CN113440726A - Achiral magnetic control micro-bracket robot and preparation method and application thereof - Google Patents

Abstract

The invention provides an achiral magnetic control micro-stent robot and a preparation method and application thereof. The achiral magnetic control micro-bracket robot bracket structure can be used for stem cell attachment, growth, proliferation and differentiation, has the functions of protecting and supporting stem cells, can realize directional movement under the control of a rotating magnetic field, and further can realize targeted therapy on the affected part of osteoarthritis.

Description

Achiral magnetic control micro-bracket robot and preparation method and application thereof

Technical Field

The invention belongs to the technical field of micro-nano robots, and relates to an achiral magnetic control micro-bracket robot and a preparation method and application thereof.

Background

Among various degenerative joint diseases, Osteoarthritis (OA) is the most common chronic disease, affecting joint tissues throughout the body. The main symptoms are knee joint pain and limited daily activities, wherein the female prevalence rate is higher than that of men, and the prevalence rate of obese people is higher than that of common people.

KOA is a disease mainly characterized by sustained destruction of articular cartilage damage, and results in thickening of articular subchondral bone, various degrees of joint synovial inflammation, ligament degeneration and the like. At present, the pathogenesis of the KOA is not clear clinically, so that a targeted prevention and treatment scheme is not provided. The scheme for treating the KOA is divided into drug treatment and non-drug treatment, the conservative effect treatment is not good, most patients in later period need surgical treatment, such as joint replacement surgery (KTA), and the surgery has the problems of large wound surface, slow recovery, high risk, high cost and the like. In response to the need for regeneration and repair of cartilage in various stages of KOA disease progression, stem cell therapy is becoming a new treatment modality to be applied clinically.

The stem cell therapy for KOA mainly utilizes the characteristic that stem cells can be rapidly differentiated into chondrocytes through induction to repair damaged cartilage. At present, the method for treating KOA clinically by using stem cells is to directly treat the stem cells extracted from a patient body and inject the treated stem cells into a knee joint so as to improve the microenvironment of a joint cavity and repair a cartilage defect part. However, the method has low utilization rate of stem cells, large demand of stem cells and slow repair process. In recent years, research teams have studied the in vitro culture of stem cells by using macroscopic scaffolds or microscopic scaffolds, and the stem cell therapy by using a surgical method or an injection method, but the macroscopic scaffolds use invasive surgery and cause the death of stem cells in the center of the scaffolds. Compared with the prior art, the micro-scaffold has the characteristics of injectability, high efficiency, accurate transportation of stem cells, easiness in entering narrow cartilage defect parts, capability of ensuring the circulation of oxygen and nutrient substances of the stem cells and the like, and has future clinical application value. At present, in order to realize accurate transportation of stem cells into cartilage damaged parts, a micro-robot concept is basically adopted for realization of the micro-scaffold.

For some time, it has been believed that only micro-robots of chiral structure can convert rotational motion into translational motion, such as helical robots. Until 2014, professor U Kei Cheang manufactured an achiral micro-robot of three-bead structure and verified its motion performance under a rotating magnetic field. With the development of the manufacturing method of the achiral micro-robot, Bradley j.

In addition, as for the driving method of the micro robot, the driving methods adopted in the micro robot currently developed include four major methods of chemical driving, magnetic field driving, acoustic wave driving and optical drive. The magnetic field drive is widely applied to a micro-control system due to the characteristics of no direct contact, timely control, no response of biological materials to a magnetic field and the like. Therefore, in the art, the development of an achiral robot capable of being driven by a magnetic field is a research focus in the art.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide an achiral magnetic control micro-support robot and a preparation method and application thereof. The achiral magnetic control micro-bracket robot realizes the high-efficiency carrying and the transportation in the joint cavity of the stem cells by using a biocompatible material and adopting the driving of a rotating magnetic field through a low-cost photoetching manufacturing technology, thereby effectively treating KOA in a noninvasive mode and other different diseases needing the targeted transportation and treatment of the stem cells in vivo.

In order to achieve the purpose, the invention adopts the following technical scheme:

in one aspect, the invention provides an achiral magnetic control micro-stent robot, which comprises a mesh-shaped stent main body, a magnetic film layer positioned on the outer layer of the mesh-shaped stent main body and a biocompatible film layer positioned on the outer layer of the magnetic film layer.

The achiral magnetic control micro-bracket robot bracket structure can be used for stem cell attachment, growth, proliferation and differentiation, has the functions of protecting and supporting stem cells, can realize directional movement under the control of a rotating magnetic field, and further can realize targeted therapy on the affected part of osteoarthritis.

Preferably, the raw material of the mesh support main body is photoresist, and preferably, the photoresist is SU-8 series photoresist.

In the invention, the reticular stent main body is obtained by photoetching through photoresist.

Preferably, the material of the magnetic film layer is any one or a combination of at least two of iron, cobalt or nickel.

Preferably, the material of the biocompatible film layer is any one or a combination of at least two of Ti, chitosan, polylactic acid and hydroxyapatite.

Preferably, the thickness of the magnetic film layer is 150-300 nm; for example 150nm, 170nm, 180nm, 200nm, 220nm, 250nm, 270nm, 290nm or 300 nm.

Preferably, the thickness of the biocompatible film layer is 20-100 nm; for example 20nm, 25nm, 30 nm, 35nm, 40nm, 45nm, 50nm, 55nm, 60nm, 65nm, 70nm, 80nm, 90nm or 100 nm.

Preferably, the overall thickness of the achiral magnetic control micro-support robot is less than or equal to 1mm, and may be 1mm, 0.8mm, 0.5mm, 0.3mm, 0.2mm, 0.1mm, 0.08mm, 0.05mm, and the like, for example.

Preferably, the achiral magnetic control micro-stent robot is in micron level;

preferably, the achiral magnetic control micro-bracket robot has the height of 40 microns, the length of 400 microns and the width of 100 microns.

In the invention, the achiral magnetic control micro-support robot is of an achiral structure, and after the achiral magnetic control micro-support robot interacts with an external magnetic field, the achiral magnetic control micro-support robot can obtain the motion characteristic of a chiral magnetic structure.

Preferably, the achiral magnetic control micro-stent robot is an approximately L-shaped achiral structure, and the included angle is 90-179 degrees, such as 90 degrees, 95 degrees, 98 degrees, 100 degrees, 110 degrees, 120 degrees, 130 degrees, 140 degrees, 150 degrees, 160 degrees, 170 degrees, 179 degrees, and the like, preferably 120 degrees.

In another aspect, the present invention provides a method for preparing the achiral magnetic control micro-stent robot, wherein the method comprises the following steps:

(1) photoetching the photoresist to obtain a mesh support main body;

(2) and sputtering a magnetic material film layer and a biocompatible film layer on the surface layer of the main body of the reticular stent in sequence to obtain the achiral magnetic control micro-stent robot.

Preferably, the photoetching of the photoresist in the step (1) specifically includes:

and spin-coating a glucan solution on the substrate, then spin-coating a photoresist, and performing ultraviolet exposure on the photoresist in different directions by rotation to complete photoetching.

In the present invention, in order to generate an approximately "L" shaped achiral structure, the L shape is composed according to the designed pattern on the reticle at the time of photoresist.

Preferably, the substrate is a silicon wafer.

Preferably, the dextran solution has a mass volume concentration of 5-20% (w/v), such as 5%, 6%, 8%, 10%, 12%, 15%, 18% or 20%, preferably 10%.

In the present invention, the dextran solution is spin-coated on the substrate because the dextran film layer can be dissolved in water, and after the fabrication is completed, the film layer is dissolved by putting the substrate in water, and the robot can be peeled off from the substrate.

Preferably, the ultraviolet exposure rotated in different directions is oblique ultraviolet exposure of the photoresist at 1 to 89 ° (e.g., 1 °, 5 °, 10 °, 15 °, 20 °, 30 °, 40 °, 50 °, 60 °, 70 °, 80 ° or 89 °), and after each exposure, the silicon wafer is rotated 90 ° about the vertical axis for a total of 4 rotation exposures.

Preferably, the photoresist is subjected to 45 ° oblique ultraviolet exposure.

In the invention, the magnetic injection in the step (2) is completed by Sputtering by using a magnetron Sputtering instrument.

Preferably, after the magnetic material film layer and the biocompatible film layer are obtained in the step (2), the achiral magnetic control micro-stent robot is peeled from the substrate. The stripping mode is that the achiral magnetic control micro-bracket robot with the substrate is immersed in water, and the dextran is easily dissolved in the water solution, so that the achiral magnetic control micro-bracket robot falls off due to the dissolution of the dextran layer.

Preferably, ultrasonic assistance is adopted when the glucan layer is dissolved, so that water is accelerated to enter the glucan layer, and the glucan dissolving speed is accelerated.

In another aspect, the present invention provides a stem cell-loaded micro-scaffold robot, comprising the achiral magnetic-controlled micro-scaffold robot as described above and a stem cell loaded on the achiral magnetic-controlled micro-scaffold robot.

The achiral magnetic control micro-bracket robot provided by the invention can realize the targeted transportation of stem cells, realizes noninvasive treatment in medical application, and has high stem cell carrying efficiency and good cell survival rate.

In the invention, the achiral magnetic control micro-stent robot is sterilized and then coated with poly-L-lysine (PLL for short) to increase the adhesion performance of stem cells in the robot. And co-culturing with the stem cells, culturing and subculturing to 3 generations, wherein the inoculation number is 1W/mL, and co-culturing for 3 days to obtain the micro-scaffold robot loaded with the stem cells.

Preferably, the sterilization includes plasma treatment, alcohol sterilization, and PBS solution washing.

Preferably, the plasma treatment is performed at a power of 50W for a period of 5-20min (e.g., 5min, 8min, 10min, 15min, or 20 min).

Preferably, the alcohol concentration is 70% and the alcohol disinfection time is 5-30min (e.g., 5min, 8min, 10min, 15min, 20min, 25min, or 30 min).

Preferably, the PBS solution concentration is 10%, washing 6 times.

Preferably, poly-L-lysine is coated by soaking in a solution containing poly-L-lysine and washing in a PBS solution.

Preferably, the poly-L-lysine solution has a specification of 10 micrograms per milliliter and a soaking time of 5-20min (e.g., 5min, 8min, 10min, 15min, or 20 min); the PBS solution with a concentration of 10% was washed 6 times.

Preferably, the stem cells are mesenchymal stem cells of thigh bone marrow of SD rat, and are cultured and passaged to 3 generations.

In another aspect, the invention provides an application of the achiral magnetic control micro-stent robot or the stem cell loaded micro-stent robot in the preparation of stem cell therapeutic drugs or medical instruments.

Preferably, the stem cell therapeutic drug or medical device is a drug or medical device for treating osteoarthritis.

In the invention, the achiral magnetic control micro-bracket robot or the stem cell-loaded micro-bracket robot can be used for treating osteoarthritis, the stem cell-loaded micro-bracket robot is injected into a joint cavity of an affected part, and the motion of the robot is controlled by using the magnetic field generator to make the robot move in a targeted manner, so that the robot accurately reaches the affected part with cartilage defect, and the targeted treatment on osteoarthritis is realized.

Preferably, the magnetic field generator is a three-dimensional Helmholtz coil, and the generated magnetic field is a three-dimensional uniform rotating magnetic field.

The achiral micro-robot has the characteristic of simple shape, is different from other micro-robots, and realizes two motions of swimming and rolling under the control of a three-dimensional uniform rotating magnetic field.

The invention can realize the internal joint cavity targeted therapy with low cost and high efficiency, and is also suitable for different diseases requiring stem cell targeted transportation therapy in other bodies.

Compared with the prior art, the invention has the following beneficial effects:

the reticular stent main body in the achiral magnetic control micro-stent robot is of a three-dimensional fibrous regular structure, and the outer layer is covered with a magnetic film layer and a biocompatible film layer. The scaffold can be attached with stem cells, is used as a growth and migration basis of the stem cells, and has the functions of protecting and supporting the stem cells; the maximum size of the micro robot is micron, and the micro robot can realize motion control under the driving of an external magnetic field; the swimming and rolling motions are realized under the control of the three-dimensional uniform rotating magnetic field. The achiral magnetic control micro-bracket robot provided by the invention has lower production cost and can be industrially, massively and uniformly prepared; after the achiral magnetic control micro-bracket robot carries out in-vitro stem cell culture proliferation, the stem cells enter a joint cavity through injection, and the target motion of the stem cells is controlled through a magnetic field to accurately reach the diseased part of cartilage defect, so that the targeted treatment on the osteoarthritis is realized. The achiral magnetic control micro-bracket robot and the preparation method thereof provided by the invention can realize targeted therapy of cartilage defect of osteoarthritis, can realize low-cost and high-efficiency in-vivo joint cavity targeted therapy, and are also suitable for other different diseases requiring stem cell targeted transportation therapy in vivo.

Drawings

FIG. 1 is a schematic diagram of a preparation process of an achiral magnetic control micro-bracket robot.

Fig. 2A is a front view of the main body of the mesh stent, fig. 2B is a side view of the main body of the mesh stent, and fig. 2C is a top view of the main body of the mesh stent.

Fig. 3 is a cross-sectional view of an achiral magnetic control micro-stent robot, wherein 1 is a mesh stent body, 2 is a magnetic film layer, and 3 is a biocompatible film layer.

FIG. 4 is a schematic diagram of the process for preparing a micro-scaffold robot loaded with stem cells.

Fig. 5 is a schematic diagram of an injection application to a cartilage defect site using a stem cell loaded micro-stent robot.

Detailed Description

The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.

Example 1

In this embodiment, an achiral magnetic-control micro-support robot is prepared, and a preparation process is shown in fig. 1, and specifically includes the following steps:

(1) photoetching and manufacturing mesh support main body

A10% strength dextran solution was spin coated onto a clean silicon wafer at an angular speed of 1500rpm for 20 seconds. After spin coating, baking at 80 deg.C for 1min, baking at 180 deg.C for 30min, and oven drying to form film. And coating SU-82050 type photoresist, wherein the spin-coating angular speed is 3000rpm, and the time duration is 30 s. And (3) baking the glued silicon wafer for 1min at 65 ℃. Fixing the sample on an objective table with the gradient of 45 degrees, carrying a mask plate above the rubber surface, exposing under vertical ultraviolet rays, rotating the objective table 90 degrees clockwise (anticlockwise), and exposing again under the same parameters. The steps of rotation and exposure are repeated for a total of 4 exposures. The exposed sample was baked at 95 ℃ for 7 min. And circularly rinsing the sample between the developing solution and the isopropanol until no white floccule appears when the sample is placed in the isopropanol, and fishing out the sample for drying.

(2) A magnetron Sputtering instrument is utilized to sequentially sputter 150nm of Ni as a magnetic material film layer and 20nm of Ti as a biological compatibility film layer through Sputtering. The samples were cleaned with 70% alcohol and then dried. Plasma treatment with power of 50W for 10 min. The samples were subjected to contact angle testing using deionized water at 10 different locations on the sample, and the final values were averaged (the final hydrophilicity was better, the contact angle was between 20 ° and 35 °, the average was 27 °, which means the sample was more hydrophilic and the cells were more likely to adhere to it). And soaking the sample in 70% alcohol, and taking out after 15 min. Washing with 10% PBS solution for 6 times, and naturally drying. And placing the sample in deionized water for ultrasonic treatment, and peeling the achiral magnetic control micro-bracket robot from the substrate to obtain the achiral magnetic control micro-bracket robot.

Fig. 2A is a front view of the main body of the mesh stent, fig. 2B is a side view of the main body of the mesh stent, and fig. 2C is a top view of the main body of the mesh stent. Fig. 3 is a cross-sectional view of an achiral magnetic control micro-stent robot, wherein 1 is a mesh stent body, 2 is a magnetic film layer, and 3 is a biocompatible film layer.

Example 2

In this embodiment, a stem cell loaded micro-scaffold robot is prepared, and the preparation process is shown in fig. 4, and specifically includes the following steps:

(1) PLL coating

The achiral magnetic control micro-bracket robot is put into a PLL solution with the concentration of 10 micrograms per milliliter and soaked for 10 min. And taking out the sample, washing the sample for 6 times by using a 10% PBS solution, and naturally drying the sample.

(2) Stem cell seeding

Counting the stem cells with proper algebra, inoculating the counted stem cells to the achiral magnetic control micro-bracket robot treated above, and culturing for 1 week every 1, 3, 7CCK-8 testing was performed once a day. Cell suspensions were prepared in two groups, one counted and plated into 96-well plates at 100. mu.l/well at 37 ℃ with 5% CO₂And performing 24h adherent culture under the environment. 10 μ l of CCK-8 solution was added to each well, cultured for 2 hours, and the absorbance (OD) at 450nm was measured by a microplate reader to calculate the cell proliferation activity. In the other group, before the pre-culture, toxic substances (medicines and chemical reagents waiting for detection substances) with different concentrations are added into each hole, the pre-culture time can be properly prolonged, the rest steps are the same as the above steps, and the cytotoxicity activity is calculated.

Also, before injection, the stem cells were mesenchymal stem cells of thigh of SD rat, cultured for passage to 3 passages, seeded at 1W/ml, and after 3 days of co-culture, transferred to a syringe with a pipette and awaited injection.

(3) Number of carried cells test

After culturing for one day, cell mounting count test was carried out using 10W, 20W and 30W cells, respectively. The test results for 10w number of cells showed an average of 18, the test results for 20w number of cells showed an average of 26, and the test results for 30w number of cells showed an average of 40.

(4) Differentiation assay

Stem cells were inoculated onto the samples, cultured to a confluency of 90-100%, and differentiation factors were added. Half-change the liquid every day, continuously inducing differentiation for 21-28 days, then formalin-fixing and embedding section, finally carrying out Alisine blue staining. The detection results show that the gene for the chondrocyte differentiation is highly expressed, and the detection results comprise the following steps: AGG, COL2A1 and SOX 9.

Example 3

In this example, a performance test was performed on a stem cell loaded micro-scaffold robot:

after carrying cells, the achiral magnetic control micro-stent robot applies a magnetic field to drive, can have good movement speed in DI water or different biological fluids, and has two different movement characteristics under the control of two magnetic fields. The achiral magnetic control micro-support robot monomer or cluster can perform long-distance target movement, can keep good movement speed and stability on the bottom surface with a three-dimensional structure and the rough bottom surface, and easily surmount obstacles. The specific performance test method is as follows:

(1) and (3) exercise testing:

placing the achiral magnetic control micro-support robot in DI water, applying a magnetic field, carrying out swimming and rolling tests, checking whether the robot can move, and observing the movement speed and stability.

The test proves that the achiral magnetic control micro-bracket robot has good motion performance in clear water.

(2) Biological fluid testing:

placing the achiral magnetic control micro-bracket robot in different biological fluids (PBS, cerebrospinal fluid and mouse serum), applying a magnetic field, carrying out swimming and rolling tests, checking whether the robot can move, and observing the moving speed and the stability.

The test proves that the achiral magnetic control micro-bracket robot has good motion performance in biological fluid.

(3) And (3) flow channel simulation test:

different kinds of flow channels, with chambers and channels connecting the chambers, are manufactured by photolithography.

And placing a single achiral magnetic control micro-bracket robot in one chamber, applying a magnetic field, controlling the robot to move to a specified chamber, and observing the motion speed and stability of the robot.

The same experiment is carried out on a plurality of achiral magnetic control micro-bracket robots, the movement speed of the robots is tested, and the percentage of the robots which can successfully reach the designated point is measured.

The test proves that the monomer or the cluster of the achiral magnetic control micro-bracket robot can perform long-distance targeted motion.

(4) Rough surface movement test:

3D structures with rough surfaces are manufactured in a reverse mode, and a robot loaded with cells is conveyed inside in a turnover mode. And (4) simulating and testing the standard reference flow channels of the single body and the group.

The test proves that the achiral magnetic control micro-support robot monomer or cluster can easily cross obstacles, and good movement speed and stability are kept on the bottom surface with the three-dimensional structure and the rough bottom surface.

The stem cell-loaded achiral magnetic control micro-scaffold robot is used for injecting the cartilage defect part, as shown in figure 5, the stem cell-loaded achiral magnetic control micro-scaffold robot can be positioned to the injury part in a targeted mode under the driving of a magnetic field for treatment.

The applicant states that the present invention is illustrated by the above examples of the process of the present invention, but the present invention is not limited to the above process steps, i.e. it is not meant that the present invention must rely on the above process steps to be carried out. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitution of the selected raw materials, addition of auxiliary components, selection of specific modes, etc., fall within the scope and disclosure of the present invention.

Claims (10)

1. The achiral magnetic control micro-stent robot is characterized by comprising a net-shaped stent main body, a magnetic film layer positioned on the outer layer of the net-shaped stent main body and a biocompatible film layer positioned on the outer layer of the magnetic film layer.

2. The achiral magnetic control micro-stent robot according to claim 1, wherein the material of the mesh stent body is photoresist;

preferably, the photoresist is SU-8 series photoresist;

preferably, the mesh stent body is obtained by photoetching through photoresist.

3. The achiral magnetic control micro-stent robot according to claim 1 or 2, wherein the material of the magnetic film layer is any one or a combination of at least two of iron, cobalt or nickel;

preferably, the material of the biocompatible film layer is any one or a combination of at least two of Ti, chitosan, polylactic acid and hydroxyapatite;

preferably, the thickness of the magnetic film layer is 150-300 nm;

preferably, the thickness of the biocompatible film layer is 20-100 nm;

preferably, the overall thickness of the achiral magnetic control micro-bracket robot is less than or equal to 1 mm.

4. The achiral magnetic control micro-gantry robot of any of claims 1-3, wherein the achiral magnetic control micro-gantry robot is on a micron scale;

preferably, the achiral magnetic control micro-bracket robot has the height of 40 microns, the length of 400 microns and the width of 100 microns.

5. The achiral magnetically controlled micro-stent robot according to any of claims 1-4, wherein the achiral magnetically controlled micro-stent robot is an approximately "L" -shaped achiral structure with an included angle of 90-179 °, preferably 120 °.

6. The method for preparing an achiral magnetically controlled micro-stent robot according to any of claims 1-5, comprising the steps of:

(1) photoetching the photoresist to obtain a mesh support main body;

(2) and sputtering a magnetic material film layer and a biocompatible film layer on the surface layer of the main body of the reticular stent in sequence to obtain the achiral magnetic control micro-stent robot.

7. The preparation method according to claim 6, wherein the step (1) of photoetching the photoresist specifically comprises:

spin-coating a glucan solution on a substrate, then spin-coating a photoresist, and performing ultraviolet exposure on the photoresist in different directions by rotation to complete photoetching;

preferably, the substrate is a silicon wafer;

preferably, the mass volume concentration of the dextran solution is 5-20%, preferably 10%;

preferably, the ultraviolet exposure rotating in different directions is oblique ultraviolet exposure of 1-89 degrees to the photoresist, after each exposure, the silicon wafer rotates 90 degrees around a vertical axis, and the rotation exposure is repeated for 4 times in total;

preferably, the photoresist is subjected to 45 ° oblique ultraviolet exposure.

8. The method according to claim 6 or 7, wherein the step (2) of sputtering is performed by a magnetron sputtering apparatus;

preferably, after the magnetic material film layer and the biocompatible film layer are obtained in the step (2), the achiral magnetic control micro-bracket robot is peeled off from the substrate.

9. A stem cell loaded micro-scaffold robot, comprising the achiral magnetic controlled micro-scaffold robot of any of claims 1-5 and a stem cell loaded on the achiral magnetic controlled micro-scaffold robot;

preferably, the achiral magnetic control micro-stent robot is sterilized, then coated with poly-L-lysine, and then loaded with stem cells;

preferably, the sterilization includes plasma treatment, alcohol sterilization and PBS solution washing;

preferably, the power of the plasma treatment is 50W, and the time is 5-20 min;

preferably, the concentration of the alcohol is 70%, and the alcohol disinfection time is 5-30 min;

preferably, the concentration of the PBS solution is 10 percent, and the washing is carried out for 6 times;

preferably, poly-L-lysine is coated, and the solution is soaked by a poly-L-lysine solution and washed by a PBS solution;

preferably, the specification of the poly-L-lysine solution is 10 micrograms per milliliter, and the soaking time is 5-20 min; the PBS solution with the concentration of 10 percent is washed for 6 times;

preferably, the stem cells are mesenchymal stem cells of thigh bone marrow of SD rat, and are cultured and passaged to 3 generations.

10. Use of an achiral magnetically controlled micro-scaffold robot according to any of claims 1-5 or a stem cell loaded micro-scaffold robot according to claim 9 in the preparation of a stem cell therapy medicament or medical device;

preferably, the stem cell therapeutic drug or medical device is a drug or medical device for treating osteoarthritis.

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