阅读说明：本技术 一种可降解多模态神经导管及其制备方法 (Degradable multi-modal nerve conduit and preparation method thereof ) 是由 吴紫萱 于 2021-01-20 设计创作，主要内容包括：本发明公开了一种可降解多模态神经导管及其制备方法,包括起到支撑作用的外层导管和负载神经生长因子的导管内层膜,所述导管两端分别设有两种电位不同的金属环,并通过电位不同金属环形成的自源电池形成电刺激功能以及导管内层膜负载的生长因子促进神经的发育与融合。本发明制备的神经导管,整体采用可降解材料,实现功效后在体内降解,避免二次取械手术。导管内两端镶嵌金属,利用不同金属腐蚀电位差,以体液为电解质液,自源产生电流刺激,促进神经发育,提高了同等效用导管的安全性和小型化。纤维膜缓释所载神经生长因子,为神经生长提供所需养份；且纤维膜卷制筒状,有利于神经沿导管方向粘附生长,提高神经组织的再生效率。(The invention discloses a degradable multi-modal nerve conduit and a preparation method thereof, and the degradable multi-modal nerve conduit comprises an outer conduit with a supporting function and a conduit inner membrane loaded with nerve growth factors, wherein two metal rings with different potentials are respectively arranged at two ends of the conduit, and an electrical stimulation function is formed by a self-source battery formed by the metal rings with different potentials and the development and fusion of nerves are promoted by the growth factors loaded by the conduit inner membrane. The nerve conduit prepared by the invention integrally adopts degradable materials, is degraded in vivo after the efficacy is realized, and avoids secondary operation of taking hands. The metal is embedded at two ends in the catheter, and the body fluid is used as electrolyte liquid by utilizing different metal corrosion potential differences, so that the current stimulation is generated by self source, the nerve development is promoted, and the safety and the miniaturization of the catheter with the same effect are improved. The fiber membrane slowly releases the carried nerve growth factor to provide the required nutrients for the growth of nerves; and the fibrous membrane is rolled into a cylinder shape, so that the adhesion growth of nerves along the direction of the catheter is facilitated, and the regeneration efficiency of nerve tissues is improved.)

1. The degradable multi-modal nerve conduit is characterized by comprising an outer conduit with a supporting function and a conduit inner layer membrane loaded with nerve growth factors, wherein two metal rings with different potentials are respectively arranged at two ends of the conduit, and an electrical stimulation function is formed by a self-source battery formed by the metal rings with different potentials and the growth factors loaded by the conduit inner layer membrane promote the development and fusion of nerves.

2. The degradable multimodal nerve conduit as claimed in claim 1, wherein the outer layer conduit, the inner layer membrane of conduit and the metal ring are made of degradable material.

3. The degradable multimodal nerve conduit as claimed in claim 2, wherein the material of the outer layer conduit is one or more selected from PLA (polylactic acid, polylactide), PGA (polyglycolic acid, polyglycolide), PTMC (polytrimethylene carbonate), PDDO (polydioxanone), PCL (polycaprolactone), PLGA (poly (lactic-co-glycolic acid)), MPEG (polyethylene glycol), PEI (polyethyleneimine), PCL (poly epsilon-caprolactone) and their copolymers.

4. The degradable multimodal nerve conduit as claimed in claim 3, wherein the outer layer conduit is made of poly (L-lactide) (PLLA) and polyethylene glycol (MPEG) copolymer, the molecular weight of poly (L-lactide) (PLLA) and the molecular weight of polyethylene glycol (MPEG) are 10000-; the weight ratio of the components is 90-10: 10-90.

5. The degradable multimodal nerve conduit as claimed in claim 2, wherein the inner wall of the outer conduit is provided with a ring groove, and the metal ring is disposed in the ring groove.

6. The degradable multimodal nerve conduit as claimed in claim 2, wherein the metal ring is made of degradable metal, and the metal ring is made of magnesium, zinc, iron, manganese and their alloy.

7. The degradable multimodal nerve conduit of claim 2, wherein the inner membrane of the conduit comprises a substrate and a substrate loaded with nerve growth factor and stabilizer, wherein the substrate is made of degradable material, and the nerve growth factor is selected from one or more of Nerve Growth Factor (NGF), Brain Derived Neurotrophic Factor (BDNF), glial cell derived nerve factor (GNDF), neurotrophic factor (NT-3), (NT-4); the stabilizer is Bovine Serum Albumin (BSA).

8. The degradable multimodal nerve conduit as claimed in claim 1 or 5, wherein the outer layer conduit has a diameter of 5-20mm, a length of 10-30mm and a thickness of 2 mm; the width of annular is 1mm, and the degree of depth is 1mm, and the distance of annular and outer layer pipe both ends is 3 mm.

9. A method for making a degradable multimodal nerve conduit as claimed in claim 1, comprising the steps of:

s1, manufacturing an outer-layer guide pipe, and forming a ring groove on the inner wall of the outer-layer guide pipe;

s2, respectively manufacturing two metal rings with different potentials;

s3, coating the metal ring with collagen, and then embedding the metal ring into the annular groove of the outer-layer guide pipe;

s4, manufacturing a catheter inner layer film;

s5, filling the inner membrane of the catheter into the inner wall of the outer catheter, and injecting collagen into the hole between the inner membrane of the catheter and the outer catheter for filling;

s6, after integral sterilization, vacuum packaging.

10. The method of claim 9, wherein the outer layer of the catheter at S1 is formed by one of injection molding, electrospinning, 3D printing, and Hot Melt Extrusion (HME); s4, selecting one of injection molding, electrostatic spinning, 3D printing and Hot Melt Extrusion (HME) as the manufacturing method of the catheter inner layer film; the manufacturing method of the metal ring comprises the steps of smelting, solid solution, sintering and laser cutting and forming.

Technical Field

The invention relates to the technical field of medical consumables, in particular to a multimode artificial nerve conduit with both an electric stimulation function and a neurotrophic factor loading function and a preparation method thereof.

Background

The injury of nerves of a human body may be caused by external force trauma, diseases and the like to be defective, and the sensory and motor functions of the far-end limb innervated by the affected nerves are lost after the peripheral nerves are damaged. The clinical scheme of neurosurgery adopts operation to enable two ends of the defective nerve to be anastomosed, and adopts an artificial material catheter in practice to protect two ends of the bridging defective nerve to induce the two ends of the bridging defective nerve to regenerate and remold to a far end and rebuild a channel with a target end; in fact, if the motor nerve pathway reconstruction is needed for the hemiplegia subsequently occurring in the moderate and severe cerebral apoplexy, the stimulation function recovery is needed after the pathway is established by developing in the catheter after the autonerve transplantation is adopted.

The development of degradable high polymer materials and metal materials provides suitable materials for the development of nerve conduits, and an environment structure is effectively built for the anastomosis of nerves at two ends; and the nerve conduit made of degradable material is self-degraded after being implanted into a human body, and does not need to be taken out by a secondary operation.

The nerve growth factor is used as nutrient for nerve growth and development, and can promote nerve growth and restore physiological structure more effectively.

Disclosure of Invention

In order to solve the technical problems, the invention provides the following scheme: a degradable multi-modal nerve conduit and a preparation method thereof. In order to achieve the purpose, the invention adopts the following technical scheme:

a degradable multi-modal nerve conduit comprises an outer conduit with a supporting function and a conduit inner layer membrane loaded with nerve growth factors, wherein two metal rings with different potentials are respectively arranged at two ends of the conduit, and an electrical stimulation function is formed by a self-source battery formed by the metal rings with different potentials and the growth factors loaded on the conduit inner layer membrane promote the development and fusion of nerves.

The invention also discloses a manufacturing method of the degradable multi-modal nerve conduit, which comprises the following steps:

s1, manufacturing an outer-layer guide pipe, and forming a ring groove on the inner wall of the outer-layer guide pipe;

s2, respectively manufacturing two metal rings with different potentials;

s3, coating the metal ring with collagen, and then embedding the metal ring into the annular groove of the outer-layer guide pipe;

s4, manufacturing a catheter inner layer film;

s5, filling the inner membrane of the catheter into the inner wall of the outer catheter, and injecting collagen into the hole between the inner membrane of the catheter and the outer catheter for filling;

s6, after integral sterilization, vacuum packaging.

As an improvement, the outer layer catheter, the catheter inner layer membrane and the metal ring are made of degradable materials.

As an improvement, the material selected for the outer layer catheter is one or more of PLA (polylactic acid, polylactide), PGA (polyglycolic acid, polyglycolide), PTMC (polytrimethylene carbonate), PDDO (polydioxanone), PCL (polycaprolactone), PLGA (polylactic-glycolic acid copolymer), MPEG (polyethylene glycol), PEI (polyethyleneimine), PCL (poly epsilon-caprolactone) and copolymers thereof.

As an improvement, the material selected for the outer layer catheter is a copolymer of L-polylactic acid (PLLA) and polyethylene glycol (MPEG), and the molecular weights of the L-polylactic acid (PLLA) and the polyethylene glycol (MPEG) are 10000-; the weight ratio of the components is 90-10: 10-90.

As an improvement, the inner wall of the outer layer conduit is provided with a ring groove, and the metal ring is arranged in the ring groove.

As an improvement, the metal ring is made of degradable metal, and the metal ring is made of magnesium, zinc, iron, manganese and alloy thereof.

As an improvement, the catheter inner layer membrane comprises a base material and nerve growth factors and stabilizing agents loaded on the base material, wherein the base material is made of degradable materials, and the nerve growth factors are selected from one or more of Nerve Growth Factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived nerve factor (GNDF), neurotrophic factor (NT-3) and NT-4; the stabilizer is Bovine Serum Albumin (BSA).

As an improvement, the diameter of the outer layer conduit is 5-20mm, the length is 10-30mm, and the thickness is 2 mm; the width of annular is 1mm, and the degree of depth is 1mm, and the distance of annular and outer layer pipe both ends is 3 mm.

As an improvement, in S1, the outer layer catheter is manufactured by one of injection molding, electrostatic spinning, 3D printing and Hot Melt Extrusion (HME); s4, selecting one of injection molding, electrostatic spinning, 3D printing and Hot Melt Extrusion (HME) as the manufacturing method of the catheter inner layer film; the manufacturing method of the metal ring comprises the steps of smelting, solid solution, sintering and laser cutting and forming.

The invention has the following advantages:

(1) the nerve conduit prepared by the invention has good medical value for repairing nerve injury and nerve transplantation function through establishing mechanical space, supplementing nerve growth factors, electrically stimulating nerve development and the like.

(2) The whole body is made of degradable materials, so that the degradable material is degraded in vivo after the efficacy is realized, and secondary operation is avoided.

(3) The metal is embedded at two ends in the catheter, and the body fluid is used as electrolyte liquid by utilizing different metal corrosion potential differences, so that the current stimulation is generated by self source, the nerve development is promoted, and the safety and the miniaturization of the catheter with the same effect are improved.

(4) The fiber membrane slowly releases the carried nerve growth factor to provide the required nutrients for the growth of nerves; and the fibrous membrane is rolled into a cylinder shape, so that the adhesion growth of nerves along the direction of the catheter is facilitated, and the regeneration efficiency of nerve tissues is improved.

(5) The invention has mature production equipment, simple process and commercially available materials; the production process has high controllability and strong reproducibility, and is suitable for large-scale mass production.

Drawings

FIG. 1 is a schematic view of a nerve conduit;

figure 2 is a schematic cross-sectional view of a nerve conduit.

Labeled as:

1-outer layer conduit, 11-ring groove, 2-conduit inner layer membrane, and 3-metal ring.

Detailed Description

The present invention will be described in detail and specifically with reference to the following examples so as to facilitate the understanding of the present invention, but the following examples do not limit the scope of the present invention.

Example one

The embodiment discloses a degradable multi-modal nerve conduit and a preparation method thereof. The catheter comprises an outer catheter 1, a catheter inner membrane 2 and a metal ring 3.

The outer catheter 1 is made of a copolymer of poly (L-lactide) (PLLA) and polyethylene glycol (MPEG). The molecular weights of the levo-polylactic acid (PLLA) and polyethylene glycol (MPEG) are 20000 and 6000, respectively; the weight ratio of parts is 75: 25. two ring grooves 11 are arranged on the inner wall of the outer layer conduit 1 close to the two ends, and two metal rings 3 with different electric potentials are arranged in the ring grooves 11. In this embodiment, a ferromanganese metal ring 31 and a magnesium-zinc metal ring 32 are used as the two metal rings.

The manufacturing method of the embodiment comprises the following steps:

s1, manufacturing an outer-layer guide pipe, and forming a ring groove on the inner wall of the outer-layer guide pipe

The levorotatory polylactic acid (PLLA) and polyethylene glycol (MPEG) copolymer was printed into a tube shape by 3D printing. 12mm in diameter, 20mm in length and 2mm in thickness.

Printing and manufacturing annular grooves at the positions 3mm away from the end ports at two ends of the inner wall of the outer layer conduit, wherein the width of each annular groove is 1mm, and the depth of each annular groove is 1 mm. And sterilizing the tube body for later use.

S2, respectively manufacturing two metal rings with different potentials

Weighing iron ingots with the Fe purity of more than or equal to 99.99 percent and manganese ingots with the Mn purity of more than or equal to 99.99 percent according to the proportion of 98:2, carrying out vacuum melting, casting to form ferromanganese alloy cast ingots, carrying out solution treatment on the alloy cast ingots, then carrying out forging air cooling to finally obtain ferromanganese alloy round bars with the diameter of 10mm, and cutting the ferromanganese metal rings into ferromanganese metal rings with the outer diameter of 10mm, the inner diameter of 8mm and the width of 1mm by laser.

Weighing magnesium ingots with the Mg purity of more than or equal to 99.99 percent and zinc ingots with the Zn purity of more than or equal to 99.99 percent according to the proportion of 98:2, carrying out vacuum melting, casting to obtain magnesium-zinc alloy ingots, carrying out solution treatment on the alloy ingots, then carrying out forging air cooling to obtain magnesium-zinc alloy round bars with the diameter of 10mm, and finally cutting the magnesium-zinc alloy round bars into magnesium-zinc metal rings with the outer diameter of 10mm, the inner diameter of 8mm and the width of 1mm by laser. The production and storage of the above metals must be protected with an inert gas to prevent oxidation of the metals. Sterilizing the metal ring for later use.

The volume of the metal ring is about 0.11cm³And calculating to obtain: iron content 0.848 g, manganese content 0.016 g, magnesium content 0.187 g and zinc content 0.016 g.

The degradation rate of the ferromanganese metal ring is 0.12-0.23 mm/y through in vitro solution test; the degradation rate of the magnesium-zinc metal ring is 0.30-0.63 mm/y.

And S3, coating the two metal rings by using collagen, and respectively embedding the two metal rings into the two ring grooves.

S4, manufacturing an inner layer film of the catheter

0.8g of polyethylene glycol (MPEG6000), 0.1g of Bovine Serum Albumin (BSA), 0.1g of nerve growth factor NGF0.1g and 10ml of a 10% electrostatic spinning solution prepared by dissolving in Phosphate Buffered Saline (PBS) with pH7.4 are weighed according to the weight ratio of 8:1: 1. Fully stirring until the mixture is completely dissolved and standing for later use.

And setting parameters of the electrostatic spinning machine. Setting voltage: 12kv, the needle head is a No. 7 needle head, the advancing speed of the injection pump is 2ml/h, the receiving distance is 5cm, an aluminum foil wrapping roller (diameter is 7.5mm) is arranged, the rotating speed of the roller is 3000r/min, and the fiber is received by winding.

S5, after the spinning is finished, taking down the cylindrical membrane to obtain the inner membrane of the catheter, naturally drying the inner membrane, then placing the inner membrane into an outer catheter, and injecting collagen to fill the gap between the outer catheter and the inner membrane of the catheter.

S6, carrying out integral sterilization and then carrying out vacuum packaging. And (5) completing the assembly of the multi-modal nerve conduit.

Example two

This example uses a poly (L-lactic acid) (PLLA) and polyethylene glycol (MPEG) copolymer in the outer catheter.

The molecular weights of the levo-polylactic acid (PLLA) and polyethylene glycol (MPEG) are 20000 and 4000, respectively; the weight ratio of 50: 50.

the manufacturing method of the embodiment comprises the following steps:

s1, manufacturing an outer-layer guide pipe, and forming a ring groove on the inner wall of the outer-layer guide pipe

The levorotatory polylactic acid (PLLA) and polyethylene glycol (MPEG) copolymer was printed into a tube shape by 3D printing. Diameter 10mm, length 10mm, thickness 2 mm.

Printing to form annular grooves at the positions 2mm away from the end ports at two ends of the inner wall of the outer layer guide pipe, wherein the width of each annular groove is 1mm, and the depth of each annular groove is 1 mm. And sterilizing the tube body for later use.

S2, respectively manufacturing two metal rings with different potentials

Weighing iron ingots with the Fe purity of more than or equal to 99.99 percent and manganese ingots with the Mn purity of more than or equal to 99.99 percent according to a ratio of 85:15, carrying out vacuum melting, casting to form ferromanganese alloy cast ingots, carrying out solution treatment on the alloy cast ingots, then carrying out forging air cooling to finally obtain ferromanganese alloy round bars with the diameter of 6mm, and cutting the ferromanganese metal rings into ferromanganese metal rings with the outer diameter of 6mm, the inner diameter of 4mm and the width of 1mm by laser.

Magnesium ingots with the Mg purity of more than or equal to 99.99 percent and zinc ingots with the Zn purity of more than or equal to 99.99 percent are weighed according to the proportion of 70:30, vacuum smelting is carried out, magnesium-zinc alloy ingots are cast, after solution treatment is carried out on the alloy ingots, forging and air cooling are carried out, magnesium-zinc alloy round bars with the diameter of 6mm are finally obtained, and the magnesium-zinc metal rings with the outer diameter of 6mm, the inner diameter of 4mm and the width of 1mm are cut by laser. The production and storage of the above metals must be protected with an inert gas to prevent oxidation of the metals. Sterilizing the metal ring for later use.

The volume of the metal ring is about 0.06cm³And calculating to obtain: iron content 0.401 g, manganese content 0.066 g, magnesium content 0.073 g, zinc content 0.128 g.

The degradation rate of the ferromanganese metal ring is 0.17-0.26 mm/y through in vitro solution test; the degradation rate of the magnesium-zinc metal ring is 0.43-0.70 mm/y.

And S3, coating the two metal rings with collagen, and respectively embedding the two metal rings into the two ring grooves.

S4, manufacturing an inner layer film of the catheter

0.9g of polyethylene glycol (MPEG6000), 0.05g of Bovine Serum Albumin (BSA), 0.05g of nerve growth factor NGF0, and 10ml of Phosphate Buffered Saline (PBS) dissolved in pH7.4 are weighed according to the weight ratio of 9:0.5:0.5 to prepare 10ml of electrostatic spinning solution. Fully stirring until the mixture is completely dissolved and standing for later use.

And setting parameters of the electrostatic spinning machine. Setting voltage: 13kv, 6-gauge needle head, the advancing speed of the injection pump is 2ml/h, the receiving distance is 8cm, an aluminum foil wrapping roller (diameter is 5.5mm) is arranged, the rotating speed of the roller is 2500r/min, and the fiber is received by winding.

S5, after the spinning is finished, taking down the cylindrical membrane to obtain the inner membrane of the catheter, naturally drying the inner membrane, then placing the inner membrane into an outer catheter, and injecting collagen to fill the gap between the outer catheter and the inner membrane of the catheter.

S6, carrying out integral sterilization and then carrying out vacuum packaging. And (5) completing the assembly of the multi-modal nerve conduit.

EXAMPLE III

In this embodiment, the outer catheter is made of a copolymer of poly (L-lactic acid) (PLLA) and polyethylene glycol (MPEG). The molecular weights of the levo-polylactic acid (PLLA) and polyethylene glycol (MPEG) are 20000 and 6000, respectively; the weight ratio is 85: 15.

the manufacturing method of the embodiment comprises the following steps:

s1, manufacturing an outer-layer guide pipe, and forming a ring groove on the inner wall of the outer-layer guide pipe

The levorotatory polylactic acid (PLLA) and polyethylene glycol (MPEG) copolymer was printed into a tube shape by 3D printing. Diameter 14mm, length 30mm, thickness 2 mm.

Printing and manufacturing annular grooves at the positions 3mm away from the end ports at two ends of the inner wall of the outer layer guide pipe, wherein the width of each annular groove is 1mm, and the depth of each annular groove is 1 mm. And sterilizing the tube body for later use.

S2, respectively manufacturing two metal rings with different potentials

Weighing an iron ingot with Fe purity being more than or equal to 99.99% and a manganese ingot with Mn purity being more than or equal to 99.99% according to a ratio of 90:10, carrying out vacuum melting, casting to obtain a ferromanganese alloy ingot, carrying out solid solution treatment on the alloy ingot, forging and air cooling to finally obtain a ferromanganese alloy round bar with phi 12mm, and cutting the ferromanganese metal ring into ferromanganese metal rings with outer diameter of 12mm, inner diameter of 10mm and width of 1mm by laser.

Weighing magnesium ingots with the Mg purity of more than or equal to 99.99 percent and zinc ingots with the Zn purity of more than or equal to 99.99 percent according to a ratio of 90:10, carrying out vacuum melting, casting to obtain magnesium-zinc alloy ingots, carrying out solution treatment on the alloy ingots, then carrying out forging air cooling to obtain magnesium-zinc alloy round bars with the diameter of 12mm, and finally cutting the magnesium-zinc alloy round bars into magnesium-zinc metal rings with the outer diameter of 12mm, the inner diameter of 10mm and the width of 1mm by laser. The production and storage of the above metals must be protected with an inert gas to prevent oxidation of the metals. Sterilizing the metal ring for later use.

The volume of the metal ring is about 0.14cm³And calculating to obtain: iron content 0.991 g, manganese content 0.104 g, magnesium content 0.219 g, zinc content 0.099 g.

The degradation rate of the ferromanganese metal ring is 0.20-0.26 mm/y through in vitro solution test; the degradation rate of the magnesium-zinc metal ring is 0.30-0.60 mm/y.

And S3, coating the two metal rings with collagen, and respectively embedding the two metal rings into the two ring grooves.

S4, manufacturing an inner layer film of the catheter

0.8g of polyethylene glycol (MPEG6000), 0.1g of Bovine Serum Albumin (BSA), 0.1g of nerve growth factor NGF0.1g and 10ml of a 10% electrostatic spinning solution prepared by dissolving in Phosphate Buffered Saline (PBS) with pH7.4 are weighed according to the weight ratio of 8:1: 1. Fully stirring until the mixture is completely dissolved and standing for later use.

And setting parameters of the electrostatic spinning machine. Setting voltage: 13kv, the needle is a No. 7 needle, the advancing speed of the injection pump is 2ml/h, the receiving distance is 8cm, an aluminum foil wrapping roller (diameter is 9.5mm) is arranged, the rotating speed of the roller is 3500r/min, and the fiber is received by winding.

S5, after the spinning is finished, taking down the cylindrical membrane to obtain the inner membrane of the catheter, naturally drying the inner membrane, then placing the inner membrane into an outer catheter, and injecting collagen to fill the gap between the outer catheter and the inner membrane of the catheter.

S6, carrying out integral sterilization and then carrying out vacuum packaging. And (5) completing the assembly of the multi-modal nerve conduit.

The embodiments of the present invention have been described in detail above, but they are merely exemplary, and the present invention is not equivalent to the above described embodiments. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, it is intended that all equivalent alterations and modifications be included within the scope of the invention, without departing from the spirit and scope of the invention.