WO2024213841A1 - Manufacture of an endoprosthesis by 3d printing - Google Patents

Abstract

The present invention proposes a method for manufacture of an endoprosthesis, in particular a vascular endoprosthesis, comprising the 3D printing (100) of a hollow membrane made of thermoplastic elastomer, and the fastening (200) of a collapsible metal framework to the hollow membrane in order to form a membrane-framework assembly. The fastening comprises (i) the 3D printing (201) of an additional membrane made of thermoplastic elastomer, the arranging (202) of the collapsible metal framework between the hollow membrane and the additional membrane in order to obtain an assembly, the immersion soaking (204) of the assembly in an organic solvent in order to obtain the membrane-framework assembly, and the drying (205) of the membrane-framework assembly; or (ii) the arranging (212) of the collapsible metal framework on the hollow membrane in order to obtain an assembly, and the dip coating (214) in a solution in an organic solvent, and then the drying (215) of the assembly.

Description

Description

Title: MANUFACTURE OF AN ENDOPROSTHESIS BY 3D PRINTING

Technical field

[1] The present disclosure relates to the field of vascular endoprostheses and in particular to methods of manufacturing vascular endoprostheses and particularly vascular endoprostheses intended for a stay of more than 30 days in the body of a patient. Such a vascular endoprosthesis allows in particular the endovascular treatment of abdominal aortic aneurysms.

Previous technique

[2] Abdominal aortic aneurysm (AAA) is a pathology resulting in a localized dilatation of the aorta at the level of the abdomen. The natural evolution of aneurysms subjected to arterial pressure is the growth of the dilatation continuously until rupture. In this case, the mortality rate is very high and reaches 80% [1].

[3] One of the preventive treatments against this complication is endovascular repair. Via the femoral route, an endoprosthesis is introduced using a catheter and then released at the level of a healthy area of the aneurysm, generally the proximal neck of the aneurysm. The endoprosthesis is deployed there in order to exclude the aneurysm from the blood flow.

[4] For example, Cook Medical, Medtronic and Vascutek offer such endoprostheses in three modules for simple aneurysms: a bifurcated main body and two iliac legs. The main body has a larger diameter tubular proximal branch extended by two smaller diameter tubular distal branches. The iliac legs, also tubular, are inserted into each of the two distal branches. Each of the modules is equipped with a frame sutured with polypropylene threads on a woven polyester membrane. This frame, called Z-stents, is made of Nitinol wires, which is a nickel-titanium-based metal alloy with shape memory. Each wire forms a ring and is folded to form zigzags. The three modules are available in several standardized sizes.

[5] In the case of complex aneurysms, that is to say when the visceral or renal arteries are involved, hospital practitioners use so-called fenestrated endoprostheses, i.e. equipped with openings to allow perfusion of the splanchnic arteries.

[6] For example, Cook Medical, Medtronic offers a stent graft in three modules: a proximal component, a bifurcated component and finally a contralateral iliac leg. The proximal component is tubular and equipped with windows in order to selectively perfuse the renal or visceral arteries. The structure of these modules is identical to that of the stent graft modules for simple aneurysms.

[7] These complex aneurysm stents must be patient-specific, i.e. designed taking into account the patient's aortic anatomy. Despite this, the modules are standardized, that is, they can only treat about 70% of patients. This figure also differs depending on the aneurysm morphology. In addition, these standardized modules are in the form of tubes.

[8] Alternatively, hospital practitioners have developed so-called “off-the-shelf” techniques using standard available endoprostheses.

[9] For example, Lobato et al. [2] developed the “sandwich” technique in 2012 to treat type I, II, II, and IV thoracoabdominal aneurysms (TAAs). For type I (type II, II, and IV, respectively), they combined in parallel self-expanding covered stents sandwiched between two segments of standard bifurcated aortic and thoracic endografts.

[10] To produce fenestrated endoprostheses, a sizing step is necessary to ensure the correct positioning of the windows at the target splanchnic arteries. After analysis and reconstruction of the CT angiography data, the positions and dimensions of the vessels are recorded and then transferred to a planning diagram. The windows are then manually created by the surgeon in the operating room just before implantation using a laser cutter.

[11] The manual nature of the sizing and positioning steps and then the creation of the windows thus induces measurement uncertainty and inter-operator variability from one step to another [3]. The measurement uncertainty as well as the inter-operator variability observed can lead to the occurrence of endoleaks, reflecting an inadequacy of the endoprosthesis. These include type III endoleaks, designating the loss of sealing at the windows in the case of fenestrated endovascular repair.

[12] In order to produce personalized endoprostheses, 3D printing has recently been used. Lei et al. [4, 5] use 3D printing as a rapid prototyping technique for a sacrificial core. This sacrificial core made of water-soluble polyvinyl acetate (PVA) is used to form a polyurethane (PU) film by coating. The framework is positioned on the sacrificial core and then enclosed between two layers of PU obtained by vertical dip-coating in a PU solution whose solvent is tetrahydrofuran (THF). After drying by evaporation of the THF, the system is immersed in water to dissolve the sacrificial core manufactured by 3D printing.

[13] Unfortunately, using a sacrificial core results in a loss of time and materials. In addition, it is necessary to manage the risk associated with the solvent and residual PVA. Finally, this technique is not very suitable for windowed endoprostheses.

[14] The present invention improves the situation.

Summary of the invention

[15] Thus, a method for manufacturing an endoprosthesis, in particular a vascular one, is proposed, comprising the 3D printing of a hollow membrane made of thermoplastic elastomer; and the securing of a foldable metal frame on the hollow membrane to form a membrane-frame assembly. The securing comprises: (i) the 3D printing of an additional membrane made of elastomer thermoplastic, arranging the foldable metal frame between the hollow membrane and the additional membrane to obtain an assembly, dipping the assembly in an organic solvent to obtain the membrane-frame assembly and drying the membrane-frame assembly; or (ii) arranging the foldable metal frame on the hollow membrane to obtain an assembly and coating by dipping in a solution in an organic solvent and then drying the assembly.

[16] This process allows the manufacture of truly personalized fenestrated or non-fenestrated endoprostheses.

[17] 3D printing may include randomization of the starting points of each of the deposited layers.

[18] The thermoplastic elastomer may be chosen from thermoplastic polyurethanes.

[19] The organic solvent may be selected from tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidine.

[20] Bonding may include coating by dipping and then drying and this is carried out 1, 2, 3, 4 or 5 times.

[21] Dip coating and then drying can be carried out up to a total thickness of between 0.6 mm and 0.9 mm.

[22] Drying may be carried out at a temperature between 20 and 70°C, preferably between 20°C and 50°C, always preferably between 20°C and 30°C. Drying may be carried out under vacuum.

[23] The method may further include crimping the stent within an introducer catheter.

[24] The shape of the hollow membrane and, if applicable, the additional membrane can be determined from anatomical data of a patient.

Brief description of the drawings

[25] Other features, details and advantages will become apparent from reading the detailed description below, and from analyzing the attached drawings, in which:

Fig. 1

[26] [Fig. 1] is a diagram showing the steps of an exemplary method of manufacturing an endoprosthesis according to the invention.

Fig. 2

[27] [Fig. 2] is a diagram showing the steps of a first example of fixing a metal frame on a hollow membrane of the method of Fig. 1. [28] [Fig. 3] is an illustration of the steps in Fig. 2.

Fig. 4

[29] [Fig. 4] is a diagram showing the steps of another example of fixing a metal frame to a hollow membrane of the method of Fig. 1.

Fig. 5

[30] [Fig. 5] is an illustration of the steps in Fig. 4.

Fig. 6

[31] [Fig. 6] is a diagram showing the steps of another example of a method of manufacturing an endoprosthesis according to the invention.

Description of the embodiments

[32] A method of manufacturing an endoprosthesis, particularly an aortic vascular endoprosthesis, according to the present invention will be described hereinafter with reference to Figs. 1 to 6.

[33] This process includes:

- 3D printing 100 of a hollow membrane 10 in thermoplastic elastomer; and

- the securing 200 of a metal frame 12 on the hollow membrane 10 to form a membrane-frame assembly 18.

[34] 3D printing 100 can be carried out by an additive manufacturing technology, for example molten material extrusion, agglomeration or hardening of material using light or even powder sintering. Among the molten material extrusion techniques, mention may be made of direct pellet printing (DPP) and fused deposition modeling (FDM). The filament used may in turn be the result of extrusion from pellets. Among the agglomeration or hardening of material using light, mention may be made of stereolithography (SLA). Finally, among the powder sintering techniques, mention may be made of selective laser sintering (SLS). Preferably, molten material extrusion techniques are preferred, in particular for their ease of shaping involving neither solvent, binder nor polymerization initiator.

[35] 3D printing 100 can be carried out in particular from medical imaging data such as preoperative CT angiography. Thus, the limitations concerning the shape of the endoprosthesis could be lifted because this technique would make the endoprosthesis truly tailor-made. Indeed, the variations in diameter as well as the different curvatures specific to the patient's aortic anatomy could be reflected in the shape of the endoprosthesis.

[36] Furthermore, with the evolution and integration into vascular surgery departments of imaging software for AAA diagnosis and stent-graft sizing, aortic stent-grafts manufactured by 3D printing from the patient's preoperative CT scan could be manufactured on site, for example in a central pharmacy. This possibility has the advantage of reducing manufacturing and delivery times. Thus, the manufacturing, sterilization and delivery stages in the clean room of the aortic endoprosthesis manufactured by 3D printing can be completed in a few days.

[37] 3D printing 100 may include randomization of the starting points, particularly for the highest thicknesses. If the starting points are not randomized, the printing may form a marked joint at the starting points along the length of the endoprosthesis. This joint potentially presents risks of bursting when handling the membrane during the manufacture of the endoprosthesis, or even during use of the latter. On the other hand, randomization of the starting points makes it possible to avoid the formation of such a joint, reinforcing the solidity of the endoprosthesis.

[38] The hollow membrane 10 may have a tubular shape, that is to say with a wall laterally closed on itself forming a lumen and two open ends. Alternatively, the hollow membrane may be bifurcated and formed of a portion of tubular trunk bifurcating at one of its ends into two tubular leg portions of smaller diameter than the trunk portion. Such a shape is particularly suitable for the abdominal aorta. One of the leg portions may be longer than the other. However, the hollow membrane is not limited to these shapes and may take any shape anatomically adapted to the site of placement of the endoprosthesis.

[39] Thermoplastic elastomers are inexpensive materials and their use as raw material for the manufacture of EDPs thus reduces the production cost.

[40] The thermoplastic elastomer may be a thermoplastic polyurethane, that is to say it comprises a urethane function -NH(CO)O- which can be obtained by polyaddition between a polyol, - (OH-R’-OH)n-, and a diisocyanate, OCN-R-NCO, giving -(R’OOC-NH-R-NH-COOR’)-.

[41] The diisocyanate may be an aromatic diisocyanate or an aliphatic diisocyanate. Aromatic diisocyanates include 4,4-diphenylmethylene diisocyanate (4,4-MDI), 2,4-toluene diisocyanate (2,4-TDI), and 2,6-toluene diisocyanate (2,6-TDI). Aliphatic diisocyanates include 1,6-hexamethylene diisocyanate (HDI), 4,4-dicyclohexylmethane diisocyanate (H12MDI), and isophorone diisocyanate (IPDI).

[42] The polyol may be a polyester, a polyether or a polycarbonate. Polyesters include polycaprolactone (PCL). Polyethers include polyethylene glycol (PEG), polytetramethylene oxide (PTMO) and polyhexamethylene glycol (PHMG). Polycarbonates include hexamethylene polycarbonate (PHMC), poly(1,6-hexyl-1,2-ethyl carbonate) (PHEC).

[43] A chain extender can be used in the synthesis of thermoplastic polyurethane. The chain extender is a low molecular weight compound (typically less than 400 g/mol) and serves to space out neighboring isocyanate groups. The chain extender can be a diol or a diamine. Diols include 1,4-butanediol (BDO). Diamines include ethylenediamine (EDA) and hexamethylenediamine (HMD).

[44] The metal frame 12 may be composed of one or more stents, in particular 2, 3, 4, 5, 6, 7, 8, 9 or 10 stents. In the case of a bifurcated hollow membrane, stents may be provided in the trunk portion and the leg portions.

[45] For example, the stents may be z-stents, i.e. annular stents composed of a zigzag metal wire. The vertices of the zigzag formed on the same side may be connected to each other by a ring metal wire or may not have one. Preferably, the metal frame is made of Nitinol.

[46] Thanks to the use of 3D printing and special fixation steps, it is possible to create custom-made personalized endoprostheses.

[47] This is why the shape of the hollow membrane 10 is adapted to anatomical data of a patient for whom the endoprosthesis is intended. Thus, the method may further comprise the recovery of anatomical data of a patient for whom the endoprosthesis is intended. This anatomical data may be obtained by medical imaging by computed tomography. From this anatomical data, a virtual model is generated allowing the 3D printing of the hollow membrane and, where appropriate, of the additional membrane so that they match the anatomy of the patient for whom they are intended.

[48] In a first embodiment, notably illustrated by FIGS. 2 and 3, the securing 200 of the assembly 18 may comprise the 3D printing 201 of an additional membrane 14 made of thermoplastic elastomer, the arrangement 202 of the foldable metal frame 12 between the hollow membrane 10 and the additional membrane 14 to obtain an assembly 18 and the soaking 204 of the assembly 18 then the drying 205 to obtain the membrane-frame assembly 18.

[49] The same 3D printing techniques mentioned above can be used for 3D printing of the additional membrane.

[50] The same elastomers mentioned above can be used for 3D printing of the additional membrane.

[51] The additional membrane 14 has an outer diameter smaller than the inner diameter of the hollow membrane 10 to be inserted therein, thus forming a space between the two membranes. The space is large enough to accommodate the metal frame, in particular the stents 12. For example, the space between the hollow membrane 10 and the additional membrane 14 can measure from 0.1 to 1 mm.

[52] The additional membrane 14 is typically similar to the hollow membrane 10 but adapted to fit inside the hollow membrane 10. [S3} The arrangement 202 may comprise the positioning of the metal frame 12, in particular the stents, on the external surface of the additional membrane and the threading of the hollow membrane 10 onto the assembly 18 of the metal frame 12 and the additional membrane 14.

[54] Alternatively, the arrangement 202 may comprise positioning the metal frame 12, in particular stents, on the internal surface of the hollow membrane 10 and threading the additional membrane 14 inside the hollow membrane-metal frame assembly 18.

[55] Dipping 204 can be carried out by dipping in a solution 2 of thermoplastic elastomer whose solvent is organic. The thermoplastic elastomers which can be used have been mentioned above. The organic solvent can be tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulphoxide (DMSO) or N-methylpyrrolidine (NMP).

[56] The soaking 204 in the thermoplastic elastomer solution, for example thermoplastic polyurethane, allows the solution to penetrate by capillarity into the free space between the hollow membrane 10 and the additional membrane 14 and cause the swelling of the macromolecular chains of the thermoplastic elastomer on the surface of each of the two membranes 10, 14. The macromolecular chains on the surface of the two membranes 10, 14 and those of the thermoplastic elastomer in solution become entangled, thus adding material.

[57] The concentration of the solution measured by weight of thermoplastic elastomer to volume of solvent can be chosen so as to have a viscosity of less than 3 Pa.s, or even less than 2.8 Pa.s, or even less than 2.7 Pa.s; the viscosity being measured by rotary rheometer equipped with a 20 mm flat spindle, at a shear rate of 100 s ^-1 and at a temperature of 20°C. This concentration can be between 5 and 15 g per 100 mL of solvent, for example 7.5%, 10%, or even 12.5%.

[58] Alternatively, soaking 204 may be performed by soaking in organic solvent 3. Organic solvent 2 may be tetrahydrofuran (THF), dimethylformamide (DMF), dimethylsulphoxide (DMSO), and N-methylpyrrolidine (NMP).

[59] Soaking 204 in the organic solvent 2 alone allows the solvent to penetrate by capillarity into the free space between the hollow membrane 10 and the additional membrane 14 and cause the swelling of the macromolecular chains of the thermoplastic elastomer on the surface of each of the two membranes 10, 14 causing the two membranes 10, 14 to become solid by entanglement of the macromolecular chains on the surface of the two membranes 10, 14.

[60] According to another embodiment, notably illustrated by FIGS. 4 and 5, the securing 200 may comprise the arrangement 212 of the metal frame 12, notably foldable stents, on the hollow membrane 10 to obtain an assembly 18 and the coating by dipping 214 then drying 215 of this assembly 18. In particular, the metal frame 14 may be arranged on the external surface of the hollow membrane 10 or on the internal surface of the hollow membrane 10.

[61] The coating by dipping 214 then drying 215 of the assembly 18 can be carried out using the same solution 2 of thermoplastic elastomer as described above. [62] In this embodiment, a layer of thermoplastic elastomer covers the hollow membrane 10 and the metal frame 12. This layer can be thickened by performing several cycles 216 of coating by dipping 214 and drying 215. For example, the coating by dipping 214 and drying 215 can be performed 1, 2, 3, 4 or 5 times.

[63] The coating by dipping 214 and drying 215 can be carried out until a total thickness of between 0.6 and 0.9 mm is obtained.

[64] In both embodiments, the drying 205, 215 may be carried out under a flow of hot air. The drying 205, 215 may be carried out at a temperature between 20 and 70°C, preferably between 20°C and 50°C, always preferably between 20°C and 30°C.

[65] The drying 205, 215 can be carried out by rotation at a speed of between 150 and 230 rpm, preferably between 170 and 210 rpm, always preferably between 180 and 200 rpm, for example at 190 rpm and using a heat gun. This drying 205, 215 is preferably carried out under ambient pressure conditions.

[66] The drying 205, 215 can be carried out under a vacuum of 55 to 85 cmHg, preferably of 60 to 80 cmHg, always preferably of 65 to 75 cmHg, for example at 70 cmHg. Preferably the drying 205, 215 is carried out at a temperature between 19°C and 25°C. This drying 205, 215 can be carried out for a duration of between 20 and 30 h, preferably between 22 and 27 h, always preferably between 23 and 26 h.

[67] Drying 205, 215 can further be carried out in two stages: a first stage at ambient pressure conditions and a second stage under vacuum as described above.

[68] For example, the drying 205, 215 may comprise two stages, a first stage with rotation at the speeds described above for 15 to 25 min, preferably for 18 to 22 min, still preferably for 19 to 21 min, for example for 20 min; and a second stage under vacuum at the above values for 19 to 29 h, preferably for 21 to 27 h, still preferably for 22 to 26 h, for example for 24 h.

[69] In both embodiments, the joining 200 may comprise a heat treatment followed by cooling 203, 213, in particular before the soaking 204, 214 and the drying 205, 215. The heat treatment followed by the cooling 203, 213 causes a reorganization of the macromolecular chains and the contraction of the membrane(s) 10, 14 around the metal frame 12.

[70] The heat treatment 203, 213 can be carried out at a temperature between 130 and 190°C, preferably between 145 and 175°C, always preferably between 150 and 170°C, for example 160°C.

[71] The heat treatment 203, 213 can be carried out for a duration of between 8 and 12 min, preferably between 9 and 11 min, always preferably between 9.5 and 10.5 min, for example for 10 min. [72] The securing 200 may further comprise the insertion of a metal bar inside the membrane-frame assembly 18 before the heat treatment 203, 213, in particular when the organic solvent used is THF, before the heat treatment.

[73] The method may further comprise crimping 300 the assembly 18 inside the introducer catheter. The crimping 300 allows the assembly 18 to fold back on itself. The crimping 300 allows the assembly to be inserted inside the introducer catheter. Ideally, the crimping 300 may be star-shaped.

Bibliography

[74] 1. Reimerink, J. J. et al., “Systematic Review and Meta-Analysis of Population-Based Mortality from Ruptured Abdominal Aortic Aneurysm,” in BJS (British Journal of Surgery) 2013, 100 (11), 1405-1413. https://doi.org/10.1002/bjs.9235.

[75] 2 Lobato, A. C. et al., “A New Technique to Enhance Endovascular Thoracoabdominal Aortic Aneurysm Therapy — The Sandwich Procedure,” in Seminars in Vascular Surgery 2012, 25 (3), 153-160. https://doi.Org/10.1053/j.semvascsurg.2012.07.005.

[76] 3 Banno, H. et al., “Inter-Observer Variability in Sizing Fenestrated and/or Branched Aortic Stent-Grafts,” in European Journal of Vascular and Endovascular Surgery 2014, 47 (1), 45-52. https://doi.Org/10.1016/j.ejvs.2013.10.008.

[77] 4 Lei, Y. et al., “A New Process for Customized Patient-Specific Aortic Stent Graft Using 3D

Printing Technique”, in Medical Engineering & Physics 2020, 77, 80-87. https://doi.Org/10.1016/j.medengphy.2019.12.002.

[78] 5 Lei, Y. et al., “An Innovative Customized Stent Graft Manufacture System Assisted by 3D Printing Technology,” in The Annals of Thoracic Surgery 2020. https://d0i.0rg/l 0.1016/j.athoracsur. 2020.07.013.

Claims

Claims [Claim 1] Method for manufacturing an endoprosthesis, in particular a vascular one, comprising: - 3D printing (100) of a hollow membrane (11) in thermoplastic elastomer; and - the securing (200) of a metal frame (12) which can be folded onto the hollow membrane to form a membrane-frame assembly (18); in which the securing comprises: - 3D printing (201) of an additional membrane (14) made of thermoplastic elastomer, arranging (202) the foldable metal frame between the hollow membrane and the additional membrane to obtain an assembly, soaking (204) the assembly in an organic solvent to obtain the membrane-frame assembly and drying (205) the membrane-frame assembly; or - the arrangement (212) of the foldable metal frame on the hollow membrane to obtain an assembly and the coating by dipping (214) in a solution whose solvent is organic, then drying (215) of the assembly. [Claim 2] The method of claim 1, wherein 3D printing comprises randomizing the starting points of each of the deposited layers. [Claim 3] A method according to claim 1 or claim 2, wherein the thermoplastic elastomer is selected from thermoplastic polyurethanes. [Claim 4] A method according to claim 1 or claim 2, wherein the organic solvent is selected from tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and N-methylpyrrolidine. [Claim 5] Method according to one of claims 1 to 3, in which the joining comprises coating by dipping then drying and this is carried out 1, 2, 3, 4 or 5 times. [Claim 6] A method according to claim 5, wherein the coating by dipping and then drying is carried out to a total thickness of between 0.6 mm and 0.9 mm. [Claim 7] Method according to one of claims 1 to 6, in which the drying is carried out at a temperature between 20 and 70°C, preferably between 20°C and 50°C, always preferably between 20°C and 30°C. [Claim 8] Method according to one of claims 1 to 7, in which the drying is carried out under vacuum. [Claim 9] The method of one of claims 1 to 8, further comprising crimping the stent within an introducer catheter. [Claim 10] Method according to one of claims 1 to 9, in which the shape of the hollow membrane and, where appropriate, of the additional membrane is determined from anatomical data of a patient.