CN113143843A - Medical nano-particle fixed-point treatment device and manufacturing method thereof - Google Patents
Medical nano-particle fixed-point treatment device and manufacturing method thereof Download PDFInfo
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- CN113143843A CN113143843A CN202110278313.3A CN202110278313A CN113143843A CN 113143843 A CN113143843 A CN 113143843A CN 202110278313 A CN202110278313 A CN 202110278313A CN 113143843 A CN113143843 A CN 113143843A
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- 239000002105 nanoparticle Substances 0.000 title claims abstract description 27
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 11
- 239000002184 metal Substances 0.000 claims description 20
- 229910052751 metal Inorganic materials 0.000 claims description 20
- 229920002120 photoresistant polymer Polymers 0.000 claims description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 229920001721 polyimide Polymers 0.000 claims description 11
- 239000004642 Polyimide Substances 0.000 claims description 10
- 238000002560 therapeutic procedure Methods 0.000 claims description 10
- 238000000151 deposition Methods 0.000 claims description 7
- 238000009413 insulation Methods 0.000 claims description 6
- 238000004804 winding Methods 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 4
- 238000004140 cleaning Methods 0.000 claims description 4
- 238000009713 electroplating Methods 0.000 claims description 4
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 4
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 4
- 239000010453 quartz Substances 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000005520 cutting process Methods 0.000 claims description 3
- 239000008367 deionised water Substances 0.000 claims description 3
- 229910021641 deionized water Inorganic materials 0.000 claims description 3
- 229920000052 poly(p-xylylene) Polymers 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011248 coating agent Substances 0.000 claims description 2
- 238000000576 coating method Methods 0.000 claims description 2
- 238000004544 sputter deposition Methods 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 18
- 238000000034 method Methods 0.000 abstract description 11
- 239000002122 magnetic nanoparticle Substances 0.000 abstract description 9
- 210000004204 blood vessel Anatomy 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 description 9
- 239000000758 substrate Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 5
- 239000010949 copper Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- VRBFTYUMFJWSJY-UHFFFAOYSA-N 28804-46-8 Chemical compound ClC1CC(C=C2)=CC=C2C(Cl)CC2=CC=C1C=C2 VRBFTYUMFJWSJY-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 238000000429 assembly Methods 0.000 description 2
- 230000000712 assembly Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000006249 magnetic particle Substances 0.000 description 2
- 229940126585 therapeutic drug Drugs 0.000 description 2
- 238000005452 bending Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- 230000005674 electromagnetic induction Effects 0.000 description 1
- SZVJSHCCFOBDDC-UHFFFAOYSA-N ferrosoferric oxide Chemical compound O=[Fe]O[Fe]O[Fe]=O SZVJSHCCFOBDDC-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000001259 photo etching Methods 0.000 description 1
- 238000000206 photolithography Methods 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F41/00—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties
- H01F41/02—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties for manufacturing cores, coils, or magnets
- H01F41/04—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties for manufacturing cores, coils, or magnets for manufacturing coils
- H01F41/041—Printed circuit coils
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F41/00—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties
- H01F41/02—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties for manufacturing cores, coils, or magnets
- H01F41/04—Apparatus or processes specially adapted for manufacturing or assembling magnets, inductances or transformers; Apparatus or processes specially adapted for manufacturing materials characterised by their magnetic properties for manufacturing cores, coils, or magnets for manufacturing coils
- H01F41/041—Printed circuit coils
- H01F41/042—Printed circuit coils by thin film techniques
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- Engineering & Computer Science (AREA)
- Power Engineering (AREA)
- Health & Medical Sciences (AREA)
- Manufacturing & Machinery (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Materials For Medical Uses (AREA)
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Abstract
The invention relates to the technical field of nano medicine, and provides a medical nano particle fixed-point treatment device, which comprises a pipeline; a wire wound around an outer layer of the pipe; and the biological insulating layer coats the lead. The invention also proposes a method for manufacturing said component. The invention can be implanted into a biological blood vessel to guide the injected magnetic nanoparticles to gather at a specific position of the blood vessel and gradually release the medicine, thereby realizing fixed-point and quantitative treatment, and having controllable dosage of the medicine and small side effect range; and has the advantages of small heat productivity, low magnetic field intensity and accurate position location.
Description
Technical Field
The invention relates to the technical field of nano medicine, in particular to a medical nano particle fixed-point treatment device and a manufacturing method thereof.
Background
In recent years, medical science has extensively studied a therapeutic method in which therapeutic drugs are carried in nanoparticles and released at specific sites in a living body. However, the research direction is mostly limited to exploring the diversity of drugs for modifying magnetic nanoparticles, not the method of achieving site-directed release of drugs. Therefore, the prior art has the problems that the fixed-point and quantitative treatment of the drug release position cannot be controlled, and the dosage is often overlarge during the administration, so that side effects exist.
Disclosure of Invention
Aiming at the problem that the precise positioning is difficult to realize when the nano-particles carry therapeutic drugs to realize the fixed-point release of the drugs in the prior art, the invention provides a medical nano-particle fixed-point therapeutic device, which comprises:
a pipeline;
a wire wound around an outer layer of the pipe; and
and the biological insulating layer coats the lead.
In one embodiment of the invention, it is provided that the tube comprises a polyimide tube, a PMMA tube or a quartz tube; the outer diameter of the pipeline is 0.9-1.1mm, and the inner diameter of the pipeline is 0.8-1 mm.
In one embodiment of the invention, the line width of the conducting wire is 50-100 um; the wire is the coil that the slope spiral winding formed, and the interval of winding is 50-100um, and the number of turns of winding is more than 10 circles.
In one embodiment of the invention, it is provided that the bio-insulating layer comprises a parylene bio-insulating layer or a polyimide bio-insulating layer; the thickness of the biological insulation layer is 1-5 um.
In one embodiment of the invention, it is provided that the medical nanoparticle site directed therapy device further comprises a micro-hole or an array of micro-holes, which is arranged in front of the lead.
The invention also provides a method for manufacturing the medical nanoparticle site-specific treatment device, which is characterized by comprising the following steps of:
cleaning the surface of the pipeline;
forming a wire on the outer surface of the pipeline; and
and depositing a biological insulating layer on the outer layer of the lead.
In yet another embodiment of the present invention, it is provided that forming the conductive wire on the outer surface of the pipe comprises:
sputtering a metal seed layer on the surface of the pipeline;
coating photoresist on the metal seed layer, and pre-baking to solidify the photoresist;
exposing the surface of the photoresist, and developing by using a developing solution to obtain a coil pattern;
electroplating to obtain a metal coil; and
the photoresist on the surface is removed and the seed layer is etched using a metal etchant.
In a further embodiment of the present invention, it is provided that the cleaning of the surface of the flexible medical tube comprises: the surface of the medical flexible tube was cleaned using HCl solution and NaOH solution, and the surface was ultrasonically cleaned with deionized water.
In yet another embodiment of the invention, it is provided that the photoresist surface is exposed using a programmable rotary ultraviolet exposure system.
In yet another embodiment of the present invention, it is provided that the method for manufacturing the medical nanoparticle site directed therapy device further comprises cutting the surface of the medical flexible tube at a position 1-2mm in front of the coil of the metallic copper wire to form the micro-pore array using a laser before depositing the bio-insulation layer.
The invention has at least the following beneficial effects: the magnetic nano particles can be implanted into a biological blood vessel to guide the injected magnetic nano particles to gather at a specific position of the blood vessel and gradually release the medicine, so that the fixed-point and quantitative treatment is realized, the dosage of the medicine is controllable, and the side effect range is small; and has the advantages of small heat productivity, low magnetic field intensity and accurate position location.
Drawings
To further clarify the advantages and features that may be present in various embodiments of the present invention, a more particular description of various embodiments of the invention will be rendered by reference to the appended drawings. It is appreciated that these drawings depict only typical embodiments of the invention and are therefore not to be considered limiting of its scope. In the drawings, the same or corresponding parts will be denoted by the same or similar reference numerals for clarity.
Fig. 1 is a front view of a nanoparticle site specific treatment device in accordance with an embodiment of the present invention.
Fig. 2 is a reverse structural view showing a medical nanoparticle site-directed therapeutic device in an embodiment of the present invention.
Fig. 3 shows a schematic diagram of a coil structure of a metal copper wire wound on an outer layer of a medical flexible tube according to an embodiment of the present invention.
FIG. 4 shows a scanning electron microscope view of a coil structure in one embodiment of the invention.
FIG. 5 shows a scanning electron microscope observation of a linear region of a coil structure in one embodiment of the invention.
FIG. 6 shows a scanning electron microscope observation of the bending region of the coil structure in one embodiment of the invention.
Fig. 7 shows the working principle of the nanoparticle site specific therapy device for medical use in one embodiment of the present invention.
Detailed Description
It should be noted that the components in the figures may be exaggerated and not necessarily to scale for illustrative purposes. In the figures, identical or functionally identical components are provided with the same reference symbols.
In the present invention, "disposed on …", "disposed over …" and "disposed over …" do not exclude the presence of an intermediate therebetween, unless otherwise specified. Further, "disposed on or above …" merely indicates the relative positional relationship between two components, and may also be converted to "disposed below or below …" and vice versa in certain cases, such as after reversing the product direction.
In the present invention, the embodiments are only intended to illustrate the aspects of the present invention, and should not be construed as limiting.
In the present invention, the terms "a" and "an" do not exclude the presence of a plurality of elements, unless otherwise specified.
It is further noted herein that in embodiments of the present invention, only a portion of the components or assemblies may be shown for clarity and simplicity, but those of ordinary skill in the art will appreciate that, given the teachings of the present invention, required components or assemblies may be added as needed in a particular scenario. Furthermore, features from different embodiments of the invention may be combined with each other, unless otherwise indicated. For example, a feature of the second embodiment may be substituted for a corresponding or functionally equivalent or similar feature of the first embodiment, and the resulting embodiments are likewise within the scope of the disclosure or recitation of the present application.
It is also noted herein that, within the scope of the present invention, the terms "same", "equal", and the like do not mean that the two values are absolutely equal, but allow some reasonable error, that is, the terms also encompass "substantially the same", "substantially equal". By analogy, in the present invention, the terms "perpendicular", "parallel" and the like in the directions of the tables also cover the meanings of "substantially perpendicular", "substantially parallel".
The numbering of the steps of the methods of the present invention does not limit the order of execution of the steps of the methods. Unless specifically stated, the method steps may be performed in a different order.
The embodiment of the invention provides a novel medical nanoparticle site-specific treatment device which can be implanted into a biological blood vessel and can guide injected magnetic nanoparticles (such as ferroferric oxide nanoparticles) to gather at a specific position of the blood vessel and gradually release a medicament, so that the purpose of site-specific and quantitative treatment is realized. The method has the advantages of small heat productivity, low magnetic field intensity, accurate position location and the like.
The invention is further elucidated with reference to the drawings in conjunction with the detailed description.
As shown in figures 1 and 2, the substrate is selected from a Polyimide Tube (Polyimide Tube), a PMMA Tube or a quartz Tube with an outer diameter of 0.9-1.1mm and an inner diameter of 0.8-1mm, and the medical nanoparticle site-specific therapeutic device has high flexibility, high elasticity and excellent biocompatibility, and can be cut into different sizes such as 20-80mm in length. The outer layer of the substrate is provided with a spiral metal wire. For example, the metal wire is a copper wire, the line width is 50-100um, the interval is 50-100um, and the number of turns of the coil can be more than 10. However, it should be understood by those skilled in the art that the material, size, spacing, etc. parameters of the spiral-shaped metal wire are not limited to the specific examples described above. The helical wire may be a smooth spiral, as shown in fig. 1 and 2, or an inclined spiral having a turning point at a specific angle at both ends of the inclined wire, as shown in fig. 3-6. It will be appreciated by those skilled in the art that the particular helical pattern of the helical metal wire is not limited to the particular embodiments described above. The outer layer of the metal wire is coated with a biological insulating layer by a deposition method and is used for isolating the wire from external biological tissues. The bio-insulating layer may be a Parylene film (Parylene-C) or a polyimide film.
The device preparation process flow is as follows:
first, the substrate is cleaned. In one embodiment of the present invention, the substrate is selected from a Polyimide Tube (Polyimide Tube), a PMMA Tube or a quartz Tube, the surface of the substrate is cleaned with 3% HCl solution and 5% NaOH solution, respectively, to remove oil stains and other impurities, and then the surface is ultrasonically cleaned with deionized water.
Next, a conductive line is formed on the outer surface of the substrate.
In one embodiment of the present invention, the spiral-shaped metal wire may be formed on the outer surface of the tubular base by a photolithography, plating, or the like process. Specifically, a seed layer is first formed on the outer surface of the substrate. For example, a Cr/Cu seed layer is sputtered as the bottom conductive layer. And forming photoresist on the surface of the seed layer and curing. For example, a layer of positive photoresist is coated by a dip coating method or a spray coating method, the thickness of the photoresist is more than 10um, and the photoresist is cured by prebaking for more than 30 minutes at 90 ℃ in an oven. And carrying out a photoetching process to form a coil pattern in the photoresist. For example, a photoresist surface is exposed using a programmable rotary ultraviolet exposure system and developed using a developer solution to obtain an inclined coil pattern. And forming a metal layer with a certain thickness in the coil pattern through an electroplating process. For example, electroplating is performed using a high-purity Cu metal plate as an anode to increase the thickness of the metal layer in the coil pattern to be consistent with the thickness of the photoresist. Finally, the photoresist and the seed layer are removed. For example, the photoresist on the surface is removed using acetone or NaOH solution, and the Cr/Cu seed layer is etched using a metal etchant (Cu etchant, Cr etchant).
And depositing a biological insulating layer on the outer layer of the device. For example, Parylene-C or polyimide is deposited as a bio-insulating layer with a thickness of 1-5um to insulate the metal coil from the external environment.
The working principle of the device is as follows: direct current is applied to the inclined spiral coil, and due to the electromagnetic induction principle, the electrified coil can generate a magnetic field surrounding the coil, and the magnetic field is stronger at the position close to the coil and weaker at the position far away from the coil. The magnetic nanoparticles modified by the drugs are injected into the blood, the particles are acted by a magnetic field force when flowing through the device, and when the magnetic field force is larger than the viscous resistance of the particles moving in the blood, the nanoparticles move along the direction of the magnetic field line and reach the pipe wall of the polyimide pipe. The drug is only locally diffused, so the influence range is limited to the biological tissue at the release position, the dosage of the applied drug can be determined by controlling the amount of the injected magnetic nanoparticles, and the preparation method has the characteristics of controllable dosage, small side effect range and the like.
In another embodiment of the present invention, before the step of depositing the insulating layer, the step of cutting the surface of the flexible medical tube at a position 1-2mm in front of the tilted coil by using a laser to form the micro-hole array is further included in the preparation process flow. For example, the diameter of the holes may be 100-.
The device of this embodiment works taking into account the presence of magnetic particles in the conduit after the introduction of the magnetic nanoparticles, the principle is shown in fig. 7. When direct current is applied to the coil, the magnetic field generated by the coil generates magnetic force action on particles inside and outside the catheter, so that the magnetic particles move along the direction of the magnetic field lines. Particles outside the catheter are gathered to the area near the outer wall, and particles inside the catheter penetrate through the wall of the catheter through the micropore array to reach the outer side, contact with biological cells or tissues and release drugs, so that the effects of locally releasing the drugs and performing fixed-point treatment are achieved. The dosage of the medicine can be determined by controlling the amount of the injected magnetic nanoparticles, and the medicine has the characteristics of controllable dosage, small side effect range and the like.
While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. It will be apparent to persons skilled in the relevant art that various combinations, modifications, and changes can be made thereto without departing from the spirit and scope of the invention. Thus, the breadth and scope of the present invention disclosed herein should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.
Claims (10)
1. A medical nanoparticle site directed therapy device comprising:
a pipeline;
a wire wound around an outer layer of the pipe; and
and the biological insulating layer coats the lead.
2. The medical nanoparticle site-directed treatment device of claim 1, wherein: the pipeline comprises a polyimide pipe, a PMMA pipe or a quartz pipe; the outer diameter of the pipeline is 0.9-1.1mm, and the inner diameter of the pipeline is 0.8-1 mm.
3. The medical nanoparticle site-directed treatment device of claim 1, wherein: the line width of the conducting wire is 50-100 um; the wire is the coil that the slope spiral winding formed, and the interval of winding is 50-100um, and the number of turns of winding is more than 10 circles.
4. The medical nanoparticle site-directed treatment device of claim 1, wherein: the biological insulation layer comprises a parylene biological insulation layer or a polyimide biological insulation layer; the thickness of the biological insulation layer is 1-5 um.
5. The medical nanoparticle site-directed treatment device of claim 1, wherein: further comprising a micro-hole or an array of micro-holes arranged in front of the wire.
6. A method of manufacturing a medical nanoparticle site-directed therapy device according to any one of claims 1 to 5, characterized in that it comprises the following steps:
cleaning the surface of the pipeline;
forming a wire on the outer surface of the pipeline; and
and depositing a biological insulating layer on the outer layer of the lead.
7. The method of manufacturing a medical nanoparticle site directed therapy device of claim 6, wherein forming a wire on the outer surface of the conduit comprises:
sputtering a metal seed layer on the surface of the pipeline;
coating photoresist on the metal seed layer, and pre-baking to solidify the photoresist;
exposing the surface of the photoresist, and developing by using a developing solution to obtain a coil pattern;
electroplating to obtain a metal coil; and
the photoresist on the surface is removed and the seed layer is etched using a metal etchant.
8. The method of manufacturing a medical nanoparticle site directed therapy device according to claim 6, wherein cleaning the surface of the medical flexible tube comprises: the surface of the medical flexible tube was cleaned using HCl solution and NaOH solution, and the surface was ultrasonically cleaned with deionized water.
9. The method of manufacturing a medical nanoparticle site directed therapy device of claim 6, wherein the photoresist surface is exposed using a programmable rotary ultraviolet exposure system.
10. The method of manufacturing a medical nanoparticle site directed therapy device according to any of claims 6-9, further comprising cutting with a laser at a position 1-2mm in front of the coil of metallic copper wire on the surface of the medical flexible tube to form an array of micropores before depositing the bio-insulating layer.
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2021
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Non-Patent Citations (6)
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