CN115554400A - Degradable magnetic control micro robot with high mechanical strength and preparation method and application thereof - Google Patents
Degradable magnetic control micro robot with high mechanical strength and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a degradable magnetic control micro robot with high mechanical strength and a preparation method and application thereof. The magnetic control micro robot is a porous hollow sphere formed by a plurality of repeated triangular grid units; the triangular grid unit is a triangle formed by three support rods in a surrounding mode, and each support rod is used as a common support rod for the triangles on the two sides of the support rod; a plurality of thorn-shaped bulges extend outwards from the junction of the support rods on the surface of the porous hollow sphere; the magnetic control micro robot is made of a magnetic degradable material. According to the invention, the triangular structure is used as the minimum filling unit of the magnetic control micro-robot to improve the mechanical strength, the controllable degradation time is realized by regulating and controlling the proportion of two hydrogel manufacturing materials, and finally the magnetic control micro-robot is manufactured by using the femtosecond laser direct writing method.
Description
Technical Field
The invention belongs to the technical field of design and manufacture of micro robots, and particularly relates to a high-mechanical-strength degradable magnetic control micro robot and a preparation method and application thereof.
Background
In recent years, with the development of micro-nano technology, magnetic control micro robots get wide attention, and especially have very important potential application values in the aspects of precise medical treatment, minimally invasive surgery and the like.
The characteristics of degradability and mechanical strength are contradictory for many materials currently used to make microrobots. Materials with short degradation times generally have lower mechanical strength, and materials with higher mechanical strength generally have longer degradation times. The degradable materials currently used for preparing microrobots mainly comprise: hydrogel, gelatin, starch or sodium alginate, etc. However, the micro-robot prepared by the single material has relatively fixed degradation time and cannot realize autonomous regulation and control. In addition, the conventional micro-robot has a minimum packing unit generally having a quadrilateral, pentagonal, hexagonal, etc. structure, and the micro-robot has poor mechanical strength.
In performing in vivo delivery tasks in clinical applications, there is an urgent need for microrobots with high mechanical strength as a support carrier for cells or drugs; while being degradable by the body and being expelled from the body after delivery is complete. The aim is to develop a micro-robot with short degradation time and high mechanical strength.
Disclosure of Invention
Based on the defects of the prior art, the first object of the invention is to provide a magnetic control micro-robot; the second purpose of the invention is to provide a preparation method of the magnetic control micro-robot; the third purpose of the invention is to provide the application of the magnetic control micro-robot in the precise delivery of drugs or cells. The invention discloses a magnetic control micro-robot which is based on the structural design of the micro-robot to improve the mechanical strength of the micro-robot and is matched with the degradation performance of degradable materials to develop the magnetic control micro-robot capable of synchronously improving the degradation performance and the mechanical strength performance.
The purpose of the invention is realized by the following technical scheme:
in one aspect, the present invention provides a magnetically controlled microrobot which is a porous hollow sphere composed of a plurality of repeated triangular lattice cells; the triangular grid unit is a triangle formed by three support rods in a surrounding mode, and each support rod is used as a common support rod of the triangles on two sides of the support rod; a plurality of thorn-shaped bulges extend outwards from the junction of the support rods on the surface of the porous hollow sphere; the magnetic control micro robot is made of a magnetic degradable material.
In the magnetic control micro-robot, the 'a plurality of thorn-shaped bulges extending outwards from the intersection point of the support rod on the surface of the porous hollow sphere' means that the thorn-shaped bulges extend outwards from the intersection point of the support rod and the support rod, the intersection point of the support rod and the support rod can extend outwards to form a thorn-shaped bulge or a thorn-free bulge, and the thorn-shaped bulges can extend outwards perpendicular to the tangent plane of the sphere or outwards extend outwards at an angle with the tangent plane of the sphere.
In the magnetic control micro robot of the invention, the whole magnetic control micro robot is made of the same material, for example: the material of the support rod is the same as that of the thorn-shaped bulges, and the support rod and the thorn-shaped bulges are prepared by mixing raw materials for preparing the magnetic control micro-robot.
The magnetic control micro-robot adopts the triangular structure as the minimum filling grid unit, compared with the traditional quadrilateral, pentagonal and hexagonal structures, the triangular structure is more stable, more support sites can be provided, and the mechanical strength of the magnetic control micro-robot can be improved through more triangular grid supports; furthermore, the magnetic control micro-robot is matched with degradable and magnetic materials, so that the degradable performance of the magnetic control micro-robot can be improved on the premise of improving the mechanical strength of the magnetic control micro-robot, the shorter degradation time is achieved, and the function of automatic navigation and accurate delivery of drugs and cells is realized by controlling the magnetism of the magnetic control micro-robot by a magnetic field; the porous hollow sphere structure can reduce the fluid resistance of the magnetic control micro-robot when swimming in blood vessels, simultaneously minimize the damage to tissues and be easily fused with the tissues; the porous structure characteristic can provide an exchange channel, which is beneficial to nutrient supply and tissue vascularization; the spiny bulge structure can be used as an attachment site of cells and used for improving the load capacity of the cells.
In the above-described magnetic control micro-robot, the porous hollow sphere preferably has a diameter of 50 to 100 μm.
In the above magnetic-control micro-robot, preferably, the length of the support rod is 5 to 10 μm; the diameter is 1-3 μm.
In the above-mentioned magnetic control micro robot, preferably, the raw material for preparing the magnetic degradable material of the magnetic control micro robot comprises degradable raw material and magnetic raw material.
In the above magnetic-control micro-robot, preferably, the degradable raw material is composed of polyethylene glycol (glycol) diacrylate (PEGDA) and pentaerythritol triacrylate (PETA). Both the PEGDA and the PETA are liquid hydrogels.
In the above magnetic-control micro-robot, preferably, the volume ratio of the polyethylene glycol (diol) diacrylate to the pentaerythritol triacrylate is (50 to 90): (10 to 50).
In the magnetic control micro robot, the higher the PEGDA content is, the shorter the degradation time is; while the higher the PETA content, the higher the mechanical strength. According to the invention, the ratio of the two hydrogel materials is regulated, so that the independent regulation and control of the degradation time and the mechanical strength can be realized.
In the above magnetic-control micro-robot, preferably, the magnetic material includes an organic solution containing ferroferric oxide nanoparticles.
In the above magnetically controlled micro robot, preferably, the organic solution containing the ferroferric oxide nanoparticles is a γ -butyrolactone solution of the ferroferric oxide nanoparticles.
In the above magnetically controlled micro robot, preferably, the concentration of the ferroferric oxide nanoparticles in the gamma-butyrolactone solution of the ferroferric oxide nanoparticles is 260mg/mL (i.e., each mL of gamma-butyrolactone contains 260mg of ferroferric oxide nanoparticles).
In the above magnetic-control micro-robot, preferably, the particle size of the ferroferric oxide nanoparticles is 100-200 nm.
In the above-mentioned magnetic control micro robot, preferably, the raw material for preparing the magnetic control micro robot further comprises a photoinitiator and a photosensitizer.
In the above-mentioned magnetron micro-robot, preferably, the photo-initiator includes one or more of ethyl 4-dimethylaminobenzoate, 2-methyl-1- [ 4-methylthiophenyl ] -2-morpholinyl-1-propanone and 2-ethylhexyl-4-dimethylaminobenzoic acid, but is not limited thereto.
In the above-mentioned magnetron micro-robot, preferably, the photosensitizer includes one or more of 2-isopropyl thioxanthone, 2-chloro thioxanthone, 1-chloro-4-propoxy thioxanthone and 2, 4-diethyl thioxanthone, but is not limited thereto.
In the magnetic control micro robot, the crosslinking and curing of the magnetic control micro robot are realized through the photoinitiator and the photosensitizer.
In the above-mentioned magnetic-control micro-robot, preferably, the volume ratio of the degradable raw material, the photoinitiator, the photosensitizer and the magnetic raw material is 1: (4-5%): (1-2%): (2% to 3%).
In the above-mentioned magnetic-control micro-robot, preferably, the volume ratio of the degradable raw material, the photoinitiator, the photosensitizer and the magnetic raw material is 1:4%:1%:2 percent.
In the above-mentioned magnetic control micro-robot, preferably, the length of the thorn-shaped protrusion is not more than one third of the diameter of the porous hollow sphere.
In the above-mentioned magnetic-control micro-robot, the length of the spinous projections is preferably 5 to 10 μm and the diameter thereof is preferably 1 to 3 μm.
On the other hand, the invention also provides a preparation method of the magnetic control micro-robot, which comprises the following steps:
uniformly mixing raw materials for preparing the magnetic control micro-robot to obtain a mixed material solution, and processing the mixed material solution into the magnetic control micro-robot according to the structural form of a porous hollow sphere by using a femtosecond two-photon laser direct writing method.
In the above preparation method, preferably, the specific method for processing the mixed material solution into the magnetic control micro-robot according to the structural form of the porous hollow sphere by using the femtosecond two-photon laser direct writing method comprises:
dropping one drop of the mixed material solution onto a glass sheet, and loading the glass sheet into a Nanocribe two-photon photoetching system; and then introducing an STL file according to the structural form of the porous hollow sphere of the magnetic control micro-robot, starting processing, after the laser direct writing is finished, developing by using isopropanol to remove uncured solution, and naturally airing to obtain the magnetic control micro-robot.
In still another aspect, the present invention further provides the use of the above-described magnetically controlled microrobot for targeted and precise delivery of drugs or cells for non-therapeutic purposes.
The invention has the beneficial effects that:
according to the invention, the triangular structure is used as the minimum filling unit of the magnetic control micro-robot to improve the mechanical strength, the controllable degradation time is realized by regulating and controlling the proportion of two hydrogel manufacturing materials, and finally the magnetic control micro-robot is manufactured by using the femtosecond laser direct writing method.
Drawings
FIG. 1 is a diagram showing the structural characteristics and stress analysis of the magnetic control micro-robot in the embodiment of the present invention.
FIG. 2 is a graph of comparative experimental data of mechanical strength tests of the magnetic control micro-robot in the embodiment of the present invention.
FIG. 3 is a diagram showing the results of the in vitro degradation test of the magnetic control micro-robot in the embodiment of the present invention.
FIG. 4 is a diagram showing the results of the degradation test in the magnetic control micro-robot in the embodiment of the present invention.
FIG. 5 is a diagram of a magnetic control system for controlling a micro-robot in an embodiment of the present invention.
FIG. 6 is a data diagram of an automatic navigation experiment of the magnetic control micro-robot in the embodiment of the present invention.
Detailed Description
The technical solutions of the present invention will be described in detail below in order to clearly understand the technical features, objects, and advantages of the present invention, but the present invention is not limited to the practical scope of the present invention. The raw materials and the operation methods in the following examples are all conventional in the art unless otherwise specified.
Example 1: preparation of magnetic control micro robot
The present embodiment provides a magnetic control micro-robot and a method for preparing the same, wherein the magnetic control micro-robot is a porous hollow sphere (with a diameter of about 100 μm) composed of a plurality of repeated triangular grid cells; the triangular grid unit is a triangle surrounded by three support rods, and each support rod is used as a common support rod (the length of the common support rod is about 10 mu m, and the diameter of the common support rod is about 2 mu m) of the triangles on two sides of the common support rod; a plurality of thorn-shaped bulges (with the length of about 10 μm and the diameter of about 2 μm) extend outwards from the intersection points of the support rods on the surface of the porous hollow sphere; the magnetic control micro robot is made of a magnetic degradable material.
The raw materials for preparing the magnetic control micro robot comprise: polyethylene glycol (glycol) diacrylate (PEGDA, from Sigma,437441, liquid hydrogel), pentaerythritol triacrylate (PETA, from Sigma,246794, liquid hydrogel), ethyl 4-dimethylaminobenzoate (from photolabile chemical, china), 2-isopropyl thioxanthone (from photolabile chemical, china) and gamma-butyrolactone solution of ferroferric oxide nanoparticles (concentration 260mg/mL, average particle size 100nm, from chemicell GmbH).
Wherein, the volume dosage of the degradable materials PEGDA and PETA is as follows: 75vol.% PEGDA:25vol.%, PETA80vol.% PEGDA:20vol.% PETA, 85vol.% PEGDA:15vol.% PETA and 90vol.% PEGDA:10vol.% PETA. The volume dosage of the 4-dimethylamino ethyl benzoate is 4vol.% of the total dosage volume of the degradable material; the volume dosage of the 2-isopropyl thioxanthone is 1vol.% of the total dosage volume of the degradable material; the volume dosage of the gamma-butyrolactone solution of the ferroferric oxide nano particles is 2 vol% of the total dosage volume of the degradable material.
The preparation process of the magnetic control micro-robot of the embodiment is as follows:
uniformly mixing and shaking gamma-butyrolactone solutions of PEGDA, PETA, 4-ethyl dimethylaminobenzoate, 2-isopropyl thioxanthone and ferroferric oxide nanoparticles according to a proportion, dripping one drop of the mixed material solution onto a glass sheet, and loading the glass sheet into a Nanocrabe two-photon photoetching system; and then introducing an STL file according to the structural form of the porous hollow sphere of the magnetic control micro-robot, starting processing, after the laser direct writing is finished, developing by using isopropanol for 5min to remove uncured solution, naturally airing, and then obtaining the magnetic control micro-robot on a glass sheet.
Example 2: comparison of force analysis
This example prepares a magnetic control micro-robot (denoted as a quadrangular micro-robot) having a quadrangular structure unit and a magnetic control micro-robot (denoted as a hexagonal micro-robot) having a hexagonal structure unit by the same method as in example 1 using STL documents of structural forms of porous hollow spheres designed with a quadrangular structure unit (including pentagons) and a hexagonal structure unit (including pentagons), respectively.
Fig. 1 is a diagram comparing the structural characteristics and force-receiving analysis of the magnetron micro-robot (denoted as triangular micro-robot, C in fig. 1) having triangular structural units, the quadrangular micro-robot (B in fig. 1), and the hexagonal micro-robot (a in fig. 1) in example 1 of the present invention.
As can be seen from FIG. 1, the magnetically controlled micro-robot using the triangular structural unit of the present invention has more enhanced supporting grids, which can increase the mechanical strength of the robot.
Example 3: mechanical Property test
The magnetic control micro-robotic mechanical testing was done in a Scanning Electron Microscope (SEM) room, performed by an in-situ micro/nano mechanical characterization platform with 100 micron indenter. Loading a measurable force on a magnetron micro-robot structure processed by different combination ratios of PEGDA and PETA materials until reaching 3 microns of deformation, and then removing to recover to the original position; comparing the quadrilateral micro robot and the hexagonal micro robot, the experimental result is shown in fig. 2, and fig. 2 is the mechanical strength test comparison experimental data of the magnetic control micro robot.
A in fig. 2 shows mechanical testing of three types of micro-robots, a hexagonal micro-robot, a quadrilateral micro-robot, and a triangular micro-robot, manufactured using 75vol.% PEGDA:25vol.% PETA and 90vol.% PEGDA:10vol.% PETA, respectively. The comparison finds that: for the same microrobot structure, the mechanical strength decreases with increasing PEGDA component in the microrobot material.
As shown by B in fig. 2, the micro-robot having the smallest packing unit in the triangular structure exhibits the highest mechanical strength when the PEGDA and PETA materials have the same composition. This finding shows that the triangular design with the reinforcing support grid can improve the mechanical strength of the micro-robot compared to the hexagonal and quadrilateral structure designs.
Example 4: test for degradation Properties
The in vivo degradation performance test was performed on the magnetic control micro-robot prepared in example 1. In order to track the degradation of the magnetic control micro-robot in real time, in the preparation process of the magnetic control micro-robot of example 1, RB-PEG-SH (thiol polyethylene glycol rhodamine) fluorescence (molecular weight = 1000) was added to the mixed material solution of example 1 (1 mg of RB-PEG-SH was added per mL of the mixed solution material) to manufacture a magnetic control micro-robot that can be tracked by fluorescence.
The in vitro degradation test of the magnetic control micro-robot is respectively carried out in 1M sodium hydroxide solution and 1M PBS solution so as to rapidly demonstrate the degradation of the magnetic control micro-robot. The image of the magnetic control micro-robot is shot by a fluorescence microscope at the designated degradation time point, the fluorescence intensity of the magnetic control micro-robot is analyzed by ImageJ software, the experimental result is shown in figure 3, and figure 3 is a graph of the in-vitro degradation test result of the magnetic control micro-robot in the embodiment 1 of the invention.
As shown by a in fig. 3, the magnetron micro-robot is rapidly degraded and disappeared after 10 hours in an alkaline environment. As shown by B in fig. 3, the microrobot degradation in the PBS environment was slow with a small amount of burr disappearing after 24 hours. Since the degradation mechanism of the magnetron micro-robot is similar to that of PBS in an alkaline environment, the alkaline environment is generally used to shorten the degradation time of the micro-robot.
As shown by C in fig. 3 and D in fig. 3, in both cases, the fluorescence intensity of the triangular magnetron micro-robot fabricated using 90vol.% PEGDA:10vol.% PETA decayed faster, representing a shorter degradation time, than the hexagonal magnetron micro-robot fabricated using 75vol.% PEGDA:25vol.% PETA.
Example 5: degradation experiments in mice
The in vivo degradation of the magnetron micro-robot of example 1 was tested in subcutaneous tissue of mice (Balb/c, male, six weeks). The magnetron micro-robot was subcutaneously implanted into the left or right side of the mouse through an open incision (about 7 mm long). Mice were sacrificed weekly to obtain subcutaneous tissue embedded with microrobots. Excised tissue was fixed in 4% formaldehyde solution overnight. Cut to a thickness of 50 microns using a cryomicrotome. An image of the micro-robot embedded in the tissue is photographed, the fluorescence intensity of the micro-robot is analyzed by using ImageJ software, and the sliced tissue is stained by using a hematoxylin-eosin staining kit, and the experimental result is shown in fig. 4, wherein fig. 4 is a graph of the result of the in-vivo degradation test of the magnetic control micro-robot in example 1 of the present invention compared with the hexagonal magnetic control micro-robot.
A and B in fig. 4 indicate: the fluorescence intensity of the hexagonal magnetron micro-robot manufactured using 75vol.% PEGDA:25vol.% PETA decayed 62% and the fluorescence intensity of the triangular magnetron micro-robot manufactured using 90vol.% PEGDA:10vol (example 1) decayed 80% within 4 weeks. These results indicate that the use of a triangular pattern structure in a magnetically controlled micro-robot with 90vol.% PEGDA:10vol.% PETA can significantly improve the degradation performance of the micro-robot over the use of a hexagonal pattern structure in a magnetically controlled micro-robot with 75vol.% PEGDA:25vol.% PEGDA, while maintaining the mechanical strength of the same micro-robot.
Example 6: magnetic field control experiment of magnetic control micro robot
A magnetic control system manufactured in a laboratory for providing a gradient magnetic force to drive a micro-robot, as shown in fig. 5, includes: power supply, coil, operation interface and electromagnetic coil.
The present embodiment performs an autopilot experiment of the micro-robot in the Y-shaped microfluidic channel by processing the image obtained by photographing the micro-robot, including background subtraction, threshold segmentation and position correlation. From the position of the image, a PID controller was used to determine the current input to the magnetic coil and to drive the micro-robot along the desired path, the experimental results being shown in figure 6.
As shown by a in fig. 6, the magnetron micro-robot can move from a start position a to a target position d along a planned path of a-b, b-c and c-d. It is shown by the position error analysis of B in fig. 6 that the magnetically controlled micro-robot can be precisely navigated to the target position.
In conclusion, the triangular structure is used as the minimum filling unit of the magnetic control micro-robot to improve the mechanical strength, the controllable degradation time is realized by regulating and controlling the proportion of two hydrogel manufacturing materials, and finally the magnetic control micro-robot is manufactured by using the femtosecond laser direct writing method.
Claims (10)
1. A magnetic control micro robot is a porous hollow sphere composed of a plurality of repeated triangular grid units; the triangular grid unit is a triangle formed by three support rods in a surrounding mode, and each support rod is used as a common support rod for the triangles on the two sides of the support rod; a plurality of thorn-shaped bulges extend outwards from the junction of the support rods on the surface of the porous hollow sphere; the magnetic control micro robot is made of a magnetic degradable material.
2. The magnetron micro-robot according to claim 1, wherein the diameter of the porous hollow sphere is 50 to 100 μm.
3. The magnetron micro-robot according to claim 1, wherein the length of the support rod is 5 to 10 μm; the diameter is 1-3 μm.
4. The magnetically controlled microrobot of claim 1, wherein the raw materials for preparing the magnetically degradable material of the magnetically controlled microrobot comprise degradable raw materials and magnetic raw materials.
5. The magnetically controlled microrobot of claim 4, wherein the degradable raw material is comprised of polyethylene glycol (diol) diacrylate and pentaerythritol triacrylate;
preferably, the volume ratio of the polyethylene glycol (glycol) diacrylate to the pentaerythritol triacrylate is (50 to 90): (10 to 50).
6. The magnetically controlled microrobot of claim 4, wherein the magnetic feedstock comprises an organic solution comprising ferroferric oxide nanoparticles;
preferably, the organic solution containing the ferroferric oxide nanoparticles is a gamma-butyrolactone solution of the ferroferric oxide nanoparticles;
preferably, in the gamma-butyrolactone solution of the ferroferric oxide nanoparticles, the concentration of the ferroferric oxide nanoparticles is 260mg/mL;
preferably, the particle size of the ferroferric oxide nano particles is 100-200 nm.
7. The magnetically controlled microrobot of claim 4, wherein the raw materials for preparing the magnetically controlled microrobot further comprise a photoinitiator and a photosensitizer;
preferably, the photoinitiator comprises one or more of ethyl 4-dimethylaminobenzoate, 2-methyl-1- [ 4-methylthiophenyl ] -2-morpholinyl-1-propanone and 2-ethylhexyl-4-dimethylaminobenzoic acid;
preferably, the photosensitizer comprises one or more of 2-isopropylthioxanthone, 2-chlorothioxanthone, 1-chloro-4-propoxythioxanthone and 2, 4-diethylthioxanthone;
preferably, the volume ratio of the degradable raw material, the photoinitiator, the photosensitizer and the magnetic raw material is 1: (4-5%): (1-2%): (2% -3%);
preferably, the volume ratio of the degradable raw material, the photoinitiator, the photosensitizer and the magnetic raw material is 1:4%:1%:2 percent.
8. The magnetically controlled microrobot of claim 1, wherein the length of the spinous process is no more than one third of the diameter of the porous hollow sphere;
preferably, the length of the spine-shaped protrusions is 5 to 10 μm and the diameter is 1 to 3 μm.
9. The method for preparing a magnetron micro-robot as claimed in any one of claims 1 to 8, comprising the steps of:
uniformly mixing raw materials for preparing the magnetic control micro-robot to obtain a mixed material solution, and processing the mixed material solution into the magnetic control micro-robot according to the structural form of a porous hollow sphere by using a femtosecond two-photon laser direct writing method;
preferably, the specific method for processing the mixed material solution into the magnetic control micro-robot according to the structural form of the porous hollow sphere by using the femtosecond two-photon laser direct writing method comprises the following steps:
dropping one drop of the mixed material solution onto a glass sheet, and loading the glass sheet into a Nanocribe two-photon photoetching system; and then introducing an STL file according to the structural form of the porous hollow sphere of the magnetic control micro-robot, starting processing, after the laser direct writing is finished, developing by using isopropanol to remove uncured solution, and naturally airing to obtain the magnetic control micro-robot.
10. Use of the magnetically controlled microrobot of any one of claims 1-8 for targeted precise delivery of drugs or cells for non-therapeutic purposes.
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