Implantable capsule

Abstract

An implantable capsule comprising a cell-containing portion (2) including a porous membrane (5) surrounding a cell-containing chamber (13) for containing therein immortalized cells in a liquid medium for secreting a therapeutic agent, the capsule further comprising a cell support matrix (7) inserted within the cell-containing chamber (13) configured to align the immortalized cells within the cell-containing chamber.

Description

[Technical Field]

[0001] The present invention relates to an implantable capsule for encapsulating cells for the release of therapeutic proteins or adjuvants. The present invention can be used in particular in the field of encapsulating immortalized cell lines for the release of therapeutic proteins or adjuvants. [Background technology]

[0002] Cell encapsulation technology allows for the long-term and / or localized administration of macromolecules in a variety of areas. This technology is based on the implantation into a subject of one or more biocompatible capsules containing genetically modified cells for the production of a therapeutic protein of interest. This type of capsule generally consists of a semipermeable membrane that provides mechanical protection for the modified cells, thus preventing contact between the cells and the host's immune cells, thereby prolonging the survival of the encapsulated cells. In addition, the semipermeable membrane allows the influx of nutrients and oxygen to the implanted cells and the outflow of the protein of interest to the host, thus enabling sustained production.

[0003] Ex vivo gene therapy using removable encapsulated cellular implants has been developed as an effective strategy for local and / or long-term delivery of therapeutic proteins. In particular, modulating the activity of a patient's immune system is considered to be an innovative approach to treating various disorders, and therapeutic schemes using genetically engineered encapsulated cells have been developed, such as the long-term administration of monoclonal antibodies for passive immunization against neurodegenerative diseases and the local delivery of cytokines as adjuvants for anti-cancer vaccines (Non-Patent Document 1 and Non-Patent Document 2).

[0004] Recently, a technique for anticancer immunization using encapsulated cells secreting granulocyte-macrophage colony-stimulating factor (GM-CSF) has been developed. Genetically modified allogeneic cells (MVX-1 cells) enable the standardized release of GM-CSF, which has immunoprotective and enhancing activities useful for tumor regression. Patient immunization is performed in healthy skin distant from the tumor deposit by combining two capsules containing irradiated autologous tumor cells and MVX-1 cells producing huGM-CSF at a concentration of more than 20 ng / 24 h. This allows the production of GM-CSF at the injection site and exposes the immune system to tumor-associated antigens (TAAs) expressed by the autologous tumor cells. Local expression of GM-CSF recruits and activates antigen-presenting cells (APCs), which induce both antibody-dependent cell-mediated cytotoxicity (ADCC) and cytotoxic T lymphocyte responses at the injection site and throughout the body (Patent Document 1). The results of a clinical trial using such capsules are reported in Non-Patent Document 3.

[0005] To optimize the application of encapsulation technology to humans, it is absolutely essential to generate safe, effective, and implantable human cell lines as a platform for in vivo secretion of recombinant proteins of interest. Therefore, there is a need to develop capable cell lines that are particularly suitable for encapsulation technology in terms of safety and long-lasting efficacy. Furthermore, for some applications, cells must be frozen for storage and transportation, and there is great interest in developing capsules that ensure high levels of cell viability during storage and transportation, especially after thawing frozen cells, in order to advance therapeutic strategies using encapsulated cells.

[0006] Implanted capsules may remain in the patient's body for extended periods ranging from several days to several months, depending on the application and treatment regimen. For patient comfort, particularly to facilitate capsule implantation and removal while minimizing discomfort, a particularly compact, small-diameter implant is desirable. However, the internal volume of the capsule and the surface area of ​​the membrane in contact with the surrounding tissue affect cell viability and, therefore, the amount of therapeutic protein or adjuvant released from the capsule.

[0007] It is therefore desirable to have a mechanism that allows for efficient cell encapsulation with high yields and release rates of desired therapeutic agents, particularly for compact implantable capsules. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2017 / 064571 [Non-patent literature]

[0009] [Non-Patent Document 1] Lathuiliere et al., 2015, Int.J.Mol.Sci., 16, 10578~10600 [Non-patent document 2] Schwenter et al., 2011, Cancer Gene Therapy., 18, 553-562 [Non-patent document 3] Annals of Oncology, 2015, 26 (Suppl. 8): 1-4. 10.1093 / annonc / mdv513 Summary of the Invention [Problem to be solved by the invention]

[0010] In light of the foregoing, it is an object of the present invention to provide an implantable capsule for encapsulating cells for the release of a therapeutic agent that is compact, easily implantable and removable, and that allows for a high yield and release rate of the desired therapeutic agent.

[0011] It would be advantageous to provide an implantable capsule that is well suited for encapsulating both adherent and non-adherent cells.

[0012] It would also be advantageous to provide an implantable capsule for cell encapsulation that preserves cell viability over time.

[0013] It would also be advantageous to provide an implantable capsule for cell encapsulation that can be used in different procedures with different types of cells.

[0014] It would also be advantageous to provide an implantable capsule that is easy to insert and remove with minimal patient discomfort.

[0015] It would also be advantageous to provide an implantable capsule that can be frozen and thawed while maintaining the encapsulated cells under favorable survival conditions such that the ability of the cells to secrete high levels of a protein of interest is retained after thawing. [Means for solving the problem]

[0016] The object of the present invention has been achieved by providing a mechanism according to claim 1.

[0017] Disclosed herein is an implantable capsule including a cell-containing portion including a porous membrane surrounding a cell-containing chamber for containing therein immortalized cells in a liquid medium for secreting a therapeutic agent, the implantable capsule further including a cell support matrix inserted within the cell-containing chamber configured to align the immortalized cells within the cell-containing chamber, the cell support matrix including at least one yarn.

[0018] "Yarn," as it is commonly understood, means a plurality of strands of fibers braided or spun together into a single strand.

[0019] In one advantageous embodiment, said at least one yarn consists of or comprises a polyester material.

[0020] In one advantageous embodiment, the cell support matrix comprises a plurality of said yarns.

[0021] In an advantageous embodiment, the plurality of yarns is in the range of 5 to 20 yarns, preferably in the range of 5 to 15 yarns, for example around 10 yarns.

[0022] In one advantageous embodiment, the yarn extends within the cell containment chamber for substantially the entire length of the chamber or at least 80 percent of the length of the cell containment chamber.

[0023] In one advantageous embodiment, the cell containing chamber comprises polyester yarn.

[0024] In one advantageous embodiment, the cell storage portion further includes a membrane support mounted within the cell storage chamber configured to provide structural support for the porous membrane, the membrane support consisting of or including a coil made of a biocompatible material, for example, a stainless steel coil.

[0025] In one advantageous embodiment, the capsule further comprises an extractor portion coupled to the extractor end of the cell containing portion configured to allow extraction of the implantable capsule from the implantation site with a surgical tool, the extractor portion comprising a withdrawal string.

[0026] In one advantageous embodiment, the withdrawal string is made of polypropylene string.

[0027] In one advantageous embodiment, the extractor portion comprises an anchor tube (8) having a cavity into which the anchor portion (15) of the withdrawal string (9) is inserted and adhered.

[0028] In one advantageous embodiment, the anchor tube consists of or comprises a polyurethane material.

[0029] In one advantageous embodiment, the extractor portion is connected to the cell storage portion by a connection portion including a connector, the connector including a portion inserted into the extractor end of the porous membrane and a second portion inserted into the connection end of the anchor tube.

[0030] In one advantageous embodiment, the connector is glued to the anchor tube and the cell containing portion by means of an adhesive, in particular a light-curing adhesive, for example of the light-curing urethane methacrylate type.

[0031] In one advantageous embodiment, the capsule has an outer diameter in the range of 0.5 mm to 3 mm, preferably in the range of 0.8 mm to 1.5 mm, and a length in the range of 5 mm to 25 mm, preferably in the range of 8 mm to 20 mm.

[0032] In one advantageous embodiment, the ratio of the length to the diameter of the capsule is in the range of 5-20.

[0033] Further objects and advantageous aspects of the present invention will become apparent from the claims, the following detailed description and the accompanying drawings.

[0034] The invention will now be described with reference to the accompanying drawings, in which: [Brief explanation of the drawings]

[0035] [Figure 1] 1 is a schematic diagram of an implantable capsule according to one embodiment of the present invention. [Figure 2] FIG. 2 is a cross-sectional view taken along line II-II in FIG. [Figure 3] FIG. 3 is a cross-sectional view similar to FIG. 2, with the inner matrix of the capsule removed. [Figure 4]FIG. 4 is a detailed view of circle IV in FIG. 3. [Figure 5] FIG. 3 is a detailed view of circle V in FIG. 2. [Figure 6] 1 is a graph showing the results of a test using a conventional capsule and a capsule according to one embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0036] With reference to the drawings, an implantable capsule 1 according to one embodiment of the invention comprises a cell-containing portion 2 and an extractor portion 3 connected to each other by a connector 4. The cell-containing portion 2 has a substantially cylindrical outer shape with a diameter that can typically be in the range of 0.5 mm to 3 mm, and a length that can typically be in the range of 5 mm to 20 mm, for example around 10 mm. The ratio L / D of the length L to the diameter D is preferably in the range of 5 to 20, preferably in the range of 5 to 15. The capsule can be implanted in the patient's tissue by means of an implantation tool that is per se well known in the field of implants and does not need to be described further here.

[0037] The cell-containing portion 2 includes a porous membrane 5 configured to allow therapeutic agents produced by the encapsulated cells 24 to pass through the membrane into the surrounding tissue and to allow bodily fluids, electrolytes, and nutrients for the cells 24 to pass from the surrounding tissue through the membrane and into the capsule. Thus, the porosity and type of membrane can depend on the particular application and type of cells to be contained within the capsule. In one example, the membrane is in the form of a polyethersulfone (PES) membrane having a porosity of around 0.65 μm, for example, configured to allow passage of target molecules through the membrane. An example of a membrane that can be used in the present invention is described in detail below.

[0038] One exemplary embodiment of the membrane comprises polyethersulfone due to its biocompatible chemical composition, structural properties, and inherent membrane performance such as excellent flow rate, downstream cleanliness, low protein binding affinity, etc. This material can be extruded into small tubing in a variety of shapes and diameters.

[0039] Depending on the protein to be secreted and the site of implantation of the device, the cell-containing portion 2 may take the form of a flat plate as described in Lathuillere et al., 2014, Biomaterials 35 780-790, or WO 2014 / 173441, or a hollow fiber such as those described in Lathuillere et al., 2015, supra.

[0040] The cell storage section 2 can store, for example, approximately 1.0 × 10 cells depending on the purpose. 4 pieces ~ cells 8×l0 5 between cells (e.g., 1.0 × 10 4 pieces, 5.0×10 4 pieces, 1.0×10 5 pieces, 3.0×10 5 pieces, 5.0×10 5 pieces, 8×10 5 Pieces or 10 6 An effective amount of cells, such as 1000 (10 ...

[0041] The porous membrane 5 surrounds the cell-containing chamber 13 and a membrane support 6 within the cell-containing chamber 13. The membrane support serves to mechanically support the porous membrane, maintaining the stability of the volume of the cell-containing chamber 13 and preventing membrane rupture. In the illustrated embodiment, the membrane support is in the form of a coil, in particular a stainless steel coil known per se, for example as described in WO 2017 / 0645701. The membrane support 6 also serves to secure the extractor part 3 by the connector 4.

[0042] In the illustrated embodiment, the connection part 4 includes a connector 10 having a portion 10a inserted into the membrane support 6, specifically, in this example, into a cylinder surrounded by a stainless steel coil. The diameter of the connector insertion portion 10a can be set to fit the extractor end of the coil so that they are firmly connected to each other. The connection part 4 further includes a fixing portion 10b for hooking the anchor 8 of the extractor part 3. In the illustrated embodiment, the anchor 8 is in the form of a tube, preferably a polyurethane (PU) tube, fitted over the second end 10b of the connector 10. An adhesive 18a can be applied to the connector 10 prior to insertion of the extractor end 12b of the cell-containing part and the connecting end 8a of the anchor 8 on the connector 10. The adhesive can advantageously be in the form of a light-curing adhesive, for example, of the light-curing urethane methacrylate type (e.g., Dymax 1187 M SV).

[0043] The extractor portion 3 serves to provide a means for withdrawing the implant from the patient's tissue at the end of its use. In the illustrated embodiment, the extractor portion further includes a withdrawal string 9 including an anchor portion 15 secured to the anchor tube 8 and a thread portion 16 extending beyond the anchor tube that is configured to allow the thread to be captured by a surgical tool to withdraw the implantable capsule. In the illustrated embodiment, the withdrawal string 9 is made of a biocompatible yarn or thread, for example of the polypropylene type (such as Prolene™ suture).

[0044] In one embodiment, a single thread extends into hollow anchor tube 8 and includes knot 15a, anchor portion 15 being held within the tube by an adhesive, such as a light-curable adhesive as described above, with the knot increasing the strength of the attachment of the withdrawal thread to the anchor tube. Thus, the withdrawal thread is flexible and very thin to reduce patient discomfort and allow for easy removal of the implant.

[0045] It may be mentioned that the extractor portion 3 may have different shapes and configurations with the aim of allowing a surgical tool to grasp the implant and extract it from the patient's tissue.

[0046] In one variation, the withdrawal string may be secured directly to or integral with connector 10 without the presence of an anchor tube. In such a variation, the connector may include, for example, an opening to allow the thread to pass through, allowing the implanted capsule to be withdrawn from the patient's tissue. Advantageously, polyurethane tubing, or any other material with reasonable mechanical and biological properties, provides a structure to support the attachment of the withdrawal string. This may also be used as a support for tweezers during handling, whether during assembly or implantation.

[0047] The cell-containing portion 2 further includes a cell support matrix 7 inserted within the cell-containing chamber 13. In a preferred embodiment, the cell support matrix 7 includes one or more yarns 14, preferably a plurality of yarns, of a biocompatible material extending longitudinally within the cell-containing chamber 13. In a preferred embodiment, the yarns extend from at or nearest the extractor end 12b of the membrane 5 to at or nearest the cell-loading end 12a. Preferably, the yarns span the entire length or a majority of the length of the cell-containing chamber 13. In a preferred embodiment, the yarns can be advantageously made of clinical-grade polyester (PE), which is known per se and has already been approved for surgical implant applications. Such polyester yarns are typically used for suturing tissue within a patient's body. An example of a polyester yarn that can be used in a preferred embodiment of the present invention is 44 / 27-PET-5540-FTT-SS (Textile Development Associates, Inc.). This material is a 40-denier, 27-filament yarn made of textured polyester.

[0048] The cell support matrix 7 has been found to substantially improve the performance of immortalized cells contained in the cell containment chambers, increasing their activity and durability in therapeutic drug release over time, particularly for adherent cells. Such adherent cells include, for example, genetically engineered cells useful in cell therapy, such as genetically engineered immortalized human myoblasts, mouse myoblasts, human retinal pigment epithelial cells, stem cells, stem cell-derived cell lines, and the like. Somehow, it has been found that these cells 24 tend to align along the fibers of the yarn 14, thus improving cell density and spacing, optimized for therapeutic drug release and nutrient uptake. The yarn also advantageously provides a large overall surface area for cells to attach to.

[0049] In one exemplary embodiment, immortalized human myoblast cells secreting GM-CSF are loaded into the cell-containing portion 2 of the capsule of the present invention. Such capsules are useful in personalized anti-tumor cell immunotherapy.

[0050] Cells are placed in the cell housing in a cell growth medium appropriate for the cell type, such as Ham's F12 or DMEM supplemented with growth factors or fetal bovine serum, and for cells to be frozen, a freezing medium / cryopreservative, such as glycerol, is also added to the cell growth medium.

[0051] In one exemplary embodiment, cell-containing cavity 13 may contain, for example, 5 to 20 yarns 14 arranged in parallel within the cavity and spanning substantially the entire length of the cavity. The yarns may be inserted into cell-containing cavity 13 by pulling one end of the yarn through the cavity, and connector 4 may be attached to extractor end 12b of cell-containing portion 2 after membrane support 6 and yarns 14 have been attached within porous membrane 5.

[0052] It may be stated that the cell support matrix 7 may be pre-assembled to the membrane support 6, for example by inserting it through the inside of the coil, and then the pre-assembled coil and cell support matrix may be inserted into the tubular porous membrane 5.

[0053] Thus, the cell support matrix 7, particularly in the form of yarns 14, has the highly beneficial effect of optimizing the ordered distribution of cells within the cell-containing chamber for a given volume, improving secretion yield and rate. Furthermore, this configuration allows for easy lengthening or shortening of the cell-containing section by simply changing the cut length of the yarns to the corresponding length of the porous membrane tube and coil of membrane support 6. Moreover, the use of well-characterized implantable biocompatible polyesters does not adversely affect the safety of the device.

[0054] It has also been observed that the presence of cell support matrix 7 allows the contained cells to be frozen and thawed without affecting cell viability. This is particularly advantageous because the presence of matrix 7 improves the freezing and thawing properties of the capsules, allowing them to be stored in a frozen state for extended periods of time, ready for use in treating a patient when required. In particular, the improved distribution of cells, and in particular attached cells, along the yarns appears to contribute to maintaining a high percentage of viability during the freezing and thawing process.

[0055] Cells in liquid medium can be inserted into the cell storage chamber 13 by a cell insertion device 20 (only partially and diagrammatically shown in the illustration) that includes an outlet nozzle 22 inserted into the cell loading end 12a of the porous membrane 5.

[0056] The implantable capsule 1 can also be supplied in a pre-assembled arrangement with a cell loading device attached. In this embodiment, the nozzle 22 of the cell loading device can be attached to the cell loading end 12a of the membrane, for example, by adhesive 18c, such as a light-curable adhesive as already described above. The cell loading device can include a catheter tube to allow cells in a liquid medium to be injected into the cell-containing chamber of the capsule via the catheter, with air contained within the cell-containing capsule being forced through the porous membrane 5.

[0057] However, as noted above, the capsules may be filled with immortalized cells and media in a ready-to-use state, with the cell-containing end 12 hermetically sealed with a plug (not shown), and then frozen until needed for patient treatment.

[0058] According to one particular embodiment, immortalized human myoblast cells suitable in the context of the present invention may be derived from primary human myoblast cells, which have been further genetically engineered to express CDK4 and hTERT, retain myoblast characteristics, and secrete a protein of interest, such as a human, humanized, or chimeric monoclonal antibody (or recombinant protein (e.g., murine or human)).

[0059] According to a further particular aspect, a suitable immortalized human myoblast cell line in the context of the present invention may be the immortalized human myoblast cell line deposited at CCOS under accession number 1902, or a composition or progeny thereof, which may be further engineered to secrete proteins. For example, such cells may be advantageously transduced to express a target protein of interest under the control of a promoter that is hyperactivated in hypoxic conditions, such as a PGK (phosphoglycerate kinase) promoter, in particular the human phosphoglycerate kinase (hPGK) promoter as described in Salmon, 2013, Methods Mol Biol.; 945:417-48.

[0060] According to a further specific embodiment, immortalized human myoblast cells suitable in the context of the present invention may be derived from primary human myoblast cells, which have been further genetically engineered to express CDK4 and hTERT, retain myoblast characteristics, and secrete GM-CSF. For example, an immortalized human myoblast cell line suitable in the context of the present invention may be the genetically engineered immortalized myoblast cells that secrete GM-CSF deposited under CCOS 1901 (a derived cell line deposited under CCOS 1902). [Example]

[0061] In vitro and in vivo studies of the delivery of human GM-CSF by the capsules of the present invention In the following experiment, two types of implantable capsules are compared: capsules as shown in FIG. 1 for groups A and B, and a capsule as described in Patent Document 1 (conventional capsule) for group C for comparison. Group A: The capsules are loaded with the cells of the present invention (an immortalized human myoblast cell line expressing human GM-CSF (the cell line deposited under the number CCOS1901). Group B: Capsules are loaded with a control cell line: K562 human erythroleukemia cells, which express human GM-CSF. Group C: Capsules are loaded with the same control cell line: K562 human erythroleukemia cells expressing human GM-CSF.

[0062] Conventional capsules do not contain a support matrix and are therefore not suitable for loading adherent cells such as human myoblasts. To compare the efficiency of two different capsules to produce huGM-CSF over time, we used the K562 human erythroleukemia cell line, which expresses human GM-CSF.

[0063] The data for Groups B and C provide a direct comparison of the performance of the capsules of the present invention, as they are a direct comparison of two different capsules containing the same genetically engineered cell line expressing the same therapeutic protein of interest. The data for Group A confirm that the combination of the capsules of the present invention with adherent cells, such as immortalized human myoblast cells, is particularly advantageous over the standard capsule, K562 human erythroleukemia cells (Group C), for expression of the protein of interest as GM-CSF.

[0064] Approximately 800,000 cells were loaded into the capsules under sterile culture conditions. The capsules were maintained in culture medium at 37°C and 5% CO2. Delivery of human GM-CSF was quantified in the culture medium using an ELISA (Kit No. KHC2011, Thermo Fischer) and reported in ng / 24 h (Figure 6A).

[0065] The capsules were implanted in the subcutaneous tissue of mice for one week. After sacrifice, the capsules were removed from the animals and placed in culture medium to quantify human GM-CSF delivery (Figure 6B). In addition, GM-CSF was quantified in mouse serum (Figure 6C) and the subcutaneous tissue surrounding the capsule (Figure 6D).

[0066] These data confirm that the capsules of the present invention are particularly useful for culturing adherent cells, such as immortalized human myoblast cells, because they enable sustained, stable, and most efficient GM-CSF production by the encapsulated cells both in vitro and in vivo. [Explanation of symbols]

[0067] 1 capsule 2 Cell storage area 12 Cell storage end 12a Cell loading end 12b Extractor end 5 Porous membrane, PES membrane 13 Cell storage chamber, cell storage cavity 6 Membrane support, coil, stainless steel coil 7. Cell Support Matrix 14 Yarn, Polyester Yarn 3 Extractor part 8 anchor tube 8a Connection end 9 Removal line 15 Anchor part 15a anchor knot 16 Thread part 18a Adhesive 4 Connecting part 10 Connectors 18b Adhesives, (photo)curable adhesives 20 Cell loading device 22 outlet nozzle, connection (to the capsule of the cell loading device) 18c adhesive 24 cells D Membrane diameter (internal) L membrane length L / D length / diameter ratio

Claims

1. An implantable capsule comprising a cell-containing portion (2) including a porous membrane (5) surrounding a cell-containing chamber (13) for containing immortalized cells in a liquid medium for secreting a therapeutic agent, a cell support matrix (7) including at least one yarn (14) inserted into said cell containing chamber (13), configured to align immortalized cells within said cell containing chamber; The cell storage portion further includes a membrane support (6) configured to provide structural support for the porous membrane (5) and mounted in the cell storage chamber (13), The implantable capsule is characterized in that the membrane support comprises a coil made of a biocompatible material, the cell support matrix (7) being inserted inside the coil.

2. 10. The implantable capsule of claim 1, wherein at least one of the yarns is made of or comprises a polyester material.

3. 2. The implantable capsule of claim 1, wherein the cell support matrix (7) comprises a plurality of the yarns.

4. 4. The implantable capsule of claim 3, wherein the plurality of yarns ranges from 5 to 20 yarns.

5. 2. The implantable capsule of claim 1, wherein the yarn extends within the cell containing chamber for substantially the entire length of the cell containing chamber or for at least 80 percent of the length of the cell containing chamber.

6. 2. The implantable capsule of claim 1, wherein the cell-containing chamber (13) comprises polyester yarn.

7. an extractor portion (3) connected to the extractor end (12b) of the cell-containing portion, the extractor portion (3) being configured to allow extraction of the implantable capsule from the implantation site by a surgical tool; 2. The implantable capsule of claim 1, wherein the extractor portion comprises a withdrawal string (9).

8. 8. An implantable capsule according to claim 7, wherein the withdrawal string (9) is made of polypropylene string.

9. 8. The implantable capsule of claim 7, wherein the extractor portion comprises an anchor tube (8) having a cavity into which the anchor portion (15) of the withdrawal string (9) is inserted and adhered.

10. 10. The implantable capsule of claim 9, wherein the anchor tube (8) consists of or comprises a polyurethane material.

11. The extractor portion (3) is connected to the cell storage portion (2) by a connecting portion (4) including a connector (10), 8. The implantable capsule of claim 7, wherein the connector (10) comprises a portion (10a) inserted into the extractor end (12b) of the porous membrane (5) and a second portion (10b) inserted into the connection end (8a) of the anchor tube (8).

12. 12. The implantable capsule of claim 11, wherein the connector (10) is adhered to the anchor tube (8) and the cell-containing portion (2) by an adhesive (18a).

13. 10. The implantable capsule of claim 1, wherein the outer diameter of the capsule ranges from 0.5 millimeters to 3 millimeters and the length ranges from 5 millimeters to 25 millimeters.

14. 10. The implantable capsule of claim 1, wherein the capsule has a length to diameter ratio in the range of 5-20.

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