, according to one set of embodiments;

[0023] FIG. 3A shows a schematic cross-section of a multi-tube catheter, according to one set of embodiments;

[0024] FIG. 3B shows a schematic cross-section of a multi-tube catheter, according to one set of embodiments;

[0025] FIG. 3C shows a perspective view schematic of a multi-tube catheter, according to one set of embodiments;

[0026] FIG. 4A shows a schematic cross-section of a coiled catheter, according to one set of embodiments;

[0027] FIG. 4B shows a perspective view schematic of a coiled catheter, according to one set of embodiments;

[0028] FIG. 5 shows an illustration of a perspective and cross-sectional view of a catheter comprising clusters of living cells, according to some embodiments;

[0029] FIG. 6A shows an illustration of a dual-lumen catheter, according to one set of embodiments;

[0030] FIG. 6B shows an illustration of a dual-lumen catheter, according to one set of embodiments;

[0031] FIG. 6C shows an illustration of a coiled catheter, according to one set of embodiments; FIG. 6D shows an illustration of a multi-tube catheter, according to one set of embodiments;

[0032] FIG. 7A shows a photograph of an apparatus used to form pores in a tube, according to one set of embodiments;

[0033] FIG. 7B shows a tube comprising a pattern of pores, according to one set of embodiments;

[0034] #15083003vlFIG. 7C shows a schematic illustration of an apparatus for performing a three-point bending test;

[0035] FIG. 7D shows a comparison of the mechanical performance of catheters comprising a pattern of pores on their surfaces, according to one set of embodiments;

[0036] FIG. 7E is a chart showing measurements of flexural strength of catheters comprising a pattern of pores on their surfaces, according to one set of embodiments;

[0037] FIG. 8A shows a catheter having multiple components, according to one set of embodiments;

[0038] FIG. 8B shows a schematic of an apparatus for performing tensile strength measurements;

[0039] FIG. 8C shows a photograph of an apparatus for performing tensile strength measurements;

[0040] FIG. 8D is a chart showing the results of a tensile strength test for a catheter, according to one set of embodiments;

[0041] FIG. 8E is a chart showing the comparative tensile force at break for various components of a catheter, according to one set of embodiments;

[0042] FIG. 8F is a chart showing the tensile force at break for the overall catheter and for a commercially available catheter, according to one set of embodiments;

[0043] FIG. 8G is a table providing a summary of a coagulation test, hematology test, and thrombus test performed on a catheter, according to one set of embodiments;

[0044] FIG. 8H is a chart showing the partial thromboplastin time of the catheter relative to a negative control and a positive control, according to one set of embodiments;

[0045] FIG. 81 is a chart showing the relative erythrocyte (RBC) and leukocyte (WBC) counts normalized to a negative control for the catheter, a negative control, and a positive control, according to one set of embodiments;

[0046] FIG. 9 shows a catheter comprising multiple holes in its surface for drug infusion, according to one set of embodiments;

[0047] FIG. 10 shows a catheter comprising a refill septum and suture wings, according to one set of embodiments;

[0048] FIG. 11 shows a rotating jig for catheter loading, according to one set of embodiments; FIG. 12A shows a catheter loaded with a cell clusters in a hydrogel, according to one set of embodiments;

[0049] FIG. 12B shows the distribution of cell clusters in a catheter loaded with cell clusters in a hydrogel, according to one set of embodiments;

[0050] #15083003vlFIG. 12C is a chart showing the comparative cell cluster distribution within a catheter when using or not using a rotating jig to perform loading of the cell clusters within the catheter, according to one set of embodiments;

[0051] FIG. 13A shows a distribution of cell cluster diameters, according to one set of embodiments;

[0052] FIG. 13B shows an enlarged image of a single cell cluster, according to one set of embodiments;

[0053] FIG. 13C shows an enlarged image of a single cell cluster, according to one set of embodiments;

[0054] FIG. 13D shows a photograph of a catheter, according to one set of embodiments;

[0055] FIGS. 13E-13F show photographs of a catheter loaded with cell clusters by a hydrogel, showing the relative distribution of the cell clusters, according to one set of embodiments;

[0056] FIG. 13G shows a computer rendering of a catheter loaded with cell clusters by a hydrogel, showing the relative distribution of the cell clusters, according to one set of embodiments;

[0057] FIG. 14 shows a schematic overview of an experimental procedure for catheter testing in vitro, according to one set of embodiments;

[0058] FIG. 15A shows a comparison of cell cluster functionality in catheters having different designs, according to one set of embodiments;

[0059] FIG. 15B shows images from viability and functionality assays performed on cell clusters in a hydrogel and contained within a catheter, according to one set of embodiments;

[0060] FIG. 15C is a chart showing the functionality of cell clusters in a hydrogel and contained within a catheter at various cluster densities, according to one set of embodiments;

[0061] FIG. 15D is a chart showing the functionality of cell clusters in a hydrogel and contained within a catheter at various cluster densities, according to one set of embodiments;

[0062] FIG. 16 shows the comparative performance of bare cells, cells in a hydrogel, and cells in a hydrogel and contained within a catheter, according to one set of embodiments; FIG. 17A shows a photograph of a 20 cm-long catheter, according to one set of embodiments;

[0063] FIG. 17B is a chart showing the comparative functionality of cells contained within a 2 cm long catheter and a 20 cm long catheter, according to one set of embodiments;

[0064] FIG. 17C is a chart showing the comparative functionality of cells contained within a 2 cm long catheter and a 20 cm long catheter, according to one set of embodiments;

[0065] FIG. 18 shows a schematic overview of an experimental procedure for catheter testing in vivo, according to one set of embodiments;

[0066] #15083003vlFIG. 19 shows photographs and ultrasound scan images of in vivo insertion of a catheter, according to one set of embodiments;

[0067] FIG. 20A is a chart showing the comparative blood glucose levels in a test subject with an implanted catheter comprising cells and control subjects, according to one set of embodiments;

[0068] FIG. 20B is a chart showing the comparative AUC of a test subject with an implanted catheter comprising cells and control subjects, according to one set of embodiments;

[0069] FIG. 20C is a chart showing human insulin secretion in a test subject with an implanted catheter comprising cells before and after glucose infusion, according to one set of embodiments;

[0070] FIG. 21 A shows ex vivo insertion testing of a dual-lumen catheter, according to one set of embodiments;

[0071] FIG. 2 IB shows photographs of a dual-lumen catheter at its tip and mid-shaft positions within an explanted vessel, according to one set of embodiments;

[0072] FIGS. 21C-21H are charts showing load vs. position for six different catheter configurations, according to one set of embodiments; and

[0073] FIG. 21 J shows the annotated dimensions relative to key anatomic resistant points along an insertion path, according to one set of embodiments.

[0074] DETAILED DESCRIPTION

[0075] In some embodiments, an implant (e.g., an intravascular implant) is provided. In some embodiments, the implant is a catheter. In some embodiments, the catheter is configured to be implantable in and retrievable from a subject. In some embodiments, the catheter may be configured to be implanted in the vascular system of the subject. For example, the catheter may be a central venous catheter. In some embodiments, the catheter may contain living cells (e.g., transplanted cells). Such living cells may be encapsulated (e.g., encapsulated in a hydrogel or other polymer matrix). The living cells may also be dispersed (e.g., dispersed in and / or on a hydrogel or other polymer matrix). Advantageously, the catheters described herein may facilitate the delivery of and / or enhance the performance of transplanted cells by, for example, allowing for adequate oxygen and nutrient supply to the transplanted cells. In some embodiments, the catheter may be configured to supply a localized, sustained-release therapeutic agent to the vascular system of a subject.

[0076] In some embodiments, the systems described herein are administered to a subject (e.g., surgically, endoscopically, orally). In certain embodiments, the system may be administered

[0077] #15083003vl-1-surgically (e.g., implanted), orally (e.g., swallowed, endoscopically), rectally (e.g., endoscopically), vaginally, nasally, or uretherally. In some embodiments, upon administration of the article, living cells may be thus present at the location internal to the subject (e.g., living cells loaded within the article). In some embodiments, the location internally of the subject is the colon, the duodenum, the ileum, the jejunum, the stomach, or the esophagus. In some embodiments, the location internally of the subject is in the buccal space, in the venous system (e.g., an artery, a vein), in the respiratory system (e.g., lung), in the renal system, in the urinary system, and / or in the gastrointestinal system. As described herein, in some embodiments, an active pharmaceutical ingredient may be released during and / or after administration of the article.

[0078] As used herein, a “subject” refers to any animal such as a mammal (e.g., a human). Nonlimiting examples of subjects include a human, a non-human primate, a cow, a horse, a pig, a sheep, a goat, a dog, a cat or a rodent such as a mouse, a rat, a hamster, a bird, a fish, or a guinea pig. Generally, the invention is directed toward use with humans. In some embodiments, a subject may demonstrate health benefits, e.g., upon administration of the article.

[0079] As used herein, a “fluid” is given its ordinary meaning, i.e., a liquid or a gas. A fluid cannot maintain a defined shape and will flow during an observable time frame to fill the container in which it is put. Thus, the fluid may have any suitable viscosity that permits flow. If two or more fluids are present, each fluid may be independently selected among essentially any fluids (liquids, gases, and the like) by those of ordinary skill in the art.

[0080] In some embodiments, the catheter comprises a tube (e.g., a multi-lumen tube). In some embodiments, a surface (e.g., an external surface of the tube) of the tube may comprise a surface of one or more tubes having a lumen (e.g., a tube comprising a first lumen, one or more tubes each comprising a secondary lumen).

[0081] In some embodiments, the catheter comprises a first lumen. The first lumen may have any suitable average diameter. For example, in some embodiments, the first lumen has an average diameter of greater than or equal to 1 mm, greater than or equal to 2.5 mm, greater than or equal to 5 mm, greater than or equal to 7.5 mm, greater than or equal to 10 mm, or greater than or equal to 25 mm. In some embodiments, the first lumen has an average diameter of less than or equal to 50 mm, less than or equal to 25 mm, less than or equal to 10 mm, less than or equal to 5 mm, or less than or equal to 2.5 mm. Combinations of these ranges are also possible (e.g., in some embodiments, the first lumen has an average diameter of greater than or equal to 1 mm and less than or equal to 50 mm, or greater than or equal to 2.5 mm and less than or equal to 25 mm). Other ranges are also possible.

[0082] #15083003vlIn some embodiments, the catheter comprises one or more secondary lumens. For example, in some embodiments, the catheter comprises 1 secondary lumen, 2 secondary lumens, 3 secondary lumens, 4 secondary lumens, 5 secondary lumens, 6 secondary lumens, 8 secondary lumens, 10 secondary lumens, 12 secondary lumens, 16 secondary lumens, 20 secondary lumens, 24 secondary lumens, or more.

[0083] In some embodiments, the catheter comprises an annular secondary lumen. For example, in the non-limiting exemplary embodiments shown illustratively in FIGS. 1A-1B, the catheter may comprise a first lumen 101 and a secondary lumen 102. In some embodiments, the secondary lumen forms an annular ring having a cross-section that is concentric or nearly concentric with the first lumen (e.g., the position of the center of the cross section of the secondary may deviate only slightly from the center of the first lumen, for example by less than or equal to 10%). In some embodiments, the first lumen is useful as a lumen of a guidewire that is reversibly administered into lumen 101. In some embodiments, as shown illustratively in FIGS. 2A-2B, the first lumen 201 may comprise an oxygen generator 210 (e.g., an insertable and / or refillable oxygen generator) which is contained within the first lumen. Any of the catheters shown in FIGS. 1A-1B and FIGS. 2A-2B may be referred to as a dual lumen catheter.

[0084] In some embodiments, as described in more detail below, a plurality of cells (e.g., living cells) or other organisms may be present within with second lumen (e.g., actively loaded into the second lumen).

[0085] In some embodiments, the secondary lumen may have an annular thickness defined by the average shortest distance from the outer diameter of the secondary lumen to the inner diameter of the secondary lumen (which, in some embodiments, corresponds to the outer diameter of the first lumen). The secondary lumen may have any of a variety of suitable annular thicknesses. For example, in some embodiments, the secondary lumen has an annular thickness of greater than or equal to 5 pm, greater than or equal to 10 pm, greater than or equal to 25 pm, greater than or equal to 50 pm, greater than or equal to 75 pm, greater than or equal to 100 pm, greater than or equal to 150 pm, greater than or equal to 200 pm, greater than or equal to 250 pm, greater than or equal to 300 pm, greater than or equal to 350 pm, greater than or equal to 400 pm, greater than or equal to 450 pm, greater than or equal to 500 pm, or greater than or equal to 550 pm. In some embodiments, the secondary lumen has an annular thickness of less than or equal to 600 pm, less than or equal to 550 pm, less than or equal to 500 pm, less than or equal to 450 pm, less than or equal to 400 pm, less than or equal to 350 pm, less than or equal to 300 pm, less than or equal to 250 pm, less than or equal to 200 pm, less than or equal to

[0086] 150 pm, less than or equal to 100 pm, less than or equal to 75 pm, less than or equal to 50 pm,

[0087] #15083003vlless than or equal to 25 pm, or less than or equal to 10 m. Combinations of these ranges are also possible (e.g., in some embodiments, the secondary lumen has an annular thickness of greater than or equal to 5 m and less than or equal to 600 pm, greater than or equal to 50 pm and less than or equal to 500 pm, or greater than or equal to 250 pm and less than or equal to 500 pm). Other ranges are also possible. In some embodiments, the secondary lumen may have an annular thickness such that a single layer of encapsulated cells is present within the secondary lumen.

[0088] In some embodiments, the catheter may comprise more than one secondary lumen. For example, in the non-limiting exemplary embodiment shown in FIGS. 3A-3C, the catheter may be a multi-tube catheter. In the non-limiting embodiments shown in FIGS. 3A-3C, the multitube catheter comprises six tubes 310, each having a lumen 302, such that the catheter comprises six secondary lumens. It should be noted a multi-tube catheter could comprise any number of tubes 310, and in FIGS. 3A-3C, six tubes are shown for illustrative purposes. In some such embodiments, the tubes comprising the secondary lumens are arranged such that that they are in contact, forming a primary enclosed tube defined by the tubes comprising the secondary lumens, such that the primary enclosed tube comprises a lumen which is the first lumen 301. In some embodiments, as shown in FIG. 3B, each tube comprising one of the secondary lumens may itself comprise an additional, tertiary lumen 303. In some embodiments, the tertiary lumen may be the lumen of a guide wire catheter and / or comprise an oxygen generator as described above.

[0089] In some embodiments, the catheter comprises a tube having a secondary lumen which is wrapped around a central core to form a coil, as shown in FIGS. 4A-4B. For example, the catheter may be a coiled catheter. In FIGS. 4A-4B, the tube 410 comprises a secondary lumen 402, which is coiled as shown in FIG. 4B to form a primary tube. In some embodiments, the primary tube formed by the coil coiled tube forms a lumen which is the first lumen of the catheter.

[0090] The tube which comprises the secondary lumen of a coiled catheter and the one or more tubes comprising the one or more secondary lumens of a multi-tube catheter may have any of a variety of suitable diameters. For example, in some embodiments, the tube may have a diameter of greater than or equal to 0.25 mm, greater than or equal to 0.5 mm, greater than or equal to 0.75 mm, greater than or equal to 1 mm, greater than or equal to 1.5 mm, greater than or equal to 2 mm, greater than or equal to 2.5 mm, greater than or equal to 3 mm, greater than or equal to 3.5 mm, greater than or equal to 4 mm, or greater than or equal to 4.5 mm. In some embodiments, the tube may have a diameter of less than or equal to 5 mm, less than or equal to 4.5 mm, less than or equal to 4 mm, less than or equal to 3.5 mm, less than or equal to 3 mm,

[0091] #15083003vlless than or equal to 2.5 mm, less than or equal to 2 mm, less than or equal to 1.5 mm, less than or equal to 1 mm, less than or equal to 0.75 mm, or less than or equal to 0.5 mm. Combinations of these ranges are also possible (e.g., the tube may have a diameter of greater than or equal to 0.25 mm and less than or equal to 5 mm, or greater than or equal to 0.5 mm and less than or equal to 2.5 mm). Other ranges are also possible.

[0092] In some embodiments, the one or more secondary lumens are configured for cell loading in vivo. For example, in some embodiments, the one or more secondary lumens may comprise living cells (e.g., cells to be transplanted to a subject for cell therapy). In some embodiments, the living cells may be in the form of encapsulated cell clusters (e.g., islets). In some embodiments, the clusters may have an average diameter of greater than or equal to 10 pm, greater than or equal to 25 pm, greater than or equal to 50 pm, greater than or equal to 75 pm, greater than or equal to 100 pm, greater than or equal to 150 pm, greater than or equal to 200 pm, greater than or equal to 250 pm, greater than or equal to 300 pm, or greater than or equal to 350 pm. In some embodiments, the clusters may have an average diameter of less than or equal to 400 pm, less than or equal to 350 pm, less than or equal to 300 pm, less than or equal to 250 pm, less than or equal to 200 pm, less than or equal to 150 pm, less than or equal to 100 pm, less than or equal to 75 pm, less than or equal to 50 pm, or less than or equal to 25 pm.

[0093] Combinations of these ranges are also possible (e.g., the clusters may have an average diameter of greater than or equal to 10 pm and less than or equal to 400 pm, greater than or equal to 25 pm and less than or equal to 350 pm, or greater than or equal to 50 pm and less than or equal to 300 pm). Other ranges are also possible.

[0094] In some embodiments, the one or more secondary lumens may comprise living cells. Non-limiting examples of suitable living cells for use in accordance with the methods, articles, and systems described herein include human islet cells (primary beta cells) (e.g., for insulin secretion in diabetes treatment), glucagon-secreting alpha cells (e.g., to regulate hypoglycemia), thyroid follicular cells (e.g., for thyroid hormone replacement), stem cell-derived beta cells (e.g., for insulin secretion in diabetes treatment), and stem cell-derived hepatocyte-like cells (e.g., for liver support and / or detoxification). Other types of living cells and / or types of treatments are also possible. In an exemplary set of embodiments, the living cells are insulin-secreting cells (e.g., INS-1 cells). In some embodiments, the one or more secondary lumens may comprise living cells which are stem cells.

[0095] In an exemplary set of embodiments, the living cells are selected from the group consisting of insulin secreting beta cells, islets, stem cell-derived beta cells, pancreatic alpha

[0096] #15083003vlcells, mesenchymal stem cells, hepatocyte-like cells, thyroid follicular cells, and combinations thereof.

[0097] In some embodiments, the one or more secondary lumens may comprise an immune-protective material. In some embodiments, the immune-protective material may advantageously enhance the viability and / or functionality of the living cells in the one or more secondary lumens and / or minimize undesirable immune responses. The immune-protective material may comprise alginate, hyaluronic acid, chitosan, collagen, fibrin, and / or gelatin. In some embodiments, the immune-protective material may comprise a hydrogel (e.g., an alginate hydrogel and / or a hydrogel comprising any of the above-listed immune-protective materials). The immune-protective material may comprise a variety of other polymers and / or polymer networks, as described elsewhere herein.

[0098] As used herein, the term “hydrogel” refers to a polymer network capable of absorbing a relatively high amount of water (e.g., a high weight percentage of water as compared to the weight of the polymer network e.g., greater than 70 wt% water).

[0099] In some embodiments, the living cells may be encapsulated to form encapsulated living cells and / or encapsulated clusters of living cells comprising a core disposed within a shell. In some embodiments, the core may comprise one or more living cells, and the shell may comprise a crosslinked polymer (e.g., a non-covalently crosslinked polymer) layer. The core may have a diameter as described above for cell clusters. Advantageously, the encapsulated living cells (and / or clusters of living cells) described herein may have a number of benefits including, for example, local immune protection via a semi-permeable polymer shell, maintenance of cell viability and secretory function during encapsulation, and / or minimally invasive deliverability as described in more detail herein.

[0100] In some embodiments, the shell of the encapsulated living cells and / or encapsulated clusters of living cells may comprise any of a variety of suitable polymers. For example, the polymer may comprise an immune-protective material as described above (e.g., alginate, hyaluronic acid, chitosan, collagen, fibrin, and / or gelatin). In some embodiments, the polymer may comprise a natural polymer. For example, the natural polymer may comprise a biodegradable polymer (e.g., dextran), a water-soluble polymer capable of forming stable hydrogels (e.g., Pullulan), a non-toxic polymer (e.g., agarose), and / or a polymer that forms a structurally stable polymer network and / or has tunable degradation kinetics (e.g., silk fibroin).

[0101] In some embodiments, the polymer may comprise a synthetic polymer. For example, the synthetic polymer may comprise a non-immunogenic polymer and / or a polymer that has tunable mechanical properties (e.g., polyethylene glycol), a polymer that is biodegradable and / or

[0102] #15083003vlcommonly approved for use in biological applications (e.g., polylactic acid and / or poly(lactic-co-glycolic acid), a polymer that has slow degradation kinetics (e.g., polycaprolactone), a polymer that has slow degradation kinetics (e.g., gelatin methacryloyl), and / or a highly biocompatible polymer (e.g., zwitterionic alginate). Other synthetic polymers having these advantageous properties could be used.

[0103] As used herein, the term “crosslink” refers to a connection between two polymer strands, or a connection between two points one a single polymer strand. The crosslink may either be a chemical bond, a single atom, or multiple atoms. The crosslink may be formed by reaction of a pendant group in one polymer strand with the backbone of a different polymer strand, or by reaction of one pendant group with another pendant group. Crosslinks may exist between separate polymer strands, and may also exist between different points of the same polymer strand. As used herein, the term “polymer strand” refers to an oligomeric or polymeric chain of one monomer unit, or an oligomeric or polymeric chain of two or more different monomer units. As used herein, the term “prepolymer” refers to oligomeric or polymeric strands which have not undergone crosslinking to form a network.

[0104] As used herein, the term “crosslink moiety” or “crosslinking moiety” refers to the bond or atom(s) making up the crosslink between two polymer strands (or between different points on the same polymer strand). In some embodiments, the crosslink moiety comprises one or more chemical bonds, such as an ionic bond, a covalent bond, a hydrogen bond, Van der Waals interactions, and the like. The covalent bond may be, for example, carbon-carbon, carbonoxygen, oxygen-silicon, sulfur- sulfur, phosphorus-nitrogen, carbon-nitrogen, metal-oxygen, or other covalent bonds. The hydrogen bond may be, for example, between hydroxyl, amine, carboxyl, thiol, and / or similar functional groups. The ionic bond may comprise, for example, a polyvalent cation. Non-limiting examples of polyvalent cations include calcium, barium, strontium, iron, aluminum. Other polyvalent cations are also possible. In an exemplary embodiment, the polyvalent cation is calcium. In a preferred embodiment, the crosslinking moiety comprises non-covalent bonds.

[0105] In some embodiments, the crosslink moiety may be formed by mixing a polymer (or polymer precursor and / or monomer) with a crosslinking agent. Non-limiting examples of suitable crosslinking agents include diamine crosslinkers, dicarboxyl crosslinkers, disulfhydryl crosslinkers, dicarbonyl crosslinkers, disulfide crosslinkers, carbodiimide, NHS ester, imidoester, maleimide, haloacetyls, pryidyldisulfide, thiosulfonate, hydrazide, calcium sulphate N,N’-bis(acryloyl)cystamine, catechol-based crosslinkers (e.g., dopamine-functionalized hydrogels), and ionotropic and photo-crosslinking hybrids. In an exemplary embodiment, the

[0106] #15083003vlfirst crosslink moiety is formed from calcium sulphate (e.g., for a crosslink moiety comprising an ionic bond comprising calcium) and the second crosslink moiety is formed from a disulfide crosslinker such as N,N’-bis(acryloyl)cystamine (e.g., for a crosslink moiety comprising a covalent bond such as a disulfide bond). In another exemplary embodiment, alginate may be ionically crosslinked with calcium ions (e.g., Ca2+) and stabilized with UV-polymerizable methacrylated gelatin (UV-GelMA). Other crosslinking agents are also possible and those of ordinary skill in the art would be capable of selecting suitable crosslinking agents based upon the teachings of this specification.

[0107] In an illustrative embodiment, and without wishing to be limited as such, catechol-based crosslinkers (e.g., dopamine-functionalized hydrogels) may be potentially useful for vascular environments as these crosslinkers advantageously exhibit strong but reversible bonding in wet conditions. In another illustrative embodiment, dual mode systems (e.g., alginate ionically crosslinked with Ca2+then stabilized with UV-GelMA) may be used to provide tunable control over degradation and / or stiffness. Those of ordinary skill in the art would be capable of selecting other suitable crosslinking agents and combinations thereof based upon the teachings of this specification.

[0108] In some embodiments, the shell may have a thickness of greater than or equal to 5 microns and less than or equal to 30 microns. For example, in some embodiments, the shell has a thickness of greater than or equal to 5 microns, greater than or equal to 7.5 microns, greater than or equal to 10 microns, greater than or equal to 12.5 microns, greater than or equal to 12.5 microns, greater than or equal to 15 microns, greater than or equal to 17.5 microns, greater than or equal to 20 microns, greater than or equal to 22.5 microns, greater than or equal to 25 microns, or greater than or equal to 27.5 microns. In some embodiments, the shell has a thickness of less than or equal to 30 microns, less than or equal to 27.5 microns, less than or equal to 25 microns, less than or equal to 22.5 microns, less than or equal to 20 microns, less than or equal to 17.5 microns, less than or equal to 15 microns, less than or equal to 12.5 microns, less than or equal to 10 microns, or less than or equal to 7.5 microns. Combinations of these ranges are also possible (e.g., the shell may have thickness of greater than or equal to 5 microns and less than or equal to 30 microns, or greater than or equal to 7.5 microns and less than or equal to 25 microns). Other ranges are also possible.

[0109] In some embodiments, a catheter as described herein may comprise a reservoir associated with one or more secondary lumens of the catheter. In some embodiments, the reservoir may comprise living cells (e.g., insulin- secreting cells, stem cells, or clusters thereof, as described above) and an immune-protective material. In some embodiments, the immune-protective

[0110] #15083003vlmaterial comprises a hydrogel (e.g., an alginate hydrogel and / or a hydrogel comprising any of the immune protective materials described above for loading in the one or more secondary lumens). In some embodiments, the reservoir comprises living cells encapsulated in the immune-protective materials (e.g., the cells may be encapsulated in a hydrogel). In some embodiments, the reservoir comprises living cells and / or encapsulated living cells dispersed in the immune-protective material.

[0111] In some embodiments, the reservoir associated with the catheter may be refillable. In some embodiments, the catheter may comprise a refill septum associated with the reservoir. For example, in some embodiments, the refill septum is configured to be positioned adjacent a subject’s skin upon implantation of at the catheter in a user. The septum may allow a syringe to fluidly couple to the reservoir through the skin such that a therapeutic compound may be injected into the reservoir through the skin to replenish a supply of the therapeutic compound in the reservoir. Of course, any suitable port for allowing an external volume of fluid to be inserted into a reservoir of the catheter may be employed, as the present disclosure is not so limited. Accordingly, the catheter of exemplary embodiments described herein may be refilled so that multiple doses and / or multiple supplies of a sustained-release active pharmaceutical agent (e.g., a localized, sustained-release active pharmaceutical agent) may be delivered over a long period of time. In some embodiments, the refill septum and reservoir of the catheter may be configured such that living cells (e.g., encapsulated living cells) and / or an immune-protective material (e.g., a hydrogel) may be delivered to the reservoir of the catheter.

[0112] In some embodiments, the catheter may comprise a refill septum associated with the first lumen and / or one or more secondary lumens of the catheter. In some embodiments, the first lumen and / or one or more secondary lumens of the catheter are configured to receive one or more drugs, thereby transmitting a dose of the drug (e.g., a sustained-release dose) to a subject in which the catheter is implanted. Accordingly, the first lumen and / or one or more secondary lumens of the catheter of exemplary embodiments described herein may be refilled so that multiple doses and / or multiple supplies of a drug may be delivered over a relatively long period of time via the first lumen and / or one or more secondary lumens of the catheter. In some embodiments, the refill septum and reservoir of the catheter may be configured to deliver one or more drugs (e.g., anti-thromboresistant drugs) to a subject when the catheter is implanted in the subject.

[0113] In some embodiments, a catheter as described herein may comprise one or more holes which connect a first lumen of the catheter to the surface of the catheter. For example, in some embodiments, the catheter may comprise one or more holes which pass from the first lumen,

[0114] #15083003vlthrough one or more surfaces (e.g., surfaces associated with one or more tubes) and / or one or more secondary lumens of the catheter, and to an external surface of the catheter. In some embodiments, the holes are configured to deliver a therapeutic agent and / or drug to a subject when the catheter is implanted in the subject by allowing the therapeutic agent and / or drug to pass from the first lumen, through one or more holes, and to the surface of the catheter, thereby coming into contact with the subject’s blood and facilitating vascular delivery of the drug and / or therapeutic agent. In some embodiments, the first lumen is configured to be loaded with the drug and / or therapeutic agent. In some embodiments, the first lumen is refillable. In some embodiments, the first lumen is configured to be refilled with a drug and / or therapeutic agent via a refill septum, as described above.

[0115] In some embodiments, a catheter as described herein may have any of a variety of suitable overall diameters. For example, in some embodiments, the catheter has an overall diameter of less than or equal to 50 mm, less than or equal to 25 mm, less than or equal to 10 mm, less than or equal to 7.5 mm, or less than or equal to 5 mm. In some embodiments, the catheter has an overall diameter of greater than or equal to 2.5 mm, greater than or equal to 5 mm, greater than or equal to 10 mm, or greater than or equal to 25 mm. Combinations of these ranges are also possible (e.g., the catheter may have an overall diameter of greater than or equal to 2.5 mm and less than or equal to 50 mm, or greater than or equal to 5 mm and less than or equal to 25 mm). Other ranges are also possible.

[0116] In some embodiments, a catheter as described herein may have any of a variety of suitable lengths. For example, in some embodiments, the catheter has a length of greater than or equal to 2 cm, greater than or equal to 5 cm, greater than or equal to 10 cm, greater than or equal to 12 cm, greater than or equal to 15 cm, greater than or equal to 20 cm, greater than or equal to 25 cm, greater than or equal to 30 cm, greater than or equal to 35 cm, greater than or equal to 40 cm, or greater than or equal to 45 cm. In some embodiments, the catheter has a length of less than or equal to 50 cm, less than or equal to 45 cm, less than or equal to 40 cm, less than or equal to 35 cm, less than or equal to 30 cm, less than or equal to 25 cm, less than or equal to 20 cm, less than or equal to 15 cm, less than or equal to 12 cm, less than or equal to 10 cm, or less than or equal to 5 cm. Combinations of these ranges are also possible (e.g., the catheter may have a length of greater than or equal to 2 cm and less than or equal to 50 cm, greater than or equal to 10 cm and less than or equal to 40 cm, or greater than or equal to 20 cm and less than or equal to 50 cm). Other ranges are also possible.

[0117] In some embodiments, the catheter comprises a surface. In some embodiments, the surface is an external surface of the catheter. The surface may, for example, be part of a tube

[0118] #15083003vlwhich encloses the lumens of the catheter (e.g., the surface may be an external surface of a multi-lumen tube). In some embodiments, such as those in which the catheter comprises more than one secondary lumen, the surface may be made up of the external surfaces of the tubes which comprise the secondary lumens.

[0119] In some embodiments, at least a portion of the surface of the catheter is semi-permeable. For example, in some embodiments, at least a portion of the surface may be permeable to one or more gases. In some embodiments, at least a portion of the surface of the catheter may comprise and / or be formed from a material which is permeable to the one or more gases. In some embodiments, at least a portion of the surface is permeable to oxygen. For example, at least a portion of the surface of the catheter may comprise and / or be formed from polydimethylsiloxane (PDMS), polytetrafluoroethylene (PTFE), expanded polytetrafluoroethylene (ePTFE), polyvinyl chloride (PVC), polyurethane, or other materials which are permeable to oxygen.

[0120] In some embodiments, at least a portion of a surface of the catheter may comprise a plurality of pores. In some embodiments, the pores may allow the portion of the surface to become semi-permeable. In some embodiments, the pores may allow the surface to become permeable to oxygen, even when the surface comprises and / or is formed from a material which is not otherwise highly permeable to oxygen, such as stainless steel, cobalt-chromium alloys, nitinol, nylon, or other materials which are not permeable to oxygen or have poor oxygen permeability. A surface or portion of a surface comprising an oxygen-permeable material as described above may also comprise a plurality of pores.

[0121] In some embodiments, at least a portion of a surface of the catheter may comprise a plurality of pores having any of a variety of suitable sizes. In some embodiments, each pore may have an average diameter of greater than or equal to 0.001 mm, greater than or equal to 0.0025 mm, greater than or equal to 0.005 mm, greater than or equal to 0.0075 mm, greater than or equal to 0.01 mm, greater than or equal to 0.025 mm, greater than or equal to 0.05 mm, greater than or equal to 0.075 mm, greater than or equal to 0.1 mm, greater than or equal to 0.25 mm, greater than or equal to 0.5 mm, or greater than or equal to 0.75 mm. In some embodiments, each pore may have an average diameter of less than or equal to 1 mm, less than or equal to 0.75 mm, less than or equal to 0.5 mm, less than or equal to 0.25 mm, less than or equal to 0.1 mm, less than or equal to 0.075 mm, less than or equal to 0.05 mm, less than or equal to 0.025 mm, less than or equal to 0.01 mm, less than or equal to 0.0075 mm, less than or equal to 0.005 mm, or less than or equal to 0.0025 mm. Combinations of these ranges are also possible (e.g., each pore may have an average diameter of greater than or equal to 0.001 mm and less than or equal to 1 mm, greater than or equal to 0.0025 mm and less than or equal to

[0122] #15083003vl0.75 mm, or greater than or equal to 0.005 mm and less than or equal to 0.5 mm). Other ranges are also possible.

[0123] In some embodiments, at least a portion of a surface of the catheter may comprise pores forming any of a variety of suitable patterns. For example, in some embodiments, the catheter may comprise pores having a grid formation, a diagonal grid formation, an irregular pattern, a circular pattern, a radial pattern, a hexagonal pattern, a spiral pattern, a random distribution, or another suitable pattern. In some embodiments, the pores may be spaced at regular intervals across the portion of the surface.

[0124] In certain embodiments, at least a portion of a surface of the catheter may comprise pores in a variety of surface densities. For example, in some embodiments, greater than or equal to 1 % of the portion of the surface and less than or equal to 50 % of the portion of the surface may be occupied by pores.

[0125] In some embodiments, a surface of the catheter may comprise one or more coatings. In some embodiments, the catheter may be configured to deliver a localized, sustained-release active pharmaceutical agent (e.g., via a surface coating or another component of the catheter, such as a hydrogel loaded in the catheter). In some embodiments, the surface comprises one or more hydrophilic coatings, one or more hydrophobic coatings, one or more protein coatings, and / or one or more drug-loaded coatings. For example, in some embodiments, the surface comprises one or more microbial coatings, one or more coatings configured to improve lubricity, one or more antibiotic coatings, and / or one or more coagulant coatings. In some embodiments, the coating and / or localized, sustained-release active pharmaceutical agents may comprise one or more antimicrobials (e.g., silver and / or one or more antibiotics), one or more antibiotics (e.g., vancomycin and / or cefazolin), one or more anticoagulants (e.g., heparin), and / or one or more antithrombotic agents (e.g., low molecular weight heparin and / or rivaroxaban). The coatings and / or localized, sustained-release active pharmaceutical agents may each serve a potentially advantageous function in the catheter. For example, antimicrobials may be used to prevent infections, antibiotics may be used to treat bloodstream infections, anticoagulants may be used to prevent blood clots, and / or antithrombotic agents may be used to prevent thrombosis at an insertion site of the catheter. Any of the above-listed coatings and / or localized, sustained-release active pharmaceutical agents may be used individually or together in any combination.

[0126] According to some embodiments, the articles and methods described herein are compatible with one or more therapeutic, diagnostic, and / or enhancement agents, such as drugs, nutrients, microorganisms, in vivo sensors, and tracers. In some embodiments, the active substance, is a therapeutic, nutraceutical, prophylactic or diagnostic agent. While much of the

[0127] #15083003vlspecification describes the use of therapeutic agents, other agents listed herein are also possible. In some embodiments, one or more living cells present within the article provide a therapeutic agent (e.g., produced by the living cells, carried by the living cells, excreted by the living cells) and / or the presence of the living cells causes the subject to release one or more endogenous therapeutic agents.

[0128] Agents can include, but are not limited to, any synthetic or naturally-occurring biologically active compound or composition of matter which, when administered to a subject (e.g., a human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. For example, useful or potentially useful within the context of certain embodiments are compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals, Certain such agents may include molecules such as proteins, peptides, hormones, nucleic acids, gene constructs, etc., for use in therapeutic, diagnostic, and / or enhancement areas, including, but not limited to medical or veterinary treatment, prevention, diagnosis, and / or mitigation of disease or illness (e.g., HMG co-A reductase inhibitors (statins) like rosuvastatin, nonsteroidal anti-inflammatory drugs like meloxicam, selective serotonin reuptake inhibitors like escitalopram, blood thinning agents like clopidogrel, steroids like prednisone, antipsychotics like aripiprazole and risperidone, analgesics like buprenorphine, antagonists like naloxone, montelukast, and memantine, cardiac glycosides like digoxin, alpha blockers like tamsulosin, cholesterol absorption inhibitors like ezetimibe, metabolites like colchicine, antihistamines like loratadine and cetirizine, opioids like loperamide, proton-pump inhibitors like omeprazole, anti(retro)viral agents like entecavir, dolutegravir, rilpivirine, and cabotegravir, antibiotics like doxycycline, ciprofloxacin, and azithromycin, anti-malarial agents, and synthroid / levothyroxine); substance abuse treatment (e.g., methadone and varenicline); family planning (e.g., hormonal contraception); performance enhancement (e.g., stimulants like caffeine); and nutrition and supplements (e.g., protein, folic acid, calcium, iodine, iron, zinc, thiamine, niacin, vitamin C, vitamin D, and other vitamin or mineral supplements).

[0129] In certain embodiments, the active substance is one or more specific therapeutic agents. As used herein, the term “therapeutic agent” or also referred to as a “drug” refers to an agent that is administered to a subject to treat a disease, disorder, or other clinically recognized condition, or for prophylactic purposes, and has a clinically significant effect on the body of the subject to treat and / or prevent the disease, disorder, or condition. Listings of examples of known therapeutic agents can be found, for example, in the United States Pharmacopeia (USP), Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill, 2001; Katzung, B. (ed.) Basic and Clinical Pharmacology, McGraw-Hill / Appleton & Lange; 8th

[0130] #15083003vledition (September 21, 2000); Physician’s Desk Reference (Thomson Publishing), and / or The Merck Manual of Diagnosis and Therapy, 17th ed. (1999), or the 18th ed (2006) following its publication, Mark H. Beers and Robert Berkow (eds.), Merck Publishing Group, or, in the case of animals, The Merck Veterinary Manual, 9th ed., Kahn, C.A. (ed.), Merck Publishing Group, 2005; and “Approved Drug Products with Therapeutic Equivalence and Evaluations," published by the United States Food and Drug Administration (F.D.A.) (the “Orange Book"). Examples of drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. In certain embodiments, the therapeutic agent is a small molecule. Exemplary classes of therapeutic agents include, but are not limited to, analgesics, anti-analgesics, anti-inflammatory drugs, antipyretics, antidepressants, antiepileptics, antipsychotic agents, neuroprotective agents, antiproliferatives, such as anti-cancer agents, antihistamines, antimigraine drugs, hormones, prostaglandins, antimicrobials (including antibiotics, antifungals, antivirals, antiparasitics), antimuscarinics, anxioltyics, bacteriostatics, immunosuppressant agents, sedatives, hypnotics, antipsychotics, bronchodilators, anti-asthma drugs, cardiovascular drugs, anesthetics, anticoagulants, inhibitors of an enzyme, steroidal agents, steroidal or non-steroidal antiinflammatory agents, corticosteroids, dopaminergics, electrolytes, gastro-intestinal drugs, muscle relaxants, nutritional agents, vitamins, parasympathomimetics, stimulants, anorectics and anti-narcoleptics. Nutraceuticals can also be incorporated into the drug delivery device. These may be vitamins, supplements such as calcium or biotin, or natural ingredients such as plant extracts or phytohormones.

[0131] In some embodiments, the therapeutic agent is one or more antimalarial

[0132] drugs. Exemplary antimalarial drugs include quinine, lumefantrine, chloroquine, amodiaquine, pyrimethamine, proguanil, chlorproguanil-dapsone, sulfonamides such as sulfadoxine and sulfamethoxypyridazine, mefloquine, atovaquone, primaquine, halofantrine, doxycycline, clindamycin, artemisinin and artemisinin derivatives. In some embodiments, the antimalarial drug is artemisinin or a derivative thereof. Exemplary artemisinin derivatives include artemether, dihydroartemisinin, arteether and artesunate. In certain embodiments, the artemisinin derivative is artesunate.

[0133] In another embodiment, the therapeutic agent is an immunosuppressive

[0134] agent. Exemplary immunosuppressive agents include glucocorticoids, cytostatics (such as alkylating agents, antimetabolites, and cytotoxic antibodies), antibodies (such as those directed against T-cell recepotors or 11-2 receptors), drugs acting on immunophilins (such as

[0135] #15083003vlcyclosporine, tacrolimus, and sirolimus) and other drugs (such as interferons, opioids, TNF binding proteins, mycophenolate, and other small molecules such as fingolimod).

[0136] In certain embodiments, the therapeutic agent is a hormone or derivative thereof. Nonlimiting examples of hormones include insulin, growth hormone (e.g., human growth hormone), vasopressin, melatonin, thyroxine, thyrotropin-releasing hormone, glycoprotein hormones (e.g., luteinzing hormone, follicle-stimulating hormone, thyroid-stimulating hormone), eicosanoids, estrogen, progestin, testosterone, estradiol, cortisol, adrenaline, and other steroids.

[0137] In some embodiments, the therapeutic agent is a small molecule drug having molecular weight less than about 2500 Daltons, less than about 2000 Daltons, less than about 1500 Daltons, less than about 1000 Daltons, less than about 750 Daltons, less than about 500 Daltons, less or than about 400 Daltons. In some cases, the therapeutic agent is a small molecule drug having molecular weight between 200 Daltons and 400 Daltons, between 400 Daltons and 1000 Daltons, or between 500 Daltons and 2500 Daltons.

[0138] In some embodiments, the therapeutic agent is selected from the group consisting of active pharmaceutical agents such as insulin, nucleic acids, peptides, bacteriophage, DNA, mRNA, human growth hormone, monoclonal antibodies, adalimumab, epinephrine, GLP-1 Receptor agoinists, semaglutide, liraglutide, dulaglitide, exenatide, factor VIII, small molecule drugs, progrstin, vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, and conjugate vaccines, toxoid vaccines, influenza vaccine, shingles vaccine, prevnar pneumonia vaccine, mmr vaccine, tetanus vaccine, hepatitis vaccine, HIV vaccine Ad4-env Clade C, HIV vaccine Ad4-mGag, dna vaccines, ma vaccines, etanercept, infliximab, filgastrim, glatiramer acetate, rituximab, bevacizumab, any molecule encapsulated in a nanoparticle, epinephrine, lysozyme, glucose-6-phosphate dehydrogenase, other enzymes, certolizumab pegol, ustekinumab, ixekizumab, golimumab, brodalumab, gusellu,ab, secikinumab, omalizumab, tnf-alpha inhibitors, interleukin inhibitors, vedolizumab, octreotide, teriperatide, crispr cas9, insulin glargine, insulin detemir, insulin lispro, insulin aspart, human insulin, antisense oligonucleotides, and ondansetron.

[0139] In an exemplary embodiment, the therapeutic agent is insulin.

[0140] In some embodiments, the tissue-interfacing component described herein comprises two or more types of therapeutic agents.

[0141] In certain embodiments, the therapeutic agent is present in the tissue interfacing component at a concentration such that, upon release from the tissue interfacing component, the therapeutic agent elicits a therapeutic response.

[0142] #15083003vlA catheter as described herein may have a variety of mechanical properties. The mechanical properties of the catheter may be configured to be facilitate insertion into, retention within, and / or removal of the catheter from a subject (e.g., without causing internal injury to the subject). For example, in some embodiments, it may be desirable for a catheter to have a relatively high flexural strength (e.g., a relatively high flexural load at break as measured by a three-point bending test). In some embodiments, the catheter may have a maximum flexural load at break of greater than or equal to 1 N, greater than or equal to 1.5 N, greater than or equal to 2 N, greater than or equal to 2.5 N, greater than or equal to 3 N, or greater than or equal to 3.5 N. In some embodiments, the catheter may have a maximum flexural load at break of less than or equal to 4 N, less than or equal to 3.5 N, less than or equal to 3 N, less than or equal to 2.5 N, less than or equal to 2 N, or less than or equal to 1.5 N. Combinations of these ranges are also possible (e.g., the catheter may have a flexural strength of greater than or equal to 1 N and less than or equal to 4N, or greater than or equal to 1.5 N and less than or equal to 3.5 N). Other ranges are also possible.

[0143] In some embodiments, it may be desirable for a catheter to have a relatively high tensile strength (e.g., a relatively high tensile force at break). This may be advantageous by reducing the risk of the catheter fracturing during retrieval of the catheter from a subject after at least a portion of the catheter has been retained internal to the subject for a period of time. For example, in some embodiments, the catheter may have a tensile force at break of greater than or equal to IO N, greater than or equal to 20 N, greater than or equal to 40 N, greater than or equal to 60 N, greater than or equal to 80 N, or greater than or equal to 100 N. In some embodiments, the catheter may have a tensile force at break of less than or equal to 120 N, less than or equal to 100 N, less than or equal to 80 N, less than or equal to 60 N, less than or equal to 40 N, or less than or equal to 20 N. Combinations of these ranges are also possible (e.g., the catheter may have a tensile force at break of greater than or equal to 10 N and less than or equal to 120 N, greater than or equal to 20 N and less than or equal to 100 N, or greater than or equal to 60 N and less than or equal to 120 N). Other ranges are also possible.

[0144] In some embodiments, a catheter as described herein may have any suitable in vivo oxygen level (pO2). For example, the catheter may have an in vivo arterial oxygen level of greater than or equal to 75 mmHg, greater than or equal to 80 mmHg, greater than or equal to 85 mmHg, greater than or equal to 90 mmHg, greater than or equal to 95 mmHg, greater than or equal to 100 mmHg, or greater than or equal to 105 mmHg. In some embodiments, the catheter may have an in vivo arterial oxygen level of less than or equal to 110 mmHg, less than or equal to 105 mmHg, less than or equal to 100 mmHg, less than or equal to 95 mmHg, less than or

[0145] #15083003vlequal to 90 mmHg, less than or equal to 85 mmHg, or less than or equal to 80 mmHg.

[0146] Combinations of these ranges are also possible (e.g., the catheter may have an in vivo arterial oxygen level of greater than or equal to 75 mmHg and less than or equal to 110 mmHg, or greater than or equal to 100 mmHg and less than or equal to 110 mmHg). Other ranges are also possible.

[0147] In some embodiments, a catheter as described herein may have any suitable in vivo venous oxygen level. In some embodiments, the catheter has an in vivo venous oxygen level of greater than or equal to 5 mmHg, greater than or equal to 10 mmHg, greater than or equal to 15 mmHg, greater than or equal to 20 mmHg, greater than or equal to 25 mmHg, greater than or equal to 30 mmHg, or greater than or equal to 35 mmHg. In some embodiments, the catheter has an in vivo venous oxygen level of less than or equal to 40 mmHg, less than or equal to 35 mmHg, less than or equal to 30 mmHg, less than or equal to 25 mmHg, less than or equal to 20 mmHg, less than or equal to 15 mmHg, or less than or equal to 10 mmHg. Combinations of these ranges are also possible (e.g., the catheter may have an in vivo venous oxygen level of greater than or equal to 5 mmHg and less than or equal to 40 mmHg, or greater than or equal to 10 mmHg and less than or equal to 30 mmHg). Other ranges are also possible.

[0148] In certain embodiments, at least a portion of the catheter is configured to be retained at a location internal to a subject for a relatively long period of time after the catheter has been implanted into the subject. For example, in some embodiments, at least a portion of the catheter is retained at the location internal to the subject for period of greater than or equal to 1 day, greater than or equal to 3 days, greater than or equal to 7 days, greater than or equal to 2 weeks, greater than or equal to 1 month, greater than or equal to 2 months, greater than or equal to 6 months, or greater than or equal to 1 year. In certain embodiments, at least a portion of the catheter is retained at the location internal to the subject for less than or equal to 2 years, less than or equal to 1 year, less than or equal to 1 month, less than or equal to 1 week, or less than or equal to 3 days. Combinations of these ranges are also possible (e.g., the catheter may be configured to be retained for a period of greater than or equal to about 1 day and less than or equal to 2 years, greater than or equal to 1 week less than or equal to 6 months, or greater than or equal to 2 weeks and less than or equal to 6 months). Other ranges are also possible.

[0149] In some embodiments, the catheter is configured such that, during the duration in which at least a portion of the catheter is retained at a location internal to a subject, vascularization of the catheter does not occur, or only limited vascularization of the catheter occurs.

[0150] In some embodiments, a catheter as described herein may comprise one or more components which are configured to facilitate insertion and / or removal of the catheter in a

[0151] #15083003vlsubject. For example, in some embodiments, the catheter may comprise an insertion tip. In some embodiments, the insertion tip may comprise a conical section of the catheter having a first diameter at an end of the insertion tip which is directly proximate to and / or continuous with the main body of the catheter, and a second diameter at a distal end of the insertion tip.

[0152] In some embodiments, a catheter as described herein may comprise a guidewire. In some embodiments, the guidewire may comprise a thin, flexible wire. In some embodiments, the guidewire may comprise a metallic wire (e.g., a nitinol wire, a stainless- steel wire). In some embodiments, the guidewire comprises one or more coatings. In some embodiments, the guidewire comprises a polymer coating (e.g., a polyurethane coating, a silicone coating, a PTFE coating, etc.). In some embodiments, a distal end of then guidewire (e.g., an end of the guidewire which may be contained within and / or protrude from a distal end of an insertion tip of the catheter) may have a particular configuration. For example, in some embodiments, the distal end of the guidewire may be straight, J-shaped, or have another configuration chosen to facilitate the use of the catheter in a particular application.

[0153] In some embodiments, a catheter as described herein may comprise one or more reinforcement structures. In some embodiments, the reinforcement structure may comprise a stent. In some embodiments, the reinforcement structure is configured to enhance the stiffness of the catheter. For example, in some embodiments, the reinforcement structure may have a higher stiffness than the main body of the catheter and may thereby increase the overall stiffness of the catheter (e.g., during insertion and / or removal of the catheter in a subject).

[0154] In some embodiments, the reinforcement structure is configured to be placed adjacent to and / or around the catheter. For example, in some embodiments, the reinforcement structure may comprise a lumen which is configured to receive the catheter. In some configurations, the reinforcement structure may surround at least a portion of the main body of the catheter. In some embodiments, the catheter is configured to be removable from the support structure. For example, in some embodiments, the reinforcement structure may be placed adjacent to the catheter during insertion of the catheter into the subject, and removed after successful insertion, leaving only the catheter implanted in the subject. In some embodiments, the reinforcement structure may not be configured to be removed from the catheter. For example, in some embodiments, the reinforcement structure is configured to remain in the subject after insertion along with the catheter.

[0155] In some embodiments, the catheter may comprise one or more securement mechanisms configured to hold the catheter in place following insertion into a subject. For example, the catheter may comprise one or more suture wings which are configured to be secured to the skin

[0156] #15083003vlof a subject after insertion of the catheter (e.g., via stitching sutures through one or more openings in the suture wing). In some embodiments, the catheter may comprise one or more securement regions configured to be secured to the skin of a subject using an adhesive. In some embodiments, the adhesive may be applied to a side of the securement region which is configured to be adjacent to the skin of a subject. In some embodiments, the adhesive comprises tape and / or dressings which are configured to be placed over at least a portion of the securement region and on the skin of the subject, thereby securing the catheter.

[0157] In some embodiments, methods for making a cell-loaded catheter are described. In some embodiments, the method comprises forming pores on at least a portion of a surface of the catheter. In some embodiments, the method comprises forming a pattern of pores on at least a portion of the surface of the catheter. For example, a multi-lumen tube formed from a polymer may be provided. Pores and / or a pattern of pores may be formed on at least a portion surface of the tube by ablating, etching, performing ultrasonic drilling, and / or performing electrical discharge machining on at least a portion of the surface. In some embodiments, the ablating may comprise laser ablation.

[0158] In some embodiments, the method comprises flowing a fluid comprising living cells into a lumen of the catheter, thereby forming the cell-loaded catheter. In some embodiments, the fluid may comprise clusters of living cells (e.g., islets). In some embodiments, the fluid comprises one or more polymers. In some embodiments, the fluid comprises a hydrogel and / or one or more hydrogel precursors, a growth medium, phosphate-buffered saline (PBS), and / or a natural and / or synthetic polymer.

[0159] In some embodiments, the hydrogel and / or one or more materials which form a surface of the catheter may be non-toxic. In some embodiments, the hydrogel and / or one or more materials which form a surface of the catheter may individually or together facilitate the formation of a non-toxic environment in a cell cluster.

[0160] The term “non-toxic” refers to a substance that is not toxic (i.e., does not comprise a toxic reagent in an amount sufficient to have a damaging effect). Toxic reagents include, e.g., oxidative stressors, nitrosative stressors, proteasome inhibitors, inhibitors of mitochondrial function, ionophores, inhibitors of vacuolar ATPases, inducers of endoplasmic reticulum (ER) stress, and inhibitors of endoplasmic reticulum associated degradation (ERAD). In some embodiments a toxic reagent selectively causes damage to nervous system tissue. Toxic reagents include compounds that are directly toxic and reagents that are metabolized to or give rise to substances that are directly toxic. It will be understood that the term “toxic compounds" typically refers to reagents that are not ordinarily present in a cell’s normal environment at

[0161] #15083003vlsufficient levels to exert detectable damaging effects. However, in some cases, the toxic reagents may be present in a cell’s normal environment but at concentrations significantly less than present in the auxiliary materials described herein. Typically, toxic reagents exert damaging effects when present at a relatively low concentration, e.g., at or below 1 mM, e.g., at or below 500 microM, e.g., at or below 100 microM. It will be understood that a toxic reagent typically has a threshold concentration below which it does not exert detectable damaging effects. The particular threshold concentration will vary depending on the agent and, potentially, other factors such as cell type, other agents present in the environment, etc.

[0162] In some embodiments, a catheter loading system is provided. In some embodiments, the system comprises a rotation jig. In some embodiments, the system is configured to receive a multi-lumen catheter on the rotation jig. For example, in some embodiments, the rotation jig comprises an extended member which is configured to fit within a lumen of the catheter (e.g., a first lumen of the catheter). In some embodiments, the rotation jig comprises a clamp configured to hold stationary at least one end of the catheter. In some embodiments, the system comprises a motor associated with the rotation jig. In some embodiments, the motor is configured to drive rotation of the rotation jig.

[0163] In some embodiments, the rotation jig is configured to rotate at a rate of greater than or equal to 1 RPM, greater than or equal to 5 RPM, greater than or equal to 10 RPM, greater than or equal to 15 RPM, greater than or equal to 20 RPM, greater than or equal to 25 RPM, greater than or equal to 30 RPM, greater than or equal to 35 RPM, greater than or equal to 40 RPM, greater than or equal to 45 RPM, greater than or equal to 50 RPM, or greater than or equal to 55 RPM. In some embodiments, the rotation jig is configured to rotate at a rate of less than or equal to 60 RPM, less than or equal to 55 RPM, less than or equal to 50 RPM, less than or equal to 45 RPM, less than or equal to 40 RPM, less than or equal to 35 RPM, less than or equal to 30 RPM, less than or equal to 25 RPM, less than or equal to 20 RPM, less than or equal to 15 RPM, less than or equal to 10 RPM, or less than or equal to 5 RPM. Combinations of these ranges are also possible (e.g., the rotation jig may be configured to rotate at a rate of greater than or equal to 1 RPM and less than or equal to 60 RPM, greater than or equal to 5 RPM and less than or equal to 50 RPM, or greater than or equal to 10 RPM and less than or equal to 40 RPM). Other ranges are also possible.

[0164] In some embodiments, the system is configured to load at least a first lumen of the multilumen catheter with a plurality of living cells. In some embodiments, the system is configured to load a fluid comprising living cells into a lumen of the catheter (e.g., to flow a fluid comprising living cells into a lumen of the catheter). In some embodiments, the fluid comprises

[0165] #15083003vla growth medium, phosphate-buffered saline (PBS), and / or one or more components selected from alginate, hyaluronic acid, chitosan, collagen, fibrin, gelatin, natural polymers (e.g., as described in more detail above), and synthetic polymers (e.g., as described in more detail above). In some embodiments, the system is configured to load a semi-solid material (e.g., a gel) comprising living cells into at least a first lumen of the catheter. In some embodiments, the semi-solid material comprises a hydrogel (e.g., an alginate hydrogel).

[0166] In some embodiments, a method of treating a subject is described. In some embodiments, the method comprises implanting a catheter as described herein, wherein one or more secondary lumens of the catheter comprise living cell clusters, in a subject.

[0167] In some embodiments, the method comprises removing the catheter and the plurality of living cells from the subject after a duration of time. The duration of time may be of any of a variety of suitable lengths. For example, in some embodiments, the duration may be greater than or equal to 1 day, greater than or equal to 3 days, greater than or equal to 7 days, greater than or equal to 2 weeks, greater than or equal to 1 month, greater than or equal to 2 months, greater than or equal to 6 months, or greater than or equal to 1 year. In certain embodiments, the duration may be less than or equal to 2 years, less than or equal to 1 year, less than or equal to 1 month, less than or equal to 1 week, or less than or equal to 3 days. Combinations of these ranges are also possible (e.g., the duration may be greater than or equal to about 1 day and less than or equal to 2 years, greater than or equal to 1 week less than or equal to 6 months, or greater than or equal to 2 weeks and less than or equal to 6 months). Other ranges are also possible.

[0168] In some embodiments, a catheter as described herein may be configured to be removed from a subject after a duration of time without requiring surgical intervention (e.g., in some embodiments, the catheter is configured to be removed under local anesthesia). In some embodiments, the catheter is configured such that vascularization of the catheter does not occur. In some embodiments, as described above, the catheter may have a high tensile strength and / or high flexural strength, which may allow for the catheter to be removed from the subject without causing fracturing of the catheter and / or internal injury to the subject.

[0169] In some embodiments, a system for inserting a catheter into a subject is provided. In some embodiments, the system comprises a catheter as described herein, wherein one or more secondary lumens of the catheter comprise living cell clusters. In some embodiments, the system comprises a reinforcement structure configured to support the catheter. In some embodiments, the support structure is configured to enhance the stiffness of the catheter. In some embodiments, the support structure comprises a stent. In some embodiments, the reinforcement structure is configured to be separable from the catheter (e.g., in some

[0170] #15083003vlembodiments, the reinforcement structure may be present only during insertion of the catheter into a subject). The support structure may comprise and / or be formed from any of the materials described above for forming surfaces of the catheter and / or tubes.

[0171] In some embodiments, a method of making a system for insertion of a catheter into a subject is provided. In some embodiments, the method comprises providing a catheter as described herein, wherein one or more secondary lumens of the catheter comprise living cell clusters. In some embodiments, the method comprises providing a reinforcement structure associated with the catheter. In some embodiments, the reinforcement structure may be configured to enhance the stiffness of the catheter. In some embodiments, the method may comprise placing the reinforcement structure around and / or adjacent to the catheter prior to insertion of the catheter into a subject.

[0172] EXAMPLES

[0173] The following examples are intended to illustrate certain embodiments described herein, including certain aspects of the present invention, but do not exemplify the full scope of the invention.

[0174] EXAMPLE 1

[0175] Multi-lumen catheters having various configurations were designed and analyzed. As shown in FIG. 5 and FIGS. 6A-6B, a dual-lumen catheter comprising first lumen was designed. In one exemplary embodiment, as shown in FIG. 6A, the first lumen comprises a guidewire. In another exemplary embodiment, as shown in FIG. 6B, the first lumen comprises an oxygen generator (e.g., an insertable and / or refillable oxygen generator). In both of these exemplary embodiments, the first lumen is defined by a primary tube. The designed dual-lumen catheters comprise a secondary lumen, the secondary lumen comprising a hydrogel and cell clusters. The secondary lumen of the dual-lumen catheter comprises an annular lumen, wherein the first lumen occupies the region defined by the inner diameter of the secondary lumen. Two configurations of this dual-lumen catheter were contemplated: design DC-250, comprising a secondary lumen having an annular thickness of 250 pm (e.g., a maximum distance between a cell cluster and the blood of a subject into which the catheter has been inserted of 250 pm), and design DC-500, comprising a secondary lumen having an annular thickness of 500 pm (e.g., a maximum distance between a cell cluster and the blood of a subject into which the catheter has been inserted of 500 pm).

[0176] As shown in FIG. 6C, a coil-shaped catheter was designed. The coil-shaped catheter comprises a secondary tube having a secondary lumen comprising a hydrogel and cell clusters.

[0177] #15083003vlIn this exemplary embodiment, a catheter was designed in which the secondary tube is coiled to form a primary tube having a first lumen. A first a coil-shaped catheter was designed, the catheter comprising a secondary tube with an inner diameter of 500 pm (such that a maximum distance between a cell cluster and the blood of a subject into which the catheter has been inserted is 250 pm) and a length of 3.3 m, where the secondary tube is coiled to form a primary tube having a total diameter of 4.7 mm. This design was denoted CC-250. A second coilshaped catheter was designed, the catheter comprising a secondary tube with an inner diameter of 1 mm (such that a maximum distance between a cell cluster and the blood of a subject into which the catheter has been inserted is 500 pm) and a length of 1.6 m, where the secondary tube is coiled to form a primary tube having a total diameter of 4.7 mm. This design was denoted CC-500.

[0178] As shown in FIG. 6D, a multi-tube catheter comprising a first lumen and multiple secondary lumens was designed. In such designs, the multi-tube catheter may comprise a plurality of tubes. One multi-tube catheter in this exemplary embodiment, as shown in FIG. 6D, was designed to have 6 individual tubes, each having a secondary lumen. The 6 individual tubes were positioned in a ring shape, such that each individual tube was in contact with two other tubes, forming an enclosed primary tube whose walls comprised the surfaces of the individual tubes. The primary tube had a lumen, which is the first lumen. Two additional embodiments of the multi-tube catheter were designed. In one embodiment, the catheter comprises 8 tubes, and each tube comprises a lumen, which is a secondary lumen and which comprises a hydrogel and living cell clusters. In this embodiment, which was denoted MC-500, each tube had an inner diameter of 1 mm, such that a maximum distance between a cell cluster in a secondary lumen and the blood of a subject into which the catheter has been inserted is 500 pm. In another embodiment that was designed in this example, a multi-tube catheter comprising 24 tubes, where each tube comprises a lumen which is a secondary lumen, and which comprises a hydrogel and living cell clusters. This design was denoted MC-250, and each of the 24 had an inner diameter of 0.5 mm, such that a maximum distance between a cell cluster in the secondary lumen and the blood of a subject into which the catheter has been inserted is 250 pm.

[0179] In another embodiment that was designed in this example and shown in FIG. 6D, each tube in the plurality of tubes comprises a secondary lumen and a tertiary lumen, wherein the secondary lumen is annular lumen and the tertiary lumen occupies the region defined by the inner diameter of the secondary lumen. In an embodiment that was designed in this example, each tube comprises a secondary lumen having an annular thickness of 250 pm, such that a maximum distance between a cell cluster and the blood of a subject into which the catheter has

[0180] #15083003vlbeen inserted of 250 pm. The tertiary lumen of each tube was designed such that it could be occupied by a guide wire and / or an oxygen generator (e.g., an insertable and / or refillable oxygen generator).

[0181] Table 1 below presents the physical dimensions and specifications of the catheters DC-250, DC-500, CC-250, CC-500, MC-250, and MC-500 as described above.

[0182] Table 1: Dimensions and specifications of multi-lumen catheter designs Catheter Secondary tube Max. Total volume of secondary lumen(s) Design dimensions blood / cell (cm3)

[0183] I.D. (mm) O.D. (mm) distance (pm) 20cm long 30cm long 40 cm long DC-250 3.9 4.4 250 0.65 0.98 1.3 DC-500 3.4 4.4 500 1.22 1.84 2.45 CC-250 0.5 0.7 250 0.66 0..99 1.32 CC-500 1.0 1.2 500 1.3 1.95 2.6 MC-250 0.5 0.7 250 0.94 1.41 1.88 MC-500 1.0 1.2 500 1.26 1.88 2.51

[0184]

[0185] EXAMPLE 2

[0186] Tubes for use in a multi-lumen catheter were designed, fabricated, and subjected to mechanical testing. Tubes formed from polytetrafluoroethylene (PTFE) were provided. PTFE was chosen as the material for the tubes due to its excellent durability, flexibility, biocompatibility, and hemocompatibility, as well as other advantageous properties such as its high melting point and dielectric strength. Additionally, PTFE is compatible with the use of CO2 laser-based fabrication techniques due to its high carbon content and ability to absorb optical energy from the laser.

[0187] Pores were formed on the surfaces of each of the three tubes using a CO2 laser operated at 60 W. The tubes were mounted on a rotating axis mount (as shown in FIG. 7A), and pulsing of the CO2 laser at regular interval was used to ablate material from the tube to a vapor or fine powder. The pulsing of the laser was controlled to form different patterns of pores in the surface of each of the three tubes. Clean pores were formed, as shown in FIG. 7B, without observed degradation of the PTFE surrounding the pores. Deburring of the pores was then performed using several processes including scrubbing with a nylon brush, sanding with sandpaper, sonication, and exposure to compressed air.

[0188] #15083003vlThe mechanical performance of the tubes was then tested using a three-point bending test. A schematic of an experimental apparatus for performing a three-point bending test is shown in FIG. 7C. Three tubes were tested, each having a grid pattern of pores with different pore densities, as shown in FIG. 7D. The maximum load and slope of each tube was measured and compared to a commercially available catheter, as shown in Table 2. It was observed that the high-pore density tube had a maximum load and slope comparable to that of the commercial catheter. The deflection of each tube was also determined when subjected to a force approaching its maximum load, as shown in FIG. 7E.

[0189] Table 2: Flexural properties of tubes with patterned pores

[0190] Pore Density Maximum Load (N) Slope

[0191] Low 3.330 1.2424

[0192] Medium 3.288 1.1199

[0193] High 2.010 0.7477

[0194] None (Commercial 2.133 0.7080

[0195] Catheter)

[0196]

[0197] A catheter comprising a tube with patterned pores was also fabricated and subjected to tensile testing. The catheter comprised an insertion tip A, main catheter body B, and securement portion C, as shown in FIG. 8A. A schematic of a tensile testing apparatus is shown in FIG. 8B, and a photograph of the same is shown in FIG. 8C. A chart showing tensile load on the catheter vs. position for one trial of tensile testing on the catheter body is shown in FIG. 8D. FIG. 8E provides a summary of the tensile force at break for each component of the catheter, as well as for a commercially available catheter. FIG. 8F provides a summary of the tensile force at break for the overall catheter and for a commercially available catheter. It was observed that the main catheter body had a substantially higher tensile force at break than the commercially available catheter. The securement portion of the catheter was also observed to have a significantly higher tensile force at break than the commercially available catheter.

[0198] The hemocompatibility of the catheter was then tested via a coagulation test, hematology test, and thrombus test, as shown in FIG. 8G. FIG. 8H provides a summary of the partial thromboplastin time of the catheter relative to a negative control (comprising polyethylene) and a positive control. The difference between the catheter and the negative control was not significant. FIG. 81 provides a summary of the relative erythrocyte (RBC) and leukocyte (WBC) counts normalized to a negative control for the catheter, a negative control, and a positive

[0199] #15083003vlcontrol. The difference between the catheter and the negative control was not significant. These results indicate that the catheter was highly hemocompatible.

[0200] EXAMPLE 3

[0201] Catheters were designed fabricated comprising a refill septum configured for local drug delivery. The catheters were designed to have a plurality of holes in an outer surface of the catheter which were configured for drug delivery, as shown in FIG. 9. The catheters designed and fabricated in this example comprised a refill septum as shown in FIG. 10, configured to deliver a drug to a lumen of the catheter (e.g., a first lumen, a secondary lumen). In one catheter that was designed, the refill septum was configured to deliver a drug to a guidewire catheter having a lumen, where the lumen of the guidewire catheter was the first lumen of the catheter.

[0202] These catheters were designed to support several surface modifications to facilitate the successful implantation of the catheter in a subject with minimal complications. For example, the catheters were configured to be compatible with hydrophilic surface modifications in order to decrease protein reabsorption; to be compatible with protein coatings, such as albumin anti-thrombogenic surface modifications; to be capable of being functionalized with hydrophobic polymers to facilitate the absorption of proteins and repel water masses; to be capable of being impregnated with antibiotics and / or active pharmaceutical agents or combinations of active pharmaceutical agents and / or antibiotics, such as chlorhexidine / silver sulfadiazine, minocycline / rifampin, or silicone minocycline / rifampin.

[0203] EXAMPLE 4

[0204] A system was developed to facilitate the loading of a catheter with a hydrogel comprising clusters of living cells. A rotating jig, as shown in FIG. 11, was designed and fabricated. The rotating jig has a member configured to receive a catheter such that when the jig rotates, the body of the catheter is rotated as well. For catheter loading experiments, a catheter comprising pores on at least a portion of its surface was provided and placed on the rotating jig and rotated as a hydrogel and cell clusters were introduced to the catheter. This coated the interior surface of the catheter with the hydrogel and cell clusters, ensuring homogeneous distribution of the cell clusters.

[0205] FIG. 12A shows images of a 20 cm-long catheter comprising pores in its surface after loading with a 2% alginate hydrogel comprising 0.5 % rhodamine and clusters of living cells. FIG. 12B shows a close-up image of cell cluster distribution in a catheter loaded without the use of the rotating jig, and FIG. 12C is a chart showing the distribution of cell clusters through the

[0206] #15083003vlbottom, middle, and top of the catheter when the catheter is loaded with the rotating jig and without the rotating jig. It was observed that the use of the rotating jig resulted in substantially greater homogeneity in the distribution of the cell clusters in the catheter. Experiments were performed in which the catheter was loaded with the hydrogel and cell clusters as the jig and catheter rotated at rates of 10 RM, 25 RPM, and 40 RPM. It was observed that a rotation rate of 25 RPM resulted in the most even distribution of the cell clusters within the catheter, without undesirable effects, like cell clusters escaping the catheter through the pores in the surface of the catheter, that may occur at very high rotation rates.

[0207] EXAMPLE 5

[0208] In vitro characterization of several dual-lumen catheters having pores in at least a portion of the catheter surface was performed. The catheters were loaded with a hydrogel and clusters of INS- 1 cells, where the clusters had diameters of 100-300 pm with an average diameter of approximately 200-250 pm, as shown in FIG. 13A. FIGS. 13B-13C show images of individual cell clusters comprising a plurality of cells.

[0209] The structure of a shortened dual-lumen catheter (having a length of 2 cm) is shown in FIG. 13D, showing that the catheter has a main catheter body and a guidewire catheter having a first lumen. FIGS. 13E-13G show the distribution of the cell clusters within the catheter, showing that a homogeneous distribution of the cell clusters along the inner surface of the catheter was achieved.

[0210] FIG. 14 shows a schematic diagram of the experimental procedure used for in vitro characterization of the catheter. First, the cell clusters were formed under normal oxygenation conditions. The catheter was then loaded with a hydrogel and the cell clusters using the system described in Example 4. The catheter was then stored, with the cell clusters and the hydrogel under hypoxic conditions (in an approximately 5 % oxygen environment) for 7 days. Catheters having a variety of cell cluster concentrations relative to the hydrogel were tested, and the corresponding islet equivalent units were determined, as shown in Table 3.

[0211] Table 3: Islet equivalent density for different cell cluster concentrations

[0212] Cluster concentration (%) 3 10 20 30

[0213] K IEQs 2 7 14 21

[0214]

[0215] Additional testing was performed to determine the impact of the lumen structure on the catheter performance. As shown in FIG. 15 A, the functionality of cell clusters was studied for

[0216] #15083003vlthree different lumen structures containing cell clusters of different diameters. It was observed that a catheter having the design DC-500 as described in Example 1 loaded with an alginate hydrogel and cell clusters with a diameter of 50-200 pm holds the most function IEQ per unit length of the catheter, while a catheter having the design DC-250 as described in Example 1 loaded with an alginate hydrogel and cell clusters with a diameter of 50-200 pm has the highest per-cluster functionality, with over 99% of clusters being functional. It was generally observed that cell clusters having a diameter of 50-200 pm results in a greater percentage of functional clusters in the catheter, as these clusters are better oxygenated than those with larger diameters. For example, a catheter having the design DC-500 as described in Example 1 loaded with a hydrogel and cell clusters with a diameter of 50-300 pm held the least functional IEQ per unit length among the catheters tested, along with the lowest overall per-cluster functionality.

[0217] The biocompatibility of the catheters with the INS-1 cell clusters was also studied using a viability assay (a live / dead staining assay), and an insulin expression assay (an

[0218] immuno staining assay) to study cell clusters at a variety of cluster densities, as shown in FIG. 15B. While the cell clusters exhibited viability (i.e., were alive) at a variety of cluster densities, the results of the insulin secretion assay, as shown in FIGS. 15C and 15D, indicated that the functionality of the cell clusters was impacted by cluster density. It was observed that a cluster density of approximately 10 % resulted in the cell clusters in the catheter having the greatest functionality.

[0219] Finally, the insulin secretion kinetics of the cells in a hydrogel contained within a catheter and cells in a hydrogel not contained within a catheter were studied and compared to the insulin secretion kinetics of bare cells, as shown in FIG. 16. It was observed that the insulin secretion kinetics of cells in a hydrogel were comparable in the bare cells, regardless of whether the cells were contained within the catheter. The insulin secretion kinetics were also studied in a scaled-up catheter having a length of 20 cm (as shown in FIG. 17A), and these results were compared to the those measured in a catheter having a length of 2 cm. As shown in FIG. 17B, total insulin secretion was observed to be approximately 9 times higher in the 20 cm catheter than in the 2 cm catheter. The insulin secretion kinetics of the cell clusters in a hydrogel within the 20 cm device was also shown to be comparable to those of bare cells., as shown in FIG. 17C.

[0220] EXAMPLE 6

[0221] In vivo characterization of a dual-lumen catheter having pores in at least a portion of the catheter surface was performed. A schematic description of the in vivo characterization process is shown in FIG. 18. First, the catheter was loaded with an alginate hydrogel and clusters of

[0222] #15083003vlINS-1 cells. The catheter was loaded with the hydrogel and cells using the system described in Example 4. The catheter was then inspected to ensure that the cells are living and evenly distributed.

[0223] The catheter was then implanted into the jugular vein of a porcine test subject. The catheter insertion was a minimally invasive procedure, which was similar to conventional intravenous catheter insertion. After insertion, placement of the device was confirmed with ultrasonic scanning. Images of the insertion site and ultrasonic scanning images are shown in FIG. 19.

[0224] After insertion of the catheter, the blood glucose level of the subject was monitored. Blood collection was also performed. A glucose injection was then performed, and continued glucose monitoring and blood collection was performed. The blood collected at each phase was tested for human insulin secretion levels. FIGS. 20A and 20B show the results of the blood glucose level monitoring. It was seen that the subject which had the catheter implanted had an overall lower and more stable blood glucose level than test subjects in a control group, which did not have implanted catheters. FIG. 20C shows the levels of human insulin secretion measured at different points after the insertion of the catheter into the subject. It was observed that the level of human insulin secretion increased significantly after a glucose infusion was performed, indicating that the implanted cells within the catheter were alive, active, and capable of performing the function of secreting human insulin.

[0225] EXAMPLE 7

[0226] Ex vivo insertion testing of a dual-lumen catheter having pores in at least a portion of the catheter surface was performed in a tissue phantom, as shown in FIG. 21 A. Representative photographs showing the device at positions A (tip) and B (mid-shaft) within an explanted vessel are shown in FIG. 2 IB Intraluminal force-position profiles, showing load (N) vs. position (mm) for six catheter / device configurations are shown in FIGS. 21C-21I. Annotated dimensions indicate key anatomical resistance points along the insertion path are shown in FIG.

[0227] 21J.

[0228] While several embodiments of the present invention have been described and illustrated herein, those of ordinary skill in the art will readily envision a variety of other means and / or structures for performing the functions and / or obtaining the results and / or one or more of the advantages described herein, and each of such variations and / or modifications is deemed to be within the scope of the present invention. More generally, those skilled in the art will readily

[0229] #15083003vlappreciate that all parameters, dimensions, materials, and configurations described herein are meant to be exemplary and that the actual parameters, dimensions, materials, and / or configurations will depend upon the specific application or applications for which the teachings of the present invention is / are used. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. It is, therefore, to be understood that the foregoing embodiments are presented by way of example only and that, within the scope of the appended claims and equivalents thereto, the invention may be practiced otherwise than as specifically described and claimed. The present invention is directed to each individual feature, system, article, material, and / or method described herein. In addition, any combination of two or more such features, systems, articles, materials, and / or methods, if such features, systems, articles, materials, and / or methods are not mutually inconsistent, is included within the scope of the present invention.

[0230] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.”

[0231] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified unless clearly indicated to the contrary. Thus, as a non-limiting example, a reference to “A and / or B,” when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A without B (optionally including elements other than B); in another embodiment, to B without A (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0232] As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and / or” as defined above. For example, when separating items in a list, “or” or “and / or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of’ or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e. “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting

[0233] #15083003vlessentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law.

[0234] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0235] As used herein, “wt%” is an abbreviation of weight percentage. As used herein, “at%” is an abbreviation of atomic percentage.

[0236] Any terms as used herein related to shape, orientation, alignment, and / or geometric relationship of or between, for example, one or more articles, structures, forces, fields, flows, directions / trajectories, and / or subcomponents thereof and / or combinations thereof and / or any other tangible or intangible elements not listed above amenable to characterization by such terms, unless otherwise defined or indicated, shall be understood to not require absolute conformance to a mathematical definition of such term, but, rather, shall be understood to indicate conformance to the mathematical definition of such term to the extent possible for the subject matter so characterized as would be understood by one skilled in the art most closely related to such subject matter. Examples of such terms related to shape, orientation, and / or geometric relationship include, but are not limited to terms descriptive of: shape - such as, round, square, gomboc, circular / circle, rectangular / rectangle, triangular / triangle, cylindrical / cylinder, elliptical / ellipse, (n)polygonal / (n)polygon, etc.; angular orientation - such as perpendicular, orthogonal, parallel, vertical, horizontal, collinear, etc.; contour and / or trajectory - such as, plane / planar, coplanar, hemispherical, semi-hemispherical, line / linear, hyperbolic, parabolic, flat, curved, straight, arcuate, sinusoidal, tangent / tangential, etc.; direction

[0237] #15083003vl- such as, north, south, east, west, etc.; surface and / or bulk material properties and / or spatial / temporal resolution and / or distribution - such as, smooth, reflective, transparent, clear, opaque, rigid, impermeable, uniform (ly), inert, non- wettable, insoluble, steady, invariant, constant, homogeneous, etc.; as well as many others that would be apparent to those skilled in the relevant arts. As one example, a fabricated article that would described herein as being “ square" would not require such article to have faces or sides that are perfectly planar or linear and that intersect at angles of exactly 90 degrees (indeed, such an article can only exist as a mathematical abstraction), but rather, the shape of such article should be interpreted as approximating a “square," as defined mathematically, to an extent typically achievable and achieved for the recited fabrication technique as would be understood by those skilled in the art or as specifically described. As another example, two or more fabricated articles that would described herein as being “aligned" would not require such articles to have faces or sides that are perfectly aligned (indeed, such an article can only exist as a mathematical abstraction), but rather, the arrangement of such articles should be interpreted as approximating “aligned,” as defined mathematically, to an extent typically achievable and achieved for the recited fabrication technique as would be understood by those skilled in the art or as specifically described.

[0238] Some embodiments may be embodied as a method, of which various examples have been described. The acts performed as part of the methods may be ordered in any suitable way. Accordingly, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include different (e.g., more or less) acts than those that are described, and / or that may involve performing some acts simultaneously, even though the acts are shown as being performed sequentially in the embodiments specifically described above.

[0239] Use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed, but are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term) to distinguish the claim elements.

[0240] When a portion (e.g., a layer, a structure, a region) is “on”, “adjacent”, “above”, “over”, “overlying”, or “supported by” another portion, it can be directly on the portion, or an intervening portion (e.g., layer, structure, region) may also be present. Similarly, when a portion is “below” or “underneath” another portion, it can be directly below the portion, or an intervening portion (e.g., layer, structure, region) may also be present. A portion that is “directly adjacent”, “directly on”, “immediately adjacent”, “in contact with”, or “directly supported by” another portion means that no intervening portion is present. It should also be understood that

[0241] #15083003vlwhen a portion is referred to as being “on”, “above”, “adjacent”, “over”, “overlying”, “in contact with”, “below”, or “supported by” another portion, it may cover the entire portion or a part of the portion.

[0242] In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03.

[0243] #15083003vl

Claims

CLAIMSWhat is claimed is:

1. An implantable and / or retrievable catheter, comprising:a first lumen;one or more secondary lumens proximate the first lumen;wherein at least a portion of a surface of the implantable catheter is semi-permeable; andwherein the one or more secondary lumens are configured for cell loading in vivo, the catheter having an overall diameter less than or equal to 5 cm.

2. A method of making a cell-loaded catheter, comprising:providing a multi-lumen tube formed from a polymer;forming a pattern of pores on at least a portion of a surface of the tube; and flowing a fluid comprising living cells into a lumen of the catheter thereby forming the cell-loaded catheter.

3. A method as in claim 2, wherein the forming the pattern of pores comprises ablating, etching, performing ultrasonic drilling, and / or performing electrical discharge machining.

4. A method of treating a subject, comprising:implanting a catheter as in claim 1, wherein secondary lumen comprises a plurality of living cell clusters; andafter a duration of time, removing the catheter and the plurality of living cell clusters.

5. A method of making a cell-loaded catheter, comprising:providing a multi-lumen tube formed from a polymer, wherein at least a portion of a surface of the tube is semi-permeable;flowing living cells into a lumen of the catheter.#15083003vl6. A system, comprising:a catheter as in claim 1, wherein a secondary lumen comprises a plurality of living cell clusters; anda reinforcement structure configured to support the catheter, thereby enhancing the stiffness of the catheter.

7. A method of making a system for insertion of a catheter, comprising:providing a catheter as in claim 1, wherein a secondary lumen comprises a plurality of living cell clusters; andproviding a reinforcement structure associated with the catheter, wherein the reinforcement structure is configured to enhance the stiffness of the catheter.

8. An implantable and / or retrievable catheter, comprising:a first lumen;one or more secondary lumens proximate the first lumen;a plurality of pores associated with at least a portion of a surface of the implantable catheter;a reservoir associated with the one or more secondary lumens, wherein the one or more secondary lumens are configured for cell loading in vivo,' anda refill septum associated with the reservoir,the catheter having an overall diameter less than or equal to 5 cm.

9. A catheter loading system, comprising:a rotation jig;a motor associated with the rotation jig;the system configured to receive a multi-lumen catheter on the rotation jig; and the system configured to load at least a first lumen of the multi-lumen catheter with a plurality of living cells.

10. A system as in claim 9, wherein the motor is configured to rotate at greater than or equal to 5 RPM and less than or equal to 50 RPM, such that the plurality of living cells remain substantially homogeneously distributed within the first lumen.#15083003vl11. A catheter as in any preceding claim, wherein the living cells are encapsulated.

12. A catheter as in any preceding claim, further comprising a refill septum.

13. A catheter as in any preceding claim, wherein the surface comprises one or more hydrophilic coatings, one or more hydrophobic coatings, one or more protein coatings, and / or one or more drug-loaded coatings.

14. A catheter as in any preceding claim, having an overall diameter of less than or equal to 10 mm.

15. A catheter as in any preceding claim, wherein the catheter has an in vivo oxygen level (pCh) of greater than or equal to 10 venous and / or greater than or equal to 100 arterial.

16. A catheter as in any preceding claim, wherein the one or more secondary lumens comprise a hydrogel.

17. A catheter as in any preceding claim, wherein the one or more secondary lumens have a cross-sectional dimension of greater than or equal to 200 microns and less than or equal to 1 micron.

18. A catheter as in any preceding claim, wherein a thickness of the secondary lumen is such that a single layer of encapsulated cells is present within the secondary lumen.

19. A catheter as in any preceding claim, wherein an average diameter of each pore is greater than or equal to 0.001 mm and less than or equal to 1 mm.

20. A catheter as in any preceding claim, wherein the catheter comprises PDMS, Polyurethane, Polyvinyl chloride, PTFE, stainless steel, cobalt-chromium alloy, nitinol, ePTFE, nylon, any combinations thereof, or the like.#15083003vl21. A catheter as in any preceding claim, further comprising an insertion tip.

22. A catheter as in any preceding claim, further comprising a guide wire.

23. A catheter as in any preceding claim, having a tensile force at break of greater than or equal to 60 N.

24. A catheter as in any preceding claim, having an overall diameter of less than or equal to 5 mm.

25. A catheter as in any preceding claim, wherein the at least a portion of the surface that is semi-permeable is permeable to one or more gases.

26. A catheter as in any preceding claim, wherein the at least a portion of the surface that is semi-permeable is permeable to oxygen.

27. A catheter as in any preceding claim, wherein the at least a portion of the surface that is semi-permeable comprises pores.

28. A catheter as in any preceding claim, wherein the surface comprises one or more antimicrobial coatings, one or more coatings configured to improve lubricity, one or more antibiotic coatings, one or more antithrombotic coatings, and / or one or more anticoagulant coatings.

29. A catheter as in any preceding claim, wherein the catheter is configured to deliver a localized, sustained-release active pharmaceutical agent.

30. A catheter as in any preceding claim, wherein the coating and / or localized, sustained-release active pharmaceutical agent comprises one or more of silver, vancomycin, cefazolin, heparin, low molecular weight heparin, rivaroxaban, or the like.#15083003vl31. A catheter as in any preceding claim, wherein the plurality of living cells are selected from the group consisting of insulin secreting beta cells, islets, stem cell-derived beta cells, pancreatic alpha cells, mesenchymal stem cells, hepatocyte-like cells, thyroid follicular cells, and combinations thereof.

32. A catheter as in any preceding claim, wherein the fluid comprises growth medium, alginate, PBS, or the like.#15083003vl

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