Process for manufacturing a biomimetic implantable neural guide and biomimetic implantable neural guide

Abstract

The present invention generally relates to a process (100) for manufacturing an implantable neural guide (10) which has a hollow tubular structure having an internal lumen conformation and at least one tubular structure thickness (t), the process comprising the steps consisting of providing (110) a collector (50) with a predominantly elongated development along a collector axis, made of at least partially conductive material, having an external conformation substantially corresponding to the internal lumen conformation; placing (120) the collector (50) in rotation around a rotation axis (A) coinciding with the collector axis; dispensing and accelerating by electrospinning (130) at least a plurality of nanofibres, at least part of which is made of medical grade thermoplastic polyurethane, in the direction of the rotating collector (50), to form at least one sleeve of nanofibres around the collector (50); subjecting the at least one sleeve of nanofibres to heat treatment (140) for a sufficient time frame to bring it to a temperature close to or substantially equal to a glass transition temperature of the thermoplastic polyurethane in which the at least part of the plurality of nanofibres is made, obtaining a structure of at least partially mutually crystallized nanofibres at least partially welded together that make up the tubular structure of the implantable neural guide (10); and separating (150) the thus obtained implantable neural guide (10) from the collector (50).

Description

[0001] PROCESS FOR MANUFACTURING A BIOMIMETIC IMPLANTABLE NEURAL GUIDE

[0002] AND BIOMIMETIC IMPLANTABLE NEURAL GUIDE

[0003] TECHNICAL FIELD

[0004] The present invention relates in particular to a process for manufacturing an implantable artificial neural guide used for regenerating nerves, in particular peripheral nerves, capable of making guides of suitable dimensions which not only have excellent biocompatibility characteristics, but which are also biomimetic. The present invention also relates to biocompatible and biomimetic artificial neural guides.

[0005] BACKGROUND

[0006] Peripheral nerve injuries are common and serious injuries that affect a non-negligible percentage of traumatized patients every year and generally lead to permanent disabilities. Repair of the peripheral nerve injuries has been attempted in many different ways, all of which have in common the goal of directing the fibres to be regenerated into the correct distal endoneural tubes.

[0007] A particularly effective method of nerve fibre repair makes use of artificial neural guides which, thanks to their mechanical support and the possibility of providing chemical stimulation for axonal elongation, allow communication between the nerve stumps and provide physical guidance for axon generation. The artificial neural guides are, in fact, normally cylindrical conduits within which nerve regeneration can take place, finding protection from the surrounding environment and a spatial orientation. The neural guides, therefore, serve as a connection between the injured nerve endings, favour the regeneration of the nerve towards the distal segment and prevent the infiltration of fibrous scar tissue during recovery.

[0008] The neural guides are preferably made of a material characterized by a good biocompatibility and specific biochemical and mechanical properties, such as for example a mechanical seal and flexibility suitable for supporting the regenerating nerve fibres.

[0009] By way of example, nowadays silicone guides are known to have good stability and flexibility characteristics. Silicone guides, however, are non-porous and non-biodegradable. While, on the one hand, the guide must minimize fibroblast infiltration from the outside, at the same time it must have a certain degree of porosity in order to allow the migration and colonization of the cells inside.

[0010] In general terms, the characteristics of an ideal neural guide include: structural characteristics aimed at longitudinally aligning the regenerating axons, mechanical properties compatible with the encapsulated tissue, a sufficient permeability to provide trophic support, as well as a biomimetic architecture in a biodegradable and biocompatible material that allows tissue integration after complete regeneration.

[0011] Within the scope of the present description and in the appended claims, by "biomimetic" it is intended to indicate a material capable of emulating and reproducing at least part of the phenomena observed in biological processes such as for example the nesting and subsequent long-term cell growth when implanted within a living host organism.

[0012] Unlike the silicone guides, the permeable neural guides with interconnected and / or through cavities or pores can increase the exchange between the lumen and the external environment, allowing blood vessels, nutrients, oxygen, and growth factors to permeate the structure.

[0013] Within the scope of the present description and in the appended claims, reference will be made indifferently to cavities and pores, meaning thereby a "space filled with fluid (liquid or gaseous), such as a channel or a vacuum or open space, within an otherwise solid or gelatinous material" in line with the definition 3.1.10 provided by the ASTM F2450-18 standard "Standard Guide for Assessing Microstructure of Polymeric Scaffolds for Use in Tissue-Engineered Medical Products" .

[0014] In addition, porous guides allow migration of Schwann cells from the adjacent nerve tissue, resulting in the formation of aligned structures similar to the Biingner bands. To this end, a correct selection of the degree of porosity of the guide is essential to promote optimal nerve regeneration.

[0015] Last but not least, the porous guides reproduce a biomimetic architecture capable of favouring nesting and subsequent cell growth.

[0016] The processes for manufacturing neural guides known today are not without drawbacks.

[0017] The dip coating technique is simple to implement, but it is not able to create porous structures. Freeze drying is not able to provide good control of the porosity of the structure obtained. Solvent casting and particulate leaching offer good control of pore dimension during manufacture, but make use of highly toxic solvents or porogenic particles that are difficult to remove completely.

[0018] Several other techniques are also known, which, however, in addition to being highly complex, do not allow obtaining porous structures with suitable mechanical properties, in particular, for suturing the neural guide to the physiological tissues during implantation. In addition, the processes known today clash with the dimensional limits relating to the diameter of the internal lumen and the thickness of the achievable structure, below which they are not able to go. To date, therefore, the processes for manufacturing known neural guides are not able to produce neural guides suitable, for example, for the regeneration of the facial nerve and of the accessory nerve, which have an average diameter of about 0.80 mm and 0.63 mm respectively.

[0019] It is therefore strongly felt the need to devise a process for manufacturing neural guides that is able to obtain a porous structure and at the same time stable and resistant, while having a thickness and / or internal diameter smaller than the respective dimensions of the implantable neural guides of the state of the art.

[0020] OBJECTS AND SUMMARY OF THE INVENTION

[0021] In light of the above, the problem underlying the present invention is to devise a process for manufacturing an implantable neural guide that allows obtaining neural guides with controlled porosity and with mechanical properties suitable for suturing during implantation.

[0022] Within the scope of this problem, an object of the present invention is to devise a process for manufacturing an implantable neural guide capable of obtaining neural guides having internal lumen dimension and / or structure thickness smaller than the respective dimensions of the implantable neural guides of the state of the art.

[0023] Another object of the present invention is to realize a process for manufacturing an implantable neural guide capable of obtaining implantable neural guides that allow blood vessels, nutrients, oxygen and growth factors to permeate the structure in an optimized manner.

[0024] A further object of the present invention is to realize a process for manufacturing an implantable neural guide capable of obtaining neural guides that, in addition to high biocompatibility characteristics, are biomimetic.

[0025] Not least object of the present invention is to manufacture an implantable neural guide that is biomimetic and present at the same time mechanical seal and flexibility suitable for suturing during implantation.

[0026] In accordance with a first aspect thereof, the invention therefore relates to a process for manufacturing an implantable neural guide which has a tubular structure having an internal lumen conformation and at least one tubular structure thickness t, the process comprising the steps consisting of:

[0027] - providing a collector with a predominantly elongated development along a collector axis, made of at least partially conductive material, having an external conformation substantially corresponding to the internal lumen conformation;

[0028] - placing the collector in rotation around a rotation axis coinciding with the collector axis;

[0029] - dispensing and accelerating by electrospinning at least a plurality of nanofibres, at least part of which is made of medical grade thermoplastic polyurethane, in the direction of the rotating collector, to form at least one sleeve of nanofibres around the collector;

[0030] - subjecting the at least one sleeve of nanofibres to heat treatment for a time frame to bring it to a temperature close to or substantially equal to a glass transition temperature of the medical grade thermoplastic polyurethane in which the at least part of the plurality of nanofibres is made, obtaining a tubular structure of at least partially mutuality crystallized nanofibres at least partially welded together that make up the tubular structure of the implantable neural guide; and

[0031] - separating the thus obtained implantable neural guide from the collector.

[0032] Within the scope of this description and in the appended claims, by "medical grade" it is intended to indicate a material that meets the requirements of at least one national or international regulation that regulates the biocompatibility of materials for the purpose of their use in medical devices, such as EU Regulation 2017 / 745 (MDR) or ISO 10993 standard or FDA regulations or USP Class VI standard.

[0033] The Applicant has identified that with the process according to the invention it becomes possible to manufacture implantable neural guides that have a porosity closely linked to the rotation speed of the collector, therefore controllable, and obtained in a substantially continuous / monolithic wall that is created through the subsequent heat treatment that leads to the at least partial welding of the electrophilated fibres. This also provides the necessary structural stability.

[0034] With the process according to the invention it also becomes possible to make implantable neural guides starting from 20 pm in thickness of structure and 200 pm of internal lumen, which are biomimetic and with elastic and resistance properties that make them easily suturable.

[0035] In addition, the particular choice of the material used allows to obtain important properties of elasticity that are decisive to support regrowth and deformations of the nerve during and after regeneration, also reducing the mechanical tension of the sutures.

[0036] In accordance with a second aspect thereof, the invention relates to an implantable neural guide comprising a hollow tubular structure having an internal lumen conformation and at least one tubular structure thickness t, wherein the hollow tubular structure is made at least of polyurethane (PU) fibres at least partially welded together and incorporates in its structure thickness a plurality of irregular cavities with first portions having a diameter varying between 2 pm and 100 pm, preferably between 2 pm and 90 pm, more preferably between 2 pm and 80 pm and second portions with a sub-micrometric diameter extending through the tubular structure thickness such as to allow the passage of gases and / or liquids.

[0037] Within the scope of the present description and in the appended claims, by "diameter of a cavity or a cavity portion" it is intended to indicate the diameter of the largest sphere that can be inscribed in the cavity or cavity portion.

[0038] Advantageously, the thus configured implantable neural guide allows to achieve the same advantages described with reference to the process for manufacturing an implantable neural guide according to the invention.

[0039] Further characteristics of the preferred embodiments of the process for manufacturing an implantable neural guide according to the present invention as well as the implantable neural guide itself are subject-matter of the dependent claims.

[0040] The different characteristics in the individual configurations can be combined with each other at will according to the previous description, if the advantages resulting specifically from a particular combination were to be used.

[0041] BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Further characteristics and advantages of the present invention will be more evident from the following description of some preferred embodiments thereof made with reference to the appended drawings.

[0043] In such drawings, figure 1 is a block diagram of a preferred embodiment of the process for manufacturing an implantable neural guide according to the present invention; figure 2 is a schematic representation of a plant suitable for implementing the process of figure 1 ; figure 3 is a SEM (scanning electron microscopy) image of a partial cross-section of an implantable neural guide obtained through the process of figure 1; figures 3a and 3b are SEM images respectively of a first and a second porous implantable neural guide of the state of the art; figure 4 is a partial longitudinal section of an implantable neural guide obtained through the process of figure 1; figure 5 is a microscope image of an implantable neural guide obtained through the process of figure 1 after 7 days of in vitro culture with MSC cells; figure 6 is a partial longitudinal section of an implantable neural guide obtained through the process of figure 1 whose internal surface is added with nanoparticles; and figure 7 is a schematic perspective view of an implantable neural guide obtained through the process of figure 1 added with nanofibres. DETAILED DESCRIPTION OF THE INVENTION

[0044] For the illustration of the drawings, use is made in the following description of identical numerals or symbols to indicate construction elements with the same function. Moreover, for clarity of illustration, certain references may not be repeated in all figures.

[0045] While the invention is susceptible to various modifications and alternative constructions, certain preferred embodiments are shown in the drawings and are described hereinbelow in detail. It must in any case be understood that there is no intention to limit the invention to the specific embodiment illustrated, but, on the contrary, the invention intends covering all the modifications, alternative and equivalent constructions that fall within the scope of the invention as defined in the claims.

[0046] The use of "for example", "etc.", "or" indicates non-exclusive alternatives without limitation, unless otherwise indicated. The use of "comprises" and "includes" means "comprises or includes, but not limited to", unless otherwise indicated.

[0047] Referring to figure 1, a preferred embodiment of a process for manufacturing an implantable neural guide 10 according to the present invention is illustrated, generally indicated with 100. The implantable neural guide 10 which can be manufactured starting from the process according to the invention has a hollow tubular structure, with an internal lumen having a predominantly elongated development conformation along a longitudinal development axis B of the neural guide 10 which, depending on the embodiment, may have a substantially constant or variable diameter d and / or structure thickness t along the development axis B, both measured in a section transverse to said longitudinal development axis B.

[0048] In a preferred embodiment, the implantable neural guide 10 which can be manufactured starting from the process according to the invention has a hollow tubular structure with a cylindrical internal lumen, i.e. it has a diameter d substantially constant along the longitudinal development axis B.

[0049] The process comprises a first step 110 in which a collector 50 with a predominantly elongated development along a collector axis is provided, which is made of at least partially conductive material, such as for example metallic material. The collector 50 has an external conformation that substantially defines the conformation of the internal lumen of the implantable neural guide 10.

[0050] In particular, the collector 50 can be cylindrical, with a preferably circular section having a diameter dcsubstantially corresponding to the diameter d of the internal lumen that characterizes the neural guide 10 with the cylindrical internal lumen to be manufactured. In particular, the collector 50 has a cylinder diameter dcbetween 200 pm and 4.00 mm, preferably between 250 pm and 3.00 mm, more preferably between 300 pm and 2.50 mm.

[0051] In alternative embodiments, not illustrated, the collector can be conical or, in general terms, can have a shape suitable for reproducing a geometry of an internal lumen of a guide to be manufactured.

[0052] The collector 50 is preferably made of or plated with a stainless and / or sterilizable material, such as stainless steel and / or titanium. Furthermore, the collector 50 is preferably made of or plated with a material having a low roughness, such as for example a roughness characterized by surface projections having dimensions of less than 1 pm, preferably less than 0.7 pm such as for example protrusions having dimensions of less than 0.2 pm.

[0053] Within the scope of the present description and in the appended claims, by "dimensions of a surface projection" it is intended to indicate the diameter of the smallest hemisphere which, developing in even partial projection from the surface, encloses the surface projection.

[0054] In a subsequent step (step 120) the collector 50 is placed in rotation about a rotation axis A corresponding to its collector axis. The collector 50 is placed in rotation at an initially low speed, such as for example a speed less than or equal to 200 rpm.

[0055] A step of electrospinning (step 130) of a set of nanofibres of which at least one type is made of biocompatible polyurethane (PU) or medical grade thermoplastic polyurethane takes place. By way of example, biocompatible type polyurethanes or medical grade thermoplastic polyurethanes available on the market are Elastollan® TPU manufactured by the company BASF or Carbothane™ TPU manufactured by the company Lubrizol.

[0056] As part of the electrospinning step, at least one precursor solution of the nanofibres is accelerated by an electric field in the direction of the rotating collector 50. Nanofibers are thus created and deposited on the collector, forming a tubular structure or sleeve (not illustrated) around the collector 50.

[0057] The electrospinning step 130 takes place by applying a voltage between 5 kV and 40 kV to a plurality of emitting needles and dispensing one or more nanofibre precursor solutions with a flow rate between 0.1 ml / h and 50 ml / h for each needle. The voltage applied to the individual needles of the plurality of emitting needles, as well as the set flow rate and the processed material, may differ from needle to needle within the indicated ranges.

[0058] The speed at which the collector 50 is placed in rotation can also reach 6,000 rpm. Depending on the rotation speed of the collector 50, the resulting sleeve has a predominantly random or predominantly circumferentially aligned distribution of nanofibres. Still, the rotation speed of the collector 50 affects the porosity of the resulting tubular structure. In particular, the higher the rotation speed, the more aligned the nanofibres will be and the smaller the diameters of the cavities or pores that will be created in the structure. The rotation speed of the collector 50 is also chosen based on the diameter of the collector 50 itself and the thickness of the sleeve to be manufactured.

[0059] The nanofibre sleeve is therefore subjected to a heat treatment step (step 140) which involves heating the sleeve for a sufficient time frame to bring it to a temperature close to or substantially equal to a glass transition temperature of the thermoplastic polyurethane in which at least part of the nanofibres that make up the sleeve is made. By way of example, the sleeve can be placed in an oven preheated to at least 180°C for a time varying between 2 s and 5 min depending on the diameter of the sleeve.

[0060] A crystalline tubular structure of the polyurethane is thus generated in which the thermoplastic polyurethane nanofibres are partially welded together. Such a crystalline tubular structure with fibres that are at least partially welded together forms the implantable neural guide 10.

[0061] Subsequently, a separation step 150 takes place, in which the thus created sleeve is separated from the collector 50 also by resorting, if necessary, to the disassembly and / or destruction of one or more components that make up the collector 50.

[0062] Preferably, once separated from the collector 50, the sleeve is added with nanoparticles (step 160). In the addition step 160, at least one material in the shape of nanoparticles is applied on the internal surface of the sleeve, by immersing it or causing a suspension thereof to flow inside the sleeve. The nanoparticles 20 are preferably chosen from the group consisting of graphene, carbon in the shape of nanotubes or mXene. Such materials have demonstrated their ability to promote nerve regeneration with their electrical conductivity. Figure 6 shows a portion of sleeve to which nanoparticles 20 have been added.

[0063] Alternatively or in addition to the nanoparticles 20, the addition step 160 involves using carbon nanofibres 30 in suspension to make them flow inside the sleeve to coat or fill the hole with material preferably aligned in the longitudinal development direction B to favour nerve regeneration. Figure 7 shows a portion of sleeve to which carbon nanofibres 30 have been added.

[0064] In conclusion, the sleeve is then sterilized and packaged (step 170).

[0065] FIRST EXAMPLE ACCORDING TO THE INVENTION

[0066] The following describes the instrumentation and process parameters used in an exemplary implementation of the process 100 according to the present invention that has made it possible to manufacture an implantable neural guide 10 with a length between 60 mm and 90 mm, internal lumen having a diameter d equal to about 0.8 mm substantially constant and structure thickness t less than 100 pm.

[0067] In particular, the thus obtained implantable neural guide 10 qualifies for the fact that in a same section transverse to the longitudinal development axis B, the distribution of the diameter of the cavities and the thickness t of the structure are substantially constant with respect to an angular variation around the axis B, being able, however, to vary from section to section along the development axis B.

[0068] The following components were used for the electrospinning step 130:

[0069] • 10 ml glass syringe

[0070] • Gauge needle G21

[0071] • Rotating cylindrical collector: diameter 0.8 mm, length 90 mm

[0072] The first steps of the process (steps 110-130) were carried out with the following process parameters:

[0073] • Flow rate: 1-3 ml / h

[0074] • Tension: 30 kV

[0075] • Needle / collector distance: 90 mm

[0076] • Collector rotation speed: 50 rpm

[0077] • Translation speed: 50 mm / s

[0078] • Electrospinning time: 900 s

[0079] The heating step 140 was carried out with the following process parameters:

[0080] • Heating temperature: 200°C

[0081] • Heating rime: 20-40 s in preheated oven

[0082] The thus obtained neural guide 10 has elasticity characteristics and mechanical properties, such as mechanical tensile strength and elongation at break, which are compatible with the mechanical and elasticity properties that characterize the encapsulated tissue to which the guide must be sutured, thus favouring implantation and suture surgical operations.

[0083] In addition, the thus obtained neural guide 10 has a tubular structure with fibres at least partially welded together having its own structure thickness t, shown in exemplary terms in figure 3, which comprises a plurality of irregular cavities, at least partially interconnected with each other ( through-pores), included in the structure constituted by the fibres at least partially welded together.

[0084] In particular, the plurality of irregular cavities comprises cavities with at least first portions having micrometric diameter and cavities with at least second portions having sub-micrometric diameter (not visible in figure 3). More frequently, the cavities comprise both first portions having a micrometric diameter and second portions having a sub-micrometric diameter which extend through the thickness of the tubular structure such as to allow the passage of gases and / or liquids along passages 11 (schematized in figure 3) that are thus created. A minimal exchange between the lumen and the external environment is thus allowed, which allows the migration and colonisation of the cells inside.

[0085] Last but not least, the thus obtained neural guide 10 has a substantially elastic tubular structure that allows to support regrowth and deformations of the nerve during and after regeneration, also reducing the mechanical tension of the sutures.

[0086] In essence, the neural guide 10 consists of a porous membrane that prevents the crossing by particles of dimensions greater than 800 nm, preferably greater than 400 nm, more preferably greater than 100 nm, but allows the passage of smaller particles from the inside to the outside and vice versa, such as for example particles of nutrients, metabolites, carbon dioxide and oxygen.

[0087] Within the scope of the present description and in the appended claims, by "dimensions of a particle" it is intended to indicate the diameter of the smallest sphere that can contain the particle.

[0088] In addition, the high porosity of the neural guide 10 is suitable for favouring the migration of cells within the guide, but in the absence of outward dispersion. This effect is due to the reduced diameters of the second portions of sub-micrometric cavities and to the tortuosity of the path defined by the set of the first portions of micrometric cavities and of the second portions of sub- micrometric cavities through the thickness of the structure that makes it suitable for retaining particles of the dimensions indicated above.

[0089] As can be noted from the image reported in figure 3, the cavities are open or passing through and extend along the thickness t of the structure of the neural guide 10 according to the present invention, which forms a continuous structure of fibres that are partially welded together. Good transpiration characteristics are thus guaranteed, differing from a first typical structure 60 of the state-of-the-art neural guides, shown by way of example in figure 3 a (taken from patent US11730479B2 of Integra LifeSciences Corp.), which has a sponge structure with a predominantly closed porosity or blind bottom. At the same time, greater control over the porosity of the structure and improved mechanical properties are guaranteed compared to a second typical structure 70 of the state-of-the-art neural guides obtained by mere electrospinning without subsequent heat treatment, shown by way of example in figure 3b (taken from the scientific publication "A Controlled Design of Aligned and Random Nanofibers for 3D Bifunctionalized Nerve Conduits Fabricated via a Novel Electrospinning Set-up", Jeong In Kim et al., Scientific Reports 6:23761).

[0090] Figure 4 shows a portion of the internal wall of the thus obtained neural guide 10. From the image reported in figure 4, the first portions of micrometric cavities present on the internal wall of the neural guide 10 according to the present invention in which the cells can nest, adhere and proliferate are visible. Considering the extension of the cavities along the entire thickness t of this neural guide 10, similar first portions of micrometric cavities are also present on the external wall of the guide 10.

[0091] Such a porous structure makes the thus obtained neural guide 10 biomimetic, allowing groups of cells to nest in the cavities and live inside, as visible from figure 5 which shows a neural guide 10 manufactured by means of the process according to the present invention downstream of a 7- day in vitro culture with MSC cells (mesenchymal stem cells). The light dots represent the living cells, fixed on the surface of the guide (black part).

[0092] Advantageously, by suitably choosing the electrospinning time it is possible to manufacture implantable neural guides 10 according to the present invention with structure thickness t between 20 pm and 200 pm, preferably between 20 pm and 100 pm, more preferably between 20 pm and 80 pm.

[0093] Furthermore, in the case of cylindrical collector 50, by appropriately selecting the diameter dc, it is possible to manufacture implantable neural guides 10 according to the present invention with internal lumen having diameter d between 200 pm and 4 mm, preferably between 250 pm and 3.00 mm, more preferably between 300 pm and 2.50 mm.

[0094] Last but not least, as mentioned above, by suitably varying the rotation speed of the collector 50, it is possible to obtain a sleeve of nanofibres with a predominantly random or predominantly circumferentially aligned distribution and, consequently, downstream of the heat treatment (step 140), implantable neural guides 10 with irregular through cavities comprised of the entire structure consisting of fibres that are partially welded together with first portions having a maximum distributed diameter between 2 pm and 100 pm, preferably between 2 pm and 90 pm, more preferably between 2 pm and 80 pm interconnected by second portions with a sub- micrometric diameter.

[0095] In a preferred variant, the electrospinning step 130 involves modulating the rotation speed of the collector 50 so as to create layers of nanofibres with different densities, i.e. a plurality of sleeves with different densities, which are concentric and integral with each other.

[0096] Within the scope of the present invention and in the appended claims, by "concentric sleeves" it is intended to indicate a series of coaxial sleeves, having different diameters, contained in each other and integral with each other.

[0097] In particular, it is advantageous to create an intermediate sleeve with a higher density than an external sleeve and an internal sleeve both with a lower density.

[0098] SECOND EXAMPLE ACCORDING TO THE INVENTION

[0099] A second exemplary implementation of the process 100 according to the present invention is briefly described below, which has made it possible to manufacture an implantable neural guide 10 with different cavity densities along the thickness t of its structure and characterized by a length between 60 mm and 90 mm, an internal lumen having a diameter equal to about 0.8 mm and structure thickness t less than 100 pm.

[0100] The second implementation made use of the same instrumentation as the first implementation example and used the same process parameters, except for the rotation speed of the collector which was varied. In particular, the execution time of the electrospinning step 130 was divided into three time frames (for example three intervals of equal duration) and for each time frame a different rotation speed was used as reported in the following table

[0101] The thus obtained structure, once subjected to heat treatment, has, in the innermost and outermost layers, a plurality of irregular cavities with first portions having a distributed diameter between 2 pm and 100 pm which is ideal for nesting and cell growth, making the structure thus obtained biomimetic. In the intermediate layer, on the other hand, the irregular through cavities have first portions with diameters less than 50 pm, for example distributed diameters between 2 pm and 50 pm, which give the intermediate layer excellent elasticity properties, making the tubular structure of the guide 10 particularly suitable for suturing. At the same time, the diameters of the first portions of the cavities in the intermediate layer do not prevent the passage of small particles such as nutrients, metabolites, carbon dioxide and oxygen from the inside to the outside and vice versa as this intermediate layer also has second portions of pass-through cavities with a sub-micrometric diameter that extend through the thickness of the tubular structure creating passages 11 for gases and / or liquids.

[0102] In a further preferred variant, the electrospinning step 130 may involve varying the material of the accelerated nanofibres in the direction of the collector 50, thus making a structure of concentric sleeves which differ in the material that compose them, in addition possibly also in the density of the material. By way of example, the intermediate layer can be made of a material other than medical grade thermoplastic polyurethane (PU), such as polytetrafluoroethylene (PTFE), thereby obtaining an intermediate layer capable of imparting greater rigidity to the entire structure. In particular, considering that PTFE has a higher melting temperature, during the heat treatment step 140, the outermost and innermost PU layers tend to incorporate the PTFE fibres of the intermediate layer, thus obtaining an overall more resistant structure that is particularly suitable in the case of neural guide implantation at points that are strongly subject to stress, such as for example at joints such as the wrist, elbow, ankle or knee. According to further preferred variants, it is also possible to provide structures having a greater number of concentric sleeves that differ in the density of the material and / or in the material that compose them. By way of example, additional sleeves can be made, for example by electrospinning nanofibres of biodegradable material.

[0103] The innermost layer, or in general terms the internal surface of the neural guide 10 according to the present invention, may preferably contain a luminal filling substance to fill the space between the severed nerve ends. The filling substances may consist of extracellular matrix components with or without supporting cells and / or neurotrophic factors to promote axonal growth and provide a luminal support structure for the budding axons.

[0104] In addition or alternatively, the internal surface and / or at least part of the luminal space of the neural guide 10 according to the present invention may preferably be coated / filled with graphene nanoparticles 20, carbon nanotubes, mXene nanoparticles and / or carbon nanofibres 30, the latter preferably aligned along the longitudinal development axis B of the hollow tubular structure.

Claims

CLAIMS1. Process (100) for manufacturing an implantable neural guide (10) which has a hollow tubular structure having an internal lumen conformation and at least one tubular structure thickness (t), the process comprising the steps consisting of:- providing (110) a collector (50) with a predominantly elongated development along a collector axis, made of at least partially conductive material, having an external conformation substantially corresponding to the internal lumen conformation;- placing (120) the collector (50) in rotation around a rotation axis (A) coinciding with the collector axis;- dispensing and accelerating by electrospinning (130) at least a plurality of nanofibres, at least part of which is made of medical grade thermoplastic polyurethane, in the direction of the rotating collector (50), to form at least one sleeve of nanofibres around the collector (50);- subjecting the at least one sleeve of nanofibres to heat treatment (140) for a time frame to bring it to a temperature close to or substantially equal to a glass transition temperature of the thermoplastic polyurethane in which the at least part of the plurality of nanofibres is made, obtaining a structure of at least partially mutually crystallized nanofibres at least partially welded together that make up the tubular structure of the implantable neural guide (10); and- separating (150) the thus obtained implantable neural guide (10) from the collector (50).

2. Process (100) according to claim 1, wherein the heat treatment step (140) is such as to obtain a tubular structure which incorporates in the at least one structure thickness (t) a plurality of irregular cavities with at least first portions having diameter varying between 2 pm and 100 pm, preferably between 2 pm and 90 pm, more preferably between 2 pm and 80 pm and irregular cavities with at least second portions with a sub-micrometric diameter extending through the tubular structure thickness such as to allow the passage of gases and / or liquids.

3. Process (100) according to claim 1 or 2, further comprising the step of adding the separate implantable neural guide (10) with at least one between a material in the shape of nanoparticles (20) and a material in the shape of nanofibres (30),- wherein the material in the shape of nanoparticles (20) is preferably added by immersing the implantable neural guide (10) in a suspension of nanoparticles (20) and / or by making a suspension of nanoparticles (20) flow within the implantable neural guide (10); and / or- wherein the material in the shape of nanofibres (30) is preferably added by making a suspension of nanofibres (30) flow inside the implantable neural guide (10); and / or- wherein the nanoparticle material (20) comprises at least one of graphene nanoparticles, carbon nanotubes and mXene nanoparticles; and / or- wherein the material in the shape of nanofibres (30) at least comprises carbon nanofibres.

4. Process (100) according to any one of claims 1 to 3, wherein the collector (50) is cylindrical and has a collector diameter (dc) between 200 pm and 4.00 mm, preferably between 250 pm and 3.00 mm, more preferably between 300 pm and 2.50 mm.

5. Process (100) according to any one of the preceding claims, wherein the rotation step (120) of the collector (50) involves placing the collector (50) in rotation at a rotation speed that varies during the electrospinning step (130), and wherein, preferably, the rotation speed is initially maintained below 200 rpm, preferably below 100 rpm, more preferably equal to about 50 rpm; and / or wherein, preferably, the rotation speed is initially maintained below 200 rpm for a time frame of at least 100 s, preferably at least 200 s, more preferably equal to about 300 s; and / or wherein, preferably, after a first step at a first lower speed, the rotation speed is brought to at least 1,000 rpm, preferably to at least 2,000 rpm, even more preferably to a value equal to about 10,000 rpm.

6. Process (100) according to any one of the preceding claims, wherein the heat treatment step (step 140) comprises placing the nanofibre sleeve in an oven preheated to at least 180 °C for a time ranging from 2 s to 5 min.

7. Process (100) according to any one of the preceding claims, wherein the step of dispensing and accelerating by electrospinning (130) takes place:- by applying a voltage between 5 kV and 40 kV to a plurality of emitting needles; and / or- by dispensing at least one precursor solution of the at least one plurality of nanofibres with a flow rate between 0.1 ml / h and 50 ml / h for each needle.

8. Process (100) according to any one of the preceding claims, wherein the rotation step (120) of the collector (50) involves placing the collector (50) in rotation at a rotation speed that varies during the electrospinning step (130) so as to deposit on the collector (50) at least two substantially concentric layers of nanofibres with different densities or to form at least two sleeves of nanofibres with different densities which are concentric and integral to each other.

9. Process (100) according to any one of the preceding claims, wherein the electrospinning step (130) additionally involves dispensing and accelerating in the direction of the collector (50) by electrospinning (130) a plurality of nanofibres in at least one second material different from the medical grade thermoplastic polyurethane, so as to form at least onesleeve of nanofibres of the second material which is concentric and integral with the sleeve of thermoplastic polyurethane nanofibres.

10. Implantable neural guide (10) comprising a hollow tubular structure having an internal lumen conformation and at least one tubular structure thickness (t), wherein the hollow tubular structure is made at least of polyurethane fibres (PU) at least partially welded together and incorporates in its structure thickness (t) a plurality of irregular cavities with at least first portions having a diameter varying between 2 pm and 100 pm, preferably between 2 pm and 90 pm, more preferably between 2 pm and 80 pm and irregular cavities with at least second portions with a sub -micrometric diameter extending through the tubular structure thickness such as to allow the passage of gases and / or liquids.

11. Implantable neural guide (10) according to claim 10, wherein the plurality of irregular cavities have at least first portions with a diameter that varies along the at least one structure thickness (t), wherein preferably an internal wall and / or an external wall of the hollow tubular structure have a plurality of irregular cavities at least with first portions with a distributed diameter between 2 pm and 100 pm, preferably between 2 pm and 90 pm, more preferably between 2 pm and 80 pm and an intermediate layer of the hollow tubular structure has a plurality of irregular cavities at least with first portions with a distributed diameter between 2 pm and 50 pm.

12. Implantable neural guide (10) according to claim 10 or 11, wherein- the hollow tubular structure has an internal lumen with a substantially cylindrical shape with a diameter (d) between 200 pm and 4 mm, preferably between 250 pm and 3.00 mm, more preferably between 300 pm and 2.50 mm; and- the at least one structure thickness (t) is between 20 pm and 200 pm, preferably between 20 pm and 100 pm, more preferably between 20 pm and 80 pm.

13. Implantable neural guide (10) according to any one of claims 10 to 12, wherein an internal surface of the hollow tubular structure comprises at least one of nanoparticles (20) and nanofibres (30),- where the nanoparticles (20) comprise at least one of graphene nanoparticles, carbon nanotubes and mXene nanoparticles; and / or- wherein the nanofibres (30) comprise at least carbon nanofibres, preferably aligned along a longitudinal development axis (B) of the hollow tubular structure.

14. Implantable neural guide (10) according to any one of claims 10 to 13, wherein the hollow tubular structure has an internal lumen with a substantially cylindrical shape with diameter (d) substantially constant along the development axis (B); and / or wherein the at least one structure thickness (t) is substantially constant along the development axis (B); and / or wherein the structure thickness (t) is substantially constant in each section transverse to the development axis (B) with respect to an angular variation around the axis (B); and / or wherein, in each section transverse to the development axis (B), a distribution of the diameter of the cavities in that section is substantially constant with respect to an angular variation around the axis (B).

15. Implantable neural guide (10) according to any one of claims 10 to 14, wherein the polyurethane (PU) is medical grade thermoplastic polyurethane.

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