CN114081999A

CN114081999A - Composite nerve conduit and preparation method thereof

Info

Publication number: CN114081999A
Application number: CN202111355755.XA
Authority: CN
Inventors: 王秀梅; 赵勇刚
Original assignee: Tsinghua University
Current assignee: Tsinghua University
Priority date: 2021-11-16
Filing date: 2021-11-16
Publication date: 2022-02-25

Abstract

The application discloses nerve conduit includes: mineralized collagen nanofibers doped with active elements; the mineralized collagen nanofiber contains hydroxyapatite crystals; the calcium element in the crystal lattice of the hydroxyapatite is replaced by a cation containing the active element, and/or the phosphate in the crystal lattice of the hydroxyapatite is replaced by an anion containing the active element; the nerve conduit provided by the application can effectively and controllably release the doping element by introducing the doping element and using the positive ions or negative ions of the doping element to mineralize phosphorus or calcium in the hydroxyapatite crystal lattice in the collagen nanofiber, and can effectively promote the regeneration of human tissues such as nerves, blood vessels and the like compared with the nerve conduit without involving the doping element.

Description

Composite nerve conduit and preparation method thereof

Technical Field

The present invention relates to but is not limited to the field of biomedical materials, and particularly relates to but is not limited to a composite nerve conduit and a preparation method thereof.

Background

The artificial nerve conduit is an ideal material for replacing the autologous nerve. The nerve conduit material is required to have good biocompatibility and is beneficial to the migration of Schwann cells. In addition, it should have adhesion resistance, physical support (prevention of collapse of tubular shape), and the like.

The preparation of multifunctional nerve conduits is a recent trend of research based on structural and compositional considerations. The nerve conduit material prepared in vitro has the advantages of sufficient source and low immunogenicity. However, in clinical needs, it is important that the repair of nerve defects not only take into consideration the properties such as biocompatibility, but also have a function of promoting the migration and growth of blood-activating cells. A plurality of trace elements can influence the growth of nerves, while the existing nerve conduit material generally does not comprise the trace elements, and even if the related trace elements are introduced, the corresponding effect is difficult to play.

Disclosure of Invention

The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

The application relates to a novel directional nerve conduit stent which is used for repairing peripheral nerve critical defects. The catheter stent is composed of a spinning fiber membrane, and has good biocompatibility, porosity, physical support characteristics and even anti-crosslinking effect. In addition, mineralized collagen fibers and active elements are introduced, and calcium ions and active element ions are synergistic in the degradation and slow release process, so that the regeneration of nerves and blood vessels can be promoted, and the degradation can be completely realized.

The nerve conduit provided by the application has excellent porosity and can ensure good transportation of nutrients and metabolic substances. The scaffold material is not limited to the kind of material, such as bioactive material Polycaprolactone (PCL), poly-L-lactic acid (PLLA), collagen, gelatin, chitosan, etc. The composite of the materials may be one or more of them. In the aspect of structural design, the composite design of the directional and non-directional structures is adopted, so that the multi-layer structure of the conduit is compounded, and the good matching of strength and toughness can be met. Therefore, the novel composite nerve conduit bracket has wide applicability, simple and convenient production process, and the fiber membranes with different polymer bases can be mutually jointed, etc.

The application provides a nerve conduit, which comprises active element doped mineralized collagen nano fibers, wherein the weight of inorganic matters in the active element doped mineralized collagen nano fibers accounts for 8 to 35 percent of the whole nerve conduit, and preferably, the weight of inorganic matters in the active element doped mineralized collagen nano fibers accounts for 8 to 12 percent of the whole nerve conduit;

optionally, the nerve conduit has a porosity of 60% to 70%;

optionally, the nerve conduit has a density of 1.3g/cm³To 1.5g/cm³。

In one embodiment provided herein, the nerve conduit has an inner lumen diameter of 1.5mm to 2.5 mm;

in one embodiment provided herein, the nerve conduit has a wall thickness of 1mm to 1.5 mm;

in one embodiment provided herein, the nerve conduit has a length of 1.5cm to 5 cm.

In one embodiment provided herein, all or a portion of the nerve conduits, comprising the mineralized collagen nanofibers doped with the active element and the biodegradable polymer form fibrils that make up the nerve conduits.

In one embodiment provided herein, a fiber membrane composed of filaments in the same direction is designated as fiber membrane a; the fibrous membrane consisting of the fibers with random directions is marked as a fibrous membrane B;

in one embodiment provided herein, a fiber membrane consisting of fibers in the same direction is defined as a fiber membrane in which a majority of the fibers are arranged in the same direction.

In one embodiment provided herein, the fibrous membrane a is crimped into a tube as an inner layer structure of the nerve conduit; the fiber membrane B is curled into a tube as an outer layer structure of the nerve conduit;

in one embodiment provided herein, the nerve conduit comprises a plurality of inner layers, and the fiber direction between adjacent inner layers is at an angle of 30 ° to 90 °.

The nerve conduit in the present application may further include: a biodegradable polymer comprising any one or more of poly epsilon-caprolactone, poly-L-lactic acid, poly-caprolactone-co-L-lactic acid, poly-lactic acid-co-glycolic acid, collagen, gelatin, silk fibroin, fibrinogen, cellulose, chitosan;

in yet another aspect, the present application provides a method of preparing the nerve conduit, the method of preparing the nerve conduit including:

1) selecting the mineralized collagen nanofibers, selecting a biodegradable polymer and a solvent, and uniformly mixing the raw materials to obtain a mixture;

the mass ratio of the mineralized collagen nano fiber doped with the active element, the biodegradable polymer and the solvent is (0.3-1.8): (0.6-0.9): (10-20); optionally, the active element doped mineralized collagen nanofibers, the biodegradable polymer, and the solvent are in a mass ratio of (0.3 to 0.45): (0.6 to 0.9): (10 to 20);

2) preparing the mineralized collagen nanofibers doped with the active elements and the biodegradable polymer into fiber filaments by electrostatic spinning or air jet spinning;

preparing a fiber membrane consisting of fiber yarns with the same direction by using a high-speed roller method, and marking the fiber membrane as a fiber membrane A, and/or preparing a fiber membrane consisting of fiber yarns with random directions by using a flat plate method or a low-speed roller method, and marking the fiber membrane as a fiber membrane B;

optionally, the rotation speed of the drum in the high-speed drum method is 2500 rpm or more, and the rotation speed of the drum in the low-speed drum method is 1500 rpm or less;

3) when a layer of fibrous membrane A and/or fibrous membrane B is used for preparing the nerve conduit, the prepared fibrous membrane A and/or fibrous membrane B is curled into a tube, and the nerve conduit is obtained; when the nerve conduit is prepared by using the multilayer fibrous membrane A and/or the fibrous membrane B, the multilayer fibrous membrane A and/or the fibrous membrane B are laminated and then curled into a tube, and the nerve conduit is obtained;

in one embodiment provided herein, the mixing in step 1) is stirring for 28 to 50 hours; alternatively, the solvent in step 1) is selected from any one or more of hexafluoroisopropanol and trifluoroethanol;

in one embodiment provided herein, the method for preparing a nerve conduit further comprises: laminating a plurality of fiber membranes A at an included angle of 30-60 degrees in the fiber direction and then integrally curling the fiber membranes A into a tube, or laminating a layer of fiber membranes A and a layer of fiber membranes B and then curling the fiber membranes A into a tube, or laminating a plurality of fiber membranes A at an included angle of 30-60 degrees in the fiber direction and then laminating the fiber membranes A and the fiber membranes B and then curling the fiber membranes A into a nerve conduit;

in one embodiment provided herein, the fibrous membrane a forms an inner wall of a nerve conduit.

In one embodiment provided herein, the degradable polymer material fibers and the mineralized collagen nanofibers doped with active elements are spun by electrostatic spinning or air jet spinning, and then the spun fibers are collected to form a film by any one or more of a flat plate method, a low-speed drum method or a high-speed drum method.

In one embodiment provided herein, the electrospinning process can be referred to as "[ 1] lie, Huang Waring.

In one embodiment provided herein, reference may be made to "Song J, Li Z, Wu H. Blowspinning: a new choice for nanofibers [ J ]. ACS Applied Materials & Interfaces,2020,12(30): 33447-.

In one embodiment provided herein, the wall of the nerve conduit is physically or chemically fixed between the membrane layers; alternatively, the chemical method is cross-linking the collagen with a cross-linking agent.

In one embodiment provided herein, the cross-linking agent is selected from any one or more of the cross-linking agents selected from the group consisting of carbonyldiimine, N-hydroxysuccinimide, and genipin;

in one embodiment provided herein, the solvent of the crosslinker solution comprises any one or more of water and ethanol; optionally, the temperature of the crosslinking is 0 ℃ to 4 ℃ (water at 0 ℃ does not freeze); the crosslinking time is 0.5h to 8 h.

In one embodiment provided herein, the preparation method further comprises removing the unreacted cross-linking agent after the cross-linking is completed.

In one embodiment provided herein, the nerve conduit is compressed to enhance fixation between the membrane layers; optionally, the pressure of the pressing is 15MPa to 1.5GPa, preferably, the pressure is 100MPa to 1.5GPa, more preferably, the pressure is 200MPa to 800 MPa.

In another aspect, the application also provides a nerve conduit prepared by the preparation method.

The nerve conduit in the present application comprises mineralized collagen nanofibers, which are characterized and prepared by the following steps:

the mineralized collagen nano fiber consists of collagen fiber and needle-shaped hydroxyapatite crystal;

part of calcium in the crystal lattice of the hydroxyapatite crystal can be replaced by cations containing the active element or not;

and/or, part of the phosphate groups in the crystal lattice of the hydroxyapatite crystal are replaced by anions containing the active elements, and can also not be replaced; the anion of the active element can be an oxyacid group of the active element anion.

The active element comprises any one or more of silicon, selenium, magnesium, zinc, strontium, silver, iron (e.g. ferric iron) and copper (e.g. cupric copper);

the ratio of the stoichiometric number of the calcium element to the sum of the active element-containing cation and the phosphate radical and the active element-containing anion is (1.45:1) to (1.80: 1);

contains the molar ratio of active element cation to calcium ion (5 to 8) to (92 to 95); contains the molar ratio of the active element anion to the phosphate radical (5 to 7) to (93 to 95).

In one embodiment provided herein, the mineralized collagen nanofibers have an average length of 250nm to 300 nm;

in one embodiment provided herein, the mineralized collagen nanofibers have an average diameter of 5nm to 7 nm.

In another aspect, the present application provides a method for preparing the mineralized collagen nanofibers, comprising: preparing the mineralized collagen nanofibers by using an in-situ co-assembly method, wherein when the mineralized collagen nanofibers doped with active elements of the mineralized collagen nanofibers are added, cations containing the active elements are added at the same time when calcium salt ions are added, and/or anions containing the active elements are added at the same time when phosphate ions are added.

In one embodiment provided herein, a method for preparing mineralized collagen nanofibers comprises the following steps:

(a) mixing the type I collagen sponge with a phosphoric acid solution to completely dissolve the type I collagen sponge to obtain a collagen template solution for later use;

when the active element is doped in the form of anion, firstly, the salt containing the anion is mixed with the phosphoric acid solution until the salt is completely dissolved, and then, the salt is mixed with the type I collagen sponge;

(b) preparing a calcium salt solution, wherein the calcium salt solution and the collagen template solution have the same volume;

when the active element is doped in the form of cation, firstly, the salt containing the cation is mixed with the calcium salt solution until the salt is completely dissolved, and then the salt is mixed with the collagen template solution;

(c) preparing a buffer solution;

(d) titrating the collagen template solution and the calcium salt solution in a buffer solution to obtain a mixed solution after titration is finished; during the titration, the pH value of the mixed solution is maintained between 8 and 10;

(e) carrying out high-speed centrifugation on the mixed solution obtained in the step (d), replacing the supernatant obtained by the centrifugation with ultrapure water with the same volume until the pH value of the measured supernatant is about 7-8, and stopping the high-speed centrifugation;

(f) removing the water content of the precipitate obtained in the step (e) to obtain mineralized collagen nanofibers;

alternatively, the preparation method consists of the above.

In one embodiment provided herein, when the mineralized collagen nanofibers are active element doped mineralized collagen nanofibers, the molar ratio of active element-containing cations to calcium ions is (5 to 10): (95 to 90); and/or the molar ratio of anions containing the active element to calcium ions is (5 to 10) to (95 to 90); the ratio of the stoichiometric numbers of (calcium ion + active element cation)/(phosphate ion + active element anion) is (1.65:1) to (1.8: 1);

in one embodiment provided herein, the concentration of the phosphoric acid solution of step (a) is 0.5 to 2mol/L, and the ratio of the mass of the type I collagen sponge to the volume of the phosphoric acid solution is 0.1 to 10 g/L;

in one embodiment provided herein, the mixing of step (a) is for a mixing time of 4 to 12 hours; optionally, the mixing temperature of the mixing is 35 ℃ to 38 ℃.

In one embodiment provided herein, the calcium salt solution in step (c) further comprises hydroxide, and the molar ratio of the sum of the calcium ions and the active element cations to the hydroxide is 2: 1.

In one embodiment provided herein, the buffer solution of step (c) is selected from any one or more of Tris-HCl and phosphate buffer solutions.

In one embodiment provided herein, the flow rate of the titration of step (d) is from 400ml/h to 500 ml/h;

in one embodiment provided herein, after the titration in step (d) is completed, stirring for 12 to 36 hours; optionally, the reaction temperature is controlled at 30 ℃ to 37 ℃ after the titration is completed.

In one embodiment provided herein, the centrifugation of step (e) is at a speed of 3000 rpm to 17000 rpm.

In one embodiment provided herein, the removing of water in step (f) is lyophilization, comprising: drying the precipitate at 4-8 ℃, and then removing residual water by adopting freeze drying; optionally, the freeze dryer has a cold well temperature of between 2 ℃ and 4 ℃, a vacuum degree of between 10Pa and 30Pa, and a freeze drying duration of between 24h and 72 h.

In one embodiment provided herein, the resulting mixture is thoroughly mixed using a magnetic stirrer for agitation.

The nerve conduit material provided by the application builds the components and the structure of the material on a multi-dimensional and multi-scale. The specific regular arrangement from nano-scale to micron-scale not only improves the physical and chemical properties of the material, but also greatly improves the biological properties. And the introduction of active elements has good promotion effect on vascularization and neurogenesis. For example, the introduced magnesium element has the functions of promoting the vascularization, promoting the angiogenesis, and accelerating the nutrition and metabolic processes. The introduced calcium element promotes the generation and the nervonism of the nerve axons.

And the nerve conduit material provided by the application is orderly arranged, so that the suture toughness of the conduit is increased.

Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. Other advantages of the present application may be realized and attained by the invention in its aspects as described in the specification.

Drawings

The accompanying drawings are included to provide an understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the examples serve to explain the principles of the disclosure and not to limit the disclosure.

FIG. 1 is an SEM image of a fiber membrane composed of fiber filaments of the same direction prepared in the examples of the present application.

Detailed Description

In order to make the objects, technical solutions and advantages of the present application more apparent, embodiments of the present application are described in detail below. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.

In the examples provided herein, the raw materials were sourced as follows: sodium silicate (Na)₂SiO₃Analytically pure), anhydrous calcium chloride (CaCl)₂Analytically pure), sodium hydroxide (NaOH, analytically pure) and ammonia (NH)₄OH analytical pure) was purchased from pharmaceutical chemicals, ltd; strontium chloride hexahydrate (SrCl)₂·6H₂O, 99.5%), hexafluoroisopropanol (HFIP, 99.5%) carbonyl diimine (EDC), N-hydroxysuccinimide (NHS) available from shanghai alatin biochem ltd; type I collagen sponge (atelocollagen from oxtail skin, MW 300,000 oxtail, north river collectison); phosphoric acid (H)₃PO₄Analytically pure, Shanghai Tantake Technique, Inc.); Tris-HCl (C)₄H₁₁NO₃HCl, analytical pure, beijing baidi biotechnology limited).

Example 1

(1) Doping with anion Salts (SiO) according to a predetermined value₃) Adding the phosphoric acid into the phosphoric acid ultrapure water solution according to the relative mol percentage of 6 percent, and uniformly stirring. And dissolving the I-type collagen sponge in the phosphoric acid ultrapure water solution, wherein the concentration of the phosphoric acid solution is 0.5mol/L, and the volume ratio of the mass of the I-type collagen sponge to the phosphoric acid solution is 0.1g: 1L. And fully mixing the obtained mixture by using a magnetic stirrer for 6 hours to fully dissolve the added I-type collagen template, and marking as an anionic solution for later use. The temperature of the system was maintained between 35 ℃ and 38 ℃ during stirring.

(2) Preparing calcium chloride ultrapure water solution and rootCaCl is added according to a preset mol relative percentage of 9 percent of doped cation salt (Mg)₂The solution is stirred and dissolved uniformly.

Preparing an ultrapure aqueous NaOH solution, and ensuring that the molar ratio of (calcium ions + magnesium ions)/OH is 2. Adding NaOH solution into calcium-containing magnesium cation solution, and recording as cation solution for standby.

(3) Tris-HCl buffer solution with the solubility of 1mol/L is prepared, namely 0.2mol of Tris-HCl is weighed and dissolved in 200ml of ultrapure water to be used as reaction kettle liquid. And adjusting the pH value of the reaction kettle liquid to be between 8 and 10 by using 0.5mol/L ammonia water and HCl solution.

(4) Simultaneously titrating the anion solution and the cation solution in the reaction kettle liquid, controlling the flow rate to be maintained at 500ml/h, ensuring that the pH value of the reaction kettle liquid is maintained between 8 and 10 in the titration process, controlling the reaction temperature to be 37 ℃ after the titration is finished, and fully stirring for 16h in a dark place. And finishing titration of the anion solution and the cation solution with equal volumes.

(5) And (5) transferring the system in the step (4) into a centrifugal tube for high-speed centrifugation. And after each centrifugation, collecting the supernatant, measuring the pH value of the supernatant, adding ultrapure water with the same volume as the supernatant into the centrifuge tube, stirring the precipitate by using a glass rod to make the precipitate fully contact with the ultrapure water so as to clean the precipitate, and centrifuging again. This was repeated two to three times (3000 rpm) until the pH of the eluate was measured at around 7 to 8; finally 17000 r/min to obtain the cleaned precipitate.

(6) Drying the precipitate obtained after cleaning at 4 deg.C, and removing residual water by freeze dryer with freeze well temperature of 4 deg.C, vacuum degree of 30Pa, and freeze drying duration of 50 hr or more. And drying to obtain the mineralized collagen nanofiber doped with the active elements.

As shown in table 1, the stoichiometric ratio of (calcium ion + magnesium ion)/(phosphate ion + silicate ion) in the mineralized collagen nanofibers doped with active elements prepared in this example was 1.45: 1.

As shown in table 1, the molar ratio of silicate to phosphate in the mineralized collagen nanofibers doped with active elements prepared in this example is 5: 95;

as shown in table 1, the molar ratio of magnesium ions to calcium ions in the mineralized collagen nanofibers doped with active elements prepared in this example is 7.8: 92.2;

the mineralized collagen nano fiber doped with active elements prepared by the embodiment has the average length of 250nm to 300nm and the average diameter of 5nm to 7 nm.

Table 1 elemental distribution of mineralized collagen nanofibrils doped with active elements prepared in example 1

Element(s)	Mass percentage of	Atomic number percentage
			C	28.24	39.55
O	46.11	47.31
			Mg	0.86	0.61
Si	0.5	0.27
			P	9.41	5.08
Ca	14.88	7.18
			Total of	100.00	100.00

Example 2

In this embodiment, the preparation of the fibrous membrane using the mineralized collagen nanofibers doped with active elements prepared in example 1 as raw materials includes the following steps:

(1) the mineralized collagen nanofibers doped with the active elements prepared in example 1 were taken, mixed with collagen and hexafluoroisopropanol, and continuously stirred vigorously for 28h to ensure thorough and uniform mixing. The mass ratio of the mineralized collagen nanofibers doped with active elements, collagen and hexafluoroisopropanol solution prepared in example 1 was 1.0:0.6: 10.

(2) The raw materials are subjected to electrostatic spinning to prepare fiber yarns, the prepared fiber yarns are collected by a high-speed roller method, and the obtained fiber membrane (the fiber membrane with the same fiber direction) is marked as a fiber membrane 1, and the electrostatic spinning process can refer to 'Liyan, Huang Waiguing, electrostatic spinning of polymers [ J ]. high molecular report, 2006(05): 12-19' or the conventional electrostatic spinning process in the field.

The rotating speed of the roller in the high-speed roller method is more than 2500 rpm;

collecting the prepared filaments by using a low-speed roller method through electrostatic spinning, and marking the obtained fiber membrane as a fiber membrane 2;

the rotating speed of the roller in the low-speed roller method is 1500 rpm or less;

collecting the prepared filaments by using a flat plate method through air jet spinning, and marking the obtained fiber membrane as a fiber membrane 3;

reference may be made to "Song J, Li Z, Wu H. blowing spinning: a new choice for nanofibers [ J ]. ACS Applied Materials & Interfaces,2020,12(30): 33447) 33464" or to air-jet spinning processes conventional in the art;

the flat plate method is to spray the fiber obtained by the air jet spinning method onto a flat plate and obtain a fiber membrane after a period of time;

example 3

The length of the nerve conduit can be 1.5cm to 5cm or a specific length can be prepared according to actual needs; the diameter of the inner lumen of the nerve conduit can be 1.5mm to 2.5mm or prepared into a specific length according to actual needs;

preparing an artificial nerve conduit with an I-type structure: the fiber membranes 1, 2 and 3 are prepared in example 2, wherein 1 fiber membrane is selected to be independently curled to obtain the nerve conduit, the nerve conduit is pressed under the pressure of 350MPa, the wall thickness of the nerve conduit is about 1.5mm, the porosity of the nerve conduit is controlled to be 60-70%, and the density is 1.3g/cm³To 1.5g/cm³And is marked as a type I nerve conduit.

Preparing the artificial nerve conduit with the II-type structure: using a fiber membrane 1 as an inner layer of a nerve conduit and a fiber membrane 2 as an outer layer of the nerve conduit, overlapping the fiber membrane 1 and the fiber membrane 2 in sequence, then curling into a tube, wherein the thickness of the fiber membrane 1 is about 2mm, the thickness of the fiber membrane 2 is about 1mm, pressing is carried out under the pressure of 350MPa, the wall thickness of the nerve conduit is about 1.5mm, the porosity of the nerve conduit is controlled to be 60-70%, and the density is 1.3g/cm³To 1.5g/cm³And is marked as the artificial nerve conduit with the II-type structure.

Preparing the artificial nerve conduit with the III-type structure: overlapping a plurality of fiber membranes 1, wherein the adjacent fiber membranes 1 form an included angle of 30-90 degrees based on the fiber direction, and are arranged in a staggered manner, for example, the adjacent fiber membranes 1 form an included angle of 30 degrees based on the fiber direction; for example, each fiber membrane 1 may have a thickness of 1mm, 3 layers of the fiber membranes 1 may be rolled into a tube and pressed under a pressure of 350MPa, the wall thickness of the nerve conduit may be about 1.5mm, the porosity of the nerve conduit may be controlled to 60% to 70%, and the density may be 1.3g/cm³To 1.5g/cm³(ii) a Is marked as type III nerve conduit.

According to the artificial nerve conduit with the I-type structure, the artificial nerve conduit with the II-type structure and the artificial nerve conduit with the III-type structure, which are prepared by the embodiment of the application, by introducing the doping elements, the cations or the anions of the doping elements are phosphate radicals or calcium ions in hydroxyapatite crystal lattices in mineralized collagen nanofibers, so that the doping elements can be effectively and controllably released, and compared with the nerve conduit without the doping elements, the regeneration of human tissues such as nerves, blood vessels and the like can be effectively promoted.

Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.

Claims

1. A nerve conduit, comprising: mineralized collagen nanofibers doped with active elements;

the mineralized collagen nano fiber doped with the active elements contains hydroxyapatite crystals;

the calcium element in the crystal lattice of the hydroxyapatite is replaced by the cation containing the active element,

and/or the phosphate groups in the crystal lattice of the hydroxyapatite are replaced by anions containing the active element;

optionally, the active element comprises any one or more of silicon, selenium, magnesium, zinc, strontium, silver, iron and copper;

optionally, the ratio of elemental calcium to the stoichiometric number containing the active element cation to the stoichiometric number of the sum of the phosphate and the active element-containing anion is from (1.45:1) to (1.80: 1);

optionally, a molar ratio (5 to 8) of active element cations to calcium ions (92 to 95); contains the molar ratio of the active element anion to the phosphate radical (5 to 7) to (93 to 95).

2. The nerve conduit of claim 1, wherein the active element doped mineralized collagen fibers have an average length of 250nm to 300 nm;

optionally, the active element-doped mineralized collagen fibers have an average diameter of 5nm to 7 nm.

3. A nerve conduit according to claim 1, wherein the inner lumen of the nerve conduit is 1.5mm to 2.5mm in diameter,

optionally, the nerve conduit has a wall thickness of 1mm to 1.5 mm;

optionally, the nerve conduit is 1.5cm to 5cm in length.

4. The nerve conduit of any one of claims 1 to 3, wherein the nerve conduit further comprises a biodegradable polymer comprising any one or more of poly epsilon-caprolactone, levopolylactic acid, polycaprolactone-levolactic acid copolymer, polylactic acid-glycolic acid copolymer, collagen, gelatin, silk fibroin, fibrinogen, cellulose, chitosan;

optionally, the weight of the inorganic matter in the active element doped mineralized collagen nanofibers accounts for 8% to 35% of the total nerve conduit, preferably, the weight of the inorganic matter in the active element doped mineralized collagen nanofibers accounts for 8% to 12% of the total nerve conduit;

optionally, the nerve conduit has a porosity of 60% to 70%;

optionally, the nerve conduit has a density of 1.3g/cm³To 1.5g/cm³。

5. The nerve conduit of claim 4, wherein all or a portion of the nerve conduit comprises mineralized collagen nanofibers doped with the active element and the biodegradable polymer forming a fiber filament;

optionally, the fiber membrane composed of fiber filaments in the same direction is denoted as fiber membrane a; the fibrous membrane consisting of the fibers with random directions is marked as a fibrous membrane B;

optionally, the fiber membrane a is crimped into a tube as an inner layer structure of the nerve conduit; the fiber membrane B is curled into a tube as an outer layer structure of the nerve conduit;

optionally, the nerve conduit comprises a plurality of inner layers, and the fiber directions between adjacent inner layers are at an included angle of 30-90 °.

6. The method for preparing a nerve conduit according to claim 4 or 5, comprising the steps of:

1) selecting the mineralized collagen nanofibers, selecting a degradable polymer and a solvent, and uniformly mixing the raw materials to obtain a mixture;

the mass ratio of the mineralized collagen nano fiber doped with the active element, the degradable polymer and the solvent is (0.3-1.8): (0.6-0.9): (10-20); optionally, the active element doped mineralized collagen nanofibers, the biodegradable polymer, and the solvent are in a mass ratio of (0.3 to 0.45): (0.6 to 0.9): (10 to 20);

optionally, the preparation method of the nerve conduit further comprises: laminating a plurality of fiber membranes A at an included angle of 30-60 degrees in the fiber direction and then integrally curling the fiber membranes A into a tube, or laminating a layer of fiber membranes A and a layer of fiber membranes B and then curling the fiber membranes A into a tube, or laminating a plurality of fiber membranes A at an included angle of 30-60 degrees in the fiber direction and then laminating the fiber membranes A and the fiber membranes B and then curling the fiber membranes A into a nerve conduit;

optionally, the mixing in step 1) is stirring for 28 to 50 hours; alternatively, the solvent in step 1) is selected from any one or more of hexafluoroisopropanol and trifluoroethanol.

7. The method for preparing a nerve conduit according to claim 6, wherein the wall of the nerve conduit is fixed between the membrane layers by physical or chemical means;

alternatively, the chemical method is cross-linking the collagen with a cross-linking agent.

8. The nerve conduit of claim 7, wherein the cross-linking agent is selected from any one or more of the cross-linking agents selected from the group consisting of carbonyldiimine, N-hydroxysuccinimide, and genipin;

optionally, the solvent of the crosslinker solution comprises any one or more of water and ethanol; optionally, the temperature of the crosslinking is 0 ℃ to 4 ℃ (water at 0 ℃ does not freeze); the crosslinking time is 0.5h to 8 h.

9. The method of manufacturing a nerve conduit according to claim 7 or 8, further comprising removing the crosslinking agent after completion of the crosslinking.

10. The method for manufacturing a nerve conduit according to claim 7, wherein the nerve conduit is press-fitted to enhance fixation between membrane layers; optionally, the pressure of the pressing is 15MPa to 1.5GPa, preferably, the pressure is 100MPa to 1.5GPa, more preferably, the pressure is 200MPa to 800 MPa.