Multilayer hydrogel magnetically driven micro-robot and preparation method and application thereof

Abstract

The present application relates to the technical field of micro robot, especially to a multi-layer hydrogel magnetic driving micro robot, a preparation method and application, the robot from top to bottom is micro 3D printing tool bit, hydrogel layer and magnetic nano particle layer, the micro 3D printing tool bit and magnetic nano particle layer are bonded by the hydrogel layer.The hydrogel micro robot of the present application has good biocompatibility, no side effect, safety and reliability compared with traditional magnetic driving micro robot, and can be conveniently recycled, and is used for assisting internal limiting membrane peeling operation, can simply and quickly realize internal limiting membrane lifting film, effectively reduces the operation difficulty of operation, shortens the operation time, fully plays the advantages of minimally invasive ophthalmic surgery, and is expected to become the beneficial aid of ophthalmologist, and has wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of microrobot technology, and in particular to multilayer hydrogel magnetically driven microrobots, their fabrication methods, and applications. Background Technology

[0002] Macular holes are full-thickness defects of the neuroepithelial layer of the retina in the macula. They are caused by trauma, vitreous traction, degeneration, high myopia, etc. In severe cases, they can lead to significant vision loss and retinal detachment. For smaller holes with a tendency to retinal detachment, laser treatment can be performed to close the hole. For larger holes, vitrectomy and internal limiting membrane peeling are required.

[0003] The internal limiting membrane (ILM) is located in the innermost layer of the retina, with a thickness of approximately 1–2 μm. ILM peeling surgery, completely removing the ILM while ensuring no damage to the retina, is far more difficult than peeling a raw egg while keeping the membrane intact. This type of vitreoretinal surgery faces three main challenges. First, high precision is required: the average surgeon's hand tremor is around 100 μm, while the ideal surgical precision is 10 μm. Second, there is the issue of weak force feedback during surgery: during the procedure, 75% of ophthalmic surgical instruments and the force exerted on the posterior segment of the eye is less than 7.5 mN, while surgeons can generally only perceive 19% of this contact force, further limiting the surgical procedure. Third, there is the issue of weak visual feedback during surgery: because the surgery occurs in the posterior segment, fiber optic illumination is required, and since both the ILM and retina are transparent, visual feedback during the surgery is extremely weak. For these reasons, this type of surgery requires multiple tools, involves a complex surgical procedure, and is performed collaboratively by the chief surgeon and several assistant surgeons.

[0004] To overcome the limitations of human hands in microscopic manipulation, reduce the difficulty of surgery, and further leverage the advantages of minimally invasive ophthalmic surgery, hydrogel magnetically driven microrobots—characterized by their minimally invasive nature, ease of operation, high precision, and good biocompatibility—have attracted significant research interest from scientists. Compared to posterior segment surgery, magnetically driven microrobots are less invasive within the eye, eliminate the need for complex surgical procedures, and can precisely move to the target area under a suitable magnetic field, overcoming the limitations of human capabilities in ophthalmic surgery. Therefore, using hydrogel magnetically driven microrobots to assist in internal limiting membrane dissection surgery can reduce the difficulty of the procedure while also minimizing damage to the fundus.

[0005] However, existing hydrogel magnetically driven microrobots are still relatively large in size, failing to meet the requirements of minimally invasive ophthalmology. Furthermore, most are limited to simple movements, such as horizontal zigzag motion, lacking the ability to achieve complex movements and functions. In contrast, the hydrogel magnetically driven microrobot of this invention is small in size, meeting the requirements of minimally invasive ophthalmology, and possesses excellent magnetic control performance, enabling precise control. Summary of the Invention

[0006] The first aspect of the present invention provides a multilayer hydrogel magnetically driven microrobot, wherein the robot comprises, from top to bottom, a micro 3D printed cutter head, a hydrogel layer and a magnetic nanoparticle layer, wherein the micro 3D printed cutter head and the magnetic nanoparticle layer are bonded together by the hydrogel layer.

[0007] In some embodiments, the micro 3D printing tip includes a needle and a base, the needle being shaped as an oblique cone or a straight cone.

[0008] In some embodiments, the height of the needle is 30-90 μm, and the number of needles is 1-5. The height and number of needles should be determined according to the specific implementation conditions. For example, if the internal limiting membrane is thick, a higher height and a larger number of needles should be selected. If the selected needle height and number are inappropriate, it may cause damage to the retina.

[0009] In some embodiments, the raw materials for preparing the hydrogel layer include PVA, gelatin, and water.

[0010] Furthermore, the preparation method of the hydrogel layer includes: adding 1.8g of PVA to 20mL of distilled water to prepare a 9% (w / v) PVA solution, allowing it to swell fully before use; adding 8g of gelatin to the PVA solution, allowing it to swell, and then heating it in a water bath to 75°C while stirring to ensure it is fully dissolved.

[0011] Furthermore, the gelatin has a strength of 240-270 g Bloom. Gelatin with this strength is easier to form a film and has a more stable bond. It is available commercially.

[0012] Furthermore, the PVA is PVA-210 with a relative molecular weight of no more than 67,000. This relative molecular weight of PVA is conducive to spin coating film formation and was purchased from Shenzhen Huinuo Electronics Co., Ltd.

[0013] Because PVA has unique adhesive properties, smoothness, solvent resistance and abrasion resistance, its solution in water has good adhesive and film-forming properties. Adding an appropriate amount of PVA helps the gelatin solution form a film during spin coating.

[0014] In some embodiments, the raw materials for preparing the magnetic nanoparticle layer include PEGDA, an initiator, and unmagnetized NdFeB. Experimental analysis shows that excessively high or low molecular weights both lead to poor film formation.

[0015] Furthermore, the method for preparing the magnetic nanoparticle layer includes: adding 2 mL of PEGDA and 50 mg of initiator to a 10 mL centrifuge tube, then adding 1000 mg of unmagnetized NdFeB particles, and mixing the solution evenly using a vortex mixer.

[0016] Furthermore, the initiator may be selected from those commonly used in the art, including but not limited to diphenyl (2,4,6-trimethylbenzoyl)phosphine oxide.

[0017] Furthermore, the PEGDA is PEGDA 700, with an average molecular weight of 700. The film formed by PEGDA with this molecular weight has moderate hardness and toughness. The higher the degree of polymerization, the more brittle and hard the film is, which is not conducive to subsequent operation and control. It was purchased from Shenzhen Huinuo Electronics Co., Ltd.

[0018] PEGDA is biocompatible and biodegradable, and can be polymerized under ultraviolet light irradiation with a certain amount of photoinitiator. It is also easy to spin-coat into a film.

[0019] A second aspect of the present invention provides a method for fabricating a multilayer hydrogel magnetically driven microrobot, the method comprising the following steps:

[0020] S1. Spin-coating the mixed hydrogel layer preparation raw materials onto the surface of the pretreated flat plate medium, and obtaining the hydrogel layer-flat plate medium after solidification;

[0021] S2. The raw materials for preparing the mixed magnetic nanoparticle layer are spin-coated onto the surface of the hydrogel layer of the hydrogel layer-planar medium and cured to obtain the nanoparticle layer-hydrogel layer-planar medium.

[0022] S3. Peel the nanoparticle layer-hydrogel layer from the plate medium, and magnetize the obtained nanoparticle layer-hydrogel layer bilayer structure to obtain a magnetic nanoparticle layer-hydrogel layer.

[0023] S4. Install a micro 3D printed blade on the surface of the hydrogel layer of the magnetic nanoparticle layer-hydrogel layer to create a multi-layer hydrogel magnetically driven microrobot.

[0024] In some embodiments, the thickness of the hydrogel layer is 10 μm, and the thickness of the magnetic nanoparticle layer is 30 μm.

[0025] In some embodiments, the flat substrate may be selected from types commonly used in the art, including but not limited to silicon wafers.

[0026] Furthermore, the pretreatment method includes: ultrasonically cleaning and drying the plate medium in an aqueous solution of 75% alcohol.

[0027] The micro-3D-printed blade head of this invention is used for membrane initiation of the internal limiting membrane (IPM). Printed using a 3D printer with a precision of 2μm, it comprises 1-5 micrometer-sized needles and a 1×1mm base. The hydrogel layer, a connecting layer, connects the micro-3D-printed blade head and the magnetic nanoparticle layer, and is composed of PVA-210 and gelatin. The magnetic nanoparticle layer, a control layer, moves the hydrogel robot to the target area under the control of a magnetic field, inserting the needles into the IPM. This movement assists in IPM initiation, facilitating further surgical procedures. After completion, the nanoparticles are retrieved under magnetic field control, and the nanoparticle layer is composed of PEGDA 700 and NdFeB magnetic particles.

[0028] A third aspect of the invention provides the application of multilayer hydrogel magnetically driven microrobots in assisted peeling of the inner limiting membrane.

[0029] A fourth aspect of the invention provides the application of multilayer hydrogel magnetically driven microrobots in the preparation of targeted drug delivery and cell delivery reagents.

[0030] The fifth aspect of the present invention provides the application of multilayer hydrogel magnetically driven microrobots in disease detection instruments.

[0031] Compared with the prior art, the present invention has the following beneficial effects:

[0032] (1) The multilayer hydrogel magnetically driven microrobot of the present invention is composed of hydrogel and NdFeB magnetic particles, wherein the NdFeB magnetic particles are encapsulated by the hydrogel and will not diffuse into the surrounding environment (e.g., Figure 5 As shown in the figure, it does not introduce any toxic or dangerous reagents, so it has good biocompatibility, will not produce side effects on intraocular tissues, and is safe and reliable.

[0033] (2) The multilayer hydrogel magnetically driven microrobot of the present invention is small in size and can easily enter the eyeball. Under the control of the magnetic field, it can move precisely to the target area to assist doctors in performing internal limiting membrane peeling surgery. After completing the task, it can be retrieved under the control of the magnetic field. While ensuring safety, it also has the advantages of being minimally invasive and retrievable.

[0034] (3) The multilayer hydrogel magnetically driven microrobot of the present invention has high motion precision and is easy to operate. It does not require the use of other complex instruments and can easily assist surgeons in achieving the initiation of the internal limiting membrane, reducing the difficulty of the surgeon's operation, shortening the operation time, and further leveraging the advantages of minimally invasive ophthalmic surgery.

[0035] (4) Compared with traditional magnetically driven microrobots, the hydrogel microrobot of the present invention has good biocompatibility, no side effects, and is safe and reliable. It can also be easily recycled and used to assist in internal limiting membrane dissection surgery. It can easily and quickly remove the internal limiting membrane, effectively reduce the difficulty of the operation, shorten the operation time, give full play to the advantages of minimally invasive ophthalmic surgery, and is expected to become a useful assistant for ophthalmologists, with broad application prospects. Attached Figure Description

[0036] Figure 1 This is a flowchart of the fabrication process of the multilayer hydrogel magnetically driven microrobot of the present invention, wherein 1 is a spin coating platform, 2 is a silicon wafer, 3 is a hydrogel layer, and 4 is a magnetic nanoparticle layer.

[0037] Figure 2 A schematic diagram of magnetizing the nanoparticle layer-hydrogel layer bilayer structure.

[0038] Figure 3 This is a schematic diagram of the structure of the multilayer hydrogel magnetically driven microrobot of the present invention, wherein 5 is the magnetic nanoparticle layer, 6 is the hydrogel layer, and 7 is the micro 3D printing head.

[0039] Figure 4 This is a diagram showing the biocompatibility experimental results of the multilayer hydrogel magnetically driven microrobot of this invention.

[0040] Figure 5 The images shown are electron micrographs of the hydrogel layer and magnetic nanoparticle layer of the multilayer hydrogel magnetically driven microrobot of this invention, where 8 is the magnetic nanoparticle layer and 9 is the hydrogel layer.

[0041] Figure 6 This is an experimental diagram illustrating the biocompatibility of the multilayer hydrogel magnetically driven microrobot of this invention. Detailed Implementation

[0042] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0043] Example 1

[0044] Multilayer hydrogel magnetically driven microrobots, such as Figure 3 As shown, the robot consists of a micro 3D printed blade, a hydrogel layer, and a magnetic nanoparticle layer from top to bottom. The micro 3D printed blade and the magnetic nanoparticle layer are bonded together by the hydrogel layer.

[0045] The micro 3D printing head includes a needle and a base, and the needle is shaped like a straight circular cone.

[0046] The height of the needle is 90 μm, and the number of needles is 5.

[0047] The preparation method of the hydrogel layer includes: adding 1.8g PVA to 20mL of distilled water to make a 9% (w / v) PVA solution, allowing it to swell fully before use; adding 8g gelatin to the PVA solution, allowing it to swell, and then heating it in a water bath to 75°C while stirring to ensure it is fully dissolved.

[0048] The method for preparing the magnetic nanoparticle layer includes: adding 2 mL of PEGDA and 50 mg of diphenyl (2,4,6-trimethylbenzoyl)phosphine oxide to a 10 mL centrifuge tube, then adding 1000 mg of unmagnetized NdFeB (magnetic nanoparticles), and mixing the solution evenly using a vortex mixer.

[0049] A method for fabricating a multilayer hydrogel magnetically driven microrobot, the method comprising the following steps:

[0050] S1. Spin-coating the mixed hydrogel preparation material onto the pretreated silicon wafer surface at a speed of 1150 rpm for 30 seconds, and obtaining the hydrogel layer-plate medium after solidification.

[0051] S2. The raw materials for preparing the mixed magnetic nanoparticle layer are spin-coated onto the surface of the hydrogel layer of the hydrogel layer-plate medium at a speed of 300 rpm for 20 seconds. After curing, the nanoparticle layer-hydrogel layer-plate medium is obtained.

[0052] S3. Peel the nanoparticle layer-hydrogel layer from the plate medium, and fix the resulting nanoparticle layer-hydrogel layer bilayer structure in the middle of the magnetizer, such as... Figure 2 As shown, the magnetizer voltage is 53V, the current is 5A, and the magnetization time is 3 minutes. After the magnetization is completed, the magnetizer is removed to obtain a magnetic nanoparticle layer-hydrogel layer. A square area of ​​about 1mm×1mm in size is cut out in the middle of the double membrane with a scalpel for later use.

[0053] S4. Install a micro 3D printed blade on the surface of the hydrogel layer of the magnetic nanoparticle layer-hydrogel layer to create a multi-layer hydrogel magnetically driven microrobot.

[0054] The thickness of the hydrogel layer is 10 μm, and the thickness of the magnetic nanoparticle layer is 30 μm.

[0055] Comparative Example 1

[0056] The specific implementation method is the same as in Example 1, except that NdFeB is replaced with iron tetroxide nanoparticles.

[0057] Performance testing

[0058] Swimming speed test:

[0059] The hydrogel magnetically driven microrobots of the examples and comparative examples were placed in a cuboid test channel with a length of 90 mm, wherein the medium was deionized water. An external magnetic field was applied to make them move from one end to the other while timing was performed. After repeated testing, the swimming speed of Example 1 was 45 mm / s and the swimming speed of Comparative Example 1 was 10 mm / s.

[0060] Biocompatibility experiment:

[0061] Experimental group: Hydrogel microrobots prepared in Example 1 were added to human corneal epithelial cells;

[0062] Control group: human corneal epithelial cells;

[0063] The experimental and control groups were incubated in a 37℃ incubator for 24 hours, and then the results were measured using a fluorescence microscope. (See attached image.) Figure 4 The cell survival rates of the experimental group and the control group were almost the same, indicating that the multilayer hydrogel magnetically driven microrobot of the embodiment has good biocompatibility.

[0064] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing a multi-layer hydrogel magnetically driven micro-robot, characterized in that, The preparation method includes the following steps: S1. Spin-coating the mixed hydrogel layer preparation raw materials onto the surface of the pretreated flat plate medium, and obtaining the hydrogel layer-flat plate medium after solidification; S2. The raw materials for preparing the mixed magnetic nanoparticle layer are spin-coated onto the surface of the hydrogel layer of the hydrogel layer-planar medium and cured to obtain the nanoparticle layer-hydrogel layer-planar medium. S3. Peel the nanoparticle layer-hydrogel layer from the plate medium, and magnetize the obtained nanoparticle layer-hydrogel layer bilayer structure to obtain a magnetic nanoparticle layer-hydrogel layer. S4. Install a micro 3D printed blade on the surface of the hydrogel layer of the magnetic nanoparticle layer-hydrogel layer to create a multi-layer hydrogel magnetically driven microrobot.

2. The method of claim 1, wherein the method further comprises: The thickness of the hydrogel layer is 10 μm, and the thickness of the magnetic nanoparticle layer is 30 μm.

3. The method for fabricating a multilayer hydrogel magnetically driven microrobot according to claim 1, characterized in that, The robot consists of a micro 3D printed blade, a hydrogel layer, and a magnetic nanoparticle layer from top to bottom. The micro 3D printed blade and the magnetic nanoparticle layer are bonded together by the hydrogel layer. The micro 3D printing head includes a needle, which is shaped like an oblique cone or a straight cone.

4. The method for fabricating a multilayer hydrogel magnetically driven microrobot according to claim 3, characterized in that, The height of the needle is 30-90μm, and the number of needles is 1-5.

5. The method for fabricating a multilayer hydrogel magnetically driven microrobot according to claim 1, characterized in that, The raw materials for preparing the hydrogel layer include PVA, gelatin, and water.

6. The method for fabricating a multilayer hydrogel magnetically driven microrobot according to claim 1, characterized in that, The raw materials for preparing the magnetic nanoparticle layer include: PEGDA, initiator, and unmagnetized NdFeB.

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