System for producing vascular prostheses

Abstract

The present invention relates to a system for producing vascular prostheses or grafts, which comprises an enclosed space; an extractor hood; a support structure disposed inside the space; a mandrel assembly, a vascular-prosthesis core rod attached at one end to the mandrel assembly, and a rod positioning assembly comprising electromechanical and robotic movement means for moving, supporting and orienting, as an effector, the mandrel assembly and the rod in a first, second, third and fourth immersion position; a nanofibre ejector assembly and a nanofibre ejector positioning assembly comprising electromechanical and robotic movement means for moving, supporting and orienting, as an effector, the nanofibre ejector assembly; a first, second and third immersion container, arranged in the first, second and third immersion positions in the support structure; an immersion container with a heater and UV-based curing means, which is disposed in the fourth position in the support structure; and a control console.

Description

[0001] FACILITY FOR MANUFACTURING VASCULAR PROSTHESES

[0002] DESCRIPTIVE MEMORY

[0003] TECHNICAL FIELD

[0004] The present invention relates to the production of vascular prostheses, in particular, to an installation for manufacturing vascular prostheses in a controlled manner and suitable for biomedical applications.

[0005] BACKGROUND OF THE INVENTION

[0006] The manufacture of vascular prostheses has been a constantly evolving area of ​​research and development in the medical field. These prostheses, also known as vascular grafts, play a crucial role in the treatment of various vascular diseases, including arterial occlusion, aneurysms, and arteriovenous malformations. They are also used in patients with chronic or end-stage renal disease requiring hemodialysis treatments, to create vascular access with an arteriovenous graft using a vascular prosthesis as a bridge, replacing an arteriovenous fistula.

[0007] Several procedures have been developed for biomedical applications using vascular prostheses or grafts. These grafts are harvested from the patient and have certain advantages, such as biocompatibility and a low incidence of infection. However, they also have limitations, such as adequate vasculature and the invasiveness of the procedure. Subsequently, synthetic vascular prostheses were introduced, made from materials such as polyester (Dacron) and expanded polytetrafluoroethylene (ePTFE). These materials demonstrated excellent biocompatibility and wear resistance, allowing the manufacture of grafts with specific characteristics for each patient and each application. However, these synthetic materials also have their own limitations, such as a tendency toward thrombosis and stenosis.

[0008] Current vascular prostheses, whether synthetic or biological, present limitations in terms of availability, cost, variability, and postoperative complications. Synthetic prostheses, such as those made of ePTFE or polyester, often present problems related to thrombus formation, intimal hyperplasia, atherosclerosis, and infection. Biological prostheses, although superior, also have limitations, such as their partial availability, high cost, and high degree of variability.

[0009] Below, some relevant state-of-the-art publications related to the production of vascular prostheses for biomedical applications are discussed.

[0010] Prior art

[0011] U.S. patent application publication US20120232643A1 describes tubular casting processes, such as dip coating, that can be used to form substrates from polymer solutions for fabricating implantable devices, such as stents. Operating parameters such as the number of dips, the length of each dip within a solution, as well as the delay time between each dip or the drying or curing time between dips and withdrawal speeds of the mandrel from the solution are set forth, each of which can be controlled to vary the mechanical characteristics.Thus, this publication specifically addresses the operating parameters of a dip-coating manufacturing process to ensure its mechanical strength and ductility to prevent or inhibit brittle fracture when used as a stent for implantation within a patient's body. However, the technical means for producing the implants are briefly mentioned, such as a base that can support a column housing a drive column and a support arm. A motor can drive the drive column vertically along the column to move the support arm accordingly. A mandrel is attached to the support arm above the container, which can be filled with a polymer solution (e.g., PLLA, PLA, PLGA, etc.) into which the mandrel can be immersed by a linear motion.Additional motors are mentioned to impart further rotation to the mandrel, as well as the possibility of providing a controlled atmosphere, with relative humidity and immersion temperature limits. Thus, it is noted that the production methods developed in this document are primarily restricted to the dip coating process with the operating parameters described therein.

[0012] The inventors of the present invention have developed the invention described in the United States patent application publication US10688694, which describes a versatile method for manufacturing multilayered hollow tubes using a layer-by-layer rod dipping approach and using different biomaterials. Precise control of manufacturing parameters such as up / down speeds, rod rotation speed, and crosslinking or polymerization time is enabled. This technology allows for the generation of more complex multilayered hollow tubes, such as structures resembling systemic vasculature, urethral grafts, prostate grafts, and the like.

[0013] These same inventors have also published their previous work in the following publications:

[0014] • “Akentjew, T. L., Terraza, C., Suazo, C., Maksimcuka, J., Wilkens, C. A., Vargas, F., ... & Valenzuela, L. M. (2019). Rapid fabrication of reinforced and cell-laden vascular grafts structurally inspired by human coronary arteries. Nature communications, 10(1 ), 1 -15.

[0015] • “Wilkens, C. A., Rivet, C. J., Akentjew, T. L., Alverio, J., Khoury, M., & Acevedo,

[0016] J. P. (2016). Layer-by-layer approach for a uniformed fabrication of a cell patterned vessel-like construct. Biofabrication, 9(1 ), 015001.

[0017] Thus, the inventors of the present invention have previously developed a method and a vascular prosthesis with a multilayer structure and appropriate fiber orientation. The parameters disclosed in these publications allow for the establishment of the necessary biomaterials, appropriate concentrations, temperature ranges, solution flow, and several other manufacturing process variables. However, the robotic device for producing these vascular prostheses is only briefly described and extremely schematically illustrated. Robotic device designs are presented that are completely restricted in their capabilities and follow the steps of the production method widely discussed in these publications. This has the drawbacks of a rigid design suitable only for that specific method and an oversimplified design that must be modified when attempting to reproduce it.Indeed, the description of its general components regarding the use of various platforms, pulleys, belts, stepper motors controlled by electronic circuits, does not allow to visualize an advantageous design that would satisfy the requirements of vascular prostheses for their respective biomedical applications.

[0018] Furthermore, to design a reliable manufacturing apparatus that can produce viable vascular prostheses for biomedical applications, it must be able to produce prostheses that meet certain acceptance criteria, for example, the following criteria can be considered:

[0019] ■ The vascular prosthesis must have a wall thickness of 0.1 mm ±10%.

[0020] ■ An endotoxin assessment of a cross-section of the vascular prosthesis must be within an endotoxin limit of 0.5 EU / mL or 20 EU / prosthesis.

[0021] ■ The vascular prosthesis must not have a dissection of its multilayers.

[0022] ■ The vascular prosthesis must have an adequate wall structure, without imperfections such as cracks or bubbles.

[0023] ■ The vascular prosthesis must have an adequate general structure evaluated by macroscopic examination.

[0024] If these criteria are not met, the produced vascular prosthesis and raw materials must be discarded, and the production equipment must be cleaned and calibrated.

[0025] Technical problem

[0026] Although some level of automation has been introduced in the manufacturing media proposed as robotic devices for the manufacture of vascular prostheses, several drawbacks remain that must be overcome to achieve industrial scaling and systematization in the production of these devices. In addition, strict quality controls must be met to adapt them to the biomedical applications for which they are intended. The robotic devices for manufacturing vascular prostheses of the prior art have a vertically positioned rod that is submerged in a slender, vertically oriented container. The solutions contained in this container require a constant temperature and some type of agitation to maintain homogeneous concentrations of their components throughout the volume of the container to ensure even immersion coating throughout the rod.The proposed and simplified designs of prior art prosthesis manufacturing apparatus do not include all the control, temperature, and agitation methods that should be used in these devices. Thus, operator intervention would be necessary in many steps of the methods developed to manufacture a vascular prosthesis, which could be a source of defects due to variability between prostheses or contamination of the final product.

[0027] Furthermore, potential spills and drips of solutions from the container tubes or from the stem are not considered either, during the stem immersion process or in the subsequent filament blow-coating stage, so continuous operation, at an industrial level, of robotic devices for manufacturing vascular prostheses of the prior art would generate large material losses, making the product more expensive and decreasing process efficiency.

[0028] Therefore, there is a clear need to develop an automated device or machine that allows for the efficient production of reliable and affordable vascular prostheses that meet the stated acceptance criteria and all the criteria required for their intended biomedical application, for example, for patients receiving hemodialysis for the treatment of end-stage renal disease and other biomedical applications. Scalability and reproducibility remain significant challenges in biomedical applications where each implant may be unique.

[0029] Technical solution

[0030] To address the aforementioned problems, one object of the present invention is a facility for manufacturing vascular prostheses or grafts that operates in an autonomous, repetitive, and controlled manner, for the purpose of scalability and reduction of the costs associated with developing a vascular prosthesis, while ensuring the quality of the manufactured prostheses. To this end, human intervention is minimized by automating the stages of the prosthesis production methods, ensuring compliance with the acceptance criteria required for medical applications. For these purposes, the facility for manufacturing vascular prostheses comprises an enclosure with a controlled atmosphere inside; an extractor hood that allows controlling a laminar flow of clean air into the enclosure; a support structure arranged inside the enclosure;a mandrel assembly, a vascular prosthesis web stem held at one end by said mandrel assembly, and a stem positioning assembly comprising electromechanical and robotic movement means for moving, supporting, and orienting, as an effector, said mandrel assembly and said stem in a first, second, third, fourth, and fifth position; a nanofiber ejector assembly and a nanofiber ejector positioning assembly comprising electromechanical and robotic movement means for moving, supporting, and orienting, as an effector, said nanofiber ejector assembly; a first, second, and third immersion container arranged in said first, second, and third immersion positions on said support structure; an immersion container with a heater and UV light curing means arranged in said fourth position on said support structure; and a control console.

[0031] Advantages of the present invention

[0032] The present invention reduces the costs and increases the availability of vascular prostheses by automating processes that were previously artisanal and laboratory-based using electromechanics, robotics, and controlled environments. This has made their implementation in biomedical applications difficult. Thus, the present invention allows vascular prostheses to be manufactured without operator intervention during the combined manufacturing stages, using dip coatings and compressed air spraying of nanofibers, ensuring the final quality of the prosthesis.

[0033] The present invention allows a vascular prosthesis to be manufactured in less than one hour, or even in up to 30 minutes, while meeting the aforementioned acceptance criteria and assembling it with bio-inspired structural configurations of concentric cell patterns with fibers at specific angles and wavy arrangements.

[0034] The present invention allows the manufacture of small caliber vascular grafts or prostheses that exhibit the “J” shaped mechanical response and flexibility of human coronary arteries.

[0035] Comparative studies conducted by the inventors demonstrate the advantages offered by the present invention compared to the vascular prosthesis manufacturing apparatus disclosed in the inventors' patent, US10688694. These studies demonstrate an improvement in that the present invention allows for less variability in the mechanical strength of the grafts produced, allowing for greater reliability and precision in manufacturing. These experimental results, presented in Figure 14, are discussed in the detailed description of the invention.

[0036] BRIEF DESCRIPTION OF THE FIGURES

[0037] Described below are figures of preferred embodiments of the present invention. It should be appreciated that the figures are provided for illustrative purposes only and that the invention is not limited by these illustrations. The figures are not necessarily to scale, and some features may be exaggerated or minimized to show details of particular components. Well-known components, materials, or methods are not necessarily described in great detail to avoid obscuring the present disclosure. Any specific structural and functional details described herein should not be construed as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art how to variously employ the invention.

[0038] Figure 1 schematically represents, in a front view, an installation for manufacturing vascular prostheses according to an embodiment of the present invention.

[0039] Figure 2 schematically represents, in a side view, the vascular prosthesis manufacturing facility of Figure 1. Figure 3 schematically represents the vascular prosthesis manufacturing facility of Figure 1 in a different operating position.

[0040] Figure 4 schematically represents the vascular prosthesis manufacturing facility in Figure 1 in a different operating position.

[0041] Figure 5 schematically represents the vascular prosthesis manufacturing facility of Figure 1 in yet another different operating position.

[0042] Figure 6 schematically represents, in a front view, an installation for manufacturing vascular prostheses according to another embodiment of the present invention.

[0043] Figure 7 schematically represents, in a front view, an installation for manufacturing vascular prostheses according to another additional embodiment of the present invention.

[0044] Figure 8 schematically represents, in a top view, the installation for manufacturing vascular prostheses in Figure 7.

[0045] Figure 9 schematically represents, in a front view, an installation for manufacturing vascular prostheses according to yet another additional embodiment of the present invention.

[0046] Figure 10 schematically represents, in an isometric view, a container of immersion solution present in the installation for manufacturing vascular prostheses in Figures 7 and 8.

[0047] Figure 11 illustrates, in exploded view, a blown nanofiber ejector assembly of the present invention.

[0048] Figure 12 illustrates, in a perspective view, the blown nanofiber ejector assembly of Figure 1 1 .

[0049] Figure 13 illustrates, in a cross-sectional view, the nozzle of the blown nanofiber ejector assembly of Figures 11 and 12.

[0050] Figure 14 illustrates a comparative graph of stress versus strain of grafts produced with the present invention and according to the prior art.

[0051] DETAILED DESCRIPTION OF THE INVENTION In the following detailed description of the invention, reference is made to the accompanying figures that form a part of this detailed description. The illustrative embodiments described in this detailed description and represented in the figures are not intended to be limiting. Other embodiments may be used and other changes may be made without departing from the spirit or scope of the present invention as defined in the appended claims.

[0052] In this document, vascular prostheses or grafts are understood to be devices and materials used to replace or repair vascular tissue, including, for example, tubular constructs, patches, and other devices intended to create barriers that, when in contact with blood, allow its circulation.

[0053] With reference to Figures 1 and 2, the present invention consists of an installation for manufacturing vascular prostheses or grafts comprising: a closed enclosure (10) with air inlets with filters that allow controlling the atmosphere, its content of microorganisms and providing a sterile and closed environment inside; an extractor hood (20) with a particle and / or microorganism filter, biosafety, hermetic and with good manufacturing practice (GMP) operation that allows controlling a flow of clean air inside the enclosure (10); a support structure (100) arranged inside the enclosure (10);a mandrel or rotating support assembly (201 ), a vascular prosthesis web stem (202) held at one end by said mandrel assembly (201 ), and a stem positioning assembly comprising electromechanical and robotic movement means (203, 204, 205, 206, 207, 208) for moving, supporting, and orienting, as an effector, said mandrel assembly (201 ) and said stem (202) in a first, second, third, fourth, and fifth position (A, B, C, D, and E); a nanofiber ejector assembly (301 ) and a nanofiber ejector positioning assembly comprising electromechanical and robotic movement means (302, 303, 304) for moving, supporting, and orienting, as an elector, said blown nanofiber ejector assembly (301 ); a first, second and third immersion container (401, 402, 403) arranged in said first, second and third position (A, B, C) on said support structure (100);an immersion container (501) with heater and UV light curing means (506, 507, 508) arranged in said fourth position (D) in said support structure (100); and a control console (600) comprising computing means, memory, access means such as keyboards and controllers, storage unit readers and communication means to connect by cables or wirelessly to the controllers of the electromechanical and robotic movement means (203, 204, 205, 206, 207, 208, 302, 303, 304), of the heater of the immersion container (501) and the UV light curing means.;

[0054] For example, said immersion container (501) with heater is configured to maintain the contained solution at a temperature of about 37°C.

[0055] Preferably, said closed enclosure (10) has a hermetic environment that is not in contact with the exterior, and is arranged in a room that allows compliance with the standards of good manufacturing practices (GMP) such as controlled access and special cleaning, with sterilization means, such as UV light and a compartment separate from the enclosure, to sterilize solid materials before entering the enclosure such as supplies and accessories.

[0056] Preferably, said extractor hood (20) produces a laminar flow from the enclosure (10).

[0057] Preferably, said electromechanical and robotic movement means of said stem positioner assembly comprises a horizontal stem positioner mobile support (204); a stem positioner lifting pillar (205); a stem positioner lifting mobile support (206); stem positioner cross rails (207); a stem positioner transverse mobile support (208) and lower heles for stem positioner (203).

[0058] Preferably, said electromechanical and robotic movement means of said nanofiber ejector positioning assembly comprise an ejector positioner lifting pillar (302); an ejector positioner angular variation unit (304); a mobile ejector positioner lifting support (303).

[0059] According to a preferred embodiment of the present invention, the vascular prosthesis manufacturing facility comprises an air compressor (305) arranged outside of said enclosure (10) and connected to said nanofiber ejector assembly (301) by means of a compressed air line or hose (306). Alternatively, a compressed air line available in the enclosure (10) may supply compressed air to said nanofiber ejector assembly (301) instead of said hose (306). For example, the compressed air is delivered at a pressure of about 4 bar (80 PSI). Particularly, said first, second and third immersion vessels (401, 402, 403) are arranged on a support fixed to the support structure (100) and optionally with a dip tube collector (404) to recover polymer solution spills and facilitate maintenance of the apparatus.

[0060] Alternatively, said first, second and third immersion containers (401, 402, 403) comprise temperature control and stirring means.

[0061] Particularly, said immersion container (501) in said support structure (100) is supported by a container positioning assembly with electromechanical and robotic movement means (504, 505) to locate said immersion tube in a use position (F) and in a withdrawal position (G), said positioning assembly comprises lower and longitudinal rails (505); a mobile support of the tube positioning assembly (504).

[0062] According to one embodiment, said UV curing means comprises a UV LED panel mounted directly on the structure (100) to illuminate said vascular prosthesis core stem (202) when it is located in said fourth position (D) and immersed in said immersion container (501). Alternatively, said UV curing means comprises a UV light power source (506); a UV light guide (507) powered by said power source (506) and supported on a UV light holder (508) on said structure (100). For example, a known commercial device OmniCure® S2000 can be used as UV curing means, with a UV light holder (508) arranged such that the UV light guide (507) is located about 2 cm from the stem (201), with a wavelength of 365 nm and power of 1.21 W. 2 .

[0063] Particularly and without being illustrated, said mandrel assembly or rotating support (201) comprises a mandrel housing, a stepper motor connected (wirelessly or by cables) to said control console (600) and a mandrel driven by said motor which rotatably holds said rod (202) which can have a diameter less than 5 mm, for example, a diameter around 4 mm, even a diameter of around 0.5 mm useful in vascular microsurgery, and a variable length, for example, at least 15 cm. Other measurements of said rod (202) are possible, for example, a diameter of around 10 mm, even around 50 mm, for a vascular patch manufacture.

[0064] As can be seen in Figures 1, 3, 4 and 5, the stem positioning assembly can locate the stem (202) in the respective positions (A, B, C, D and E), thanks to the controlled movement of the horizontal mobile stem positioning support (204) to carry out immersion steps in different solutions of the respective containers (401, 402, 403 and 501), moving the stem (202) in a controlled manner according to the steps of the methods described in the prior art, for example, in document US10688694. Preferably, said nanofiber ejector positioning assembly positions said nanofiber ejector assembly (301)

[0065] As can be seen in Figures 4 and 5, the stem positioning assembly is also positioned in position (E) so that the nanofiber ejector positioning assembly arranges the nanofiber ejector assembly (301 ) in the first height position (H) with a first angular orientation, thanks to said ejector positioner angular variation unit (304) and said mobile ejector positioner lifting support (303). In said first height and angular orientation position (H), the nanofiber ejector assembly (301 ) can eject a fiber by means of pressure applied to a syringe with a polymer, for example, Polycaprolactone (PLC) and compressed air blowing circulating annularly to the syringe, for example, compressed air at 4 bar, at an angle of incidence with respect to the stem (202) of 21 °, with its nozzle at a distance L1 from the core stem (201 ), for example, around 30 cm.In Figure 5, it can be observed that the stem positioning assembly is maintained in position (E), and the ejector positioning mobile lifting support (303) is raised to the second height position (I) with a second angular orientation thanks to said ejector positioning angular variation unit (304), where the angle of incidence of the ejected fiber on the stem (202) increases to 67°, according to the steps of the methods described in the prior art, for example, in document US10688694.

[0066] According to a first embodiment illustrated in Figures 1 to 6, the containers (401, 402, 403, 501) with immersion solution are copper or stainless steel tubes arranged vertically, and the first, second, third and fourth positions (A, B, C and D) of the stem (202) are aligned vertically and on a respective first, second, third and fourth vertical tube (401, 402, 403, 501).

[0067] According to said first embodiment, said immersion container (501) comprises a self-closing lid (502) and a rotary actuator (503) that allows the immersion container (501) to rotate on a transverse axis, for stirring the solution in the container (501).

[0068] Alternatively and as illustrated in Figure 6, said stem positioning assembly comprises a robotic manipulator arm (210), for example, with 6 axes as means of electromechanical and robotic movements, wherein the mandrel assembly (201) is arranged as an effector of said manipulator arm, and said nanofiber ejector positioning assembly also comprises a robotic manipulator arm (310), for example, with 6 axes as means of electromechanical and robotic movements, wherein the nanofiber ejector assembly (301) is arranged as an effector of said manipulator arm, both robotic manipulator arms (210, 310) being controlled by said control console (600), to carry out the steps of the vascular prosthesis manufacturing methods.For example, said stem positioning assembly allows the stem (202) to be moved vertically for immersion in the containers (401, 402, 403, 501), for example, at a speed of 2 mm / sec. over a distance of 17 cm. The mandrel assembly (201) allows the stem (202) to be rotated at the same time as it is immersed in the solutions, for example, an alternating rotation, with a clockwise rotation of 252° followed by a counterclockwise rotation of 126°, or vice versa, during an entire immersion stage.

[0069] According to a second embodiment and with reference to figures 7, 8, 9 and 10, the containers (401, 402, 403, 501) with immersion solution are horizontal channels and the first, second, third and fourth positions (A, B, C and D) of the stem (202) are longitudinally aligned with these channels (401, 402, 403, 501). These channels (best illustrated in figure 10) can also be made of copper or stainless steel and comprise a cylindrical bottom wall (401 1) and a closed distal end (4013) and a proximal end with a passage opening (4012) to the center of the notional cylinder forming the bottom wall. The stem positioning assembly is assembled with said rotating mandrel or support assembly (201) arranged with its axis of rotation and oriented a core stem (2020) horizontally, parallel or slightly inclined with respect to the containers (401, 402, 403, 501).The horizontal movable stem positioner support (204) is located so as to position the stem (2020) in a fifth position (E) that allows the nanofiber ejector assembly (301) to project a filament onto it. Said core stem may comprise a notch (2021) that allows the stem to be lowered even further through the passage opening (4012) to facilitate contact of the stem with the contained solution. When the stem rotates within one of the containers (401, 402, 403, 501), the solution is dragged by contact with the moment produced in the stem and covers the entire stem, thus achieving the immersion coating steps of the vascular prosthesis production methods.

[0070] Additionally, in this second embodiment, it is contemplated as illustrated in Figure 8, that the ejector positioner assembly also comprises a horizontal movable ejector positioner support (306) on a set of horizontal rails (307) arranged parallel to the rod and the containers (401, 402, 403, 501), so that the nanofiber ejector assembly (301) can travel the length of the rod (2020) in a step of the vascular prosthesis production methods, and project at least one nanofiber filament onto said rod, from a position (H) of first height and angular orientation and from a position (I) of second height and angular orientation, which vary in height and angle of incidence of the ejected filament on the rod (2020). For example, said angle of incidence is 21 ° in a position (H), and 67 ° in a position (I).In Figure 7, said nanofiber ejector assembly (301) is illustrated in a position (H) of first height and angular orientation.

[0071] Alternatively and similarly to the first embodiment, as illustrated in Figure 9, said stem positioning assembly comprises a robotic manipulator arm (210), for example, of 6 axes as means of electromechanical and robotic movements, and said nanofiber ejector positioning assembly also comprises a robotic manipulator arm (310), for example, of 6 axes as means of electromechanical and robotic movements, both robotic manipulator arms (210, 310) being controlled by said control console (600), to carry out the steps of the vascular prosthesis manufacturing methods.

[0072] As can be seen in Figures 11, 12 and 13, said nanofiber ejector assembly (301), for example Polycaprolactone (PCL) nanofibers, comprises a microfluidic pump formed by an actuator, for example a linear actuator, and support (3010) that houses a main body (301 1) with an external compressed air inlet and internal compressed air circulation channels, best seen in Figure 13; a polymer syringe with a metal needle (3017, illustrated in Figure 12 and partially in Figure 13) with Polycaprolactone (PCL) arranged in said main body and pressed by said actuator of said microfluidic pump;a plug (3012) of said main body (301 1) that prevents the passage of air, that is to say that prevents the escape of air through the duct where the syringe (3017) is located, with a central opening through which the needle of the polymer syringe (3017) is arranged, an outer cover (3014) with an internal thread to couple with the main body, a nozzle (3013) with an internal thread to couple with the outer cover (3014) and a central opening for the passage of the polymer syringe needle (3017) with an annular separation of greater diameter for the passage of compressed air, wherein the inner face of the nozzle (3013) and the outer face of the plug (3012) form an annular pointed nozzle (aerospike nozzle type) for an air outlet channel; internal seals (3015, 3016) between the plug (3012) and the main body (3011) and between the outer cover (3014) and the main body (3011);wherein said plug (3012) and said outer cover (3014) form a compressed air circulation channel, of substantially constant cross-sectional area, from the internal compressed air circulation channels to the air outlet channel of said annular tip nozzle, said circulation channel follows a path mainly of curves.;

[0073] According to one embodiment, said polymer syringe (3017) may be made of plastic. Preferably, said polymer syringe (3017) is made of glass, which allows for improved flow and ejection of the polymer through said syringe.

[0074] For example, said blown nanofiber ejector assembly (301) allows, by advancing the linear actuator of the microfluidic pump and the compressed air flow at around 4 bar, a polymer output flow of around 120 pL / min.

[0075] Preferably, the facility for manufacturing vascular prostheses further comprises automatic packaging means that include automated means for stem removal (202, 2020) and sterile packaging, such as, for example, laser cutters for gentle ablation at the ends of the vascular grafts or prostheses produced in said stem (202, 2020) and a cylindrical stop around its upper end that moves towards the lower end pushing the graft out of the stem (202, 2020). So that an automatic manufacturing of vascular prostheses or grafts in the closed area (10) is ensured without human intervention that could contaminate the product.

[0076] Experimental results:

[0077] Figure 14 shows an improvement of the present invention in terms of variability in mechanical strength, graphing the stress versus deformation of circumferential curves of the vascular grafts produced by the present invention (curve A) and the state-of-the-art apparatus (curve B), described by these inventors in US10688694. Thus, it can be seen that both curves A and B tend to be similar in the stresses that the grafts withstand when subjected to elongation. However, it is also observed that for a deformation of 5%, the coefficient of variation of the grafts manufactured with the present invention is CVA = 29.6%, while the coefficient of variation of the grafts manufactured with the prostheses manufactured in the state-of-the-art apparatus described in US10688694 is CVB = 63.5%. It is also noted that for a deformation of 10%, CVA = 23.2% and CVB = 51.9%.This indicates that the grafts manufactured in the facility of the present invention have a lower degree of variability compared to the prostheses manufactured on the previous platform, allowing for greater precision and reliability in the manufacturing of vascular prostheses or grafts.

[0078] The terminology used herein is intended to describe particular embodiments only and is not intended to be limiting of the disclosed subject matter. As used herein, the singular forms "a," "an," "an," and "an" are intended to include plural forms as well, unless the context clearly indicates otherwise. It is further understood that the terms "comprises" and / or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0079] The structures, materials, acts, and corresponding equivalents of all media elements or steps plus functions in the claims below are intended to include any structure, material, or act for performing the function in combination with other claimed elements as specifically claimed. The description of the present disclosed subject matter has been presented for illustrative and descriptive purposes, but is not intended to be exhaustive or limited to the disclosed subject matter in the disclosed form. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the disclosed subject matter. The embodiment was chosen and described to best explain the principles of the disclosed subject matter and practical application, and to enable others skilled in the art to understand the disclosed subject matter for various embodiments with various modifications that are suitable for the particular use contemplated.

Claims

CLAIMS 1.- A facility for manufacturing vascular prostheses or grafts, CHARACTERIZED in that it comprises: an enclosure (10) with air inlets with filters that allow controlling the atmosphere, its microorganism content and providing a sterile and closed environment inside; an extractor hood with a particle and / or microorganism filter (20) that allows controlling a flow of clean air inside the enclosure (10); a support structure (100) arranged inside the enclosure (10); a rotating mandrel or support assembly (201 ), a vascular prosthesis web stem (202) held at one end by said mandrel assembly (201 ) and a stem positioning assembly comprising electromechanical and robotic movement means (203, 204, 205, 206, 207, 208) for moving, supporting and orienting, as an effector, said mandrel assembly (201 ) and said stem (202) in a first, second, third, fourth and fifth position (A, B, C, D and E);a nanofiber ejector assembly (301 ) and a nanofiber ejector positioning assembly comprising electromechanical and robotic movement means (302, 303, 304) for moving, supporting and orienting, as an effector, said nanofiber ejector assembly (301 ); a first, second and third immersion container (401 , 402, 403) arranged in said first, second and third positions (A, B, C) on said support structure (100); an immersion container (501 ) with heater and UV light curing means (506, 507, 508) arranged in said fourth position (D) on said support structure (100);and a control console (600) comprising computational means, memory, access means such as keyboards and controllers, storage unit readers and communication means to connect by cables or wirelessly to the controllers of the electromechanical and robotic movement means (203, 204, 205, 206, 207, 208, 302, 303, 304), the immersion container heater (501) and the UV light curing means. 2.- The installation according to claim 1, CHARACTERIZED in that said nanofiber ejector assembly (301) comprises a microfluidic pump formed by a linear actuator and support (3010) that houses a main body (3011) with an external compressed air inlet and internal compressed air circulation channels; a polymer syringe (3017) with Polycaprolactone (PCL) arranged in said main body and pressed by said actuator of said microfluidic pump;a plug (3012) of said main body (3011) that prevents the passage of air, with a central opening through which the needle of said polymer syringe (3017) is arranged, an outer cap (3014) to couple with the main body, a nozzle (3013) to couple with the outer cap (3014) and a central opening for the passage of the polymer syringe needle (3017) with an annular separation of greater diameter for the passage of compressed air, wherein the inner face of the nozzle (3013) and the outer face of the plug (3012) form an annular tip nozzle for an air outlet channel; wherein said plug (3012) and said outer cap (3014) form a compressed air circulation channel, of substantially constant cross-sectional area, from the internal compressed air circulation channels to the air outlet channel of said annular tip nozzle, said circulation channel follows a mainly curved path; 3.- The installation according to claim 1, CHARACTERIZED in that said electromechanical and robotic movement means of said stem positioning assembly comprise a horizontal stem positioner mobile support (204); a stem positioner lifting pillar (205); a stem positioner mobile lifting support (206); stem positioner transverse rails (207); a stem positioner transverse mobile support (208) and lower rails for stem positioner (203). 4.- The installation according to claim 1, CHARACTERIZED in that said electromechanical and robotic movement means of said nanofiber ejector positioning assembly comprise an ejector positioner lifting pillar (302); an ejector positioner angular variation unit (304); a mobile ejector positioner lifting support (303). 5.- The installation according to claim 1, CHARACTERIZED in that it comprises an air compressor (305) arranged outside said enclosure (10) and which is connected to said nanofiber ejector assembly (301) by means of a line or hose for compressed air (306). 6.- The installation according to claim 1, CHARACTERIZED in that a compressed air line available in the enclosure (10) can supply compressed air to said nanofiber ejector assembly (301) instead of said hose (306). 7.- The installation according to claim 1, CHARACTERIZED in that said first, second and third immersion tubes (401, 402, 403) are arranged in a support and immersion tube collector (404) to recover polymer solution spills and facilitate maintenance of the apparatus. 8.- The installation according to claim 1, CHARACTERIZED in that said immersion container (501) in said support structure (100), is supported by a container positioning assembly with electromechanical and robotic movement means (504, 505) to locate said immersion tube in a use position (F) and in a withdrawal position (G). 9.- The installation according to claim 1, CHARACTERIZED in that said UV light curing means comprise a UV LED panel mounted directly on the structure (100) to illuminate said vascular prosthesis core rod (202) when it is located in said fourth position (D) and submerged in said immersion container (501).

10. The installation according to claim 1, CHARACTERIZED in that said UV light curing means (506, 507, 508) comprise a UV light power supply (506); a UV light guide (507) powered by said power supply (506) and supported on a UV light support (508) in said structure (100). 1.- The installation according to claim 1, CHARACTERIZED in that the stem positioning assembly can locate the stem (202) in the respective positions (A, B, C, D and E), thanks to the controlled movement of the horizontal mobile stem positioner support (204) to carry out immersion stages in different solutions of the respective containers (401, 402, 403 and 501). 12.- The installation according to claim 1, CHARACTERIZED in that, when the rod positioning assembly is positioned in position (E), the nanofiber ejector positioning assembly can arrange the nanofiber ejector assembly (301) in the first height position (H) with a first angular orientation, thanks to said ejector positioner angular variation unit (304) and said ejector positioner mobile lifting support (303) and in the second height position (l)9 with a second angular orientation thanks to said ejector positioner angular variation unit (304). 13.- The installation according to claim 1, CHARACTERIZED in that said rod positioning assembly comprises a 6-axis robotic manipulator arm (210) as means of electromechanical and robotic movements, and said nanofiber ejector positioning assembly also comprises a 6-axis robotic manipulator arm (310) as means of electromechanical and robotic movements, both robotic manipulator arms (210, 310) being controlled by said control console (600). 14.- The installation according to claim 1, CHARACTERIZED in that said containers (401, 402, 403, 501) with immersion solution are tubes arranged vertically, and the first, second, third and fourth position (A, B, C, D) of the rod (202) is aligned vertically and on a respective first, second, third and fourth vertical tube (401, 402, 403, 501). 15.- The installation according to claim 14, CHARACTERIZED in that said immersion container (501) comprises a lid with automatic closing (502) and a rotary actuator (503) that allows the immersion container (501) to rotate on a transverse axis, for stirring the solution in the container (501). 16.- The installation according to claim 1, CHARACTERIZED in that the containers (401, 402, 403, 501) with immersion solution are horizontal channels and the first, second, third and fourth positions (A, B, C and D) of the rod (202) are longitudinally aligned with these channels, wherein the rod positioning assembly is assembled with said mandrel or rotating support assembly (201) arranged with its axis of rotation and orienting a web rod (2020) horizontally, parallel or slightly inclined with respect to the containers (401, 402, 403, 501), and wherein the horizontal mobile rod positioning support (204) is located so as to be able to position the rod (2020) in a fifth position (E);and wherein the ejector positioning assembly further comprises a horizontal movable ejector positioner support (306) on a set of horizontal rails (307) arranged parallel to the rod and to the containers (401, 402, 403, 501), such that the blown nanofiber ejector assembly (301) can travel the length of the rod (2020) and project at least one nanofiber filament onto said rod (2020), from a first position (H) and from a second position (I), wherein said first and second positions vary in height and angle of incidence of the filament on the rod (2020).; 17.- The installation according to claim 16, CHARACTERIZED in that said core rod (2020) can comprise a notch (2021) that allows the rod to be lowered even further through a passage opening (4012) of the containers (401, 402, 403, 501). 18.- The installation according to claim 16, CHARACTERIZED in that said rod positioning assembly comprises a 6-axis robotic manipulator arm (210) as means of electromechanical and robotic movements, and said nanofiber ejector positioning assembly also comprises a 6-axis robotic manipulator arm (310) as means of electromechanical and robotic movements, both robotic manipulator arms (210, 310) being controlled by said control console (600).

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