Implant designed for releasing a bioactive compound in a region to be treated of subject in need

Abstract

The invention concerns an Implant (14) for delivering a bioactive compound, comprising a body (141) extending along a longitudinal axis (XX), the body (141) consisting in a cylinder comprising a top base (142) and a bottom base (143) and a groove (144) formed on the body (141), the groove (143) extending helically on the body (141) along the longitudinal axis, the implant being a cylinder which is helically twisted along the longitudinal axis (XX) for comprising a non-regular transversal section so that the implant (14) is adapted for hanging the tissue of a region of interest of a subject to be treated.

Description

[0001] TITLE: Implant designed for releasing a bioactive compound in a region to be treated of subject in need

[0002] TECHNICAL FIELD

[0003] The present disclosure relates to a surgical tool in particular a laparoscopic tool designed to insert an implant designed for releasing a bioactive compound in a region to be treated. The present disclosure also relates to the implant and to a surgical method using such a tool and / or the implant.

[0004] In particular, the present disclosure relates to a device releasing dihydrostestosterone (DHT) over a certain period, e.g., several years, at a given implantation location and inserted during a laparoscopic procedure at the vicinity of the portal vein using a surgical tool (implantation tool), and the corresponding method.

[0005] BACKGROUND

[0006] Several surgical steps are mandatory to achieve a positive outcome of a treatment using locally implanted bioactive molecule, all of which require sequential insertion of dedicated laparoscopic tools. Furthermore, in order to administer the molecule precisely, the region to be treated being often narrow, a complex image guided procedure is preferable with continuous localization of the tip of the instruments.

[0007] Therefore, such a procedure involves several tools to be inserted or removed from the patient. This multiplicity of insertions increases injury risk for the patient (especially at the vicinity of critical organs e.g., liver or vascular beds). Also, it is necessary to ensure that the implant remains in the region to be treated once it has been inserted at the correct anatomical location. This last step requires further interventions and additional tools.

[0008] SUMMARY

[0009] The present application aims at providing a tool suitable for laparoscopy and capable of depositing a bioactive molecule in a targeted region to be treated without extraction and reinsertion of multiple tools in the abdominal cavity of the patient.

[0010] To this end, the present application concerns a laparoscopic implantation tool comprising, along a main axis: - a casing extending longitudinally along a main axis, the casing an inner channel extending across the casing along the main axis from an input to an output, the casing comprising a cavity formed along the inner channel, the cavity being adapted for receiving a shuttle containing an implant to be inserted in a subject;

[0011] - a main shaft comprising a proximal end and a distal end; the main shaft extending from the output of the casing;

[0012] - a auxiliary shaft configured to slide within the main shaft when exercising a pushing to the auxiliary shaft the auxiliary shaft being configured, when moving along the main shaft, to first release the implant from the shuttle and to second moving the implant through the main shaft.

[0013] The laparoscopic implantation tool of the present application is advantageously completed by the following features, taken alone or in any technically possible combination thereof

[0014] - The laparoscopic implantation tool comprises a cap, the auxiliary shaft being connected to the cap, the auxiliary shaft extending from the cap to a tip, the auxiliary shaft being adapted to be pushed using the cap through the main shaft.

[0015] - The distal end of the main shaft is made smooth to prevent tissue damage during insertion of the main shaft in the subject.

[0016] - The tip comprises a tapered part forming a dissection device for defining an implant lodge into the subject.

[0017] - The laparoscopic implantation tool comprises a localizing system the localizing system comprising a location sensor housed into the tapered part, the localizing system being configured to be detected by an external localizer for locating continuously the tip during a surgery.

[0018] - The auxiliary shaft comprises an inner cavity extending from the cap to the tapered part, the inner cavity permitting to insert or to remove the localizing system from the auxiliary shaft.

[0019] - The localizing system comprises an electrical wire attached to the location sensor for powering the location sensor, the electrical wire extending along the auxiliary shaft in the inner cavity and is attached to the cap by means of a connecting system for connecting the localizing system to the cap in order to maintain the localizing system in place into the auxiliary shaft.

[0020] - The connecting system is a Luer Lock system.

[0021] - The casing and the cap comprise complementary part for locking the cap to the casing.

[0022] - The laparoscopic implantation tool comprises a handle attached to the casing for operating the laparoscopic tool.

[0023] - The casing comprises an opening for accessing the cavity.

[0024] The present disclosure concerns a laparoscopic kit, comprising a laparoscopic implantation tool according to the present disclosure, and a shuttle containing an implant to be delivered into a subject.

[0025] The present application concerns a laparoscopic kit according to the present disclosure, wherein the shuttle is a semi-transparent tube.

[0026] The present application concerns a method for inserting an implant into a region of interest of patient, comprising the following steps:

[0027] Providing a laparoscopic kit according to the present disclosure;

[0028] Introducing the main shaft into the patient;

[0029] Introducing the auxiliary shaft into the main shaft;

[0030] Dissecting the tissue by means of the dissection device for creating a lodge in the region of interest to be treated;

[0031] Withdrawing the auxiliary shaft for unmasking the cavity;

[0032] Inserting the shuttle into the cavity of the casing;

[0033] Pushing the auxiliary shaft for displacing the implant from the shuttle to the main shaft of the implantation tool until the implant is delivered into the lodge;

[0034] Withdrawing the main shaft and the auxiliary shaft from the patient.

[0035] Also, the present application concerns an implant that is capable to stay in position for delivering its active compound.

[0036] To this end, the present application concerns an implant for delivering a bioactive compound, comprising a body extending along a longitudinal axis, the body consisting in a cylinder comprising a top base and a bottom base and a groove formed on the body, the groove extending helically on the body along the longitudinal axis, the implant being a cylinder which is helically twisted along the longitudinal axis for comprising a nonregular transversal section so that the implant is adapted for hanging the tissue of a region of interest of a subject to be treated.

[0037] The implant is advantageously completed by the following features, taken alone or in any technically possible combination thereof:

[0038] - The cylinder is helically twisted so that the groove on the surface of the cylinder along the longitudinal axis defines a U-shaped transversal section. - The body comprises a medical grade flexible material with memory shape enriched with a bioactive compound to be delivered and radio-opaque medium.

[0039] - The medical grade flexible material is silicon rubber and the bio-active compound is dihydrostestosterone, DHT.

[0040] - The implant comprises 20 % to 50 % DHT, preferably 40 % DHT.

[0041] - The implant comprises a length comprised between 10 and 25 mm, preferably greater or equal to 15 mm.

[0042] - The implant has a diameter between, 3 and 7 mm, preferably 5 mm, the diameter being adapted to a laparoscopic shaft for delivering the implant.

[0043] The present disclosure concerns an implant assembly comprising a shuttle and an implant, the shuttle comprising a tube configured to be inserted into a casing of an implantation tool.

[0044] The shuttle is preferably made of plastic or glass.

[0045] The present application concerns a method for manufacturing an implant according to the present disclosure comprising obtaining a mold comprising two halves defining a 3D imprint for obtaining the body of the implant; injecting in the mold a mixture of a material in the mold; vulcanizing the material into the mold for obtaining the implant; unmolding the implant.

[0046] The solution of the present application presents the following advantages:

[0047] For the implant:

[0048] • The implant is small enough to be inserted in the vicinity of the portal vein preferably between the pancreatic hismus and the hepatic hilium.

[0049] • The implant is radio-opaque to be easily located by Xray imaging of the abdominal region

[0050] • The implant is soft enough to avoid possible damage on close vascular structures even during an abdominal trauma irrespective of its origin

[0051] • The implant is capable of releasing a minimum of 100 pg daily of DHT during extended period typically 4 to 5 years

[0052] • The implant is produced according good manufacturing processes (GMP) and matching the requirements for human implantation with specific reference to sterility, apyrogenicity and toxic tissular reactions.

[0053] • The implant is capable to maintain itself in position after its insertion in the adequate location by the implantation device described below • The implant is capable to be extracted with ease once its DHT releasing capacity has been exhausted

[0054] For the implantation tool :

[0055] • The implantation tool is able to create an empty virtual cavity within the connective tissue surrounding the portal vein after the opening of the mesenteric fascia.

[0056] • The implantation tool is able to position the implant in the virtual cavity created above

[0057] • The implantation tool is able to achieve the two former steps in one single abdominal insertion of the insertion device

[0058] • The implantation tool is able to achieve these performances during a laparoscopic procedure and therefore being capable of insertion through a 5 mm in diameter classical laparoscopic canula.

[0059] • The implantation tool is also able to be 3D localizable if required using an electromagnetic tridimensional localizer inserted within the tip of the instrument

[0060] • The implantation tool is capable of supplying high pressure jet like water for improved dissection during the creation of the virtual cavity, the water supply duct being also capable for aspiration purposes on demand.

[0061] • The implantation tool is usable within the surgical theater and matching the requirement for human grade surgical tool.

[0062] The surgical insertion tool along with the implant are a solution to produce and to insert surgically a new type of implant capable of delivery minute doses of DHT within the vicinity of the portal vein as a therapeutic solution for diabetes type 2 patients. This implant is aimed to be placed during a laparoscopic procedure using a dedicated insertion tool (named afterwards implantation device).

[0063] BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Other features and advantages of the present disclosure will appear in the following detailed description. Embodiments of the invention will be described with reference to the drawings:

[0065] - Figures 1 , 2, and 3 show a laparoscopic implantation tool according to an embodiment;

[0066] - Figure 4 shows an auxiliary shaft of the laparoscopic implantation tool according to an embodiment; - Figure 5 shows a laparoscopie kit comprising a laparoscopie implantation tool according to an embodiment, and a shuttle containing an implant to be delivered into a subject;

[0067] - Figures 6, 7 and 8 show an implant according to an embodiment;

[0068] - Figure 9 shows a shuttle according to an embodiment;

[0069] - Figures 10 and 11 show a mold for manufacturing an implant according to an embodiment;

[0070] - Figure 12 shows steps of a method of manufacturing an implant according to an embodiment;

[0071] - Figure 13 shows steps of an implantation of an implant using a laparoscopic kit according to an embodiment;

[0072] - Figure 14 shows steps of a method for implanting an implant into a subject;

[0073] - Figure 15 shows CT image of a region to be treated with the implant 14 in place and the segmentation of the organs around the implant;

[0074] - Figure 16 shows results of high-performance liquid chromatography demonstrating the actual release of the bioactive molecule from the implant using an in vitro set-up;

[0075] - Figure 17 shows an hybrid PET / CT image of a region to be treated with the implant demonstrating the upregulation of GLP-1 r at the location of the implant.

[0076] DESCRIPTION

[0077] Implantation tool

[0078] General description of the implantation tool according to an embodiment

[0079] In relation to figures 1 to 5, the implantation tool 100 is designed as a single use laparoscopic tool capable of handling an implant 14 and inserting it at a correct location alongside a region of interest (e.g., the portal vein connective tissue) without additional surgical tools or devices.

[0080] The implantation tool 100 consists in three essential parts: a casing 5, a main shaft 6 and an auxiliary shaft 3 adapted to be inserted into the main shaft 6 each extending along a main axis AA.

[0081] The casing 5 comprises an inner channel 51 extending across the casing 5 from an input 52 to an output 53. A cavity 10 adapted for receiving a shuttle 9 during the surgical procedure according to the arrow 12, the shuttle 9 containing the implant 14, is formed along the inner channel 51. The shuttle 9 is an envelope, preferably sterile, containing the implant 14. The cavity 10 is disposed alongside the main axis AA and is built within the casing 5. The cavity 10 can be accessed by means of an opening 54 arranged into the casing 5.

[0082] The casing 5 is preferably made of plastic and includes a handle 4 for manipulating the implantation tool 100.

[0083] The casing 5 is adapted for holding the main shaft 6. In particular, the main shaft 6 comprises a proximal end 61 and a distal end 62 and extends from the internal channel 51 of the casing 5. The main shaft 6 is thus in communication with the cavity 10. The main shaft 6 comprises an internal channel 63 extending across it from the proximal end 61 to the distal end 62.

[0084] The main shaft 6 is preferably made of stainless steel of 400 mm long, for instance and attached to the casing 5 on one side and made smooth on the other side to prevent tissue damage during insertion of the implantation tool 100 in the region if interest of the patient. The main shaft 6 is for instance attached to the casing 5 by means of glue. For example, the main shaft 6 has an external diameter of 5 mm and an internal diameter of 4.4 mm and is polished with 1 .6 pm finish or less. Also, as an example, fifty (50) mm of the main shaft 6 is inserted in the casing 5 specially reinforced at the congruence of the main shaft 6 to withstand the lateral forces generated during the laparoscopic procedure with the implantation tool 100.

[0085] The auxiliary shaft 3 is configured to slide within the main shaft 6 when exercising a pushing, along the arrow 13, to the auxiliary shaft 3. As a result, the auxiliary shaft 3 is configured, when moving along the main shaft 6, to first release the implant 14 from the shuttle 9 and to second moving the implant 14 along the main shaft 6 from the cavity 10 to the distal end 62 of the main shaft 6.

[0086] A cap 2 is connected to the auxiliary shaft 3 and extends from the cap 2 to a tip 32, the auxiliary shaft 3 is adapted to be pushed through the cap 2.

[0087] The cap 2 can be locked to the casing 5 by means of complementary parts (not shown) disposed on the casing 5 and on the cap 2 after the auxiliary shaft 3 is inserted totally into the main shaft 6.

[0088] For example, auxiliary shaft 3 has an external diameter of 4 mm and an internal diameter of 3 mm and made of T300 carbon fibers in epoxy resin. The auxiliary shaft 3 is preferably glued on the cap 2 which is designed as a male bayonet lock while the female bayonet was part of the casing 5.

[0089] The auxiliary shaft 3 comprises an inner cavity 31 extending from an input port 1 protruding from the cap 2 to a free tip 32. The input port 1 is preferably a luer lock male connector whose inner hole is connected to the inner cavity 31 of the auxiliary shaft 3. Therefore, it is possible to inject water in the inner cavity 31 of the auxiliary shaft 3 so that the water can be expelled at the opposite side of the auxiliary shaft 3, i.e., the tip 32.

[0090] The tip 32 of the auxiliary shaft 3 comprises a tapered part 8 (in plastic for instance) forming a dissection device thanks to this shape. Other shapes can be designed to this end. The tapered part 8 comprises an extension part 7 adapted to be inserted in the inner cavity 31 of auxiliary shaft 3. The external diameter of the extension part 7 is designed to fit within internal diameter of the main shaft 6 (e.g., 4.4 mm) during the retraction procedure (see arrow 11 ) according to which the auxiliary shaft 3 is retracted from the main shaft 6.

[0091] Localization of the implantation tool tip

[0092] The tip 32 of the implantation tool is capable of being localized continuously during surgery within the 3 dimensions of patient space by integrating a localizing system comprising a location sensor 43 at the tip 32 of the auxiliary shaft 3. The location sensor 43 is for instance an electronic coil. The electronic coil is a dedicated piece of equipment such as Aurora 5DOF sensor ref 10002320 from NDI™ that is designed to be connected to a Aurora system control unit also attached to a computer running a dedicated software (not shown). The purpose of this software and the detection apparatus is described in document WO 2024 / 068881 A1 .

[0093] An electrical wire 40 connects permits to power the coil 3. This electrical wire 40 is preferably a soft wire connecting the coil 43 to the Aurora system and is attached to the cap 2 of the implantation tool 100 using a purpose made connecting system 41 , 42 that is attached to the cap 2 using for instance a Luer Lock system. This allows to remove quickly the localizing system by twisting the electrical wire 40 and the location sensor 43 and render the inner cavity 31 of the auxiliary shaft 3 free for drainage or water injection procedure if necessary. The electrical wire 40 is maintained in place by the compression of a O ring (not shown) placed between the two elements of the connecting system 41 , 42. The connecting system is indeed constituted by two elements 41 , 42, a build in male and female screw, able to compress the O ring resulting in circumferential compression and ultimately further grip of the electrical wire 40.

[0094] Implant

[0095] General description of the implant

[0096] Figures 6 to 8 illustrate three views of the implant according to an embodiment.

[0097] The implant 14 comprises a body 141 extending along a longitudinal axis XX, the body 141 consisting in a cylinder comprising a top base 142 and a bottom base 143 and a groove 144 formed on the body 141. The groove 143 extends helically on the body 141 along the longitudinal axis XX. Thus, the implant 14 is a cylinder which is helically twisted along the longitudinal axis and comprising a non-regular transversal section so that the implant is adapted for hanging the tissue of a region of interest of a subject to be treated. The top base 142 is not exactly superimposed to the bottom base 143 and are turned in relation to each other.

[0098] Indeed, the most optimal shape in terms of volume is a U-shaped longitudinally twisted cylinder, which is deformed to improve attachment to connective tissue alongside the portal vein. Thus, once inserted, the implant 14 can be retained by the tissue and stay in position for delivering the bioactive compound.

[0099] As illustrated, the cylinder 141 is helically twisted to form a recess 144 on the surface of the cylinder 141 along the longitudinal axis XX while it has a U-shaped transversal section. The implant 141 thus consists in a cylinder with trans-sectional U shape ultimately helically twisted (figures 6 and 8) alongside the longitudinal axis XX.

[0100] The implant 141 is preferably made of medical grade flexible material with memory shaping capability while under circumferential stress and enriched with the bioactive compound to be delivered and radio-opaque medium.

[0101] The flexible material with memory shape can be silicon rubber and the bioactive compound can be DHT. The radio-opaque medium which could be either BaSO4 or ioxaglate sodium permits identifying the implant once implanted by means of Xray imaging of the abdomen.

[0102] According to the flexibility of the material, compared to a corresponding cylinder not twisted, the overall diameter D of the implant 14 is reduced by about 1 / 4 relative to its more expended condition. Also, the implant 14 can be constrained to be inserted in the shuttle 9 and afterwards pushed forward in the implantation tool 100. The unconstrained diameter of the implant is for instance 3.95 mm. This diameter is mainly dictated by physical constraints. It relates to: the size of the main shaft 6 (e.g., 5mm for classical laparoscopic cannula); the strength of the main shaft 6 of the implantation device 100 that is supposed to withstand significant lateral force during the laparoscopic procedure. The required rigidity of the auxiliary shaft 3 itself dictates the wall thickness of the shaft 6 - hence the size of the inner diameter of the main shaft 6 which must be also sufficient for the implant 14 diameter itself.

[0103] The length of the implant 14 depends on the duration of the release process required and of course to the capability to insert the implant itself in its lodge (e.g., the connective tissue lodge). With a 40% DHT loading target of the silicone rubber / DHT / radio-opaque mixture and targeting a release capability of 1 to 2 years, in vitro and in vivo studies showed that the length L of the implant must be a minimum of 15 mm.

[0104] The implant is manufactured by means of a molding procedure (see below). Once un-moulded, the implant 141 is inserted into the shuttle 9 which is preferably a semitransparent tube 91 suitable for insertion in the implantation tool (see figure 9). The shuttle 9 can be made of plastic or glass. The shuttle 9 comprises openings 92, 94 at this extremity so that the auxiliary shaft 3 can be inserted into the shuttle for pushing outside the shuttle 9, the implant 14 itself during the implantation by means of the implantation tool 100. The tube 91 of the shuttle 9 comprises a diameter Ds greater than the diameter D of the implant 14 so that the implant 14 can be inserted into the tube 91 of the shuttle by retracting it. The implant 14 comprises a material with memory shape, the implant 14 is able recovering its initial shape after the implantation.

[0105] Molding procedure - method of manufacturing the implant

[0106] The method of manufacturing the implant is based on a mold 19 (step S1 ) defining a 3D imprint for obtaining the body 141 of the implant 14 (figure 12).

[0107] The method of manufacturing the implant is a molding procedure (figures 10, 11 and 12) based on pressure injection of a mixture of flexible material / bioactive compound / radio-opaque fluid (e.g., silicon rubber / DHT / radio-opaque fluid) within a dedicated mold 19 produced for instance by 3D printing (step S2). The mold 19 consists in two halves 191 , 192 joined together using a vice-like grip for the duration of the flexible material vulcanization. The two halves 191 , 192 are positioned relative to each other with the help of two mating plots 15. A luer-tipped syringe (typically 2 mL size) can be manually filled with the mixture. Then, this mixture is forcefully inserted in the entrance 17 of the mold 19. By means of the syringe or alternate pressure driven pump, the mixture is then slowly injected until it fills the entire cavity of the mold 19 and after the partial overflow of the mixture out of the the venting hole 18. The pressure is maintained until the top cavity 193 of the mold 19 is filled by the silicon based mixture. When the injection is complete, the vulcanization starts without removal of the injecting syringe to avoid retraction of the flexible material during vulcanization (step S3).

[0108] In a preferred embodiment, a 2 mL silicon rubber mixture contains 40% of DHT which approximate to 817 mg DHT (CAS - 521-18-6). Since silicon rubber density is close to 1.1 , the 0.105 mL implant (calculated from the 3D software-based estimation of the volume of the mold) holds about 46.2 mg DHT. This amount of DHT according to is capable to sustain adequate DHT release according to document W02023 / 041980 suggested DHT daily dosage for 460 days. Extended-release schedule could be obtained through implant 14 additional length while preserving the overall shape of the implant 14. For example, a 30 mm long (D) implant 14 is theoretically capable of delivering adequate dosing of DHT for 920 days. The length of the shuttle 9 and the cavity 54 of the implant tool 100 is designed to accommodate these variations of length of the implant 14.

[0109] At the completion of vulcanization that depends on the characteristics of the flexible material (typically 1 hour at 80°C for PRO-4928 silicon rubber from Nusil), the two halves 191 , 192 of the mold are carefully separated and the cured flexible material removed from the mold as one single piece (step S4). The cured flexible material part consists in a single U shape matrix ending on one side by the injecting syringe and on the other by the partially filled reservoir 193. The silicon rubber cylinders connecting the implant 14 and located at the injecting 17 and venting 18 segments are cut and removed from the actual implant 14. Finally, the implant 14 is trimmed under binocular using iridectomy knife to remove unwanted flaps. After this final step, the implant is ready for packaging, quality control tests and sterilization procedures. It is in particular ready to be inserted into the shuttle 9.

[0110] Insertion and delivery of the implant (figures 13, 14 and 15)

[0111] Figure 13 shows the surgical procedure during which the shuttle 9 and the implantation device 100 are used in a sterile fashion. The left panel shows the implantation tool ready for insertion. The central panel shows the implantation tool in the insertion position with the auxiliary shaft 3 inserted in the main shaft 6. The right panel shows a laparoscopic image of the main shaft 6 of the implantation tool inserted in the connective tissue close the portal vein 35 (the region of interest to be treated). On this image, the liver 38 is reclined by gravity alone avoiding the additional use of a liver retractor. This avoidance is further facilitated by the design of the implantation tool 100.

[0112] Delivery of the implant in the surgical theatre is based on the already described shuttle 9 which is preferably a special piece of semi-transparent plastic. The shuttle 9 is designed to handle the implant 14 partially folded axially so the implant could expend itself (through its shape memory) upon extraction for further anchoring while pushed in the region of interest (e.g., the portal connective tissue). The implant 14 is inserted before surgery under sterile conditions in the shuttle 9.

[0113] The method for delivering the implant 14 by means of the implantation tool (step S10) here described comprises the following steps once an opening is created on the subject to access a region of interest to be treated.

[0114] The surgeon introduces the main shaft 6 into the opening (step S11 ) and introduces the auxiliary shaft 3 into the main shaft 6 (S12) and preferably locked it to the cap 2 (step S13).

[0115] By means of the tip of the auxiliary shaft 3 acting as a dissection device, the future implant lodge is created in the region of interest to be treated (e.g., the portal connective tissue) (step S14). Then the surgeon withdraws the auxiliary shaft 3 in the loading position using a backward motion as indicated by the arrow 11 (position B of the implantation tool) (step S15). This motion unmasks the cavity 10 in the casing 5 of the implantation tool.

[0116] Then shuttle 9 is inserted (step S16), and the auxiliary shaft 3 is pushed forward partially (as indicated by the arrow 13, position B of the implantation tool) to displace the implant 14 from the shuttle to the main shaft 6 of the implantation tool (step S17). By pushing the auxiliary shaft 3, the implant 14 is delivered at the tip of the auxiliary shaft 3 to the region to be treated. Finally, the surgeon withdraws the main shaft 6 (step S18). During all the procedure, the surgeon handles the implantation tool 4 by means of the handle 4 attached to the casing 5.

[0117] Anatomical location of the implant (figure 15)

[0118] Once implanted, the implant 14 can be easily identified using CT imaging thanks to the use of a radiopaque mixture. For instance, the material comprises 100 pL of radiopaque mixture (ioxaglate sodium 320 mg / mL or BaSO4) incorporated in the silicon rubber / DHT mixture. The implant 14 is indicated as an arrow on figure 15, right panel, showing a CT obtained 15 days after implantation in miniature pig weighting 60 kg. On the CT image and its 3D segmented counterpart (on the left panel on figure 15) the following can be easily identified: Spleen 30, Pancreas body part 31 , Vertebra 32, Abdominal aorta 33, Veina cava 34, Portal vein 35, Pancreas head part 36, Pancreatic hismus 37, Liver 38.

[0119] Example of a preferred application

[0120] The GLP-1 receptor (GLP-1 r) is expressed in several abdominal organs and tissues where its canonical form is linked closely to the homeostatic control of glucose metabolism1and the promotion of R> cell proliferation in the pancreas2. The GLP-1 r exhibits substantial down-regulation following its sustained internalization, leading to a reduction in cell surface expression, primarily, albeit not exclusively, in pancreatic R> cells3,4. This down-regulation is evident during hyperglycemia5and in obese insulin-resistant (IR) animals6. It has been shown that, in insulin-resistant obese miniature pigs, a comparable marked down-regulation is evident within the wall of the portal vein. This impairs signaling of peripheral post-prandial glucose signaling to the brain because of the marked reduction in vagal trafficking from GLP-1 r dependent vagal afferents originating from juxta-hepatic portal receptors1. Because the integrity of vagal afferent information is fundamental to glucose uptake, fat metabolism8and insulin secretion, and, accordingly, glucose homeostasis, there is a compelling rationale for strategies to potentially restore the impaired vagal trafficking resulting from the markedly reduced expression of the GLP-1 r within the wall of the portal vein as a novel approach to the treatment of insulin resistance1.

[0121] Dihydrotestosterone (DHT) - the non-aromatizable androgen replacement therapeutic agent9, have been shown, in insulinoma-derived cells, to enhance Glplr gene expression and GLP-1 r up-regulation associated with promotion of insulin secretion, both in normal and diabetic mice10. Furthermore, the androgen receptor (AR) has been shown to amplify GLP-1 r-mediated insulinotropic activity, in pancreatic beta cells, via several pathways involving classical G protein GLP-1 r activation11.

[0122] It has been demonstrated that DHT infusion and DHT releasing implants inserted in the vicinity of the portal vein were able to restore GLP-1 r expression within a localized area comprised between the pancreatic isthmus and the hepatic hilus. This restoration was equally effective in obese insulin-resistant animals and animals made diabetic by the partial destruction of pancreatic beta cells after a single IV administration of Streptozotocin at 25 mg / kg BW. Restoration of GLP-1 r within the portal connective tissue was associated with the recovery of insulin sensitivity either measured in the key organs of glucose metabolism (myocardium, pancreas, small intestine and skeletal muscle) and also for the entire body as demonstrated by euglycemic hyperinsulinémie clamp studies.

[0123] The implantation tool 100 and the implant 14 that have been described are a solution to produce and to insert surgically a new type of implant capable of delivery minute doses of DHT within the vicinity of the portal vein as a therapeutic solution for diabetes type 2 patients.

[0124] Validation of the amount of DHT released

[0125] In vitro assays

[0126] In vitro assays were performed to evaluate the amount of DHT released daily by the implant12. Two types of dissolution mixtures were used: a first one consisting in PBS buffer which aims to mimics the daily in vivo release and a second one consisting in PBS - Methanol (95 / 5 v / v) with 0.5 % Tween 8012. According to the water solubility of DHT (10 pg / mL -13), the first mixture requires 30 mL per implant, and 2 mL per implant for the second dissolution mixture to comply with Sink condition14,15.

[0127] The second mixture is preferred because it required only a small amount of dissolution mixture resulting in larger concentration hence a more accurate quantification using LIV based HPLC detection. The procedure for dynamic control of daily release is derived from16and involved sampling at predetermined time interval of a small aliquot (300 pL typically), used this aliquot for DHT HPLC measurement (Figure 16 - right column lower panel) then immediately replacing the aliquot volume by an identical volume of fresh dissolution solution17. This option preserved the concentration overtime. The procedure is performed during continuous gentle stirring of the dissolution medium by gravity using a laboratory rotation wheel while the dissolution vial and the rotation device were maintained at 38°5 C.

[0128] DHT concentration measurement was performed using gradient HPLC with UV detection using a method derived from18. Briefly, chromatographic separation of DHT was performed using Phenomenex Luna 3 pm C18(2) 100 A (3 mm x 150 mm, 3 pm), column oven temperature of 30°C and eluted with mobile phase flow rate of 0.7 ml / min. The mobile phase was composed of Water+TFA 0.1 % / Acetonitrile+TFA 0.1% using the following gradient: 0 minutes 60 / 40, 8 minutes 30 / 70 %; 15 minutes 30 / 70 for water / acetonitrile respectively. Detection was achieved at 210 nm using a UV diode array detector. The DHT peak was identified at 6.09 min for an injection volume of 20 pL. This set-up allows computation of a calibration curve using quadratic regression ranging from 5 pg / mL DHT up to 100 pg / mL using serial dilution of a stock DHT solution of 100 pg / mL (water-acetonitrile 50 / 50 v / v dissolved initially at 60°C under continuous stirring) - figure 16, left column.

[0129] In vivo assays

[0130] In vivo assays were performed using the capability of locally delivered DHT using an implant located along the portal vein and designed to up-regulate GLP-1 r according to document W02023 / 041980 and to19. After administration of the GLP-1 r radioligand built according to20in an insulin resistant miniature pig, the radioactivity was found located around the portal vein and centered at the location of the implant. This is depicted in figure 17 (arrow) showing PET / CT hybrid images of the GLP-1 r density along the portal vein. In difference with19and21, the rétroprojection of the PET sinogram resulting in the radioactivity-based picture was not achieved using attenuation error option of the iterative reconstruction algorithm since the presence of radio-opaque medium in the implant itself prevented an accurate 3D reconstruction of the GLP-1 r distribution. Indeed, it is well known that radio-opaque device or medium such as the one that are used for Xray enhancement are not compatible with PET reconstruction algorithm22. Nevertheless, the absence of radioactivity at distance of the implant location in an insulin resistant miniature pig demonstrates that the diffusion of DHT at more than 2 cm distance of the implant is negligible resulting in minute to none up-regulation of GLP-1 r. On the contrary, there is a significant increase in GLP-1 r density (as demonstrated by increased radioactive ligand binding) at the location of the implant demonstrating the efficacy of DHT released from the implant to up-regulate GLP-1 r.

[0131] REFERENCES

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Claims

Claims1. Implant (14) for delivering a bioactive compound, comprising a body (141 ) extending along a longitudinal axis (XX), the body (141 ) consisting in a cylinder comprising a top base (142) and a bottom base (143) and a groove (144) formed on the body (141 ), the groove (143) extending helically on the body (141 ) along the longitudinal axis, the implant being a cylinder which is helically twisted along the longitudinal axis (XX) for comprising a non-regular transversal section so that the implant (14) is adapted for hanging the tissue of a region of interest of a subject to be treated.

2. Implant as claimed in claim 1 , wherein the cylinder is helically twisted so that the groove (143) on the surface of the cylinder along the longitudinal axis defines a U-shaped transversal section.

3. Implant as claimed in claims 1 to 2, wherein the body (141 ) comprises a medical grade flexible material with memory shape enriched with a bioactive compound to be delivered and radio-opaque medium.

4. Implant as claimed in claim 3, wherein the medical grade flexible material is silicon rubber and the bio-active compound is dihydrostestosterone, DHT.

5. Implant as claimed in claim 4, comprising 20 % to 50 % DHT, preferably 40 % DHT.

6. Implant as claimed in claims 1 to 5, comprising a length comprised between 10 and 25 mm, preferably greater or equal to 15 mm.

7. Implant as claimed in claims 1 to 6, comprising a diameter between, 3 and 7 mm, preferably 5 mm, the diameter being adapted to a laparoscopic shaft for delivering the implant.

8. Implant assembly comprising a shuttle (9) and an implant (14) as claimed in claims 1 to 7, the shuttle comprising a tube (91 ) configured to be inserted into a casing of an implantation tool.

9. Implant assembly as claimed in claim 8, wherein the shuttle (9) is made of plastic or glass.

10. A method for manufacturing an implant according to any one of claims 1 to 9, comprising- (S1 ) a mold (19) comprising two halves (191 , 192) defining a 3D imprint for obtaining the body (141 ) of the implant (14);- injecting (S2) in the mold a mixture of a material in the mold;- vulcanizing (S3) the material into the mold for obtaining the implant; - unmolding (S4) the implant.

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