Magnetically-driven electromechanical stimulation nerve conduit and construction method thereof

Abstract

The invention discloses a magnetically-driven electromechanical stimulation nerve conduit and a construction method thereof.The magnetically-driven electromechanical stimulation nerve conduit is composed of a tubular functional section of a negative Poisson's ratio structure and suture rings of spiral structures located at the two ends of the tubular functional section, the magnetically-driven electromechanical stimulation nerve conduit is formed by printing, phase separation and curing through a four-axis 3D printer, and after the phase separation reaction of a tubular stent is sufficient, the suture rings are separated and cured. The nerve conduit is taken down from the rotating shaft, then the tubular stent is placed between the two magnets which attract each other, and mechanical stimulation is formed to promote nerve restoration; the tubular stent is placed in an alternating magnetic field, and generated induction current stimulates cell growth and differentiation through the catheter. The preparation method disclosed by the invention is low in manufacturing cost, high in speed and high in process flexibility, and the middle part of the prepared engineering scaffold can provide a multifunctional tissue microenvironment and has relatively good biocompatibility; the suture rings at the two ends can generate mechanical deformation through magnetic driving, and the middle functional section is promoted to generate auxetic change, so that the cells are guided to grow directionally.

Description

Technical Field

[0001] The present invention relates to the technical field of high-end biomaterial manufacturing, and in particular to a magnetically driven electromechanically stimulated nerve conduit and a construction method thereof. Background Art

[0002] Peripheral nerve injuries (PNIs) are one of the most common traumatic injuries of the nervous system, affecting millions of people worldwide, with unsatisfactory clinical outcomes and resulting in huge healthcare costs each year. Therefore, peripheral nerve regeneration has become a hot topic of clinical concern, and rapid reconstruction of structural integrity is essential to optimize repair outcomes. In the clinic, autologous nerve transplantation is generally considered the gold standard for treatment. However, the lack of suitable sources of autologous tissue and donor grafts has limited the development of tissue transplantation, and only a few patients have recovered normal motor function and sensory perception. In addition, for patients with multiple nerve deficits, donor nerves are far from enough.

[0003] Tissue engineering scaffolds, composed of cells, materials, and bioactive molecules, are potential alternatives to autologous grafts for the treatment of nerve repair. In the past few decades, various bioactive molecules have been integrated to propagate regenerative signals in the development of biomimetic neural scaffolds for nerve repair. In recent decades, a lot of research has been invested in the development of nerve guide conduits (NGCs) as synthetic alternatives to provide temporary mechanical support and a favorable microenvironment for nerve regeneration.

[0004] Studies have shown that mechanical stimulation changes the microenvironment of cells through physical effects. When cells are subjected to mechanical stimulation such as stretching and compression, they will undergo morphological and structural changes, which will activate the signal transduction pathways on the cell membrane and promote cell growth. Secondly, appropriate mechanical stimulation can enhance the adhesion between cells and promote the production of extracellular matrix, which not only improves the survival ability of cells, but also provides better growth conditions for cell proliferation. In addition, mechanical stimulation can increase the energy supply in cells, improve the metabolic activity of cells, provide cells with necessary nutrients and energy, and support rapid cell division; electrical stimulation has shown good application potential in promoting cell growth. First, electrical stimulation can enhance the permeability of cell membranes, promote the intake of nutrients and the discharge of metabolic waste, thereby providing cells with a good growth environment. Secondly, electric current can stimulate signal transduction in cells. Therefore, electrical stimulation can not only accelerate cell proliferation, but also guide cell differentiation, thereby promoting tissue repair and regeneration.

[0005] Magnetically driven electromechanical stimulation applies a magnetic field externally, so that the tubular stent can not only guide cell growth through mechanical stimulation, but also use the generated induced current to activate the regeneration mechanism of related nerve cells in the body, thus providing a novel idea for the repair of damaged nerve conduits. At the application level, the magnetically driven electromechanical stimulation method has the advantages of non-invasiveness and controllability, which makes it have broad application prospects in clinical treatment. By adjusting the intensity and frequency of the magnetic field, researchers can precisely control the response of nerve cells, which is expected to open up new avenues for personalized treatment. Summary of the invention

[0006] In order to solve the above technical problems, the first purpose of the present invention is to provide a method for manufacturing a magnetically driven electromechanical nerve stimulation catheter. The second purpose is to provide a magnetically driven electromechanical nerve stimulation catheter with low manufacturing cost, high speed and great process flexibility.

[0007] To achieve the above first objective, the present invention is implemented by the following technical solutions: A method for constructing a magnetically driven electromechanically stimulated nerve catheter, characterized in that the magnetically driven electromechanically stimulated nerve catheter is composed of a tubular functional segment with a negative Poisson's ratio structure and a suture ring with a spiral structure located at both ends of the tubular functional segment, and is completed according to the following steps:

[0008] (1) Preparation of the mixed liquid of the tubular functional segment printing material: the polymer matrix and the solvent are heated and stirred to mix, and then the conductive nanomaterial is added until it is completely dissolved and mixed evenly, so that it has conductivity and promotes the repair efficiency of the peripheral nerve.

[0009] (2) Preparation of a mixed liquid of suture ring printing materials, heating and stirring a polymer matrix and a solvent, and then adding a magnetic nanomaterial to make it magnetic, thereby using external stimulation to drive the nerve conduit to undergo mechanical deformation;

[0010] (3) Printing of the tubular functional segment: start the 4-axis 3D printer, the fourth axis is a rotating axis, and the rotating axis is half placed in the printing material mixture; the printing material mixture passes through the extruder, and as the rotating axis rotates and cooperates with the movement of the X-axis, phase separation and solidification are performed through rotation, and finally a tubular bracket with a negative Poisson's ratio structure is formed;

[0011] (4) Printing of the sewing ring: replace the syringe and the sewing ring material mixture, extrude it, and let the material rotate at a constant speed through the rotating shaft to form a spiral structure. After printing, the material is separated by rotation, and the two parts of the material are well physically cross-linked;

[0012] (5) After the phase separation reaction of the tubular stent is sufficient, the nerve conduit is removed from the rotating shaft, and then the tubular stent is placed between two magnets that attract each other. The parallel magnetic field generated by the magnets causes the entire stent to extend axially and the functional segment with a negative Poisson's ratio structure to expand around the axis, thereby forming a mechanical stimulation to promote nerve repair;

[0013] (6) The tubular stent is placed in an alternating magnetic field, and the induced current generated passes through the catheter to stimulate cell growth and differentiation.

[0014] In the above scheme: the polymer matrix is ​​one of PCL, TPU, PDMS, and PLA.

[0015] In the above scheme: the conductive nanomaterial is one of MXene, carbon nanotubes, and conductive graphene. Other conductive materials that can produce conductive effects can also be used while ensuring biocompatibility.

[0016] In the above scheme: the solvent is one of DMSO, THF, DMF

[0017] In the above scheme: in the tubular functional section, the mass of the conductive nanomaterial is 25%-35% of the total mass of the polymer matrix and the solvent, and the polymer matrix accounts for 15%-20% of the total mass of the polymer matrix and the solvent.

[0018] In the above scheme, the magnetic nanomaterial is one of Fe3O4 and NdFeB particles. Other magnetic materials can also be used while ensuring biocompatibility.

[0019] In the above scheme: in the suture ring, the polymer matrix accounts for 15%-20% of the total mass of the polymer matrix and the solvent, and the added amount of the magnetic nanomaterial is 20%-30% of the total mass of the polymer matrix and the solvent.

[0020] A magnetically driven electromechanically stimulated nerve conduit prepared by the method for constructing a magnetically driven electromechanically stimulated nerve conduit.

[0021] The functional section of the nerve conduit is configured as a negative Poisson's ratio structure with a tensile effect, which can provide a multifunctional tissue microenvironment to guide cell growth and has good biocompatibility; the suture ring is a spiral structure, which applies an external magnetic field to stretch the conduit axially, driving the middle negative Poisson's ratio structure to expand around the axis, thereby guiding the directional growth of cells, and achieving excellent mechanical properties, high biocompatibility, and adjustable size. Conductive active materials are added to the middle part, making it conductive, which greatly promotes the regeneration of peripheral nerves. The induced current generated by the alternating magnetic field promotes cell proliferation and differentiation through electrical stimulation, which can effectively promote the regeneration of damaged nerves and functional recovery. This method provides important guidance for the design and preparation of ideal nerve conduits, and can also be extended to other tubular tissue engineering fields such as trachea and blood vessels.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] 1. In the present invention, magnetic nanomaterials are added to the suture ring part, and the catheter is stretched and deformed along the direction of the magnetic field by driving with an external magnetic field. A negative Poisson's ratio structure is constructed in the middle part, so that the nerve catheter can be expanded around the catheter midline while being axially stretched, thereby generating mechanical stimulation to guide the directional growth of cells, etc., which greatly promotes the regeneration speed and functional recovery effect of peripheral nerves.

[0024] 2. In the present invention, conductive nanomaterials are added to the functional segment to make the tubular stent have excellent conductivity. The alternating magnetic field is used to cut the magnetic flux lines to generate induced current passing through the tubular stent, thereby generating electrical stimulation to the cells, improving the cell proliferation and differentiation ability, and accelerating the repair rate of damaged tissues.

[0025] 3. In the present invention, the molding principle of phase separation is fully utilized to stably obtain the solidified material. Moreover, the solidified material through phase separation will form a dense porous structure, which is beneficial to the repair of peripheral nerves.

[0026] 4. The preparation process of the present invention is simple, easy to operate, and the material selection is flexible. The nerve conduit structure prepared by the preparation method has good stability, the connection and cross-linking between the middle part and the suture ring are good, and it is not easy to fall off; not only that, the size of the nerve conduit obtained by the preparation method is adjustable; the addition of conductive nanomaterials also makes it have good functions such as guiding the directional growth of cells. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 A schematic diagram of a magnetically driven electromechanically stimulated nerve conduit prepared by the present invention;

[0028] Figure 2 This is the printing principle diagram of the 4-axis 3D printing of the present invention;

[0029] Figure 3 This is a schematic diagram of mechanical deformation of the tubular stent of the present invention;

[0030] Figure 4 This is a schematic diagram of electrical stimulation of the tubular stent of the present invention. DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with the accompanying drawings and embodiments.

[0032] Example 1

[0033] A method for constructing a magnetically driven electromechanically stimulated nerve catheter, which is composed of a tubular functional segment with a negative Poisson's ratio structure and suture rings with a spiral structure located at both ends of the tubular functional segment, is completed according to the following steps:

[0034] (1) Preparation of the mixed liquid of the tubular functional segment printing material: the polymer matrix and the solvent are heated and stirred to mix, and then the conductive nanomaterial is added until it is completely dissolved and mixed evenly, so that it has conductivity and promotes the repair efficiency of the peripheral nerve.

[0035] (2) Preparation of the suture ring printing material mixture: the polymer matrix and the solvent are heated and stirred to mix, and then the magnetic nanomaterial is added to make it magnetic, so as to use external stimulation to drive the nerve conduit to undergo mechanical deformation. The polymer matrix is ​​PCL, the conductive nanomaterial is MXene, and the solvent is DMSO. The mass of the conductive nanomaterial is 25% of the total mass of the polymer matrix and the solvent, and the mass ratio of the polymer matrix to the solvent is 15:85.

[0036] (3) Printing of the tubular functional segment: start the 4-axis 3D printer, the fourth axis is the rotating axis, and the rotating axis is half placed in the printing material mixture; the printing material mixture passes through the extruder, and as the rotating axis rotates and cooperates with the movement of the X-axis, phase separation and solidification are carried out through rotation, and finally a tubular bracket with a negative Poisson's ratio structure is formed; the magnetic nanomaterial is Fe3O4, the mass ratio of the polymer matrix and the solvent is 15:85, and the amount of the magnetic nanomaterial added is 20% of the total mass of the polymer matrix and the solvent.

[0037] (4) Printing of the sewing ring: replace the syringe and the sewing ring material mixture, extrude it, and let the material rotate at a constant speed through the rotating shaft to form a spiral structure. After printing, the material is separated by rotation, and the two parts of the material are well physically cross-linked;

[0038] (5) After the phase separation reaction of the tubular stent is sufficient, the nerve conduit is removed from the rotating shaft, and then the tubular stent is placed between two magnets that attract each other. The parallel magnetic field generated by the magnets causes the entire stent to extend axially and the functional segment with a negative Poisson's ratio structure to expand around the axis, forming mechanical stimulation to promote nerve repair.

[0039] (6) The tubular stent is placed in an alternating magnetic field, and the induced current generated passes through the catheter to stimulate cell growth and differentiation.

[0040] Example 2

[0041] A method for constructing a magnetically driven electromechanically stimulated nerve conduit is completed according to the following steps:

[0042] (1) Preparation of the mixed liquid of the tubular functional segment printing material: the polymer matrix and the solvent are heated and stirred to mix, and then the conductive nanomaterial is added until it is completely dissolved and mixed evenly, so that it has conductivity and promotes the repair efficiency of the peripheral nerve.

[0043] (2) Preparation of the suture ring printing material mixture: the polymer matrix and the solvent are heated and stirred, and then the magnetic nanomaterial is added to make it magnetic, so as to use external stimulation to drive the nerve conduit to undergo mechanical deformation. The polymer matrix is ​​TPU, the conductive nanomaterial is carbon nanotubes, and the solvent is DMF. The mass of the conductive nanomaterial is 30% of the total mass of the polymer matrix and the solvent, and the mass ratio of the polymer matrix to the solvent is 20:80.

[0044] (3) Printing of the tubular functional segment: start the 4-axis 3D printer, the fourth axis is the rotating axis, and the rotating axis is half placed in the printing material mixture; the printing material mixture passes through the extruder, and as the rotating axis rotates and cooperates with the movement of the X-axis, phase separation and solidification are carried out through rotation, and finally a tubular bracket with a negative Poisson's ratio structure is formed; the magnetic nanomaterial is NdFeB particles, the mass ratio of the polymer matrix and the solvent is 20:80, and the amount of magnetic nanomaterial added is 25% of the total mass of the polymer matrix and the solvent.

[0045] (4) Printing of the sewing ring: replace the syringe and the sewing ring material mixture, extrude it, and let the material rotate at a constant speed through the rotating shaft to form a spiral structure. After printing, the material is separated by rotation, and the two parts of the material are well physically cross-linked;

[0046] (5) After the phase separation reaction of the tubular stent is sufficient, the nerve conduit is removed from the rotating shaft, and then the tubular stent is placed between two magnets that attract each other. The parallel magnetic field generated by the magnets causes the entire stent to extend axially and the functional segment with a negative Poisson's ratio structure to expand around the axis, forming mechanical stimulation to promote nerve repair.

[0047] (6) The tubular stent is placed in an alternating magnetic field, and the induced current generated passes through the catheter to stimulate cell growth and differentiation.

[0048] Example 3

[0049] A method for constructing a magnetically driven electromechanically stimulated nerve conduit is completed according to the following steps:

[0050] (1) Preparation of the mixed liquid of the tubular functional segment printing material: the polymer matrix and the solvent are heated and stirred to mix, and then the conductive nanomaterial is added until it is completely dissolved and mixed evenly, so that it has conductivity and promotes the repair efficiency of the peripheral nerve.

[0051] (2) Preparation of the suture ring printing material mixture: the polymer matrix and the solvent are heated and stirred to mix, and then the magnetic nanomaterial is added to make it magnetic, so as to use external stimulation to drive the nerve conduit to undergo mechanical deformation. The polymer matrix is ​​PDMS, the conductive nanomaterial is conductive graphene, and the solvent is THF. The mass of the conductive nanomaterial is 35% of the total mass of the polymer matrix and the solvent, and the mass ratio of the polymer matrix to the solvent is 20:80.

[0052] (3) Printing of the tubular functional segment: start the 4-axis 3D printer, the fourth axis is the rotating axis, and the rotating axis is half placed in the printing material mixture; the printing material mixture passes through the extruder, and as the rotating axis rotates and cooperates with the movement of the X-axis, phase separation and solidification are carried out through rotation, and finally a tubular bracket with a negative Poisson's ratio structure is formed; the magnetic nanomaterial is Fe3O4, the mass ratio of the polymer matrix and the solvent is 20:80, and the amount of the magnetic nanomaterial added is 30% of the total mass of the polymer matrix and the solvent.

[0053] (4) Printing of the sewing ring: replace the syringe and the sewing ring material mixture, extrude it, and let the material rotate at a constant speed through the rotating shaft to form a spiral structure. After printing, the material is separated by rotation, and the two parts of the material are well physically cross-linked;

[0054] (5) After the phase separation reaction of the tubular stent is sufficient, the nerve conduit is removed from the rotating shaft, and then the tubular stent is placed between two magnets that attract each other. The parallel magnetic field generated by the magnets causes the entire stent to extend axially and the functional segment with a negative Poisson's ratio structure to expand around the axis, forming mechanical stimulation to promote nerve repair.

[0055] (6) The tubular stent is placed in an alternating magnetic field, and the induced current generated passes through the catheter to stimulate cell growth and differentiation.

[0056] Example 4

[0057] A method for constructing a magnetically driven electromechanically stimulated nerve conduit is completed according to the following steps:

[0058] (1) Preparation of the mixed liquid of the tubular functional segment printing material: the polymer matrix and the solvent are heated and stirred to mix, and then the conductive nanomaterial is added until it is completely dissolved and mixed evenly, so that it has conductivity and promotes the repair efficiency of the peripheral nerve.

[0059] (2) Preparation of the suture ring printing material mixture: the polymer matrix and the solvent are heated and stirred to mix, and then the magnetic nanomaterial is added to make it magnetic, so as to use external stimulation to drive the nerve conduit to undergo mechanical deformation. The polymer matrix is ​​PLA, the conductive nanomaterial is MXene, and the solvent is DMF. The mass of the conductive nanomaterial is 30% of the total mass of the polymer matrix and the solvent, and the mass ratio of the polymer matrix to the solvent is 20:80.

[0060] (3) Printing of the tubular functional segment: start the 4-axis 3D printer, the fourth axis is the rotating axis, and the rotating axis is half placed in the printing material mixture; the printing material mixture passes through the extruder, and as the rotating axis rotates and cooperates with the movement of the X-axis, phase separation and solidification are carried out through rotation, and finally a tubular bracket with a negative Poisson's ratio structure is formed; the magnetic nanomaterial is Fe3O4, the mass ratio of the polymer matrix and the solvent is 20:80, and the amount of the magnetic nanomaterial added is 20% of the total mass of the polymer matrix and the solvent.

[0061] (4) Printing of the sewing ring: replace the syringe and the sewing ring material mixture, extrude it, and let the material rotate at a constant speed through the rotating shaft to form a spiral structure. After printing, the material is separated by rotation, and the two parts of the material are well physically cross-linked;

[0062] (5) After the phase separation reaction of the tubular stent is sufficient, the nerve conduit is removed from the rotating shaft, and then the tubular stent is placed between two magnets that attract each other. The parallel magnetic field generated by the magnets causes the entire stent to extend axially and the functional segment with a negative Poisson's ratio structure to expand around the axis, forming mechanical stimulation to promote nerve repair.

[0063] (6) The tubular stent is placed in an alternating magnetic field, and the induced current generated passes through the catheter to stimulate cell growth and differentiation.

[0064] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for constructing a magnetically driven electromechanically stimulated nerve conduit, characterized in that: The magnetically driven electromechanical stimulation nerve catheter is composed of a tubular functional segment with a negative Poisson's ratio structure and a suture ring with a spiral structure located at both ends of the tubular functional segment, and is completed according to the following steps: (1) Preparation of a mixed liquid of tubular functional segment printing materials: heating and stirring a polymer matrix and a solvent, and then adding a conductive nanomaterial until the materials are completely dissolved and mixed evenly, so that the materials have conductivity and promote the repair efficiency of peripheral nerves; (2) Preparation of a mixed liquid of suture ring printing materials, heating and stirring a polymer matrix and a solvent, and then adding a magnetic nanomaterial to make it magnetic, thereby using external stimulation to drive the nerve conduit to undergo mechanical deformation; (3) Printing of the tubular functional segment: start the 4-axis 3D printer, the fourth axis is a rotating axis, and the rotating axis is half placed in the printing material mixture; the printing material mixture passes through the extruder, and as the rotating axis rotates and cooperates with the movement of the X-axis, phase separation and solidification are performed through rotation, and finally a tubular bracket with a negative Poisson's ratio structure is formed; (4) Printing of the sewing ring: replace the syringe and the sewing ring material mixture, extrude it, and let the material rotate at a constant speed through the rotating shaft to form a spiral structure. After printing, the material is separated by rotation, and the two parts of the material are well physically cross-linked; (5) After the phase separation reaction of the tubular stent is sufficient, the nerve conduit is removed from the rotating shaft, and then the tubular stent is placed between two magnets that attract each other. The parallel magnetic field generated by the magnets causes the entire stent to extend axially and the functional segment with a negative Poisson's ratio structure to expand around the axis, thereby forming a mechanical stimulation to promote nerve repair; (6) The tubular stent is placed in an alternating magnetic field, and the induced current generated passes through the catheter to stimulate cell growth and differentiation.

2. The method for constructing a magnetically driven electromechanically stimulated nerve conduit according to claim 1, characterized in that: The polymer matrix is ​​one of PCL, TPU, PDMS and PLA.

3. The method for constructing a magnetically driven electromechanically stimulated nerve conduit according to claim 2, characterized in that: The conductive nanomaterial is one of MXene, carbon nanotubes and conductive graphene.

4. The method for constructing a magnetically driven electromechanically stimulated nerve conduit according to claim 3, characterized in that: The solvent is one of DMSO, THF and DMF.

5. The method for constructing a magnetically driven electromechanically stimulated nerve conduit according to any one of claims 1 to 4, characterized in that: In the tubular functional section, the mass of the conductive nanomaterial is 25%-35% of the total mass of the polymer matrix and the solvent, and the polymer matrix accounts for 15%-20% of the total mass of the polymer matrix and the solvent.

6. The method for constructing a magnetically driven electromechanically stimulated nerve conduit according to claim 5, characterized in that: The magnetic nano material is one of Fe3O4 and NdFeB particles.

7. The method for constructing a magnetically driven electromechanically stimulated nerve conduit according to claim 6, characterized in that: In the sewing ring, the polymer matrix accounts for 15%-20% of the total mass of the polymer matrix and the solvent, and the added amount of the magnetic nano material is 20%-30% of the total mass of the polymer matrix and the solvent.

8. A magnetically driven electromechanically stimulated nerve conduit prepared by the method for constructing a magnetically driven electromechanically stimulated nerve conduit according to any one of claims 1 to 7.

Images